CORD-19_Custom_license_subset  

CORD-19:932bcdd2f6c6d487386e8bf983e4874387771be1 JSONTXT 9 Projects

Annnotations TAB TSV DIC JSON TextAE

Id Subject Object Predicate Lexical cue
T1 0-46 Sentence denotes 1 -18 Plenary lectures and concurrent symposia
T2 48-56 Sentence denotes Abstract
T3 57-289 Sentence denotes Virus-specific CD8+ T cell-mediated immunity will be reviewed from the aspect of CD8+ T cell effector function in different anatomical sites, and in the context of the nature and limitations of immune memory and the recall response.
T4 290-461 Sentence denotes Particular attention will be given to recent experiments that use reverse genetics technology to explore the interaction between responses to bmajorQ and bminorQ epitopes.
T5 462-610 Sentence denotes The relative importance of quantity versus quality of response will be considered, together with the characteristics of immunodominance hierarchies.
T6 611-790 Sentence denotes Factors determining the nature of T cell receptor (TCR) repertoires will be explored using approaches that combine single cell PCR with mutational and structural biology analysis.
T7 791-981 Sentence denotes We are beginning to understand the chemistry of the TCR/epitope interaction in ways that will hopefully inform both our fundamental insights and practical considerations like vaccine design.
T8 982-1062 Sentence denotes The molecular diversity of CD8+ T cell response profiles will also be discussed.
T9 1063-1307 Sentence denotes Primed individuals not only can mount secondary immune responses that are more rapid and effective than primary responses, but also maintain, in the absence of further boosting, a certain level of effector T cells and antibodies for a lifetime.
T10 1308-1377 Sentence denotes These aspects of immunological memory have a distinct cellular basis.
T11 1378-1625 Sentence denotes Recall responses are mediated in secondary lymphoid organs by central memory T cells and memory B cells, while immediate protection is mediated in peripheral tissues by effector memory T cells and by antibodies produced by long-lived plasma cells.
T12 1626-1721 Sentence denotes I will review the experimental evidence supporting a bstem cell modelQ of immunological memory.
T13 1722-1987 Sentence denotes Central memory T cells and memory B cells are intermediates of a progressive differentiation process, which have acquired the capacity to proliferate and differentiate in response to polyclonal stimuli such as cytokines, microbial products or bystander T cell help.
T14 1988-2148 Sentence denotes While self renewing, central memory T cells and memory B cells continuously spill out effector T cells and plasma cells, thus replenishing those that turn over.
T15 2149-2313 Sentence denotes I will describe in detail the mechanisms that sustain serum antibody levels following vaccination and discuss the implications of these findings for vaccine design.
T16 2314-2572 Sentence denotes The finding that the central nervous system (CNS) embodies neurogenetic regions enriched of neural stem cells (NSCs) has spurred a flurry of studies on both their basic biology and their perspective application for the therapy of many neurological disorders.
T17 2573-2662 Sentence denotes NSCs are multipotential precursors that grow and selfrenew for extensive time in culture.
T18 2663-2880 Sentence denotes It has recently been argued that NSCs undergo rapid, spontaneous transformation, which would represent an obstacle to their use both in therapeutic applications for neurological disorders as well as in basic research.
T19 2881-3284 Sentence denotes In my talk, I shall present an overview of the state of the art in this field and discuss recent findings that demonstrate the extreme functional stability of NSCs, particularly of human origin, their actual capacity to act as therapeutic entities in the damaged CNS and their involvement in the formation and propagation of the most malignant adult human brain tumor, i.e., the glioblastoma multiforme.
T20 3285-3357 Sentence denotes CNS-reactive T cell clones are present in the healthy immune repertoire.
T21 3358-3416 Sentence denotes They attack their target tissue only upon full activation.
T22 3417-3479 Sentence denotes Invasion of the CNS by inflammatory cells occurs in two waves.
T23 3480-3559 Sentence denotes Shortly after transfer, some few activated T cells pass through the intact BBB.
T24 3560-3619 Sentence denotes They reside in the CNS for 72-96 h without causing disease.
T25 3620-3746 Sentence denotes Then, a second, much larger wave of cells invades the CNS and apparently precipitates neurological defects and loss of weight.
T26 3747-3868 Sentence denotes We have traced the migratory pathways of encephalitogenic T cells before, during and after clinical EAE in the Lewis rat.
T27 3869-4052 Sentence denotes We study retrovirally transduced GFP expressing (bgreenQ) myelin specific T cells combining serial 2-photon imaging with real-time assays of gene transcription and protein expression.
T28 4053-4307 Sentence denotes We find that activated encephalitogenic T cells radically re-program their gene expression pattern during a first 72 h prodromal period while sitting in peripheral immune organs, by down-regulating activation markers and upregulating chemokine receptors.
T29 4308-4381 Sentence denotes After 72-96 h, large numbers of these T cells invade the CNS via the BBB.
T30 4382-4515 Sentence denotes Two-photon imaging reveals that many of the cells rapidly cruises through the brain parenchyma, while the others seem to be arrested.
T31 4516-4606 Sentence denotes We shall present evidence that the arrested cells recognize locally presented autoantigen.
T32 4607-4727 Sentence denotes Intra-parenchymal T cell activation seems to underlie the pathogenic inflammatory response responsible for clinical EAE.
T33 4728-4824 Sentence denotes Shortly after re-activation, most, if not all of the green T cells undergo apoptotic cell death.
T34 4825-4909 Sentence denotes Their depletion from the CNS coincides with termination of the clinical EAE episode.
T35 4910-4946 Sentence denotes Neural and immune synaptic relations
T36 4948-5025 Sentence denotes Inflammation is a local, protective response to microbial invasion or injury.
T37 5026-5172 Sentence denotes It must be fine-tuned and regulated precisely because deficiencies or excesses of the inflammatory response cause morbidity and shorten life span.
T38 5173-5360 Sentence denotes The discovery that cholinergic neurons inhibit acute inflammation has qualitatively expanded our understanding of how the nervous system modulates immune responses (Tracey KJ, Nature 420:
T39 5361-5377 Sentence denotes 853-859, 2002 ).
T40 5378-5516 Sentence denotes The nervous system reflexively regulates the inflammatory response in real time, just as it controls heart rate and other vital functions.
T41 5517-5694 Sentence denotes The vagus nerve transmits anti-inflammatory cholinergic signals to the reticuloendothelial system, inhibiting acute cytokine release during the response to injury and infection.
T42 5695-5853 Sentence denotes This is a selective and reversible dhard-wiredT neural system that is a critical control point, and it can be manipulated to therapeutic advantage in animals.
T43 5854-5926 Sentence denotes Pattern recognition receptors: innate immunity, inflammation and more A.
T44 5927-5998 Sentence denotes Mantovani Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
T45 5999-6057 Sentence denotes Pentraxins are a group of proteins conserved in evolution.
T46 6058-6161 Sentence denotes Long pentraxins represent a discrete subfamily, the prototype of which is the first cloned member PTX3.
T47 6162-6286 Sentence denotes In addition to PTX3 other long pentraxins include neuronal pentraxin 1 and neuronal pentraxin 2, as well as the NP receptor.
T48 6287-6500 Sentence denotes The prototypic long pentraxin PTX3 is a multifunctional pattern recognition receptor produced by diverse cell types and tissues, including the central and peripheral nervous system, in response to diverse signals.
T49 6501-6675 Sentence denotes Evidence suggests that PTX3 plays a non redundant role in innate immunity against selected pathogens, female fertility and inflammation/ repair in the central nervous system.
T50 6676-6792 Sentence denotes Progress in the definition of ligands recognized by PTX3 and in vitro as well as in vivo function will be discussed.
T51 6793-6864 Sentence denotes The role of TREM-2 receptor in myeloid cell development and function M.
T52 6865-7154 Sentence denotes Colonna Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA Triggering receptors expressed on myeloid cells (TREM) belong to a rapidly expanding family of receptors that activate myeloid cells by signaling through the adaptor protein DAP12.
T53 7155-7292 Sentence denotes While TREM-1 triggers phagocyte secretion of proinflammatory chemokines and cytokines, TREM-2 activates monocyte-derived dendritic cells.
T54 7293-7524 Sentence denotes Remarkably, TREM-2 deficiency leads to a severe disease characterized by dementia and bone cysts, which implies that under homeostatic conditions TREM-2 may also regulate the function of brain microglial cells and bone osteoclasts.
T55 7525-7630 Sentence denotes To address TREM-2 function in vivo, we have generated TREM2À/À mice and compared them with DAP12À/À mice.
T56 7631-7794 Sentence denotes Results demonstrate a critical function of TREM-2/DAP12 in the development of microglia and osteoclasts and in the function of dendritic cells in immune responses.
T57 7795-7849 Sentence denotes Innate immunity: neuroprotection or neurodegeneration?
T58 7850-7852 Sentence denotes S.
T59 7853-7930 Sentence denotes Rivest CHUL Research Center and Laval University, Quebec City, Quebec, Canada
T60 7931-8136 Sentence denotes Innate immune response is initiated by the binding of pathogen-associated molecular patterns (PAMPs) to their cognate Toll-like receptors (TLRs) expressed on the surface of antigen-presenting cells (APCs).
T61 8137-8359 Sentence denotes Because of the blood-brain barrier (BBB) that restricts the access of immune mediators and cells from the blood, the mechanisms leading to proinflammatory signaling in the brain are different from those of systemic organs.
T62 8360-8567 Sentence denotes For this reason, the term bimmune-privileged organQ has long been used to describe the reduced exposure of the brain to inflammatory events and its inability to mount an immune response and process antigens.
T63 8568-8784 Sentence denotes Contrary to this notion, there is an elegant innate immune response that takes place in a very well organized and coordinated manner in the central nervous system (CNS) during systemic infection and cerebral insults.
T64 8785-8862 Sentence denotes Like systemic APCs, brain microglia react to PAMPs in a TLR-dependent manner.
T65 8863-9049 Sentence denotes Emerging evidence suggests that innate immunity plays beneficial roles in host defense and recovery, although microglial reactivity is becoming a hallmark of neurodegenerative processes.
T66 9050-9278 Sentence denotes This lecture will present both sites of the story and highlight the mechanisms involved in control of the inflammatory response in the brain that either protect neurons or is the direct cause of some neurodegenerative disorders.
T67 9279-9339 Sentence denotes Activation and deactivation of regulatory T cell function E.
T68 9340-9594 Sentence denotes Shevach Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA Naturally occurring regulatory CD4+CD25+ T cells serve a vital function as cellular attenuators of immune responses.
T69 9595-9779 Sentence denotes In most instances, suppression does not dominate raising the important question as to the nature of the factors that control the maintenance and activation of suppressor cell function.
T70 9780-9951 Sentence denotes Although the main function of CD4+CD25+ T cells is to suppress IL-2 production by CD4+CD25Àeffector cells, suppression is still manifest in the presence of exogenous IL-2.
T71 9952-10029 Sentence denotes Moreover, the addition of anti-IL-2 completely abrogates suppressor function.
T72 10030-10135 Sentence denotes Thus, IL-2 must first be produced by the responder cells prior to initiation of suppressor cell function.
T73 10136-10310 Sentence denotes Non-activated CD4+CD25+ regulatory T cells constitutively express GITR, a TNFR-family member, whose engagement was thought to abrogate regulatory T cell-mediated suppression.
T74 10311-10462 Sentence denotes However, using GITRÀ/À mice, the capacity of anti-GITR to abrogate suppression could be shown to be mediated by its action on CD25À, not CD25+ T cells.
T75 10463-10587 Sentence denotes Mouse antigen presenting cells constitutively express GITR-L, which is downregulated following Toll-like receptor signaling.
T76 10588-10746 Sentence denotes Thus, GITR-L provides an important signal for CD25À T cells, rendering them resistant to CD25(+)-mediated regulation at the initiation of the immune response.
T77 10747-10916 Sentence denotes The downregulation of GITR-L by inflammatory stimuli may enhance the susceptibility of effector T cells to suppressor activity during the course of an infectious insult.
T78 10917-11042 Sentence denotes Manipulation of GITR/GITR-L interactions may prove to be an effective way of manipulating regulatory T cell function in vivo.
T79 11043-11126 Sentence denotes Regulatory T cells: a privileged target for the treatment of autoimmune diseases L.
T80 11127-11323 Sentence denotes Chatenoud Hopital Necker, Paris, France Autoimmune responses are controlled by CD4+ regulatory T cells that, depending on the model, may express distinct phenotypic and functional characteristics.
T81 11324-11444 Sentence denotes In the thymus these regulatory cells are CD25+ like CD4+ cells shown to control physiologic organ-specific autoimmunity.
T82 11445-11541 Sentence denotes In contrast, in the periphery, both CD4+CD25+ and CD4+CD25À cells exhibit regulatory capacities.
T83 11542-11657 Sentence denotes Antibodies to CD3 are potent immunosuppressants now generally applied as non Fc-receptor (FcR) binding monoclonals.
T84 11658-11819 Sentence denotes Data from our laboratory were the first to show that CD3 antibodies could reverse autoimmune diabetes in NOD mice by restoring self-tolerance to b cell antigens.
T85 11820-11975 Sentence denotes This led to clinical trials, presently ongoing, in recent onset type 1 diabetic patients using non Fc-receptor (FcR) binding monoclonals antibodies to CD3.
T86 11976-12171 Sentence denotes Concerning mechanistic aspects CD3 antibodies promote immediate clearance of insulitis, followed by bresettingQ of specialized subsets of immunoregulatory CD4+ T cells mediating active tolerance.
T87 12172-12406 Sentence denotes In treated mice regulatory T cells concentrate in the CD4+CD62L+ compartment and some share the CD25 marker, their proportion increase in pancreatic and mesenteric lymph nodes and they are TGF-beta-dependent both in vivo and in vitro.
T88 12407-12623 Sentence denotes Antibodies to CD3 appear thus as the first representatives of a novel category of immunotherapeutic agents that provide a cure for established autoimmunity through their capacity of boosting immunoregulatory T cells.
T89 12624-12758 Sentence denotes It is foreseeable that this proof of concept in autoimmune diabetes could be extended in the near future to other autoimmune diseases.
T90 12759-12819 Sentence denotes Vaccination against beta-amyloid in Alzheimer's disease R.M.
T91 12820-12833 Sentence denotes Nitsch and C.
T92 12834-13028 Sentence denotes Hock Division of Psychiatry Research, University of Zurich, Zurich, Switzerland Immunization against beta-amyloid can reduce amyloid plaque load and improve impaired behavior in transgenic mice.
T93 13029-13407 Sentence denotes To determine whether antibodies against beta-amyloid are also effective in human patients with Alzheimer's disease (AD), we participated in the Wyeth/Elan AN-1792 Phase 2A clinical trial, and included 30 patients with mild to moderate dementia who received two subsequent doses of pre-aggregated Abeta42 and QS-21 as an adjuvant in a randomized, placebo-controlled study design.
T94 13408-13707 Sentence denotes We observed the generation of antibodies against beta-amyloid in the patient sera, and found that the antibodies were characterized by remarkable specificity for bona fide beta-amyloid plaques in brain tissue, and by absent detectable cross-reaction with full-length APP or monomeric forms of Abeta.
T95 13708-13936 Sentence denotes Therefore, we developed a tissue amyloid plaque immunoreactivity (TAPIR) assay to quantify the ability of the antibodies to react with brain beta-amyloid plaques in brain tissue of transgenic mice expressing ADcausing mutations.
T96 13937-14211 Sentence denotes Patients who generated TAPIR-positive antibodies over a 1-year period, showed significantly slower rates of decline of cognitive functions and activities of daily living, and scored better on hippocampusdependent memory tests as compared to patients without such antibodies.
T97 14212-14408 Sentence denotes The beneficial clinical effects were also present in patients who had experienced transient episodes of immunization-related aseptic meningoencephalitis as an unwanted side effect of immunization.
T98 14409-14555 Sentence denotes These data show that the generation of antibodies against beta-amyloid in response to immunization can slow cognitive decline in patients with AD.
T99 14556-14699 Sentence denotes Provided that the tolerability can be improved, they suggest that vaccination against betaamyloid is a valuable option for the treatment of AD.
T100 14700-14782 Sentence denotes Prospects and limitations in the genetic analysis of common autoimmune diseases F.
T101 14783-14799 Sentence denotes Cucca a and M.G.
T102 14800-15002 Sentence denotes Marrosu b a Dipartimento di Scienze Biomediche e Biotecnologie, University of Cagliari, Cagliari, Italy; b Centro Sclerosi Multipla, Dipartimento di Neuroscienze, University of Cagliari, Cagliari, Italy
T103 15003-15127 Sentence denotes The genetic analysis of multifactorial traits such as multiple sclerosis and type 1 diabetes is complicated by many factors.
T104 15128-15289 Sentence denotes These include interlocus and allelic heterogeneity, interactions between different disease loci, and interactions between disease loci and environmental factors.
T105 15290-15433 Sentence denotes Further complications are caused by low penetrance which may be compounded by the small individual genetic effects of most of the disease loci.
T106 15434-15631 Sentence denotes Some of the aforementioned difficulties could be alleviated by concentrating our research on an isolated and relatively homogenous population such as that from the Mediterranean island of Sardinia.
T107 15632-15742 Sentence denotes This population has one of the highest incidences of both type 1 diabetes and multiple sclerosis in the world.
T108 15743-15829 Sentence denotes Moreover, there is evidence for the co-inheritance of these two disorders in Sardinia.
T109 15830-15981 Sentence denotes This is consistent with the suggestion that there are highly penetrant gene(s) present, with a central role in general autoimmunity in this population.
T110 15982-16183 Sentence denotes The Sardinians represent an ancient genetic isolate of accepted pre-Neolithic origin in which the substantial lack of population sub-structure reduces the risk of artifacts due to population admixture.
T111 16184-16413 Sentence denotes The present-time Sardinian population is the result of a fixation of genetic variants which are rare or absent in other European derived populations and which are particularly useful for pinpointing the etiological polymorphisms.
T112 16414-16577 Sentence denotes The results obtained from this population so far, clearly illustrate the advantages of using genetic isolates for the genetic analysis of multifactorial disorders.
T113 16578-16786 Sentence denotes The relative importance of population-demographic and chromosome-region specific variables as well as the relevance of the interaction between loci in the genetic analysis of complex traits will be discussed.
T114 16787-16853 Sentence denotes Genetic analysis of multiple sclerosis: linkage and association A.
T115 16854-17112 Sentence denotes Compston Department of Clinical Neurosciences, Cambridge, UK Using linkage and association, several candidate genes show some reproducibility for an effect on susceptibility, resistance, and the clinical course and phenotype but most are resolutely negative.
T116 17113-17210 Sentence denotes The best supported are effects on susceptibility at HLA-DR/DQ, TNFalpha, IL-1Ra, IL-4, and CTLA4.
T117 17211-17262 Sentence denotes Protection may be provided by Fas-670 and IL-12p40.
T118 17263-17336 Sentence denotes The course may be influenced by polymorphisms for IL-10, CNTF, and ApoE4.
T119 17337-17421 Sentence denotes The phenotype of multiple sclerosis is determined by mutations of mitochondrial DNA.
T120 17422-17559 Sentence denotes The whole genome linkage and association screens suggest that effects may be encoded at 2p, 5p, 6p, 10p, 11p, 16p, 17q, 19q, 22q, and Xp.
T121 17560-18229 Sentence denotes Eventually, six main categories of susceptibility gene can be predicted: genes which determine susceptibility to the process of inflammation across a range of disorders-the autoimmune genes; those which determine the specificity of that process for the development of multiple sclerosis-the ubiquitous genes; those which are relevant for the pathogenesis in isolated populations-the domestic genes; those which determine particular phenotypes-the pleotropic genes; those which determine variations in the clinical course-the modifying genes; and those which cluster to provide specifically different (heterogenous) contributions to the pathogenesis-the epistatic genes.
T122 18230-18340 Sentence denotes A major part of future studies will be to resolve the question of disease heterogeneity in multiple sclerosis.
T123 18341-18432 Sentence denotes The HLA complex is associated with a large number of diseases including Multiple Sclerosis.
T124 18433-18506 Sentence denotes In the case of MS, there is a strong association with the DR15 haplotype.
T125 18507-18566 Sentence denotes It remains uncertain exactly how this translates into risk.
T126 18567-18745 Sentence denotes The commonly believed notion is that this is in some way analogous to IR genes in experimental animal models and relates to differential presentation by MHC molecules to T cells.
T127 18746-18929 Sentence denotes There are however significant difficulties with this interpretation, not the least of which is that there is equal evidence for linkage through non DR 15 haplotypes for sibling pairs.
T128 18930-19049 Sentence denotes We report a comprehensive analysis of MAC Class 2 typing in a thousand families with MS covering some 5000 individuals.
T129 19050-19151 Sentence denotes This locus is complex being characterised by cis and trans effects and a hierarchical susceptibility.
T130 19152-19227 Sentence denotes These are interpreted in terms of the known genetic analysis of other loci.
T131 19228-19303 Sentence denotes Animal models as a genetic tool to enlight multiple sclerosis complexity R.
T132 19304-19484 Sentence denotes Holmdahl Medical Inflammation Research, Lund University, Lund, Sweden Inbred animals are useful for studies of the identification of genes associated with complex diseases like MS.
T133 19485-19651 Sentence denotes Many but not all of the basic disease pathways leading to MS is likely to be shared with other autoimmune chronic inflammatory disease like rheumatoid arthritis (RA).
T134 19652-19781 Sentence denotes We have used several different models for MS and RA to identify the underlying gene regions and genes that contribute to disease.
T135 19782-19973 Sentence denotes This is in principal done by analysis of genetically segregating crosses of inbred strains with varying disease susceptibility followed by linkage of the genotypic and phenotypic information.
T136 19974-20191 Sentence denotes By this method, we and others have isolated the most important gene regions and bred these into congenic strain in which each loci can be studied separately and through each contributing gene can eventually be cloned.
T137 20192-20422 Sentence denotes Such congenic strains have been shown to be useful for studies on the MHC region genes but also genes outside the MHC region and some examples have been reported; the MHC class II Ab gene in the mouse and the Ncf1 gene in the rat.
T138 20423-20535 Sentence denotes The Ncf1 protein is a part of the NADPH oxidase complex involved in generation of the inducible oxidative burst.
T139 20536-20711 Sentence denotes The discovery of the Ncf1 polymorphism led to a new proposed pathway in which oxygen radicals modify antigen presentation and the resulting activation of autoreactive T cells.
T140 20712-20909 Sentence denotes New data will be presented on the role of the Ncf1 gene in models for MS and also the importance of identifying genetic and environmental interactions to identify genes in complex diseases like MS.
T141 20910-21013 Sentence denotes Molecular mechanisms driving transendothelial migration of leukocytes across the blood-brain barrier B.
T142 21014-21175 Sentence denotes Engelhardt Theodor Kocher-Institute, University of Bern, Bern, Switzerland Diapedesis of encephalitogenic T lymphocytes across the blood-brain barrier is unique.
T143 21176-21651 Sentence denotes By applying intravital fluorescence microscopy that allows us to visualize the interaction of circulating encephalitogenic T lymphoblasts within the CNS microvasculature in vivo, we demonstrated that encephalitogenic T cell blasts interact with the spinal cord white matter microvasculature without rolling and that a4-integrin mediates the Gprotein independent capture and subsequently the G-protein-dependent adhesion strengthening of T cell blasts to microvascular VCAM-1.
T144 21652-21770 Sentence denotes LFA-1 was found to be involved in transendothelial migration of T cell blasts across spinal cord microvessels in vivo.
T145 21771-21828 Sentence denotes Endothelial ICAM-1 and ICAM-2 are both ligands for LFA-1.
T146 21829-21954 Sentence denotes To define their exact role during T cell extravasation we used mouse T cells and ICAM-1À/ÀICAM-2À/À brain endothelioma cells.
T147 21955-22062 Sentence denotes ICAM-1À/ÀICAM-2À/À brain endothelioma cells did not support transendothelial migration of T cells in vitro.
T148 22063-22363 Sentence denotes Re-expression of different ICAM-1 mutants in the ICAM-1À/ÀICAM-2À/À endothelioma cells demonstrated that the extracellular domain of ICAM-1 suffices to support T cell adhesion while presence of the cytoplasmic tail was strictly required for TEM and Rho GTPase activation within the endothelial cells.
T149 22364-22491 Sentence denotes Surprisingly, tyrosine-phosphorylation of endothelial ICAM-1 was not necessary for TEM of T cells nor for RhoGTPase activation.
T150 22492-22695 Sentence denotes The cytoplasmic tail of endothelial ICAM-1-independent from tyrosine phosphorylation-is therefore essential for supporting TEM of T lymphocytes probably by activating Rho-signalling in endothelial cells.
T151 22696-22802 Sentence denotes It is generally believed that this signal is required to open endothelial junctions for T cell diapedesis.
T152 22803-22895 Sentence denotes At the blood-brain barrier, endothelial cells are interconnected by complex tight junctions.
T153 22896-23284 Sentence denotes By serial section electron microscopy, we found that in experimental autoimmune encephalomyelitis mononuclear cells traverse cerebral microvessels by a transcellular pathway leaving the endothelial tight junctions intact whereas morphological evidence for the involvement of tight junctions in the diapedesis of mononuclear cells across the inflamed BBB could not be obtained in any case.
T154 23285-23415 Sentence denotes The unique molecular mechanisms driving transendothelial migration of leukocytes across the blood-brain barrier will be discussed.
T155 23416-23492 Sentence denotes The Jun/JNK axis in regulation of neurodegeneration and neuroinflammation T.
T156 23493-23542 Sentence denotes Herdegen Institute of Pharmacology, Kiel, Germany
T157 23543-23660 Sentence denotes The c-Jun N-terminal kinases (JNK) are essential mediators of the proinflammatory actions of peripheral immune cells.
T158 23661-23770 Sentence denotes In striking contrast, the actions of JNKs in the immune cells of the nervous system remains to be elucidated.
T159 23771-23957 Sentence denotes We have demonstrated for the first time that microglia express the JNK1, JNK2 and JNK3 isoforms in primary brain microglial cultures from neonatal mice and rats [Hidding et al., Biochem.
T160 23958-23964 Sentence denotes Pharm.
T161 23965-23968 Sentence denotes 65:
T162 23969-23986 Sentence denotes 781-788 (2002) ].
T163 23987-24048 Sentence denotes Here, we present data on the activation and function of JNKs.
T164 24049-24220 Sentence denotes Lipopolysaccharide (LPS), tumor necrosis factor alpha (TNFalpha) and thrombin induced a rapid and lasting activation of JNKs, which are not activated in resting microglia.
T165 24221-24457 Sentence denotes Stimulation with LPS increased the total amount of nuclear JNKs, whereas the pool of activated JNKs rapidly decreased, however, the phosphorylation of the high affinity substrate and transcription factor c-Jun was dramatically enhanced.
T166 24458-24577 Sentence denotes Analysis of nuclear JNK isoforms revealed that the amount of JNK1 declined, while JNK2 increased and JNK3 did not vary.
T167 24578-24680 Sentence denotes This observation suggests that JNK2 is mainly responsible for the activation of transcription factors.
T168 24681-24767 Sentence denotes Upstream of JNKs, LPS induced a lasting activation of the constitutively present MKK4.
T169 24768-24850 Sentence denotes Interleukin signaling pathways and role in autoimmune inflammation of the CNS C.L.
T170 24851-24863 Sentence denotes Langrish, Y.
T171 24864-24877 Sentence denotes Chen and D.J.
T172 24878-25041 Sentence denotes Cua DNAX Research Inc., Palo Alto, CA, USA Interleukin-23 is a heterodimeric cytokine comprised of a unique p19 subunit and a common p40 subunit shared with IL-12.
T173 25042-25190 Sentence denotes IL-23 signals through a receptor complex consisting of IL-12R-beta-1 and the newly discovered IL-23R which activates Jak-stat DNA-binding complexes.
T174 25191-25358 Sentence denotes Engagement of IL-23 receptor complex is required for the expansion of a highly encephalitogenic T cell population that produces IL-6, IL-17, and TNF but not IFN-gamma.
T175 25359-25586 Sentence denotes Thus, IL-23 plays an important role in the development and expansion of an alternative T cell subset-distinct from the classical Th1-and Th2-type responses, that are critical for the pathogenesis of CNS autoimmune inflammation.
T176 25587-25660 Sentence denotes Detrimental and beneficial cytokine signaling in Alzheimer's disease M.P.
T177 25661-25951 Sentence denotes Mattson Laboratory of Neurosciences, National Institute on Aging IRP, Baltimore, MD, USA Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which synapses become dysfunctional, neurites degenerate and neurons die resulting in memory impairment and psychiatric problems.
T178 25952-26087 Sentence denotes Excessive production and accumulation of cytotoxic forms of amyloid beta peptide (Abeta) is believed to be a pivotal abnormality in AD.
T179 26088-26312 Sentence denotes Deposits of Abeta are associated with increased levels of pro-inflammatory cytokines and activated microglial cells and astrocytes, and Abeta induces the production of the same cytokines in cultured microglia and astrocytes.
T180 26313-26449 Sentence denotes The mechanisms responsible for the inflammatory responses involve increased oxidative stress and perturbed cellular calcium homeostasis.
T181 26450-26607 Sentence denotes Data suggest that cytokines may either promote or protect against neuronal degeneration, depending upon the cell type and signaling pathway(s) they activate.
T182 26608-26827 Sentence denotes For example, tumor necrosis factor (TNF) can activate receptors on neurons that are coupled to the activation of the transcription factor NF-kB which activates genes that encode proteins that can prevent neuronal death.
T183 26828-26948 Sentence denotes On the other hand, TNF stimulates microglia to produce damaging reactive oxygen species (nitric oxide) and excitotoxins.
T184 26949-27225 Sentence denotes Studies of transgenic mice and cultured neural cells that express mutant forms of amyloid precursor protein and presenilin-1 that cause inherited forms of AD have shown that the mutations result in enhanced production of TNF, IL-1beta and IL-6 in response to immune challenge.
T185 27226-27400 Sentence denotes Thus, activation of innate immune responses may contribute to the demise of neurons in AD and drugs that suppress the damaging cytokine cascades may have therapeutic benefit.
T186 27401-27621 Sentence denotes On the other hand, recent studies have demonstrated striking beneficial effects of immunization of bAD miceQ with Abeta, suggesting that it may be possible to prevent AD by stimulating a humoral immune response to Abeta.
T187 27622-27888 Sentence denotes We developed an infection-induced molecular mimicry model of CNS autoimmune disease induction by engineering a non-pathogenic variant of Theiler's virus (TMEV) to encode a 30-39mer peptides encompassing the immunodominant myelin PLP139-151 epitope or epitope mimics.
T188 27889-28149 Sentence denotes SJL mice infected with TMEV encoding either the native PLP139-151 determinant or a molecular mimic, H. influenzae protease IV (HI574-586) which shares only 6/13 amino acids, develop an earlyonset demyelinating disease mediated by PLP139-151-specific Th1 cells.
T189 28150-28403 Sentence denotes The autoimmune nature of the disease was shown by the fact that tolerance to either the native mouse PLP139-151 epitope or the HI574-586 mimic epitope prevented clinical disease and induction of associated autoreactive PLP139-151-specific Th1 responses.
T190 28404-28716 Sentence denotes Disease and PLP139-151-specific cross-reactive responses could also be induced by infection with a virus engineered to express a 39-mer peptide encompassing the HI574-586 mimic epitope (HI39-TMEV) indicating that the mimic peptide is a natural mimic epitope capable of being processed from its flanking residues.
T191 28717-29092 Sentence denotes However, mice immunized multiple times with the core HI574-586 core peptide in complete Freund's adjuvant (CFA) exhibited no clinical disease symptoms due to failure to secrete high levels of IFN-gamma in response to in vitro re-challenge with PLP139-151 indicating the importance of virus-induced innate immune signals in triggering autoimmune disease via molecular mimicry.
T192 29093-29442 Sentence denotes Viral infections and autoimmunity-a double-edged sword M. von Herrath La Jolla Institute for Allergy and Immunology, San Diego, USA Intuitively one tends to associate viral infections that frequently induce profound inflammation in multiple organs with enhancement of autoimmune processes and diseases such as type 1 diabetes and multiple sclerosis.
T193 29443-29673 Sentence denotes There is substantial evidence that viral infections can increase the incidence of autoimmune diseases (i.e., NOD mouse and Coxsackie B3 infection) or precipitate inflammatory disorders with autoimmune components (Theiler's virus).
T194 29674-29797 Sentence denotes This can occur either by antigennonspecific bystander events or through cross-reactivity between viral and self-components.
T195 29798-29994 Sentence denotes We will show data for the second scenario (mimicry) and illustrate that molecular mimicry is more likely to enhance an already ongoing autoimmune process rather than precipitating disease de novo.
T196 29995-30145 Sentence denotes However, recently, it has become increasingly clear that the opposite situation, prevention of autoimmunity by viral infections, might be more common.
T197 30146-30239 Sentence denotes There is accumulating evidence that viruses such as Coxsackie B or LCMV can prevent diabetes.
T198 30240-30280 Sentence denotes How can viral infections be good for us?
T199 30281-30458 Sentence denotes We will show recent findings that demonstrate how chemokine gradients established by viral infections can lure autoaggressors away from the site of organ or tissue inflammation.
T200 30459-30521 Sentence denotes The reversal of disease appears in most cases to be permanent.
T201 30522-30665 Sentence denotes This finding fits with the recent increasing trend in autoimmune diseases, as well as asthma, in industrialized nations (bhygiene hypothesisQ).
T202 30666-30704 Sentence denotes Coronavirus-induced immunopathology M.
T203 30705-30723 Sentence denotes Buchmeier a and J.
T204 30724-31003 Sentence denotes Rempel b a The Scripps Research Institute, La Jolla, CA, USA; b University of Manitoba, Winnipeg, Canada Differences in disease outcome between the highly neurovirulent MHV-JHM and mildly neurovirulent MHV-A59 have been attributed to variations within the spike (S) glycoprotein.
T205 31004-31256 Sentence denotes We found that MHV-JHM neurovirulence was marked by diminished expression of IFNgamma mRNA and recruitment of CD8 T cells into the CNS concomitant with heightened MIP-1 transcript levels and greater macrophage infiltration relative to MHV-A59 infection.
T206 31257-31376 Sentence denotes Here, the ability of the S and non-spike genes to regulate these immune responses was evaluated using chimeric viruses.
T207 31377-31516 Sentence denotes Chimeric viruses, WTR13 and S4R22, were made on MHV-A59 variant backgrounds and, respectively, contained the S gene of MHV-A59 and MHV-JHM.
T208 31517-31621 Sentence denotes Unexpectedly, genes other than S appeared to modulate events critical to viral replication and survival.
T209 31622-31798 Sentence denotes Unlike unresolving MHV-JHM infections, the clearance of MHV-A59, WTR13 and S4R22 infections coincided with strong IFNgamma transcription and increased CD8 T cells infiltration.
T210 31799-32010 Sentence denotes Even in the absence of viral replication, approximately 40% of S4R22 infected mice succumbed within 3 weeks indicating that the enhanced mortality following S4R22 infection was not associated with viral fitness.
T211 32011-32235 Sentence denotes Rather, similar to the MHV-JHM infection, reduced survival following S4R22 infection was observed in the presence of elevated MIP-1alpha and MIP-1beta mRNA accumulation and enhanced macrophage numbers within infected brains.
T212 32236-32403 Sentence denotes These observations suggest that the S protein of MHV-JHM influences neurovirulence through the induction of MIP-1alpha and MIP-1beta driven macrophage immunopathology.
T213 32404-32448 Sentence denotes Supported by NIH grants AI43103 and AI25913.
T214 32449-32644 Sentence denotes HHV-6 is a b-herpesvirus characterized by a distinct neurotropism, which has been implicated in various neurologic disorders, including seizures, meningitis, encephalitis, and multiple sclerosis.
T215 32645-32890 Sentence denotes We previously demonstrated that the cellular receptor for HHV-6 is CD46, a ubiquitous complement-regulatory protein that prevents the cytolytic attack of autologous complement and that also serves as a receptor for other human infectious agents.
T216 32891-33055 Sentence denotes Evidence suggests that the viral use of CD46 does not merely represent a cell surface anchoring mechanism, but may also have profound implications for pathogenesis.
T217 33056-33168 Sentence denotes We developed a novel in vitro experimental model to investigate the mechanisms of HHV-6-mediated neuropathology.
T218 33169-33369 Sentence denotes Long-term cultures of primary neural stem cells derived from human fetal brain were differentiated and studied for their susceptibility to infection by HHV-6 and subsequent complement-mediated damage.
T219 33370-33472 Sentence denotes These cultures typically consist of astrocytes (80-85%), neurons (15-20%), and oligodendrocytes (b1%).
T220 33473-33658 Sentence denotes Productive infection was detected with HHV-6 A, but not with HHV-6 B, as determined by quantitativecalibrated real-time PCR, and was associated with giant multinucleated cell formation.
T221 33659-33865 Sentence denotes Expression of HHV-6 antigens was observed in both astrocytes and neurons, although infection was associated with a loss of typical lineage-associated markers (GFAP for astrocytes, beta-tubulin for neurons).
T222 33866-34105 Sentence denotes Treatment of neural cells with purified HHV-6 virions or anti-CD46 antibodies followed by exposure to human complement resulted in a massive deposition of opsonic C3 fragments, as detected by confocal microscopy, and widespread cell death.
T223 34106-34329 Sentence denotes These results suggest that the cytopathic effects associated with HHV-6 replication in the CNS may be amplified by the direct engagement of CD46, which results in a dramatic impairment of its complement-regulatory function.
T224 34330-34384 Sentence denotes Self representation in the thymus: an extended view B.
T225 34385-34443 Sentence denotes Kyewski German Cancer Research Center, Heidelberg, Germany
T226 34444-34709 Sentence denotes The prevailing notion that tolerance to peripheral self-antigens is solely covered by post-thymic mechanisms has been revised by the recent finding that tissue-specific antigens are expressed by thymic stromal cells, a phenomenon termed promiscuous gene expression.
T227 34710-34904 Sentence denotes Promiscuous expression of tissue-antigens in the thymus is a property of thymic epithelial cells rather than bone marrow-derived antigen presenting cells, implying cell-type specific regulation.
T228 34905-35084 Sentence denotes Thymic medullary epithelial cells express a unique range of tissue antigens at the mRNA level when compared to other antigen presenting cells or epithelial cells of other tissues.
T229 35085-35276 Sentence denotes This set of genes (N400) includes many tissue-specific antigens, clinically relevant auto-antigens, and cancer-germ line genes without sharing apparent structural or functional commonalities.
T230 35277-35415 Sentence denotes Antigen expression, when restricted to this cell type, is sufficient to confer specific T-cell tolerance attesting to its functional role.
T231 35416-35662 Sentence denotes While the overall contribution of promiscuous gene expression to central tolerance induction can be inferred from the range and level of self-antigens expressed in this manner, the tolerance state for each antigen has to be analyzed individually.
T232 35663-35796 Sentence denotes Implications of these results for the regulation of promiscuous gene expression and the scope of central tolerance will be discussed.
T233 35797-35853 Sentence denotes Making and breaking tolerance to myelin basic protein J.
T234 35854-35869 Sentence denotes Goverman a , S.
T235 35870-35884 Sentence denotes Cabbage a , T.
T236 35885-35899 Sentence denotes Brabb a , E.S.
T237 35900-35915 Sentence denotes Huseby b and D.
T238 35916-36021 Sentence denotes Liggitt a a University of Washington, Seattle, WA, USA; b National Jewish Medical Centre, Denver, CO, USA
T239 36022-36159 Sentence denotes The activation of immune responses to myelin antigens is believed to be one of the early steps in the pathogenesis of multiple sclerosis.
T240 36160-36355 Sentence denotes This process has been extensively studied using the animal model experimental allergic encephalomyelitis (EAE), which is induced by immunization with myelin antigen in complete Freund's adjuvant.
T241 36356-36531 Sentence denotes The ability to trigger myelin-specific T cells in the periphery indicates that these T cells escaped immune tolerance mechanisms that normally eliminate self-reactive T cells.
T242 36532-36748 Sentence denotes Our interests focus on defining the role of tolerance mechanisms in shaping the repertoire of peripheral myelin-specific T cells and on determining how a breakdown of these mechanisms contributes to CNS autoimmunity.
T243 36749-36910 Sentence denotes To pursue these studies, our laboratory generated T cell receptor transgenic models of CD4+ T cell responses to different epitopes of myelin basic protein (MBP).
T244 36911-37187 Sentence denotes We found that clonal deletion in the thymus was an important tolerance mechanism only for T cells undergoing high avidity interactions with their MBP epitope on antigen-presenting cells while T cells undergoing low avidity interactions with their MBP epitope escaped deletion.
T245 37188-37320 Sentence denotes Our results also showed that regulatory T cells can prevent autoimmunity mediated by both high and low avidity MBP-specific T cells.
T246 37321-37405 Sentence denotes How regulatory T cells function in both the CNS and the periphery will be discussed.
T247 37406-37480 Sentence denotes Expression of myelin antigens in the thymus: a little goes a long way V.K.
T248 37481-37492 Sentence denotes Kuchroo, Z.
T249 37493-37502 Sentence denotes Illes, A.
T250 37503-37518 Sentence denotes Anderson and J.
T251 37519-37774 Sentence denotes Reddy Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Using Class II PLP 139-151/IAs tetramers, we have determined the frequency of PLP 139-151 reactive T cells in the naRve repertoire of the SJL mice.
T252 37775-37919 Sentence denotes Although frequency varies with age, approximately 0.5% of CD4+ cells in the peripheral repertoire of SJL mice bind specifically to the tetramer.
T253 37920-38112 Sentence denotes The EAE-resistant B10.S mice, also show a similar frequency of the PLP 139-151 reactive T cells in the peripheral repertoire but these cells cannot be expanded following specific immunization.
T254 38113-38366 Sentence denotes We now find that while the tetramer reactive T cells in the naRve peripheral repertoire of the SJL mice are in the CD4+, CD25À compartment, the vast majority of PLP 139-151 tetramer reactive cells in the resistant B10.S mice are in the CD4+, CD25+ gate.
T255 38367-38482 Sentence denotes This may be one of the reasons why the PLP 139-151-specific T cells cannot be expanded in the resistant B10.S mice.
T256 38483-38637 Sentence denotes Deletion of CD25+ T cell, prior to immunization with PLP 139-151 results in expansion of T cells and induction of disease in the EAE-resistant B10.S mice.
T257 38638-38875 Sentence denotes Preliminary data suggest that expression of myelin PLP vs. DM20 isoform in the thymus and peripheral lymphoid tissue may play a key role in affecting susceptibility and resistance to EAE by affecting the generation of regulatory T cells.
T258 38876-38953 Sentence denotes Antigen recognition patterns of autoreactive T cells in multiple sclerosis R.
T259 38954-39168 Sentence denotes Martin Neuroimmunology Branch, NINDS, NIH, Bethesda, MD, USA MS is considered a T cell-mediated autoimmune disease with central nervous system (CNS) inflammation, demyelination and varying degrees of axonal damage.
T260 39169-39439 Sentence denotes While the effector mechanisms of CNS damage include antibodies, complement, cytokines, CD8+ T cell lysis and others as well as factors intrinsic to CNS tissue, e.g., vulnerability to insult, most evidence indicates that CD4+ T cells induce and perpetuate of the disease.
T261 39440-39614 Sentence denotes The specificity spectrum of autoreactive CD4+ T cells in MS for self-and foreign antigens is not completely understood, but a number of myelin antigens are among the targets.
T262 39615-40096 Sentence denotes We have recently addressed two questions related to the biological role of autoreactive CD4+ T cells in MS: (1) do the specificity and function of high avidity myelin-specific T cells in MS differ from controls, and is there a correlation between specificity and clinical phenotype? (2) Can we identify the specificity of CSF-infiltrating T cells in an unbiased way using combinatorial peptide chemistry as well as expression libraries employing cDNAs derived from MS brain tissue?
T263 40097-40152 Sentence denotes Both projects have lead to numerous novel observations.
T264 40153-40334 Sentence denotes In brief, high avidity myelin-specific T cells are enriched in MS patients, are more frequently of Th1 phenotype, and specific myelin peptides clearly are more relevant than others.
T265 40335-40431 Sentence denotes The specificity and phenotype of CD4+ myelin-specific T cells is related to clinical phenotypes.
T266 40432-40554 Sentence denotes Furthermore, our unbiased approaches identified viral antigens as triggers for CSFinfiltrating, clonally expanded T cells.
T267 40555-40688 Sentence denotes CSF-infiltrating T cells recognize a number of different self antigens, among them brain-specific as well as ubiquitous autoantigens.
T268 40689-40755 Sentence denotes Oligodendrogenesis and neurogenesis in multiple sclerosis brain A.
T269 40756-40767 Sentence denotes Chang, S.M.
T270 40768-40787 Sentence denotes Staugaitis and B.D.
T271 40788-40957 Sentence denotes Trapp The Cleveland Clinic Foundation, Cleveland, OH, USA Multiple Sclerosis (MS) is an inflammatory disease of the CNS that destroys myelin, oligodendrocytes and axons.
T272 40958-41065 Sentence denotes We and others have described the generation of new oligodendrocytes in chronically demyelinated MS lesions.
T273 41066-41141 Sentence denotes Here, we present evidence that the MS brain is also generating new neurons.
T274 41142-41293 Sentence denotes MAP2 immunohistochemistry highlights a population of cells with mature neuronal morphology in the subcortical and deep white matter of the human brain.
T275 41294-41404 Sentence denotes These cells have pyramidal or fusiform cell bodies and one to three major processes that branch several times.
T276 41405-41480 Sentence denotes Their cell bodies measure up to 25 mm and their processes, up to 5 mm long.
T277 41481-41582 Sentence denotes MAP2-positive neurons are seen throughout normal white matter of control and MS cerebral hemispheres.
T278 41583-41711 Sentence denotes Cells with neuronal morphologies are also PSA-NCAM-positive and some white matter neurons express neuronal NOS and somatostatin.
T279 41712-41755 Sentence denotes All white matter neurons are NeuN-positive.
T280 41756-41884 Sentence denotes When compared to normal appearing white matter, the number of white matter neurons is significantly decreased within MS plaques.
T281 41885-41949 Sentence denotes NeuN-positive neurons, however, are increased around MS plaques.
T282 41950-42120 Sentence denotes Interestingly, bipolar NeuN and PSA-NCAMpositive cells are also detected in the subventricular zone (SVZ) of MS lesions but not in the SVZ of aged-matched control brains.
T283 42121-42358 Sentence denotes The identification of PSA-NCAM/NeuN-positive cells with an immature morphology in the SVZ and an increase in NeuN-positive cells at the lesion periphery raises the possibility that there is neurogenesis within demyelinated lesions of MS.
T284 42359-42599 Sentence denotes Numerous oligodendrocyte precursor cells and premyelinating oligodendrocytes could be preserved within multiple sclerosis lesions attesting that, in this disease, myelin repair is not only limited by the depletion of oligodendroglial cells.
T285 42600-42755 Sentence denotes Neurotrophic factors could be of therapeutical interest in MS as they might promote either oligodendrocyte survival, myelin formation or axonal protection.
T286 42756-42900 Sentence denotes Using a recently developed index of myelination, we have shown that synthetic neuroprotective sigma agonists could strongly enhance myelination.
T287 42901-43004 Sentence denotes We further analyzed whether some endogenous neurotrophic factors could also stimulate myelin formation.
T288 43005-43150 Sentence denotes We found that CNTF-related factors activating LIFR/gp130 receptors are able to stimulate myelination via the activation of the JAK/ STAT pathway.
T289 43151-43322 Sentence denotes In addition CNTF-related cytokines are also able to promote oligodendrocyte survival by the activation of a distinct signaling pathway involving the kinases PI3-K and AKT.
T290 43323-43594 Sentence denotes This pathway appears to be crucial in regulating oligodendrocyte death and survival as most of the factors aimed at protecting oligodendroglial cells from apoptosis (either neurotrophic factors or antioxydant molecules) require the direct or indirect activation of PI3-K.
T291 43595-43793 Sentence denotes We have further analyzed the oligodendroglial expression of two G-protein coupled receptor named Edg2/LPA1 and Edg-8/S1P5 activated respectively by lysophosphatidic acid and sphingosine-1-phosphate.
T292 43794-44010 Sentence denotes These receptors are specifically expressed by oligodendrocytes in the post-natal brain, and we have observed that their activation could enhance survival of mature oligodendrocyte by activating the PI3-K/AKT pathway.
T293 44011-44096 Sentence denotes Therefore this new family of receptors might also be of therapeutical interest in MS.
T294 44097-44177 Sentence denotes The role of inflammation in creating a pro-remyelination signalling cascade M.R.
T295 44178-44194 Sentence denotes Kotter a , W.-W.
T296 44195-44204 Sentence denotes Li a , F.
T297 44205-44226 Sentence denotes Molina-Holgado a , C.
T298 44227-44238 Sentence denotes Zhao a , A.
T299 44239-44281 Sentence denotes Setzu a,b , C. ffrench-Constant b and R.J.
T300 44282-44711 Sentence denotes Franklin a a Cambridge Centre for Brain Repair, Department of Vetenirary Medicine, University of Cambridge, Cambridge, UK; b Cambridge Centre for Brain Repair, Department of Vetenirary Pathology, University of Cambridge, Cambridge, UK Remyelination is one the few spontaneous regenerative process in the adult mammalian CNS, restoring saltatory conduction to demyelinated axons and potentially exerting an axon-protective effect.
T301 44712-44870 Sentence denotes This process is mediated by oligodendrocyte precursor cells (OPCs), recruited to areas of demyelination and differentiating into myelinating oligodendrocytes.
T302 44871-44963 Sentence denotes The environmental factors that orchestrate this process have attracted much recent interest.
T303 44964-45111 Sentence denotes A picture is emerging of a complex matrix of factors that changes with time, initially promoting OPC recruitment and then inducing differentiation.
T304 45112-45379 Sentence denotes Several studies indicate that the inflammatory response associated with demyelination is critical for triggering a sequence of events involving cross-talk between inflammatory cells and reactive astrocytes that lead to the creation of a pro-remyelination environment.
T305 45380-45525 Sentence denotes These studies have mainly used toxin-models of demyelination, where inflammation is a result of oligodendrocyte injury and not its primary cause.
T306 45526-45702 Sentence denotes For example, slow remyelination that occurs in old adult animals is associated with a delayed inflammatory response and intrinsic changes in the properties of ageing microglia.
T307 45703-45921 Sentence denotes Furthermore, suppressing the macrophage response to toxin-induced demyelination by monocyte depletion or using the microglia activation inhibitor minocycline lead to an impaired OPC response and impaired remyelination.
T308 45922-46047 Sentence denotes Conversely, promoting an inflammatory response substantially enhances myelination by OPCs injected into the adult rat retina.
T309 46048-46226 Sentence denotes In acute experimental autoimmune encephalitis (EAE), Th2/3 cell-derived signals may not only downregulate the immune response but also induce central nervous system (CNS) repair.
T310 46227-46358 Sentence denotes Remyelination is initiated by recruitment and differentiation of oligodendrocyte precursor cells (OPC) in demyelinated CNS lesions.
T311 46359-46544 Sentence denotes Our data show that the Th2/3 cytokine transforming growth factor (TGF)-beta induces microglia to secrete a chemotactic factor for OPC, identified here as hepatocyte growth factor (HGF).
T312 46545-46856 Sentence denotes Gene microarray analysis and functional studies show that (i) TGF-beta-1-2-3 and also interferon (IFN)-beta, a cytokine used to treat multiple sclerosis (MS) patients, induce HGF secretion by microglia and (ii) antibodies to the HGF receptor cMET abrogate OPC chemotaxis induced by TGF-beta-2-treated microglia.
T313 46857-46985 Sentence denotes In EAE, HGF expression is seen in macrophages and microglia in the recovery phase of EAE, but not in the acute stage of disease.
T314 46986-47174 Sentence denotes Taken collectively, the Th2/3 cytokine TGFbeta may play a pivotal role in remyelination by inducing microglia to release HGF which is both a chemotactic and differentiation factor for OPC.
T315 47175-47245 Sentence denotes Antibodies at the neuromuscular junction-effects on gene expression S.
T316 47246-47339 Sentence denotes Berrih-Aknin CNRS UMR 8078, UPS, IPSC, Hopital Marie Lannelongue, Le Plessis Robinson, France
T317 47340-47503 Sentence denotes Myasthenia gravis (MG) is a neuromuscular disorder mediated by antibodies directed against the acetylcholine receptor (AChR) found in about 85% of patients (SPMG).
T318 47504-47605 Sentence denotes The remaining 15% patients have either autoantibodies to Musk or to a not yet defined antigen (SNMG).
T319 47606-47781 Sentence denotes To analyze the molecular mechanisms involved at the muscular target site, we studied the expression of selected genes by quantitative PCR, in muscle biopsies from MG patients.
T320 47782-47935 Sentence denotes We found that the levels of AChR subunit transcripts were increased in severely affected MG patients, independently of the level of anti-AChR antibodies.
T321 47936-48065 Sentence denotes We also observed an upregulation of utrophin, ErbB2, ErbB3, ErbB4, and Musk while rapsyn and MCK were unchanged in most patients.
T322 48066-48145 Sentence denotes Interestingly, these changes were similarly observed in SNMG and SNPG patients.
T323 48146-48327 Sentence denotes To complete these results with an overview of the events occurring in the patient's muscle, we compared the transcriptome of muscles from SNMG and SPMG to a reference normal muscle.
T324 48328-48539 Sentence denotes In both groups of patients, the subcategories of upregulated genes were essentially involved in muscle development and in chaperone activity, while that of down regulated genes was extracellular matrix category.
T325 48540-48695 Sentence denotes Altogether, these data suggest the existence of a compensatory mechanism regulating the expression of several genes involved in the neuromuscular junction.
T326 48696-48841 Sentence denotes Most dysregulated genes are common between SNMG and SNPG patients, suggesting common mechanisms of autoimmune attack in these groups of patients.
T1 48842-48892 Sentence denotes Autoantibodies and the autonomic nervous system S.
T2 48893-49040 Sentence denotes Vernino Mayo Clinic, Rochester, MN, USA Many cases of acute or subacute peripheral autonomic failure are associated with neurological autoimmunity.
T3 49041-49266 Sentence denotes Antibodies specific for ganglionic acetylcholine receptors (nicotinic receptors that mediate fast synaptic transmission in autonomic ganglia) are found in about 50% of patients with idiopathic autoimmune autonomic neuropathy.
T4 49267-49487 Sentence denotes Seropositive patients have a characteristic clinical profile with prominent parasympathetic failure (dry eyes, dry mouth and impaired pupillary responses), impaired bowel and bladder motility and orthostatic hypotension.
T5 49488-49645 Sentence denotes Antibody levels correlate with severity of clinical symptoms, and the sera from some patients inhibit binding of agonist to the ganglionic receptor in vitro.
T6 49646-49852 Sentence denotes In addition, a clinical response to intravenous immunoglobulin or plasma exchange and evidence in experimental animal models indicate that ganglionic AChR antibodies are a direct cause of autonomic failure.
T7 49853-50026 Sentence denotes Other cases of autoimmune autonomic failure or severe gastrointestinal dysmotility occur in association with small-cell lung carcinoma (paraneoplastic autonomic neuropathy).
T8 50027-50190 Sentence denotes These patients may have one or more serum autoantibody markers including ANNA-1 (anti-Hu) and may manifest symptoms of other paraneoplastic neurological disorders.
T9 50191-50233 Sentence denotes Paraneoplastic antibodies-Novel targets J.
T10 50234-50445 Sentence denotes Dalmau University of Pennsylvania, Philadelphia, PA, USA It has been 40 years since the first antibody to neuronal antigens was identified in the serum of patients with paraneoplastic neurologic disorders (PND).
T11 50446-50610 Sentence denotes Since then, additional antibodies have been reported in association with PND, 12 of them currently considered clinically relevant markers of paraneoplasia (PND-Ab).
T12 50611-50838 Sentence denotes The ability to test for these markers and an increased awareness of clinicians for PND is resulting in early recognition and management of these disorders with preliminary evidence that this is impacting the neurologic outcome.
T13 50839-50977 Sentence denotes On a more basic level, PND-Ab are used to isolate the target antigens that often play critical roles in neuronal biology and neurogenesis.
T14 50978-51077 Sentence denotes Overall,~50% of patients with PND of the CNS harbor one or more of the 12 wellcharacterized PND-Ab.
T15 51078-51190 Sentence denotes Among the other 50% of patients, many show signs of inflammation in the CNS or CSF suggesting immune mechanisms.
T16 51191-51299 Sentence denotes Several strategies that have been applied to these patients have lead to the identification of novel PND-Ab.
T17 51300-51586 Sentence denotes These include single case observations (i.e., antibodies to Zic4); identification of groups of patients with similar neuro-oncologic/immunologic findings (i.e., antibodies to Ma proteins), or grouping patients with similar syndromes that have previously been considered PND-Ab negative.
T18 51587-51827 Sentence denotes In the latter group, changes in tissue processing or probing techniques (i.e., immunoprecipitation or modified cDNA library screening) have uncovered novel immunities and the identity of the target antigens, some of which will be discussed.
T19 51828-51867 Sentence denotes Antibodies in demyelinating diseases C.
T20 51868-52171 Sentence denotes Linington Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK There is increasing evidence that antibody-dependent mechanisms are involved in the pathogenesis of demyelination in multiple sclerosis, but the identity of the antigens targeted by this pathogenic response remains uncertain.
T21 52172-52362 Sentence denotes Studies using myelin oligodendrocyte glycoprotein (MOG) as a model antigen reveal that antibody-mediated demyelination must be viewed as an epitope-, rather than antigen-specific phenomenon.
T22 52363-52519 Sentence denotes The demyelinating antibody response to MOG selectively targets discontinuous MOG epitopes, whilst the responses to linear MOG epitopes are generally benign.
T23 52520-52823 Sentence denotes The solution of the crystal structure of MOG and its complex with a Fab fragment of a demyelinating antibody demonstrates the importance of structural constraints in determining the balance between autoaggression and benign autoimmunity, which is further influenced by genetic and environmental factors.
T24 52824-53155 Sentence denotes These results will be discussed with respect to the relevance of MOG as a target for antibody mediated demyelination in human disease, and the use of animal models and proteomic/bioinformatic-based methodologies to identify pathophysiologically relevant autoantibody responses to novel autoantigens of low physical abundance in MS.
T25 53156-53257 Sentence denotes Gangliosides as autoantibody targets at the neuromuscular junction in immune-mediated neuropathies H.
T26 53258-53605 Sentence denotes Willison University of Glasgow, Glasgow, Scotland Progress in our understanding of the Guillain-Barré syndromes has been greatly accelerated by the identification of humoral responses to glycolipids in a significant proportion of cases, and the identification of molecular mimicry with preceding infections as a key mechanism of disease induction.
T27 53606-53899 Sentence denotes Using in vivo and ex vivo mouse neuromuscular junction preparations as a model system to test for effects of antiglycolipid antibodies at nerve terminals, we have shown complementdependent, alpha latrotoxin-like effects comprising a block of evoked ACh release and destruction of the terminal.
T28 53900-54119 Sentence denotes Studies on GM2/GD2 synthase and GD3 synthase null-mutant mice that lack different gangliosides provide insights into the role of ganglioside composition and density in neuronal membranes that predisposes them to injury.
T29 54120-54306 Sentence denotes The terminal attack complex of complement forms membrane pores that allow free ionic movement, and is critical to the development of the structural disorganisation of the nerve terminal.
T30 54307-54464 Sentence denotes This talk will review our current understanding of this complex field and address new approaches to testing novel treatments for these debilitating diseases.
T31 54465-54530 Sentence denotes Molecular mimicry and disease model of Guillain-Barré syndrome N.
T32 54531-54820 Sentence denotes Yuki Department of Neurology, Dokkyo University School of Medicine, Tochigi, Osaka, Japan Molecular mimicry between microbial and self components is postulated as the mechanism that accounts for the antigen and tissue specificity of immune responses in post-infectious autoimmune diseases.
T33 54821-55006 Sentence denotes Little direct evidence exists, and research in this area has focused principally on T cell-mediated, anti-peptide responses, rather than on humoral responses to carbohydrate structures.
T34 55007-55200 Sentence denotes Guillain-Barré syndrome, the most frequent cause of acute neuromuscular paralysis, occurs 1 to 2 weeks after various bacterial and viral infections, particularly Campylobacter jejuni enteritis.
T35 55201-55408 Sentence denotes Carbohydrate mimicry between the bacterial lipo-oligosaccharide and human GM1 ganglioside is seen as having relevance to the pathogenesis of Guillain-Barré syndrome, and conclusive evidence is reported here.
T36 55409-55529 Sentence denotes On sensitization with C. jejuni lipo-oligosaccharide, rabbits developed anti-GM1 IgG antibody and flaccid limb weakness.
T37 55530-55654 Sentence denotes Paralyzed rabbits had pathological changes in their peripheral nerves identical to those present in Guillain-Barré syndrome.
T38 55655-55796 Sentence denotes Immunization of mice with the lipooligosaccharide generated a monoclonal antibody that reacted with GM1 and bound to human peripheral nerves.
T39 55797-56010 Sentence denotes The monoclonal antibody and anti-GM1 IgG from patients with Guillain-Barré syndrome blocked muscle action potentials in a muscle-spinal cord co-culture, indicative that anti-GM1 antibody can cause muscle weakness.
T40 56011-56104 Sentence denotes These findings show that carbohydrate mimicry is an important cause of autoimmune neuropathy.
T41 56105-56166 Sentence denotes Cytokines and T-cell immunity in inflammatory neuropathies J.
T42 56167-56450 Sentence denotes Zhu Karolinska Institute, Stockholm, Sweden Acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome, GBS) and its animal model experimental autoimmune neuritis (EAN) are prototypes of T cell mediated autoimmune diseases affecting the peripheral nervous system (PNS).
T43 56451-56724 Sentence denotes Perivascular accumulation of T lymphocytes and macrophages in the PNS, and high levels systemically of PNS myelin antigen-reactive T cells are characteristic features of both diseases, thereby suggesting a pathogenic role for specific T cell and immunoregulatory cytokines.
T44 56725-56867 Sentence denotes Apoptosis of autoreactive myelin specific T cells may be an important mechanism to limit the immunoinflammatory response and to abort disease.
T45 56868-56964 Sentence denotes Th1/Th2/Th3 cytokines are differently upregulated during various clinical phases of EAN and GBS.
T46 56965-57120 Sentence denotes However, the role of cytokines in immune regulation and autoimmune inflammatory neuropathies is more complex than a simple Th1-Th2 dichotomy would suggest.
T47 57121-57295 Sentence denotes New treatments may be searched for that augments T cell apoptosis and inhibits T cell responses towards peripheral myelin and that counteract this complex cytokine imbalance.
T48 57296-57546 Sentence denotes Treatments with antibodies that selectively target certain proinflammatory cytokines, as well as with immunomodulatory preparations that promote cytokines that beneficially influence the disease course should be in focus of future therapeutic trials.
T49 57547-57715 Sentence denotes The Rockefeller University, New York, NY, USA Dendritic cells (DCs) are a distinct lineage of hematopoietic cells that control several facets of immunity and tolerance.
T50 57716-57828 Sentence denotes It is now feasible to directly study and modify a major reservoir of DCs in peripheral lymphoid tissues of mice.
T51 57829-57974 Sentence denotes To do so, antigens are incorporated into antibodies that selectively target to DCs, currently antibodies to an endocytic receptor, DEC-205/CD205.
T52 57975-58087 Sentence denotes With these engineered antibodies, there is greatly enhanced presentation in vivo on MHC class I and II products.
T53 58088-58151 Sentence denotes Simultaneously, it is important to control DC maturation state.
T54 58152-58310 Sentence denotes Appropriate stimuli can differentiate DCs and render them immunogenic, whereas in the steady state, most DCs are immature and can induce peripheral tolerance.
T55 58311-58500 Sentence denotes These in vivo antigen targeting strategies are now being pursued to better control the induction of tolerance to autoantigens, and the induction of immunity to microbial and tumor antigens.
T56 58501-58557 Sentence denotes DC function can also be studied with ex vivo approaches.
T57 58558-58666 Sentence denotes A broadly recognized mechanism for peripheral tolerance induction involves regulatory or suppressor T cells.
T58 58667-58778 Sentence denotes It has become apparent that DCs induce and/or expand these regulators, including CD4+ CD25+ suppressor T cells.
T59 58779-58958 Sentence denotes We find that DCs serve as presenting cells to expand antigen-specific suppressors ex vivo, and that the expanded cells efficiently control the development of diabetes in NOD mice.
T60 58959-59120 Sentence denotes Although this field is just beginning, we would like to suggest that more direct consideration be given to DCs in the design of therapies for autoimmune disease.
T61 59121-59181 Sentence denotes Traffic of antigen presenting cells to and from the brain T.
T62 59182-59192 Sentence denotes Newman, R.
T63 59193-59209 Sentence denotes Carare-Nnadi, M.
T64 59210-59228 Sentence denotes Bernades-Silva, R.
T65 59229-59244 Sentence denotes Weller and V.H.
T66 59245-59297 Sentence denotes Perry The University of Southampton, Southampton, UK
T67 59298-59363 Sentence denotes In the normal healthy rodent brain, there are no dendritic cells.
T68 59364-59511 Sentence denotes However, following acute brain injury, and in immune mediated lesions, small numbers of OX62+ve dendritic cells appear in the rat brain parenchyma.
T69 59512-59644 Sentence denotes To investigate the origin of these cells, rats with acute excitotoxic lesions were subjected to a number of different manipulations.
T70 59645-59900 Sentence denotes Depletion of the ED2+ perivascular macrophages by intracerebroventricular injection of chlodronate liposomes did not prevent the appearance of OX62+ve cells in the parenchyma, but bone marrow depletion by whole body irradiation abrogated their appearance.
T71 59901-60000 Sentence denotes Thus, the OX62+ve cells are derived from blood and not transformation of resident cell populations.
T72 60001-60329 Sentence denotes To investigate whether potential antigen presenting cells in the brain parenchyma, such as the perivascular cells, traffic from brain to the peripheral immune system fluorescent microspheres approximating the size of a virus (0.02 micrometre) or a bacterium (1.00 micrometre) were microinjected into distinct brain compartments.
T73 60330-60468 Sentence denotes Injection into the meninges or ventricles led to the appearance of the fluorescent microspheres in the cervical lymph nodes and the liver.
T74 60469-60583 Sentence denotes In contrast no fluorescent microspheres were found peripherally following injections restricted to the parenchyma.
T75 60584-60647 Sentence denotes The microspheres were observed within perivascular macrophages.
T76 60648-60793 Sentence denotes A local inflammatory response within the brain resulted in a dramatic alteration of the distribution of microspheres delivered to the parenchyma.
T77 60794-60846 Sentence denotes On the function of dendritic cells in CNS disease T.
T78 60847-60859 Sentence denotes Suter a , G.
T79 60860-60874 Sentence denotes Biollaz a , D.
T80 60875-60887 Sentence denotes Gatto a , L.
T81 60888-60905 Sentence denotes Bernasconi a , C.
T82 60906-60920 Sentence denotes Cretton a , T.
T83 60921-60934 Sentence denotes Herren a , W.
T84 60935-60949 Sentence denotes Reith b and A.
T85 60950-61166 Sentence denotes Fontana a a University Hospital, Zurich, Switzerland; b University of Geneva Medical School, Geneva, Switzerland Dendritic cells (DC) are unique in their ability to prime naive T cells and initiate adaptive immunity.
T86 61167-61346 Sentence denotes In recent years, DC were identified in the inflamed central nervous system (CNS), but their role in the initiation or regulation of the tissue specific immune response is unknown.
T87 61347-61635 Sentence denotes We report that DC isolated from mice with experimental autoimmune encephalomyelitis (EAE) exhibit a maturational phenotype similar to immature bone marrow-derived DC or splenic DC as characterized by intermediate surface MHC class II and low expression of the costimulatory molecule CD80.
T88 61636-61684 Sentence denotes However, they are unable to prime naive T cells.
T89 61685-61773 Sentence denotes Moreover, they inhibit T cell proliferation stimulated by mature bone marrow-derived DC.
T90 61774-61897 Sentence denotes TGF-beta, IL-10 and TRAIL were found to significantly contribute to the CNS-DC-mediated inhibition of T cell proliferation.
T91 61898-61995 Sentence denotes Thus, CNS-DC may be the key responsible for maintaining immune privilege within the inflamed CNS.
T92 61996-62134 Sentence denotes The molecular basis of cell-cell interactions that regulate the function and activation of myeloid lineage cells is now coming into focus.
T93 62135-62396 Sentence denotes Foremost are activating receptors, such as the TREM family, usually associated with the ITAM-expressing DNAX Adapter Protein (DAP)-12, that signals cellular activation, while inhibitory receptors commonly express ITIMs that trigger cellular inhibitory pathways.
T94 62397-62491 Sentence denotes OX2 (CD200) is a very broadly expressed Ig-superfamily molecule, including neurons of the CNS.
T95 62492-62571 Sentence denotes CD200 has a very short cytoplamic tail devoid of any obvious signaling domains.
T96 62572-62763 Sentence denotes Gene targeting of CD200 resulted in enhanced macrophage and microglial activation in situ, suggesting that CD200 may be a ligand that normally engages an inhibitory receptor on myeloid cells.
T97 62764-62975 Sentence denotes The CD200 receptor (CD200R) has been cloned, extensively characterized, and shown to transduce potent inhibitory activities in a range of myeloid cells in vitro and in vivo despite the absence of a classic ITIM.
T98 62976-63170 Sentence denotes Fresh insights into the role of CD200R in regulating microglial cell function will be described as will data from gene expression profiling of adult microglial cells and other brain macrophages.
T99 63171-63357 Sentence denotes These studies have revealed a number of molecules, but especially certain activating receptors that characterize a unique molecular fingerprint for microglial cells within the adult CNS.
T100 63358-63432 Sentence denotes That these molecules normally regulate microglial cells in situ is likely.
T101 63433-63472 Sentence denotes Effect of GM-CSF on microglial cells L.
T102 63473-63629 Sentence denotes Santambrogio Albert Einstein College of Medicine, New York, NY, USA Microglial cells derive from bone marrow precursors which colonize the brain parenchyma.
T103 63630-63748 Sentence denotes They have important functions in CNS inflammatory, degenerative, traumatic conditions as well as in brain homeostasis.
T104 63749-63988 Sentence denotes In contrast with other organs where terminally differentiated dendritic cells and macrophages are the resident population, the rather undifferentiated state of microglial cells in the brain could contribute to its bimmunoprivileged stateQ.
T105 63989-64176 Sentence denotes A global gene expression analysis on the extent and consequences of GM-CSF and M-CSF treatment in microglial cells revealed substantial expression reprogramming upon cytokine stimulation.
T106 64177-64358 Sentence denotes Primary murine microglial cells stimulated with M-CSF-induced transcription of genes involved in tissue organization and remodeling, maintenance and regulation of brain homeostasis.
T107 64359-64533 Sentence denotes On the other handed, GM-CSF stimulation induced transcription of genes important in antigen processing, T cell stimulation, chemotaxis, innate immunity and immunosuppression.
T108 64534-64684 Sentence denotes This GM-CSF promotion of microglial participation in adaptive immune responses is distinct from its known function in cell proliferation and survival.
T109 64685-64759 Sentence denotes Non-neuronal cells in ALS neurodegeneration: mechanisms and therapies J.D.
T110 64760-64970 Sentence denotes Rothstein Johns Hopkins University, Department of Neurology, Baltimore, MD, USA Amyotrophic lateral sclerosis is an adult onset neurodegenerative disease characterized clinically by muscle wasting and weakness.
T111 64971-65060 Sentence denotes Traditionally, the disease is characterized by loss of cortical and spinal motor neurons.
T112 65061-65278 Sentence denotes However, recent studies have strongly suggested that disease progression and death of motor neurons depends upon participation of non-neuronal cells including focal inflammatory responses and dysfunction of astroglia.
T113 65279-65464 Sentence denotes Chimeric animal studies and multiple transgenic mouse studies provide evidence for the critical participation of non-neuronal cells in the ultimate degeneration of spinal motor neurons.
T114 65465-65574 Sentence denotes In addition, human and animal model studies demonstrate multiple abnormalities in astroglial function in ALS.
T115 65575-65683 Sentence denotes These abnormalities are detectable even in astroglia and neuronal stem cells derived from transgenic models.
T116 65684-65884 Sentence denotes Using these data, attempts at therapies include the use of neuronal and astroglial stem cells and successful engraftment of motor neuron stem cells as well as astroglial stem cells have been achieved.
T117 65885-66104 Sentence denotes Finally, pharmacological means to modulate CNS inflammation (e.g., COX2 inhibition) and astroglial dysfunction (e.g., glutamate transporter enhancement) will be presented in both animal models and human clinical trials.
T118 66105-66210 Sentence denotes Activation of complement in the central nervous system: roles in neurodegeneration and neuroprotection P.
T119 66211-66345 Sentence denotes Gasque Department of Medical Biochemistry, Brain Inflammation and Immunity Group, University of Wales College of Medicine, Cardiff, UK
T120 66346-66507 Sentence denotes The vertebrate brain has developed its own innate defence and clearance systems against pathogens and apoptotic cells based upon the activation of resident glia.
T121 66508-66685 Sentence denotes The complement inflammatory cascade is an essential component of the phylogenetically ancient innate immune response and is crucial to our natural ability to ward off infection.
T122 66686-66826 Sentence denotes For instance, complement is involved in host defence by triggering the generation of a membranolytic complex at the surface of the pathogen.
T123 66827-67095 Sentence denotes Complement fragments (named opsonins; i.e., C1q, C3b, iC3b) interact with complement cell-surface receptors (C1qRp, CR1, CR3 and CR4) to promote phagocytosis and a local pro-inflammatory response that, ultimately, contributes to the protection and healing of the host.
T124 67096-67369 Sentence denotes Moreover, complement biosynthesis and activation also occurs in neurodegenerative disorders such as Alzheimer's, Huntington's as well as Pick's disease and the cytolytic/ cytotoxic activities of complement are thought to contribute to neuronal loss and brain tissue damage.
T125 67370-67506 Sentence denotes However, recent data suggest that at least some of the complement components have the ability to contribute to neuroprotective pathways.
T126 67507-67725 Sentence denotes The emerging paradigm is that complement is involved in the clearance of toxic cell debris (e.g., amyloid fibrils) and apoptotic cells, as well as promoting tissue repair through the antiinflammatory activities of C3a.
T127 67726-67943 Sentence denotes Knowledge of the unique molecular and cellular innate immunological interactions that occur in the development and resolution of pathology in the brain should facilitate the design of effective therapeutic strategies.
T128 67944-68108 Sentence denotes Protective autoimmunity as a defense mechanism against destructive self-compounds: role of CD4+CD25+ regulatory T cells and prospects for therapeutic vaccination M.
T129 68109-68364 Sentence denotes Schwartz Weizmann Institute of Science, Rehovot, Israel Slowly progressing neurodegenerative diseases of the central nervous system (CNS), caused by numerous factors in addition to the primary trigger, can potentially benefit from neuroprotective therapy.
T130 68365-68626 Sentence denotes We suggest that all self-compounds that participate in the progression of neurodegenerative diseases should be viewed as potential enemies of endogenous origin, some of which cause inappropriate activation of the resident microglia (e.g., TNF-alpha, NO, COX-2).
T131 68627-68867 Sentence denotes It was found that the adaptive arm of the immune response, in the form of T cells directed against CNS self-antigens that reside in the site of injury (but not against the threatening compounds themselves), shape the phenotype of microglia.
T132 68868-69016 Sentence denotes Naturally occurring CD4+CD25+ regulatory T cells were found to be the cells that restrict the spontaneous ability to elicit beneficial autoimmunity.
T133 69017-69212 Sentence denotes Brainassociated neuropeptides/neurotransmitters were shown to act as signaling molecules through which the inhibitory activity and trafficking of the regulatory T cells can be switched on or off.
T134 69213-69390 Sentence denotes Boosting of autoimmunity without invoking autoimmune disease can be achieved by weakening the activity of regulatory cells or by vaccinating with a weak agonist of selfantigens.
T135 69391-69590 Sentence denotes These findings have far-reaching implications for risk-free therapy of neurodegenerative diseases in general, and in particular when the same individual is suffering from more than one such disorder.
T136 69591-69642 Sentence denotes Beta-amyloid vaccination and Alzheimer's disease T.
T137 69643-69869 Sentence denotes Tabira National Institute for Longevity Sciences, Aichi, Japan Alzheimer's disease (AD) is a disorder characterized by senile plaques with amyloid deposits and primitive immune responses due to activated microglia/macrophages.
T138 69870-70047 Sentence denotes It was shown that immunization of amyloid precursor protein (APP) gene transgenic mice with aggregated amyloid beta protein (A-beta)1-42 reduced the amyloid burden in the brain.
T139 70048-70243 Sentence denotes The clinical trial of this vaccination therapy in AD patients was halted because of acute meningoencephalitis as a side effect, which was thought to be induced by CD4+ T cells reactive to A-beta.
T140 70244-70370 Sentence denotes However, the clinical decline was found much less in patients who developed antibodies to beta amyloid than those who did not.
T141 70371-70493 Sentence denotes It is interesting to know that an autopsy case who had received the vaccine suggested the disappearance of senile plaques.
T142 70494-70552 Sentence denotes Thus, development of a better vaccine for AD is warranted.
T143 70553-70642 Sentence denotes We have developed a safe vaccine using adeno-associated virus vector carrying Abeta cDNA.
T144 70643-70774 Sentence denotes Administration of this vaccine once by an oro-gastric tube induced antibodies to beta amyloid, which lasted for more than 6 months.
T145 70775-70943 Sentence denotes We found that this vaccine was quite effective and safe in APP transgenic mice (tg2576), which might be explained by the shift from Th1 to Th2 in the gut immune system.
T146 70944-71075 Sentence denotes The neurotransmitters glutamate and dopamine activate their specific receptors in human T-cells and trigger key T-cell functions M.
T147 71076-71089 Sentence denotes Levite and Y.
T148 71090-71142 Sentence denotes Ganor Weizmann Institute of Science, Rehovot, Israel
T149 71143-71198 Sentence denotes Do T-cells express specific neurotransmitter-receptors?
T150 71199-71260 Sentence denotes Can neurotransmitters by themselves trigger T-cell functions?
T151 71261-71463 Sentence denotes Glutamate: we discovered for the first time that normal, cancer and autoimmune encephalitogenic Tcells, alike neurons and glia cells, express high levels of ion-channel (ionotropic) glutamate-receptors.
T152 71464-71604 Sentence denotes The evidence for glutamate/AMPA receptor subtype-3 (GluR3) in human T-cells includes RT-PCR, western blot and immunostaining/flow-cytometry.
T153 71605-71681 Sentence denotes Sequencing showed identity between the T-cell's GluR3 and the brain's GluR3.
T154 71682-71774 Sentence denotes Further, glutamate on it own (~10 nM) potently triggers several T-cell functions among them:
T155 71775-71909 Sentence denotes (1) integrin-mediated-adhesion to laminin and fibronectin, and 2) CXCR4mediated chemotactic-migration towards the key chemokine SDF-1.
T156 71910-71919 Sentence denotes Dopamine:
T157 71920-72487 Sentence denotes We discovered for the first time that normal human T-cells express on their outer membranes functional dopamine receptors of the D3 and D2 subtypes, and that dopamine (~10 nM) or selective dopaminereceptor agonists trigger various T-cells functions among them: (1) differential cytokine-secretion of either inflammatory (TNFalpha) or anti-inflammatory (IL-10) cytokines, different from the robust nonselective cytokine-secretion btriggered by classicalQ TCR-activation, (2) integrin-mediated adhesion to extracellular glycoproteins, (3) unique denovo gene-expression.
T158 72488-72900 Sentence denotes The ability of glutamate and dopamine on their own to trigger T-cell functions and gene-expression could be of substantial scientific and clinical importance for numerous conditions in health and disease, among them: (a) transmigration of bgoodQ T-cells into the brain for different patrolling/protecting tasks, (b) Detrimental activation and maintenance of bbadQ T-cells in the CNS, e.g., in multiple-sclerosis.
T159 72901-73010 Sentence denotes The presentation of self in the thymus network: a novel way for prevention and cure of autoimmune diseases V.
T160 73011-73083 Sentence denotes Geenen Liege University Center of Immunology, Liege-Sart Tilman, Belgium
T161 73084-73228 Sentence denotes The thymus ensures the establishment of self-tolerance by deleting selfreactive T cells and generating self-antigen specific regulatory T cells.
T162 73229-73305 Sentence denotes A repertoire of neuroendocrine genes is transcribed by thymic stromal cells.
T163 73306-73564 Sentence denotes Thymic neuroendocrine precursors engage two types of interactions with pre-T cells either as ligands that bind with high affinity to neuroendocrine receptors expressed by thymocytes, or after processing as self-antigens presented by the thymic MHC machinery.
T164 73565-73771 Sentence denotes Thus, in the thymus, a confrontation occurs throughout life between previously emerged neuroendocrine families and a recently evolved system characterized by stochastic generation of its response diversity.
T165 73772-73919 Sentence denotes All members of the insulin gene family are transcribed in the thymus: IGF2 (TEC/TNC)NIGF1 (macrophages)JINS (medullary TEC and/or dendritic cells).
T166 73920-74008 Sentence denotes IGF2 transcription is defective in the thymus of more than 80% of diabetesprone BB rats.
T167 74009-74158 Sentence denotes The sequence Ins B9-23 is a dominant h-cell autoantigen presented by DQ8, a MHC-II allele conferring genetic susceptibility to type 1 diabetes (T1D).
T168 74159-74239 Sentence denotes The homologous sequence IGF-2 B11-25 competes with Ins B9-23 for binding to DQ8.
T169 74240-74395 Sentence denotes However, compared to Ins B9-23, presentation of IGF-2 B11-25 to PBMCs purified from DQ8+ T1D adolescents elicits a suppressive/regulatory cytokine profile.
T170 74396-74652 Sentence denotes With regard to T1D prevention, administration of IGF-2 derived self-antigen(s) constitutes an innovative approach that combines antagonism for binding to a major susceptibility MHC-II allele, as well as promotion of a specific antigen tolerogenic response.
T171 74653-74709 Sentence denotes Receptor mechanisms of IL-1-induced sickness behavior R.
T172 74710-74721 Sentence denotes Dantzer, A.
T173 74722-74734 Sentence denotes Nadjar, R.M.
T174 74735-74745 Sentence denotes Bluthé, P.
T175 74746-74761 Sentence denotes Parnet and J.P.
T176 74762-74812 Sentence denotes Konsman Integrative Neurobiology, Bordeaux, France
T177 74813-74954 Sentence denotes The signaling pathways that mediate the behavioral effects of interleukin-1 (IL-1) during the acute phase reaction have not yet been studied.
T178 74955-75204 Sentence denotes The behavioral effects of IL-1 are mediated by the interaction of this cytokine with the type I IL-1 receptor (IL-1RI) and its accessory protein as demonstrated by the use of mice in which the gene coding for IL-1R1 or for IL-1RacP has been deleted.
T179 75205-75308 Sentence denotes Immunoneutralization experiments with an antibody specific of IL-1RI confirm the role of this receptor.
T180 75309-75412 Sentence denotes IL-1 receptors are expressed at low abundance in the central nervous system of the rat and mouse brain.
T181 75413-75546 Sentence denotes Immunohistochemistry techniques reveal a predominant expression of IL-1RI at the level of the blood-brain interface in the rat brain.
T182 75547-75709 Sentence denotes Double immunolabeling techniques show that this expression is restricted to endothelial cells of venules within the brain parenchyma and circumventricular organs.
T183 75710-75895 Sentence denotes Activation of IL-1 receptors is associated with nuclear factor kappa B (NF-kappaB) nuclear translocation and a robust transcriptional activation of inhibitor of kappa B alpha (IkappaB).
T184 75896-75972 Sentence denotes NF-kappaB translocation is a better marker of IL-1R activation than IkappaB.
T185 75973-76390 Sentence denotes Prevention of NF-kappaB activation by intracerebroventricular administration of a NEMO-binding domain peptide that selectively inhibits the IKKgamma/IKKbeta interaction abrogated sickness behavior induced by intraperitoneal but not by intracerebroventricular injection of IL-1, confirming the predominant role of IL-1 receptors at the blood-brain interface in the neural transduction of the peripheral immune message.
T186 76391-76438 Sentence denotes Stress-induced augmentation of skin immunity F.
T187 76439-76692 Sentence denotes Dhabhar Health Sciences Center, The Ohio State University, Columbus, OH, USA Cell-mediated immune (CMI) responses exert important immunoprotective (resistance to infectious agents) or immunopathological (allergic or autoimmune hypersensitivity) effects.
T188 76693-76801 Sentence denotes We have utilized the skin CMI response as an in vivo model for studying neuro-endocrine-immune interactions.
T189 76802-77030 Sentence denotes We initially hypothesized that just as an acute stress response prepares the cardiovascular and musculoskeletal systems for fight or flight, it may also prepare the immune system for challenges that may be imposed by a stressor.
T190 77031-77151 Sentence denotes The skin CMI model enabled us to examine the effects of stress at the time of primary and secondary exposure to antigen.
T191 77152-77364 Sentence denotes Studies showed that acute (2 h) stress experienced before either primary (innate immune response) or secondary (adaptive immune response) antigen exposure induces a large and long-lasting enhancement of skin CMI.
T192 77365-77428 Sentence denotes Adrenalectomy eliminates the stress-induced enhancement of CMI.
T193 77429-77574 Sentence denotes Acute administration of physiological (stress) concentrations of corticosterone and/or epinephrine to adrenalectomized animals enhances skin CMI.
T194 77575-77778 Sentence denotes Compared with controls, CMI sites from acutely stressed animals show significantly greater erythema and induration, numbers of infiltrating leukocytes, and levels of cytokine gene and protein expression.
T195 77779-77952 Sentence denotes In contrast to acute stress, chronic stress is immunosuppressive and chronic exposure to corticosterone, or acute exposure to dexamethasone, significantly suppress skin CMI.
T196 77953-78144 Sentence denotes These results suggest that during acute stress, endogenous stress hormones enhance skin immunity by increasing leukocyte trafficking and cytokine gene expression at the site of antigen entry.
T197 78145-78221 Sentence denotes Basic mechanistic experiments as well as clinical studies will be discussed.
T198 78222-78246 Sentence denotes Inflammatory stress G.P.
T199 78247-78313 Sentence denotes Chrousos PREB, NICHD, NIH and University of Athens, Athens, Greece
T200 78314-78431 Sentence denotes Like the stress response, the inflammatory reaction of an individual is crucial for survival of the self and species.
T201 78432-78521 Sentence denotes Also like the stress response, inflammation is tailored to the stimulus and time-limited.
T202 78522-78678 Sentence denotes A fully fledged systemic inflammatory reaction consists of activation of immune and immune accessory cells and resultant stimulation of four major programs:
T203 78679-78982 Sentence denotes (1) the acute phase reaction, (2) the sickness syndrome, (3) the pain program, mediated by the afferent sensory and autonomic systems, and (4) the stress program, mediated by the stress system, i.e. the hypothalamicpituitary-adrenal (HPA) axis and the locus ceruleus-norepinephrine / sympathetic system.
T204 78983-79502 Sentence denotes The main effector substances of the systemic inflammatory response are inflammatory cytokines, such as TNFalpha, IL-1 and IL-6, chemokines,, and other mediators of inflammation; the acute phase reactants, such as C-reactive protein (CRP), cell adhesion molecules, fibrinogen and plasminogen activator inhibitor 1; the effectors of the sensory afferent system, such as substance P; and, of the stress system, namely hypothalamic CRH and vasopressin, cortisol, norepinephrine and epinephrine, and peripheral neuronal CRH.
T205 79503-79736 Sentence denotes The sickness syndrome consists of anorexia/nausea, fatigue and/or depressed affect, somnolence, hyperalgesia, sleep disturbances, elevated temperature and an increased metabolic rate, all manifestations suppressed by glucocorticoids.
T206 79737-79896 Sentence denotes Yet, peripheral neuronal CRH activated by stress or the inflammatory reaction, and substance P, activated by the inflammatory reaction potentiate inflammation.
T207 79897-80156 Sentence denotes We recently found that during a systemic inflammatory reaction, as in ARDS or sepsis, there is inadequate activation of cortisol secretion and significant cytokine-induced glucocorticoid resistance, both suggesting beneficial actions of added glucocorticoids.
T208 80157-80266 Sentence denotes Corticotropin-releasing hormone (CRH) and the immune/inflammatory response: lessons from the knockout mice K.
T209 80267-80534 Sentence denotes Karalis Division of Endocrinology, Children's Hospital, Harvard Medical School and IIBEAA, Institute for Biomedical Research, Academy of Athens, Athens, Greece CRH, a neuropeptide isolated from the hypothalamus, is the main mediator of the stress response in mammals.
T210 80535-80681 Sentence denotes CRH is expressed in inflamed human and rodent peripheral tissues and exerts potent proinflammatory effects in experimental models of inflammation.
T211 80682-80815 Sentence denotes We have used the CrhÀ/À mouse to characterize the immunomodulatory properties of CRH and identify the pathways mediating its effects.
T212 80816-80988 Sentence denotes The CrhÀ/À mice respond to inflammatory stimuli with a compromised ACTH response and a delayed, although finally similar to that of the Crh+/+ mice, rise in corticosterone.
T213 80989-81162 Sentence denotes This response differs from that of the Crh receptor 1À/À suggesting that other receptor(s) may also mediate the effects of CRH on the pituitary following an immune stressor.
T214 81163-81296 Sentence denotes It should be highlighted that immune activation is the only stressor that can induce a pituitary-adrenal response in the CrhÀ/À mice.
T215 81297-81449 Sentence denotes We have found that CrhÀ/À mice have reduced inflammatory responses to local stimuli, such as carrageenin, confirming the proinflammatory effects of CRH.
T216 81450-81656 Sentence denotes These experiments revealed proinflammatory effects of epinephrine unmasked by Crh deficiency and suggested the coordinated action of epinephrine and CRH in the regulation of the acute inflammatory response.
T217 81657-81833 Sentence denotes Systemic inflammatory responses in the CrhÀ/À mice were also of significantly reduced magnitude, as well as autoimmune diseases such as experimental allergic encephalomyelitis.
T218 81834-82006 Sentence denotes The pathways mediating the proinflammatory responses of CRH were studied and demonstrated specific CRH-mediated induction of the NFÀkB DNA binding activity in immune cells.
T219 82007-82116 Sentence denotes Interestingly, CrhÀ/À mice had profound anorexia and weight loss despite their reduced inflammatory response.
T220 82117-82273 Sentence denotes The latter suggests that in cases of Crh deficiency the pathways mediating the inflammation-induced anorexia are not dependent on the level of inflammation.
T221 82274-82385 Sentence denotes Identification of polymorphic genes regulating inflammatory diseases may unravel crucial pathogenic mechanisms.
T222 82386-82569 Sentence denotes Initial steps to map such genes using linkage analysis in F2 intercross or backcross populations, however, result in broad quantitative trait loci (QTLs) containing hundreds of genes.
T223 82570-82812 Sentence denotes In the present study, an advanced intercross line (AIL), in combination with congenic strains, was used to fine-map Eae18 on rat chromosome 10 in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (MOG-EAE).
T224 82813-82912 Sentence denotes MOG-EAE is a chronic relapsing disease that closely mimics key features of multiple sclerosis (MS).
T225 82913-82996 Sentence denotes Congenic DA.ACI rat strains localized Eae18 to an approximately 30 Mb large region.
T226 82997-83159 Sentence denotes Fine-mapping was then performed in an AIL consisting of a (DAÂPVG.1AV1) F7 intercross, resulting in two adjacent EAE-regulating QTLs designated Eae18a and Eae18b.
T227 83160-83285 Sentence denotes The two QTLs span 5.5 and 3 Mb, respectively, and Eae18b contains as few as 10 genes, including a cluster of chemokine genes.
T228 83286-83401 Sentence denotes Eae18a and Eae18b are syntenic to human chromosome 17p13 and 17q11, respectively, which both display linkage to MS.
T229 83402-83570 Sentence denotes Thus, Eae18 consists of at least two EAE-regulating genes, providing additional evidence that clustering of disease-regulating genes in QTLs is an important phenomenon.
T230 83571-83783 Sentence denotes The overlap between Eae18a and Eae18b with previously identified QTLs in humans and mice further supports the notion that susceptibility alleles in inflammatory disease are evolutionary conserved between species.
T231 83784-83901 Sentence denotes T cell gene expression profiling identifies molecularly and clinically distinct subgroups of multiple sclerosis J.-I.
T232 83902-83911 Sentence denotes Satoh, M.
T233 83912-83925 Sentence denotes Nakanishi, H.
T234 83926-83935 Sentence denotes Onoue, T.
T235 83936-83950 Sentence denotes Aranami and T.
T236 83951-84019 Sentence denotes Yamamura National Institute of Neuroscience, Tokyo, Japan Objective:
T237 84020-84121 Sentence denotes To clarify the molecular background underlying the phenotypic variability of multiple sclerosis (MS).
T238 84122-84130 Sentence denotes Methods:
T239 84131-84386 Sentence denotes Using a 1258 cDNA microarray, a comprehensive gene expression profile of T cells of 72 MS patients (65 RR and 7 SP) with various MRI lesion distributions before and after IFN-beta treatment was compared with that of 22 age-and sexmatched healthy subjects.
T240 84387-84395 Sentence denotes Results:
T241 84396-84689 Sentence denotes Hierarchical cluster analysis of 286 genes expressed differentially between IFN-untreated MS patients and controls as a discriminator identified four distinct subgroups of MS designated A, B, C, and D, among which the subgroup A showed the expression pattern most similar to the control group.
T242 84690-84803 Sentence denotes The patients presenting with the lesion distribution restricted in the cerebrum were clustered in the subgroup C.
T243 84804-85033 Sentence denotes When the 286 genes were categorized into five different classes numbered 1 to 5, the subgroup B showing the highest upregulation of class #5 genes, including nine chemokines, was associated with the most severe clinical activity.
T244 85034-85203 Sentence denotes Furthermore, the IFNbeta responder was clustered in subgroups A and B, and was characterized by a persistent induction of IFN-responsive genes during IFN-beta treatment.
T245 85204-85216 Sentence denotes Conclusions:
T246 85217-85499 Sentence denotes These results indicate that microarray analysis of the gene expression profile of T cells could classify a heterogenous population of MS into four molecularly distinct subgroups closely associated with the disease activity, lesion distribution, and therapeutic response to IFN-beta.
T247 85500-85591 Sentence denotes A clinical-genetic study of multiple sclerosis in a Dutch genetically isolated community R.
T248 85592-85603 Sentence denotes Hintzen, E.
T249 85604-85630 Sentence denotes Croes, C. van Duijn and I.
T250 85631-85709 Sentence denotes Hoppenbrouwers Erasmus MC, Department of Neurology, Rotterdam, The Netherlands
T251 85710-85721 Sentence denotes Background:
T252 85722-85903 Sentence denotes Next to large genome screens, the study of genetically isolated populations is an alternative approach in order to identify the genetic factors involved in multiple sclerosis (MS) .
T253 85904-85915 Sentence denotes Objectives:
T254 85916-86030 Sentence denotes To identify MS cases within a Dutch genetically isolated population and attempt to link them to a common ancestor.
T255 86031-86140 Sentence denotes Secondly, to assess familial association of type I diabetes mellitus (DM), autoimmune thyroid disease and MS.
T256 86141-86177 Sentence denotes Thirdly, to perform a genome screen.
T257 86178-86253 Sentence denotes Methods: MS patients were traced and an extensive family history was taken.
T258 86254-86323 Sentence denotes Special emphasis was paid to the co-occurrence of autoimmune disease.
T259 86324-86398 Sentence denotes Genealogical data extended up until 14 generations (around the year 1680).
T260 86399-86407 Sentence denotes Results:
T261 86408-86467 Sentence denotes Thirty-five female and 13 male MS patients were identified.
T262 86468-86537 Sentence denotes Mean age at onset of symptoms was 32 years and at diagnosis 38 years.
T263 86538-86621 Sentence denotes Forty patients had a relapsing-remitting course and 8 a primary progressive course.
T264 86622-86706 Sentence denotes Twenty of the 48 patients could be linked to a common ancestor in 12-14 generations.
T265 86707-86798 Sentence denotes The clinical characteristics of these 20 patients were not different from those not linked.
T266 86799-86867 Sentence denotes Familial co-occurrence of MS was observed in 21% of the 48 patients.
T267 86868-86912 Sentence denotes Thyroid disease in 17% and type I DM in 10%.
T268 86913-86994 Sentence denotes HLA-Dr2 was not found significantly more often in the MS patients as in controls.
T269 86995-87007 Sentence denotes Conclusions:
T270 87008-87129 Sentence denotes Familial aggregation of MS is high in this Dutch genetic isolate, with a high co-occurrence of other autoimmune diseases.
T271 87130-87182 Sentence denotes HLA-Dr2 was not specifically linked to the MS cases.
T272 87183-87296 Sentence denotes Several studies have shown that multiple sclerosis (MS) is associated with the HLA class II specificity HLA-DR15.
T273 87297-87449 Sentence denotes In Japan, an association has been reported between HLA-DR4 and a subpopulation of conventional-MS patients that lack oligoclonal bands (OCB) in the CSF.
T274 87450-87568 Sentence denotes Though DR15 increases the risk for OCB-positive conventional MS in Japan, it is not a risk factor for OCB-negative MS.
T275 87569-87791 Sentence denotes To investigate whether the OCBnegative and OCB-positive subpopulations of MS patients from Sweden show HLA-DR frequencies similar to those seen in Japan, patients were diagnosed according to the criteria of McDonald et al.
T276 87792-87911 Sentence denotes HLA-DR genotypes were determined, for all patients and controls, with a resolution corresponding to serological typing.
T277 87912-88002 Sentence denotes OCB were detected by isoelectric focusing and IgG-specific immunofixation of CSF proteins.
T278 88003-88124 Sentence denotes DR15 and DR4 phenotype frequencies were compared in 55 OCB-negative patients, 228 OCB-positive patients and 284 controls.
T279 88125-88252 Sentence denotes In OCB-negative patients, DR15 was significantly less common, and DR4 significantly more common, than in OCB-positive patients.
T280 88253-88405 Sentence denotes The frequency of DR15 was significantly higher in OCB-positive patients than in controls, but did not differ between OCB-negative patients and controls.
T281 88406-88557 Sentence denotes The frequency of DR4 was significantly higher in OCB-negative patients than in controls, but did not differ between OCB-positive patients and controls.
T282 88558-88652 Sentence denotes The present study, performed on Swedish MS patients, confirms results first reported in Japan.
T283 88653-88821 Sentence denotes Thus, it appears that OCB-positive MS and OCB-negative MS may be distinct disease subtypes, each associated with a particular predispositional HLA class II specificity.
T284 88822-88832 Sentence denotes Objective:
T285 88833-88938 Sentence denotes Iron misregulation, oxidative stress and inflammation play interacting roles in Alzheimer's disease (AD).
T286 88939-89126 Sentence denotes We therefore examined polymorphisms in two genes of iron metabolism in the risk of AD: the C2 variant of the transferrin (TF) gene and the C282Y allele of the haemochromatosis (HFE) gene.
T287 89127-89135 Sentence denotes Methods:
T288 89136-89251 Sentence denotes We genotyped 269 elderly controls, 191 AD cases and 69 with mild cognitive impairment (MCI) from the OPTIMA cohort.
T289 89252-89260 Sentence denotes Results:
T290 89261-89364 Sentence denotes Each of the two variants was associated with an increased risk of AD only in the presence of the other.
T291 89365-89451 Sentence denotes Carriers of both variants were at 5 times greater risk of AD compared with all others.
T292 89452-89538 Sentence denotes The interaction was significant by logistic regression and by synergy factor analysis.
T293 89539-89638 Sentence denotes Carriers of these two alleles plus apolipoprotein E4 (APOE4) were at exceptionally high risk of AD.
T294 89639-89651 Sentence denotes Conclusions:
T295 89652-89842 Sentence denotes We suggest that the combination of TF C2 and HFE C282Y may lead to an excess of redoxactive iron and the induction of oxidative stress in neurones, which is exacerbated in carriers of APOE4.
T296 89843-89986 Sentence denotes As 4% of Northern Europeans carry both iron-related variants and since iron overload is a treatable condition, these results merit replication.
T297 89987-90061 Sentence denotes Age, parent, and season at immunization influence susceptibility to EAE E.
T298 90062-90080 Sentence denotes Blankenhorn a , C.
T299 90081-90096 Sentence denotes Teuscher b , J.
T300 90097-90110 Sentence denotes Bunn b and P.
T301 90111-90428 Sentence denotes Fillmore a a University of Illinois at Urbana-Champaign, Urbana, IL, USA; b University of Vermont School of Medicine, Burlington, Vermont, USA Experimental allergic encephalomyelitis (EAE), the principal animal model of multiple sclerosis (MS), is a complex trait influenced by both genetic and environmental factors.
T302 90429-90546 Sentence denotes We examined the role of age and season at immunization, sex, and parent-of-origin (POO) in N1800 (B10.SÂSJL) F2 mice.
T303 90547-90756 Sentence denotes Logistic regression analyses indicated that the odds of being affected increase by 4% for each increasing week of age, and were 90% greater for animals injected in the summer, compared to the winter or spring.
T304 90757-90977 Sentence denotes The odds also differed significantly depending on the POO, where male F2 progeny of SJL maternal granddams and B10.S paternal grandsires were more than twice as likely to show EAE than males from reciprocal grandparents.
T305 90978-91108 Sentence denotes Surprisingly, CNS inflammation in male mice was not affected by POO, and female progeny were not influenced by POO effects at all.
T306 91109-91397 Sentence denotes Linkage analysis to eae1(H2)/eae5 using 6-to 12-week-old and 13-to 18-week-old cohorts of F2 mice failed to detect significant linkage to chromosome 17 marker loci in the older and winter/spring populations whereas significant linkage was detected with the younger and summer populations.
T307 91398-91704 Sentence denotes Our results provide a new model for environmental effects in MS, and may help explain the fact that although linkage to HLA is the most consistent finding in MS genetics studies, the HLA-linked MS susceptibility locus may be influenced by the effects of age, season, or other non-Mendelian genetic factors.
T308 91705-91716 Sentence denotes Background:
T309 91717-91846 Sentence denotes Several studies demonstrated the involvement of the myelin oligodendrocyte glycoprotein (MOG) protein in multiple sclerosis (MS).
T310 91847-91950 Sentence denotes We wanted to verify the presence of betiologicQ polymorphisms of the MOG gene in Sardinian MS patients.
T311 91951-92014 Sentence denotes Methods: MOG gene was fully sequenced in 21 healthy Sardinians.
T312 92015-92223 Sentence denotes The MOG51 micros and all SNPs showing a frequency N5% in sequencing were typed in a first data set of 249 trios families (one affected and both parents) and examined by transmission disequilibrium test (TDT).
T313 92224-92373 Sentence denotes MOG variants significantly ( Pb0.05) associated with MS and 3 SNPs not associated used as controls were again tested in a second set of 152 families.
T314 92374-92418 Sentence denotes Final significant values were set at Pb0.01.
T315 92419-92427 Sentence denotes Results:
T316 92428-92498 Sentence denotes Sequencing of MOG gene revealed 37 novel and 82 previously found SNPs.
T317 92499-92568 Sentence denotes TDT showed evidence of association ( Pb0.05) in 12/40 SNPs and MOG51.
T318 92569-92755 Sentence denotes TDT in the whole set of 401 families confirmed association with the G16457A ( P=0.001), A15643G ( P=0.004), C11544T ( P=0.003), C10495G ( P=0.0001) variants and MOG51 allele 8 ( P=0.01).
T319 92756-92828 Sentence denotes Conclusions: MOG gene is involved in susceptibility to MS in Sardinians.
T320 92829-92924 Sentence denotes An extension of the study in a large set of sporadic patients to confirm these data is ongoing.
T321 92925-93042 Sentence denotes MHC class II molecules (MHCII) present antigens to CD4+ T cells, which is a key feature of adaptive immune responses.
T322 93043-93185 Sentence denotes We have previously identified the Vra4 locus on rat chromosome 10 with major influence on nerve injury-induced MHC II expression on microglia.
T323 93186-93360 Sentence denotes The F8 generation of an advanced intercross line (AIL; DAxPVG.1AV1) was used for genetic fine mapping of Vra4, revealing linkage to MHCII expression with a LOD score of 26.4.
T324 93361-93445 Sentence denotes MHC II immunolabeling was measured in spinal cord after ventral root avulsion (VRA).
T325 93446-93569 Sentence denotes A microsatellite-based haplotype map over Vra4 in a panel of inbred rat strains identified two haplotypes extending 2.7 Mb.
T326 93570-93664 Sentence denotes This fragment contains the mhc2ta gene encoding CIITA, a known regulator of MHC II expression.
T327 93665-93782 Sentence denotes Sequencing of mhc2ta revealed two distinct haplotypes segregating inbred strains with high and low MHC II expression.
T328 93783-93997 Sentence denotes Analysis of the expression of CIITA and the CIITA-induced invariant chain in spinal cord tissue revealed lower levels of both transcripts in PVG.1AV1 rats compared to DA, both under normal conditions and after VRA.
T329 93998-94183 Sentence denotes There was also a strong correlation between CIITA and invariant chain in a group of F8 animals stratified for parental allele at the max marker, which is located within the mhc2ta gene.
T330 94184-94305 Sentence denotes These results identify genetic heterogeneity in the mhc2ta gene to modulate inflammatory processes in the nervous system.
T331 94306-94479 Sentence denotes Identification of QTL controlling cortical motor evoked potentials in experimental autoimmune encephalomyelitis: correlation with incidence, onset and severity of disease I.
T332 94480-94492 Sentence denotes Mazon a , S.
T333 94493-94506 Sentence denotes Vogler a , U.
T334 94507-94521 Sentence denotes Strauss b , P.
T335 94522-94537 Sentence denotes Wernhoff a , A.
T336 94538-94552 Sentence denotes Rolfs b and S.
T337 94553-94832 Sentence denotes Ibrahim a a Institute of Immunology, University of Rostock, Rostock, Germany; b Department of Neurology, University of Rostock, Rostock, Germany Experimental autoimmune encephalomyelitis (EAE) is a polygenic chronic inflammatory demyelinating disease model of multiple sclerosis.
T338 94833-94959 Sentence denotes Previous studies have identified multiple quantitative trait loci (QTL) controlling different aspects of disease pathogenesis.
T339 94960-95067 Sentence denotes However, direct genetic control of motor-evoked potentials as a measure of demyelination was not addressed.
T340 95068-95278 Sentence denotes In this study, we examined the genetic control of different traits of EAE in a F2 intercross population generated from the EAE susceptible SJL/J and EAE resistant C57Bl/10.S mouse strains involving 460 animals.
T341 95279-95449 Sentence denotes All animals were genotyped with 150 microsatellite markers and interval mapping was used to identify QTLs controlling disease severity, onset and Motor Evoked Potentials.
T342 95450-95478 Sentence denotes Six new QTL were identified.
T343 95479-95668 Sentence denotes Three QTL mapped to chromosome 2, 10 and 18 controlled the severity of the disease, whereas QTL on 1, 8 and 15 were associated with the latency in the corticomotor evoked potentials (CMEP).
T344 95669-95708 Sentence denotes Two of the loci were influenced by sex.
T345 95709-95724 Sentence denotes One QTL on Chr.
T346 95725-95947 Sentence denotes 8 cM 15-53(EAE31) controlled CMEP latencies before immunizations and correlated with disease onset suggesting a possible role of myelination patterns and or the structure of central motor pathways in susceptibility to EAE.
T347 95948-96002 Sentence denotes Mapping and functional characterization of rat Eae4 R.
T348 96003-96012 Sentence denotes Nohra, M.
T349 96013-96027 Sentence denotes Jagodic and T.
T350 96028-96228 Sentence denotes Olsson Karolinska Institute, Stockholm, Sweden Eae4, a locus regulating disease chronicity and cytokine production in experimental autoimmune encephalomyelitis, was initially mapped in (DAxBN)F2 rats.
T351 96229-96351 Sentence denotes A congenic rat strain, DAc9BN-Eae4, has been established and a phenotypic effect of the isolated locus has been confirmed.
T352 96352-96471 Sentence denotes Eae4 is being further narrowed down in recombinant congenic strains and the locus is currently mapped to a 3-Mb region.
T353 96472-96784 Sentence denotes The EAE chronicity phenotype has so far been linked to the cytokine production phenotype (mainly measured as high or low TNF-alpha production in ConA stimulated naive splenocytes) in all currently analyzed recombinant strains, suggesting that identical or closely localized gene(s) regulate these two phenotypes.
T354 96785-96944 Sentence denotes In parallel with the production of still smaller recombinant strains, high-resolution mapping is attempted in a (DAxPVG.AV1)F10 advanced intercross line (AIL).
T355 96945-97113 Sentence denotes Furthermore, preliminary immunological data map the cytokine production phenotype to the CD4+ T cell lineage and not to CD8+ T cells, monocytes/macrophages or NK cells.
T356 97114-97282 Sentence denotes Eae4 is, thus, a locus with effects in EAE and possibly also in other inflammatory conditions where cytokine dysbalance is implicated and positional cloning is ongoing.
T1 97283-97407 Sentence denotes High-resolution mapping of quantitative trait loci that influence an experimental model for multiple sclerosis in the rat M.
T2 97408-97417 Sentence denotes Marta, M.
T3 97418-97429 Sentence denotes Jagodic, T.
T4 97430-97445 Sentence denotes Olsson and J.C.
T5 97446-97686 Sentence denotes Lorentzen Karolinska Institutet, Stockholm, Sweden Inbred rat strains show varying susceptibility or resistance to myelin oligodendrocyte glicoprotein (MOG) induced encephalomyelitis (EAE), which closely mimics multiple sclerosis in humans.
T6 97687-97856 Sentence denotes We previously reported that transfer of a 10-cM rat chromosome 4 region (C4R3) from resistant PVG.1AV1 rats to susceptible DA rats affects the susceptibility to MOG-EAE.
T7 97857-97867 Sentence denotes Objective.
T8 97868-97924 Sentence denotes To genetically dissect the influence of C4R3 on MOG-EAE.
T9 97925-97933 Sentence denotes Methods.
T10 97934-98044 Sentence denotes A 10th generation of an advanced intercross line (AIL) of DA and MHC identical PVG.1AV1 was injected with MOG.
T11 98045-98153 Sentence denotes Clinical disease was followed and individuals in the test-cross were genotyped using microsatellite markers.
T12 98154-98254 Sentence denotes Genotype-phenotype analysis was performed within C4R3 using R/qtl to detect quantitative trait loci.
T13 98255-98403 Sentence denotes In addition, subcongenic rats with a 0.8 cM PVG.1AV1 region (C4R11) inserted on DA background were compared with DA rats for MOG-EAE susceptibility.
T14 98404-98412 Sentence denotes Results.
T15 98413-98484 Sentence denotes The AIL analysis revealed two narrow and closely situated QTLs in C4R3.
T16 98485-98613 Sentence denotes The smaller C4R11 interval overlaps with one of the QTLs, and C4R11 congenic rats were also less susceptible than DA to MOG-EAE.
T17 98614-98625 Sentence denotes Conclusion.
T18 98626-98693 Sentence denotes The C4R3 interval harbors at least two genes that regulate MOG-EAE.
T19 98694-98821 Sentence denotes One of these genes lies within the C4R11 interval previously reported to regulate oil-induced arthritis (QTL designated Oia2) .
T20 98822-98885 Sentence denotes This gene(s) may be a general regulator of autoimmune diseases.
T21 98886-98960 Sentence denotes An advanced intercross line localizes Eae5 to a region containing Ncf-1 K.
T22 98961-98977 Sentence denotes Becanovic a , M.
T23 98978-98994 Sentence denotes Jagodic a , J.R.
T24 98995-99007 Sentence denotes Sheng a , I.
T25 99008-99022 Sentence denotes Dahlman a , E.
T26 99023-99039 Sentence denotes Wallstrfm a , F.
T27 99040-99058 Sentence denotes Aboul-Enein b , P.
T28 99059-99074 Sentence denotes Olofsson c , R.
T29 99075-99090 Sentence denotes Holmdahl c , H.
T30 99091-99108 Sentence denotes Lassmann b and T.
T31 99109-99387 Sentence denotes Olsson a a Karolinska Institute, Stockholm, Sweden; b University of Vienna, Vienna, Austria; c Lund University, Lund, Sweden Eae5 in rats was originally identified in two F2 intercrosses (DAÂBN) and (DAÂE3), displaying linkage to CNS inflammation and EAE severity, respectively.
T32 99388-99467 Sentence denotes This region overlaps with Pia4, which was also identified in the (DAÂE3) cross.
T33 99468-99590 Sentence denotes Two congenic strains, BN.DA-Eae5 and BN.DA-Eae5.R1, encompassing the previously described Eae5 and Pia4, were established.
T34 99591-99770 Sentence denotes DA alleles within the chromosome 12 fragment conferred an increase in disease susceptibility as well as increased inflammation and demyelination in the CNS compared to BN alleles.
T35 99771-99944 Sentence denotes To enable a more precise fine-mapping of EAE regulatory genes, we utilized a rat advanced intercross line (AIL) between the susceptible DA and the resistant PVG.1AV1 strain.
T36 99945-100127 Sentence denotes Linkage analysis performed in the advanced intercross line considerably narrowed down the MOG-EAE regulatory locus (Eae5) to a 1.4-Mb region with a defined number of candidate genes.
T37 100128-100344 Sentence denotes We here demonstrate a regulatory effect of Eae5 on MOG-EAE, using both congenic strains as well as fine-mapping these effects to a region containing Ncf-1, a gene with reported effects also in experimental arthritis.
T38 100345-100447 Sentence denotes Studies of animal models of MS have provided important insight into the immunopathogenesis of disease.
T39 100448-100549 Sentence denotes Genetic analyses of these models overcome certain obstacles encountered when studying human patients.
T40 100550-100697 Sentence denotes MOG-EAE like MS is complex genetic disease with contributions from major histocompatibility complex (MHC) genes and multiple unknown non-MHC genes.
T41 100698-100920 Sentence denotes Linkage analysis have been used to map EAE-linked loci on rat chromosome in an F2 cross between susceptible DA and resistant ACI rats, a region with disease regulating influences on MOG-EAE has been found on chromosome 15.
T42 100921-101417 Sentence denotes In the present study, a direct examination of this loci was undertaken in congenic strains by transferring this region from resistant ACI rats to the susceptible DA background, phenotypic comparing among DA and congenic DA.ACI-D15Rat6-D15Rat 71 (25cM) and subcongenic recombinants 1(R1)-D15Rat 6-D15Rat13 (10 cM) show the congenic and R1 are resistant to MOG-EAE with low level of anti-MOG antibodies tendency in the sera and low inflammation or demyelination index in the central nervous system.
T43 101418-101625 Sentence denotes It is very promising to keep the retained phenotypic difference by creating congenic strain and collecting recombinants in different congenic segments and permit rapid fine mapping within a few centiMorgans.
T44 101626-101805 Sentence denotes Thus, the results indicate that this region harbors EAE regulating genes contributing to the protection against EAE and may reflect both the T and B cell arms of MOG autoimmunity.
T45 101806-101973 Sentence denotes In conclusion, this studies will provide the approach for testing the human homologous gene in MS and unveiling the mechanisms of genes regulating the MS like disease.
T46 101974-102050 Sentence denotes A novel SNP in the coding region of PSGL-1 in multiple sclerosis patients C.
T47 102051-102066 Sentence denotes Fenoglio a , D.
T48 102067-102084 Sentence denotes Galimberti a , R.
T49 102085-102099 Sentence denotes Clerici a , M.
T50 102100-102114 Sentence denotes Ronzoni a , M.
T51 102115-102128 Sentence denotes De Riz a , L.
T52 102129-102142 Sentence denotes Piccio a , A.
T53 102143-102155 Sentence denotes Gatti a , E.
T54 102156-102173 Sentence denotes Venturelli a , L.
T55 102174-102186 Sentence denotes Berti a , G.
T56 102187-102204 Sentence denotes Constantin b , N.
T57 102205-102222 Sentence denotes Bresolin a and E.
T58 102223-102413 Sentence denotes Scarpini a a Ospedale Maggiore, Milano, Italy; b University of Verona, Verona, Italy Lymphocyte recruitment into the brain is a critical event in the pathogenesis of multiple sclerosis (MS).
T59 102414-102522 Sentence denotes Selectins are expressed by inflamed endothelium and participate in lymphocyte adhesion to the brain vessels.
T60 102523-102658 Sentence denotes P-selectin glycoprotein ligand 1 (PSGL-1) is the main ligand of E-and P-selectins and has a crucial role during lymphocyte recruitment.
T61 102659-102856 Sentence denotes Genomic DNA was isolated from whole blood and mutational scanning of PSGL-1 has been carried out in 100 Italian patients with MS as well as in 100 age-matched controls, to detect new polymorphisms.
T62 102857-102941 Sentence denotes The frequency of new mutations has then been compared between patients and controls.
T63 102942-103130 Sentence denotes A novel Single Nucleotide Polymorphism (SNP), involving a GRA substitution, which results in an aminoacidic change at position 62 (M62I) in the coding region of PSGL-1 gene was determined.
T64 103131-103220 Sentence denotes A different frequency of the M62I SNP in MS patients compared with controls was observed.
T65 103221-103311 Sentence denotes Stratifying by age at onset or gender, no differences in allele frequencies were observed.
T66 103312-103507 Sentence denotes This is the first evidence of the presence of M62I in Caucasians.This SNP could have an effect on the function of PSGL-1 as it is located within the region involved in the binding with selectins.
T67 103508-103626 Sentence denotes Analysis of the Asp299Gly polymorphism in the Toll-like receptor 4 (TLR-4) gene in patients with multiple sclerosis A.
T68 103627-103640 Sentence denotes Kroner a , B.
T69 103641-103654 Sentence denotes Rosche b , A.
T70 103655-103673 Sentence denotes Kolb-M7urer a , N.
T71 103674-103686 Sentence denotes Kruse c , K.
T72 103687-103699 Sentence denotes Toyka a , B.
T73 103700-103713 Sentence denotes Hemmer b , P.
T74 103714-103732 Sentence denotes Rieckmann a and M.
T75 103733-103882 Sentence denotes M7urer a a University of Würzburg, Würzburg, Germany; b Heinrich Heine University, Düsseldorf, Germany; c University of Göttingen, Göttingen, Germany
T76 103883-104060 Sentence denotes In multiple sclerosis, disease deterioration often occurs in association with bacterial infections, particularly with lipopolysaccharide (LPS) containing gram negative bacteria.
T77 104061-104136 Sentence denotes LPS is known to activate immune cells via the toll-like-receptor-4 (TLR-4).
T78 104137-104244 Sentence denotes A recently described Asp299Gly polymorphism in the tlr-4 gene was shown to cause hyporesponsiveness to LPS.
T79 104245-104378 Sentence denotes We therefore investigated the functional role and the allelic distribution of this TLR-4 polymorphism in a population of MS-patients.
T80 104379-104437 Sentence denotes DNA was obtained from 890 patients and 350 healthy donors.
T81 104438-104598 Sentence denotes The polymorphism was analysed with allelic discrimination(AD)-PCR and confirmed by PCR-restriction-fragment-length-polymorphism (RFLP) and automatic sequencing.
T82 104599-104724 Sentence denotes PBMCs from donors with different genotypes were stimulated with LPS and inactivated gram-negative and gram-positive bacteria.
T83 104725-104790 Sentence denotes Proliferation and production of IL-6 and TNF-alpha were measured.
T84 104791-104941 Sentence denotes Genotyping revealed 809 (90.9%) wildtype individuals, 79 (8.9%) patients with heterozygous and two individuals (0.2%) with homozygous mutant genotype.
T85 104942-105048 Sentence denotes No association of different genotypes with MS susceptibility, subtypes or disease severity could be found.
T86 105049-105192 Sentence denotes Significantly lower proliferation rates ( p=0.023) in PBMCs derived from heterozygous individuals could be detected after stimulation with LPS.
T87 105193-105316 Sentence denotes We could not find an association between Asp299Gly genotypes and disease course of multiple sclerosis in our MS population.
T88 105317-105438 Sentence denotes However, we could confirm the functional relevance of the Asp299Gly polymorphism after exposure of immune cells with LPS.
T89 105439-105482 Sentence denotes Multiple sclerosis and autoimmune diseases.
T90 105483-105536 Sentence denotes Risk and HLA-DR association in Northern-east Italy P.
T91 105537-105549 Sentence denotes Gallo a , A.
T92 105550-105563 Sentence denotes Laroni a , M.
T93 105564-105580 Sentence denotes Calabrese a , P.
T94 105581-105596 Sentence denotes Perini a , M.P.
T95 105597-105613 Sentence denotes Albergoni b , F.
T96 105614-105630 Sentence denotes Ranzato a and L.
T97 105631-105997 Sentence denotes Battistin a a Multiple Sclerosis Center, Department of Neurological Sciences, University of Padova, Padova, Italy; b Blood Bank, University Hospital, Padova, Italy An autoimmune background is thought to characterize the families of multiple sclerosis (MS) patients, but disease patterns and HLA-DR association seem to vary considerably among different ethnic groups.
T98 105998-106230 Sentence denotes We studied the occurrence of 37 autoimmune diseases in 250 MS patients and 250 age-/sex-matched normal controls (NC), original of and living in the Northern-east Italy, and in almost all their first-degree relatives (2800 subjects).
T99 106231-106275 Sentence denotes HLA-DR expression was analysed in MS and NC.
T100 106276-106693 Sentence denotes The risk of having autoimmune diseases was not increased in MS patients (22/250,9%) compared to NC (15/250,6%)(MS vs NC: x2=1.052, p=0.3), but 40 families with multiple autoimmune pathology (autoimmune families, AF) were identified in the MS group [16%; only 4 in the NC group (1.6%) (x2=29.470, p=0.000; OR=11.4] and a significant excess of autoimmunity was found in first-degree relatives of MS patients ( p=0.000).
T101 106694-106779 Sentence denotes An association of MS with Type 1 Diabetes Mellitus was also noticed (T1DM) ( p=0.04).
T102 106780-106922 Sentence denotes DR4 expression in MS patients from AF was significantly higher (32%) than in reference MS patients (9%; x2: p=0.001) and NC (14%) (x2:p=0.02).
T103 106923-106996 Sentence denotes Fifty percent of DR4-positive MS patients expressed the allele DRB1*0401.
T104 106997-107212 Sentence denotes Our data suggest a significant risk of autoimmunity in first-degree relatives of MS patients, a role for DR4 in autoimmune predisposition, and a preferential association of MS with T1DM, at least in Southern Europe.
T105 107213-107322 Sentence denotes The CD14 C(-260)T promoter polymorphism is associated with disease severity in multiple sclerosis patients A.
T106 107323-107340 Sentence denotes Lutterotti a , R.
T107 107341-107354 Sentence denotes Ehling a , H.
T108 107355-107370 Sentence denotes Lassmann b , F.
T109 107371-107390 Sentence denotes Deisenhammer a , T.
T110 107391-107406 Sentence denotes Berger a and M.
T111 107407-107743 Sentence denotes Reindl a a Clinical Department of Neurology, Innsbruck Medical University, Innsbruck, Austria; b Brain Research Institute, Vienna Medical University, Vienna, Vienna CD14 is a membrane receptor expressed on cells of the monocyte lineage known to be an essential mediator in innate host defense and in the phagocytosis of apoptotic cells.
T112 107744-107972 Sentence denotes The aim of our study was to investigate a possible association of the -260 C-T promoter polymorphism in the CD14 gene with the susceptibility and disease severity in 225 patients with clinically definite multiple sclerosis (MS).
T113 107973-108171 Sentence denotes Outcome measures were disease severity measured by the progression index (EDSS/disease duration), the MS severity score, and the time to reach the hallmark EDSS 6 as well as the annual relapse rate.
T114 108172-108275 Sentence denotes We established a new PCR assay with sequencespecific primers to analyze CD14 genotypes in our patients.
T115 108276-108368 Sentence denotes Furthermore, we analyzed CD14 expression within MS lesions of 31 patients by histopathology.
T116 108369-108538 Sentence denotes Carriers of the CD14-260 C allele have a more severe disease course (progression index, MS severity score) and a significantly shorter time to reach the hallmark EDSS 6.
T117 108539-108622 Sentence denotes We found no association between CD14-260 C-T polymorphism and susceptibility to MS.
T118 108623-108692 Sentence denotes CD14 is upregulated in MS lesions, most prominently in acute lesions.
T119 108693-108908 Sentence denotes This is the first study to describe an association of the -260 C-T polymorphism within the promoter region of the CD14 gene, a receptor of the innate immune system, with the longterm disease severity in MS patients.
T120 108909-109017 Sentence denotes Knowledge-base of interactions of candidate genes and susceptibility loci: a portal to multiple sclerosis S.
T121 109018-109031 Sentence denotes Möller a , P.
T122 109032-109058 Sentence denotes Serrano-Fernández a , U.K.
T123 109059-109071 Sentence denotes Zettl b , P.
T124 109072-109090 Sentence denotes Wernhoff a , H.-J.
T125 109091-109105 Sentence denotes Thiesen a , D.
T126 109106-109123 Sentence denotes Koczan a and S.M.
T127 109124-109230 Sentence denotes Ibrahim a a Institute of Immunology and b Department of Neurology, University of Rostock, Rostock, Germany
T128 109231-109278 Sentence denotes Multiple sclerosis (MS) is a polygenic disease.
T129 109279-109384 Sentence denotes Many unknown genetic factors lead to a set of clinical phenotypes of different intensity and periodicity.
T130 109385-109571 Sentence denotes The scientific community applies a variety of approaches on tissues from patients and animal models of the disease in order to determine candidate genes for the phenotypic manifestation.
T131 109572-109708 Sentence denotes With genetic linkage studies, transcriptomics and proteomics experiments on different tissues a wealth of information are now available.
T132 109709-109851 Sentence denotes The sheer number of publications and genes described the interpretation of results from novel experiments a laborious and time consuming task.
T133 109852-109993 Sentence denotes To help setting up new hypotheses, we here present a web interface to query a database we providing new evidences for the pathogenesis of MS.
T134 109994-110154 Sentence denotes The database includes individual genes and chromosomal loci of the human supplemented with data from animal models of the disease and links to public resources.
T135 110155-110216 Sentence denotes The interaction of genes and loci may be graphically browsed.
T136 110217-110368 Sentence denotes The database is primarily presenting information from RNA and protein expression data, i.e., the differential expression in healthy vs. disease tissue.
T137 110369-110426 Sentence denotes It includes data from blood, urin, spinal cord and brain.
T138 110427-110485 Sentence denotes If available, the regulatory interactions are represented.
T139 110486-110657 Sentence denotes Chromosomal susceptibility loci from genetic linkage analyses for the human disease and its animal models are interlinked with the genes via the EnsEMBL genome annotation.
T140 110658-110882 Sentence denotes Intergenomic synteny of chromosomal loci is further applied both to characterise genes and to transfer data from interacting loci from the animal model of the disease (experimental autoimmune encephalomyelitis) to the human.
T141 110883-111029 Sentence denotes Lymphocyte recruitment into the brain is a critical event in the pathogenesis of multiple sclerosis (MS), and is controlled by adhesion molecules.
T142 111030-111226 Sentence denotes It involves: (1) initial contact (tethering) and rolling along the vessel wall mediated by selectins and integrins; (2) chemoattractantinduced integrin activation; (3) firm arrest; (4) diapedesis.
T143 111227-111336 Sentence denotes Both E-and Pselectins are required for efficient tethering and rolling of neutrophils in mouse brain vessels.
T144 111337-111489 Sentence denotes The distribution of G89T and A561C polymorphisms in E-selectin gene in a population of 200 patients with MS and in 238 age-matched controls was studied.
T145 111490-111598 Sentence denotes A significantly increased frequency of the TT genotype of the G98T polymorphism in MS patients was observed.
T146 111599-111805 Sentence denotes No differences in the distribution of A561C between patients and controls were shown, but patients bearing the wild-type allele had an increased probability to develop the disease after the age of 40 years.
T147 111806-112048 Sentence denotes The presence of the TT genotype of the G98T polymorphism seems to increase the susceptibility to develop MS, possibly by up regulating Eselectin transcription rate and thus facilitating the recruitment of activated lymphocytes into the brain.
T148 112049-112184 Sentence denotes Besides, A561C polymorphism does not seem to be a susceptibility factor for MS, although its presence could influence the age at onset.
T149 112185-112280 Sentence denotes IFN-beta exerts its functionality by binding to the subunits IFNAR1 and IFNAR2 of its receptor.
T150 112281-112691 Sentence denotes The aim of this work is to establish genotype frequencies for a SNP within the promoter region of the IFNAR1 gene (at À408bp relative to start of transcription), and 2 polymorphisms in coding regions (SNP18417 in exon 4 of IFNAR1 and SNP11876 in exon 2 of IFNAR2 gene), to evaluate the impact of these polymorphisms on the response to IFN-beta, and to assess the influence of SNP-408 on IFNAR1 mRNA expression.
T151 112692-112819 Sentence denotes 147 MS patients on IFN-beta therapy and 205 controls were evaluated for these SNPs by RFLP analysis of PCR-amplified fragments.
T152 112820-112865 Sentence denotes IFNAR1-mRNA was measured by real time RT-PCR.
T153 112866-113008 Sentence denotes Significant differences on the genotype distribution between patients and controls for SNP18417 and for SNP11876 were found by Chi 2 analysis.
T154 113009-113131 Sentence denotes SNP-408 does not seem to have an influence on the response to IFN-beta therapy, nor on the levels of expression of IFNAR1.
T155 113132-113261 Sentence denotes No significant differences in the distribution of responders and non responders were observed when stratified by any of the SNPs.
T156 113262-113450 Sentence denotes Whether these differences in the distribution of the genotypes for the SNPs in the coding regions between controls and patients have any functional significance need to be further studied.
T157 113451-113492 Sentence denotes Chromosome 2q33 and multiple sclerosis A.
T158 113493-113542 Sentence denotes Bonetti University of Helsinki, Helsinki, Finland
T159 113543-113663 Sentence denotes Multiple sclerosis (MS) is a demyelinating disease of the central nervous system with suspected autoimmune pathogenesis.
T160 113664-113732 Sentence denotes Both genetic and environmental factors play a role in its aetiology.
T161 113733-113796 Sentence denotes MS is considered a genetically heterogeneous polygenic disease.
T162 113797-113941 Sentence denotes In MS, there is evidence from linkage studies and allelic association studies suggesting that chromosome 2q33 would harbour a predisposing gene.
T163 113942-114048 Sentence denotes We have performed a two-stage study to analyse the association of polymorphism on chromosome 2q33 with MS.
T164 114049-114192 Sentence denotes In all, 17 markers were analysed in stage-1 in 134 Finnish MS families and the observed associations were tested in stage-2 in 186 MS families.
T165 114193-114274 Sentence denotes We did not find previously reported allelic or haplotype associations with CTLA4.
T166 114275-114376 Sentence denotes We obtained a weak signal of two distinct predisposing genes, one proximal the other distal of CTLA4.
T167 114377-114617 Sentence denotes The putative proximal gene was associated with the marker rs3977 in families lacking HLA-DR2 ( P=0.02 and 0.02) and the other distal gene was associated with D2S1271 in families from a high-risk region in western Finland ( P=0.02 and 0.01).
T168 114618-114766 Sentence denotes Based on the N3 cM distance and the lack of linkage disequilibrium between these loci, we conclude that the two association signals are independent.
T169 114767-114874 Sentence denotes Our results provide preliminary evidence for two distinct MS susceptibility genes on 2q33 outside of CTLA4.
T170 114875-114886 Sentence denotes Background:
T171 114887-115026 Sentence denotes To evaluate correlation between HLA-DRB1-DQB1 haplotype and age-at-onset in a population of multiple sclerosis (MS) patients from Sardinia.
T172 115027-115035 Sentence denotes Methods.
T173 115036-115127 Sentence denotes A total of 1242 MS patients and 1918 healthy controls (C) were typed at the DRB1-DQB1 loci.
T174 115128-115398 Sentence denotes The individual frequencies of the HLA class II genotypes observed in patients and in controls were compared by estimating odds ratio (OR) determined by genotype frequencies in patients with early onset (b16 years) vs. those with adult onset (N16 years) and vs, controls.
T175 115399-115440 Sentence denotes Level of significance was set at Pb0.001.
T176 115441-115449 Sentence denotes Results.
T177 115450-115503 Sentence denotes We identified 76 (6.5%) individuals with early onset.
T178 115504-115722 Sentence denotes Risk of MS increased in adult onset patients carrying the DR3/ DR13 (OR=6.0, P=1.2Â10 À9 ), DR3/DR2 (OR=5.7, P=4.8Â10 À6 ), DR3/ DR3 (OR=2.9, P=1.2Â10 À15 ), DR3/DR4 DQ3.5 (OR=2.9, P=3.9Â10 À6 ) genotype compared to C.
T179 115723-115918 Sentence denotes In early onset patients, compared to C, risk was increased in carriers of DR3/DR13 (OR=10.3, P=6.1Â10 À4 ), DR3/ DR4DQ3.1 (OR=7.9, P=5.8Â10 À9 ) and DR3/DR4DQ3.2 (OR=6.2, P=4.8Â10 À7 ) genotypes.
T180 115919-116154 Sentence denotes Comparison of adult and early onset patients showed that risk of early onset was specifically associated with the DR3/ DR4DQ3.2 (OR=3.9, P=3.8Â10 À4 ) genotype (genotype frequency 10.5% in early onset and 2.9% in adult onset patients).
T181 116155-116167 Sentence denotes Conclusions.
T182 116168-116286 Sentence denotes This results indicate that in Sardinians MS patients HLA-DRB1-DQB1 molecules contribute to early onset of the disease.
T183 116287-116384 Sentence denotes Interestingly, risk of early onset is associated with the autoimmune diabetes high-risk genotype.
T184 116385-116396 Sentence denotes Background:
T185 116397-116636 Sentence denotes To analyze the distribution of men and women in a cohort of Sardinian MS patients, according to their HLA-DRB1-DQB1 haplotype and to examine the inheritance of the DR3 and DR4 MS-associated alleles according to their parental transmission.
T186 116637-116645 Sentence denotes Methods.
T187 116646-116732 Sentence denotes The study comprised 1097 (339 men and 758 women) MS patients and 329 healthy siblings.
T188 116733-116800 Sentence denotes Typing of HLA-DRB1 and -DQB1 was performed as previously described.
T189 116801-116909 Sentence denotes A logistic model was used to test the parent-of-origin (PO) and maternal genotype effects of the DR3 allele.
T190 116910-116918 Sentence denotes Results.
T191 116919-117080 Sentence denotes In the whole cohort of patients, the F/M ratio was 2.24, ranging from 2.88 in the DR3/DR3, to 2.52 in the DR3/DRX and 1.36 in the DR4/DRY (DRY#DR3) sub-category.
T192 117081-117208 Sentence denotes An excess of paternally transmitted DR3 in affected (IM=0.61, P=0.05) but not in healthy offspring (IM=1.63, P=0.14) was found.
T193 117209-117337 Sentence denotes The PO effect on DR3 transmission from fathers was evident in affected women (IM=0.55, P=0.04) but not in men (IM=0.77, P=0.57).
T194 117338-117485 Sentence denotes An effect of two copies of the maternal non-transmitted DR3 genotype was found in DR3 females (S2=2.21, P=0.05) but not in males (S2=1.43, P=0.57).
T195 117486-117498 Sentence denotes Conclusions.
T196 117499-117741 Sentence denotes Present findings demonstrate that in Sardinia the relative risk of MS due to the HLA-DRB1-DQB1 locus is heterogeneous, with one etiological pathway associated with DR3 and possibly involving both paternal and maternal effects on disease risk.
T197 117742-117994 Sentence denotes Based on the nationwide series of Italian twins with MS, we collected information about family aggregation; perinatal, early and late life events; physiological, medical and surgical history and other items that may represent nonheritable risk factors.
T198 117995-118196 Sentence denotes Data from 70 twin pairs were prosecuted using a logistic regression model through stepwise forward selection procedure in order to identify only the best subset of covariates in terms of MS prediction.
T199 118197-118432 Sentence denotes The selection process was based on a formal Likelihood Ratio test procedure that allowed the identification of a subset of covariables which seem to have a significant impact on the raise of the disease and on its concordance in twins.
T200 118433-118739 Sentence denotes This logistic approach has been further generalized by adding a Gaussian random effect accounting for potential heterogeneity among twin pairs and dependence between twins in the same pair; this model has been estimated using both a GEE (generalized estimating equations) and a maximum likelihood approach.
T201 118740-119050 Sentence denotes All analyses were performed with STATA (release 7.0, College Station, TX) and confirmed that early life infections, later life infections, breast feeding, mumps, herpes virus infection, red measles and the assumption of milk are covariables with a significant positive or negative association with the disease.
T202 119051-119119 Sentence denotes The role of herpesvirus entry receptors for the development of MS F.
T203 119120-119132 Sentence denotes Vogel a , B.
T204 119133-119146 Sentence denotes Rosche a , S.
T205 119147-119159 Sentence denotes Cepok a , S.
T206 119160-119171 Sentence denotes Stei b , V.
T207 119172-119186 Sentence denotes Grummel a , A.
T208 119187-119200 Sentence denotes Kroner c , M.
T209 119201-119214 Sentence denotes M7urer c , P.
T210 119215-119231 Sentence denotes Rieckmann c , N.
T211 119232-119247 Sentence denotes Sommer b and B.
T212 119248-119392 Sentence denotes Hemmer a a University of Düsseldorf, Düsseldorf, Germany; b University of Marburg, Marburg, Germany; c University of Würzburg, Würzburg, Germany
T213 119393-119505 Sentence denotes Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS).
T214 119506-119660 Sentence denotes Although the cause of MS is still uncertain, it is well accepted that both genetic and environmental factors are important for the development of disease.
T215 119661-119773 Sentence denotes Common viral infections have been implicated as environmental factors influencing onset and activity of disease.
T216 119774-119881 Sentence denotes In this study, we focused on genes coding for common Herpes virus entry receptors (PRR1, PVR1, PRR2, CD21).
T217 119882-119979 Sentence denotes Some of the genes were located in regions previously linked to MS in genome wide linkage studies.
T218 119980-120148 Sentence denotes All the receptors are expressed in the brain and immune system and may play an important role for inter-cellular adhesion and entry of neurotropic viruses to the brain.
T219 120149-120226 Sentence denotes The exons of the genes were sequenced in 15 MS patients and healthy controls.
T220 120227-120306 Sentence denotes We identified a number of new and confirmed previously described polymorphisms.
T221 120307-120430 Sentence denotes They were tested for their relevance in MS by a casecontrol (266 MS patients, 227 controls) and TDT study (60 MS families).
T222 120431-120488 Sentence denotes So far, none of the polymorphisms was associated with MS.
T223 120489-120679 Sentence denotes This observation was complemented by expression analyses of the receptors on peripheral mononuclear cells, which did not demonstrate differential expression between MS patients and controls.
T224 120680-120787 Sentence denotes In summary, we did not find evidence that herpes virus receptor genes play a role in the development of MS.
T225 120788-120857 Sentence denotes Complement activation is a central feature of inflammatory processes.
T226 120858-121035 Sentence denotes Previously, we have demonstrated rat strain differences in complement C3 expression after lumbar ventral root avulsions (VRA), a model of nerve injury-induced neurodegeneration.
T227 121036-121140 Sentence denotes Thus, in situ hybridization labeling for C3 mRNA after VRA was twice as high in DA rats compared to PVG.
T228 121141-121316 Sentence denotes Furthermore, in a large scale microarray experiment, C3 mRNA levels significantly differed between the two strains both at baseline in naive rats, and 5 and 14 days after VRA.
T229 121317-121493 Sentence denotes We have here extended these observations by genetic mapping of C3 mRNA expression in a F2(DAxPVG) intercross (n=186) by in situ hybridization and computer-based image analysis.
T230 121494-121543 Sentence denotes All rats were genotyped with 177 microsatellites.
T231 121544-121710 Sentence denotes This demonstrates a suggestive linkage (LOD score 3.0) of C3 expression to Vra1, a genetic locus on chromosome 8 that regulates neurodegeneration in the VRA paradigm.
T232 121711-121801 Sentence denotes In addition, C3 mRNA expression in PVG and DA rats was studied in a brain contusion model.
T233 121802-121956 Sentence denotes One week after unilateral brain contusion levels of C3 mRNA measured with real time PCR were more than twice as high in DA rats compared to PVG ( pb0.01).
T234 121957-122213 Sentence denotes These results demonstrate substantial differences in the regulation of C3 expression after mechanical nerve-injuries as well as a potential link between genetically determined differences in nerve cell survival in the VRA paradigm and the expression of C3.
T235 122214-122288 Sentence denotes Cytogenetic and molecular-genetic markers of age changes of lymphocytes S.
T236 122289-122350 Sentence denotes Kuznetsova Institute of Gerontology, Kiev, Ukraine Objective:
T237 122351-122410 Sentence denotes Study on Y-chromosome polymorphism in three ethnic regions:
T238 122411-122522 Sentence denotes Abkhasia and Azerbaijan (high) and Ukraine (medium longevity level) for establishing ethnic longevity variants.
T239 122523-122531 Sentence denotes Methods:
T240 122532-122694 Sentence denotes In 105 centenarians of Abkhasia and Azerbaijan, the Y chromosome polymorphism by C heterochromatin and Y chromosome length according to Y/F index were determined.
T241 122695-122703 Sentence denotes Results:
T242 122704-122877 Sentence denotes In long-lived of Abkhasia and Azerbaijan, the length of Y-chromosome was bigger than that in Ukraine (Y/F index is 1.16F0.04; 1.08F0.03 and 0.99F0.10, pb0.05, respectively).
T243 122878-122983 Sentence denotes In middle-aged population segment, ethnic differences were more marked compared to those of centenarians.
T244 122984-123088 Sentence denotes Sizes of the C band on Y-chromosome in centenarians of three study regions did not differ significantly:
T245 123089-123179 Sentence denotes 65.39F1.19% in Abkhasia, 1.02F0.03, pb0.05 in Azerbaijan and 0.86F0.02, pb0.05 in Ukraine.
T246 123180-123271 Sentence denotes However, there were ethnic differences of C band size on Y-chromosome in middle-aged group.
T247 123272-123391 Sentence denotes The longest C band was registered in Azerbaijan nationality (70.51F1.81%); it was shorter in Abkhasians and Ukrainians:
T248 123392-123445 Sentence denotes 51.28F2.93%, and 45.28F1.36% ( pb0.05), respectively.
T249 123446-123458 Sentence denotes Conclusions:
T250 123459-123687 Sentence denotes The absence of marked ethnic differences of Y-chromosome and C band sizes in long-lived and their presence in middle-aged groups point to the presence of general Y-chromosome polymorphism variants in long-lived of three regions.
T251 123688-123824 Sentence denotes The sizes of Y-chromosome and C band in individuals with ethnic longevity (Abkhasia and Azerbaijan) are similar to indices of longlived.
T252 123825-123969 Sentence denotes This fact suggests that Y-chromosomal polymorphism variants constitute the cytogenetic markers of both individual and probably ethnic longevity.
T253 123970-124214 Sentence denotes Leber's hereditary optic neuropathy (LHON) is associated with point mutations in the mitochondrial DNA and characterized by bilateral, usually sequential, optic neuropathy that may co-occur with multiple sclerosis (MS)like white matter lesions.
T254 124215-124446 Sentence denotes Despite of repeated clinical reports including magnetic resonance imaging as well as histopathological examination of the visual system, there is a paucity of histopathological descriptions of LHON associated with MS-like syndrome.
T255 124447-124685 Sentence denotes We present here the case of a female patient with the T14484C mutation, who presented bilateral optic neuropathy and consecutively developed Hashimoto thyreoiditis as well as widespread demyelinating CNS lesions outside the visual system.
T256 124686-124732 Sentence denotes She died of bronchopneumonia at the age of 44.
T257 124733-125009 Sentence denotes Immunohistochemical analysis revealed a spectrum of neuropathological changes, including actively and inactively demyelinating plaques in the white matter and optic nerve, vacuolation and cystic necrosis with CD8+ T-cells in the frontal lobe, axonal damage and shadow plaques.
T258 125010-125190 Sentence denotes Massive tissue destruction, cystic necrosis, respectively, was associated with immunohistochemically detectable inducible nitric oxide synthase (iNOS) in macrophages and microglia.
T259 125191-125394 Sentence denotes This variable phenotype of extraoptic LHON disease suggests that mtDNA mutations may affect the nervous system on a common metabolic basis and occasionally may aggravate or initiate autoimmune pathology.
T260 125395-125537 Sentence denotes Guillain-Barré syndrome (GBS) is a post-infectious polyradiculoneuropathy characterized by inflammatory demyelination and axonal degeneration.
T261 125538-125627 Sentence denotes Macrophages and ganglioside-specific IgG have been implicated in the pathogenesis of GBS.
T262 125628-125825 Sentence denotes We recently demonstrated the capacity of antiganglioside IgG to induce leukocyte activation via crosslinking of IgG receptors (FcgammaR), suggesting inflammatory potential of autoantibodies in GBS.
T263 125826-126105 Sentence denotes Three FcgammaR family members, FcgammaRIIa, FcgammaRIIIa and FcgammaRIIIb, display functional bi-allelic polymorphisms (FcgammaRIIa: H131 vs. R131; FcgammaRIIIa: V158 vs. F158; FcgammaRIIIb: NA1 vs. NA2), and determine the efficacy of IgGmediated cellular inflammatory responses.
T264 126106-126317 Sentence denotes FcgammaRIIa-H131 binds IgG2 and IgG3 immune complexes more efficiently than FcgammaRIIa-R131, whereas FcgammaRIIIa-V158 and FcgammaRIIIb-NA1 display increased binding capacity for IgG1-and IgG3-immune complexes.
T265 126318-126416 Sentence denotes Therefore, FcgammaR polymorphisms could influence the vigour of antibody-induced immune responses.
T266 126417-126665 Sentence denotes To assess the relevance of FcgammaR polymorphisms for susceptibility to and severity of GBS, we determined FcgammaR genotype distributions in 192 Dutch and 91 British patients with GBS, and 514 Dutch and 111 British controls by allele-specific PCR.
T267 126666-126832 Sentence denotes The FcgammaRIIIb-NA2/2 genotype frequency was increased among Dutch patients with severe disease compared to patients with mild disease (OR=2.03 (1.06-3.90), p=0.03).
T268 126833-127207 Sentence denotes A meta-analysis incorporating all previously published data, encompassing a total of 345 GBS patients and 714 controls, confirmed the association of the FcgammaRIIIb-NA2 allele with severe disease, and additionally showed an enrichment of the FcgammaR-IIIa-F/F158 genotype in patients with mild disease compared to patients with severe disease (OR=0.64 (0.40-1.02), p=0.06).
T269 127208-127295 Sentence denotes FcgammaRIIIa and FcgammaRIIIb genotypes may represent disease-modifying factors in GBS.
T270 127296-127374 Sentence denotes No association of IL-10 and IL-12 polymorphisms with myasthenia gravis (MG) V.
T271 127375-127392 Sentence denotes Yilmaz a,b , Y.G.
T272 127393-127406 Sentence denotes Parman c , P.
T273 127407-127424 Sentence denotes Serdaroglu c , F.
T274 127425-127441 Sentence denotes Deymeer c and G.
T275 127442-127743 Sentence denotes Saruhan-Direskeneli b a DETAE, Department of Immunology; b DETAE, Department of Physiology and c DETAE, Department of Neurology, Istanbul Medical Faculty, Istanbul, Turkey MG is characterized by autoantibodies (Ab) to acetylcholine receptor on the post-synaptic membrane of the neuromuscular junction.
T276 127744-127809 Sentence denotes The production of these Ab is regulated by T cells via cytokines.
T277 127810-127908 Sentence denotes Interindividual differences in cytokine profiles appear related to allelic polymorphisms of genes.
T278 127909-128018 Sentence denotes Differences in the distribution of polymorphic alleles may have implications on genetic susceptibility to MG.
T279 128019-128358 Sentence denotes To analyze the genetic susceptibility to MG, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was applied to screen single nucleotide polymorphisms at À3575(T/A) and À2763(C/A) positions of the IL-10 promoter and at +16974 (A/C) 3V UTR of the IL-12p40 genes in 106 patients and 152 healthy controls (HC).
T280 128359-128450 Sentence denotes Among the MG group, 74% were seropositive and 30 of selected 63 patients had anti-titin Ab.
T281 128451-128629 Sentence denotes Comparisons of allele, haplotype and genotype frequencies of IL10 and IL12p40 polymorphisms between MG and HC groups or subgroups of MG did not reveal any significant difference.
T282 128630-128749 Sentence denotes However, an association of IL-12p40 3V UTR C allele with anti-titin antibody positivity is detected (OD=4.25, pc=0.02).
T283 128750-128873 Sentence denotes These results implicate that the selected IL10 and IL12p40 polymorphisms do not contribute to genetic susceptibility in MG.
T284 128874-128948 Sentence denotes This study is supported by the Istanbul University Research Fond (T-1125).
T285 128949-129104 Sentence denotes Myasthenia gravis (MG) is an autoimmune disorder mediated by autoantibodies against the nicotinic acetylcholine receptor (nAChR) of neuromuscular junction.
T286 129105-129183 Sentence denotes The production of autoanti-nAChR antibodies in MG is dependent on T-cell help.
T287 129184-129386 Sentence denotes A polymorphism in the cytotoxic Tlymphocyte-associated antigen-4 (CTLA4) gene has been reported to alter T cell activation and confirm genetic susceptibility to several autoimmune diseases including MG.
T288 129387-129739 Sentence denotes To determine the role of CTLA4 gene polymorphisms in predisposition to MG, we investigated 101 patients with MG and 135 ethnically matched healthy controls for allelic determinants at two polymorphic sites of this gene (in the promoter region and in the first exon at position +49) by MseI and BstEII restriction enzyme digest analyses correspondingly.
T289 129740-129887 Sentence denotes Allele frequencies of C-318T gene polymorphism in patients and in healthy controls for allele C were found to be 86.74% and 88.15% correspondingly.
T290 129888-130008 Sentence denotes The frequency of the allele A of A+49G polymorphism was 48.91% in the MG group compared with 50.0% in the control group.
T291 130009-130136 Sentence denotes There was no significant difference in the allele frequencies distribution of these loci between patients and healthy controls.
T292 130137-130246 Sentence denotes Our results did not show any evidence of association of C-318T and A+49G of CTLA4 gene polymorphisms with MG.
T293 130247-130410 Sentence denotes Myasthenia gravis (MG) is an autoimmune disorder in which antibodies are directed against the human nicotinic acetylcholine receptor at the neuromuscular junction.
T294 130411-130502 Sentence denotes An association with HLA class II antigens and the disease was described in other countries.
T295 130503-130672 Sentence denotes In an ethnically mixed group of Brazilian MG patients, an association with HLA-DR5 was found in the global group (n=78) when compared with case-controls studies (n=237).
T296 130673-130849 Sentence denotes Interestingly, HLA-DR11 and HLA-DR12, splits of HLA DR5, were significantly over-represented in male MG and in female patients (pc=0.01), when compared to sex-matched controls.
T297 130850-130919 Sentence denotes Severe MG was associated with HLA-DR2 and HLA-DR3 ( p=0.04 for both).
T298 130920-131072 Sentence denotes The co-occurance of HLA-DR1 with HLA-DR5 ( p=0.03) or HLA-DR5 homozigozity ( p=0.006) appears to have a multiplying effect on the risk of developing MG.
T299 131073-131228 Sentence denotes In contrast, HLA DR6 appears to be involved in protection as well as HLA DR7, a common protective marker for male MG patients or nonthymomatous thymectomy.
T300 131229-131354 Sentence denotes On the other hand, an strong association between HLA DR7 and early-onset disease was found in female MG patients ( p=0.0005).
T301 131355-131531 Sentence denotes In summary, association with HLA-DR class II in Brazilian MG patients will contribute to understand the complexity of the disease and the HLA phenotype role on MG pathogenesis.
T302 131532-131565 Sentence denotes Supported by FAPESP (00/11889-9).
T303 131566-131643 Sentence denotes Age-related changes in the inflammatory response to cytokines in the brain S.
T304 131644-131661 Sentence denotes Campbell and D.C.
T305 131662-131891 Sentence denotes Anthony University of Southampton, Southampton, UK Adult rat brain is resistant to the action of pro-inflammatory mediators and to the recruitment of leukocytes following injury, but this resistant phenotype may be age-dependent.
T306 131892-132095 Sentence denotes In this study, we examined whether age-related changes in the inflammatory response reflect altered responses to the pro-inflammatory cytokines interleukin-1h (IL-1h) or tumour necrosis factor-a (TNF-a).
T307 132096-132369 Sentence denotes In response to equivalent brain microinjections of IL-1h or TNF-a, juvenile and 18-month-old aged rats displayed increased leukocyte recruitment to the brain and a loss of specificity of the leukocyte recruitment profile compared to the responses in 2-month-old adult rats.
T308 132370-132519 Sentence denotes Neutrophil recruitment through vessel walls was associated with loss of the tight-junction protein claudin-1, and with blood-brain barrier breakdown.
T309 132520-132702 Sentence denotes Leukocyte recruitment to the liver, a surrogate marker for the hepatic acute-phase response after brain injury, was also elevated in juvenile and aged rats as compared to adult rats.
T310 132703-132929 Sentence denotes These studies suggest that windows of susceptibility exist in the rodent brain, at either end of the age spectrum, which should guide experimental design to assess anti-inflammatory strategies for age-related neuropathologies.
T311 132930-133022 Sentence denotes Chemokines modulate calcium dynamics and electrophysiological properties of CNS neurons D.L.
T312 133023-133059 Sentence denotes Gruol a , K.L.I. van Gassen b , J.G.
T313 133060-133357 Sentence denotes Netzeband a and P.N.E. de Graan b a The Scripps Research Institute, La Jolla, CA, USA; b Rudolf Magnus Institute for Neuroscience, Utrecht, The Netherlands CCL2 is one of a number of chemokines that belong to the cytokine superfamily and are involved in inflammatory and chemoattractive processes.
T314 133358-133515 Sentence denotes CCL2 is produced at high levels in the central nervous system (CNS) during viral infection, injury, neuroinflammation and other neurodegenerative conditions.
T315 133516-133704 Sentence denotes CNS cells including neurons and glia express receptors for CCl2 and other cytokines suggesting that pathologic conditions are communicated to CNS cells through cytokine signaling pathways.
T316 133705-133857 Sentence denotes However, our understanding of the consequences of activation of cytokine signaling systems in the CNS is relatively limited, especially for CNS neurons.
T317 133858-133936 Sentence denotes In many cell types, chemokine signaling alters intracellular calcium dynamics.
T318 133937-134057 Sentence denotes Therefore, we have investigated the potential involvement of this mechanism in the neuronal signaling activated by CCL2.
T319 134058-134133 Sentence denotes In addition, we have examined the effects of CCL2 on neuronal excitability.
T320 134134-134264 Sentence denotes The studies focused on the cerebellar Purkinje neuron, an identified CNS neuronal type that expresses CCR2, the receptor for CCL2.
T321 134265-134365 Sentence denotes The studies were carried out in a culture preparation and CCL2 was tested by acute bath application.
T322 134366-134461 Sentence denotes High concentrations (25-100 nM) of CCL2 were used to reflect conditions during a disease state.
T323 134462-134628 Sentence denotes Results show that CCL2 increased resting calcium levels, enhanced the calcium response evoked by a metabotropic glutamate receptor agonist and depressed excitability.
T324 134629-134771 Sentence denotes These modulatory effects of CCL2 on neuronal properties are likely to contribute to alter CNS function associated with CNS disease and injury.
T325 134772-134807 Sentence denotes Supported by MH63712 and HD0382310.
T326 134808-134984 Sentence denotes Microglia and infiltrating macrophages are involved in phagocytosis of apoptotic cells and myelin debris in multiple sclerosis (MS) lesions in the central nervous system (CNS).
T327 134985-135074 Sentence denotes The accumulation of ingested lipids is associated with a foamy appearance of these cells.
T328 135075-135234 Sentence denotes It is generally assumed that foamy macrophages contribute to a local pro-inflammatory environment, but this assumption is based on surprisingly scant evidence.
T329 135235-135491 Sentence denotes Since many lipid mediators are actually known to be mediators of immune suppression, we addressed the hypothesis that foamy macrophages demonstrate an anti-inflammatory phenotype in situ, and that this can be mimicked in vitro by myelin-lipid preparations.
T330 135492-135769 Sentence denotes We demonstrate that the large majority of foamy macrophages in postmortem MS brain express markers characteristic for anti-inflammatory alternatively activated macrophages (aamf), including IL-1ra, CCL18 and CD163, and produce the antiinflammatory molecules IL-10 and TGF-beta.
T331 135770-135849 Sentence denotes Expression patterns vary strongly and depend on the location within the lesion.
T332 135850-135960 Sentence denotes Macrophages in perivascular infiltrates do express pro-inflammatory cytokines, such as TNF-alpha and IL-1beta.
T333 135961-136094 Sentence denotes Preliminary in vitro data suggest that myelin-lipid preparations decrease LPS-induced TNF production and induce IL-10 by macrophages.
T334 136095-136297 Sentence denotes Thus, during MS, foamy macrophages within CNS lesions resemble aamf, which may be caused by lipid mediators since myelinderived lipids interfere with pro-inflammatory mechanisms in macrophages in vitro.
T335 136298-136394 Sentence denotes Our data suggest that phagocytic macrophages may display regulatory functions within MS lesions.
T336 136395-136571 Sentence denotes The surface unit of MSRV (multiple sclerosis associated retroviral element) envelope protein induces an immune bias in patients with MS that correlates with disease activity A.
T337 136572-136586 Sentence denotes Rolland a , E.
T338 136587-136607 Sentence denotes Jouvin-Marche a , M.
T339 136608-136624 Sentence denotes Saresella b , P.
T340 136625-136932 Sentence denotes The presence of MSRV, a retroviral element defining a novel family of human endogenous retroviruses (HERV-W) has now been confirmed in serum and cerebrospinal fluids (CSF) of patients with multiple sclerosis (MS) and a correlation between circulating MSRV virion load and MS evolution has been demonstrated.
T341 136933-137152 Sentence denotes In an attempt to link the potential effects of MSRV with MS disease, the pro-inflammatory properties of the surface unit of MSRV envelope protein were evaluated in PBMC of MS patients and compared with healthy controls.
T342 137153-137225 Sentence denotes We observed divergent reactivity to ENV-SU between MS and control PBMCs.
T343 137226-137381 Sentence denotes This was reflected by a significant increase of IFN-gamma, IL-6 and IL-12p40 productions by the overall MS population when compared with the control group.
T344 137382-137439 Sentence denotes TNF-alpha, IL-1-beta and IL-10 were similarly stimulated.
T345 137440-137586 Sentence denotes Interestingly, the over productions of IL-6 and IL-12p40 were found to correlate with the Expanded Disability Status Scale (EDSS) of the patients.
T346 137587-137759 Sentence denotes The surface unit of MSRV envelope protein can thus affect the immune system of patients with MS and the immune bias thus created appears to increase with disease evolution.
T347 137760-137908 Sentence denotes The pro-inflammatory properties of ENV-SU could be compatible with a relationship between MSRV expression, MS immunopathology and disease evolution.
T348 137909-138006 Sentence denotes TRADD interacts with STAT-1alpha and influences IFN-gamma signaling in macrophages/microglia E.N.
T349 138007-138021 Sentence denotes Benveniste, H.
T350 138022-138029 Sentence denotes Qin, N.
T351 138030-138045 Sentence denotes Kokorina and D.
T352 138046-138366 Sentence denotes Wesemann University of Alabama at Birmingham, Birmingham, Alabama, USA Inflammatory events in the Central Nervous System (CNS) contribute to the pathology underlying diseases such as multiple sclerosis, Alzheimer's disease and HIV-1-associated dementia, and activated macrophages/ microglia are central to this response.
T353 138367-138511 Sentence denotes Macrophages/microglia respond to cytokines upon engagement of cell surface receptors and activation of complex intracellular signaling pathways.
T354 138512-138658 Sentence denotes IFN-gamma and TNF-alpha are potent activator of macrophages and microglia and are aberrantly expressed in the CNS in the diseases mentioned above.
T355 138659-138828 Sentence denotes Tumor necrosis factor receptor-1 (TNFR1)-associated death domain protein (TRADD) plays an essential role in recruiting signaling molecules to the TNFRI receptor complex.
T356 138829-138943 Sentence denotes IFN-gamma utilizes signal transducer and activator of transcription-1alpha (STAT-1 alpha) for signal transduction.
T357 138944-139053 Sentence denotes Herein, we demonstrate that IFN-gamma induces the formation of a nuclear-localized TRADD-STAT-1alpha complex.
T358 139054-139159 Sentence denotes IFN-gamma-mediated STAT-1alpha phosphorylation is prolonged in macrophages with reduced TRADD expression.
T359 139160-139329 Sentence denotes Moreover, an increase in IFN-gamma-mediated STAT-1alpha DNA binding activity, nuclear presence and transcriptional potential is observed in the TRADD bknock-downQ cells.
T360 139330-139514 Sentence denotes These data indicate that TRADD may play a role in IFN-gamma signaling by forming a complex with STAT-1alpha within the nucleus, and regulating IFN-gammamediated STAT-1alpha activation.
T361 139515-139691 Sentence denotes Thus, TRADD has a functional role in regulating the response of macrophages/microglia to IFN-gamma, impacting on cellular activation and subsequent neuroinflammatory responses.
T362 139692-139808 Sentence denotes Identification of a complement 5a-like receptor from astrocytes: characterization of anti-inflammatory properties V.
T363 139809-139825 Sentence denotes Gavrilyuk a , S.
T364 139826-139840 Sentence denotes Kalinin a , B.
T365 139841-139855 Sentence denotes Hilbush b , A.
T366 139856-139873 Sentence denotes Middlecamp b , S.
T367 139874-139892 Sentence denotes McGuire c and D.L.
T368 139893-140164 Sentence denotes Feinstein a a University of Illinois, Chicago, IL, USA; b Digital Gene Technology, San Diego, CA, USA; c Loyola University, Chicago, IL, USA Brain inflammation is regulated by endogenous substances, including noradrenaline (NA) which can increase anti-inflammatory genes.
T369 140165-140294 Sentence denotes To identify NA-regulated, anti-inflammatory genes, we used TOGA (total gene expression analysis) to screen astrocyte-derived RNA.
T370 140295-140454 Sentence denotes NA-inducible cDNA clone DST11 encodes a form of the complement C5a receptor (C5aR), with 39% identity to rat C5aR, and 56% identity to human C5aR variant C5L2.
T371 140455-140581 Sentence denotes Quantitative PCR shows that in astrocytes DST11 mRNA is increased by NA, whereas in vivo depletion of NA reduced DST11 levels.
T372 140582-140680 Sentence denotes Western blot analysis demonstrated basal and NA-induced expression of DST11 in primary astrocytes.
T373 140681-140798 Sentence denotes Immunocytochemical staining revealed DST11-immunoreactivity throughout brain, co-localized to neurons and astrocytes.
T374 140799-140978 Sentence denotes In astrocytes, induction of nitric oxide synthase type 2 or IL-beta was increased by treatment with antisense oligonucleotides to DST11, and reduced in cells overexpressing DST11.
T375 140979-141056 Sentence denotes Levels of human C5L2 andC5aR, were lower in MS and AD brains versus controls.
T376 141057-141199 Sentence denotes These results demonstrate that DST11 is a C5aR isoform expressed by glia and neurons, regulated by NA, and exerts anti-inflammatory functions.
T377 141200-141292 Sentence denotes Changes in DST11 levels in brain could contribute to the progression of inflammatory damage.
T378 141293-141337 Sentence denotes This work was sponsored by a grant from NIH.
T379 141338-141456 Sentence denotes IL-1 activates interferon regulatory factor-3: implications for an antiviral response in human primary astrocytes M.A.
T380 141457-141475 Sentence denotes Rivieccio a , G.R.
T381 141476-141489 Sentence denotes John b , H.S.
T382 141490-141500 Sentence denotes Suh a , X.
T383 141501-141514 Sentence denotes Song a , S.C.
T384 141515-141529 Sentence denotes Lee a and C.F.
T385 141530-141641 Sentence denotes Brosnan a a Albert Einstein College of Medicine, New York, USA; b Mount Sinai School of Medicine, New York, USA
T386 141642-141827 Sentence denotes The cytokine interleukin-1 (IL-1) is a major activator of astrocytes, leading to the production of a wide range of cytokines and chemokines important for host defense against pathogens.
T387 141828-141911 Sentence denotes IL-1, like LPS, signals via the MyD88/ IRAK-1 pathway linked to NF-kappaB and AP-1.
T388 141912-142224 Sentence denotes Recent studies have shown that the TLR4 ligand LPS signals independently of MyD88 resulting in the activation of interferon regulatory factor-3 (IRF-3), a transcription factor required for induction of primary anti-viral response genes such as type 1 interferons and the chemokines RANTES/CCL5 and IP-10/ CXCL10.
T389 142225-142520 Sentence denotes Considering the apparent similarities between IL-1 and TLR4 signaling, we hypothesized that IL-1 is also capable of activating IRF-3 in human primary astrocytes and that this activation would result in the expression of IRF-3-dependent type I interferons necessary for innate antiviral immunity.
T390 142521-142624 Sentence denotes Using Q-PCR and ELISA, we found that IL-1-induced IFNbeta, RANTES/CCL5, and IP-10/CXCL10 in astrocytes.
T391 142625-142762 Sentence denotes We also observed that IL-1 induced IRF3 nuclear translocation by immunofluorescence and by cell fractionation followed by immunoblotting.
T392 142763-142902 Sentence denotes We confirmed the dependency of type I interferon expression on IRF3 activation by utilizing a dominant negative IRF3 expressing adenovirus.
T393 142903-143107 Sentence denotes These data are the first to show that IL-1, in addition to TLR's, can stimulate IRF3 in human primary astrocytes, implicating this cytokine as an activator of genes involved in innate antiviral responses.
T394 143108-143198 Sentence denotes Downregulation of Abeta-induced cytokine expression in glial cells using NFkappaB decoy L.
T395 143199-143209 Sentence denotes Fisher, M.
T396 143210-143224 Sentence denotes Samuelsson, V.
T397 143225-143240 Sentence denotes Cortes Toro, U.
T398 143241-143252 Sentence denotes Soomets, J.
T399 143253-143262 Sentence denotes Yang, Ü .
T400 143263-143276 Sentence denotes Langel and K.
T401 143277-143497 Sentence denotes Iverfeldt Department of Neurochemistry and Neurotoxicology, Stockholm University, Stockholm, Sweden Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with impairments in cognition and memory.
T402 143498-143595 Sentence denotes The beta-amyloid (Abeta) plaques seen in AD are surrounded by activated astrocytes and microglia.
T403 143596-143778 Sentence denotes It is believed that these activated glial cells contribute to neurotoxicity through the induction of oxidative damage and proinflammatory cytokines like interleukin-1beta (IL-1beta).
T404 143779-144034 Sentence denotes The activation of glial cells is believed to be an early event in the development of AD, and both IL-1beta and interleukin-6 (IL-6) have been detected early in AD brains, suggesting that these cytokines may play an important role in the development of AD.
T405 144035-144165 Sentence denotes For many inflammatory events, including the cytokine induction in glial cells, the transcription factor NFkappaB plays a key role.
T406 144166-144319 Sentence denotes This suggests that therapeutical strategies aimed to control the development of AD could include administration of drugs that hinder NFkappaB activation.
T407 144320-144524 Sentence denotes In this study, the effects mediated by IL-1beta and the Abeta (1-42) and Abeta (25-35) peptides on NFkappaB binding activity and cytokine expression in rat primary mixed glial cell cultures were examined.
T408 144525-144689 Sentence denotes We also investigated the possibility to block the action of NFkappaB using double-stranded oligonucleotides containing the consensus sequences for NFkappaB binding.
T409 144690-144787 Sentence denotes We investigated the effect of blocking the NFkappaB action on cytokine expression in these cells.
T410 144788-144906 Sentence denotes In order to increase the cellular uptake of the NFkappaB decoy, we have used the cell penetrating peptide Transportan.
T411 144907-144976 Sentence denotes Role of TNF in axonal lesion-induced microglial activation in vivo C.
T412 144977-144987 Sentence denotes Fenger, N.
T413 144988-145000 Sentence denotes Drbjdahl, M.
T414 145001-145014 Sentence denotes Meldgaard, R.
T415 145015-145025 Sentence denotes Ladeby, K.
T416 145026-145043 Sentence denotes Lambertsen and B.
T417 145044-145202 Sentence denotes Finsen University of Southern Denmark, Odense C, Denmark TNF is known to exert strong auto-and paracrine effects on microglia in vitro and presumably in vivo.
T418 145203-145357 Sentence denotes Here, we investigated the role of TNF and its receptors on the microglial response to Wallerian and terminal synaptic degeneration within the hippocampus.
T419 145358-145563 Sentence denotes Quantitative PCR of microdissected, perforant path-denervated hippocampus showed a 22-fold upregulation of TNF mRNA, and a 2-to 3-fold upregulation of TNF-p55R and -p75R mRNA at days 2 and 5, respectively.
T420 145564-145618 Sentence denotes The presence of TNF was confirmed by Western blotting.
T421 145619-145819 Sentence denotes In situ hybridization showed microglial expression of TNF mRNA at day 2, and upregulation of TNF-p55R and -p75R mRNA in microglial-like cells starting at day 2, when microglia underwent proliferation.
T422 145820-145949 Sentence denotes Lesioning induced a 3-fold increase in microglial number in wildtype mice at day 5 (251F20, lesioned n=11; 81F7, unlesioned n=5).
T423 145950-146278 Sentence denotes Comparison of microglial numbers in wildtype (251F20, n=11; 81F7, n=5), TNF-KO (219F15, n=14; 85F5, n=7), and TNF-p55p75R-KO (221F11, n=13; 95F3, n=4) mice pointed towards a reduced lesion-induced increase in microglial number in TNF-and TNF-R-KO mice, which, however, was not statistically significant ( P=0.16, two-way ANOVA).
T424 146279-146418 Sentence denotes The data suggest that endogenously produced TNF may be redundant in terms of lesion-induced expansion of the microglial population in vivo.
T425 146419-146465 Sentence denotes Production of interferon-gamma by microglia J.
T426 146466-146481 Sentence denotes Kawanokuchi, T.
T427 146482-146492 Sentence denotes Mizuno, H.
T428 146493-146501 Sentence denotes Kato, H.
T429 146502-146514 Sentence denotes Takeuchi, J.
T430 146515-146523 Sentence denotes Wang, G.
T431 146524-146533 Sentence denotes Zhang, N.
T432 146534-146545 Sentence denotes Mitsuma, R.
T433 146546-146554 Sentence denotes Kuno, S.
T434 146555-146565 Sentence denotes Jin and A.
T435 146566-146684 Sentence denotes Suzumura Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
T1 146685-146855 Sentence denotes Because of the lack of major histocompatibility complex (MHC) antigen expression, neural cells had been considered not to interact with immune cells in a specific manner.
T2 146856-146965 Sentence denotes Interferon-gamma (IFN-gamma) enables the interaction via induction of MHC antigen expression in neural cells.
T3 146966-147060 Sentence denotes IFNgamma also induces inflammatory mediators such as TNF-alpha or nitric oxide in glial cells.
T4 147061-147201 Sentence denotes Thus, IFN-gamma is a critical cytokine in the development of CNS pathologies including neuronal degeneration and inflammatory demyelination.
T5 147202-147280 Sentence denotes However, IFN-gamma is considered to be produced exclusively by lymphoid cells.
T6 147281-147557 Sentence denotes Here, we show that murine microglia, brain macrophages, are able to produce IFN-gamma in response to IL-12, IL-18 and both, by means of RT-PCR method for induction of IFN-gamma mRNA, Western blotting and immunofluorescence for cytoplasmic expression of IFN-gamma in microglia.
T7 147558-147702 Sentence denotes A murine microglial cell line, 6-3 cells, are also induced to produce IFN-gamma whereas astrocytes did not produce IFN-gamma with above stimuli.
T8 147703-147800 Sentence denotes Induction of IFN-gamma resulted in the induction of class II MHC antigen expression in microglia.
T9 147801-148042 Sentence denotes Since IL-12 and IL-18 are produced in the CNS by glial cells, these cytokines may play a critical role in initiation of neural cells-immune cells interaction to induce autoimmune processes in the CNS, in either autocrine or paracrine manner.
T10 148043-148114 Sentence denotes Biological roles of two new haemopoietic factors in brain and thymus A.
T11 148115-148129 Sentence denotes Kikuchi a , H.
T12 148130-148145 Sentence denotes Tomoyasu b , T.
T13 148146-148161 Sentence denotes Yamamoto c , M.
T14 148162-148177 Sentence denotes Kusakabe d , N.
T15 148178-148197 Sentence denotes Sakuragawa e and I.
T16 148198-148464 Sentence denotes Kamo e a National Institute of Neuroscience, Tokyo, Japan; b Ohmori Red Cross Hospital, Tokyo, Japan; c Institute of Medical Science, University of Tokyo, Tokyo, Japan; d ANB Tsukuba Institute, Tsukuba, Japan; e School of Medicine, Toho University, Sagamihara, Japan
T17 148465-148552 Sentence denotes We found new 80-kDa and 100-kDa haemopoietic factors from coned rat thymic myoid cells.
T18 148553-148737 Sentence denotes Many cells that produce these factors were detected in myasthenic hyperplastic thymi, and in normal brains, suggesting that they have biological roles other than monocytic cell growth.
T19 148738-148851 Sentence denotes In the present study, we aimed to understand their potential biological roles in the brain and myasthenic thymus.
T20 148852-148960 Sentence denotes New born rat brain, and rabbit anti-80-kDa and 100-kDa factor IgG were used for immunohistochemical studies.
T21 148961-149032 Sentence denotes Neural cells obtained form rat cerebrum were cultured for kinase assay.
T22 149033-149114 Sentence denotes The 80-kDa and 100-kDa factors were detected in young and aged rat brain tissues.
T23 149115-149184 Sentence denotes Cultured brain cells and glial cell lines produced these two factors.
T24 149185-149271 Sentence denotes The two factors purified from these cultures stimulate the growth of microglial cells.
T25 149272-149315 Sentence denotes The two antibodies react with neural cells.
T26 149316-149357 Sentence denotes These factors support neural cell growth.
T27 149358-149433 Sentence denotes In hyperplastic myasthenic thymi, these factors were consistently detected.
T28 149434-149485 Sentence denotes The two factors also support the growth of B cells.
T29 149486-149633 Sentence denotes These results suggest that the two new haemopoietic factors play important physiological roles in brain and regulatory roles in autoimmune disease.
T30 149634-149755 Sentence denotes Chemokine secretion and chemokine receptor expression in brain cell aggregate cultures treated with interferon-gamma F.A.
T31 149756-149769 Sentence denotes Marques, I.A.
T32 149770-149782 Sentence denotes Romero, D.K.
T33 149783-149796 Sentence denotes Male and A.J.
T34 149797-150060 Sentence denotes Loughlin The Open University, Milton Keynes, UK A 3-dimensional brain cell aggregate culture system, which approximates to the brain in vivo in terms of glial and neuronal development and cell-cell interactions, was used as a model of the CNS parenchyma in vitro.
T35 150061-150152 Sentence denotes Cultures were established from brain tissue of 16-day gestation Sprague-Dawley rat embryos.
T36 150153-150258 Sentence denotes In untreated aggregates, the chemokine receptors CCR1, CCR5 and CX3CR1 were detectable at the mRNA level.
T37 150259-150353 Sentence denotes Treatment with IFNgamma resulted in an increase in expression of CCR5 and CX3CR1 but not CCR1.
T38 150354-150508 Sentence denotes There was no detectable expression of CCR2 or CXCR3 in unstimulated aggregates, nor was the expression of these receptors affected by IFN-gamma treatment.
T39 150509-150628 Sentence denotes At the protein level, CCR5 and CX3CR1 were detected by immunocytochemistry, though IFN-gamma had no discernable effect.
T40 150629-150759 Sentence denotes IFN-gamma induced secretion of the ligands for these receptors (CCL5 and CX3CL1 respectively) in a time-and dose-dependent manner.
T41 150760-150883 Sentence denotes The responses to IFN-gamma observed in this study are modest compared to those observed in isolated glial cell populations.
T42 150884-151132 Sentence denotes These results suggest that the nature and extent of the inflammatory response in the CNS cannot be predicted from studies of isolated cell populations, but critically depends on interactions between cells and a complex milieu of secreted mediators.
T43 151133-151299 Sentence denotes Our approach complements existing in vivo and in vitro studies and allows us to assess the effect of inflammatory mediators on cells within a complex CNS environment.
T44 151300-151404 Sentence denotes Capsaicin up-regulates the production of cytokines by dorsal root ganglion (DRG) neurons in culture N.E.
T45 151405-151414 Sentence denotes Saade, H.
T46 151415-151430 Sentence denotes Al Tannoury, M.
T47 151431-151444 Sentence denotes El-Sabban, B.
T48 151445-151471 Sentence denotes Safieh-Garabedian and S.J.
T49 151472-151546 Sentence denotes Jabbur American University of Beirut, Beirut, Lebanon Background and Aims:
T50 151547-151709 Sentence denotes Previous work from our laboratory has characterized the effects of endotoxin (ET) treatment on the secretion of proinflammatory cytokines by cultured DRG neurons.
T51 151710-151921 Sentence denotes The aim of this study was to investigate whether the challenge of DRG cells by capsaicin can alter their secretion of tumor necrosis factor (TNF) alpha, interleukins (IL) 1, 6 and 10 and prostaglandin E2 (PGE2).
T52 151922-151930 Sentence denotes Methods:
T53 151931-152089 Sentence denotes Primary cultures of adult rat DRG neurons were treated at day 4, with either ET (5 microg in 1 ml) or with capsaicin (0.1, 1 or 10 microg in 1 ml) for 30 min.
T54 152090-152211 Sentence denotes After treatment, cells were washed and re-supplied with fresh media and the supernatant was sampled at 1.5, 3 and 4.5 h .
T55 152212-152277 Sentence denotes The concentrations of all the mediators were determined by ELISA.
T56 152278-152286 Sentence denotes Results:
T57 152287-152423 Sentence denotes Capsaicin produced a significant increase of the levels of IL6, IL10 and PGE2, reaching more than 10 folds their initial concentrations.
T58 152424-152515 Sentence denotes This increase was comparable to (albeit slightly less than that observed with ET challenge.
T59 152516-152597 Sentence denotes The optimal effects were obtained with the concentration of 1microg of capsaicin.
T60 152598-152848 Sentence denotes Conclusion: (1) Capsaicin challenge to DRG culture upregulates the level of pro and anti-inflammatory mediators. (2) Our results provide a molecular background for the concept of neurogenic inflammation. (Supported by grants from CDRE and the LNCSR).
T61 152849-152908 Sentence denotes Effects of chronic expression of IL-1beta in the brain C.C.
T62 152909-152925 Sentence denotes Ferrari a , A.M.
T63 152926-152939 Sentence denotes Depino a , F.
T64 152940-152952 Sentence denotes Prada a , O.
T65 152953-152969 Sentence denotes Podhajcer a , H.
T66 152970-152982 Sentence denotes Perry b , D.
T67 152983-152999 Sentence denotes Anthony c and F.
T68 153000-153415 Sentence denotes Pitossi a a Gene Therapy Laboratory, Institute for Biochemical Research, Buenos Aires, Argentina; b CNS Inflammation Group, University of Southamptom, Southampton, UK; c Molecular Neuropathology, University of Southampton, Southampton, UK Interleukin-1beta (IL-1) has been implicated in the pathology of several chronic neurodegenerative diseases including multiple sclerosis, Alzheimer's disease and prion disease.
T69 153416-153534 Sentence denotes However, the effects of long-term IL-1 expression in the brain parenchyma on CNS integrity have not been investigated.
T70 153535-153655 Sentence denotes We used a recombinant adenovirus producing IL-1 to examine the effects of chronic IL-1 expression in the CNS parenchyma.
T71 153656-153716 Sentence denotes IL-1 expression was detectable until 30 days post-injection.
T72 153717-153896 Sentence denotes Between days 8 and 14, there was marked and restricted recruitment of neutrophils, vasodilatation and breakdown of the blood-brain barrier (BBB) ipsilateral to the injection side.
T73 153897-153965 Sentence denotes Microglia and astrocyte activation was evident through days 2 to 14.
T74 153966-154058 Sentence denotes Disorganization of the nervous tissue and vast demyelination were observed at 8 and 14 days.
T75 154059-154103 Sentence denotes No signs of neurodegeneration were observed.
T76 154104-154177 Sentence denotes Oligodendrocytes and neurons have no evident ultrastructural alterations.
T77 154178-154329 Sentence denotes Interestingly, at 30 days, the nervous tissue has completely recovered, appearing normal with no signs of demyelination, infiltration or BBB breakdown.
T78 154330-154601 Sentence denotes In summary, our data show that chronic expression of IL-1, in contrast to its acute delivery, can reversibly damage CNS integrity and implicates this cytokine or downstream components as major mediators of demyelination in chronic inflammatory and demyelinating diseases.
T79 154602-154711 Sentence denotes Hepatic CC chemokines control the magnitude of the inflammatory response within the injured rodent brain S.J.
T80 154712-154729 Sentence denotes Campbell a , V.H.
T81 154730-154742 Sentence denotes Perry a , F.
T82 154743-154759 Sentence denotes Pitossi b , A.G.
T83 154760-154775 Sentence denotes Butchart a , M.
T84 154776-154791 Sentence denotes Chertoff b , S.
T85 154792-154809 Sentence denotes Waters a and D.C.
T86 154810-154927 Sentence denotes Anthony a a University of Southampton, Southampton, UK; b University of Buenos Aires-CONICET, Buenos Aires, Argentina
T87 154928-155096 Sentence denotes Hepatic CXC chemokines, behaving as acute phase proteins, regulate neutrophil mobilisation and recruitment following focal IL-1h-mediated inflammation to the rat brain.
T88 155097-155366 Sentence denotes To determine whether this response was specific to CXC chemokines or whether it represented a more generalised response to acute brain inflammation, we examined brain and liver production of MCP-1, a CC chemokine, when rats were microinjected with TNF-a into the brain.
T89 155367-155486 Sentence denotes As early as 2h after the TNF-a challenge, MCP-1 mRNA and protein were observed in the liver by Taqman RT-PCR and ELISA.
T90 155487-155622 Sentence denotes The serum MCP-1 level was also elevated between 2 and 4 h, which was consistent with maximal mobilisation of leukocytes into the blood.
T91 155623-155724 Sentence denotes Monocyte recruitment was most marked in the liver after 6 h, but was delayed in the brain until 24 h.
T92 155725-156035 Sentence denotes Elevated hepatic and serum chemokines are implicated in the control of leukocytosis and leukocyte recruitment to the brain and liver, since dexamethasone pretreatment attenuated the hepatic MCP-1 response, modulated leukocyte mobilisation and reduced monocyte entry not only to the brain but also to the liver.
T93 156036-156231 Sentence denotes Thus hepatic chemokine production controls and amplifies the CNS response to inflammation by controlling the rate, timing, magnitude and composition of leukocyte recruitment to the damaged brain.
T94 156232-156332 Sentence denotes Interleukin-1 beta contributes to the early regulation of inflammation after spinal cord injury T.K.
T95 156333-156345 Sentence denotes Rice, J.E.A.
T96 156346-156360 Sentence denotes Wells and V.W.
T97 156361-156404 Sentence denotes Yong University of Calgary, Calgary, Canada
T98 156405-156496 Sentence denotes After spinal cord injury (SCI), a number of inflammatory molecules become rapidly elevated.
T99 156497-156545 Sentence denotes The role of neuroinflammation in SCI is unclear.
T100 156546-156686 Sentence denotes The objective of this study is to examine neuroinflammation after SCI and to determine whether a particular molecule regulates this process.
T101 156687-156916 Sentence denotes SCI is induced in CD-1 mice using a clip compression model and the temporal expression patterns of several cytokines, chemokines and matrix metalloproteinases (MMPs) are determined using RNase Protection Assays and real-time PCR.
T102 156917-157006 Sentence denotes Interleukin (IL)-1 beta is one of the early inflammatory molecules upregulated after SCI.
T103 157007-157059 Sentence denotes IL-1 beta transcripts increase within 30 min of SCI.
T104 157060-157197 Sentence denotes Transcript levels of several chemokines (MIPs, MCP-1 and IP-10) are also elevated by 30 min after SCI, but their expression level is low.
T105 157198-157253 Sentence denotes The expression of several MMPs becomes prominent later.
T106 157254-157493 Sentence denotes To determine if IL-1 beta is involved in regulating the expression of other inflammatory molecules, wild-type mice and mice genetically deficient for IL-1 beta are compared for differences in inflammatory molecule expression following SCI.
T107 157494-157640 Sentence denotes IL-1 beta deficient mice show reduced levels of several cytokines (IL-1 alpha, IL-6), chemokines (RANTES, IP-10, MCP-1, MIPs) and MMP-3, 9 and 12.
T108 157641-157773 Sentence denotes We conclude that IL-1 beta is upregulated early after SCI and that it may be a key regulator of neuroinflammation in this condition.
T109 157774-157972 Sentence denotes Granulocyte macrophage-colony stimulating factor (GM-CSF) and triidothyronine (T3) increase oligodendrocyte production in the corpus callosum (CC) following intracerebroventricular (ICV) infusion T.
T110 157973-157986 Sentence denotes Dubois and S.
T111 157987-158031 Sentence denotes Weiss University of Calgary, Calgary, Canada
T112 158032-158140 Sentence denotes We have found that both GM-CSF and T3 produce more oligodendrocytes from embryonic neural stem cells (NSCs).
T113 158141-158249 Sentence denotes Thus, we hypothesized that these two factors would also increase oligodendrocyte production from adult NSCs.
T114 158250-158397 Sentence denotes Both GM-CSF and T3 increased the percent of terminally differentiated oligodendrocytes in neurospheres derived from adult subventricular zone NSCs.
T115 158398-158674 Sentence denotes To ask whether these factors might regulate NSC production of oligodendrocytes in vivo, we infused (ICV) solutions of either a vehicle control, GM-CSF or T3 into the lateral ventricles of adult mice and evaluated oligodendoglial development through immunocytochemical methods.
T116 158675-158957 Sentence denotes Both GM-CSF and T3 increased the numbers of immature and maturing oligodendrocyte progenitors as well as terminally differentiated oligodendrocytes in the CC, compared to control infusions, suggesting that they increase oligodendroglial production through all stages of development.
T117 158958-159076 Sentence denotes Both GM-CSF and T3 also decreased the number of TUNEL-positive cells in the CC suggesting that they reduce cell death.
T118 159077-159295 Sentence denotes However, only GM-CSF increased the percent of BrdU+ cells within the population of mature oligodendrocytes, suggesting that GM-CSF is enhancing oligodendrocyte survival whereas T3 principally regulates differentiation.
T119 159296-159558 Sentence denotes Further studies are underway to investigate the actions of these two factors following demyelinating lesions with the aim of further understanding whether enhancing the survival and differentiation of newly generated oligodendrocytes might improve remyelination.
T120 159559-159620 Sentence denotes Supported by the MS Scientific Research Foundation of Canada.
T121 159621-159736 Sentence denotes 108 Alphaviral expression of transforming growth factor beta 1 inhibits autoimmune encephalomyelitis in mice M.J.V.
T122 159737-159755 Sentence denotes Vähä-Koskela, J.C.
T123 159756-159773 Sentence denotes Holmlund and A.E.
T124 159774-159877 Sentence denotes Hinkkanen Department of Biochemistry and Pharmacy, Åbo Akademi University, Turku, Finland Introduction:
T125 159878-160077 Sentence denotes Current treatment strategies for chronic, inflammatory diseases of the central nervous system (CNS) are almost solely based on down-regulation of the immune system by systemically administered drugs.
T126 160078-160295 Sentence denotes Although some drugs may show efficacy in experimental settings, successful treatment of CNS disorders is greatly impeded by the limited access or insufficient quantities of these compounds at the site of inflammation.
T127 160296-160301 Sentence denotes Aims:
T128 160302-160434 Sentence denotes To assess the feasibility of live, neurotropic virus to interfere with CNS inflammation by expression of immunomodulatory cytokines.
T129 160435-160443 Sentence denotes Methods:
T130 160444-160652 Sentence denotes Genes for both latent and constitutively active transforming growth factor (TGF) beta 1 were cloned into replicationcompetent Semliki Forest virus vector VA7, described elsewhere (V7h7-Koskela et al., 2003) .
T131 160653-160772 Sentence denotes To study their function in vivo, vectors were administered intraperitoneally to groups of Balb/c mice induced with EAE.
T132 160773-160781 Sentence denotes Results:
T133 160782-160872 Sentence denotes The TGF beta vectors were shown to produce biologically active TGF beta-1 in cell culture.
T134 160873-161055 Sentence denotes When administered to mice with EAE, the vectors were able to significantly inhibit both the development and the mean severity of the disorder, compared to mice receiving only saline.
T135 161056-161068 Sentence denotes Conclusions:
T136 161069-161183 Sentence denotes Replication-competent, avirulent alphaviral vectors may serve as vehicles for non-invasive gene delivery into CNS.
T137 161184-161395 Sentence denotes Anti-inflammatory immunomodulation by virally mediated cytokine expression offers a formidable treatment strategy for inflammatory CNS disorders, where therapy by conventional drug administration may be limited.
T138 161396-161494 Sentence denotes Potential role of interleukin-15 (IL-15) in autoimmunity and impact of IGIV on IL-15 expression N.
T139 161495-161504 Sentence denotes Eller, S.
T140 161505-161517 Sentence denotes Inoue and D.
T141 161518-161698 Sentence denotes Scott Food and Drug Administration, Bethesda, USA Interleukin-15 (IL-15) is a four-alpha helix cytokine that shares some receptors subunit usage and biological functions with IL-2.
T142 161699-161834 Sentence denotes It is involved in the generation and regulation of a normal immune response from monocyte activation to memory CD8+ T cell development.
T143 161835-161959 Sentence denotes Immune cells such as monocytes/macrophages, microglia, and dendritic cells, are among the few cell types that produce IL-15.
T144 161960-162108 Sentence denotes Il-15 may be membranetethered or associated with the IL-15Ralpha subunit and very little is secreted from cells, making protein detection difficult.
T145 162109-162218 Sentence denotes IL-15 has been associated with autoimmune diseases such as multiple sclerosis (MS), and rheumatoid arthritis.
T146 162219-162337 Sentence denotes It is unclear whether IL-15 has a role in disease initiation or if it is a marker of disease and disease pathogenesis.
T147 162338-162480 Sentence denotes We developed a method for inducing, detecting, and modulating IL-15 on the surface of human and mouse cells or cell lines using FACs analysis.
T148 162481-162553 Sentence denotes This method can be used to correlate IL-15 levels with clinical disease.
T149 162554-162700 Sentence denotes Immune Globulin, Intravenous (IGIV) has been shown to have immunomodulatory effects and has been used in the treatment of MS with varying results.
T150 162701-162834 Sentence denotes Using a mouse macrophage cell line, RAW 264.7, we have shown that IGIV reduces expression of IL-15 and to a lesser extent, TNF-alpha.
T151 162835-162993 Sentence denotes Current studies are assessing the role of IL-15 in induction and persistence of experimental autoimmune encephalomyelitis (EAE) in an adoptive transfer model.
T152 162994-163135 Sentence denotes Differential macrophage expression of IL-12 and IL-23 upon innate immune activation defines rat experimental autoimmune encephalomyelitis Å .
T153 163136-163149 Sentence denotes Andersson, R.
T154 163150-163161 Sentence denotes Kokkola, J.
T155 163162-163171 Sentence denotes Wefer, H.
T156 163172-163198 Sentence denotes Erlandsson-Harris and R.A.
T157 163199-163381 Sentence denotes Harris Karolinska Institutet, Stockholm, Sweden Aim: we compared analysis of the activation phenotypes of MQ derived from autoimmune-susceptible and autoimmune-resistant rat strains.
T158 163382-163609 Sentence denotes We included investigation of function of expressed receptors, intracellular signaling pathways, cytokines and other soluble mediators released after activation of cells using a panel of stimuli embracing many activation routes.
T159 163610-163618 Sentence denotes Methods:
T160 163619-163679 Sentence denotes Real-Time PCR, ELISA, Western blot and Immunohistochemistry.
T161 163680-163688 Sentence denotes Results:
T162 163689-163843 Sentence denotes The major differences recorded between DA, BN and PVG rat MQ following activation were in cytokine production and in the balance of NOS/arginase activity.
T163 163844-164035 Sentence denotes The resultant phenotype representing autoimmune-susceptible DA rat MQ is lower TNF, IL-6, IL-1beta, p35 and NO production with an associated high arginase activity and high expression of p19.
T164 164036-164210 Sentence denotes Conversely, autoimmune-resistant BN MQ had a phenotype with higher TNF, IL-6, IL-1beta, p35 and NO production with an associated low arginase activity and low p19 expression.
T165 164211-164222 Sentence denotes Conclusion:
T166 164223-164653 Sentence denotes Activation of MQ from the autoimmunesusceptible strain was associated with alternative macrophage activation indicated by induction of arginase activity, a lower production of classical proinflammatory mediators and a high expression of IL-23, while MQ from the autoimmune-resistant strains was associated with a higher production of proinflammatory mediators, a classical activation phenotype and preferential induction of IL-12.
T167 164654-164763 Sentence denotes These MQ phenotypes thus reflect disparate genetic cellular programmes that define autoimmune susceptibility.
T168 164764-164822 Sentence denotes The cytokine expression after peripheral nerve injury L.M.
T169 164823-164840 Sentence denotes Kylliäinen a , K.
T170 164841-164856 Sentence denotes Kimppa a,b , S.
T171 164857-164872 Sentence denotes Ruohonen a , M.
T172 164873-164889 Sentence denotes Tenhami a and M.
T173 164890-164978 Sentence denotes Rfytt7 a a University of Turku, Turku, Finland; b Åbo Akademi University, Turku, Finland
T174 164979-165135 Sentence denotes The aim of the study was to enhance the knowledge of the gene expression during the inflammatory response after peripheral nerve transection by microarrays.
T175 165136-165190 Sentence denotes The left sciatic nerve of male SD rats was transected.
T176 165191-165366 Sentence denotes The nerves were allowed to regenerate freely and the first distal section beside the point of injury were taken 12 h, 24 h, 3, 7, 14, 21, 35 and 49 days after the transection.
T177 165367-165424 Sentence denotes Control samples were collected from non-operated animals.
T178 165425-165507 Sentence denotes Samples from four rats were pooled in each time point and total RNA was extracted.
T179 165508-165593 Sentence denotes The samples were hybridized to Affymetrix Rat Genome U34 oligonucleotide microarrays.
T180 165594-165690 Sentence denotes Sample preparations and hybridizations were performed according to Affymetrix's recommendations.
T181 165691-165766 Sentence denotes Each sample was compared to control and Signal Log Ratio (SLR) was counted.
T182 165767-165895 Sentence denotes We decided that values SLRN1.5 or SLRbÀ1.5 are relevant and the expression can then be considered either increased or decreased.
T183 165896-166019 Sentence denotes Expression of many cytokines and cytokine-related genes were detected and the results correlated well to previous findings.
T184 166020-166129 Sentence denotes An interesting finding was the significant expression of IL-6 mRNA from 12 h up to 49 days after transection.
T185 166130-166274 Sentence denotes Also increased expression of inflammatory cytokines IL-1 beta, IL-1 alpha, IL-10 and TGF-beta was noted during the first days after transection.
T186 166275-166349 Sentence denotes Chemokines MIP-1 alpha, MIP-1 beta and MCP-1 were found to be upregulated.
T187 166350-166436 Sentence denotes Interleukin-23 in acute inflammatory demyelination of the peripheral nervous system W.
T188 166437-166446 Sentence denotes Hu, H.-P.
T189 166447-166461 Sentence denotes Hartung and B.
T190 166462-166645 Sentence denotes Kieseier Heinrich-Heine University, Düsseldorf, Germany Interleukin (IL)-23 is a newly identified heterodimeric cytokine comprising the p40 subunit of IL-12 and a private p19 subunit.
T191 166646-166782 Sentence denotes Mounting evidence suggests that IL-23 rather than IL-12 is critically involved in the pathogenesis of various immune-mediated disorders.
T192 166783-167073 Sentence denotes In the present study, we analyzed the sequential mRNA expression pattern of IL-23 in sciatic nerves from Lewis rats with myelin-induced experimental autoimmune neuritis (EAN), a classical animal model of the Guillain-Barré syndrome (GBS), using a semiquantitative reverse transcriptase-PCR.
T193 167074-167301 Sentence denotes IL-23 mRNA was found to be upregulated just prior to the onset of clinical symptoms at day 11 post-immunization (p.i.), with peak levels at day 13 p.i., just preceding maximum clinical disease severity, and declined thereafter.
T194 167302-167412 Sentence denotes In sural nerves from patients with GBS, IL-23 was found to be expressed, but not in non-inflammatory controls.
T195 167413-167517 Sentence denotes Macrophages were identified as the cellular source of IL-23 in the inflamed PNS by immunohistochemistry.
T196 167518-167820 Sentence denotes Thus, our present data suggest that IL-23, primarily expressed by macrophages, plays an important role during the early phase of EAN and therefore appears to be critically involved in the initiation rather than perpetuation of an immune response in immune-mediated inflammation of the peripheral nerve.
T197 167821-167900 Sentence denotes The expression of cytokines in silicone tube-treated peripheral nerve injury M.
T198 167901-167914 Sentence denotes Röytt7 a , S.
T199 167915-167932 Sentence denotes Ruohonen a , L.M.
T200 167933-167950 Sentence denotes Kylli7inen a , K.
T201 167951-167964 Sentence denotes Rfytt7 a , I.
T202 167965-167976 Sentence denotes Kivi b , M.
T203 167977-167994 Sentence denotes H7m7l7inen a , A.
T204 167995-168016 Sentence denotes Pertovaara a and H.S.
T205 168017-168223 Sentence denotes Taskinen a a University of Turku, Turku, Finland; b Leiras Medical Company, Turku, Finland In order to help axonal reinnervation when the loss of structural continuity occurs, silicone tubes have been used.
T206 168224-168358 Sentence denotes After peripheral nerve injury, an activation of different cytokines occurs to induce inflammation and/or to help axonal reinnervation.
T207 168359-168518 Sentence denotes We investigated the expression of cytokines as well as the morphological changes after implantation of silicone tube after removal of a piece of sciatic nerve.
T208 168519-168589 Sentence denotes The clinical improvement was studied by pinprick and toe-spread tests.
T209 168590-168699 Sentence denotes The samples from the tube, distal and proximal stumps were taken 1, 3, 5, 7, 14, and 42 days postoperatively.
T210 168700-168775 Sentence denotes The following cytokines were studied: IL-1h, TNF-a, IFN-g, IL-10 and TGF-h.
T211 168776-168833 Sentence denotes Neurofilament antibody was used for axonal reinnervation.
T212 168834-168906 Sentence denotes The sutures used to fix the silicone tube induced foreign body reaction.
T213 168907-169011 Sentence denotes There was a high initial expression of the studied cytokines but then the expression somewhat decreased.
T214 169012-169090 Sentence denotes The exception was IFN-g, which showed an increased expression up to five days.
T215 169091-169188 Sentence denotes After day three the expressions in the tube increased up to day 42, except IFN-g, which declined.
T216 169189-169371 Sentence denotes The contralateral, uninjured nerve showed some expression at early time points.The present study shows that the insertion of silicone tube induces changes in the cytokine expression.
T217 169372-169466 Sentence denotes This suggests that these are involved in the building up the missing part of peripheral nerve.
T218 169467-169477 Sentence denotes Objective:
T219 169478-169705 Sentence denotes To characterize the production of monocyte chemotactic protein (MCP)-1 and interleukin-1 receptor antagonist (IL-1ra) in the cerebrospinal fluid (CSF) of the patients with Guillain-Barré syndrome (GBS) and Fisher syndrome (FS).
T220 169706-169897 Sentence denotes Methods: CSF samples from GBS patients (n=8, M/F=3:5, mean age=61:50) and FS patients (n=8, M:F=4:4, mean age=39:38) were collected by lumbar puncture (LP) within 14 days after disease onset.
T221 169898-169939 Sentence denotes In some cases repeated LP were permitted.
T222 169940-170061 Sentence denotes CSF samples from eight patients with other non-inflammatory neurological disorders (OND: ALS=4, SCD=4) served as control.
T223 170062-170136 Sentence denotes Quantitative sandwich ELISA assay for IL-1ra and MCP-1 (R&D) was employed.
T224 170137-170300 Sentence denotes Results: CSF MCP-1 levels in both GBS and FS patients were significantly increased compared to OND, however, CSF IL-1ra levels significantly increased only in GBS.
T225 170301-170408 Sentence denotes Strong correlation between CSF MCP-1 and IL-1ra levels was found in FS (R 2 =0.78), not in GBS (R 2 =0.11).
T226 170409-170465 Sentence denotes Both MCP-1 and IL-1ra levels increased at clinical peak.
T227 170466-170534 Sentence denotes In GBS, MCP-1 levels decreased prior to IL-1ra during convalescence.
T228 170535-170600 Sentence denotes Conclusions: MCP-1 may play an important role in both GBS and FS.
T229 170601-170658 Sentence denotes Contrary the up-regulation of IL-1ra in FS was not clear.
T230 170659-170768 Sentence denotes This difference may reflect the diversity of PNS involvement area or different cytokine milieu in GBS and FS.
T231 170769-170860 Sentence denotes In GBS, IL-1ra may indicate recovery from disease although further investigation is needed.
T232 170861-170934 Sentence denotes Decreased synthesis of IL-10 during the acute phase of ischemic stroke G.
T233 170935-170953 Sentence denotes Gromadzka a,b , B.
T234 170954-170969 Sentence denotes Tarnacka a , I.
T235 170970-170996 Sentence denotes Sarzynska-Dlugosz a and A.
T236 170997-171106 Sentence denotes Czlonkowska a,b a Institute of Psychiatry and Neurology, Warsaw, Poland; b Medical University, Warsaw, Poland
T237 171107-171204 Sentence denotes During the acute phase of ischemic stroke (IS) local and systemic inflammatory reaction develops.
T238 171205-171272 Sentence denotes Inflammation leads to increased brain damage and worsen IS outcome.
T239 171273-171359 Sentence denotes Important mediators inhibiting inflammatory processes are anti-inflammatory cytokines.
T240 171360-171578 Sentence denotes The aim of study was to evaluate changes in mRNA expression in peripheral blood cells (PBC), and in serum concentration of anti-inflammatory cytokine: interleukin-10 (IL-10) during the acute phase (first 7 days) of IS.
T241 171579-171600 Sentence denotes Material and methods:
T242 171601-171672 Sentence denotes 108 patients with IS and 68 healthy control subjects were investigated.
T243 171673-171727 Sentence denotes Material for investigations was: EDTA-blood and serum.
T244 171728-171880 Sentence denotes IL-10 mRNA expression in PBC was investigated by semi'quantitative RT-PCR method; serum concentration of IL-10 was investigated by immunoenzymatic test.
T245 171881-171889 Sentence denotes Results:
T246 171890-171994 Sentence denotes Decreased IL-10 mRNA expression in PBC and serum concentration of IL-10 was noticed in patients with IS.
T247 171995-172288 Sentence denotes The lowest synthesis of IL-10 was noticed in patients above 70 years of age, with superficial infarction, with multiple lesions (above 2), and with large lesion area (above 1 lobe) as noticed in CT scan of the brain performed on admission, and also in patients who died during hospitalization.
T248 172289-172301 Sentence denotes Conclusions:
T249 172302-172408 Sentence denotes During the acute phase of ischemic stroke the synthesis of anti-inflammatory cytokine IL-10 is diminished.
T250 172409-172473 Sentence denotes Decreased synthesis of IL-10 is associated with worse prognosis.
T251 172474-172598 Sentence denotes Interleukin 18 is increased in sera of acute ischaemic stroke patients and correlates with the size of early brain damage J.
T252 172599-172614 Sentence denotes Losy a,b and J.
T253 172615-172942 Sentence denotes Zaremba a a University School of Medicine, Poznan, Poland; b Institute of Experimental and Clinical Medicine, Poznan, Poland Proinflammatory cytokines released during ischaemia by activated brain resident and peripheral blood cells are important mediators of inflammatory response,the process which exacerbates cerebral damage.
T254 172943-173109 Sentence denotes Interleukin 18(IL-18) is a proinflammatory cytokine able to induce gene expression and synthesis of other proinflammatory cytokines,chemokines and adhesion molecules.
T255 173110-173205 Sentence denotes Our hypothesis is that IL-18 participates in the inflammatory response during ischaemic stroke.
T256 173206-173496 Sentence denotes The objective of the study was to determine IL-18 levels in sera of 23 ischaemic stroke patients,compare results with the group of 15 controls and study the relation between IL-18 levels and the volume of hemispheric computer tomography hypodense areas representing early ischaemic changes.
T257 173497-173564 Sentence denotes Blood sampling and cranial CT were performed within 24 h of stroke.
T258 173565-173625 Sentence denotes Fifteen tension headache patients served as a control group.
T259 173626-173712 Sentence denotes IL-18 levels were significantly higher in stroke patients in comparison with controls.
T260 173713-173820 Sentence denotes Moreover IL-18 levels correlated positively with the volume of early CT hypodense areas (r=0.82; pb0.0001).
T261 173821-173907 Sentence denotes The results suggest involvement of IL-18 in early inflammatory response during stroke.
T262 173908-174034 Sentence denotes Insulin down regulates the overproduction of pro-inflammatory cytokines in peripheral immune cells in Alzheimer's disease S.B.
T263 174035-174046 Sentence denotes Solerte, D.
T264 174047-174058 Sentence denotes Taccani, E.
T265 174059-174072 Sentence denotes Locatelli, E.
T266 174073-174087 Sentence denotes Ferrari and M.
T267 174088-174313 Sentence denotes Fioravanti Department Internal Medicine and Geriatrics, University of Pavia, Pavia, Italy Neuroinflammation and immune dysregulation have been implicated in the neurodegenerative processess linked to Alzheimer's disease (AD).
T268 174314-174537 Sentence denotes The present study was undertaken to evaluate IL-1-beta and TNF-alpha production and seceretion in the supernatants of lymphomononuclear natural killer (NK) cells (7.75Â10 6 cells/ml) of 23 subjects with mild to moderate AD.
T269 174538-174757 Sentence denotes Cytokines were measured after incubation of NK cells with LPS (1 Ag/ml), beta-amyloid 1-42 fragment (A-beta 1-42; 5 and 10 Ag/ml), IL-2 (100 U/ml) and Insulin (1 and 10 AM/ml) co-incubated with LPS, Abeta 1-42 and IL-2.
T270 174758-174968 Sentence denotes A significant increase of spontaneous and modulated (by LPS, A-beta 1-42, IL-2) release of IL-1-beta and TNF-alpha by NK cells was demonstrated in AD subjects compared to 23 matched healthy subjects ( pb0.001).
T271 174969-175107 Sentence denotes The incubation of NK cells with insulin alone significantly reduces the spontaneous secretion of both cytokines in AD subjects ( pb0.001).
T272 175108-175272 Sentence denotes The co-incubation of insulin with A-beta 1-42 and IL-2 has determined a dose-dependent normalization of IL-1-beta and TNFalpha release from NK cells in AD subjects.
T273 175273-175414 Sentence denotes However, Insulin action was completely blocked during exposure with 10 AM of p-38 mitogen-activated protein kinase (MAPK) inhibitor SB203580.
T274 175415-175541 Sentence denotes The present study confirms that NK immune cells are up regulated for the secretion of inflammatory neurotoxic cytokines in AD.
T275 175542-175705 Sentence denotes The normalizing effects of insulin could depend on MAPK modulation, so involving the insulin intracellular signaling pathways in immune-mediated AD neuropathology.
T276 175706-175795 Sentence denotes The gender influence of the IL6 gene expression in a model of Parkinson's disease (PD) A.
T277 175796-175813 Sentence denotes Ciesielska a , I.
T278 175814-175827 Sentence denotes Joniec b , A.
T279 175828-175848 Sentence denotes Przybylkowski b , I.
T280 175849-175877 Sentence denotes Kurkowska-Jastrzebska a , G.
T281 175878-175894 Sentence denotes Gromadzka a , A.
T282 175895-175915 Sentence denotes Czlonkowska a and A.
T283 175916-176023 Sentence denotes Czlonkowski b a Institute of Psychiatry and Neurology, Warsaw, Poland; b Medical University, Warsaw, Poland
T284 176024-176064 Sentence denotes The incidence of PD changes with gender.
T285 176065-176151 Sentence denotes The higher prevalence of PD in men may suggest a link between estrogens levels and PD.
T286 176152-176207 Sentence denotes The inflammation is involved in etiopathogenesis of PD.
T287 176208-176314 Sentence denotes IL6 has been suggested to play a role in regulating neuronal survival in the injured nigrostriatal system.
T288 176315-176402 Sentence denotes Estrogens could modulate the immune reaction by regulating of this cytokine expression.
T289 176403-176479 Sentence denotes We examined the contribution of IL6 in the gender difference existing in PD.
T290 176480-176717 Sentence denotes The levels of IL6 mRNA (RT-PCR) and dopamine (DA) (HPLC) were assessed in the striatum of male and female C57BL/6 mice (12 months old) after 6 h; 1, 3, 7, 14, 21 days post 1-methyl-4-phenyl-1,2,3,6 tetrahydropiridine (MPTP) intoxication.
T291 176718-176859 Sentence denotes In male and female, the decrease in the level of DA was observed within 1-14 days following MPTP injection, achieving minimal level at 7 day.
T292 176860-176924 Sentence denotes The male showed significantly greater reductions in striatal DA.
T293 176925-177052 Sentence denotes MPTP caused an increase of IL6 mRNA in striatum of male and female, but the increase in IL6 was significantly higher in female.
T294 177053-177162 Sentence denotes In female and male, IL6 expression moderately increased at 1 day and peaked at 7 days post MPTP intoxication.
T295 177163-177255 Sentence denotes MPTP induced smaller neurotoxicity and greater IL6 gene expression in female than male mice.
T296 177256-177423 Sentence denotes It couldn't be excluded that, this sexually dimorphic in IL6 mRNA expression may be, in part, responsible for some protection against MPTP intoxication in female mice.
T297 177424-177484 Sentence denotes Multiple IL-6 anomalies in patients with major depression S.
T298 177485-177498 Sentence denotes Alesci a , P.
T299 177499-177514 Sentence denotes Martinez a , S.
T300 177515-177528 Sentence denotes Kelkar a , I.
T301 177529-177543 Sentence denotes Ilias a , A.R.
T302 177544-177556 Sentence denotes Ayala a , J.
T303 177557-177573 Sentence denotes Licinio b , G.P.
T304 177574-177593 Sentence denotes Chrousos a and P.W.
T305 177594-177844 Sentence denotes Gold a a National Institutes of Health, Bethesda, USA; b University of California, Los Angeles, USA In addition to affective, cognitive, and neuroendocrine abnormalities, depressed patients have increased risk of cardiovascular disease and bone loss.
T306 177845-177996 Sentence denotes Interleukin-6 (IL-6) is a major inducer of sickness behavior, a potent proinflammatory and prothrombotic agent, and an activator of osteoclastogenesis.
T307 177997-178128 Sentence denotes In healthy individuals, IL-6 secretion increases with age, correlates with adiposity, and shows a characteristic circadian pattern.
T308 178129-178368 Sentence denotes The purpose of this study was to compare the 24-h secretion of IL-6 in nine depressed patients and nine gender-, age-and BMI-matched controls, in an attempt to link changes of this cytokine with the manifestations of major depression (MD).
T309 178369-178409 Sentence denotes Diagnosis of MD was based on the DSM-IV.
T310 178410-178461 Sentence denotes Plasma IL-6 was measured by high-sensitivity ELISA.
T311 178462-178601 Sentence denotes The rhythmicity and complexity of IL-6 secretion were assessed by cosinor analyses and approximate entropy (ApEn) algorithms, respectively.
T312 178602-178848 Sentence denotes Compared to healthy subjects, depressed patients showed highly significant elevations in mean 24 h plasma IL-6 levels (4.7F0.3 vs. 3.4F0.09 pg/ml, meanFSEM, Pb0.001), with 2-to 3fold higher morning values, and a reversal of IL-6 circadian rhythm.
T313 178849-179014 Sentence denotes The physiologic complexity of IL-6 secretion was reduced in the depressed, as shown by their lower approximate entropy values (0.828F0.029 vs. 0.963F0.024, p=0.035).
T314 179015-179230 Sentence denotes We conclude that MD is associated with multiple IL-6 abnormalities, which may contribute to the neuropsychological impairment and comorbidity of this psychiatric illness with cardiovascular disease and osteoporosis.
T315 179231-179304 Sentence denotes Cytokines and chemokines in subacute sclerosing panencephalitis (SSPE) G.
T316 179305-179333 Sentence denotes Saruhan-Direskeneli a , S.P.
T317 179334-179347 Sentence denotes Yentur a , V.
T318 179348-179365 Sentence denotes Demirbilek b , G.
T319 179366-179379 Sentence denotes Yilmaz b , E.
T320 179380-179391 Sentence denotes Onal a , O.
T321 179392-179404 Sentence denotes Cokar c , Z.
T322 179405-179418 Sentence denotes Yapici a , G.
T323 179419-179437 Sentence denotes Akman-Demir a , A.
T324 179438-179455 Sentence denotes Gokyigit a and C.
T325 179456-179591 Sentence denotes Gurses a a Istanbul University, Istanbul, Turkey; b Cerrahpasa Medical Faculties, Istanbul, Turkey; c Haseki Hospital, Istanbul, Turkey
T326 179592-179979 Sentence denotes To assess the role of cytokines and chemokines in SSPE, cerebrospinal fluid (CSF) and serum samples from 60 SSPE patients, 38 patients with neurological infectious or inflammatory diseases (IN) and 27 patients with noninflammatory neurological diseases (NIN) were examined by ELISA for IFN-gamma, IL-10, IL-4 and IL-12 as well as for CXCL8 (IL-8), CXCL10 (IP-10) and CCL2 (MCP-1) levels.
T327 179980-180029 Sentence denotes An increased IL-12 response was detected in SSPE:
T328 180030-180212 Sentence denotes Both median IL-12 CSF and serum levels (19.6 and 128.4 pg/ml) were higher in SSPE than in IN (6.5 and 68.5 pg/ml, pb0.001) and in NIN (1.8 and 70.3 pg/ml, pb0.001 and p=0.05) groups.
T329 180213-180367 Sentence denotes IL-10 CSF levels were also higher in SSPE than in NIN group (2.6 vs. 0.1 pg/ml, pb0.001), whereas IL-4 and IFN-gamma levels did not differ between groups.
T330 180368-180458 Sentence denotes CXCL10 level was increased in CSF of SSPE compared to NIN (332.2 vs. 16.2 pg/ml, pb0.001).
T331 180459-180611 Sentence denotes However, higher CXCL8 was detected in the serum of SSPE (11.5 pg/ml) compared to IN and NIN groups (3.1 and 2.2 pg/ml, p=0.03 and p=0.01, respectively).
T332 180612-180818 Sentence denotes The increased systemic and intrathecal IL-12 secretion without accompanying IFN-gamma induction may implicate an initial immune activation without an effective cellular response in the pathogenesis of SSPE.
T333 180819-180986 Sentence denotes Selective intrathecal increase of CXCL10 points to the differential attraction of inflammatory cells to nervous system accompanied by local regulatory effects of IL10.
T334 180987-181059 Sentence denotes This study is supported by the Istanbul University Research Fund (1530).
T335 181060-181171 Sentence denotes Numerous soluble mediators have been implicated but not yet convincingly documented in multiple sclerosis (MS).
T336 181172-181264 Sentence denotes Subjects from Sardinia are relatively homogeneous and ethnically distant compared to Swedes.
T337 181265-181307 Sentence denotes Both populations have a high MS incidence.
T338 181308-181566 Sentence denotes We studied cytokine expression patterns in mononuclear cells (MNC) of female untreated MS patients from Sassari, Sardinia, and Stockholm, Sweden, compared to sex-and age-matched healthy controls from both areas. mRNA expression was measured by real-time PCR.
T339 181567-181675 Sentence denotes Among 20 molecules examined, only IL-12p40 was significantly increased ( pb0.05) in MS compared to controls.
T340 181676-181799 Sentence denotes Higher expression of IL-12p40 mRNA was confined to MS from both Sardinia and Stockholm, compared to corresponding controls.
T341 181800-181903 Sentence denotes MS patients from Sardinia also expressed higher ( pb0.05) TNF-alpha compared to corresponding controls.
T342 181904-181984 Sentence denotes No difference for TNF-alpha was observed between MS vs. controls from Stockholm.
T343 181985-182132 Sentence denotes IL-6 was remarkably higher in MS compared to controls ( pb0.001) from Stockholm, and compared to MS ( pb0.05) and controls ( pb0.01) from Sardinia.
T344 182133-182384 Sentence denotes No differences were observed for other members of the IL-12 family (IL-12p35, IL-12Rbeta1 and 2, IL-23p19, IL-23R, IL-27p28); IFN-gamma and IFN-gammaR; IL-4; IL-6R; IL-10 and IL-10R1; IL-18 and IL-18R1; TGF-beta1; the signalling molecules STAT4 and 6.
T345 182385-182594 Sentence denotes The results corroborate a pro-inflammatory state in MS in general as reflected by high expression of IL-12, i.e., an inducer of pro-inflammatory cytokines, and of the inflammatory cytokines TNF-alpha and IL-6.
T346 182595-182759 Sentence denotes The extent of expression of TNF-alpha and IL-6 differs between MS patients from different areas, probably reflecting influence of genetic and environmental factors.
T347 182760-182991 Sentence denotes The object of the study was to identify changes in complement factor C3 concentrations and the degree of C3 activation in serum and cerebrospinal fluid (CSF) in early multiple sclerosis (MS), i.e., at time for diagnosis of disease.
T348 182992-183074 Sentence denotes The MS-patient group was compared to a control group with no neurological disease.
T349 183075-183400 Sentence denotes The method for determination of the protein concentration of albumin was immunoturbidimetric assay, for total C3 in serum was radial immunodiffusion used, for C3 in CSF was ELISA performed with polyclonal antibodies, and finally for activated C3 in serum and CSF were ELISA performed by use of a specific monoclonal antibody.
T350 183401-183536 Sentence denotes A significant increase of the mean value of activated C3 concentration in CSF of MS patients to that of the control group was observed.
T351 183537-183661 Sentence denotes The significant increase for MS patients was still valid upon determination of the fraction of activated to total C3 in CSF.
T352 183662-183851 Sentence denotes The activated C3 level in serum was not significantly different from that of the control group, and no significant change in concentration of total C3 was obtained in neither CSF nor serum.
T353 183852-183995 Sentence denotes The conclusion is that the complement system is activated in the CSF of a group of multiple sclerosis patients at the early stage of diagnosis.
T354 183996-184229 Sentence denotes The aim of our study was to evaluate whether high dose of methylprednisolone (1000 mg) given for five consecutive days during the disease exacerbations have any impact on immune parameters detected in peripheral blood of MS patients.
T355 184230-184552 Sentence denotes The following cells phenotypes were determined using two-colour flow cytometry before steroids and after 7 days from starting therapy: CD3+CD19-(T cells),CD3-CD19+ (B cells), CD3+CD4+ (T h cells), CD3+CD8+ (Ts/c cells), CD3-CD56+16+ (NK cells) and T cells, B cells, monocytes, granulocytes producing IL-6 and IL-8 as well.
T356 184553-184629 Sentence denotes We have studied 20 patients (12 women and 8 men) in mean age of 34.75F10.27.
T357 184630-184730 Sentence denotes Improvement of disability was found: before therapy mean EDSS was 4.1F1.48, after therapy 2.97F1.34.
T358 184731-184826 Sentence denotes Significant increase of B cells, decrease of T cells and NK cells was observed after treatment.
T359 184827-184939 Sentence denotes Trend to decrease of T cells secreting IL-8 and significant decrease of monocytes secreting IL-8 was also noted.
T360 184940-185099 Sentence denotes It is known that IL-8 might be one of the cytokines responsible for blood-brain barrier disruption and migration of immune cells to the central nervous system.
T361 185100-185198 Sentence denotes In post mortem studies of MS, patients' brains increased expresion of IL-8 receptors was detected.
T362 185199-185300 Sentence denotes In this aspect, our results might be important for explaining GS effects during the MS exacerbations.
T363 185301-185432 Sentence denotes Upregulation of STATs and interferon-stimulated genes in simian immunodeficiency virus encephalitis via IL6 and interferon-gamma E.
T364 185433-185444 Sentence denotes Roberts, M.
T365 185445-185459 Sentence denotes Zandonatti, C.
T366 185460-185469 Sentence denotes Flynn, K.
T367 185470-185484 Sentence denotes Roinick and H.
T368 185485-185538 Sentence denotes Fox The Scripps Research Institute, La Jolla, CA, USA
T369 185539-185749 Sentence denotes We previously reported upregulation of STATs 1 and 3, along with interferon (IFN)-stimulated genes (ISGs) and NF-IL6, in frontal lobes of simian immunodeficiency virus-infected monkeys with encephalitis (SIVE).
T370 185750-185871 Sentence denotes Immunohistochemistry (IHC) revealed STAT1 in astrocytes, endothelial cells, some microglia/macrophages and large neurons.
T371 185872-186045 Sentence denotes STAT1/ISG upregulation may confer anti-viral and anti-apoptotic properties in astrocytes and microglia, however, STAT1 increase in neurons is linked to dendritic retraction.
T372 186046-186202 Sentence denotes As these factors may impact on the neuropathology of human (H)IVE and HIV-associated dementia, we examined the pathways involved in STAT and ISG expression.
T373 186203-186306 Sentence denotes Using frontal lobe tissue, we found increases in IFN-gamma and IL6 mRNA, but not in IFN-alpha or -beta.
T374 186307-186527 Sentence denotes Interestingly mRNA of STAT1 and ISGs was also upregulated in acutely infected (2 weeks post inoculation) monkeys, however, IHC only showed STAT1 in perivascular cells, endothelium and a very limited number of astrocytes.
T375 186528-186606 Sentence denotes Although IL6 was upregulated in the CNS in acute infection, the IFNs were not.
T376 186607-186811 Sentence denotes These results suggests that IL6 alone is not able to induce STAT/ISGs in astrocytes and neurons, thus increases in STAT/ISG expression in encephalitis could be due to the action of both IFN-gamma and IL6.
T377 186812-187002 Sentence denotes Interestingly, many of the ISGs found in the SIVE cases have previously been described as only being upregulated by increases in IFN-alpha/beta, which may not be the scenario in these cases.
T378 187003-187161 Sentence denotes Pivotal role of IL-12 and IFN-gamma axis in controlling tissue parasitism and inflammation in the central nervous system during Trypanosoma cruzi infection J.
T379 187162-187182 Sentence denotes Lannes-Vieira a , V.
T380 187183-187206 Sentence denotes Michailowsky a,b and R.
T381 187207-187388 Sentence denotes Gazzinelli a,b a Department of Immunology-IOC, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; b Laboratory of Immunopatology, CPqR, Oswaldo Cruz Foundation, Belo Horizonte, Brazil
T382 187389-187584 Sentence denotes Cytokines are proposed to play a pivotal role controlling tissue parasitism and pathogenesis of experimental Chagas' disease, an infection caused by the intracellular protozoan Trypanosoma cruzi.
T383 187585-187756 Sentence denotes Symptomatic meningoencephalitis rarely occurs, being more frequently found in children before 2 years of age and in immunosuppressed transplanted or HIV-infected patients.
T384 187757-188017 Sentence denotes Central nervous system (CNS) alterations as enlargement of perivascular spaces and inflammatory infiltrates are observed during the acute infection of C3H/He mice with T. cruzi, while C57BL/6 mice are less susceptible (Silva et al., 1999; Roffê et al., 2003) .
T385 188018-188154 Sentence denotes Herein, we investigated the role of the Th1 cytokines IL-12 and IFN-gamma in the establishment of T. cruzi-elicited meningoencephalitis.
T386 188155-188397 Sentence denotes IL-12 and IFNgamma knockout (KO) mice in C57BL/6 background were highly susceptible to T. cruzi-induced meningoencephalitis as characterized by increased numbers of parasite nests, inflammatory infiltrates, neurological signals and mortality.
T387 188398-188531 Sentence denotes Interestingly, the inflammatory infiltrates detected in the CNS of T. cruzi-infected IL-12KO mice were mostly devoid of CD8+ T cells.
T388 188532-188775 Sentence denotes Further, when infected animals were treated with suboptimal doses of Benznidazole (an anti-parasitic drug), the CNS and the heart were the main sites of reactivation of parasitism and inflammation in IL-12KO and IFN-gammaKO mice, respectively.
T389 188776-188943 Sentence denotes Thus, our results suggest that the level of IFN-gamma deficiency is the major determinant of the site of reactivation of T. cruzi infection in immunocompromised hosts.
T390 188944-189009 Sentence denotes Human adult microglia express functional Toll-like receptors C.S.
T391 189010-189020 Sentence denotes Jack, V.C.
T392 189021-189034 Sentence denotes Montgrain, N.
T393 189035-189050 Sentence denotes Arbour and J.P.
T394 189051-189261 Sentence denotes Antel Montreal Neurological Institute, McGill University, Montreal, Canada Classical Toll-like receptor (TLR) signaling activates antigen presenting cells (APCs) and induces pro-inflammatory cytokine secretion.
T395 189262-189390 Sentence denotes An alternate pathway induced by TLR3 and TLR4 ligands leads to the production of interferon (IFN)-beta, a current therapy in MS.
T396 189391-189645 Sentence denotes The aims of our study were to assess the expression of TLRs on adult human microglia, the resident APCs of the CNS, and to determine whether signaling through TLR3 and TLR4 can stimulate production of IFN-beta and interferon-inducible protein 10 (IP-10).
T397 189646-189760 Sentence denotes TLR expression in microglia isolated from surgical specimens was assessed by RT-and QRT-PCR and by flow cytometry.
T398 189761-189851 Sentence denotes Functional signaling was assayed by ELISA (IP-10 and cytokines) and by QRT-PCR (IFN-beta).
T399 189852-189996 Sentence denotes In microglia maintained under basal culture conditions, TLR4 mRNA is consistently detected, while its surface expression is low to undetectable.
T400 189997-190135 Sentence denotes In contrast, although there is marked variation amongst individuals, TLR3 and TLR2 protein is more strongly expressed at the cell surface.
T401 190136-190321 Sentence denotes In vitro ligation of TLR3 and TLR4 by their respective ligands, double stranded (ds)RNA and LPS, consistently induces the expression of IFN-beta and the secretion of IP-10 in microglia.
T402 190322-190431 Sentence denotes Notably, ligation of TLR3 results in a significantly stronger IFN-beta and IP-10 response than TLR4 ligation.
T403 190432-190504 Sentence denotes Signaling via the above TLRs also induces TNF-alpha, IL-1beta, and IL-6.
T404 190505-190622 Sentence denotes Local production of IFN-beta within the CNS may modulate the complex pro-inflammatory responses characteristic of MS.
T405 190623-190686 Sentence denotes Microglia are resident semi-professional phagocytes of the CNS.
T406 190687-190816 Sentence denotes Microglial activation is common to many neurological conditions including virus infection, prion disease and Alzheimer's disease.
T407 190817-190993 Sentence denotes The innate immune system recognises conserved molecular patterns on microorganisms by a set of pattern recognition receptors of which the Toll-like Receptors (TLR) are members.
T408 190994-191118 Sentence denotes A multitude of TLRs have now been cloned, though their exact functions and tissue distributions are yet to be characterised.
T409 191119-191181 Sentence denotes Microglia have been shown to express a few of these receptors.
T410 191182-191411 Sentence denotes To investigate the expression profile of TLRs on microglia and other CNS cell types during viral encephalitis, groups of Balb/c, nu/nu and IFNalpha/betaRÀ/À mice were infected with SFV and tissues sampled at multiple time points.
T411 191412-191534 Sentence denotes Gene expression analysis was undertaken using quantitative RT-PCR and tissue sections were studied by immunocytochemistry.
T412 191535-191615 Sentence denotes In the resting mouse brain, there was extensive expression of TLRs in microglia.
T413 191616-191780 Sentence denotes Levels of TLRs were differentially modulated during SFV infection and in nu/nu mice demonstrated a positive correlation to levels of viral and IFNalpha transcripts.
T414 191781-191927 Sentence denotes Stimulation of cultured microglia with lipopolysaccharide resulted in a different pattern of TLR expression to that observed with virus infection.
T415 191928-192040 Sentence denotes Potential dual role of astrocytes in innate and autoimmune CNS responses induced by Theiler's virus infection P.
T416 192041-192058 Sentence denotes Carpentier and S.
T417 192059-192350 Sentence denotes Miller Northwestern University Feinberg School of Medicine, Chicago, IL, USA Theiler's murine encephalomyelitis virus (TMEV) establishes a persistent central nervous system (CNS) infection in glial cells of susceptible mice, leading to the development of an autoimmune demyelinating disease.
T418 192351-192593 Sentence denotes Because of its autoimmune nature and the prominent infiltration of CD4+ T cells and phagocytes into the central nervous system, TMEV-induced demyelinating disease (TMEV-IDD) is considered a highly relevant animal model for multiple sclerosis.
T419 192594-192824 Sentence denotes We have previously shown that innate immune stimulation of astrocytes with Toll-like receptor ligands results in the production of innate immune effector molecules, but not the induction of antigen presenting cell (APC) functions.
T420 192825-192973 Sentence denotes Here, we have infected astrocytes with TMEV and induce the expression of proinflammatory cytokines, chemokines, adhesion molecules, and type I IFNs.
T421 192974-193125 Sentence denotes The mechanisms by which astrocytes recognize viral infection is being investigated and preliminary data indicates it is dependent on replicating virus.
T422 193126-193247 Sentence denotes Later in the course of TMEV-IDD, CD4+ T cells and macrophages/microglia produce large amounts of IFN-gamma and TNF-alpha.
T423 193248-193337 Sentence denotes In contrast to viral infection, these cytokines do stimulate APC functions of astrocytes.
T424 193338-193612 Sentence denotes We therefore propose a model in which astrocytes are important for early CNS inflammation and recruitment of the peripheral immune cells to the CNS during TMEV infection, but are only capable of contributing to CD4+ T cell activation late in the autoimmune phase of disease.
T425 193613-193705 Sentence denotes Acute CNS infection by the neurotropic coronavirus JHMV is controlled by CD8+ T lymphocytes.
T426 193706-193807 Sentence denotes However, virus persistence in glia is associated with sustained inflammation and ongoing myelin loss.
T427 193808-193927 Sentence denotes During acute infection perforin mediated cytolysis controls virus replication in macrophages, microglia and astrocytes.
T428 193928-194070 Sentence denotes By contrast, infection of IFN-gamma deficient mice suggested that IFN-gamma but not perforin controlled virus replication in oligodendrocytes.
T429 194071-194327 Sentence denotes To specifically implicate an antiviral role of IFN-gamma-mediated signaling in oligodendrocytes, novel transgenic mice expressing a dominant negative IFN-gamma receptor 1 chain (dnIFN-gammaR1) under control of the proteolipid protein promoter were derived.
T430 194328-194496 Sentence denotes Expression of the transgene was readily detectable by elevated levels of the R1 chain on the surface of oligodendroglia from transgenic compared to wild type (wt) mice.
T431 194497-194570 Sentence denotes Increased R1 expression was associated with enhanced R2 chain expression.
T432 194571-194617 Sentence denotes Peripheral immune responses were not affected.
T433 194618-194719 Sentence denotes Following CNS infection, clinical scores, inflammation and demyelination were similar in both groups.
T434 194720-194843 Sentence denotes However, virus was still recovered from the CNS of transgenic mice at day 21, while wt mice controlled infection by day 14.
T435 194844-194944 Sentence denotes Histological analysis revealed an inability to clear virus from oligodendrocytes in transgenic mice.
T436 194945-195153 Sentence denotes These finding indicate that IFNgamma mediated anti-viral mechanisms are dependent on signaling in oligodendrocytes, but that demyelination is not dependent upon viral persistence in oligodendrocyte infection.
T437 195154-195288 Sentence denotes Interferon-gamma is not necessary for Borna disease virus-induced immunopathology but required for antiviral defence by CD8 T cells J.
T438 195289-195306 Sentence denotes Hausmann a , K.R.
T439 195307-195324 Sentence denotes Engelhardt a , K.
T440 195325-195338 Sentence denotes Baur a , H.J.
T441 195339-195353 Sentence denotes Rziha b and P.
T442 195354-195484 Sentence denotes Staeheli a a University of Freiburg, Freiburg, Germany; b Federal Research Centre for Virus Diseases of Animals, Tübingen, Germany
T1 195485-195644 Sentence denotes Mouse-adapted variants of the highly neurotropic, non-cytolytic Borna disease virus (BDV) cause meningoencephalitis and fatal neurological disease in MRL mice.
T2 195645-195752 Sentence denotes Disease is mediated by CD8 T cells recognizing the immunodominant epitope TELEISSI in the N protein of BDV.
T3 195753-195899 Sentence denotes N-specific immune priming of wild-type mice by a prime-boost protocol conferred CD8 T cell-dependent protection against BDV infection and disease.
T4 195900-196075 Sentence denotes Interestingly, immune priming efficiently protected perforin-deficient mice against infection with BDV, whereas no protection was seen in interferongamma-deficient (GKO) mice.
T5 196076-196187 Sentence denotes Moreover, adult GKO mice were highly susceptible to BDV infection, whereas adult wild-type mice were resistant.
T6 196188-196340 Sentence denotes Kinetic analysis of adult mice showed that BDV was able to establish an initial infection, which was subsequently cleared in wild-type but not GKO mice.
T7 196341-196592 Sentence denotes We further observed that more than 70% of brains from infected GKO but not from wild-type mice showed T cell-dependent severe neuronal damage in the hippocampus, suggesting a neuroprotective role of interferon gamma in BDV-induced meningoencephalitis.
T8 196593-196794 Sentence denotes In conclusion, BDV-specific CD8 T cells require interferon-gamma for mediating antiviral defence but not for inducing neurological disease, suggesting that two distinct effector mechanisms are at work.
T9 196795-196906 Sentence denotes Moreover, interferon gamma appears to be neuroprotective in BDV-induced central nervous system immunopathology.
T10 196907-197062 Sentence denotes Tumor necrosis factor-alpha and interleukin-1 are required for host defense in a mouse model of Staphylococcus aureus-induced experimental brain abscess T.
T11 197063-197076 Sentence denotes Kielian, E.D.
T12 197077-197090 Sentence denotes Bearden, A.C.
T13 197091-197102 Sentence denotes Baldwin, N.
T14 197103-197284 Sentence denotes Esen University of Arkansas for Medical Sciences, Little Rock, AR, USA Brain abscesses represent a significant medical problem despite recent advances made in detection and therapy.
T15 197285-197538 Sentence denotes Using the Staphylococcus aureus-induced brain abscess model established in our laboratory, we have sought to define the functional importance of IL-1, TNF-alpha, and IL-6 in the host anti-bacterial immune response using cytokine gene knockout (KO) mice.
T16 197539-197832 Sentence denotes The results demonstrate that although they share many redundant activities, IL-1 and TNF-alpha are important for containing bacterial infection in evolving brain abscesses as evident by increased mortality and bacterial burdens in IL-1 and TNF-alpha KO mice compared to wild type (WT) animals.
T17 197833-197934 Sentence denotes In contrast, IL-6 was not found to be a major contributor to the host anti-bacterial immune response.
T18 197935-198135 Sentence denotes Microarray analysis was used to evaluate the downstream consequences originating from the lack of IL-1 on subsequent proinflammatory mediator expression in brain abscesses from IL-1 KO and WT animals.
T19 198136-198406 Sentence denotes Although numerous genes were significantly induced following S. aureus infection, only IL-1 beta and two chemokines, CCL9 (macrophage inflammatory protein-1 gamma) and CXCL13 (B lymphocyte chemoattractant/BLC), were differentially regulated in IL-1 KO versus WT animals.
T20 198407-198593 Sentence denotes These results indicate that IL-1 and TNF-alpha play a pivotal role during the acute stage of brain abscess development through regulating the ensuing antibacterial inflammatory response.
T21 198594-198751 Sentence denotes The intermediate filament GFAP is important for the control of experimental murine Staphylococcus aureus-induced brain abscess and Toxoplasma encephalitis W.
T22 198752-198766 Sentence denotes Stenzel a , M.
T23 198767-198781 Sentence denotes Deckert a , S.
T24 198782-198797 Sentence denotes Soltek b and D.
T25 198798-199072 Sentence denotes Schlqter b a University of Cologne, Cologne, Germany; b University of Heidelberg, Heidelberg, Germany CNS infections can be controlled effectively by cells of the immune system, but organ specific cells such as astrocytes play an important part in the host response as well.
T26 199073-199269 Sentence denotes The functional role of astrocytes exerted via their intermediate protein glial fibrillary acidic protein (GFAP) in CNS infections was studied in murine Staphylococcus aureus-induced brain abscess.
T27 199270-199578 Sentence denotes Compared to wild type (WT) mice, GFAP0/0 mice developed larger and poorly demarcated inflammatory lesions, paralleled by a significantly increased intracerebral bacterial load, a diffuse leukocytic infiltration even of the contralateral hemisphere, purulent ventriculitis, vasculitis, and severe brain edema.
T28 199579-199764 Sentence denotes These observations were correlated with the lack of a bordering function of activated astrocytes, which strongly upregulated their GFAP expression in the abscess surrounding of WT mice.
T29 199765-199942 Sentence denotes Clinically important, this lack of restriction of inflammation markedly aggravated the course of disease with manifestation of seizures and a severe weight loss in GFAP0/0 mice.
T30 199943-200190 Sentence denotes These data were paralleled by observations in the model of Toxoplasma encephalitis (TE), during which the intracerebral parasitic load was significantly increased with tachyzoite-induced tissue necrosis in the brains of GFAP0/0 mice in chronic TE.
T31 200191-200414 Sentence denotes Collectively, these findings delineate a host defense function of astrocytes via restricting pathogenic spread and multiplication within the CNS, thereby contributing to protection of the highly vulnerable brain parenchyma.
T32 200415-200551 Sentence denotes Neurotropic coronavirus infection of mice results in acute demyelinating encephalomyelitis followed by non-productive viral persistence.
T33 200552-200700 Sentence denotes Acute replication is resolved by CD8 T cells within 2 weeks post infection (p.i.), whereas viral persistence is controlled by neutralizing antibody.
T34 200701-200778 Sentence denotes The kinetics of CNS B cell recruitment and differentiation were investigated.
T35 200779-201015 Sentence denotes Virus specific antibody secreting cells (ASC) within the CNS increased prominently between 15 and 21 days p.i. and were maintained at high frequencies during persistence; by contrast, only low frequencies were detectable in bone marrow.
T36 201016-201137 Sentence denotes Alterations in antibody specificities within CNS ASC during persistence provided evidence for ongoing dynamic regulation.
T37 201138-201291 Sentence denotes Whereas spike and nucleocapsid protein specific ASC accounted for most virus specific ASC between days 10 to 14 p.i., they gradually declined thereafter.
T38 201292-201370 Sentence denotes Furthermore, many ASC of unknown specificity were associated with persistence.
T39 201371-201502 Sentence denotes Flow cytometric analysis of infiltrates isolated from the infected CNS indicated a gradual increase in CD19+ B cells by day 15 p.i.
T40 201503-201621 Sentence denotes Delayed plasmablast recruitment was reflected by emergence of syndecan positive cells only between days 10 and 14 p.i.
T41 201622-201802 Sentence denotes While the relative percentage of syndecan positive cells remained constant after day 21, ongoing differentiation was suggested by an increasing loss of class II surface expression.
T42 201803-201936 Sentence denotes Thus, both altered specificities and phenotypes support a dynamic process within the B cell compartment during CNS viral persistence.
T43 201937-202016 Sentence denotes This contrasts the apparent senescence of T cell reactivity during persistence.
T44 202017-202115 Sentence denotes COX-2 inhibition increases CNS immune activation and SIV replication during acute SIV infection J.
T45 202116-202129 Sentence denotes Mankowski, S.
T46 202130-202139 Sentence denotes Queen, P.
T47 202140-202154 Sentence denotes Tarwater, R.J.
T48 202155-202166 Sentence denotes Adams, M.C.
T49 202167-202180 Sentence denotes Zink and J.E.
T50 202181-202421 Sentence denotes Clements Johns Hopkins University, Baltimore, MD, USA During acute infection, productive viral replication is present in the brain of SIV (simian immunodeficiency virus)-infected macaques although encephalitis does not develop at this time.
T51 202422-202604 Sentence denotes Early viral replication in the brain is accompanied by CNS immune activation including endothelial cell ICAM-1 expression and elevated microglial expression of CD68 and MHC class II.
T52 202605-202797 Sentence denotes Upregulation of COX (cyclooxygenase)-2 expression and subsequent production of arachadonic metabolites in the brain may be a key pathway regulating CNS immune responses during acute infection.
T53 202798-203068 Sentence denotes To determine whether COX-2 inhibition during acute SIV infection alters CNS immune activation, thereby modulating viral replication in the CNS, six pig-tailed macaques were treated with rofecoxib, a selective COX-2 inhibitor, during the initial 10 days of SIV infection.
T54 203069-203187 Sentence denotes CNS immune activation and CNS viral burden were measured and compared with a group of SIV-infected, untreated animals.
T55 203188-203564 Sentence denotes Both endothelial ICAM-1 expression and parenchymal microglial activation (measured by image analysis of immunostained tissue sections) were elevated in rofecoxib-treated, SIV-infected animals at 10 days post-inoculation as compared to untreated, infected animals, demonstrating that arachadonic acid metabolites such as prostaglandin E2 may down-regulate CNS immune responses.
T56 203565-203781 Sentence denotes In parallel with increases in CNS immune activation, CNS viral replication measured by real time RT-PCR was significantly elevated in the basal ganglia of rofecoxib-treated animals versus untreated, infected animals.
T57 203782-203905 Sentence denotes These findings demonstrate the complexity of immunomodulation in the CNS with COX-2 pathway products playing diverse roles.
T58 203906-203995 Sentence denotes Psychological stress has profound effects on the pathogenesis of multiple sclerosis (MS).
T59 203996-204089 Sentence denotes These effects are mediated by interactions between the endocrine, immune and nervous systems.
T60 204090-204299 Sentence denotes Our laboratory has been investigating the impact of stress on the susceptibility to Theiler's virusinduced demyelination (TVID) (a mouse model of multiple sclerosis) in genetically susceptible strains of mice.
T61 204300-204504 Sentence denotes In TVID, restraint stress activates the hypothalamic pituitary-adrenal axis and the autonomic nervous system, which results in immunosuppression mainly through the increased production of glucocorticoids.
T62 204505-204634 Sentence denotes Stressed mice have decreased NK cell activity and decreased chemokine expression (Ltn, IP-10 and RANTES) in the brain and spleen.
T63 204635-204777 Sentence denotes Reduced chemokine expression may account for the decreased inflammation in the CNS resulting in increased viral replication and dissemination.
T64 204778-204920 Sentence denotes The higher viral load subsequently leads to an earlier disease onset and more severe clinical and histological signs of demyelinating disease.
T65 204921-205226 Sentence denotes Our results have important implications for understanding the pathogenesis of MS and suggest that stressful events during early infection with an agent capable of inducing demyelination, may result in immunosuppression and failure to eliminate the pathogen which in turn may lead to the development of MS.
T66 205227-205341 Sentence denotes Funded by grants to C.J.R.W. and M.W.M. from National Multiple Sclerosis Society RG 3128 and NIH/ NINDS R01 39569.
T67 205342-205384 Sentence denotes Microglial dynamics in WNV encephalitis D.
T68 205385-205394 Sentence denotes Getts, I.
T69 205395-205415 Sentence denotes Matsumoto and N.J.C.
T70 205416-205583 Sentence denotes King University of Sydney, Sydney, Australia Fatal cases of West Nile Virus (WNV) encephalitis show microglial activation, nodule formation and leukocyte infiltration.
T71 205584-205812 Sentence denotes Because of the pivotal importance of Interferon-gamma (IFN-gamma) in both microglial activation and virus eradication, we investigated the role of IFN-gamma in microglial responses and leukocyte infiltration in WNV encephalitis.
T72 205813-205916 Sentence denotes Eight-week-old C57BL/6 (WT) and IFN-gamma knockout (IFNGKO) mice were inoculated intranasally with WNV.
T73 205917-206043 Sentence denotes Flow cytometric and immunohistochemical analysis was performed to characterise infiltrating and constitutive cell populations.
T74 206044-206154 Sentence denotes Microglial activation was clear in both strains from day 3, concurrent with detectable neuronal WNV infection.
T75 206155-206259 Sentence denotes Nodule formation, around infected neurones was evident by day 5, concurrent with leukocyte infiltration.
T76 206260-206374 Sentence denotes Nodules were significantly greater in the WT ( Pb0.01) after day 5, correlating with increased macrophage numbers.
T77 206375-206464 Sentence denotes Regions of high nodule formation did not correlate with those of high neuronal infection.
T78 206465-206596 Sentence denotes Nodule formation in both strains was maximal on day 6, with a reduction on day 7, when maximal viral and leukocyte loads were seen.
T79 206597-206775 Sentence denotes Numbers of MHC-II+ microglia remained similar in the WT, but significantly reduced in IFNGKO by day 7, compared to MHC-II+ macrophages, which increased 4-fold in the WT by day 7.
T80 206776-206875 Sentence denotes Microglial activation is IFN-gamma independent, possibly induced by signals from infected neurones.
T81 206876-207040 Sentence denotes In contrast, microglial nodule formation, correlating temporally and numerically with differential leukocyte infiltration in both strains, is enhanced by IFN-gamma.
T82 207041-207167 Sentence denotes Differential MHC-II+ cell numbers in each strain, correlating with the presence of IFN-gamma may have functional implications.
T83 207168-207197 Sentence denotes West Nile virus encephalitis:
T84 207198-207244 Sentence denotes T cell function in IFN-gamma-deficient mice S.
T85 207245-207256 Sentence denotes Rana and N.
T86 207257-207362 Sentence denotes King University of Sydney, Sydney, Australia West Nile virus (WNV) is an emerging neurotropic flavivirus.
T87 207363-207523 Sentence denotes In a murine model of WNV encephalitis, C57BL/6 wildtypes (WT) administered a sublethal dose (10^5 pfu intraperitoneal) of WNV (Sarafend) showed a 60% mortality.
T88 207524-207597 Sentence denotes However, only 20% mortality was observed in IFN-gamma knockout mice (KO).
T89 207598-207870 Sentence denotes Since IFN-gamma is an important antiviral cytokine that can modulate lymphocyte function and activation, we examined the brains, spleens and CNS-draining cervical lymph nodes (CLN) of infected mice, examining chemokine mRNA, cellular populations and effector CTL activity.
T90 207871-208023 Sentence denotes A differential upregulation of chemokine (IP-10, RANTES, MIP-1, MCP-1) mRNA was found, with surprisingly greater expression in KO compared to WT brains.
T91 208024-208189 Sentence denotes Infiltration of inflammatory leukocytes was evident from day 5 post-infection (p.i.), and was still maintained at day 30 p.i., beyond the period of detectable virus.
T92 208190-208238 Sentence denotes No difference was found between the two strains.
T93 208239-208468 Sentence denotes However, by using a sensitive fluorolysis CTL assay, we found that at day 8 p.i., the peak of CNS infection, deep CLN and CNS derived-leukocytes from KO mice have a reduced capacity to specifically lyse WNV-infected target cells.
T94 208469-208683 Sentence denotes The finding that WT and KO splenocytes are equally able to lyse targets throughout the course of infection, suggests that fewer WNV-specific CD8 T cells, possibly from the deep CLN, are trafficking into the KO CNS.
T95 208684-208805 Sentence denotes Alternatively, there may be a direct role played by IFN-gamma in mediating cytotoxic activity against WNV-infected cells.
T96 208806-208891 Sentence denotes Herpes simplex virus 1 (HSV1)-induced central nervous system (CNS) demyelination L.F.
T97 208892-208911 Sentence denotes Kastrukoff a , C.M.
T98 208912-208928 Sentence denotes Jones b and F.R.
T99 208929-209120 Sentence denotes Carbone b a University of British Columbia, Vancouver, Canada; b University of Melbourne, Melbourne, Australia HSV1 induces recurrent multifocal CNS demyelination in specific strains of mice.
T100 209121-209276 Sentence denotes Following mucosal inoculation with virus, three stages of demyelination occur with the first the result of an immune response directed at infectious virus.
T101 209277-209487 Sentence denotes To further investigate the immune mechanisms mediating the development of this stage of demyelination, 10-to 12-week-old male C57BL/6 (BL/6) nu/nu and BL/6 bg/bg mice were lip inoculated with HSV1 lab strain 2.
T102 209488-209668 Sentence denotes BL/6 mice, pretreated with anti-CD4 or anti-CD8 mAb, along with gamma-delta T-cell-deficient (B6.129P2-tcrdtm1mom) and Bcell-deficient mice (B6.129S2-Igh6tm/cgn) were also studied.
T103 209669-209763 Sentence denotes The spread of virus in the CNS along with the development of CNS demyelinaton were determined.
T104 209764-209950 Sentence denotes Virus spreads through the CNS in BL/6 nu/nu and BL/6 bg/bg mice but not in BL/6 mice treated with either anti-CD4 or anti-CD8 mAb, gamma-delta T-cell-deficient, or B-cell-deficient mice.
T105 209951-210002 Sentence denotes CNS demyelination develops only in BL/6 bg/bg mice.
T106 210003-210189 Sentence denotes Taken together, the results suggest that the local replication of virus and its spread in the peripheral nervous system (PNS) are affected by both the innate and adaptive immune systems.
T107 210190-210346 Sentence denotes In contrast, natural killer (NK) cells and T-cells play a role in the spread of virus in the CNS and in the development of the first stage of demyelination.
T108 210347-210498 Sentence denotes Herpes simplex virus (HSV) is a common neurotropic virus, which infects epithelial cells and subsequently the trigeminal ganglia (TG) and brain tissue.
T109 210499-210636 Sentence denotes In this study,d we focused on how immunomodulation with roquinimex (Linomide) affects the course of corneal HSV infection in BALB/c mice.
T110 210637-210833 Sentence denotes We addressed the questions how immunomodulation affects the local as well as the systemic immune response and whether roquinimex could facilitate the spread of HSV to central nervous system (CNS).
T111 210834-210883 Sentence denotes Viral culture was used to detect replicating HSV.
T112 210884-211021 Sentence denotes The cytokine response in brain and TG was studied with quantitative rapid real-time RT-PCR method and in stimulated splenocytes with EIA.
T113 211022-211110 Sentence denotes No increase in mortality to HSVinfection was seen, nor was the acute infection enhanced.
T114 211111-211203 Sentence denotes The expression of IL-23p19 mRNA was decreased in brains of roquinimex-treated infected mice.
T115 211204-211267 Sentence denotes Also, the expression of IL-12p35 and IFN-gamma mRNAs decreased.
T116 211268-211326 Sentence denotes At the same time the expression of IL-12p40 was increased.
T117 211327-211394 Sentence denotes No significant changes were seen in IL-4 and IL-10 mRNA expression.
T118 211395-211517 Sentence denotes In systemic immune response, Roquinimex treatment suppressed the production of IFN-gamma but also the production of IL-10.
T119 211518-211652 Sentence denotes In conclusion, downregulation of Th1-immune response in Th2-prone mice did not lead to increased mortality of corneally infected mice.
T120 211653-211755 Sentence denotes These results are important regarding the safety of immunomodulative treatment during viral infection.
T121 211756-211846 Sentence denotes Diffusion-tensor imaging of the temporal lobe in acute herpes-simplexvirus encephalitis J.
T122 211847-211858 Sentence denotes Sellner, C.
T123 211859-211869 Sentence denotes Herweh, S.
T124 211870-211881 Sentence denotes Heiland, M.
T125 211882-211897 Sentence denotes Hartmann and U.
T126 211898-211970 Sentence denotes Meyding-Lamadé Ruprecht-Karls-University Heidelberg, Heidelberg, Germany
T127 211971-212130 Sentence denotes Herpes-simplex-virus encephalitis (HSVE) still carries significant morbidity and serious sequelae in survivors despite advances in treatment and critical care.
T128 212131-212281 Sentence denotes Magnetic resonance imaging (MRI) and especially diffusionweighted MRI can improve diagnostic sensitivity and contains information of prognostic value.
T129 212282-212484 Sentence denotes Furthermore, diffusion-tensor imaging (DTI) enables the in vivo characterization of the structural and functional integrity of the brain and could be of further diagnostic and therapeutic value in HSVE.
T130 212485-212587 Sentence denotes Clinical impairment and cranial MRI changes were studied in five patients with acute, PCR-proven HSVE.
T131 212588-212755 Sentence denotes We studied the fractional anisotropy (FA) and the mean diffusability (MD) in the primarily affected temporal lobe in comparison with values from five healthy controls.
T132 212756-212906 Sentence denotes Data were aquired by placing the region of interest over the whole temporal lobe, and performed with: DSE, 6 non-colinear gradients with b=0 and 1000.
T133 212907-212996 Sentence denotes The FA was 0.204884F0.0362 in patients with HSVE and 0.208863F0.0158 in healthy controls.
T134 212997-213096 Sentence denotes Furthermore, the MD was 1097F150Â10 -6 s/mm 2 in HSVE and 1053F68Â10 -6 s/mm 2 in healthy controls.
T135 213097-213262 Sentence denotes Despite severe clinical impairment, we could not find significant differences of the FA and the MD studying the temporal lobe in a series of five patients with HSVE.
T136 213263-213373 Sentence denotes Diffusion changes in small regions might not be displayed by our data aquisition from the whole temporal lobe.
T137 213374-213482 Sentence denotes A ROI analysis in correlation with MR-changes and clinical impairment may provide more accurate information.
T138 213483-213637 Sentence denotes We investigated the cytokine response to intranasal herpes simplex virus type 1 (HSV-1) infection in trigeminal ganglia (TG) and in brains of BALB/c mice.
T139 213638-213802 Sentence denotes Four-to 6-week-old mice were infected with HSV-1 (F) and samples were taken at five time-points: day 0 (uninfected), day 5, day 7, day 10 and day 31 post infection.
T140 213803-213853 Sentence denotes Virus was detected with rapid culture and HSV-PCR.
T141 213854-214010 Sentence denotes Samples were analyzed for the cytokines interleukin (IL)-4, IL-10, IL-23, IL-12p35, IL-12p40 and IFN-gamma with the real-time PCR method, using LightCycler.
T142 214011-214084 Sentence denotes Alfa-TIF (VP16) expression was also analyzed with the LightCycler system.
T143 214085-214166 Sentence denotes Replicating virus was observed in TG after day 5 whereafter the amount decreased.
T144 214167-214212 Sentence denotes HSV-DNA was detected in brains from day 5 on.
T145 214213-214375 Sentence denotes In TG, we found a significantly elevated expression of mRNA for IFN-gamma during acute HSV infection (day 5 and day 7) when compared to uninfected mice ( pb0.05).
T146 214376-214482 Sentence denotes The IL-23 and IL-4 expressions were significantly downregulated in TG from day 7 and day 10, respectively.
T147 214483-214558 Sentence denotes The IL-4 expression decreased in brain at day 5, day 7 and day 31 in brain.
T148 214559-214732 Sentence denotes The cytokine response to intranasal infection differs in some extent from that to ocular infection (Broberg et. al 2002, Journal of Interferon and cytokine research, vol 22:
T149 214733-214743 Sentence denotes 641-651) .
T150 214744-214839 Sentence denotes Dynamics of neurotrophic factor expression in experimental herpes-simplex virus encephalitis J.
T151 214840-214854 Sentence denotes Sellner a , T.
T152 214855-214869 Sentence denotes Lenhard a , J.
T153 214870-214904 Sentence denotes Haas a , R. von Einsiedel b and U.
T154 214905-215181 Sentence denotes Meyding-Lamadé a a Ruprecht-Karls-University Heidelberg, Heidelberg, Germany; b St7dtisches Klinikum Magdeburg, Magdeburg, Germany Herpes-simplex virus 1 is the most common cause of non-epidemic focal encephalitis (HSVE) and still associated with high morbidity and mortality.
T155 215182-215315 Sentence denotes Neurotrophic factors play an important role in neuronal survival and recovery after acute injury to the central nervous system (CNS).
T156 215316-215537 Sentence denotes We studied the mRNA-expression of glial cell line-derived neurotrophic factor (GDNF), brain-derived neuroptrophic factor (BDNF) and neurotrphin-3 (NT-3) in an established model of murine Herpes-simplex-Virus encephalitis.
T157 215538-215711 Sentence denotes The regulation of these neurotrophic factors was determined during the acute phase of disease (e.g., 3 and 7 days post inoculation) and recovery (2 months post inoculation).
T158 215712-215935 Sentence denotes Our results demonstrate a sequential modulation of mRNA expression during the acute phase of GNDF ( Pb0.05) and NT-3 ( Pb0.01), and a persisting overexpression of NT-3 mRNA even 2 months after acute encephalitis ( Pb0.001).
T159 215936-216153 Sentence denotes Furthermore, the administration of acyclovir as well as adjunctive methylprednisolone to acyclovir promoted a significantly increased expression of GDNF during acute encephalitis and a downregulation of BDNF and NT-3.
T160 216154-216326 Sentence denotes Our results indicate a differential expression pattern of neurotrophic factors during acute viral encephalitis, which may have impact on neuronal survival and regeneration.
T161 216327-216497 Sentence denotes The promotion of neurotrophic factors in acute viral encephalitis may represent an additional therapeutic target for treatment of this highly disabling disease in humans.
T162 216498-216605 Sentence denotes Effects of antigen-specific tolerance of CD8+ T-cells on a viral infection of the central nervous system M.
T163 216606-216619 Sentence denotes Teague and S.
T164 216620-216964 Sentence denotes Miller Northwestern University, Chicago, Illinois, USA Antigen-specific tolerance of CD4+ T-cells induced by the injection of antigen coupled, ECDI-fixed cells into recipient mice is a procedure that has been pursued as a possible therapy for autoimmune diseases, as it prevents and/or ameliorates several CD4+ T-cell mediated diseases in mice.
T165 216965-217043 Sentence denotes We have begun to analyze the use of this method for tolerance of CD8+ T-cells.
T166 217044-217202 Sentence denotes We have found that effector function of specific CD8+ Tcells can in fact be effectively inhibited by encounter with ECDI-fixed cells bearing specific antigen.
T167 217203-217353 Sentence denotes Infection of SJL/J mice with Theiler's murine encephalomyelitis virus (TMEV) leads to a demyelinating disease similar to multiple sclerosis in humans.
T168 217354-217427 Sentence denotes C57BL/6 mice, however, clear the virus and are thus resistant to disease.
T169 217428-217501 Sentence denotes The role of CD8+ T-cells in this disease has been controversial thus far.
T170 217502-217737 Sentence denotes We have shown that in C57BL/6 mice, induction of tolerance in CD8+ T-cells specific for the immunodominant TMEV CD8+ T-cell epitope, followed by TMEV infection, renders these mice susceptible to viral persistence and motor dysfunction.
T171 217738-217832 Sentence denotes We have also shown a modest effect on viral persistence and disease in susceptible SJL/J mice.
T172 217833-217930 Sentence denotes Thus, this method can be used to assess the roles of specific CD8+ T-cells in a disease scenario.
T173 217931-218068 Sentence denotes In addition, coupled cell tolerance of CD8+ T-cells is an attractive potential therapy for diseases in which CD8+ T-cells are pathogenic.
T174 218069-218179 Sentence denotes Role of NF-kappaB in Theiler's virus-induced cytokine/chemokine gene activation and demyelinating disease B.S.
T175 218180-218189 Sentence denotes Kim, J.P.
T176 218190-218201 Sentence denotes Palma, A.C.
T177 218202-218215 Sentence denotes Fuller and H.
T178 218216-218415 Sentence denotes Kang Min Northwestern University Medical School, Chicago, USA Theiler's murine encephalomyelitis virus (TMEV) infection in the CNS induces a demyelinating disease similar to human multiple sclerosis.
T179 218416-218580 Sentence denotes To delineate the early events in the virally induced demyelinating disease, chemokine and cytokine gene activation upon viral infection in glial cells was examined.
T180 218581-218687 Sentence denotes Infection of SJL/J primary astrocyte cultures induces select proinflammatory cytokine and chemokine genes.
T181 218688-218808 Sentence denotes In addition, some of the proinflammatory cytokines function synergistically for virus-induced chemokine gene expression.
T182 218809-218884 Sentence denotes The cellular gene activation by TMEV is dependent on the NF-kappaB pathway.
T183 218885-219102 Sentence denotes These results demonstrate that infection of astrocytes and other glial cells by TMEV induces early NF-kappaB-mediated cytokine/chemokine gene activation involved in CNS inflammatory responses leading to demyelination.
T184 219103-219233 Sentence denotes Interestingly, C57BL/6 mice deficient in the NF-kappaB p50 subunit permit viral persistence in the CNS and clinical manifestation.
T185 219234-219425 Sentence denotes A significant decrease in CD8+ T cell infiltration to the CNS and an increase in CD4+ T cell and macrophage infiltration are found in these knock out mice as compared to control C57BL/6 mice.
T186 219426-219509 Sentence denotes However, fewer CNS-infiltrating T cells, both CD4+ and CD8+, are specific for TMEV.
T187 219510-219638 Sentence denotes It is clear from these studies that the NF-kappaB p50 subunit is important in the resolution of CNS infection in resistant mice.
T188 219639-219830 Sentence denotes Further studies are being undertaken to address the role of NF-kappaB subunits and upstream signals involved in the cellular activation and pathogenesis of TMEV-induced demyelinating disease.
T189 219831-219966 Sentence denotes Zinc-binding motif in leader protein of Theiler's murine encephalomyelitis virus is critical for viral persistence and demyelination K.
T190 219967-219981 Sentence denotes Asakura a , H.
T191 219982-219997 Sentence denotes Murayama b , T.
T192 219998-220013 Sentence denotes Himeda a and Y.
T193 220014-220391 Sentence denotes Ohara a a Kanazawa Medical University, Ishikawa, Japan; b Sendai City Hospital, Sendai, Japan DA strain and other members of the TO subgroup strains of Theiler's murine encephalomyelitis virus cause a biphasic disease characterized by acute self-limiting gray matter inflammation followed by chronic inflammatory demyelination in the spinal cord in susceptible strains of mice.
T194 220392-220463 Sentence denotes The second phase serves as an experimental model of multiple sclerosis.
T195 220464-220536 Sentence denotes DA subgroup synthesizes L* protein from an alternative initiation codon.
T196 220537-220580 Sentence denotes The function of L* is not fully understood.
T197 220581-220683 Sentence denotes L* is considered to play a key role in viral persistence though it is controversial for demyelination.
T198 220684-220897 Sentence denotes We previously demonstrated that L* is expressed exclusively in neurons in vivo in the acute phase of infection in the central nervous system (CNS) by generating a mutant virus which expresses epitope-tagged L* (K.
T199 220898-220916 Sentence denotes Asakura et al., J.
T200 220917-220923 Sentence denotes Virol.
T201 220924-220947 Sentence denotes 76:13049-13054, 2002) .
T202 220948-221070 Sentence denotes However, in this study, the mutant virus failed to grow in L929 though it grew in BHK-21 and failed to persist in the CNS.
T203 221071-221192 Sentence denotes Here, we explored the basis of this failure by generating a panel of new mutant viruses, which express epitope-tagged L*.
T204 221193-221382 Sentence denotes Two of the new mutant viruses successfully caused persistent infection and demyelination in the spinal cords and enabled us to identify L* immunohistochemically in the demyelinated lesions.
T205 221383-221539 Sentence denotes These mutant virus studies revealed that sparing zinc-binding motif in the leader protein of TMEV has crucial effect on its persistent infection in the CNS.
T206 221540-221672 Sentence denotes It is well established that early life stress can induce long-lasting changes in behavioral and neuroendocrine reactivity to stress.
T207 221673-221806 Sentence denotes However, little is known about the long-term consequences of neonatal stress on susceptibility to infectious and autoimmune diseases.
T208 221807-222003 Sentence denotes The present study investigated the effects of neonatal stress on susceptibility to a virally mediated animal model of multiple sclerosis, Theiler's murine encephalomyelitis virus (TMEV) infection.
T209 222004-222180 Sentence denotes TMEV induces a biphasic infection of the CNS in which polio-like symptoms are observed during acute infection followed by autoimmune-mediated demyelination during late disease.
T210 222181-222387 Sentence denotes In these experiments, BALB/cJ pups were exposed daily to one of three conditions during their first 2 weeks of life: (1) 180-min of neonatal maternal separation (NMS), (2) 15-min of NMS, or (3) undisturbed.
T211 222388-222515 Sentence denotes During adulthood, mice were inoculated intracranially with Theiler's virus and sacrificed at days 14, 21, or 35 post-infection.
T212 222516-222681 Sentence denotes Prolonged 180-min NMS decreased viral clearance in the spinal cords of male and female mice at days 21 and 35 pi, whereas brief 15-min NMS increased viral clearance.
T213 222682-222822 Sentence denotes Both the 15-and 180-min NMS mice exhibited blunted corticosterone responses to TMEV infection, and increased adrenal and lymph node weights.
T214 222823-222972 Sentence denotes These changes were accompanied by alterations in histological signs of meningitis and microgliosis in spinal cord, and alterations in motor function.
T215 222973-223118 Sentence denotes These findings suggest that maternal separation has long-term effects on neuroimmune, neuroendocrine, and behavioral responses to TMEV infection.
T216 223119-223269 Sentence denotes The present study examines the effects of social stress on an animal model of multiple sclerosis, Theiler's murine encephalomyelitis infection (TMEV).
T217 223270-223444 Sentence denotes TMEV induces a biphasic infection of the CNS in which polio-like symptoms are observed during acute infection followed by neuroinflammatory demyelination during late disease.
T218 223445-223623 Sentence denotes We have previously shown that the effects of social disruption (SDR) on acute Theiler's virus infection are dependent upon the timing of SDR application in relation to infection.
T219 223624-223798 Sentence denotes When SDR was applied prior to infection (PRE-SDR), it led to glucocorticoid (GC) resistance, and these mice developed more severe disease course, with increased inflammation.
T220 223799-223964 Sentence denotes In contrast, when SDR was applied concurrent with infection (CON-SDR), GC resistance failed to develop, disease course was less severe and inflammation was moderate.
T221 223965-224079 Sentence denotes The current study extends this line of work by examining the impact of SDR on the course chronic phase of disease.
T222 224080-224209 Sentence denotes Three groups of infected Balb/cJ mice received SDR either immediately prior to or concurrent with infection, or were nonstressed.
T223 224210-224507 Sentence denotes In addition to replicating the pattern of acute behavioral impairments, we found that the PRE-SDR group developed earlier and more severe hind limb impairment, impaired rotarod and inclined plane performance, reduced sensitivity to von Frey stimulation, and reduced spontaneous locomotor activity.
T224 224508-224648 Sentence denotes These converging lines of evidence demonstrate that social stress exacerbates both the acute and chronic phase of Theiler's virus infection.
T225 224649-224710 Sentence denotes Treatment options in SSPE: experience with beta interferon B.
T226 224711-224723 Sentence denotes Anlar a , A.
T227 224724-224740 Sentence denotes Guven b and O.F.
T228 224741-224869 Sentence denotes Aydin c a Hacettepe University, Ankara, Turkey; b Social Securitý Hospital, Ankara, Turkey; c SUCH Hospital, Ankara, Turkey Aim:
T229 224870-224957 Sentence denotes Efficient treatment methods are lacking for subacute sclerosing panencephalitis (SSPE).
T230 224958-225024 Sentence denotes We compared the results obtained with two forms of h-IFNs in SSPE.
T231 225025-225054 Sentence denotes Method: h-IFN1a in two forms:
T232 225055-225208 Sentence denotes 60 Ag/week IM, named h-IFN1a 1/wkIM, or 22 Ag 3/week SC, named h-IFN1a 3/wkSC, were given in a non-randomized fashion to 48 patients diagnosed with SSPE.
T233 225209-225250 Sentence denotes All received oral inosiplex 50-100 mg/kg.
T234 225251-225349 Sentence denotes Those who received the treatment for N3 months and had at least 1 year's follow-up were evaluated.
T235 225350-225358 Sentence denotes Results:
T236 225359-225534 Sentence denotes Treatment groups were similar in terms of age, sex, and duration of disease while stage at diagnosis differed: no Stage 1 patients were in the h-IFN1a 3/ wkSC group ( pb0.02).
T237 225535-225570 Sentence denotes Mean follow-up was 15.4F9.8 months.
T238 225571-225646 Sentence denotes More patients in the h-IFN1a 3/wkSC group stabilized or improved ( pb0.05).
T239 225647-225738 Sentence denotes Survival and duration of treatment were significantly shorter in the h-IFN1a 1/wk IM group.
T240 225739-225837 Sentence denotes Fatality rate at 6 and 12 months, and frequency of side effects were not different between groups.
T241 225838-225849 Sentence denotes Conclusion:
T242 225850-225983 Sentence denotes Despite the difference in the stages of the patients, the proportion tients with satisfactory outcome was higher with h-IFN1a 3/wkSC.
T243 225984-226030 Sentence denotes Overall progression was similar in all groups.
T244 226031-226134 Sentence denotes Randomized studies are difficult to realize in SSPE because of the clinical variability of the disease.
T245 226135-226297 Sentence denotes Open studies give some, although limited, evidence about treatment, and suggest h-IFN at high doses combined with inosiplex might constitute an applicable option.
T246 226298-226505 Sentence denotes To investigate antigen-specific T cell responses in SSPE, we analyzed proliferation and cytokine secretion from 37 SSPE patients and 45 healthy controls (HC) to specific antigens and to measles vaccine (MV).
T247 226506-226596 Sentence denotes PBMCs of SSPE and HC groups were stimulated with MBP, MOG, alpha-B-crystallin, MV and PPD.
T248 226597-226652 Sentence denotes Proliferation was measured as stimulation indices (SI).
T249 226653-226739 Sentence denotes IFNgamma, IL-12 and IL-10 production were determined in culture supernatants by ELISA.
T250 226740-226825 Sentence denotes The median SI values to MBP, MOG and alpha-Bcrystallin did not differ between groups.
T251 226826-226974 Sentence denotes There was a trend towards a decrease in IL-12 production in response to MBP in SSPE patients than in HCs (0.0 vs. 4.4 pg/ml, p=0.051, respectively).
T252 226975-227201 Sentence denotes Proliferation (1.8 vs. 25, pb0.001), as well as IFN-gamma, IL-12 and IL-10 production in response to PPD were impaired in SSPE patients (0.1 vs. 681.0, 0 vs. 14 pg/dml, both pb0.001, and 0 vs. 2.6 pg/ml, p=0.02, respectively).
T253 227202-227268 Sentence denotes Proliferative responses to MV were not different among the groups.
T254 227269-227374 Sentence denotes However, in vitro IL-12 secretion of SSPE patients to MV was lower than HCs (0.0 vs. 3.6 pg/ml, p=0.001).
T255 227375-227566 Sentence denotes The results did not demonstrate any by-stander cellular responses against myelin antigens, implicating that the central nervous system is not primary target of an autoimmune response in SSPE.
T256 227567-227653 Sentence denotes The previously reported lower IL-12 response to measles virus seem to persist in SSPE.
T257 227654-227762 Sentence denotes Role of neuroimmunophilin ligands in lipopolysaccharide (LPS) induced peripheral and central hyperalgesia A.
T258 227763-227777 Sentence denotes Singh and S.K.
T259 227778-227841 Sentence denotes Kulkarni Institution UIPS, Panjab University, Chandigarh, India
T260 227842-227961 Sentence denotes Exposure of tissues to endotoxin lipopolysaccharide (LPS) leads to induction of inducible nitric oxide synthase (iNOS).
T261 227962-228084 Sentence denotes FK506 an immunosuppressant is reported to suppress LPS-induced (iNOS) and nitrite levels in macrophages and other tissues.
T262 228085-228260 Sentence denotes The present study was aimed to assess the modulatory effect of FK506 on lipopolysaccharide induced central as well as peripheral hyperalgesia possibly through iNOS inhibition.
T263 228261-228360 Sentence denotes LPS induced a significant hyperalgesia when measured by both central as well as peripheral methods.
T264 228361-228514 Sentence denotes Dose of FK506 (0.1-0.75 mg/kg i.p.) having no analgesic activity, dose dependently and significantly reversed peripheral as well as central hyperalgesia.
T265 228515-228710 Sentence denotes Aminoguanidine, a specific iNOS inhibitor not only dose dependently (10-50 mg/kg i.p.) and significantly reversed LPS-induced hyperalgesia, but potentatiated the lower subeffective dose of FK506.
T266 228711-228849 Sentence denotes FK506 dose dependently and significantly reversed elevated nitrite levels in brain and paw of the LPS-treated mice and rats, respectively.
T267 228850-228965 Sentence denotes Elevated MPO (Myeloperoxide) levels in LPS treated paw in rats were also significantly reversed by FK506 treatment.
T268 228966-229121 Sentence denotes Again aminoguanidine not only reversed LPS-induced elevation of myloperoxide (MPO), nitrite levels but also potentaited the effects of lower dose of FK506.
T269 229122-229372 Sentence denotes FK506 possibly through iNOS inhibition reversed LPS-mediated alteration in pain (hyperalgesia) and restored elevated MPO and nitrite levels in LPS treated animals, thus may be screened as a possible adjuvant in the treatment of systemic hyperalgesia.
T270 229373-229481 Sentence denotes A novel role for olfactory ensheathing cells in neuroimmunological defence in the rodent olfactory system A.
T271 229482-229493 Sentence denotes Vincent, A.
T272 229494-229507 Sentence denotes West and M.I.
T273 229508-229555 Sentence denotes Chuah University of Tasmania, Hobart, Australia
T274 229556-229709 Sentence denotes The dendrites of olfactory receptor cells are exposed to the external environment whilst their axons project directly into the olfactory bulb in the CNS.
T275 229710-229897 Sentence denotes This provides a route for pathogens into the brain that bypasses the blood-brain barrier, yet infection via this route appears to be limited by local defences within the olfactory system.
T276 229898-230112 Sentence denotes Given the close apposition of olfactory ensheathing cells (OECs) to olfactory receptor axons along their entire projection, these glial cells could constitute an important component of the olfactory immune defence.
T277 230113-230464 Sentence denotes We recently detected enriched transcripts for several immune factors in cultured neonatal OECs by microarray analysis, including lysozyme (Lyz), the chemokines growth-regulated oncogene (Gro, CXCL1) and monocyte chemoattractant protein 1 (MCP1, CCL2), and the interleukin 6-responsive transcription factor CCAAT/enhancer binding protein beta (C/EBPb).
T278 230465-230529 Sentence denotes Lyz, MCP1 and Gro expression were confirmed by real-time RT-PCR.
T279 230530-230699 Sentence denotes We detected all gene products by immunostaining in cultured OECs, but did not detect significant levels of either chemokine in OECs in the normal adult olfactory system.
T280 230700-230855 Sentence denotes Lyz mRNA is inducible in cultured OECs in the presence of Staphylococcus aureus but not Escherichea coli (E. coli) or lipopolysaccharide (LPS, 1-25 Ag/ml).
T281 230856-230921 Sentence denotes Conversely, Gro and MCP1 are strongly induced by E. coli and LPS.
T282 230922-231030 Sentence denotes We are currently testing the function of these immune factors in OEC in culture and in the olfactory system.
T283 231031-231175 Sentence denotes Mengo virus encephalomyelitis is prevented by the polyanion COAM through interferon-independent chemokine induction and enhanced phagocytosis S.
T284 231176-231187 Sentence denotes Starckx, A.
T285 231188-231199 Sentence denotes Billiau, J.
T286 231200-231216 Sentence denotes Van Damme and G.
T287 231217-231265 Sentence denotes Opdenakker University of Leuven, Leuven, Belgium
T288 231266-231424 Sentence denotes The polyanionic compound COAM (chlorite-oxidized oxyamylose) protects mice from lethal encephalomyelitis caused by intraperitoneal (IP) Mengo virus infection.
T289 231425-231557 Sentence denotes The in vivo protective effect is associated with multiple biological activities of COAM, such as a reduction of plasma virus titers.
T290 231558-231743 Sentence denotes We found that IP injection of 2 mg COAM induces a dramatic increase in peritoneal leukocyte counts which is explained by a selective infiltration of polymorphonuclear leukocytes (PMNs).
T291 231744-231848 Sentence denotes PMNs migrate into the peritoneum in response to a gradient of granulocyte chemotactic protein-2 (GCP-2).
T292 231849-231982 Sentence denotes The presence of GCP-2 and the subsequent migration of PMNs coincide with the release of MMP-9/ gelatinase B in the peritoneal cavity.
T293 231983-232268 Sentence denotes Although the phagocytic activity of peritoneal macrophages or the two murine macrophage cell lines was not significantly affected by COAM, the increased number of PMNs in the peritoneum was responsible for the enhanced phagocytic efficiency and the accumulation of proteolytic enzymes.
T294 232269-232478 Sentence denotes The antiviral activity of COAM was not mediated by the induction of interferons since COAM, in contrast to polyI:C, does not protect mouse fibroblasts against the cytopathogenic effect of Mengo virus in vitro.
T295 232479-232562 Sentence denotes In addition, the observed effects do not rely on TLR3-or TLR4-dependent mechanisms.
T296 232563-232778 Sentence denotes Altogether, the experimental results indicate that the in vivo antiviral activity of COAM originates in the retention of the virus within the peritoneal cavity due to increased phagocytosis and killing of the virus.
T297 232779-232910 Sentence denotes The immune system plays a key role in the dissemination of prion infections from the periphery to the central nervous system (CNS).
T298 232911-233133 Sentence denotes Follicular dendritic cells are critical for prion replication in lymphoid tissue and subsequent neuroinvasion, whereas myeloid dendritic cells (DC) have been indicated as candidate vectors for prion propagation to the CNS.
T299 233134-233454 Sentence denotes Since nothing is known on the ability of DC to migrate to the CNS during prion diseases, we investigated the immunohistochemical localization of CD205+ DC in the brain of C57BL/6 mice intraperitoneally infected with the mouse-adapted KFu strain of Gerstmann-Str7ussler-Scheinker syndrome, a human genetic prion disorder.
T300 233455-233784 Sentence denotes In normal brain, CD205+ cells were present in the meninges and choroid plexus whereas in the majority of mice sacrificed from 120 to 300 days post-infection (dpi), scattered CD205+ dendritiform cells were also detected in the cerebral cortex, subcortical white matter, thalamus and cerebellum, sometimes in perivascular location.
T301 233785-233944 Sentence denotes Brains from mice in the late stage of infection showed severe spongiform degeneration in the medulla oblongata, thalamic nuclei and several white matter areas.
T302 233945-234096 Sentence denotes Accumulation of PrPSc was observed predominantly at the thalamic level at 240-260 dpi and became more diffuse during the terminal stage of the disease.
T303 234097-234264 Sentence denotes These findings demonstrate that myeloid DC can enter the CNS of prion infected mice, suggesting a possible role for these cells in the pathogenesis of prion disorders.
T304 234265-234357 Sentence denotes Cerebral malaria (CM) is a serious complication due to infection with Plasmodium falciparum.
T305 234358-234435 Sentence denotes Patients often present with neurological symptoms that can progress to death.
T306 234436-234584 Sentence denotes The pathogenesis of CM is not well understood, although it is believed to be largely a host-mediated event, with cytokines playing a prominent role.
T307 234585-234807 Sentence denotes The role of chemokines is less clear, although recent work suggests that the expression of some chemokine receptors, such as CCR5, on leukocytes sequestered within the brain may be crucial for the development of murine CM.
T308 234808-234925 Sentence denotes The expression of known chemokines and chemokine receptors was examined and compared between mouse models of malaria.
T309 234926-235216 Sentence denotes Mice infected with Plasmodium berghei ANKA develop neurological symptoms similar to human CM, and die 6-7 days postinoculation (p.i.), whereas mice infected with P. berghei K173 do not present with cerebral manifestations, but die 12-14 days p.i. with overwhelming parasitaemia and anaemia.
T310 235217-235317 Sentence denotes RT-PCR was used to determine the relative expression of chemokine genes in the brains of these mice.
T311 235318-235482 Sentence denotes Several chemokines and receptors, including CCL2 and CCR1, were found to be up-regulated in mice that presented with CM, compared to mice without cerebral symptoms.
T312 235483-235599 Sentence denotes Laser capture microdissection techniques were also employed in order to determine the cellular source of chemokines.
T313 235600-235744 Sentence denotes Vessels were separated from parenchyma cells and the mRNA levels of candidate chemokine and chemokine receptor genes were assessed using RT-PCR.
T314 235745-235838 Sentence denotes Changes in the expression of chemokines may play an important role in the pathogenesis of CM.
T315 235839-235909 Sentence denotes Parasitic glycoconjugates-role in neurocysticercosis pathogenesis J.I.
T316 235910-235926 Sentence denotes Alvarez and J.M.
T317 235927-236127 Sentence denotes Teale University of Texas Health Science Center at San Antonio, San Antonio, TX, USA Neurocysticercosis (NCC) is an infection of the central nervous system by the larvae of the helminth Taenia solium.
T318 236128-236201 Sentence denotes Symptom severity is associated with the intensity of the immune response.
T319 236202-236318 Sentence denotes First, there is a long asymptomatic period where the host immunity seems to be incapable of resolving the infection.
T320 236319-236413 Sentence denotes Helminth teguments are dynamically responsive to adverse environments and can be rapidly shed.
T321 236414-236611 Sentence denotes Because more than 95% of NCC patients exhibit humoral response against at least 2 carbohydrate antigens (glycoconjugates-GCs), we analyzed the expression of different GCs in NCC infected specimens.
T322 236612-236750 Sentence denotes To determine the GCs present in the parasite's tegument, we used fluorochrome labeled lectins with specificity to different carbohydrates.
T323 236751-236940 Sentence denotes All the lectins utilized labeled the tegument, but interestingly the GCs bound by isolectinB4, wheat germ agglutinin and concavalinA were also found to be taken up by macrophages/microglia.
T324 236941-237073 Sentence denotes Peanut lectin binding GCs, on the other hand, remained on the parasite throughout the infection and were not detected in host cells.
T325 237074-237224 Sentence denotes To confirm that the lectin-binding GCs staining cells were of parasitic origin, we developed an antibody against the 12-kDa glycoprotein of T. solium.
T326 237225-237317 Sentence denotes The antibody and lectins colocalized with macrophages/microglia indicating parasitic origin.
T327 237318-237504 Sentence denotes Thus, constant release of GCs may help the parasite to persist in the adverse host environment because massive antigen uptake by immune cells could interfere with normal immune function.
T328 237505-237637 Sentence denotes Additionally, these molecules likely provide a source of persistent antigen responsible for life-long sequelae in many NCC patients.
T329 237638-237718 Sentence denotes Gram negative lipopolysaccharides indirectly induce baxonal stunningQ in rats G.
T330 237719-237731 Sentence denotes Ifergane, M.
T331 237732-237745 Sentence denotes Bersudsky, A.
T332 237746-237757 Sentence denotes Dori and I.
T333 237758-237854 Sentence denotes Wirguin Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
T1 237855-237974 Sentence denotes While tissue dysfunction during sepsis is common, cell death in the heart, kidney, liver, and lung is relatively minor.
T2 237975-238107 Sentence denotes It was suggested that sepsis activates defense mechanisms that cause cellular processes to be reduced to basic bhousekeepingQ roles.
T3 238108-238356 Sentence denotes We examined whether similar processes are induced in the peripheral nerve when the blood-nerve barrier (BNB) is breached. we systemically injected Lewis rats (presensitized by KLH) with Campylobacter Jejuni (Cj) or E. coli lipopolysaccharide (LPS).
T4 238357-238575 Sentence denotes The exposure caused transient conduction blocks within 24 h, but only if accompanied by a simultaneous minor neural insult (intraneural (IN) injection of saline) and was not associated with morphological abnormalities.
T5 238576-238650 Sentence denotes IN injection of the LPS itself did not result in conduction abnormalities.
T6 238651-238751 Sentence denotes In a second set of experiments, we incubated Lewis rats splenocytes with Cj or E. coli-LPS for 48 h.
T7 238752-238921 Sentence denotes The splenocytes LPS reactive medium (SLRM) was injected into Lewis rats sciatic nerves, and caused a transient conduction block appearing 24-72 h after the IN injection.
T8 238922-239157 Sentence denotes Our results suggest that gram-negative LPS induces an acute immunological response mediated by soluble factors, which are capable, when penetrating the BNB to cause transient baxonal stunningQ and functionally affect neural conduction.
T9 239158-239303 Sentence denotes This pathophysiological process could be involved in the pathogenesis of critical illness neuropathy in septic patients with multisystem failure.
T10 239304-239426 Sentence denotes BBB dysfunction in HIVE is accompanied disruption of tight junctions (TJ) of brain microvascular endothelial cell (BMVEC).
T11 239427-239517 Sentence denotes TJ proteins, claudin-5 and occludin are down-regulated paralleling Mo egress into the CNS.
T12 239518-239694 Sentence denotes As small G-proteins (such as Rho) play a role in BMVEC TJ assembly, we hypothesized that loss of TJ integrity is associated with Rho activation triggered by Mo brain migration.
T13 239695-239858 Sentence denotes To investigate this, we utilized artificial BBB system to explore the relationship between TJ, Rho/Rho kinase (RhoK) activation and trans-endothelial Mo migration.
T14 239859-240045 Sentence denotes Mo passage across the BBB in response to macrophage chemotactic protein (MCP-1) (increased in HIVE) was evaluated with inhibitors of Rho (C. botulinum C3 transferase) and RhoK (Y-27632).
T15 240046-240130 Sentence denotes HIV-1 infected Mo migrated more efficiently than uninfected Mo in response to MCP-1.
T16 240131-240201 Sentence denotes Mo/BMVEC coculture led to Rho activation and occludin phosphorylation.
T17 240202-240263 Sentence denotes C3 and Y-27632 blocked passage of infected and uninfected Mo.
T18 240264-240359 Sentence denotes RhoK inhibitor prevented BBB leakage and occludin phosphorylation associated with Mo migration.
T19 240360-240572 Sentence denotes BMVEC transfection with dominant negative mutant resulted in occludin up-regulation at TJ, while dominant active (DA-RhoK) transfection led to dislocation of occludin from the membrane and loss of BMVEC contacts.
T20 240573-240678 Sentence denotes When DN-RhoK transfected BMVEC were used in BBB constructs, Mo passage across the BBB was reduced by 84%.
T21 240679-240799 Sentence denotes These observations suggest that pharmacologic manipulation of Rho/RhoK may prevent Mo egress across the BBB during HIVE.
T22 240800-241030 Sentence denotes Although HIV is present in the brains of all infected individuals, only 30% of these individuals develop neurological disease, indicating that viral and host characteristics act together in the development of neurological disease.
T23 241031-241201 Sentence denotes To identify and characterize the salient genomic and functional features that allow some viral strains to induce neuroAIDS, we used the rhesus macaque model of neuroAIDS.
T24 241202-241436 Sentence denotes We serially passaged microglia-associated SIV through the brains of rhesus macaques and isolated virus after the final passage to generate nine unique, brainadapted SIV clones from the brains of two macaques with neurological disease.
T25 241437-241659 Sentence denotes Sequence analyses of these brain-adapted clones show a remarkably high level of similarity in the gp120, gp41, nef and LTR regions of their genomes, with sequences that are distinct from other neurovirulent strains of SIV.
T26 241660-241821 Sentence denotes Functional characterization of representative brain-adapted clones shows a robust in vitro infection of CEMx174 cells, primary macrophages and primary microglia.
T27 241822-241972 Sentence denotes They also demonstrate an infectious phenotype distinct from other clones, characterized by a very early peak p27Gag levels followed by a slow decline.
T28 241973-242101 Sentence denotes This unique infection phenotype may be a result of their ability to initially infect a much larger percentage of cultured cells.
T29 242102-242285 Sentence denotes Positive in vivo selection of brain-adapted strains of SIV resulted in a near-homogeneous strain of virus with distinct properties that may give clues to the viral basis of neuroAIDS.
T30 242286-242485 Sentence denotes The cognitive and motor disorders occurring in HIV-infected individuals result in significant morbidity and mortality, and remain a serious problem even in the era of highly active antiviral therapy.
T31 242486-242609 Sentence denotes Although numerous potential neurotoxic molecules have been identified, the nature of the CNS disorder has remained elusive.
T32 242610-242762 Sentence denotes Using SIV-infected rhesus monkeys, we have carried out functional, pathological, and molecular analyses of different stages of the neurological disease.
T33 242763-242935 Sentence denotes Distinct as well as overlapping sets of genes are differentially regulated in acute infection, chronic asymptomatic infection, and during AIDS with CNS disease (neuroAIDS).
T34 242936-243087 Sentence denotes The greatest number of differences is found in neuroAIDS, where transcriptional profiling has revealed 188 known genes to be significantly upregulated.
T35 243088-243268 Sentence denotes The function of only approximately half of these genes have been characterized; another 28 upregulated transcripts were also identified which have yet to be genetically classified.
T36 243269-243470 Sentence denotes These proteins encoded by novel genes have intriguing predicted properties, including transcriptional regulation, alteration of RNA secondary structure, and control of protein subcellular localization.
T37 243471-243579 Sentence denotes The viral-host interaction occurring in the CNS environment can have profound effects on cellular processes.
T38 243580-243689 Sentence denotes The elucidation of these effects will enable the understanding of how HIV infection leads to CNS dysfunction.
T39 243690-243834 Sentence denotes Schwann cells (SC), primarily responsible for the formation of myelin within the PNS, might be involved in the local immune response in the PNS.
T40 243835-244044 Sentence denotes Several lines of evidence indicate that SCs display immune-related functions, such as the expression of MHC class II antigens, suggesting that SCs can acquire the role of a facultative antigen presenting cell.
T41 244045-244290 Sentence denotes Toll-like receptors (TLRs) have emerged as key receptors responsible for recognizing specific conserved components of microbes, such as lipopolysaccharide (LPS), and have been implicated to play a critical role in various inflammatory disorders.
T42 244291-244369 Sentence denotes LPS may be a relevant antigen causing immunemediated demyelination of the PNS.
T43 244370-244432 Sentence denotes We studied the expression of TLRs in these PNS resident cells.
T44 244433-244754 Sentence denotes In SCs from rat various TLRs were detectable in vitro, out of which TLR-2 and -4 were found to be regulated by substrates, such as interferon-alpha, or phorbol 12-myristate 13-acetate (PMA) in a time-and dose-dependent fashion, as measured on the RNA-level by RT-PCR as well as on the protein level by immunofluorescence.
T45 244755-244914 Sentence denotes After stimulation with LPS, the secretion of various inflammatory mediators was induced, as determined by a qualitative protein array and quantitated by ELISA.
T46 244915-244991 Sentence denotes These mediators include chemokines, growth factors, and protease inhibitors.
T47 244992-245128 Sentence denotes This induction was effectively blocked by specific anti-TLR-2 and anti-TLR-4 antibodies as well as inhibitors of nuclear factor-kappa B.
T48 245129-245248 Sentence denotes Thus, our data indicate that SCs might act as a link between innate and acquired immunity via TLRs in the inflamed PNS.
T49 245249-245366 Sentence denotes Skeletal muscle is an immunological microenvironment and the site of many desirable and undesirable immune reactions.
T50 245367-245517 Sentence denotes Toll-like receptors (TLR) are crucial players of the innate immune system sensing the invasion of microorganisms and inducing antimicrobial responses.
T51 245518-245707 Sentence denotes To elucidate mechanisms of innate immune responses in human muscle, we investigated the expression of TLR1-9 mRNA in cultured human myoblasts and TE671 rhabdomyosarcoma cells using QRT-PCR.
T52 245708-245765 Sentence denotes Muscle cells showed constitutive expression of TLR3 mRNA.
T53 245766-245925 Sentence denotes TLR3 was up-regulated by its ligand Poly(I:C), a synthetic analog of dsRNA, and by IFN-gamma, but not by the TLR4 ligand lipopolysaccharide (LPS) or TNF-alpha.
T54 245926-246025 Sentence denotes TLR3 protein was located mainly intracellular assessed by flow cytometry and western blot analysis.
T55 246026-246100 Sentence denotes Poly(I:C) induced NF-kappaB activation and IL-8 secretion in muscle cells.
T56 246101-246238 Sentence denotes In vivo, muscle fibers of non-inflamed muscle and of inflammatory myopathies expressed TLR3, analysed by immunhistochemistry and QRT-PCR.
T57 246239-246345 Sentence denotes Importantly, TLR-3 mRNA was highly up-regulated in HIV-myopathies corroborating our in vitro observations.
T58 246346-246530 Sentence denotes Taken together, our findings may contribute to the understanding of muscular responses to microbial stimuli during infections and the pathogenesis of autoimmune inflammatory disorders.
T59 246531-246765 Sentence denotes Guillain-Barré syndrome (GBS) is an acute autoimmune polyradiculoneuropathy with a clinical presentation of flaccid paralysis with areflexia, variable sensory disturbances, and elevated cerebrospinal fluid protein without pleocytosis.
T60 246766-246926 Sentence denotes Although GBS previously had been viewed as a unitary disorder with variations, it currently is viewed as a group of syndromes with several distinctive subtypes.
T61 246927-247126 Sentence denotes Fifteeen to 40% of the patients with GBS develop the syndrome after being infected by the Gram-negative bacterium Campylobacter jejuni (C. jejuni), a leading cause of acute gastroenteritis in humans.
T62 247127-247370 Sentence denotes There is a strong tendency for the appearance of antibodies that bind to gangliosides, particularly GM1, to be measurable in the serum of patients with GBS, particularly those with axonal variants and types associated with C. jejuni infection.
T63 247371-247514 Sentence denotes We have investigated the localization of GM1 in C. jejuni and nervous tissues by using immunoelectron microsopy and con-focal laser microscopy.
T64 247515-247589 Sentence denotes GM1 was exclusively localized in both central and peripheral nerve myelin.
T65 247590-247660 Sentence denotes GM1 was not observed in central nerve axons or peripheral nerve axons.
T66 247661-247725 Sentence denotes We could not find GM1 in C. jejuni by immunoelectron microscopy.
T67 247726-247864 Sentence denotes Further studies should be taken to clarify the role of antecedent infections of C. jejuni and the role antiganglioside antibody responses.
T68 247865-248006 Sentence denotes 162a A lentiviral expression system demonstrates that L* protein of Theiler's virus has an anti-apoptotic effect in a macrophage cell line Y.
T69 248007-248016 Sentence denotes Ohara, T.
T70 248017-248027 Sentence denotes Himeda, K.
T71 248028-248039 Sentence denotes Asakura, Y.
T72 248040-248210 Sentence denotes Kontani Kanazawa Medical University, Kahoku-gun, Ishikawa, Japan DA subgroup strains of Theiler's virus (TV) persist in the CNS of infected mice and induce demyelination.
T73 248211-248292 Sentence denotes This demyelinating disease serves as an experimental model of multiple sclerosis.
T74 248293-248371 Sentence denotes The mechanism(s) by which the virus persists and demyelinates remains unknown.
T75 248372-248490 Sentence denotes DA subgroup strains synthesize a 17-kDa protein, called L*, from an initiation site out-of-frame with the polyprotein.
T76 248491-248662 Sentence denotes Previous studies using a mutant virus, DAL*-1 (in which the L* AUG is substituted by an ACG) showed that L* has an anti-apoptotic effect in a macrophage cell line, P388D1.
T77 248663-248838 Sentence denotes In order to confirm and better characterize the anti-apoptotic effect of L*, we used a lentiviral vector to generate P388D1 that constitutively expresses L* (L*/P388D1 cells).
T78 248839-248916 Sentence denotes The expression of L* was confirmed by Western blotting with anti-L* antibody.
T79 248917-248997 Sentence denotes DNA laddering was seen in control/ P388D1 cells from 10.5 through 12 hours p.i..
T80 248998-249090 Sentence denotes In contrast, no laddering was detected following the infection of DAL*-1 in L*/P388D1 cells.
T81 249091-249217 Sentence denotes Caspase-3 was activated in control/P388D1 cells, not in L*/P388D1 cells, the same time course as in the case of DNA laddering.
T82 249218-249329 Sentence denotes The above data suggest that L* has an anti-apoptotic activity in macrophages that can function in cis or trans.
T83 249330-249410 Sentence denotes The anti-apoptotic activity of L* may play an important role in TV pathogenesis.
T84 249411-249496 Sentence denotes Identification of novel markers for encephalitogenicity of effector T cells in EAE U.
T85 249497-249513 Sentence denotes Boehlmann and B.
T86 249514-249792 Sentence denotes Becher University Hospital of Zurich, Neuroimmunology Center, Zurich, Switzerland TH1 lymphocytes were thought to play a central role in the initiation and potentially in the propagation of multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE).
T87 249793-249902 Sentence denotes We have recently shown that the TH1/TH2 paradigm cannot be used as a reliable marker for encephalitogenicity.
T88 249903-250162 Sentence denotes We identified two mutant mouse strains (IL-12/ 23p40KO and IL-12p35KO) in which auto-aggressive T cells are virtually indistinguishable by virtue of expression of known suspect genes (TH1/ TH2), yet one strain is EAE hyper-susceptible, the other is resistant.
T89 250163-250368 Sentence denotes Since the activation status of the T cells is correlated with the expression of specific genes, we used high-density gene expression arrays to discover potential encephalitogenicity genes induced by IL-23.
T90 250369-250451 Sentence denotes We have identified several genes which could have a potential pathogenic function.
T91 250452-250615 Sentence denotes Currently, the involvement in encephalitogenicity of target genes is being verified in vivo using RNAi knock-down or transgenic over-expression of the target gene.
T92 250616-250880 Sentence denotes For gene delivery in vivo, we use recombinant lentiviral vectors infecting mouse embryos to generate transgenic mice constitutively expressing the siRNA of the target gene or to infect MOG-reactive T cell lines prior to adoptive transfer into naive recipient mice.
T93 250881-251032 Sentence denotes Preliminary data clearly show that several of the newly identified genes confer encephalitogenic potential and are critical for the development of EAE.
T94 251033-251139 Sentence denotes Taken together, our approach will allow us to reliably unmask potential encephalitogenicity genes in vivo.
T95 251140-251200 Sentence denotes Silencing T-bet prevents autoimmune demyelinating disease A.
T96 251201-251203 Sentence denotes E.
T97 251204-251222 Sentence denotes Lovett-Racke, A.E.
T98 251223-251235 Sentence denotes Rocchini, J.
T99 251236-251246 Sentence denotes Choy, S.C.
T100 251247-251261 Sentence denotes Northrop, R.Z.
T101 251262-251278 Sentence denotes Hussain and M.K.
T102 251279-251427 Sentence denotes Racke UT Southwestern Medical Center, Dallas, TX, USA T-bet is a transcription factor that regulates IFN-gamma production in Th1 cells and NK cells.
T103 251428-251631 Sentence denotes We developed an anti-sense oligonucleotide (AS-Tbet) and small interfering RNA (siRNA-Tbet) specific for T-bet as a tool to determine the role of T-bet in the differentiation of encephalitogenic T cells.
T104 251632-251909 Sentence denotes Transfection of naive MBP-specific T cells with AS-Tbet or siRNA-Tbet prior to differentiation resulted in decreased IFN-gamma production and a dramatic reduction in the ability of these cells to transfer experimental autoimmune encephalomyelitis (EAE) to naive recipient mice.
T105 251910-252132 Sentence denotes In addition, in vivo administration of AS-Tbet or siRNA-Tbet to mice at the time of immunization with myelin antigen prevented EAE.T-bet and IFN-gamma expression was suppressed in the lymph nodes and spleens of these mice.
T106 252133-252251 Sentence denotes This study suggests that T-bet may be a viable target for therapy in Th1mediated diseases, such as multiple sclerosis.
T107 252252-252318 Sentence denotes Role of CD200 in immune-modulation and neural protection in EAE T.
T108 252319-252330 Sentence denotes Chitnis, J.
T109 252331-252342 Sentence denotes Imitola, W.
T110 252343-252354 Sentence denotes Elyaman, P.
T111 252355-252365 Sentence denotes Chawla, M.
T112 252366-252381 Sentence denotes Sharuk and S.J.
T113 252382-252466 Sentence denotes Khoury Brigham and Women's Hospital, Harvard Medical School, Boston, USA Background:
T114 252467-252593 Sentence denotes The CD200-CD200R pathway may play an important role in the regulation of immune responses in the periphery as well as the CNS.
T115 252594-252721 Sentence denotes Design/Methods: EAE was induced in C57BL/6 mice (WT) by immunization with peptide 35-55 of myelin oligodendrocyte glycoprotein.
T116 252722-252821 Sentence denotes CD200Fc molecule (Trillium Therapeutics) was administered iv from d0-10 or d10-20 postimmunization.
T117 252822-253013 Sentence denotes Neuronal cortical cultures were prepared from E18 Wlds and WT embryos and exposed to LPS-activated microglia in vitro, with or without an anti-CD200 blocking antibody (Trillium Therapeutics).
T118 253014-253154 Sentence denotes Results: CD200Fc (that signals the CD200R) suppressed clinical disease when administered during both the priming and effector stages of EAE.
T119 253155-253239 Sentence denotes Axonal loss and demyelination were reduced in the CNS of mice that received CD200Fc.
T120 253240-253368 Sentence denotes In treated animals, there was increased production of IL-4 by primed splenocytes in vitro after re-stimulation with MOG peptide.
T121 253369-253474 Sentence denotes We have previously found significantly higher expression of CD200 by Wlds neurons than wild-type neurons.
T122 253475-253592 Sentence denotes Neuronal cultures from Wlds mice were protected after addition of LPS-activated microglia, in contrast to WT neurons.
T123 253593-253736 Sentence denotes Addition of anti-CD200 Ab to Wlds cultures abrogated protection, suggesting that neuronal protection in Wlds is related to expression of CD200.
T124 253737-253749 Sentence denotes Conclusions:
T125 253750-253850 Sentence denotes Signaling through CD200R is associated with protection in EAE and increased Th2 cytokine production.
T126 253851-253934 Sentence denotes Neuronal overexpression of CD200 confers protection from microglial-induced injury.
T127 253935-254040 Sentence denotes Macrophage stimulating protein (MSP) modulates innate immunity through its tyrosine kinase receptor, RON.
T128 254041-254166 Sentence denotes The extent to which RON and MSP are expressed in the central nervous system (CNS) and influence neuroinflammation is unknown.
T129 254167-254327 Sentence denotes Here, we investigated the effects of RON and MSP in multiple sclerosis (MS) and an established mouse model of MS, experimental allergic encephalomyelitis (EAE).
T130 254328-254477 Sentence denotes RON mRNA and protein abundance in the CNS was diminished in both EAE ( pb0.05) and MS ( pb0.01) relative to controls while MSP levels were unchanged.
T131 254478-254574 Sentence denotes MSP inhibited TNF-alpha ( pb0.05), IL-1beta and MMP-9 ( pb0.001) expression in monocytoid cells.
T132 254575-254812 Sentence denotes During EAE, RON heterozygote and null animals showed augmented IL-1beta ( pb0.05), IL-12 ( pb0.01), MMP-12 ( pb0.05) and TNF-alpha ( pb0.001) with diminished IL-4 levels ( pb0.01) in spinal cord compared to wild type littermate controls.
T133 254813-255092 Sentence denotes Moreover, neurological disease in heterozygote and null animals exhibited a more rapid onset and overall worsened severity ( pb0.01) in terms of neurobehavioral deficits together with accentuated demyelination, axonal injury and neuroinflammation, relative to wild type controls.
T134 255093-255225 Sentence denotes Thus, the MSP-RON axis represents a distinct pathway in the CNS by which neuroinflammation and its pathogenic effects are regulated.
T135 255226-255312 Sentence denotes Experimental autoimmune encephalomyelitis in histidine decarboxylase-deficient mice R.
T136 255313-255327 Sentence denotes Pedotti a , S.
T137 255328-255340 Sentence denotes Musio a , S.
T138 255341-255355 Sentence denotes Scabeni a , B.
T139 255356-255368 Sentence denotes Gallo a , L.
T140 255369-255383 Sentence denotes Poliani a , H.
T141 255384-255398 Sentence denotes Ohtsu b and R.
T142 255399-255448 Sentence denotes Mantegazza a a National Neurological Institute C.
T143 255449-255504 Sentence denotes Besta, Milan, Italy; b Tohoku University, Sendai, Japan
T144 255505-255660 Sentence denotes Multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) are generally perceived as T helper 1 (Th1) mediated diseases.
T145 255661-255911 Sentence denotes However, recent observations suggest that both allergic and autoimmune mechanisms are involved in the development of EAE, and pharmacological blockade of histamine, one the main mediator of allergic responses in mice and in humans, might prevent EAE.
T146 255912-256126 Sentence denotes In order to study the contribution of endogenous histamine to the expression of EAE, we induced EAE in histidine decarboxylase (HDC) deficient mice, which express no histamine-producing activity and lack histamine.
T147 256127-256306 Sentence denotes Upon immunization with myelin oligodendrocyte glycoprotein (MOG) 35-55, HDCÀ/À mice developed EAE, with an incidence somehow lower compared to that of the wild type mice (HDCÀ/À).
T148 256307-256550 Sentence denotes The onset of EAE was delayed in HDCÀ/À compared to HDC+/+ mice, but those HDCÀ/À mice that developed the disease presented a more severe course compared to wild type mice, with higher EAE-related mortality and hyper acute course in some cases.
T149 256551-256712 Sentence denotes T cells proliferation to MOG 35-55 was similar in HDCÀ/À and +/+ mice, but T cells from HDCÀ/À mice producegreater amount of interleukin-10 and interferon-gamma.
T150 256713-256817 Sentence denotes Furthermore, HDCÀ/À mice produce higher levels of IgG antibodies against MOG 35-55 compared to +/+ mice.
T151 256818-256892 Sentence denotes These results suggest that endogenous histamine importantly modulates EAE.
T152 256893-257007 Sentence denotes Histamine is a ubiquitous regulator of diverse physiologic processes including inflammation and neurotransmission.
T153 257008-257070 Sentence denotes Four subtypes of histamine receptors are currently recognized.
T154 257071-257327 Sentence denotes Genetic and pharmacological studies have shown that histamine H1 and H2 receptors expressed on T-cells and antigens presenting cells play an important role in regulating T-effector cell functions leading to autoimmune inflammatory responses within the CNS.
T155 257328-257548 Sentence denotes The histamine H3 receptor, which is not expressed by hematopoietic cells, is predominantly presynaptic and serves an important autoregulatory function associated with the release of histamine and other neurotransmitters.
T156 257549-257879 Sentence denotes Here, we show that despite having identical T-cell effector responses, C57BL/6J mice with a disrupted histamine H3 receptor (H3RKO) immunized with MOG35-55 for the induction of experimental allergic encephalomyelitis develop earlier, more severe clinical signs during the acute phase of the disease compared to wild-type controls.
T157 257880-258040 Sentence denotes Enhanced clinical disease in H3RKO mice is also associated with earlier disruption of the blood-brain barrier and significantly greater histopathologic disease.
T158 258041-258284 Sentence denotes Failure of H3RKO mice to limit the acute phase of the autoimmune inflammatory response and clinical disease is consistent with inhibition of negative regulation of presynaptic autoregulatory function in maintaining tissue barrier permeability.
T159 258285-258583 Sentence denotes Additionally, genetic complementation studies indicate that a structural polymorphism within the third intracellular loop of the H3R may underlie eae8, a previously identified QTL controlling the severity of clinical signs and weight loss, a phenotype known to be regulated by central H3R activity.
T160 258584-258733 Sentence denotes Macrophage migration inhibitory factor (MIF) has recently been shown to regulate T cell activation, cell division and macrophage cytokine production.
T161 258734-258845 Sentence denotes Importantly, increased levels of MIF were found in the cerebrospinal fluid of multiple sclerosis (MS) patients.
T162 258846-258957 Sentence denotes Antibody blocking of MIF was shown to blunt acute EAE in mice by interfering with homing of T cells to the CNS.
T163 258958-259150 Sentence denotes We explored the role of MIF in relapsing-remitting EAE in wild type (WT) C57BL/6Â129 mice immunized with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 and in MIFÀ/À C57BL/6Â129 mice.
T164 259151-259311 Sentence denotes Acute EAE was similar between WT and MIFÀ/À mice, but MIFÀ/À mice showed a dramatic decrease in the number and severity of disease relapses compared to WT mice.
T165 259312-259540 Sentence denotes Pro-inflammatory cytokine levels (TNF-alpha, IFN-gamma and IL-6) were sharply decreased in MIFÀ/À mice relative to WT controls at all time points, while IL-4 and IL-10 secreting cells were significantly increased in MIFÀ/À mice.
T166 259541-259647 Sentence denotes Corticosterone levels were markedly elevated in MIFÀ/À mice during the acute disease and recovery periods.
T167 259648-259906 Sentence denotes Our results show that MIF exerts a profound effect on disease relapses, mediated in part by the regulatory effects of glucocorticoid hormones on cytokine production. (Supported by NIH grants AI43376, NS48316 and National MS Society grants RG3091 and RG3272).
T168 259907-260015 Sentence denotes Autoreactive T cells persist in rats protected against EAE and can be activated through innate immunity S.B.
T169 260016-260028 Sentence denotes Conant, N.A.
T170 260029-260042 Sentence denotes Wolf and R.H.
T171 260043-260310 Sentence denotes Swanborg Wayne State University, Detroit, USA Lewis rats are rendered unresponsive to experimental autoimmune encephalomyelitis (EAE) by immunization with myelin basic protein (MBP), or MBP68-86, the dominant encephalitogenic epitope, in incomplete Freund's adjuvant.
T172 260311-260376 Sentence denotes However, protected rats harbor inactive encephalitogenic T cells.
T173 260377-260441 Sentence denotes We investigated whether these cells could be activated in vitro.
T174 260442-260616 Sentence denotes Although they respond poorly to MBP68-86, they proliferate vigorously, and secrete IFN-gamma if cocultured with MBP68-86 plus IL-2 or IL-12, suggesting that they are anergic.
T175 260617-260832 Sentence denotes We could also activate these cells to proliferate and secrete IL-6 with peptide plus CpG oligonucleotide, but not control oligonucleotide; thus, products of innate immunity can activate anergic autoreactive T cells.
T176 260833-261046 Sentence denotes Anti-TGF-beta-1 Ab released the unresponsive T cells from the anergic state in the presence of MBP68-86 alone (i.e., without CpG), whereas TGF-beta-1 inhibited proliferation of MBP68-86 plus CpG-activated T cells.
T177 261047-261185 Sentence denotes CD4+CD25À T cells isolated using magnetic beads proliferated vigorously to CpG plus MBP68-86, whereas CD4+CD25+ cells proliferated poorly.
T178 261186-261637 Sentence denotes TGF-beta has been implicated in T regulatory cell (Treg) activity, and since Treg cells frequently express the CD4+CD25+ phenotype, our results are consistent with the hypothesis that Treg cells maintain autoreactive T cells in the anergic state, but these can be released from anergy by products of the innate immune system (e.g., CpG) which override regulatory mechanisms that maintain immune homeostasis. (Supported by NIH and National MS Society).
T179 261638-261755 Sentence denotes The failure of interferon gamma receptor null mice to recover from EAE is NOT due to the absence of nitric oxide S.A.
T180 261756-261769 Sentence denotes Fordham, M.A.
T181 261770-261787 Sentence denotes Staykova and D.O.
T182 261788-262024 Sentence denotes Willenborg Australian National University Medical School, Canberra, Australia IFN-gamma receptorÀ/À (gamma RÀ/À) mice develop severe, usually fatal EAE when immunised with MOG peptide 35-55 whereas wild type mice develop milder disease.
T183 262025-262223 Sentence denotes Furthermore, passive transfer of disease with MOG35-55 specific lymphoid cells from IFN-gamma RÀ/À mice produces, in knockout (IFN-gamma RÀ/À) mice, severe EAE from which recipients fail to recover.
T184 262224-262317 Sentence denotes Identical cells produce equally severe disease in IFN gamma R+/+ mice but recipients recover.
T185 262318-262457 Sentence denotes These results provided evidence that IFN-gamma is not essential for EAE development but plays an important role in down-regulating disease.
T186 262458-262535 Sentence denotes We hypothesised that IFN-gamma stimulates NO production which limits disease.
T187 262536-262565 Sentence denotes This hypothesis is incorrect.
T188 262566-262793 Sentence denotes Transfer of encephalitogenic T cells from immunised gamma RÀ/À mice into inducible nitric oxide synthase knockout (iNOSÀ/À) mice, which can respond to IFN-gamma but cannot make NO, results in severe EAE yet the animals recover.
T189 262794-263026 Sentence denotes We also show that EAE in 3 different strains of mice each lacking the IFN-gamma R and immunised with three different encephalitogens all develop severe, usually fatal EAE with identical pathology-extensive neutrophilic infiltration.
T190 263027-263386 Sentence denotes We conclude that the inability of IFN-gamma RÀ/À mice to recover from EAE is not due to their inability to shut off effector T cells but to the fact that the absence of IFN-gamma responsiveness results in a malignant neutrophilic inflammatory response rather than a relatively benign mononuclear response. , while in its presence, inhibition by NO is reduced.
T191 263387-263510 Sentence denotes The interaction between these two free radicals may regulate immune response intensity and autoimmunity, as studied in EAE.
T192 263511-263582 Sentence denotes The identity of the source(s) of NO and O 2 À in the spleen is unknown.
T193 263583-263755 Sentence denotes Using cell separation, we show that Gr-1 spleen cells from primed mice are responsible for regulation of T cell proliferation by NO and O 2 À in an MHC-unrestricted manner.
T194 263756-263879 Sentence denotes This was demonstrated in the presence of activated spleen cells from naRve DO11.10 mice, which do not produce NO or O 2 À .
T195 263880-263956 Sentence denotes Furthermore, non-adherent Gr-1 cells are a major source of O 2 À production.
T196 263957-264118 Sentence denotes FACS analysis indicated that these Gr-1 cells are CD11b hi , CD11c neg , B220 neg , I-A/I-E neg and F4/80 lo , possibly representing immature myeloid Gr-1 cells.
T197 264119-264192 Sentence denotes Purified Gr-1 + cells contain different stages of granulocyte maturation.
T198 264193-264374 Sentence denotes M. tuberculosis in CFA is responsible for the Gr-1 cell increase in the spleen following immunization, which starts as early as 4 days p.i. and continues until at least 4 weeks p.i.
T199 264375-264463 Sentence denotes These studies provide a novel way for innate immune cells to regulate adaptive immunity.
T200 264464-264594 Sentence denotes Antibody responses to the glial progenitor cell proteoglycan NG2/AN2 exacerbate experimental autoimmune encephalomyelitis (EAE) E.
T201 264595-264608 Sentence denotes Mathey a , A.
T202 264609-264624 Sentence denotes Schubart b , K.
T203 264625-264640 Sentence denotes Williams a , J.
T204 264641-264657 Sentence denotes Trotter c and C.
T205 264658-264807 Sentence denotes Linington a a University of Aberdeen, Aberdeen, Scotland, UK; b Harvard Medical School, Boston, USA; c Johannes Gutenberg-Universität, Mainz, Germany
T206 264808-264984 Sentence denotes Remyelination in the adult central nervous system is carried out by a population of glial progenitor cells (NG2/AN2 positive) that migrate to the lesion site and repair injury.
T207 264985-265117 Sentence denotes However, in multiple sclerosis (MS), this endogenous repair mechanism is inefficient and ultimately fails as the disease progresses.
T208 265118-265385 Sentence denotes The reasons for failure of remyelination in chronic MS lesions are poorly understood; however, the presence of autoantibodies to NG2 in the cerebrospinal fluid of MS patients may be indicative of an autoimmune response against the cells responsible for remyelination.
T209 265386-265527 Sentence denotes We have used a DNA vaccination strategy in rats to generate a specific autoantibody response to the first two LNS domains of the NG2 protein.
T210 265528-265611 Sentence denotes The antibody response can be assayed by Western blotting, ELISA and flow cytometry.
T211 265612-265819 Sentence denotes This DNA vaccination strategy has allowed us to assess the effects of an NG2-specific antibody response on the modulation of disease severity in adoptive transfer EAE and on remyelination in MOG induced EAE.
T212 265820-266010 Sentence denotes Our findings indicate that self-tolerance to the NG2 protein can be disrupted in the rat and that the consequent autoantibody response enhances the clinical and histological severity of EAE.
T213 266011-266261 Sentence denotes Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) receptors expressed in the nervous system include S1P1, S1P3 and LPA2 (in neuronal cells), LPA1 and S1P5 (in white matter tracts) and S1P2 (in both neuronal cells and white matter tracts).
T214 266262-266401 Sentence denotes In the immune system lymphocytes express S1P4, unstimulated T helper cells express LPA2 and S1P4, whilst macrophages express LPA1 and S1P3.
T215 266402-266540 Sentence denotes Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease with pathological features equivalent to multiple sclerosis (MS).
T216 266541-266667 Sentence denotes RNA prepared from spinal cords of control and EAE rats was profiled for S1P and LPA receptor expression using Taqman analysis.
T217 266668-266825 Sentence denotes Average (n=5) mRNA levels for S1P1, S1P5 and LPA1 receptors were each decreased 0.4-, 0.6-and 0.5-fold respectively, in EAE samples in comparison to control.
T218 266826-266951 Sentence denotes However, mRNA for S1P2, S1P4, LPA2 and LPA3 receptors were increased 3.3-, 12.5-, 2.7-and 1.4-fold in comparison to controls.
T219 266952-267049 Sentence denotes S1P3 receptor mRNA expression was not detected in control group but was induced in the EAE group.
T220 267050-267251 Sentence denotes The significant increase of S1P4 receptors reflects the huge infiltrating lymphocytes in the EAE model and suggests that targeting this receptor may influence the progression of EAE and potentially MS.
T221 267252-267396 Sentence denotes The multifunctional cytokine Oncostatin M (OSM) is involved in the progression and resolution of the inflammatory process (Hurst et al., 2002) .
T222 267397-267669 Sentence denotes While the exact functional role of this cytokine in neuroinflammation is currently unknown, several studies have documented elevated levels of OSM in the brains of patients with the progressive relapsing-remitting neurological inflammatory disease multiple sclerosis (MS).
T223 267670-267828 Sentence denotes OSM may play an important role in the progression of neuroinflammation by virtue of its spatial and temporal expression and its role in leukocyte recruitment.
T224 267829-267980 Sentence denotes In this study, we have evaluated the spatial and temporal expression of OSM in neuro-inflammation using the chronic relapsing Biozzi mouse model of MS.
T225 267981-268148 Sentence denotes Brain and spinal cord tissues were collected from mice at different stages of the disease process and semi-quantitative PCR used to determine the presence of OSM mRNA.
T226 268149-268286 Sentence denotes Evidence will be presented to indicate that tissue levels of OSM mRNA are associated with the severity of symptoms and phases of disease.
T227 268287-268540 Sentence denotes Cell adhesion molecules are of fundamental importance in autoimmune diseases such as multiple sclerosis (MS) and an animal model for MS, the experimental autoimmune encephalomyelitis (EAE), by affecting the interaction between target and effector cells.
T228 268541-268679 Sentence denotes Here, we define the role of a cell adhesion molecule, termed ninjurin-1, in the interaction between neurons and activated microglia cells.
T229 268680-268919 Sentence denotes In peripheral nerve regeneration, this molecule is upregulated and promotes nerve outgrowth; here, we show that ninjurin-1 expression is regulated by cytokines and located at the interface between the injured axons and activated microglia.
T230 268920-269029 Sentence denotes The homophilic binding of ninjurin-1 between neurons and microglia was efficiently blocked by a oligopeptide.
T231 269030-269105 Sentence denotes Moreover, we identified ninjurin-1 in injured axons and glial cells in EAE.
T232 269106-269258 Sentence denotes Therefore, we suggest that ninjurin-1 is implicated during the pathology of EAE whereby cytokines regulate the adhesion of glial cells to injured axons.
T233 269259-269377 Sentence denotes The role of the central dopamine depletion in regulation of experimental autoimmune encephalomyelitis in C57BL mice E.
T234 269378-269400 Sentence denotes Balkowiec-Iskra a , I.
T235 269401-269429 Sentence denotes Kurkowska-Jastrzebska b , I.
T236 269430-269443 Sentence denotes Joniec a , A.
T237 269444-269464 Sentence denotes Czlonkowska b and A.
T238 269465-269572 Sentence denotes Czlonkowski a a Medical University, Warsaw, Poland; b Institute of Psychiatry and Neurology, Warsaw, Poland
T239 269573-269690 Sentence denotes Circumstantial evidence suggests the involvement of central dopaminergic system in the regulation of immune response.
T240 269691-269838 Sentence denotes The aim of our study was to investigate the influence of central dopamine depletion on experimental autoimmune encephalomyelitis (EAE) progression.
T241 269839-269951 Sentence denotes Dopamine depletion was obtained by treatment with 1-methyl-4phenyl-1,2,3,6-tetrahydropiridine (MPTP) (40 mg/kg).
T242 269952-270040 Sentence denotes EAE was elicited 7 days after MPTP intoxication by immunization with MOG 35-55 (150 Ag).
T243 270041-270188 Sentence denotes In mice with injured dopaminergic system, onset of the symptoms was observed 15 days earlier (3 day vs. 18 day) than in mice not treated with MPTP.
T244 270189-270324 Sentence denotes In MPTP+EAE group, two attacks were noted with a longer total time comparing to EAE group, in which only one short attack was observed.
T245 270325-270411 Sentence denotes Similarly, remission of symptoms in EAE group appeared earlier than in MPTP+EAE group.
T246 270412-270473 Sentence denotes However, the disease index did not differ between the groups.
T247 270474-270654 Sentence denotes Histological analysis revealed stronger infiltration by inflammatory cells in the meninges and in perivascular space of the white matter of the lumbar spinal cord of MPTP+EAE mice.
T248 270655-270741 Sentence denotes In our previous studies, MPTP has been shown to have no direct action on immune cells.
T249 270742-270845 Sentence denotes Herein, we demonstrate, that EAE induction and progression may be dependent on central dopamine action.
T250 270846-270912 Sentence denotes We suggest indirect mechanisms to be involved in reported results.
T251 270913-271105 Sentence denotes Murine EAE is an established multiple sclerosis (MS) model generated in our laboratory by inducing autoimmunity to a peptide (amino acids 35-55) from myelin oligodendrocyte glycoprotein (MOG).
T252 271106-271294 Sentence denotes Use of a single injection protocol, and two different mouse strains, generates diseases resembling relapsing-remitting (RR) MS (NOD/Lt mice), or primary progressive (PP) MS (C57Bl/6 mice).
T253 271295-271434 Sentence denotes Current evidence of axonglia and glia-glia communication lead us to undertake a time course study of astrocyte responses in both EAE types.
T254 271435-271664 Sentence denotes We report the significant finding that the two MS types have different astrocyte response patterns: (1) in the pre-clinical period, considerable astrocyte hypertrophy occurs in RR-EAE whereas PP-EAE shows a much smaller increase;
T255 271665-271797 Sentence denotes (2) with progression, astrocyte hypertrophy occurs throughout white matter and grey matter with or without parenchymal inflammation;
T256 271798-272131 Sentence denotes (3) during remission (RR-EAE), astrocyte hypertrophy remains; (4) astrocyte processes in RR-EAE intercalate between and separate inflammatory cells into small groups whereas inflammatory foci in the PP-EAE are free of astrocyte processes; (5) in RR-EAE astrocyte response is related to disease stage; but to clinical score in PP-EAE.
T257 272132-272349 Sentence denotes These observations suggest that the astrocyte response is considerably less active in PP-EAE, giving rise to the hypothesis that the genetic context of this response may influence the particular form of MS expression.
T258 272350-272363 Sentence denotes Introduction:
T259 272364-272461 Sentence denotes The signalling molecule sonic hedgehog (SHH) is involved in several processes of CNS development.
T260 272462-272665 Sentence denotes Recently, the protein concentration of SHH has been shown to be upregulated during active disease in a spontaneously demyelinating mouse model and to be decreased in multiple sclerosis (MS) white matter.
T261 272666-272899 Sentence denotes Specific object of our study was to investigate the expression pattern of SHHduring lesion evolution in myelin-oligodendrocyte-glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), a model strongly mimicking MS.
T262 272900-272949 Sentence denotes Methods: MOG-EAE was actively induced in DA rats.
T263 272950-273066 Sentence denotes Histological evaluation was performed on paraffin-embedded CNS sections on days 20 to 120 after active immunization.
T264 273067-273075 Sentence denotes Results:
T265 273076-273209 Sentence denotes In actively demyelinating and inactive lesions immunoreactivity for SHH was present in macrophages, astrocytes and endothelial cells.
T266 273210-273284 Sentence denotes In addition, astrocytes in the lesion surrounding showed staining for SHH.
T267 273285-273454 Sentence denotes In early remyelinating and remyelinated lesions, expression of SHH was found in astrocytes, macrophages, endothelial cells and axons, which showed signs of acute injury.
T268 273455-273543 Sentence denotes The highest density of SHH expression on axons was found in early remyelinating lesions.
T269 273544-273555 Sentence denotes Conclusion:
T270 273556-273671 Sentence denotes We provide the first immunohistochemical analysis of the expression pattern of SHH in autoimmune encephalomyelitis.
T271 273672-273755 Sentence denotes Our study demonstrates that SHH plays a role in repair mechanisms of the adult CNS.
T272 273756-273875 Sentence denotes The localization of SHH on injured axons in early remyelination might indicate a role of SHH as axonal survival factor.
T273 273876-273977 Sentence denotes Alterations of neurotrophic factors during the course of experimental autoimmune encephalomyelitis J.
T274 273978-273993 Sentence denotes Ah-Sue and V.W.
T275 273994-274037 Sentence denotes Yong University of Calgary, Calgary, Canada
T276 274038-274268 Sentence denotes Neurotrophic factors can confer neuroprotection, regeneration and immunomodulation in diseases of the central nervous system, including multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE).
T277 274269-274344 Sentence denotes Elevation of certain neurotrophic factors have been observed in EAE and MS.
T278 274345-274562 Sentence denotes In this study, we sought to determine the expression profile of neurotrophic factors in relation to the stage of disease during progression and remission of EAE in order to gain insights into their possible functions.
T279 274563-274683 Sentence denotes Relapsing-remitting EAE was induced in female, 129/SvEv mice using myelin oligodendrocyte glycoprotein as the immunogen.
T280 274684-274794 Sentence denotes Mice were sacrificed 6 days postimmunization, at first sign of disease, during peak disease, and in remission.
T281 274795-274896 Sentence denotes The lumbar/sacral spinal cords were extracted and analysed using real time-polymerase chain reaction.
T282 274897-275019 Sentence denotes Multiple neurotrophic factors were elevated in EAE, including ciliary neurotrophic factor and insulinlike growth factor-1.
T283 275020-275144 Sentence denotes A prominent juncture for the upregulation of several neurotrophic factors was at peak disease and at resolution (remission).
T284 275145-275298 Sentence denotes Current experiments seek to evaluate the cellular sources and the function of neurotrophic factors in EAE, particularly with regards to immunomodulation.
T285 275299-275449 Sentence denotes Multiple sclerosis (MS) is caused by a combination of genetic predisposition and environmental factors, resulting in T cell infiltration into the CNS.
T286 275450-275575 Sentence denotes Many environmental factors have been implicated in disease although results of studies performed to date remain inconclusive.
T287 275576-275761 Sentence denotes A possible genetic/biochemical factor implicated in MS is the dysregulation of matrix metalloproteinases (MMPs), a family of zinc containing proteases with many physiological functions.
T288 275762-275842 Sentence denotes In many diseases, these proteases are upregulated and acquire harmful functions.
T289 275843-275977 Sentence denotes Specifically, MMP-9 has been implicated as detrimental in experimental autoimmune encephalitis (EAE), an animal model of MS and in MS.
T290 275978-276110 Sentence denotes In this study, we have examined the activation of MMP-9 by heavy metals, and have found that Hg exerts a biphasic response on MMP-9.
T291 276111-276183 Sentence denotes Importantly, at 100 nM, Hg increases MMP-9 activity two-fold ( pb0.001).
T292 276184-276318 Sentence denotes This combination of Hg and MMP-9 increases the levels of interferon-gamma by human and mouse T cells in culture comparably ( pb0.001).
T293 276319-276452 Sentence denotes The requirement of MMP-9 was demonstrated by the inability of Hg to increase interferon-gamma levels in T cells from MMP-9 null mice.
T294 276453-276543 Sentence denotes Recovery of cytokine levels followed exogenous addition of MMP-9 to Hg-treated null cells.
T295 276544-276634 Sentence denotes Ongoing experiments address the facilitation of EAE in Hg-treated MMP-9 and wildtype mice.
T296 276635-276777 Sentence denotes We postulate that MMP-9 dysregulation and Hg exposure, leading to altered T cell reactivity, may underlie the progression of some cases of MS.
T297 276778-276887 Sentence denotes Murine EAE is a well established model that recapitulates many clinical and physiopathological aspects of MS.
T298 276888-277013 Sentence denotes A close examination of the earliest changes in gene expression, even those preceding inflammation, has not been reported yet.
T299 277014-277194 Sentence denotes We collected serum and CNS tissue from NOD mice both before immunization with MOG 35-55 and at 13 timepoints encompassing the first clinical attack (days 3 to 19 postimmunization).
T300 277195-277417 Sentence denotes Microarray-based gene expression profiling was performed in spinal cords from four mice at each timepoint (82 arrays in total), while other three animals were used for histopathological staining at the same time intervals.
T301 277418-277579 Sentence denotes Supervised and unsupervised machine learning algorithms were used to identify expression signatures that correlated with disease stage and histological profiles.
T302 277580-277698 Sentence denotes Remarkably, the earliest expression changes in the CNS were observed before any histological evidence of inflammation.
T303 277699-277901 Sentence denotes In addition, a mass spectrometry-based proteomic profile was obtained from the sera of each animal and was correlated with gene expression patterns, in the search for early markers of neuroinflammation.
T304 277902-278013 Sentence denotes Such high frequency expression data will enable the formulation of more precise models of disease pathogenesis.
T305 278014-278205 Sentence denotes Our study demonstrates the utility of combined genomics and proteomics approaches towards unraveling the molecular pathways leading to clinical disease and recovery in EAE, and eventually MS.
T306 278206-278315 Sentence denotes Chemokine receptors CCR7, CCR8 and CX3CR1 in chronic relapsing experimental autoimmune encephalomyelitis A.R.
T307 278316-278329 Sentence denotes Glabinski, B.
T308 278330-278345 Sentence denotes Bielecki and K.
T309 278346-278385 Sentence denotes Selmaj Medical University, Lodz, Poland
T310 278386-278503 Sentence denotes Chemokines are small molecules which direct migration of inflammatory cells towards the tissue sites of inflammation.
T311 278504-278630 Sentence denotes Because of that ability, chemokines are involved in pathogenesis of inflammatory diseases of the central nervous system (CNS).
T312 278631-278901 Sentence denotes In the present study, we analyzed expression of three lately described chemokine receptors CCR7, CCR8 and CX3CR1 in the CNS and in peripheral tissues during chronic-relapsing experimental autoimmune encephalomyelitis (ChREAE), an animal model of multiple sclerosis (MS).
T313 278902-278910 Sentence denotes Methods:
T314 278911-278996 Sentence denotes Female (SWRxSJL/J)F1 mice were immunized with an encephalitogenic PLP139-151 peptide.
T315 278997-279089 Sentence denotes Chemokine receptors expression was analyzed using quantitative Rnase Protection Assay (RPA).
T316 279090-279176 Sentence denotes Analysis was performed during first attack, remission and the second attack of ChREAE.
T317 279177-279222 Sentence denotes Animals without ChREAE were used as controls.
T318 279223-279231 Sentence denotes Results:
T319 279232-279389 Sentence denotes We observed upregulation of all three analyzed chemokine receptors (CCR7, CCR8 and CX3CR1) in the spinal cord during the first and the second ChREAE attacks.
T320 279390-279442 Sentence denotes In the brains, this upregulation was less prominent.
T321 279443-279534 Sentence denotes Expression of CCR7 and CX3CR1 in the spinal cord correlated well with the disease severity.
T322 279535-279630 Sentence denotes In spleens, expression of all three chemokine receptors was comparable in all phases of ChREAE.
T323 279631-279719 Sentence denotes In the blood, expression of CCR7 was lower during ChREAE than in control normal animals.
T324 279720-279731 Sentence denotes Conclusion:
T325 279732-279922 Sentence denotes Our results suggest that chemokine receptors CCR7, CCR8 and CX3CR1 are involved in pathogenesis of ChREAE and that they may be potential target for treatment of the CNS autoimmune disorders.
T326 279923-280052 Sentence denotes 188 TWEAK, the TNF-related weak inducer of apoptosis, and its receptor Fn14 in experimental autoimmune encephalomyelitis (EAE) A.
T327 280053-280063 Sentence denotes Müller, X.
T328 280064-280073 Sentence denotes Pedré, I.
T329 280074-280085 Sentence denotes Kleiter, G.
T330 280086-280102 Sentence denotes Giegerich and A.
T331 280103-280257 Sentence denotes Steinbrecher University of Regensburg, Regensburg, Germany TWEAK, a member of the TNF superfamily, mediates prominflammatory effects by its receptor Fn14.
T332 280258-280382 Sentence denotes We examined the consequences of TWEAKand Fn14-blockade in chronic relapsing experimental autoimmune encephalomyelitis (EAE).
T333 280383-280648 Sentence denotes Inducing a neutralizing antibody response TWEAK or Fn14, respectively, we found a significant amelioration of the clinical course of MOG-induced EAE in rats and of PLP(139-151)induced EAE in SJL mice accompanied by a significant decrease of spinal cord infiltrates.
T334 280649-280829 Sentence denotes In addition, we performed DNA-vaccination with an eukaryotic expression plasmid encoding for TWEAK resulting in a more severe disease course compared to control vaccinated animals.
T335 280830-280987 Sentence denotes Further in vitro and ex vivo studies suggest that blockade of Fn14-mediated signalling interferes with the recruitment of immune effector cells into the CNS.
T336 280988-281138 Sentence denotes Expression of adrenomedullin (ADM) receptors in the central nervous system of Lewis rats during acute experimental allergic encephalomyelitis (EAE) C.
T337 281139-281152 Sentence denotes Paul a and C.
T338 281153-281259 Sentence denotes Bolton b a University of the West of England, Bristol, UK; b William Harvey Research Institute, London, UK
T339 281260-281394 Sentence denotes Loss of normal blood-brain barrier (BBB) function is an integral feature of the neuroinflammatory process in multiple sclerosis (MS) .
T340 281395-281520 Sentence denotes Previously, we demonstrated that restoration of BBB function is associated with an improved clinical outcome in models of MS.
T341 281521-281693 Sentence denotes In vitro studies have shown ADM capable of regulating BBB characteristics including transendothelial electrical resistance, permeability and p-glycoprotein pump activation.
T342 281694-281810 Sentence denotes Therefore, ADM-mediated control of BBB function may be a viable therapeutic target for controlling the course of MS.
T343 281811-281957 Sentence denotes Clearly, it is essential to determine whether the receptor pathway is intact during a neuroimmune challenge such as occurs in EAE the model of MS.
T344 281958-282197 Sentence denotes Using immunohistochemistry, we have assessed the expression of ADM receptors and receptor-activity-modifying proteins (RAMP) 2 and 3, which confer calcitonin receptor-like receptor specificity for ADM, in the CNS of animals with acute EAE.
T345 282198-282394 Sentence denotes Preliminary studies indicate that normal spinal cord RAMP2 expression is strongly associated with morphologically identified capillary structures while RAMP3 exhibits a very low vascular presence.
T346 282395-282502 Sentence denotes In EAE CNS tissues, RAMP2 expression is maintained both immediately before and after the height-of-disease.
T347 282503-282543 Sentence denotes RAMP3 expression is similarly preserved.
T348 282544-282663 Sentence denotes Hence, the receptor pathway with respect to RAMP2 and 3 expression appears intact at the cerebrovasculature during EAE.
T349 282664-282780 Sentence denotes Therefore, the potential exists to employ ADM and related agonists to restore BBB function during neuroinflammation.
T350 282781-282909 Sentence denotes Experimental autoimmune encephalomyelitis (EAE) is a well-characterised autoimmune disorder of the central nervous system (CNS).
T351 282910-283094 Sentence denotes Investigations into the enzymes controlling the complex alterations in the extracellular matrix (ECM) environment may lead to a greater understanding of their role in CNS inflammation.
T352 283095-283200 Sentence denotes ADAMTS enzymes are metalloproteinases that degrade versican, aggrecan, brevican, phosphacan and neurocan.
T353 283201-283301 Sentence denotes These are found within the CNS and promote cell adhesion, migration and influence neurite outgrowth.
T354 283302-283638 Sentence denotes To investigate the potential role of ADAMTSs, white matter from the spinal cord of rats at pre-disease, peak and recovery stages of acute EAE and naive controls were assessed for the expression of ADAMTS-1, -4 and -5, their natural inhibitor, TIMP-3 as well as the ECM components, phosphacan and neurocan, at the mRNA and protein level.
T355 283639-283851 Sentence denotes ADAMTS-4, -5, TIMP-3 and phosphacan were all downregulated in the CNS at peak disease compared to naRve controls, whereas ADAMTS-1 and neurocan were upregulated in pre-diseased animals compared to naRve controls.
T356 283852-283911 Sentence denotes This provides the first report of ADAMTS expression in EAE.
T357 283912-283955 Sentence denotes This work was funded by The Wellcome Trust.
T358 283956-284077 Sentence denotes Previous work found that MMP-12 is highly expressed in the spinal cord of mice afflicted with EAE, an animal model of MS.
T359 284078-284207 Sentence denotes Currently, we are investigating whether there is an interaction between MMP-12 and OPN, and their function(s) in EAE progression.
T360 284208-284351 Sentence denotes In vitro, we found that MMP-12 time-dependently cleaved OPN into 2 major products, which was inhibited by BB-94, a metalloproteinase inhibitor.
T361 284352-284608 Sentence denotes EAE was produced in 8-9 weeks old female C57BL/6 mice via immunization with myelin oligodendrocyte glycoprotein and animals were sacrificed either at the initiation of disease, at the ascending phase of disease, at peak disease, and at score stabilization.
T362 284609-284697 Sentence denotes The spinal cords were examined for mRNA and protein expression levels of OPN and MMP-12.
T363 284698-284856 Sentence denotes Western blot analyses showed that at disease onset, OPN cleavage products first appeared, reaching a maximum expression during the ascending phase of disease.
T364 284857-284918 Sentence denotes The mRNA expression of OPN and MMP-12 showed a similar trend.
T365 284919-285019 Sentence denotes Current experiments seek to identify the MMP-12 cleavage products of OPN, and their role in disease.
T366 285020-285131 Sentence denotes We postulate that the interaction between MMP-12 and OPN may have important roles in EAE onset and progression.
T367 285132-285319 Sentence denotes Experimental autoimmune encephalomyelitis (EAE) induced with recombinant myelin oligodendrocyte glycoprotein (rMOG) in rat is an accurate model of multiple sclerosis (MS) immunopathology.
T368 285320-285494 Sentence denotes A growing body of experimental evidence points to a critical involvement of matrix metalloproteinases (MMPs) at critical checkpoints in the immunopathogenesis of the disease.
T369 285495-285608 Sentence denotes However, our knowledge on the new MMP family members expression profile in inflammatory demyelination is limited.
T370 285609-285772 Sentence denotes In the present study, we analyzed the expression pattern of all 22 known rat MMPs in a rMOG-EAE model in DA rats during the clinical course using real time RT-PCR.
T371 285773-285944 Sentence denotes Central nervous system infiltrating T-cells were detected by immunohistochemistry on cryostat sections, and RNA was extracted from these areas out of consecutive sections.
T372 285945-286043 Sentence denotes MMP mRNA levels were measured and their variations related to early stage non-symptomatic animals.
T373 286044-286182 Sentence denotes The mRNA of MMP-12 was found to be most strikingly up-regulated, remaining highly expressed even during the recovery phase of the disease.
T374 286183-286273 Sentence denotes Membrane-bound MMP-14 and recently described MMP-23 were among other up-regulated enzymes.
T375 286274-286382 Sentence denotes On the other hand, MMP-13 and MMP-27 revealed a persistent down-regulation during the course of the disease.
T376 286383-286517 Sentence denotes Our results demonstrate a highly differential regulation of MMP mRNA expression in inflammatory infiltrates in the rMOG-EAE rat model.
T377 286518-286682 Sentence denotes Further studies on specific expression patterns of selected MMPs might help to broaden our understanding on the specific role of MMPs in inflammatory demyelination.
T378 286683-286792 Sentence denotes Inducible nitric oxide synthase (iNOS)-mediated axonal injury in experimental autoimmune encephalomyelitis F.
T379 286793-286808 Sentence denotes Aboul-Enein, P.
T380 286809-286819 Sentence denotes Weiser, M.
T381 286820-286832 Sentence denotes Bradl and H.
T382 286833-286902 Sentence denotes Lassmann Brain Research Institute, Vienna University, Vienna, Austria
T1 286903-287035 Sentence denotes Multiple sclerosis (MS) is a T-cell mediated inflammatory disease of the central nervous system (CNS) of supposed autoimmune nature.
T2 287036-287291 Sentence denotes Since the hallmark of MS pathology is the demyelinated plaque associated with relative preservation of axons despite complete destruction of their myelin sheaths, axonal injury has been interpreted only as a secondary consequence of primary demyelination.
T3 287292-287375 Sentence denotes Axonal degeneration is recognized to be an important cause of neurological deficit.
T4 287376-287505 Sentence denotes However, pathogenetic mechanisms underlying axonal injury within inflammatory diseases of the CNS remain still largely undefined.
T5 287506-287649 Sentence denotes As there is only little evidence for direct immune attack, free radicals as oxygen and/or nitrogen species may be crucial for axonal pathology.
T6 287650-287898 Sentence denotes For this purpose, we induced acute monophasic EAE in the Lewis rat by passive transfer of encephalitogenic MBPspecific T-cells in wild type and in PLP overexpressing transgenic Lewis rats in presence or absence of demyelinating anti-MOG antibodies.
T7 287899-288123 Sentence denotes Performing immunohistochemistry, we found in both experiments expression of inducible Nitric Oxide Synthase (iNOS), a key enzyme of free radical production, exclusively confined to perivascular macrophages and/ or microglia.
T8 288124-288277 Sentence denotes Acute axonal injury, identified by the accumulation of amyloid precursor protein, correlated strictly with numbers of iNOSpositive macrophages/microglia.
T9 288278-288384 Sentence denotes Anti-MOG antibody mediated demyelination resulted in an augmentation of axonal injury and iNOS expression.
T10 288385-288467 Sentence denotes Our findings may have major implications for therapy of inflammatory CNS diseases.
T11 288468-288627 Sentence denotes The BN rat is reported to be resistant to induction of Th1 type experimental autoimmune encephalomyelitis (EAE) and a number of mechanisms have been suggested.
T12 288628-288738 Sentence denotes We provide evidence that the high production of nitric oxide (NO) in the periphery results in this resistance.
T13 288739-288965 Sentence denotes Spleen cells from BN rats make 3-6 times more NO when stimulated with IFN gamma than do cells from PVG or Lewis rat and the BN rat makes substantially more NO than either EAE susceptible strain following immunisation with CFA.
T14 288966-289101 Sentence denotes If carbonyl iron is used as adjuvant, there is no increase in NO levels in the BN rats and they are rendered highly susceptible to EAE.
T15 289102-289214 Sentence denotes CFA given simultaneously with neuroantigen and carbonyl iron drives up NO levels and the resistance is restored.
T16 289215-289458 Sentence denotes EAE produced using carbonyl iron is characterised by extensive presence of macrophage/microglia in the central nervous system (CNS) lesions and the cytokine profiles in the lymph nodes and CNS do not differ from the ones in the EAE Lewis rats.
T17 289459-289504 Sentence denotes Expression of iNOS and COX-2 in TMEV-IDD N.G.
T18 289505-289518 Sentence denotes Carlson, K.E.
T19 289519-289529 Sentence denotes Hill, H.E.
T20 289530-289543 Sentence denotes Watt and J.W.
T21 289544-289614 Sentence denotes Rose VA-SLCHCS, University of Utah, Salt Lake City, UT, USA Objective:
T22 289615-289713 Sentence denotes We recently reported that COX-2 and iNOS are expressed in chronic-active plaques from MS patients.
T23 289714-289834 Sentence denotes We proposed that these enzymes contribute to enhanced glutamate-mediated excitotoxicity of oligodendrocytes and neurons.
T24 289835-290086 Sentence denotes Confocal microscopy of COX-2 and iNOS expression in the Theiler's murine encephalomyelitis virus (TMEV) induced demyelinating disease (TMEV-IDD) was examined to assess whether their expression precedes the onset of neuropathology and clinical disease.
T25 290087-290095 Sentence denotes Methods.
T26 290096-290264 Sentence denotes Mice were given IC injections of TMEV and were assessed for clinical symptoms, demyelination and inflammation and intervals of 1, 2, 3, 4, 5 and 9 weeks post injection.
T27 290265-290454 Sentence denotes Expression of iNOS and COX-2 was examined using immunofluorescence confocal microscopy in combination with the cell-specific markers CNPase (for oligodendrocytes) and GFAP (for astrocytes).
T28 290455-290561 Sentence denotes Results: COX-2 and iNOS were detected in isolated regions of the brain as early as 2 weeks post-injection.
T29 290562-290673 Sentence denotes Purkinje cells of the cerebellum expressed iNOS.iNOS and COX-2 was also observed in regions of the hippocampus.
T30 290674-290810 Sentence denotes After 4 weeks, just prior to the onset of symptoms, moderate amounts of iNOS were observed in spinal cord regions near oligodendrocytes.
T31 290811-290900 Sentence denotes COX-2 was also observed in association with iNOS both nearby and within oligodendrocytes.
T32 290901-290912 Sentence denotes Conclusion:
T33 290913-291127 Sentence denotes The expression of COX-2 that we observed in oligodendrocytes may have important consequences with respect to vulnerability of these cells to glutamate-mediated excitotoxicity analogous with neuronal excitotoxicity.
T34 291128-291236 Sentence denotes Expression of COX-2 may then render oligodendrocytes more vulnerable to glutamatemediated excitotoxic death.
T35 291237-291397 Sentence denotes Oxidative modification alters the autoantigenicity of myelin oligodendrocyte glycoprotein-implications for induction of disease and tolerance in mice and men M.
T36 291398-291413 Sentence denotes W3llberg a , J.
T37 291414-291432 Sentence denotes Bergquist b and R.
T38 291433-291523 Sentence denotes Harris a a Karolinska Institutet, Stockholm, Sweden; b Uppsala University, Uppsala, Sweden
T39 291524-291667 Sentence denotes Myelin antigens may become autoantigenic through modification of their structure, but this concept has received little or no attention to date.
T40 291668-291921 Sentence denotes Understanding the effects of chemical modification of myelin antigens by mimicking in vitro processes which are likely to occur during inflammatory reactions in vivo may provide clues as to the antigenic nature of the proteins underlying MS development.
T41 291922-292082 Sentence denotes We studied modification of myelin oligodendrocyte glycoprotein (MOG), with malondialdehyde (MDA), which is physiologically generated through lipid-peroxidation.
T42 292083-292221 Sentence denotes Using IEF, FPLC and FTICR mass spectrometric analyses, we demonstrate that MDA modification leads to changes in protein weight and charge.
T43 292222-292379 Sentence denotes DBA/1 mice immunised with MDA-MOG developed a more severe form of EAE, and antigen-specific recall responses were elevated to MDA-MOG compared to normal MOG.
T44 292380-292460 Sentence denotes Formulation of a MOG-alum vaccine with MDA-MOG improved its protective efficacy.
T45 292461-292556 Sentence denotes Finally, CSF from MS patients had higher titres of anti-MOG IgG to MDA-MOG than to control MOG.
T46 292557-292734 Sentence denotes We believe that oxidative modification of MOG leads to enhanced autoantigenicity that promotes induction of disease induction, induction of protection and diagnosis of human MS.
T47 292735-292983 Sentence denotes To develop a therapeutic strategy using single amino acid substitutions of MOG 8-21 and PLP 56-70 we first selected those alanine and lysine amino acids substitutions that did not induce EAE in the mice but in vitro induced strong T cell responses.
T48 292984-293184 Sentence denotes While many substituted peptides were encephalitogenic suggesting those residues were not critical for ether binding to MHC or activating T cells, others did not induce either disease or proliferation.
T49 293185-293333 Sentence denotes In addition several peptides were non-encephalitogenic but were immunogenic in vitro suggesting that these peptides may induce regulatory responses.
T50 293334-293587 Sentence denotes Two such alanine substitutions of MOG 8-21 (MOG P-A10 and MOG I-A11) selected on basis of not inducing EAE and with a high T-cell response in vitro were administered in a tolerance regimen during remission in an attempt to inhibit chronic relapsing EAE.
T51 293588-293599 Sentence denotes Conclusion:
T52 293600-293823 Sentence denotes While nonencephalitogenic single amino acid substitutions of MOG 8-21 and PLP 56-70 inhibit relapsing disease in mice immunised with MOG 8-21, the therapy was significantly more effective when the wild-type peptide is used.
T53 293824-293834 Sentence denotes Objective:
T54 293835-294039 Sentence denotes Intravenous injection of pertussis toxin (PT) greatly facilitates the induction of several experimental autoimmune diseases {Mochizuki, 1983 #68} including experimental autoimmune encephalomyelitis (EAE).
T55 294040-294205 Sentence denotes We investigated whether the enhancement of autoimmunity by PT is related to differences in expression of the apoptotic protein caspase 3 by autoreactive CD4 T cells.
T56 294206-294285 Sentence denotes Methods: SJL mice were immunized with proteolipid protein (PLP) 139-151 in CFA.
T57 294286-294387 Sentence denotes One experimental group of mice received in addition intravenous injections of 300 ng pertussis toxin.
T58 294388-294459 Sentence denotes Mice were examined for EAE disease score and histological signs of EAE.
T59 294460-294680 Sentence denotes Single cell suspensions were prepared from draining lymph nodes and analyzed by flow cytometry after staining with MHC class II tetramers specific for PLP139-151 (I-AsPLP139-151) and antibodies against CD4 and caspase 3.
T60 294681-294790 Sentence denotes Results: PT was required for PLP139-151/CFA immunized mice to develop clinical and histological signs of EAE.
T61 294791-294921 Sentence denotes Administration of PT increased the absolute number of autoreactive T cells in the draining lymph nodes 10 days after immunization.
T62 294922-295017 Sentence denotes The expression of caspase 3 in autoreactive T helper cells was reduced in mice that receive PT.
T63 295018-295030 Sentence denotes Conclusions:
T64 295031-295161 Sentence denotes We demonstrate that the induction of autoimmunity by PT is associated with inhibition of apoptosis in autoreactive T helper cells.
T65 295162-295313 Sentence denotes High threshold for autoantigen-specific stimulation and induction of experimental autoimmune encephalomyelitis in T cell-specific IKK2deficient mice B.
T66 295314-295461 Sentence denotes The nuclear factor (NF)-kB family of transcription factors plays a pivotal role in T cell activation and survival during adaptive immune responses.
T67 295462-295620 Sentence denotes IkB kinase 2 (IKK2 or IKK2beta) is part of the IKK complex, a central component of the intracellular signalling pathway leading to canonical NF-kB activation.
T68 295621-295783 Sentence denotes We used mice that lack IKK2 specifically in T cells to investigate the role of IKK2 in autoantigen-specific T cell activation and induction of autoimmune disease.
T69 295784-295986 Sentence denotes We found highly impaired myelinoligodendrocyte-glycoprotein (MOG)35-55-specific T cell activation in vitro and complete resistance to MOG 35-55-induced EAE in T cellspecific IKK2-deficient C57BL/6 mice.
T70 295987-296148 Sentence denotes In contrast, T cell-specific IKK2deficient mice transgenic for a pathogenic MOG35-55-specific T cell receptor (2D2 TCR) were susceptible to MOG35-55-induced EAE.
T71 296149-296324 Sentence denotes Therefore, inefficient priming and/or expansion of IKK2-deficient T cells seems to be responsible for the resistance of T cell-specific IKK2deficient mice to induction of EAE.
T72 296325-296458 Sentence denotes Pharmacological inhibition of IKK in vitro reduced MOG35-55 specific proliferation and cytokine production of 2D2 transgenic T cells.
T73 296459-296640 Sentence denotes Our data suggest an IKK2-dependent threshold for autoantigen-specific T cell activation and underscores the potential value of IKK inhibition for the therapy of autoimmune diseases.
T74 296641-296790 Sentence denotes Immunization of SJL mice with encephalitogenic peptide PLP139-151 induces EAE when the antigen is resuspended in IFA supplemented with 4 mg/ml of MT.
T75 296791-296903 Sentence denotes We have studied the effect of presence of MT during immunization on two TCR repertoires specific for PLP139-151.
T76 296904-296999 Sentence denotes Frequency of usage and polarization of these repertoires is not affected by the presence of MT.
T77 297000-297185 Sentence denotes The Th1 promoting effect of adjuvant appears to be due to recruitment towards Th1 of a wider spectrum of TCR repertoires, rather than to a more robust expansion of the same repertoires.
T78 297186-297322 Sentence denotes Th1 cells appear in the LN by day 4 after immunization, by day 10 in the spleen and in the CNS at the onset of the first episode of EAE.
T79 297323-297450 Sentence denotes They disappear from the CNS during remission and are again detectable during the plateau phase of the first relapse of disease.
T80 297451-297652 Sentence denotes To investigate the influence of MHC genes on manifestation of central nervous system (CNS) autoimmune disease, we studied myelin oligodendrocyte glycoprotein (MOG)-induced EAE in H-2 congenic C3H mice.
T81 297653-297747 Sentence denotes We found that clinical signs and pathology differ dramatically according to the MHC haplotype.
T82 297748-297873 Sentence denotes MOG-induced EAE in C3H.Fej mice (H-2k) is severe and clinically characterized by proprioception defects and spastic reflexes.
T83 297874-298025 Sentence denotes Pronounced parenchymal inflammatory infiltrates are observed in the brain, comprising both CD4+ and CD8+ T cells, B cells, macrophages and neutrophils.
T84 298026-298133 Sentence denotes CD8+ T cells preferentially localize in the brain while CD4+ T cell subsets predominate in the spinal cord.
T85 298134-298231 Sentence denotes In contrast, C3H.SW mice (H-2b) develop a mild, chronic EAE characterized by ascending paralysis.
T86 298232-298292 Sentence denotes Little inflammation is observed in the brain of C3H.SW mice.
T87 298293-298468 Sentence denotes In both strains, the spinal cord is severely targeted with large lesions composed predominantly of neutrophils, the extent of the lesions correlating with antibody deposition.
T88 298469-298621 Sentence denotes MOG-specific T cell responses in C3H.Fej mice encompass several MOG epitopes that differ from the single MOG epitope (MOG35-55) targeted in C3H.SW mice.
T89 298622-298760 Sentence denotes The role of immune cell subsets, T cell specificities and antibody responses in determining the pathogenesis of disease will be discussed.
T90 298761-298939 Sentence denotes This model will elucidate immunological parameters that influence clinical disease, and may provide insight into the complex and heterogeneous pathogenesis of multiple sclerosis.
T91 298940-299166 Sentence denotes The hypothesis that astrocytes participate in maintaining the immune privilege of the central nervous system (CNS) is mainly based on in vitro data showing that they inhibit mitogen and antigen-driven lymphocyte proliferation.
T92 299167-299374 Sentence denotes We have previously shown that rat T cells pre-incubated with astrocytes completely inhibited proliferative response of naRve lymphocytes to mitogenic stimuli when co-cultivated at 1:1000 ratio, respectively.
T93 299375-299633 Sentence denotes In this study, we demonstrated that isolated mononuclear cells from spinal cords (SCMNC) of DA rats in different phases of experimental autoimmune encephalomyelitis (EAE) are unresponsive to mitogenic stimuli during acute phase but not during relapse of EAE.
T94 299634-299791 Sentence denotes Furthermore, co-cultivation of SCMNC obtained from rats at the peak of EAE with naRve lymphocytes, inhibited proliferation to ConA of latter cell population.
T95 299792-299970 Sentence denotes This inhibitory effect was restricted to SCMNC, as cells obtained from the lymph nodes of the same animals did not influence the mitogen-induced proliferation of responder cells.
T96 299971-300095 Sentence denotes Interestingly, SCMNC isolated from animals in the recovery phase of EAE were unable to inhibit proliferation of naRve cells.
T97 300096-300259 Sentence denotes Further studies of the observed phenomena would contribute to the understanding of mechanisms involved in spontaneous recovery during inflammatory diseases of CNS.
T98 300260-300541 Sentence denotes Although there are many ways of inhibiting autoimmune demyelinating disease in rodent models, there has been poor translation of these in multiple sclerosis (MS) and progressive disease continues despite immunotherapy that inhibits blood-brain barrier dysfunction and relapse rate.
T99 300542-300704 Sentence denotes Prophylactic autoimmune tolerance can be induced by a variety of different means, yet therapeutic tolerance in established disease provides a more difficult goal.
T100 300705-301096 Sentence denotes In the robust, relapsing Biozzi ABH mouse model of MS, using a combination of a transient-deletion of primed, auto-reactive T cells (by CD4-specific antibodies) followed (1 week later) by intravenous myelin-antigen administration (antigen-coupledsplenocytes), established relapsing disease in experimental autoimmune encephalomyelitis can be effectively silenced following disease induction.
T101 301097-301365 Sentence denotes Unfortunately, when treatment was initiated late during chronicrelapsing disease (after three paralytic attacks), despite inhibition of further relapses; mice demonstrated evidence of secondary progression, including increased spasticity and deterioration in mobility.
T102 301366-301684 Sentence denotes This suggests that autoimmune therapy in MS should begin as early as possible to have an optimum chance for success and indicates that once sufficient deficit is accumulated, targeting relapsing, immunological components of disease alone is unlikely to be sufficient to control progression based on a clinical outcome.
T103 301685-301792 Sentence denotes Therefore, there appears to be correlation between that observed in humans and that found in rodent models.
T104 301793-301893 Sentence denotes The Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system.
T105 301894-302029 Sentence denotes Experimental Autoimmune Encephalomyelitis (EAE) is an animal model used to study MS and is mediated by encephalitogenic CD4+ Th1 cells.
T106 302030-302228 Sentence denotes T-box expressed in T cells, or T-bet, is a transcription factor that is believed to play a key role in regulation of the IFN-gamma gene and in the differentiation of pathogenic autoimmune Th1 cells.
T107 302229-302436 Sentence denotes To determine the role that T-bet plays in the differentiation of encephalitogenic Th1 cells, we investigated the effects of silencing T-bet expression on both the IL-12/STAT4 and the IFNgamma/STAT1 pathways.
T108 302437-302553 Sentence denotes To achieve T-bet suppression, we designed anti-sense oligonucleotides and small interfering RNAs specific for T-bet.
T109 302554-302656 Sentence denotes T-bet suppression resulted in reduced STAT1 protein levels but did not affect the IL-12/STAT4 pathway.
T110 302657-302768 Sentence denotes In addition, T-bet was found to bind the IFN-gamma and STAT1 promoters via chromatin immunoprecipitation assay.
T111 302769-302976 Sentence denotes Therefore, T-bet appears to regulate the differentiation of encephalitogenic Th1 cells through the IFN-gamma/STAT1 pathway and may be a potential target for therapeutics for Th1-mediated diseases such as MS.
T112 302977-303266 Sentence denotes Motor-evoked potentials (MEP) by transcranial electrical stimulation were studied as an in vivo method for assessing corticospinal system changes in chronic experimental autoimmune encephalomyelitis (EAE), obtained by immunizing C57Bl/6 mice with MOG35-55, in parallel with neuropathology.
T113 303267-303419 Sentence denotes Cortical MEP were recorded in 95% of EAE mice 20 days post-immunisation (20 dpi), were absent in 41.1% and 47.3% of mice at 40 and 80 dpi, respectively.
T114 303420-303490 Sentence denotes At 120 dpi, we did not record any MEP in the majority of the EAE mice.
T115 303491-303617 Sentence denotes In mice with preserved MEP, latencies were significantly increased, with a peak at 20-40 dpi and a slight revovery afterwards.
T116 303618-303716 Sentence denotes At the latest time-points, MEP amplitudes significantly decreased, suggesting chronic axonal loss.
T117 303717-303807 Sentence denotes When considering overall MEP issues, the method sensitivity almost approached 100% in EAE.
T118 303808-303979 Sentence denotes Neuropathology demonstrated inflammatory infiltrates since 10 dpi, a peak of either inflammation or demyelination at 20 dpi, then both of them tended to fade out later on.
T119 303980-304071 Sentence denotes Axon loss was firstly detectable between 20 and 40 dpi, reaching its maximum at 80-120 dpi.
T120 304072-304407 Sentence denotes Thus, the small-sized, slowed or even absent MEP observed in the latest EAE stages, in keeping with neuropathological findings, suggests that acute axonal damage and chronic axonal loss are characterizing feature of EAE in C57Bl/6 mice, perhaps as a consequence of early inflammatory/demyelinating events occurring in the first 20 dpi.
T121 304408-304590 Sentence denotes Therefore, MEP can contribute not only to gain insight on EAE pathophysiology, but also to quantitatively assess experimental neuroprotective therapies in CNS demyelinating diseases.
T122 304591-304671 Sentence denotes Estimation of EAE severity using video-based motion analysis of tail motility D.
T123 304672-304683 Sentence denotes Schmitz, T.
T124 304684-304693 Sentence denotes Tomov, W.
T125 304694-304706 Sentence denotes Neiss and D.
T126 304707-304776 Sentence denotes Angelov Institute of Anatomy, University of Cologne, Cologne, Germany
T127 304777-304902 Sentence denotes To avoid biased clinical scoring of EAE in rats, we developed a method to objectively evaluate onset and severity of disease.
T128 304903-305111 Sentence denotes Since tail atony is the earliest and most consistent symptom of EAE, we video-taped tail movements before the appearance of paraparesis [at 9 days postinduction (dpi)] and at the peak of paraparesis (13 dpi).
T129 305112-305262 Sentence denotes Using Motus 2000 (PEAK Performance Technologies), we analysed the common motor performance of tail muscles evaluating the angle between tail and body.
T130 305263-305332 Sentence denotes Under normal conditions, the tail lies loose on the inspection table.
T131 305333-305441 Sentence denotes Upon lifting the animal, the tail acquires horizontal position due to reflex contraction of the musculature.
T132 305442-305550 Sentence denotes We measured the deviation of the tail from the longitudinal axis of the animal's body in the sagittal plane.
T133 305551-305649 Sentence denotes Thereby, the dorsal flexion was estimated in negative and the ventral flexion-in positive degrees.
T134 305650-305828 Sentence denotes In intact animals the dorsal flexion was -4.608F3.108 and the ventral flexion-2.65F1.608 (n=8), showing that tail movements in intact rats occur generally in the negative region.
T135 305829-305919 Sentence denotes At 9 dpi, the dorsal flexion was À14.70F9.208 and the ventral flexion +13.60F11.208 (n=8).
T136 305920-306035 Sentence denotes Atd 13 dpi, the dorsal flexion increased dramatically to +32.42F13.88 and the ventral flexion to +35.04F14.18(n=8).
T137 306036-306168 Sentence denotes Video-based motion analysis of tail motiliy is a valuable tool to estimate onset, clinical progress and results after EAE-treatment.
T138 306169-306373 Sentence denotes Although multiple sclerosis (MS) is considered to be an autoimmune disease in the central nervous system (CNS), the immune responses that take place in the CNS and lymphoid organs remain to be elucidated.
T139 306374-306573 Sentence denotes Here, we have successfully induced various subtypes of EAE in LEW.1AV1 rats carrying RT1av1 on the Lewis background genes by immunization with recombinant rat MOG in various solutions with adjuvants.
T140 306574-306718 Sentence denotes The purpose of the present study was to analyze in more detail the clinical and immunopathological features of MOG-induced EAE in LEW.1AV1 rats.
T141 306719-306929 Sentence denotes Immunization with high doses of soluble MOG with pertussis toxin (PT) induced acute, frequently fatal, EAE, whereas medium doses of partially aggregated MOG without PT produced relapsing and remitting (RR)-EAE.
T142 306930-307086 Sentence denotes Secondary progressive (SP)-EAE was induced in some rats by immunization with the immunization protocol having the intermediate nature between the above two.
T143 307087-307243 Sentence denotes The optic nerve (approximately 60% of the immunized rats) and spinal cord (100%) were frequently involved and detectable both clinically and pathologically.
T144 307244-307527 Sentence denotes Histological examination revealed that despite of the variety in the clinical subtypes, progression of the pathological processes was strikingly uniform, i.e., initial inflammation with minimal demyelination followed by predominant demyelination with minimal lymphocyte infiltration.
T145 307528-307623 Sentence denotes These findings suggest that the lesion during the later stage is maintained by humoral factors.
T146 307624-307716 Sentence denotes Taken together, this experimental system can serve as a model of neuromyelitis optica (NMO).
T147 307717-307849 Sentence denotes Further analysis will provide useful information to elucidate the pathogenesis and to develop the immunotherapy of NMO and other MS.
T148 307850-308059 Sentence denotes Adult mouse neural precursor cells (aNPCs) were in vitro labelled with increasing concentrations of Fe using three different super paramagnetic iron oxide (SPIO) contrast media (EndoremR; ResovistR; SineremR).
T149 308060-308185 Sentence denotes Iron uptake, cell viability, proliferation and differentiation were in vitro tested 72 h and 8 days after in vitro labelling.
T150 308186-308397 Sentence denotes We prepared agarose phantoms containing dispersed unlabelled and labelled cells or free SPIO and measured at 3T (with a 23-mm surface coil) signal change with routinely used sequences and R1 and R2 relaxivities.
T151 308398-308462 Sentence denotes Increasing doses of SPIOs were used (from 0.01 to 0.8 mg/ml Fe).
T152 308463-308580 Sentence denotes Uptake of all SPIOs was much higher when aNPCs were incubated in vitro with both polylisine-L and iron nanoparticles.
T153 308581-308657 Sentence denotes Mild cell toxicity was measured when cells were incubated with 0.8 mg/ml Fe.
T154 308658-308746 Sentence denotes All relaxation parameters paralleled increased cell concentration of the iron particles.
T155 308747-308899 Sentence denotes Between contrast media tested, EndoremR showed the highest signal decrease. aNPCs can be successfully labelled in vitro with novel SPIOs contrast media.
T156 308900-308946 Sentence denotes This method might allow in vivo aNPC tracking.
T157 308947-309037 Sentence denotes Expression of endothelial selectins was documented during MS (multiple sclerosis) and EAE.
T158 309038-309186 Sentence denotes Alpha(1,3) fucosyltrasferases (FucT) catalyze glycosylation of P-selectin glycoprotein ligand-1 (PSGL-1), a ligand for endothelial E-and P-selectin.
T159 309187-309269 Sentence denotes The GOAL of this study was to determine the role of FucTs in the induction of EAE.
T160 309270-309411 Sentence denotes METHODS FucT-deficient mice for FucT-IV, FucT-VII and double deficient mice for FucT-IV and VII were generated on C57Bl/6 genetic background.
T161 309412-309483 Sentence denotes Intravital microscopy studies were performed in inflamed brain vessels.
T162 309484-309526 Sentence denotes EAE was induced by using MOG35-55 peptide.
T163 309527-309535 Sentence denotes RESULTS:
T164 309536-309614 Sentence denotes Th1, but not Th2, cells efficiently roll and arrest in inflamed brain venules.
T165 309615-309730 Sentence denotes Anti-E-and P-selectin and anti-PSGL-1 antibodies blocked tethering and rolling of Th1 lymphocytes in brain venules.
T166 309731-309864 Sentence denotes Th1 lymphocytes produced from FucT-IVÀ/À mice efficiently tethered and rolled in brain venules when compared with cells from wt mice.
T167 309865-309991 Sentence denotes In contrast, primary adhesion of Th1 lymphocytes obtained from FucT-VIIÀ/À or FucT-VII and IVÀ/À mice was drastically reduced.
T168 309992-310093 Sentence denotes The onset of actively-induced EAE in FucT-VIIÀ/À, but not FucT-IVÀ/À, mice was significantly delayed.
T169 310094-310199 Sentence denotes Disease was significantly inhibited in FucT-VII and IVÀ/À mice when compared with wt and FucT-IVÀ/À mice.
T170 310200-310345 Sentence denotes MOG35-55-specific T cells obtained from FucT-VIIÀ/À or FucT-VII and IVÀ/À mice displayed no rolling on E-and P-selectin under physiological flow.
T171 310346-310358 Sentence denotes CONCLUSIONS:
T172 310359-310579 Sentence denotes Our data unveil a critical role for FucT-VII in the recruitment of activated lymphocytes in inflamed brain venules, and suggest that FucTs play a role in the pathogenesis of autoimmune inflammatory diseases of the brain.
T173 310580-310588 Sentence denotes Methods:
T174 310589-310814 Sentence denotes Magnetic column-enriched or -depleted sub-populations of adult rat hematopoietic bone marrow cells (BMC) were transplanted alone or with chicken ovalbumin-specific rat T cells into severe combined immunodeficient (SCID) mice.
T175 310815-311017 Sentence denotes Recipient SCID mice were assessed for the location and phenotype of transplanted BMC-derived cells and for susceptibility to CNS inflammation induced subsequently by transferred myelin-specific T cells.
T176 311018-311284 Sentence denotes Results: BMC expressing low or undetectable levels of alpha 4 integrin (VLA-4) were associated with a high potential for T cell-enhanced migration to the CNS, and with the highest diseaseinducing activity, compared to BMC expressing a high level of alpha 4 integrin.
T177 311285-311477 Sentence denotes BMC expressing low or undetectable alpha M integrin (CD11b) were also associated with enhanced trafficking to the CNS and more severe disease, compared to BMC expressing high alpha M integrin.
T178 311478-311563 Sentence denotes Conclusions: CNS APC develop from BMC expressing low or undetectable CD49d and CD11b.
T179 311564-311802 Sentence denotes This developmental pathway is enhanced by non-myelin-specific T cells in an acute, pre-pathogenic time frame, and may be responsible for modulating susceptibility to and severity of CNS inflammation in diseases such as multiple sclerosis.
T180 311803-312066 Sentence denotes In many TNF-alpha-associated neuropathologies, including MS, cerebral malaria, vascular dementia and HIV encephalitis, the contribution made by high levels of cerebral TNF-alpha expression to the pathogenesis and the outcome of these conditions remain unresolved.
T181 312067-312315 Sentence denotes We have found that TNFalpha in the brain gives rise to a TNFR2-dependent endothelin-mediated reduction in regional cerebral blood volume (rCBV), which is accompanied by delayed blood-brain barrier breakdown and compromised tissue energy metabolism.
T182 312316-312472 Sentence denotes We have investigated the role of platelets in these events by microinjecting the pro-inflammatory cytokines IL-1beta or TNF-alpha into the brain parenchyma.
T183 312473-312753 Sentence denotes We have discovered that TNF-alpha, but not IL-1beta, induces accumulation of GPIIb-IIIa positive platelets within the intact cerebrovasculature and is followed by the adherence of ED-1 positive mononuclear cells in a fashion that is very reminiscent of cerebral malaria pathology.
T184 312754-312867 Sentence denotes Platelet accumulation was not restricted to the microvasculature and venules, but was also present in arterioles.
T185 312868-312977 Sentence denotes We next investigated how adenoviral-mediated chronic TNF-alpha expression might affect platelet accumulation.
T186 312978-313074 Sentence denotes We found that platelets remain within the cerebral vasculature while CBV is chronically reduced.
T187 313075-313201 Sentence denotes The chronic, adenoviral mediated expression of TNF-alpha is also associated with neuronal cell death and monocyte recruitment.
T188 313202-313314 Sentence denotes The administration of anti-selectin antibodies successfully reduced platelet and ED-1-postive cell accumulation.
T189 313315-313515 Sentence denotes These findings indicate that targeting the TNFR2 pathway and TNFinduced platelet accumulation may represent a useful target for the neuropathologies associated with elevated TNF-alpha and reduced CBV.
T190 313516-313617 Sentence denotes Infiltration of leukocytes into the CNS is a key event in the development of multiple sclerosis (MS).
T191 313618-313741 Sentence denotes Molecules involved in the interaction between leukocytes and endothelial cells are therefore candidate targets for therapy.
T192 313742-313889 Sentence denotes CD81 is a member of the tetraspanin familiy of small surface proteins, and it has been implicated in cellular adhesion, motility and proliferation.
T193 313890-313989 Sentence denotes Also, CD81 regulates the activation of VLA-4 and LFA-1, two major adhesion receptors on leukocytes.
T194 313990-314073 Sentence denotes We therefore set out to determine the function of CD81 in leukocyte transmigration.
T195 314074-314256 Sentence denotes A time lapse videomicroscopy assay was used to monitor transmigration of rat NR8383 monocytic cells across confluent monolayers of immortalised rat cerebrovascular endothelial cells.
T196 314257-314435 Sentence denotes A monoclonal antibody (mAb) against rat CD81 consistently resulted in inhibition of monocyte transmigration by 40-50% as compared to controls receiving no mAb or isotype control.
T197 314436-314633 Sentence denotes When the endothelial cells were prestimulated with a mixture of IL-1beta and IFN-gamma for 48 h, inhibition by CD81 mAb was further increased to around 60%, similar to the effect of a mAb to VLA-4.
T198 314634-314716 Sentence denotes We conclude that CD81 is important in the transendothelial migration of monocytes.
T199 314717-314823 Sentence denotes Furthermore, our results provide strong support for its further exploration as a therapeutic target in MS.
T200 314824-314929 Sentence denotes Understanding the mechanisms of immune cell migration into MS lesions offers great therapeutic potential.
T201 314930-314998 Sentence denotes This study focused on CXCL13, a chemokine classified as homeostatic.
T202 314999-315158 Sentence denotes CXCL13 is essential for B cell migration to lymph follicles, but may also affect T cells, since its receptor CXCR5 is upregulated on T cells during activation.
T203 315159-315251 Sentence denotes We report that CXCL13 was overexpressed in MS-brain lesions as detected by quantitative PCR.
T204 315252-315388 Sentence denotes Within MS lesions, CXCL13 was immunolocalized to cells with a macrophage-like appearance in the perivascular area and in the parenchyma.
T205 315389-315567 Sentence denotes In the CSF of MS patients, CXCL13 was elevated and correlated with intrathecal Ig production, the presence of B cells, plasma cells/plasma blasts, and T cells, but not monocytes.
T206 315568-315643 Sentence denotes About 20% of the T cells and almost all B cells in the CSF expressed CXCR5.
T207 315644-315797 Sentence denotes The strong correlation of CXCL13 with both T cell and B cell migration to the brain MS might qualify this chemokine as a future therapeutic target in MS.
T208 315798-315963 Sentence denotes The mononuclear inflammatory infiltrate, a common characteristic of infective and inflammatory CNS disorders, consists of T-cells, monocytes and activated microglia.
T209 315964-316083 Sentence denotes Chemokines and chemokine receptors play a key role in the recruitment of inflammatory cells into sites of inflammation.
T210 316084-316176 Sentence denotes CCR2, a CC receptor, is expressed on T-cells and monocytes in blood and interacts with CCL2.
T211 316177-316364 Sentence denotes In animal models, the disruption of CCL2/CCR2 interaction using CCL2 neutralising agents or CCL2/CCR2 knockout animals leads to a decrease in inflammatory infiltrate and clinical disease.
T212 316365-316596 Sentence denotes This study identifies the pattern of CCR2 expression on inflammatory infiltrate in a number of CNS disorders, including multiple sclerosis (MS), West Nile Encephalomyelitis (WNE), using immunohistochemistry and CCL2 binding assays.
T213 316597-316700 Sentence denotes In the CNS, the majority of T-cells expressed CCR2 whereas activated monocytes sparsely expressed CCR2.
T214 316701-316780 Sentence denotes Anti-CCR2 antibodies inhibit the binding of CCL2 to CCR2 on frozen MS sections.
T215 316781-316876 Sentence denotes In the CSF, small percentage of T-cells and the majority of activated monocytes expressed CCR2.
T216 316877-316965 Sentence denotes CCR2 expressing mononuclear cells were in close contact with activated microglia in WNE.
T217 316966-317054 Sentence denotes CCR2 expression is differentially regulated on T-cells compared to monocytes in the CNS.
T218 317055-317228 Sentence denotes CCR2 expression is either upregulated on T-cells upon transmigration across the blood-brain barrier or CCR2 immunoreactive T-cells are preferentially recruited into the CNS.
T219 317229-317302 Sentence denotes CCR2 may be a potential therapeutic target in CNS inflammatory disorders.
T220 317303-317377 Sentence denotes The role of the substance P receptor, NK-1, in CNS inflammatory disease E.
T221 317378-317391 Sentence denotes Reinke and S.
T222 317392-317404 Sentence denotes Macvilay, Z.
T223 317405-317558 Sentence denotes Fabry University of Wisconsin-Madison, Madison, WI, USA Substance P is a neuropeptide shown to affect the immune system, nervous system, and vasculature.
T224 317559-317836 Sentence denotes It has been shown to have an important role in inflammation and acts to increase activation of pro-inflammatory leukocytes; increase edema, vasodilation, and adhesion molecule expression on vascular endothelial cell; and is involved in the detection of pain by sensory neurons.
T225 317837-318179 Sentence denotes We have investigated the role of the substance P receptor, neurokinin-1 (NK-1), in central nervous system (CNS) autoimmunity using the model disease experimental autoimmune encephalomyelitis (EAE) in C57Bl/6 and NK-1 receptor knock out mice treated with a subcutaneous injection of the CNS self-peptide, myelin oligodendroglial protein (MOG).
T226 318180-318364 Sentence denotes Our data show that the NK-1 receptor is expressed on brain microvessel endothelial cells, and that mice lacking the NK-1 receptor experience a less severe disease in the chronic state.
T227 318365-318471 Sentence denotes This is characterized by lower clinical scores and less demyelination and infiltration in the spinal cord.
T228 318472-318673 Sentence denotes These results indicate that substance P and its receptor, NK-1, can contribute to CNS inflammatory diseases and opens up a new direction for possible treatments for diseases such as multiple sclerosis.
T229 318674-318808 Sentence denotes Perivascular accumulation of monocyte-derived macrophages and lymphocytes is a characteristic feature of multiple sclerosis pathology.
T230 318809-318906 Sentence denotes In order to enter the brain parenchyma, immune cells need to cross the blood-brain barrier (BBB).
T231 318907-319018 Sentence denotes This barrier is mainly composed of specialized brain endothelial cells, pericytes and perivascular macrophages.
T232 319019-319127 Sentence denotes Endothelial cells and pericytes are lined by a vascular and astroglial basement membrane (BM), respectively.
T233 319128-319281 Sentence denotes Here, we studied the molecular composition of both BMs in well-characterized MS lesions using a panel of antibodies directed against several BM proteins.
T234 319282-319440 Sentence denotes Laminin alpha-4 and -5 chains are present in the endothelial BM, whereas anti-laminin alpha-1 and -2 antibodies specifically decorate the astroglial membrane.
T235 319441-319747 Sentence denotes Laminin alpha-3, beta-1, beta-2 and gamma-1 antibodies immunostain both BMs. Similarly, fibronectin, heparan sulfate proteoglycans (HSPGs) and glycosaminoglycans (GAGs) localize to both BMs. Interestingly, we observed laminin alpha-4, beta-1 and gamma-1 chain-positive structures within perivascular cuffs.
T236 319748-319874 Sentence denotes These patterns were also immunopositive for other extracellular matrix (ECM) components including fibronectin, HSPGs and GAGs.
T237 319875-319989 Sentence denotes It has already been shown that HSPGs and GAGs can bind chemokines, small proteins that control cellular migration.
T238 319990-320182 Sentence denotes We therefore hypothesize that deposition of ECM/BM components in the perivascular space may act as a conduit network for chemokines and thereby contribute to recruitment of inflammatory cells.
T239 320183-320296 Sentence denotes Future research is warranted to study the functional role of ECM/BM molecules in multiple sclerosis pathogenesis.
T240 320297-320424 Sentence denotes The beta chemokines MCP-1 and MIP-1alpha enhance adhesion of monocytes to human brain microvessel endothelial cells in vitro K.
T241 320425-320435 Sentence denotes Liu a , R.
T242 320436-320450 Sentence denotes Prameya b , R.
T243 320451-320465 Sentence denotes Shahidi b , V.
T244 320466-320477 Sentence denotes Wu b and K.
T245 320478-320612 Sentence denotes Dorovini-Zis a a University of British Columbia, Vancouver, Canada; b Vancouver Hospital and Health Sciences Centre, Vancouver, Canada
T246 320613-320711 Sentence denotes Chemokines have been implicated in the recruitment of leukocytes to the brain in CNS inflammation.
T247 320712-320829 Sentence denotes The factors that regulate the trafficking of monocytes across the blood-brain barrier (BBB) remain poorly understood.
T248 320830-321008 Sentence denotes We investigated the effects of the beta chemokines MCP-1 and MIP-1alpha on monocyte adhesion to human brain microvessel endothelial cells (HBMEC) in an in vitro model of the BBB.
T249 321009-321111 Sentence denotes Primary cultures were grown to confluence on collagen membranes in a double chamber chemotaxis system.
T250 321112-321202 Sentence denotes MCP-1 or MIP-1alpha were placed in the lower chamber to establish concentration gradients.
T251 321203-321322 Sentence denotes HBMEC monolayers were used untreated or treated with TNF-alpha and IFN-gamma for 24 h to mimic inflammatory conditions.
T252 321323-321413 Sentence denotes Peripheral blood monocytes were placed over HBMEC and incubated for 30 to 60 min at 37 8C.
T253 321414-321615 Sentence denotes Radiolabeled MCP-1 and MIP-1alpha diffused across the collagen membranes and cytokine-treated HBMEC monolayers in a time-dependent manner and bound to the subendothelial matrix and basal cell surfaces.
T254 321616-321671 Sentence denotes Chemokine diffusion was minimal across untreated HBMEC.
T255 321672-321758 Sentence denotes Cytokine treatment increased the adhesion of monocytes to HBMEC by approximately 100%.
T256 321759-321883 Sentence denotes Concentration gradients of MCP-1 and MIP-1alpha increased the adhesion of monocytes to untreated and cytokine-treated HBMEC.
T257 321884-322031 Sentence denotes These findings suggest a potential role of MCP-1 and MIP-1alpha in the recruitment of monocytes across the BBB to sites of inflammation in the CNS.
T258 322032-322225 Sentence denotes Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nervous system (CNS) and is widely studied as an animal model of multiple sclerosis (MS).
T259 322226-322350 Sentence denotes Our EAE model is characterised by disturbances in balance and coordination causing mice to roll in an axial rotatory motion.
T260 322351-322484 Sentence denotes Inflammatory and demyelinating lesions are found primarily in the brainstem and cerebellum and to a lesser extent in the spinal cord.
T261 322485-322696 Sentence denotes The inflammatory infiltrate contains lymphocytes, monocytes/ macrophages, and also polymorphonuclear cells (PMNs), which makes this model pathologically similar to acute variants of MS such as Marburg's disease.
T262 322697-322820 Sentence denotes Cytokines and chemokines play a role in promoting the immune response and determining the lesion composition in EAE and MS.
T263 322821-322997 Sentence denotes Therefore, we have examined the cytokine, chemokine and chemokine receptor expression in our EAE model to determine the factors involved in leukocyte infiltration into the CNS.
T264 322998-323147 Sentence denotes Our results indicate that CXCL2/MIP-2 and CXCL1/KC, potent chemotactic agents for PMNs, and their receptor CXCR2 are highly expressed within the CNS.
T265 323148-323383 Sentence denotes Additionally, CCL5/ RANTES, a chemotactic agent for monocytes/macrophages, eosinophils and basophils, and its receptor CCR5, as well as proinflammatory cytokines IFN-gamma and TNF-alpha, are also expressed within the CNS in this model.
T266 323384-323466 Sentence denotes The relevance of this data and implications for future research will be discussed.
T267 323467-323567 Sentence denotes CXCL10 promotes the secretion of CXCL8 and CCL2 by human astrocytes and brain endothelial cells E.A.
T268 323568-323583 Sentence denotes Subileau a , H.
T269 323584-323597 Sentence denotes Davies a , F.
T270 323598-323611 Sentence denotes Colyer a , J.
T271 323612-323628 Sentence denotes Greenwood b , D.
T272 323629-323642 Sentence denotes Male a and I.
T273 323643-323729 Sentence denotes Romero a a Open University, Milton Keynes, UK; b University College London, London, UK
T274 323730-323845 Sentence denotes High levels of the chemokine CXCL10 and its receptor, CXCR3, have been reported in multiple sclerosis (MS) lesions.
T275 323846-323948 Sentence denotes CXCL10 plays an important role in activated lymphocyte and monocyte diapedesis towards inflamed sites.
T276 323949-324048 Sentence denotes However, little is known about the effects of CXCL10 on the cells of the blood-brain barrier (BBB).
T277 324049-324275 Sentence denotes Using transmission electron microscopy and immunogold staining of post-mortem MS brain tissue revealed the presence of CXCR3 in HBEC and surrounding astrocytes both in normal appearing white matter and in white matter lesions.
T278 324276-324396 Sentence denotes We demonstrated the expression of CXCR3 on primary human brain endothelial cells (HBEC) by immunocytochemistry in vitro.
T279 324397-324645 Sentence denotes Addition of CXCL10 to the culture medium had no effect on the permeability of HBEC monolayers to dextran-FITC 70 KDa and 4 kDa in an in vitro BBB model, nor was the expression of the adhesion molecules (ICAM-1, VCAM-1 and PECAM-1) modified on HBEC.
T280 324646-324759 Sentence denotes However, CXCL10 led to an increase in CXCL8 and CCL2 levels in the supernatant of stimulated HBEC and astrocytes.
T281 324760-324830 Sentence denotes In addition, CXCL10 induced the phosphorylation of ERK1/2 and p38MAPK.
T282 324831-325062 Sentence denotes In astrocytes, either MEK inhibitor (PD98059) or p38MAKP inhibitor (SB203580) failed to block CXCL10-mediated CXCL8 and CCL2 release suggesting that signalling pathways other than ERK1/2 and p38MAPK may be involved in this process.
T283 325063-325218 Sentence denotes Our results suggest that CXCL10 could play a role in the infiltration process by amplifying the network of chemokine signals acting on leukocyte migration.
T284 325219-325389 Sentence denotes Chemokines and their receptors are implicated in leukocyte ingress into the brain during central nervous system (CNS) inflammation, as observed during multiple sclerosis.
T285 325390-325679 Sentence denotes The expression of several chemokine receptors on T lymphocytes, particularly CCR2 and CXCR3, differs greatly depending on their location in blood, cerebral spinal fluid, or brain tissue, suggesting that these receptors may be modulated during trafficking, or may be required for migration.
T286 325680-325869 Sentence denotes We addressed receptor modulation on mononuclear cells during diapedesis into CNS parenchyma using a static in-vitro model of the blood-brain barrier (BBB) that recapitulated BBB properties.
T287 325870-326024 Sentence denotes Using this model, we performed transmigration assays with peripheral blood mononuclear cells and characterized receptor expression profiles on leukocytes.
T288 326025-326156 Sentence denotes Of T cells, only memory cells transmigrated and CXCR3 was enriched on transmigrated cells compared to input and non-migrated cells.
T289 326157-326340 Sentence denotes Studies using CXCR3-depleted populations showed that CXCR3 is a surface marker for cells that have the capacity to cross the BBB, but does not play an essential role in extravasation.
T290 326341-326440 Sentence denotes We have extended this experimental approach to additional chemokine receptors and cell populations.
T291 326441-326653 Sentence denotes This BBB transmigration assay provides useful information that promotes our understanding of the biological significance of differential chemokine receptor expression in blood compared to parenchymal CNS lesions.
T292 326654-326732 Sentence denotes Modeling monocyte/macrophage migration and reverse transmigration in the brain
T293 326733-326935 Sentence denotes The Scripps Research Institute, La Jolla, CA, USA Cells of the monocyte/macrophage lineage have been shown to be the principal targets for productive HIV-1 replication within the central nervous system.
T294 326936-327042 Sentence denotes In addition, HIV-1-associated dementia has been shown to correlate with macrophage abundance in the brain.
T295 327043-327291 Sentence denotes While accumulation of macrophages in neuroAIDS is likely initiated by increased entry of monocytes into the brain, mechanisms that prevent macrophage egress from the brain and means that prevent macrophage death may also contribute to accumulation.
T296 327292-327445 Sentence denotes We have developed a novel transendothelial migration model that will allow us to test the ability of chemokines to alter monocyte/macrophage trafficking.
T297 327446-327606 Sentence denotes The migration and accumulation of peripheral blood mononuclear cells in the ablumenal (i.e., tissue) side of an in vitro endothelial monolayer was investigated.
T298 327607-327693 Sentence denotes The migrated cells were highly enriched for monocytes, including CD14+CD16+ monocytes.
T299 327694-327810 Sentence denotes We also investigated the reverse transmigration of monocytes from the ablumenal to lumenal side (i.e., circulation).
T300 327811-327999 Sentence denotes We hypothesized that within the HIV-infected brain, molecules can be expressed that decrease reverse transmigration of these macrophages, leading to increased number of tissue macrophages.
T301 328000-328415 Sentence denotes Based on our microarray analyses that showed osteopontin, a potent chemoattractant protein, was upregulated in the brains of simian immunodeficiency virus encephalitis cases, we are currently examining the role of osteopontin in comparison to other chemokines, including fractalkine, in our transendothelial migration model with the hypothesis that osteopontin is involved in the decrease of reverse transmigration.
T302 328416-328640 Sentence denotes Lipoic acid prevents monocyte migration across the blood-brain barrier Migration of monocytes across the blood-brain barrier (BBB) is a critical step in the development of inflammatory lesions during multiple sclerosis (MS).
T303 328641-328811 Sentence denotes Transendothelial migration of monocytes requires the active participation of brain endothelial cells (BEC); they need to rearrange their cytoskeleton and tight junctions.
T304 328812-329003 Sentence denotes Previously we showed that reactive oxygen species (ROS) are essential for monocyte migration and that superoxide is the pertinent ROS that affects the integrity of the endothelial cell layer.
T305 329004-329109 Sentence denotes We investigated whether the antioxidant lipoic acid (LA) could inhibit monocyte migration across the BBB.
T306 329110-329182 Sentence denotes In vitro, LA decreased migration of monocytes across a monolayer of BEC.
T307 329183-329408 Sentence denotes Using life cell imaging techniques we now have quantitatively assessed that ROS are produced within minutes upon interaction of monocytes with endothelium, inducing changes in the cytoskeleton, which could be prevented by LA.
T308 329409-329576 Sentence denotes In vivo, LA dose-dependently prevented the development of clinical signs and monocyte infiltration into the CNS in acute Experimental Allergic Encephalomyelitis (EAE).
T309 329577-329696 Sentence denotes Together, these results indicate that oxygen radicals are essential for monocyte migration in vitro as well as in vivo.
T310 329697-329844 Sentence denotes ROS-scavengers like LA may be tools to prevent monocyte migration across the BBB and may therefore be potential candidates for the treatment of MS.
T311 329845-329950 Sentence denotes Development of microglia from mouse embryonic stem cells and their migration into the brain parenchyma T.
T312 329951-329965 Sentence denotes Tsuchiya, K.C.
T313 329966-329974 Sentence denotes Park, S.
T314 329975-329987 Sentence denotes Toyonaga, S.
T315 329988-329998 Sentence denotes Yamada, H.
T316 329999-330014 Sentence denotes Nakabayashi, E.
T317 330015-330024 Sentence denotes Nakai, N.
T318 330025-330037 Sentence denotes Ikawa and K.
T319 330038-330129 Sentence denotes Shimizu Department of Neurosurgery, Kochi Medical School, Kohasu, Nankoku-shi, Kochi, Japan
T320 330130-330224 Sentence denotes Microglia is very similar to peripheral macrophage, and exist at central nervous system (CNS).
T321 330225-330351 Sentence denotes Microglia function as an antigen presenting cell in several CNS diseases, but the detailed mechanism has remained obscure yet.
T322 330352-330418 Sentence denotes Microglial progenitor or precursor cells have been not identified.
T323 330419-330501 Sentence denotes We derived microglia from mouse embryonic stem cells (ES cells) at a high density.
T324 330502-330642 Sentence denotes Mac1-positive cells were induced by stimulation with GM-CSF following neuronal differentiation of mouse ES cells using the five-step method.
T325 330643-330705 Sentence denotes CD45low expression was high and CD45high low on induced cells.
T326 330706-330784 Sentence denotes Microglia expressed MHC class II molecules and expression was enhanced by LPS.
T327 330785-330912 Sentence denotes On the other hand, detection of MHC class I molecules was negligible on the derived microglia, irrespective of LPS stimulation.
T328 330913-331078 Sentence denotes Intravenous transfer of GFP+ microglia derived from GFP+ ES cells caused selective accumulation in brain but not in peripheral tissues such as spleen and lymph node.
T329 331079-331241 Sentence denotes GFP+ cells were detected mainly in corpus callosum and hippocampus but rarely in cerebral cortex, where Iba1, another marker of microglia, is primarily expressed.
T330 331242-331348 Sentence denotes Furthermore, both GFP+ and Iba1+ cells exhibited a ramified morphology characteristic of mature microglia.
T331 331349-331524 Sentence denotes Thus, we suggest that mature microglia induced with our protocol may function as brain-specific delivery of medicines, or other bioactive materials, such as proteins or genes.
T332 331525-331707 Sentence denotes Being an integral part of the blood-brain barrier, astrocytes play an important role in regulating homing of different leukocyte subsets to the inflamed central nervous system (CNS).
T333 331708-331839 Sentence denotes The aim of this study has been to investigate whether astrocytes produce chemokines which facilitate dendritic cell (DC) migration.
T334 331840-332111 Sentence denotes Using RNase protection assay and/or ELISA, we found that human astrocytes stimulated in vitro with interleukin-1 beta and tumor necrosis factor produce CXCL12, CCL2, CCL5 and CCL20, that act on immature myeloid DC, but not CCL19 and CCL21, that attract mature myeloid DC.
T335 332112-332319 Sentence denotes Supernatants of cytokine-stimulated astrocyte cultures were more effective than control cell-free medium and supernatants of unstimulated astrocytes in inducing the migration of monocyte-derived immature DC.
T336 332320-332583 Sentence denotes The finding that immature DC migrated toward CXCL12 and CCL20 and that desensitization of their corresponding receptors reduced DC migration in response to astrocyte supernatants indicates that astrocytes produce biologically relevant amounts of these chemokines.
T337 332584-332713 Sentence denotes Immunohistochemical studies showed that in unaffected human brain CXCL12 was expressed in neurons and cerebrovascular endothelia.
T338 332714-332856 Sentence denotes In brain tissue from multiple sclerosis (MS) patients CXCL12 immunopositivity was also detected in reactive astrocytes within chronic lesions.
T339 332857-332914 Sentence denotes Expression of CCL20 in MS lesions is under investigation.
T340 332915-333033 Sentence denotes These findings suggest that astrocytes may actively contribute to DC recruitment in the CNS during autoimmune disease.
T341 333034-333178 Sentence denotes Bone-marrow stem cells migrate across the blood-brain barrier and differentiate into microglia in normal and neurodegenerative mouse models A.R.
T342 333179-333192 Sentence denotes Simard and S.
T343 333193-333237 Sentence denotes Rivest Laval University, Quebec City, Canada
T344 333238-333357 Sentence denotes Stem cells are capable of differentiating into multiple cell types in order to develop or regenerate different tissues.
T345 333358-333580 Sentence denotes However, it is still unclear whether bone marrow-derived stem cells can migrate across the blood-brain barrier (BBB) in many regions of the central nervous system (CNS), and if these cells can differentiate into microglia.
T346 333581-333789 Sentence denotes We thus studied the differentiation of bone marrow stem cells upon immigration into the CNS by systemically transplanting stem cells that express green-fluorescent protein (GFP) into lethally irradiated mice.
T347 333790-333920 Sentence denotes We show that circulating stem cells can migrate across the BBB and differentiate into microglia throughout the CNS of normal mice.
T348 333921-334038 Sentence denotes These cells were also CD11c-positive, indicating that they may be more potent APCs compared to residential microglia.
T349 334039-334144 Sentence denotes We also tested whether stem cell immigration into the CNS would be increased in neurodegenerative models.
T350 334145-334250 Sentence denotes We thus injected the brain with sodium nitroprusside, a chemical that causes extensive neurodegeneration.
T351 334251-334401 Sentence denotes We found that GFP-positive cell migration and differentiation into microglia were significantly more prevalent in regions afflicted by neuronal death.
T352 334402-334618 Sentence denotes Taken together, our data show that microglia of blood origin can cross the BBB, are preferentially recruited to damaged areas of the brain and that they could potentially activate cells of the adaptive immune system.
T353 334619-334791 Sentence denotes These results may have great clinical relevance for both immune-derived neuronal disorders and cancer patients undergoing allogeneic hematopoietic stemcell transplantation.
T354 334792-334883 Sentence denotes Characterization of macrophage brain cell populations in experimental cerebral malaria T.F.
T355 334884-334895 Sentence denotes Pais and S.
T356 334896-334955 Sentence denotes Chatterjee Instituto Gulbenkian de Ciência, Oiras, Portugal
T357 334956-335130 Sentence denotes The brain macrophages comprise a very heterogeneous population of cells, the parenchymal microglial cells, perivascular macrophages, meningeal and choroid plexus macrophages.
T358 335131-335244 Sentence denotes The relative contribution of each population during infections of the CNS has not always been clearly determined.
T359 335245-335354 Sentence denotes In this study, we have addressed the activation of brain macrophages in the context of cerebral malaria (CM).
T360 335355-335492 Sentence denotes Plasmodium falciparum is the infectious agent of CM in humans, a severe cerebral complication characterized by reversible encephalopathy.
T361 335493-335624 Sentence denotes The kinetic of activation of brain macrophages was investigated on brain slices of infected animals by staining with tomato lectin.
T362 335625-335745 Sentence denotes Obvious morphologycal changes and increased staining on brain macrophages were observed 2 days before mice start to die.
T363 335746-335907 Sentence denotes Further characterization of leukocytes was performed by flow-cytometric analysis of several markers of T cells, monocytes, macrophages and activated macrophages.
T364 335908-336021 Sentence denotes An increased percentage of cells expressing high levels of CD45 but slightly CD11b was observed in moribund mice.
T365 336022-336214 Sentence denotes This population was mainly derived from donor cells in bone marrow chimeric mice and expressed TCR alpha/beta, CD8 alpha and considerable levels of myeloid markers such as CD11b, Gr-1 and 7/4.
T366 336215-336307 Sentence denotes A slight increase was also observed in the percentage of CD45 high and F4/80 positive cells.
T367 336308-336562 Sentence denotes However, we did not detect on brain macrophages increased expression of classical markers of macrophage activation such as MHC class II and CD40 suggesting that during cerebral malaria activated brain macrophages display a different activation phenotype.
T368 336563-336676 Sentence denotes Lymphomononuclear infiltration in the CNS of mice with acute GvHD after allogeneic bone marrow transplantation P.
T369 336677-336687 Sentence denotes Sostak, C.
T370 336688-336690 Sentence denotes S.
T371 336691-336702 Sentence denotes Padovan, A.
T372 336703-336717 Sentence denotes Gerbitz and A.
T373 336718-336773 Sentence denotes Straube Ludwig-Maximilinans-University, Munich, Germany
T1 336774-336983 Sentence denotes Graft-versus-host disease (GvHD), a systemic complication after allogeneic bone marrow transplantation (BMT), most often affects the skin and liver and more seldom may cause peripheral neuromuscular disorders.
T2 336984-337146 Sentence denotes So far, involvement of the CNS has been denied in autopsy studies, but recent clinical and experimental findings suggest that GvHD might also manifest in the CNS.
T3 337147-337310 Sentence denotes In an animal model of chronic GvHD, we could already detect cerebral lymphomononuclear infiltrations, microglial activation and upregulation of adhesion molecules.
T4 337311-337474 Sentence denotes Until now, studies on acute cerebral GvHD have been performed less systematically, therefore, we have investigated the brains of mice with experimental acute GvHD.
T5 337475-337610 Sentence denotes After conditioning with total body irradiation, the mouse strain CBA received bone marrow from B10.BR mice for induction of acute GvHD.
T6 337611-337720 Sentence denotes Syngeneic transplanted animals and mice, which were only irradiated but not transplanted, served as controls.
T7 337721-337809 Sentence denotes The mice brains were investigated 6 weeks after transplantation by immunohistochemistry.
T8 337810-337983 Sentence denotes In all of the 13 allogenic animals, we found lymphomononuclear infiltrates, most often associated with the leptomeninges and the plexus, more rarely within brain parenchyma.
T9 337984-338053 Sentence denotes Infiltrations were nearly absent in syngeneic or irradiated controls.
T10 338054-338174 Sentence denotes Compared to earlier findings, the extend of lymphomononuclear infiltration was lower in acute GvHD than in chronic GvHD.
T11 338175-338267 Sentence denotes Our data provide evidence that involvement of the CNS occurs both in acute and chronic GvHD.
T12 338268-338350 Sentence denotes The different underlying pathophysiological mechanisms need further clarification.
T13 338351-338463 Sentence denotes Essential role of VLA-4/VCAM-1 pathway in the establishment of Trypanosoma cruzi-elicited meningoencephalitis J.
T14 338464-338481 Sentence denotes Lannes-Vieira, E.
T15 338482-338491 Sentence denotes Roffê, A.
T16 338492-338506 Sentence denotes Silva and A.P.
T17 338507-338591 Sentence denotes Marino Department of Immunology-IOC, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
T18 338592-338714 Sentence denotes Central nervous system (CNS) damage can occur during Trypanosoma cruzi infection, especially in immunosuppressed patients.
T19 338715-338950 Sentence denotes The enhanced susceptibility of C3H/He mice to CD8-mediated acute meningoencephalitis is associated with higher up-regulation of vascular cell adhesion molecule-1 (VCAM-1) on CNS vascular endothelia than in the less susceptible C57BL/6.
T20 338951-339148 Sentence denotes Further, in vitro adhesion of activated peripheral blood cells to CNS blood vessels was abrogated by anti-VLA-4 antibodies that also inhibited cell migration into the CNS of T. cruzi-infected mice.
T21 339149-339284 Sentence denotes Lastly, the reactivation of meningoencephalitis in immunosuppressed chronically infected mice was associated with VCAM-1 up-regulation.
T22 339285-339413 Sentence denotes Therefore, we hypothesize that VLA-4/VCAM-1-pathway plays a pivotal role in the establishment of T. cruzi-elicited encephalitis.
T23 339414-339580 Sentence denotes Osteopontin (OPN) was found to be one of the major upregulated genes in inflammatory neuropathologies such as MS, Theiler's virus infection, EAE and SIV encephalitis.
T24 339581-339696 Sentence denotes The role of OPN as chemoattractant to inflammatory cells was studied in vivo using the rodent air pouch model (AP).
T25 339697-339749 Sentence denotes OPN was injected in subcutaneous APs in Balb/c mice.
T26 339750-339806 Sentence denotes Cells were harvested from the cavity over a 48-h period.
T27 339807-339930 Sentence denotes Predominantly mononuclear cells accumulated gradually at early time points, reaching a peak at 5 h, followed by a decrease.
T28 339931-340009 Sentence denotes Histopathology of the AP adjacent skin showed adherence of OPN-elicited cells.
T29 340010-340156 Sentence denotes The cells in the exhudate at 5 h after OPN injection into the AP were phenotypically characterized and compared with other chemoattractant, MCP-3.
T30 340157-340242 Sentence denotes OPN was more powerful than MCP-3, inducing higher number of Mac-1+ cells into the AP.
T31 340243-340559 Sentence denotes Furthermore, OPN and MCP-3-attracted cells exhibited distinct characteristics: OPN-induced macrophages expressed higher levels of CD44v6 (OPN receptor), CD16 and CD62L (involved in migration of cells to the brain parenchyma), and lower levels of CD86 (related to type-2 response), and CD14 than MCP-3-elicited cells.
T32 340560-340631 Sentence denotes Differences on expression of CD80, CD11a and CD44pan were not observed.
T33 340632-340866 Sentence denotes Overall, MCP-3 induced more immature macrophages, while OPN attracted/ stimulate cells with characteristics of migrating and type-1response-inducer macrophages (CD16+CD14low CD62L+CD80+CD86F), similar to what is found in inflamed CNS.
T34 340867-340911 Sentence denotes (This work is supported by NIH NS045534-01).
T35 340912-341030 Sentence denotes The endoneurial macrophage response during experimental slow progressive neuropathies is mainly of intrinsic origin M.
T36 341031-341041 Sentence denotes Müller, K.
T37 341042-341054 Sentence denotes Wacker, E.B.
T38 341055-341073 Sentence denotes Ringelstein and R.
T39 341074-341120 Sentence denotes Kiefer University of Münster, Münster, Germany
T40 341121-341244 Sentence denotes Macrophages have a major impact on the pathogenesis of peripheral neuropathies and increase during peripheral neuropathies.
T41 341245-341481 Sentence denotes In addition, we recently demonstrated that an important proportion of the endoneurial macrophage response in traumatic and inflammatory neuropathies is generated by resident macrophages and not only by invading hematogenous macrophages.
T42 341482-341697 Sentence denotes To prove the hypothesis that resident macrophages are capable of generating the macrophage response during slow progressive neuropathies, we used chimeric mice carrying green fluorescent protein positive bonemarrow.
T43 341698-341777 Sentence denotes These mice allow differentiation between resident and hematogenous macrophages.
T44 341778-341856 Sentence denotes After administration of acrylamid the mice developed a progressive neuropathy.
T45 341857-341975 Sentence denotes Fluorescence microscopy and immunohistochemistry was used to quantify resident GFPÀ and GFP+ hematogenous macrophages.
T46 341976-342031 Sentence denotes In addition, basic macrophage properties were examined.
T47 342032-342174 Sentence denotes We found that during acrylamide, induced neuropathy endoreurial macrophages become activated, proliferate, phagocytose and increase in number.
T48 342175-342276 Sentence denotes The ratio of GFP+ and GFPÀ macrophages changed only slightly towards an increase of GFPÀ macrophages.
T49 342277-342415 Sentence denotes In addition quantitative analysis of macrophage shape revealed that GFP+ endoneurial macrophages are more activated than GFPÀ macrophages.
T50 342416-342559 Sentence denotes Taken together, our results point towards an intrinsic generation of the macrophage response in slow progressive length-dependent neuropathies.
T51 342560-342652 Sentence denotes These macrophages share basic macrophage properties like phagocytosis and MHC-II expression.
T52 342653-342826 Sentence denotes Differences in the macrophage shape between GFP+ and GFPÀ macrophages could be interpreted as different functional states of long term resident and hematogenous macrophages.
T53 342827-342896 Sentence denotes Regulatory substrates of gelatinase B/MMP-9 in neuroinflammation P.E.
T54 342897-342914 Sentence denotes Van den Steen, I.
T55 342915-342927 Sentence denotes Nelissen, S.
T56 342928-342939 Sentence denotes Starckx, P.
T57 342940-342950 Sentence denotes Proost, J.
T58 342951-342967 Sentence denotes Van Damme and G.
T59 342968-343061 Sentence denotes Opdenakker Laboratory of Immunobiology, Rega Institute, University of Leuven, Leuven, Belgium
T60 343062-343238 Sentence denotes Gelatinase B/MMP-9 is upregulated in neuroinflammatory diseases and was shown to degrade myelin basic protein (MBP), thereby causing demyelination in, e.g., multiple sclerosis.
T61 343239-343364 Sentence denotes In addition, gelatinase B participates in the degradation of the blood-brain barrier by cleaving the junctional protein ZO-1.
T62 343365-343440 Sentence denotes Here, we show that gelatinase B cleaves several immunoregulatory molecules.
T63 343441-343492 Sentence denotes In particular, gelatinase B cleaves CXC-chemokines.
T64 343493-343676 Sentence denotes The neutrophil-attracting chemokine IL-8 and its counterpart in the mouse, GCP-2, are cleaved aminoterminally with an increased activity and a positive feedback loop as a consequence.
T65 343677-343784 Sentence denotes ENA-78 is first potentiated by aminoterminal truncation, and subsequently degraded by additional cleavages.
T66 343785-343918 Sentence denotes The activity of other neutrophil-attracting CXC-chemokines is either unaffected (human GCP-2) or downregulated (CTAP-III, GROalpha) .
T67 343919-344097 Sentence denotes In contrast to the neutrophil-attracting chemokines, the CXCR-3 ligands MIG and IP-10, which attract activated T-cells, are cleaved in the carboxyterminal region by gelatinase B.
T68 344098-344158 Sentence denotes These cleavages are expected to downregulate the activities.
T69 344159-344309 Sentence denotes Another example of an immunoregulatory substrate for gelatinase B is interferon-beta (IFN-beta), an approved therpeutical agent in multiple sclerosis.
T70 344310-344362 Sentence denotes IFN-beta is cleaved and inactivated by gelatinase B.
T71 344363-344525 Sentence denotes In particular, the aglycosyl-form of IFN-beta is more sensitive to cleavage than the glycosylated variant, indicating a role of the sugars in protease resistance.
T72 344526-344662 Sentence denotes Furthermore, gelatinase B degrades the heatshock protein alphaB-crystallin, resulting in the generation of immunogenic remnant epitopes.
T73 344663-344771 Sentence denotes These findings have important implications in the understanding and treatment of neuroinflammatory diseases.
T74 344772-344836 Sentence denotes Phenotype of infiltrating cells in brains of lupus-prone mice X.
T75 344837-344846 Sentence denotes Ma and B.
T76 344847-344852 Sentence denotes Sakic
T77 344853-344931 Sentence denotes SLE is an autoimmune disorder that affects morphology and function of the CNS.
T78 344932-345028 Sentence denotes We study lupus-prone MRL mice to elucidate behavioral dysfunction induced by lupus-like disease.
T79 345029-345143 Sentence denotes Previous studies have shown that leukocyte infiltration into brains of MRL-lpr mice coincides with neurotoxic CSF.
T80 345144-345231 Sentence denotes The intrathecal synthesis of IgG is proposed in destruction of periventricular neurons.
T81 345232-345322 Sentence denotes We predict that antibody-producing cells are present when MRL mice brains become inflamed.
T82 345323-345424 Sentence denotes Infiltrating leukocytes were characterized by mAbs to CD3, CD4, CD11b, CD19, CD69 and CD138 antigens.
T83 345425-345498 Sentence denotes The CD3e-and CD4-positive cells were mostly located in the 3rd ventricle.
T84 345499-345652 Sentence denotes Macrophages (CD11b), B-lymphocytes (CD19) and plasma cells (CD138) were less frequent but detectable in almost all infiltrates (CD11bN CD19NCD138 cells).
T85 345653-345769 Sentence denotes In comparison to age-matched MRL-lpr mice, the brains of 20-week old MRL+/+ controls did not show cell infiltration.
T86 345770-345917 Sentence denotes The predominance of CD4 lymphocytes and presence of CD11b cells suggests that T cells and macrophages play a role in cytokine-induced brain damage.
T87 345918-346042 Sentence denotes The presence of B and plasma cells provides further support for the hypothesis that toxic IgG are synthesized intrathecally.
T88 346043-346148 Sentence denotes Cytokine expression and cell phenotypes are presently being examined and will be reported at the meeting.
T89 346149-346200 Sentence denotes This work was supported by funds from the NIH to B.
T90 346201-346265 Sentence denotes Sakic, who is a recipient of the FSORC career development award.
T91 346266-346427 Sentence denotes Signaling delivered through cannabinoid receptor CB1 blocks the recruitment of encephalitogenic lymphocytes in brain venules through a PKA-dependent mechanism B.
T92 346428-346440 Sentence denotes Rossi a , S.
T93 346441-346452 Sentence denotes Bach a , M.
T94 346453-346465 Sentence denotes Fusco b , F.
T95 346466-346483 Sentence denotes Fachinetti b , A.
T96 346484-346497 Sentence denotes Leon b and G.
T97 346498-346590 Sentence denotes Constantin a a University of Verona, Verona, Italy; b Research and Innovation, Padova, Italy
T98 346591-346754 Sentence denotes It is known that cannabinoid treatment prevents the development of experimental autoimmune encephalomyelitis, but its mechanisms of action are not well elucidated.
T99 346755-346951 Sentence denotes The GOAL of this study was to determine a potential role of cannabinoid receptors in the recruitment of lymphocytes in brain venules, a critical event in the initiation of autoimmune inflammation.
T100 346952-347038 Sentence denotes Methods: PLP 139-151 autoreactive T lymphocytes were produced from SJL immunized mice.
T101 347039-347110 Sentence denotes Intravital microscopy studies were performed in inflamed brain vessels.
T102 347111-347188 Sentence denotes Expression of adhesion molecules and apoptosis was studied by flow cytometry.
T103 347189-347271 Sentence denotes The release of intracellular calcium from stores was determined by using Fura-2AM.
T104 347272-347402 Sentence denotes Results: SR141716, a selective cannabinoid CB1 receptor antagonist, and SR144528, a cannabinoid CB2 receptor antagonist were used.
T105 347403-347566 Sentence denotes Both compounds had no effect on intracellular calcium release and did not alter the expression of adhesion molecules and apoptosis of encephalitogenic lymphocytes.
T106 347567-347751 Sentence denotes Intravital microscopy studies performed in inflamed brain vessels showed that SR141716 has no effect on rolling, but consistently inhibited lymphocyte arrest in brain microcirculation.
T107 347752-347821 Sentence denotes SR144528 had no significant effect on lymphocyte recruitment in vivo.
T108 347822-347951 Sentence denotes H89, a PKA (protein kinase A) inhibitor, was able to prevent SR141716-induced inhibition of lymphocyte sticking in brain vessels.
T109 347952-347964 Sentence denotes Conclusions:
T110 347965-348186 Sentence denotes Our data help to further understand the antiinflammatory effects exerted by cannabinoids and suggest that signal transduction generated through CB1 interferes with the recruitment of lymphocytes in inflamed brain venules.
T111 348187-348256 Sentence denotes CD26 is involved in T cell activation and in cell adhesion processes.
T112 348257-348424 Sentence denotes Furthermore, CD26 exerts unique enzymatic specificity in cleaving dipeptides from chemokines (CXC3R ligands) and neuropeptides, such as neuropeptide Y and substance P.
T113 348425-348613 Sentence denotes Although all of these functions suggest a functional role of CD26 in autoimmunity, there are conflicting results regarding possible clinical applicability as well as underlying mechanisms.
T114 348614-348799 Sentence denotes We report here that two substrains of mutant Fischer 344 rats lacking endogenous DPIV enzymatic activity show reduced susceptibility to acute actively-induced EAE (MBP+ CFA+ pertussis).
T115 348800-348947 Sentence denotes A significant delay of onset was observed in male rats, while in female mutant substrains also the severity of the disease was markedly suppressed.
T116 348948-349138 Sentence denotes These suppressive like effects in CD26 negative rats were associated with a time dependent and subset-specific modulation of blood leukocyte numbers and spinal chord infiltrating leukocytes.
T117 349139-349429 Sentence denotes A reduction of circulating B cells at day 7 postimmunization (pi) and the numbers of NKT cells at day 12 pi (peak of clinical score) in the blood but increased numbers of NK and NKT cells as well as reduced number of granulocytes and T cells (CD8+ and CD4+) in the spinal cord at day 12 pi.
T118 349430-349609 Sentence denotes These results indicate protective-like effects of reduced CD26-like expression/enzymatic activity on EAE and emphasise cell migration/adhesion as a contributing mechanism in rats.
T119 349610-349775 Sentence denotes Growing evidence indicates that CD8 T cells may play a major role in the pathogenesis of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE).
T120 349776-349881 Sentence denotes The mechanisms controling the recruitment of CD8 T cells in inflamed brain venules is not yet understood.
T121 349882-349892 Sentence denotes Objective:
T122 349893-350001 Sentence denotes The study proposes to compare the behavior of autoreactive CD4 versus CD8 T cells in inflamed brain venules.
T123 350002-350063 Sentence denotes Methods: MOG35-55-specific CD8 and CD4 T cells were produced.
T124 350064-350134 Sentence denotes Binding of E-and P-selectin chimeras were determined by flow cytomery.
T125 350135-350213 Sentence denotes Intravital microscopy was performed in inflamed brain venules of C57Bl/6 mice.
T126 350214-350356 Sentence denotes Results: MOG35-55 stimulated CD8 T cells display increased expression of PSGL-1, VLA-4 and LFA-1 when compared with MOG35-55 stimulated CD4 T.
T127 350357-350440 Sentence denotes Moreover, CD8 T cells display increased binding to P-selectin-IgG chimera in vitro.
T128 350441-350616 Sentence denotes In situ analyses revealed that autoreactive CD8 T cells have increased capability to tether and roll in inflamed brain venules when compared with MOG35-55specific CD4 T cells.
T129 350617-350729 Sentence denotes Importantly, tethering and rolling of CD8 T cells was completely blocked by antibodies to PSGL-1 and P-selectin.
T130 350730-350742 Sentence denotes Conclusions:
T131 350743-350979 Sentence denotes Our findings show that inflamed brain endothelium expressing P-selectin preferentially recruit autoreactive CD8 T cells versus CD4 T cells and suggest that CD8 T cells may have a role in early inflammation during the autoimmune process.
T132 350980-351089 Sentence denotes Effects of an anti-VLA-4 antibody on chronic experimental allergic encephalomyelitis (EAE) in C57Bl/6 mice J.
T133 351090-351100 Sentence denotes Rundle, V.
T134 351101-351111 Sentence denotes Gauden, R.
T135 351112-351123 Sentence denotes Mead and M.
T136 351124-351164 Sentence denotes Christie Celltech R&D Ltd, Cambridge, UK
T137 351165-351379 Sentence denotes In Lewis rat and guinea pig EAE models treatment with antibodies or small molecule inhibitors of VLA-4 reduces clinical severity (Yednock et al., 1992; Kent et al., 1995; Piraino et al., 2002; Leone et al., 2003) .
T138 351380-351546 Sentence denotes However, in the chronic relapsing EAE model in the SJL mouse, VLA-4 inhibition may either diminish or exacerbate disease depending on time of treatment (Theien et al.
T139 351547-351575 Sentence denotes 2001 (Theien et al. , 2003 .
T140 351576-351688 Sentence denotes The present study investigated the effect of an anti-VLA-4 antibody in a chronic EAE model in the C57Bl/6 mouse.
T141 351689-351941 Sentence denotes EAE was induced in adult female C57Bl/6 mice by subcutaneous (s.c.) injections of complete Freund's adjuvant containing 0.4 mg/ml Mycobacterium and 0.2 mg of myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 in each flank (0.15 ml; days 0 and 7).
T142 351942-352028 Sentence denotes Pertussis toxin was administered intraperitoneally (200 ng/mouse; days 0, 1, 7 and 8).
T143 352029-352231 Sentence denotes Mice were treated with CRL19.11 (mouse chimeric anti-VLA-4 antibody; IgG1) or 101.4 (isotype control; 10 mg/kg s.c. twice weekly) either prophylactically (from day 0) or therapeutically (50% incidence).
T144 352232-352435 Sentence denotes Prophylactic treatment with CRL19.11 caused a 40% and 62% reduction in maximum and cumulative clinical score, respectively ( pb0.01 Mann-Whitney U), with reduced incidence ( pb0.01 Fischer's exact test).
T145 352436-352532 Sentence denotes Therapeutic treatment caused a 40% reduction in maximum clinical score ( pb0.01 Mann-Whitney U).
T146 352533-352698 Sentence denotes In conclusion, the effects of CRL19.11 in this chronic murine EAE model suggest that VLA-4-dependent mechanisms drive both initiation and maintenance of the disease.
T147 352699-352849 Sentence denotes Expression of cutaneous lymphocyte antigen (CLA) on activated lymphocytes is critical for efficient tethering and rolling in inflamed brain venules B.
T148 352850-352862 Sentence denotes Rossi a , L.
T149 352863-352876 Sentence denotes Piccio b , L.
T150 352877-352894 Sentence denotes Colantonio c , E.
T151 352895-352910 Sentence denotes Scarpini b , D.
T152 352911-352930 Sentence denotes D'Ambrosio c and G.
T153 352931-353043 Sentence denotes Constantin a a University of Verona, Verona, Italy; b University of Milan, Milan, Italy; c Bioxell, Milan, Italy
T154 353044-353204 Sentence denotes We have previously shown that endothelial selectins are expressed by the inflamed brain endothelium during EAE and experimental models of subacute inflammation.
T155 353205-353392 Sentence denotes CLA represents a fucosyltransferaseVII-induced carbohydrate modification of PSGL-1 (P-selectin glycoprotein ligand-1) responsible for the interaction of PSGL-1 with endothelial selectins.
T156 353393-353403 Sentence denotes Objective:
T157 353404-353509 Sentence denotes The goal of this study was to determine the role of CLA epitope in lymphocyte recruitment into the brain.
T158 353510-353518 Sentence denotes Methods:
T159 353519-353595 Sentence denotes Th1 and Th2 lymphocytes CLA+alpha4beta7À or CLA-alpha4beta7+ were generated.
T160 353596-353678 Sentence denotes Intravital microscopy was performed in subacutely inflamed brain microcirculation.
T161 353679-353687 Sentence denotes Results:
T162 353688-353875 Sentence denotes Human and murine Th1 cells efficiently tethered and rolled in brain venules, while in contrast, very few Th2 lymphocytes were able to roll and firmly adhere to inflamed brain endothelium.
T163 353876-353990 Sentence denotes Anti-PSGL-1 and anti-CLA antibodies almost completely abolished the recruitment of Th1 lymphocytes into the brain.
T164 353991-354149 Sentence denotes Importantly, we observed a dramatic increase of capture and rolling and subsequent arrest of Th2 lymphocytes expressing CLA when compared with Th2 cells CLAÀ.
T165 354150-354330 Sentence denotes Moreover, when we compared the adhesive interactions between Th1 cells CLA+ and CLAÀ, we observed that expression of CLA determined a significant increase of tethering and rolling.
T166 354331-354342 Sentence denotes Conclusion:
T167 354343-354549 Sentence denotes Our data unveil that CLA epitope of PSGL-1 is critical for the recruitment in inflamed brain venules and may represent an attractive pharmaceutical target to be explored in autoimmune diseases of the brain.
T168 354550-354671 Sentence denotes Infiltration of the CNS by CD4+ Th1 cells precedes onset and relapses of experimental autoimmune encephalomyelitis (EAE).
T169 354672-354944 Sentence denotes We reported that (B6ÂSJL) F1 (H-2b/s) mice, with severe relapsing-remitting disease, had extensive infiltration by CD4+ T cells compared to C57BL/6 (B6) (H-2b) mice, which developed mild low-relapsing disease in response to myelin oligodendrocyte peptide 35-55 (MOG35-55).
T170 354945-355074 Sentence denotes This observation led us to search for mechanisms that specifically regulate trafficking of CD4+ T cells in relapsing H-2b/s mice.
T171 355075-355187 Sentence denotes We found that the CD4+ cell chemoattractant cytokine IL-16 has an important role in regulation of relapsing EAE.
T172 355188-355360 Sentence denotes We found that production of IL-16 within the CNS of mice with EAE correlated well with the extent of CD4+ T cell and B cell infiltration during acute and relapsing disease.
T173 355361-355447 Sentence denotes In the CNS, IL-16 was produced by infiltrating CD4+ T cells, CD8+ T cells and B cells.
T174 355448-355562 Sentence denotes Treatment with neutralizing anti-IL-16 antibody successfully reversed paralysis and ameliorated relapsing disease.
T175 355563-355682 Sentence denotes In treated mice, diminished infiltration by CD4+ T cells, lesser demyelination and more sparing of axons were observed.
T176 355683-355877 Sentence denotes We show an important role of IL-16 in regulation of relapsing EAE and describe a novel therapeutic approach to specifically impede CD4+ T cell chemoattraction in EAE, by neutralization of IL-16.
T177 355878-355985 Sentence denotes Our findings have high relevance for the development of new therapies for relapsing EAE and potentially MS.
T178 355986-356084 Sentence denotes The role of the heme-heme oxygenase system in multiple sclerosis pathology J. van Horssen a , F.A.
T179 356085-356192 Sentence denotes Wagener b and H.E. de Vries a a VUMC, Amsterdam, The Netherlands; b UMC Nijmegen, Nijmegen, The Netherlands
T180 356193-356281 Sentence denotes Multiple sclerosis (MS) is characterized by infiltration of monocytederived macrophages.
T181 356282-356425 Sentence denotes These activated monocytes secrete inflammatory mediators like reactive oxygen species (ROS) that contribute to axonal damage and demyelination.
T182 356426-356531 Sentence denotes The inducible heme oxygenase (HO)-1 gene responds to changes in cellular redox potential provoked by ROS.
T183 356532-356732 Sentence denotes We previously demonstrated an increase of HO-1 and -2 at mRNA level by quantitative PCR and microarray analysis in experimental autoimmune encephalomyelitis (EAE) rat brains, a validated model for MS.
T184 356733-356886 Sentence denotes HO breaks down heme into free iron, carbon monoxide (CO) and biliverdin, which is converted by biliverdin reductase (BVR) into the antioxidant bilirubin.
T185 356887-356955 Sentence denotes Iron is directly sequestered and inactivated by co-induced ferritin.
T186 356956-357065 Sentence denotes Both heme-mediated ROS formation and inflammatory processes may contribute to tissue damage in EAE/MS brains.
T187 357066-357204 Sentence denotes The aim of our study is to identify the cellular source of HO-1 and -2, BVR and ferritin in EAE rat brains as well as in human MS lesions.
T188 357205-357404 Sentence denotes Our findings demonstrate that HO-1 and -2 as well as BVR and ferritin are markedly upregulated in infiltrating macrophages, while HO-2 and ferritin are also expressed by astrocytes in active lesions.
T189 357405-357525 Sentence denotes We therefore hypothesize that the heme-heme oxygenase system may be involved in transendothelial migration of monocytes.
T190 357526-357624 Sentence denotes In future, we will study the effects of heme, HO activity, CO and bilirubin on monocyte migration.
T191 357625-357733 Sentence denotes Additional research is needed to further elucidate the role of the heme-HO system in the pathogenesis of MS.
T192 357734-357814 Sentence denotes CCR6 expression defines the subset of CD25+ regulatory effectormemory T cells M.
T193 357815-357836 Sentence denotes Kleinewietfeld a , F.
T194 357837-357851 Sentence denotes Puentes a , G.
T195 357852-357869 Sentence denotes Borsellino b , L.
T196 357870-357887 Sentence denotes Battistini b , O.
T197 357888-357906 Sentence denotes Rötzschke a and K.
T198 357907-358045 Sentence denotes Falk a a Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany; b Institute of Neuroimmunology, IRCCS Santa Lucia, Rome, Italy
T199 358046-358119 Sentence denotes Regulatory CD25+ T cells are the central element of peripheral tolerance.
T200 358120-358238 Sentence denotes Little is known, however, about phenotypic and functional characteristics of regulatory T cells with regard to memory.
T201 358239-358362 Sentence denotes In this study, we show that the chemokine receptor CCR6 is expressed on a distinct subset of regulatory CD25+ CD4+ T cells.
T202 358363-358515 Sentence denotes Similar to their CD25À counterparts, CCR6+ CD25+ T cells exhibit markers of activation, expansion and memory indicative for an effector-memory function.
T203 358516-358699 Sentence denotes Although regulatory CD25+ T cells comprise only 15% of the CD4+ T cell subset, in naive mice CCR6+CD25+ T cells outnumber the respective population of CD25À T cells by a ratio of 2:1.
T204 358700-358804 Sentence denotes They are true memory T cells, generated in vivo from naRve CD25+ T cells after the encounter of antigen.
T205 358805-358951 Sentence denotes In contrast to activation markers, such as CD5 or CD44, induction of CCR6 is not immediate and evident only after several rounds of proliferation.
T206 358952-359122 Sentence denotes CCR6+CD25+ T cells are enriched in the peripheral blood and accumulate in the CNS after induction of EAE where they counteract infiltrating CCR6+ effector-memory T cells.
T207 359123-359296 Sentence denotes Thus, CCR6+CD25+ T cells seem to represent a population of bregulatory effector-memoryQ cells, destined to control destructive immune responses directly in inflamed tissues.
T208 359297-359545 Sentence denotes Here, we report that pharmacologic depletion of fibrin reverses relapsing paralysis in an established polyphasic model of remitting-relapsing experimental autoimmune encephalomyelitis (EAE) induced by proteolipid protein (PLP139-151) in SJL/J mice.
T209 359546-359708 Sentence denotes To investigate the therapeutic effects of fibrin depletion, we pharmacologically depleted mice from fibrin after the development of the first paralytic incidence.
T210 359709-359770 Sentence denotes Untreated mice relapsed on days 35 and 50 after immunization.
T211 359771-359861 Sentence denotes By contrast, fibrin-depleted mice recovered faster than untreated mice and never relapsed.
T212 359862-359990 Sentence denotes Rotarod behavioral tests demonstrated that fibrin-depleted mice had increased motor skills when compared to the untreated group.
T213 359991-360088 Sentence denotes Our current research on the cellular and molecular mechanisms of fibrin in EAE will be presented.
T214 360089-360189 Sentence denotes Overall, these experiments identify fibrin as a potential target for therapeutic intervention in MS.
T215 360190-360262 Sentence denotes Supported by the NMSS RG-3370 and the Wadsworth Foundation grants to KA.
T216 360263-360491 Sentence denotes Our previous studies demonstrated that oligomeric recombinant TCR ligands (RTL) can treat clinical signs of experimental autoimmune encephalomyelitis (EAE) and induce long-term T cell tolerance against encephalitogenic peptides.
T217 360492-360668 Sentence denotes We produced a monomeric I-AS/PLP-139-151 peptide construct (RTL401) suitable for use in SJL/J mice that develop relapsing disease after injection of PLP-139-151 peptide in CFA.
T218 360669-360951 Sentence denotes RTL401 given i.v. or s.c., but not empty RTL400 or free PLP-139-151 peptide prevented relapses and significantly reduced clinical severity of EAE induced by PLP-139-151 peptide in SJL/J or (C57BL/6ÂSJL)F1 mice, but did not inhibit EAE induced by different encephalitogenic peptides.
T219 360952-361107 Sentence denotes RTL treatment of EAE caused stable or enhanced T cell proliferation and secretion of IL-10 in the periphery, but reduced secretion of inflammatory factors.
T220 361108-361334 Sentence denotes In the central nervous system (CNS), there was a modest reduction of inflammatory cells, reduced expression of VLA-4, LFA-1, and inflammatory factors, but enhanced expression of Th2-related factors, IL-10, TGF-beta3, and CCR3.
T221 361335-361580 Sentence denotes These results suggest that monomeric RTL therapy induces a cytokine switch that curbs the encephalitogenic potential of PLP-139-151-specific T cells without fully preventing their entry into CNS, wherein they reduce the severity of inflammation.
T222 361581-361804 Sentence denotes These results strongly support the clinical application of this novel class of peptide/MHC class II constructs in patients with multiple sclerosis who have focused T cell responses to known encephalitogenic myelin peptides.
T223 361805-361911 Sentence denotes Multiple sclerosis is characterized by invasion of the central nervous system (CNS) by inflammatory cells.
T224 361912-362007 Sentence denotes Migration of monocytes across the bloodbrain barrier is crucial for disease onset and severity.
T225 362008-362190 Sentence denotes Activated monocytederived macrophages secrete inflammatory mediators such as oxygen radicals, which contribute to axonal demyelination and damage, resulting in neurological deficits.
T226 362191-362376 Sentence denotes Flavonoids are naturally occurring food compounds, with anti-inflammatory properties that scavenge oxygen radicals, implying they might suppress clinical symptoms in multiple sclerosis.
T227 362377-362499 Sentence denotes We investigated this issue by treating rats sensitized for experimental allergic encephalomyelitis (EAE), with flavonoids.
T228 362500-362677 Sentence denotes We demonstrate that the flavonoid luteolin is more potent than quercetin to suppress clinical symptoms in EAE in the Lewis rat and prevented leukocyte infiltration into the CNS.
T229 362678-362792 Sentence denotes The therapeutic potential of luteolin was assessed in a chronic relapsing-remitting EAE model in Dark-Agouti rats.
T230 362793-362920 Sentence denotes We demonstrate that luteolin substantially suppresses clinical symptoms when administered either before or after disease onset.
T231 362921-363165 Sentence denotes Luteolin treatment resulted in reduced inflammation and axonal damage in the CNS by preventing monocyte migration across the brain endothelium by modulating the activity of Rho GTPases, signal transducers involved in transendothelial migration.
T232 363166-363243 Sentence denotes Oral administration of luteolin also significantly reduced clinical symptoms.
T233 363244-363337 Sentence denotes Our results indicate the therapeutic potential for dietary adaptations in multiple sclerosis.
T234 363338-363450 Sentence denotes FTY720 is a sphingosine-1 phosphate receptor agonist under evaluation as oral monotherapy in multiple sclerosis.
T235 363451-363546 Sentence denotes It acts by redistributing lymphocytes from the blood and spleen to peripheral lymph nodes (LN).
T236 363547-363780 Sentence denotes We evaluated FTY720 in experimental autoimmune encephalomyelitis (EAE), focusing on total and myelin basic protein (MBP)-specific serum immunoglobulin (Ig) as an indicator for a T helper type 1 or 2 (Th1, Th2)-driven immune response.
T237 363781-363857 Sentence denotes Two-week oral therapy with 0.3 mg/kg FTY720 prevented EAE onset in LEW rats.
T238 363858-364020 Sentence denotes Efficacy was accompanied by N70% decrease in circulating lymphocytes, N40% reduction of splenic T cells, and downregulation of transferrin receptor on LN B cells.
T239 364021-364224 Sentence denotes Peak disease in the vehicle group 2 weeks post-immunization correlated with an increasing titer of MBP-specific IgG, which was lower in FTY720-and almost undetectable in cyclosporin A (CsA)-treated rats.
T240 364225-364316 Sentence denotes Both compounds suppressed symptoms during treatment, yet their Ig profiles vastly differed.
T241 364317-364436 Sentence denotes Compared to vehicle, total IgG levels were 80% lower with CsA and unexpectedly almost 40% higher with FTY720 treatment.
T242 364437-364599 Sentence denotes In contrast to CsA, the IgG2b (Th1)/IgG1 (Th2) ratio was markedly reduced in FTY720treated rats, primarily due to upregulation of total but not MBP-specific IgG1.
T243 364600-364795 Sentence denotes Protective effects of FTY720 may not only be based on LN retention of autoreactive effector cells but also quantitative changes of polyclonal antibody responses, possibly involving Th2 deviation.
T244 364796-364997 Sentence denotes Similarly, combination of atorvastatin and GA at suboptimal doses was associated with enhanced lymphocyte secretion of IL-4, IL-5, IL-10, and TGF-beta, and decreased to secretion of IL-2 and IFN-gamma.
T245 364998-365138 Sentence denotes Histopathological examination showed decreased infiltration of blood leukocytes into CNS tissue in animals treated with combination therapy.
T246 365139-365150 Sentence denotes Conclusion:
T247 365151-365250 Sentence denotes Combination therapy with atorvastatin and GA is effective in ameliorating clinical symptoms of EAE.
T248 365251-365368 Sentence denotes Our results are extremely promising and provide a rationale for testing the combination of atorvastatin and GA in MS.
T249 365369-365671 Sentence denotes Once intravenously (i.v.) or intrathecally (i.t.) injected in mice affected by experimental autoimmune encephalomyelitis (EAE), syngenic adult neural precursor cells (aNPCs) promote multifocal remyelination and functional recovery by selectively home within inflamed central nervous system (CNS) areas.
T250 365672-365741 Sentence denotes Here, we explored the (immune) mechanisms sustaining this phenomenon.
T251 365742-365908 Sentence denotes In C57Bl/6 and SJL mice, we found that selective aNPC homing capability was mainly mediated by the membrane expression of cell adhesion molecules (CAM) and chemokine.
T252 365909-366058 Sentence denotes As such, undifferentiated aNPCs constitutively express VLA-4 (in a high affinity state), CD44 and CCR2, CCR5, CXCR3 (only in C57Bl/6 mice) and CXCR4.
T253 366059-366189 Sentence denotes Chemokines, such as RANTES and stromal-derived factor (SDF)-1, modulated in a dosedependent manner aNPCs chemoattraction in vitro.
T254 366190-366309 Sentence denotes Intravital microscopy showed in vivo aNPCs arresting in inflamed brain venules after injection into the carotid artery.
T255 366310-366387 Sentence denotes Finally, in vivo blockage of VLA-4 significantly reduced CNS homing of aNPCs.
T256 366388-366661 Sentence denotes Our results indicate that aNPCs home specifically to inflamed brain areas during EAE, once i.v. and i.t. injected, owing to the constitutive expression of the same cell adhesion molecules (CAM) and chemokine receptors used by enchephalitogenic lymphocytes to enter the CNS.
T257 366662-366874 Sentence denotes Despite many claims for neuroprotection in experimental allergic encephalomyelitis (EAE), the data often indicate that the majority of neuroprotective effects occur secondary to inhibition of leukocyte CNS entry.
T258 366875-366971 Sentence denotes The resultant reduction in clinical disease reduces the cascades that trigger neurodegeneration.
T259 366972-367055 Sentence denotes Therefore, such agents act as immunomodulators rather than direct neuroprotectants.
T260 367056-367234 Sentence denotes However, the failure to inhibit progressive multiple sclerosis (MS) despite inhibition of lesion formation and relapses has highlighted the importance of neurodegeneration in MS.
T261 367235-367363 Sentence denotes Experimental autoimmune encephalomyelitis (EAE) is an instructive model for the human-demyelinating disease, multiple sclerosis.
T262 367364-367573 Sentence denotes Lewis (LEW) rats immunized with myelin-basic protein (MBP) suffer from EAE, characterized by a single episode of paralysis from which they recover spontaneously and become refractory to reinduction of disease.
T263 367574-367808 Sentence denotes LF 15-0195, is a novel molecule that inhibits the differentiation of autoantigen-specific CD4 T cells into effector pathogenic lymphocytes and has a potent immunosuppressive effect in several pathological manifestations including EAE.
T264 367809-368035 Sentence denotes In the present study, we demonstrate that LEW rats protected from EAE by LF 15-0195 treatment benefit from a long lasting tolerance as reimmunization with MBP in CFA 4 to 7 weeks after treatment withdrawal fails to induce EAE.
T265 368036-368229 Sentence denotes This long lasting tolerance is transferable by lymph node cells from protected rats into syngeneic recipients and is mediated by antigen-specific regulatory CD4 T cells that prevent active EAE.
T266 368230-368363 Sentence denotes These regulatory T cells are also generated in thymectomized animals and their function is not dependent on the presence of TGF beta.
T267 368364-368577 Sentence denotes Together, these data demonstrate that short-term treatment with LF 15-0195, not only prevents EAE in LEW rats, but also, permits the development of an antigen-specific tolerance mediated by regulatory CD4 T cells.
T268 368578-368685 Sentence denotes Effect of NGF and anti-NGF antibodies on bstem cellsQ and inflammatory response in the brain of EAE rats V.
T269 368686-368699 Sentence denotes Triaca and L.
T270 368700-368749 Sentence denotes Aloe National Research Council (CNR), Rome, Italy
T271 368750-368944 Sentence denotes Using experimental allergic encephalomyelitis (EAE) rats, we have investigated effects of nerve growth factor (NGF) and anti-nerve growth factor antibodies (anti-NGF) in the brain of these rats.
T272 368945-369085 Sentence denotes NGF is a neurotrophin crucial for neuronal growth, differentiation and maintenance during development and in the adulthood after CNS injury.
T273 369086-369212 Sentence denotes EAE has been shown to cause a marked circulating and brain synthesis of NGF and a higher responsiveness of brain cells to NGF.
T274 369213-369395 Sentence denotes Here, we show that radiolabelled NGF, injected in the ventricle of control rats, was mainly localized in SVZ cells, which co-expressed the NGF-receptor TrkA 12 h after the treatment.
T275 369396-369537 Sentence denotes After 48 h, radioactivity was virtually absent in the SVZ and almost exclusively detectable in some cells of the parenchyma adjacent the SVZ.
T276 369538-369632 Sentence denotes These cells were also positive for markers of mature neurons, oligodendrocytes and astrocytes.
T277 369633-369761 Sentence denotes Early neuronal markers, as neurofilament and nestin, were preminent expressed by SVZ cells of EAE brain following NGF injection.
T278 369762-370019 Sentence denotes We investigated the effect of NGF and anti-NGF on SVZ cells proliferation and we found that EAE per se stimulates and NGF further enhances BrdU incorporation in the SVZ, while anti-NGF reduces the number of BrdU incorporating cells, as compared to EAE rats.
T279 370020-370153 Sentence denotes Our results suggest that NGF has a protective action on EAE brain, most probably acting on both damaged brain cells and immune cells.
T280 370154-370405 Sentence denotes To further explore the protecting role of adult neural precursor cells (aNPCs) in mice with experimental autoimmune encephalomyelitis (EAE), we have intravenously (i.v.)-injected syngenic aNPCs into mice with a relapsing-remitting form of the disease.
T281 370406-370766 Sentence denotes SJL mice were immunized subcutaneously with proteolipid protein (PLP)139-151 and i.v. injected with 1Â10 6 millions of syngenic aNPCs both at the onset of the disease and after the first relapse. aNPCs entered both the brain and the spinal cord, selectively reached inflamed CNS areas, and showed to be able to survive for up to 120 days after transplantation.
T282 370767-370975 Sentence denotes Three months after immunization, mice transplanted at disease onset or after the first relapse showed a significant ( pb0.05) decrease of the disease score, the cumulative score and of the number of relapses.
T283 370976-371061 Sentence denotes A significant decrease of the extent of demyelination and axonal loss was also found.
T284 371062-371349 Sentence denotes Interestingly, the majority of the transplanted aNPCs maintained over time an undifferentiated phenotype within the host CNS and accumulated mainly around brain venules where gliogenic and neurogenic factors (e.g. BMP-4)-possibly maintaining aNPCs in a quiescent state-were co-localized.
T285 371350-371616 Sentence denotes Our data indicate that aNPCs-once i.v. transplanted-may survive within the CNS for long periods of time and protect from relapsing-remitting EAE owing to their capability to selectively reach perivenular inflamed area where stem cell surviving factors are expressed.
T286 371617-371628 Sentence denotes Background:
T287 371629-371797 Sentence denotes Although neural precursor cells remyelinate focal lesions, the mechanism of their beneficial effect in clinically relevant models of multiple sclerosis (MS) is unclear.
T288 371798-371926 Sentence denotes We therefore examined the clinical, neuropathological and immunological effects of neural sphere transplantation in chronic EAE.
T289 371927-371935 Sentence denotes Methods:
T290 371936-372083 Sentence denotes Multipotential neural spheres from newborn GFPtransgenic mice were transplanted intraventricularly to MOG35-55-induced chronic EAE in C57Bl/6 mice.
T291 372084-372223 Sentence denotes Sham-and sphere-transplanted animals were scored clinically and sacrificed at days 18 and 80 post-induction for histopathological analysis.
T292 372224-372374 Sentence denotes Demyelination and axonal pathology were assessed by Kluver-Barrera staining, amyloid precursor protein immunohistochemistry and Bielschowski staining.
T293 372375-372502 Sentence denotes Inflammation was quantified by counting perivascular infiltratesand by image analysis of ICAM-1 and LFA-1 immunohistochemistry.
T294 372503-372566 Sentence denotes Brain CD25+,CD62L+ cells were identified by immunofluorescence.
T295 372567-372644 Sentence denotes Lymphocyte proliferation was examined in vitro by 3H-thymidine incorporation.
T296 372645-372705 Sentence denotes Cytokine production was examined by real time PCR and ELISA.
T297 372706-372782 Sentence denotes Results: EAE-attracted transplanted cell migration into white matter tracts.
T298 372783-372906 Sentence denotes Neural sphere transplantation attenuated the clinical course of chronic EAE and reduced demyelination and axonal pathology.
T299 372907-373043 Sentence denotes Neural sphere transplantation inhibited the inflammatory brain process by all 3 parameters and increased brain regulatory CD25+ T-cells.
T300 373044-373123 Sentence denotes Transplantation decreased the inflammatory infiltrate-associated axonal damage.
T301 373124-373309 Sentence denotes Addition of neural spheres to EAE-derived lymphocytes in vitro inhibited their proliferative responses to ConA and to MOG peptide and reduced MOG-induced production of interferon-gamma.
T302 373310-373322 Sentence denotes Conclusions:
T303 373323-373414 Sentence denotes Neural sphere transplantation attenuates clinical and pathological features of chronic EAE.
T304 373415-373497 Sentence denotes The graft effect is mediated by modulation of the autoimmune-inflammatory process.
T305 373498-373583 Sentence denotes Tolerance induction by bone marrow transplantation in a multiple sclerosis model M.M.
T306 373584-373596 Sentence denotes Herrmann, S.
T307 373597-373612 Sentence denotes Gaertner and R.
T308 373613-373709 Sentence denotes Weissert Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
T309 373710-373808 Sentence denotes Bone marrow transplantation (BMT) is a experimental treatment approach in multiple sclerosis (MS).
T310 373809-373910 Sentence denotes MS is a chronic autoimmune disease with a T cell, macrophage and autoantibody dependent pathogenesis.
T311 373911-374095 Sentence denotes Myelinoligodendrocyte-glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in rats reproduces these pathological features and is therefore used as a model for MS.
T312 374096-374234 Sentence denotes There is only sparse knowledge on the impact of genetic factors, timing, tissue repopulation and immuneregulatory mechanisms by BMT in MS.
T313 374235-374508 Sentence denotes We used MHC (RT1 in rats) identical EAE susceptible DA (RT1av1) and resistant ACI (RT1av1) rats and performed BMT studies before disease induction, at the peak of disease and in remission of EAE in DA rats with DA or ACI bone marrow after whole body irradiation with 10 Gy.
T314 374509-374699 Sentence denotes In contrast to controls, BMT resulted in strong disease protection if applied after CNS lesions and clinical symptoms had evolved for subsequent autoantigen-induced relapses and CNS lesions.
T315 374700-374925 Sentence denotes The protective effect was associated with a change in the relative size of the T and B cell compartment, a shift in the T cell recognition of different MOG epitopes, and a significant reduction in MOG-specific autoantibodies.
T316 374926-375134 Sentence denotes The data indicate that the protective effect of BMT in a relevant animal model of MS is mainly due to tolerogenic effects on autoantigenspecific T and B cells with subsequent reduction of autoantibody titers.
T317 375135-375257 Sentence denotes Astrocytes are able to induce regulatory T cells, which can completely abolish proliferative response of T cells in vitro.
T318 375258-375392 Sentence denotes The aim of our study was to test this inhibitory capacity of astrocyte-induced regulatory T cells in vivo, using EAE model in DA rats.
T319 375393-375579 Sentence denotes The rat spinal cord homogenateimmunized animals received on a day 7 p.i. lymph node cells (LNC) previously incubated with astrocytes (astro-LNC group) or in medium alone (control group).
T320 375580-375713 Sentence denotes The severity of clinical signs was markedly reduced in astro-LNC group as judged by mean clinical score and cumulative disease index.
T321 375714-375800 Sentence denotes Alleviation of EAE symptoms correlated with the results of pathohistological analysis.
T322 375801-375864 Sentence denotes Astro-LNC were also able to interfere with the transfer of EAE.
T323 375865-376189 Sentence denotes When MBP-immunized rats were treated on a day 6 p.i. with astro-LNC or control LNC and 2 days later, draining LNC were collected, restimulated in vitro and injected into naRve recipients, 9 out of 10 control animals developed EAE while none of six animals that received cells from astro-LNC group showed any sign of disease.
T324 376190-376336 Sentence denotes Interestingly, no protective effect was observed when the astro-LNC were administered to naive animals simultaneously with encephalitogenic cells.
T325 376337-376450 Sentence denotes Our results suggest important role of astrocyte-induced regulatory T cells in the regulation of CNS inflammation.
T326 376451-376685 Sentence denotes Experimental autoimmune encephalomyelitis (EAE) is an animal model for the human demyelinating disease multiple sclerosis (MS) characterized by a CD4+ T cell mediated inflammatory response to central nervous system (CNS) autoantigens.
T327 376686-376790 Sentence denotes Interaction between encephalitogenic T cells and APC in the CNS is a crucial step in disease initiation.
T328 376791-376893 Sentence denotes Astrocytes have been suggested to play essential roles in initiating and maintaining CNS autoimmunity.
T329 376894-376973 Sentence denotes Elevated IFN-gamma is observed in MS and EAE and is deleterious in MS-patients.
T330 376974-377243 Sentence denotes We addressed the effect of astrocyte unresponsiveness to IFN-gamma in EAE by studying transgenic (tg) mice expressing a dominant-negative IFN-gamma receptor under control of the GFAP-promoter (GFAP-dIFNgR mice) in comparison to age matched wild type (wt) syngenic mice.
T331 377244-377379 Sentence denotes No differences in peripheral immune responses assessed by T cell proliferation and cytokine secretion were seen between tg-and wt-mice.
T332 377380-377490 Sentence denotes EAE was induced by immunization with MOG35-55 peptide/CFA and animals were scored daily for clinical symptoms.
T333 377491-377593 Sentence denotes Tg-mice were as susceptible to EAE as wt-controls with the same average day of disease onset (day 13).
T334 377594-377776 Sentence denotes However, GFAP-dIFNgR mice exhibited significantly more severe clinical symptoms (peak disease score 4 vs. 3, cumulative score 48 vs. 33) and higher mortality (39% vs 1%) than wtmice.
T335 377777-377959 Sentence denotes Histopathological evaluation of spinal cord sections revealed slight increases in extent of cellular infiltration and severity of demyelination in tg-animals compared to wt-controls.
T336 377960-378080 Sentence denotes Our findings support an important role of IFN-gamma mediated astrocyte signaling in ameliorating CNS autoimmune disease.
T337 378081-378208 Sentence denotes Multiple sclerosis (MS) is a demyelinating disease of the CNS, where myelin and axons are lost in multiple foci called plaques.
T338 378209-378348 Sentence denotes Sporadic repair occurs giving the appearance of dshadow plaquesT or areas of thin remyelination; however, this process is often incomplete.
T339 378349-378523 Sentence denotes It is well established that inhibition of alpha 4 beta 1 integrin (VLA-4) blocks immune cell influx into the CNS and provides benefit to patients and in animal model systems.
T340 378524-378698 Sentence denotes We have utilized this mechanism to examine whether the presence of inflammatory cells suppresses spontaneous myelin repair in experimental autoimmune encephalomyelitis (EAE).
T341 378699-378938 Sentence denotes EAE was induced in Hartley guinea pigs, and animals were chosen for treatment based on two criteria: (1) animals were in the chronic stage of disease (Nday 40 post immunization); and (2) animals had hind limb paresis (clinical score of 2).
T342 378939-379095 Sentence denotes Animals received either saline or CT301 for 10, 20, 30 or 40 days, and tissues were examined by light and electron microscopy for evidence of remyelination.
T343 379096-379184 Sentence denotes We found (1) 87% of plaques showed evidence of remyelination after 40 days of treatment;
T344 379185-379245 Sentence denotes (2) myelin repair occurred in half of the total lesion area;
T345 379246-379294 Sentence denotes (3) half of the animals regained motor function.
T346 379295-379380 Sentence denotes There was no significant repair or gain of motor function in vehicle treated animals.
T347 379381-379528 Sentence denotes Therefore, prolonged inhibition of CNS inflammation, in the absence of targeted myelin repair, facilitated mechanisms of spontaneous remyelination.
T348 379529-379749 Sentence denotes We established a cytokine-delivery system within the central nervous system (CNS) using helper-dependent adenoviral vectors (HD-Ad) engineered with the IL-4 gene and the green fluorescence protein (GFP) as reporter gene.
T349 379750-379933 Sentence denotes HD-Ad vectors injected into the cisterna magna (i.c.) of mice diffused in all ventricular and subarachnoid spaces infecting ependymal and leptomeningeal cells surrounding these areas.
T350 379934-380300 Sentence denotes When injected in mice affected by myelin-oligodendrocyte-glycoprotein (MOG)35-55-induced experimental autoimmune encephalomyelitis (EAE) the day of clinical onset, IL-4-treated mice displayed a progressive clinical recovery, and 80 days after immunization had an average EAE score of 1.0 (F1.0) vs. 1.62 (F0.4) in control mice ( pb0.05) treated with an empty vector.
T351 380301-380526 Sentence denotes Motorevoked potentials (MEP) were recordable in only 50% of control mice, and in all but one of the IL-4-treated mice ( pb0.05) and central conduction time was significant decreased in IL-4-treated vs. control mice ( pb0.05).
T352 380527-380640 Sentence denotes Recovery was associated to a significantly increased number of CNSinfiltrating CD4+CD69ÀCD25+ regulatory T cells.
T353 380641-380858 Sentence denotes We conclude that IL-4 gene therapy using HD-Ad vectors determines the recruitment of CD4+CD25+ T cells with suppressant function able to induce clinical and functional recovery in a murine model of multiple sclerosis.
T354 380859-380980 Sentence denotes Prevention of EAE by treatment with a neurotropic alphavirus vector expressing tissue inhibitor of metalloproteinase-2 P.
T355 380981-380989 Sentence denotes Furu, S.
T356 380990-381002 Sentence denotes Grfnberg, J.
T357 381003-381018 Sentence denotes Heikkil7 and A.
T358 381019-381067 Sentence denotes Hinkkanen Åbo Akademi University, Turku, Finland
T359 381068-381078 Sentence denotes Objective:
T360 381079-381230 Sentence denotes In experimental autoimmune encephalomyelitis (EAE), enhanced activity of matrix metalloproteinases (MMPs), has been implicated in disease pathogenesis.
T361 381231-381507 Sentence denotes Prompted by our recent observations of increased MMP-8 and MMP-9 with simultaneous downregulation of TIMP-2 and TIMP-3 mRNA in the CNS of mice with severe EAE, we used Semliki Forest virus (SFV) to transfer and express recombinant murine TIMP-1-3 genes in the CNS of EAE mice.
T362 381508-381621 Sentence denotes Results: TIMP-1, TIMP-2 and TIMP-3 expression was confirmed in cultured cells and in the CNS of infected animals.
T363 381622-381748 Sentence denotes Following intraperitoneal infection with 10 6 pfu of SFV-TIMP focal TIMP protein expression was achieved throughout the brain.
T364 381749-381915 Sentence denotes Although already treatment with empty vector inhibited development of EAE to some extent, the expression of TIMP-2 by the virus significantly enhanced the inhibition.
T365 381916-382023 Sentence denotes TIMP-3 administered mice also had lower disease grade but the inhibition was not statistically significant.
T366 382024-382109 Sentence denotes In contrast, SFV-TIMP-1 had no effect, similar to coinfection with TIMP-2 and TIMP-3.
T367 382110-382265 Sentence denotes We found TIMP-2 expression also by non-infected CNS resident cells surrounding the SFV-TIMP-2 virus positive areas suggesting a bystander TIMP-2 induction.
T368 382266-382278 Sentence denotes Conclusions:
T369 382279-382496 Sentence denotes These data strengthen the view that MMPs are involved in the pathogenesis of EAE and provide clear evidence that virus-mediated delivery of their protein inhibitors can be effective in preventing the clinical disease.
T370 382497-382607 Sentence denotes TIMPs might be candidates for novel treatment regimens in CNS autoimmune disorders such as multiple sclerosis.
T371 382608-382619 Sentence denotes Background:
T372 382620-382815 Sentence denotes Immunoglobulin for intravenous administration (IVIG) possesses multiple immunomodulatory properties and represents a way of interfering with the pathological processes in multiple sclerosis (MS).
T373 382816-382942 Sentence denotes In experimental autoimmune encephalomyelitis (EAE), infusions of IVIG have been shown to significantly ameliorate the disease.
T374 382943-383135 Sentence denotes However, it is at present not known whether IVIG enters the CNS in sufficient amounts to influence the local immune response, or if the treatment effects are due to peripheral actions of IVIG.
T375 383136-383146 Sentence denotes Objective:
T376 383147-383353 Sentence denotes The purpose of the present study was to evaluate if IVIG enters the CNS by passing through the blood-brain barrier during the acute course of EAE, and to assess if IVIG accumulates at the inflammatory foci.
T377 383354-383488 Sentence denotes Methods: EAE was induced in susceptible rats, and the animals were treated with IVIG infusions during the acute attack of the disease.
T378 383489-383551 Sentence denotes The immunoglobulin was radiolabelled with 99mTc-pertechnetate.
T379 383552-383677 Sentence denotes After in vivo administration, the 99mTc-IVIG was localised and visualised in CNS tissue sections by means of autoradiography.
T380 383678-383769 Sentence denotes Studies evaluating the 99mTc-IVIG biodistribution and plasma half-life were also performed.
T381 383770-383778 Sentence denotes Results:
T382 383779-383949 Sentence denotes We observed a significant increased binding of IVIG to CNS tissue in rats with EAE that correlated with the degree of inflammation as assessed by histological evaluation.
T383 383950-384121 Sentence denotes Furthermore, by autoradiography the radiolabelled IVIG was localised to the regions of the brain where inflammatory infiltrates and areas of demyelination were also found.
T384 384122-384210 Sentence denotes Lack of apolipoprotein E (ApoE) exacerbates experimental autoimmune encephalomyelitis M.
T385 384211-384230 Sentence denotes Nakanishi a , J.-I.
T386 384231-384243 Sentence denotes Satoh b , T.
T387 384244-384258 Sentence denotes Aranami b , G.
T388 384259-384274 Sentence denotes Hirose a and T.
T389 384275-384354 Sentence denotes Yamamura b a Kanazawa-Medical University, Ishikawa, Japan; b NCNP, Tokyo, Japan
T390 384355-384496 Sentence denotes Recent studies have shown that MS patients having the 4 allele exhibit rapid progression and severe disability than those with non-4 alleles.
T391 384497-384660 Sentence denotes We studied an immunoregulatory role of ApoE in the development of EAE, an immune-mediated demyelinating disease by using ApoE-knockout (KO) mice as a model system.
T392 384661-384809 Sentence denotes EAE was induced in 6-to 9-week-old female ApoE-KO mice and wild type (WT) B6 mice by immunizing with myelin oligodendrocyte glycoprotein (MOG)35-55.
T393 384810-385014 Sentence denotes The clinical score, antigenspecific proliferation response and cytokine production of regional lymph node (LN) cells, anti-MOG35-55 IgG antibody titers, and histopathology of the spinal cord were studied.
T394 385015-385073 Sentence denotes Cannabinoids may alleviate symptoms of multiple sclerosis.
T395 385074-385138 Sentence denotes Furthermore, cannabinoids might also modulate neuroinflammation.
T396 385139-385384 Sentence denotes We saw that delta9tetrahidrocannabinol (D-THC) was ineffective in the passive variety of experimental autoimmune encephalomyelitis (EAE) of Lewis rats; however, R(+)-WIN 55,212-2, a synthetic cannabinoid, significantly syppressed clinical signs.
T397 385385-385573 Sentence denotes As cannabinoids may exert either pro-or antiapoptotic effects, depending on cell types, we investigated possible changes in T cell apoptosis, related to the protective of this cannabinoid.
T398 385574-385735 Sentence denotes By means of flow cytometry, we found that R(+)-WIN 55,212-2 induced a profound increase of apoptosis in an encephalitogenic T cell line, time and dose dependent.
T399 385736-385938 Sentence denotes To ascertain type of cannabinoid receptor involved, the T cell line was cultured with CB1 and CB2 receptor antagonists (SR141716A and SR144528 respectively), and S(À)-WIN 55,212-2 (the inactive isomer).
T400 385939-386122 Sentence denotes Whereas SR141716A had no effects, SR144528 and S(À)-WIN 55,212-2 prevented the induction of apoptosis in a dose-dependent way, indicating the involvement of CB2 but not CB1 receptors.
T401 386123-386319 Sentence denotes However, the concentration of R(+)-WIN 55,212-2 required and the moderate effect of S(À)-WIN 55,212-2, strongly suggest that the observed effects might be in part cannabinoid receptor independent.
T402 386320-386474 Sentence denotes As R(+)-WIN 55,212-2 has more affinity for CB2 receptors than D-THC, these findings may help explain the observed discrepancies in protection against EAE.
T403 386475-386575 Sentence denotes Immunoregulation of a model of multiple sclerosis using the synthetic cannabinoid R(+)WIN55,212 J.L.
T404 386576-386591 Sentence denotes Croxford and T.
T405 386592-386649 Sentence denotes Yamamura National Institute of Neuroscience, Tokyo, Japan
T1 386650-386790 Sentence denotes Multiple sclerosis (MS) is a human autoimmune demyelinating disease of the central nervous system, whereby the immune system attacks myelin.
T2 386791-386857 Sentence denotes Symptoms include spasticity, tremor, bladder dysfunction and pain.
T3 386858-386953 Sentence denotes Current therapies, beta-interferon and copaxone decrease the MRI-lesion load and relapse rates.
T4 386954-387005 Sentence denotes However, disease progression is largely unaffected.
T5 387006-387072 Sentence denotes Therefore, novel therapeutic agents are required for MS treatment.
T6 387073-387236 Sentence denotes Anecdotal evidence and clinical surveys suggest that many MS patients derive subjective improvements in spasticity, chronic pain and spasms from smoking marijuana.
T7 387237-387315 Sentence denotes Cannabinoid agonists mediate their effects through cannabinoid receptors (CB).
T8 387316-387410 Sentence denotes CB1 is mainly expressed on CNS neurons and is involved in the regulation of neurotransmission.
T9 387411-387510 Sentence denotes In contrast, CB2 is expressed only peripherally, and is thought to have immunomodulatory functions.
T10 387511-387625 Sentence denotes Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS mediated by myelin-specific CD4+ T cells.
T11 387626-387750 Sentence denotes Therefore we investigated the use of a synthetic cannabinoid agonist, R(+)WIN55,212 with which to treat ongoing EAE disease.
T12 387751-387893 Sentence denotes We demonstrate that treatment with R(+)WIN55,212 at the onset of clinical symptoms can significantly inhibit disease severity and progression.
T13 387894-388041 Sentence denotes This was associated with the inhibition of myelin specific T cell proliferation, differentiation to Th1 phenotype and autoimmune humoral responses.
T14 388042-388118 Sentence denotes Furthermore, this therapeutic effect was absent in IFN-gamma-deficient mice.
T15 388119-388281 Sentence denotes In conclusion, cannabinoids are potent therapeutic agents which may be beneficial in MS as a symptomatic treatment for spasticity and as immunosuppressive agents.
T16 388282-388292 Sentence denotes Rationale:
T17 388293-388473 Sentence denotes Phospholipase A2 (PLA2) hydrolyzes phosphatidylcholine to lysophosphatidylcholine and arachidonic acid (AA), which can cause myelin breakdown and induce inflammation, respectively.
T18 388474-388614 Sentence denotes There are two major forms of PLA2: cytosolic (cPLA2) and secreted (sPLA2). cPLA2 is thought to be the major form contributing to AA release.
T19 388615-388720 Sentence denotes We therefore studied the role of cPLA2 in the pathogenesis of EAE, an animal model of multiple sclerosis.
T20 388721-388887 Sentence denotes Methods: EAE was generated in C57BL/6 mice, which have a naturally occurring null mutation for a major form of sPLA2, and SJL/J mice, which contain all forms of PLA2.
T21 388888-388987 Sentence denotes We blocked cPLA2 using arachidonyl trifluromethyl ketone (AACOCF3), a selective inhibitor of cPLA2.
T22 388988-389147 Sentence denotes To assess the role of cPLA2 in the onset and progression of disease, we inhibited this enzyme at the time of EAE induction or after the first paralytic attack.
T23 389148-389306 Sentence denotes Results: C57BL/6 mice and SJL/J mice treated with a cPLA2 inhibitor at the time of EAE induction showed a remarkable decrease in the incidence of the disease.
T24 389307-389512 Sentence denotes Delaying treatments after the peak of the first paralytic episode in C57BL/6 mice also resulted in significant reduction in inflammatory burden and recovery from the relapsingremitting from of the disease.
T25 389513-389525 Sentence denotes Conclusions:
T26 389526-389634 Sentence denotes These findings suggest that inhibiting cPLA2 may play an important role in the onset and progression of EAE.
T27 389635-389806 Sentence denotes Estrogen treatment has been shown to exert a protective effect on experimental autoimmune encephalomyelitis (EAE), and is under clinical trial for multiple sclerosis (MS).
T28 389807-390064 Sentence denotes Whilst it is commonly assumed that estrogens exert their effect by modulating immune functions, we show here that 17h-estradiol (E2) treatment can inhibit mouse EAE without affecting autoantigen-specific T cell responsiveness and type-1 cytokine production.
T29 390065-390238 Sentence denotes Using mutant mice in which estrogen receptor alpha (ERalpha) has been unambiguously inactivated, we found that ERalpha was responsible for the E2-mediated inhibition of EAE.
T30 390239-390436 Sentence denotes We next generated irradiation bone marrow chimeras in which ERalpha expression was selectively impaired in inflammatory T lymphocytes or was limited to the radiosensitive hematopoietic compartment.
T31 390437-390584 Sentence denotes Our data show that the protective effect of E2 on clinical EAE and CNS-inflammation was not dependent on ERalpha-signaling in inflammatory T cells.
T32 390585-390732 Sentence denotes Likewise, EAE development was not prevented by E2-treatment in chimeric mice that selectively expressed ERalpha in the systemic immune compartment.
T33 390733-391029 Sentence denotes In conclusion, our data demonstrate that the beneficial effect of E2 on this autoimmune disease does not involve ERalpha-signaling in blood-derived inflammatory cells, and indicate that ERalpha expressed in other tissues, such as CNS-resident microglia or endothelial cells, mediates this effect.
T34 391030-391184 Sentence denotes N-acetylcysteine (NAC) is a well-known anti-oxidant that acts as a scavenger for reactive oxygen species and as a precursor for reduced glutathione (GSH).
T35 391185-391421 Sentence denotes It has recently been reported that NAC exerts also an immunomodulatory activity, such as induction of Th2 polarization of T cell response and inhibition of B cell and dendritic cell function by downregulation of costimulatory molecules.
T36 391422-391590 Sentence denotes Therefore, we tested whether NAC was capable of preventing MOG35-55-induced experimental autoimmune encephalomyelitis (EAE), an established model of multiple sclerosis.
T37 391591-391779 Sentence denotes NAC was administrated orally at a daily dosage of 10 mg/ml in drinking water starting at the day of immunization and it significantly prevented EAE progression as compared to control mice.
T38 391780-391896 Sentence denotes This was associated with a reduction of CNS infiltrating T cells and macrophages as well as decreased demyelination.
T39 391897-392028 Sentence denotes We then tested NAC in a therapeutic protocol and disease progression was again inhibited when compared to vehicle-treated controls.
T40 392029-392158 Sentence denotes We found that NAC inhibited the stimulation of encephalitogenic T cells only by MOG35-55 but not by anti-CD3 plus anti-CD28 mAbs.
T41 392159-392237 Sentence denotes This was probably due to an immmunosuppressive effect of NAC at the APC level.
T42 392238-392360 Sentence denotes We also show that NAC inhibits T cell migration towards CXCL10 and CCL5, chemokines involved in T cells homing to the CNS.
T43 392361-392463 Sentence denotes Our data indicate that NAC can effectively interfere with the autoimmune reaction associated with EAE.
T44 392464-392703 Sentence denotes Attempts to exploit the powerful immunoregulatory properties of transforming growth factor-beta (TGF-beta) for autoimmune disease therapy have been compromised by its stimulatory effects on fibrogenesis and extracellular matrix generation.
T45 392704-392845 Sentence denotes TGF-beta-functions are locally regulated through activation of latent TGF-beta and subsequent intracellular signalling via the Smad proteins.
T46 392846-392940 Sentence denotes Smad7 blocks TGF-beta-signalling and is upregulated by TGF-beta and proinflammatory cytokines.
T47 392941-393086 Sentence denotes We hypothesized that Smad7 inhibition should enhance TGF-beta-signalling at sites of local inflammation such as the central nervous system (CNS).
T48 393087-393295 Sentence denotes Administration of Smad7-antisense-oligonucleotides (Smad7-as) in vivo ameliorated clinical signs of active and adoptively transferred experimental autoimmune encephalomyelitis and diminished CNS inflammation.
T49 393296-393374 Sentence denotes Smad7-as-treatment did not result in increased extracellular matrix formation.
T50 393375-393513 Sentence denotes Autoreactive T cells exposed to Smad7-as during antigenic priming or secondary activation showed considerably reduced encephalitogenicity.
T51 393514-393727 Sentence denotes In conclusion, Smad7 inhibition represents a novel systemic treatment strategy targeting autoimmune inflammation, augmenting TGF-beta-signalling at sites of TGFbeta-activation without TGF-beta-associated toxicity.
T52 393728-393826 Sentence denotes T cell activation is a critical step in the development of an autoimmune attack against the brain.
T53 393827-393938 Sentence denotes Methylation are emerging as a novel posttransductional mechanism involved in the regulation of cell signalling.
T54 393939-394095 Sentence denotes We have found previously that 5'-methylthioadenosine (MTA), an inhibitor of methylation reactions, prevented macrophage activation in a murine sepsis model.
T55 394096-394104 Sentence denotes Methods:
T56 394105-394221 Sentence denotes Experimental autoimmune encephalomyelitis (EAE) was induced in Lewis rats immunized with myelin basic protein (MBP).
T57 394222-394324 Sentence denotes Animals were treated with MTA (100 microM) intraperitoneal (i.p.) daily or placebo after immunization.
T58 394325-394387 Sentence denotes Clinical and histological scores were compared between groups.
T59 394388-394396 Sentence denotes Results:
T60 394397-394489 Sentence denotes We found that animals treated with MTA have a milder disease (mean clinical score MTA group:
T61 394490-394510 Sentence denotes 0.12, placebo group:
T62 394511-394561 Sentence denotes 1.09. p=0.002) and a delayed onset of the disease.
T63 394562-394681 Sentence denotes In addition MTA-treated animals have less inflammatory infiltrates and demyelinating areas compared to placebo animals.
T64 394682-394816 Sentence denotes Conclusion: MTA, a potent inhibitor of methylation reactions, prevents the development of a full autoimmune response in the EAE model.
T65 394817-394957 Sentence denotes The therapeutic efficacy of M2000 as a novel immunosuppressive and anti-inflammatory agent in T cell-mediated autoimmune disease was tested.
T66 394958-395119 Sentence denotes The influence of M2000 on myelin basic protein (MBP)-induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis was assessed.
T67 395120-395268 Sentence denotes The onset and symptoms of EAE in Lewis rats could be suppressed by intraperitoneally administration of M-2000 during the induction phase of disease.
T68 395269-395443 Sentence denotes Disease suppression was associated with a marked suppression of MBP-specific T cell reactivity in vitro, without any evidence for a generalized impairment of T cell activity.
T69 395444-395602 Sentence denotes Collectively, our data suggest that M2000 may provide a novel therapeutic option for T cell-mediated autoimmune diseases in animal models and possibly in man.
T70 395603-395905 Sentence denotes The aim of the present study was to evaluate the effect of murine interferonbeta (mIFN-beta) or dexamethasone (DEX) on myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in female C57BL/6 mice, a murine model for the human disease multiple sclerosis (MS).
T71 395906-396101 Sentence denotes EAE was induced by a subcutaneous injection of MOG(35-55)-peptide in incomplete Freund's Adjuvant mixed with Mycobacterium tuberculosis, followed by intraperitoneal injections of pertussis toxin.
T72 396102-396250 Sentence denotes The mice were treated with subcutaneous injections of mIFN-beta in doses of 5000 or 15,000 units/mouse or DEX in doses of 1 or 10 mg/kg body weight.
T73 396251-396410 Sentence denotes The treatment started at day 7 after EAE-induction with administration once every second day until day 23, and the course of disease was followed up to day 31.
T74 396411-396554 Sentence denotes The results demonstrate a significant reduction of the individual average and maximum clinical score in mice treated with 1 or 10 mg/kg of DEX.
T75 396555-396651 Sentence denotes Treatment with DEX also effectively reduced the inflammation and demyelination in mice with EAE.
T76 396652-396805 Sentence denotes However, the only effect of mIFN-beta was a significant reduction of the individual maximum clinical score in mice that received 5000 units of mIFN-beta.
T77 396806-396918 Sentence denotes Effects of EGIS-8332, an AMPA antagonist, in transient focal cerebral ischemia and multiple sclerosis in rats K.
T78 396919-396930 Sentence denotes Mó ricz, G.
T79 396931-396941 Sentence denotes Gigler, M.
T80 396942-396953 Sentence denotes Albert, É .
T81 396954-396977 Sentence denotes Matucz, M. Á goston, A.
T82 396978-396986 Sentence denotes Simó, A.
T83 396987-396998 Sentence denotes Benedek, J.
T84 396999-397014 Sentence denotes Barkó czy, L.G.
T85 397015-397026 Sentence denotes Hársing, G.
T86 397027-397039 Sentence denotes Lévay and G.
T87 397040-397092 Sentence denotes Szénási EGIS Pharmaceuticals Ltd., Budapest, Hungary
T88 397093-397190 Sentence denotes A role for AMPA receptors in the pathogenesis of neurodegenerative disorders is well established.
T89 397191-397372 Sentence denotes EGIS-8332 is a negative allosteric modulator of AMPA receptors with good anticonvulsant and neuroprotective effects in animal models of global and permanent focal cerebral ischemia.
T90 397373-397592 Sentence denotes In the present study we compared the neuroprotective effects of EGIS-8332 and GYKI 53405, a structurally analogue compound, in transient focal cerebral ischemia and experimental autoimmune encephalomyelitis (EAE) tests.
T91 397593-397811 Sentence denotes The middle cerebral artery was occluded intraluminally for 60 min using a monofilament, and the effects of the two compounds administered 60 min after occlusion at 20 mg/kg i.p. were evaluated after a 24-h reperfusion.
T92 397812-397937 Sentence denotes EGIS-8332 and GYKI 53405 reduced both the core (56%, 50%, respectively) and total brain infarctions (33%, 28%, respectively).
T93 397938-398144 Sentence denotes Male Lewis rats were treated with guinea pig myelin basic protein for the induction of EAE, and both compounds were administered at 3 mg/kg i.p. twice daily for 7 days starting on day 10 after immunization.
T94 398145-398292 Sentence denotes EGIS-8332 reduced cumulative neurological score and partially reversed histopathological damage while the effect of GYKI 53405 was not significant.
T95 398293-398447 Sentence denotes The favourable neuroprotective effect of EGIS-8332 indicates good perspectives for further development for the treatment of stroke and multiple sclerosis.
T96 398448-398464 Sentence denotes Object of study:
T97 398465-398641 Sentence denotes The study was undertaken to enlighten influence of major effectors of stress response-endocrine catecholamines (CA) and neuronally released noradrenaline on development of EAE.
T98 398642-398649 Sentence denotes Method:
T99 398650-398903 Sentence denotes Adult DA rats were treated with either saline or propranolol chloride (0.4 mg/100 g/ day, PT) s.c. and on day 4 after the beginning of treatment were immunized by guinea pig spinal cord homogenate in complete Freund's adjuvant with B. pertussis vaccine.
T100 398904-399151 Sentence denotes When the clinical sings of disease were at maximum the expression of CD4/CD8/TCRalpha/beta on thymocytes, thymocyte proliferative and apoptotic indexes and expression of CD4/25 and CD8/25 on peripheral blood lymphocytes (PBL) were analyzed by FCA.
T101 399152-399214 Sentence denotes Results: PT decreased morbidity and mortality rate of disease.
T102 399215-399310 Sentence denotes In propranolol-treated rats the maximal sign of disease, as well as its duration, were reduced.
T103 399311-399391 Sentence denotes PT did not affect the thymocyte yield, but altered thymocyte phenotypic profile.
T104 399392-399655 Sentence denotes The percentages of CD4-8-TCRalpha/betaÀ cells, that of CD4+8+TCRalpha/betaÀ cells, and the relative proportion of all subsets of thymocytes expressing TCRalpha/beta+ (except CD4-8À) were decreased, while the percentage of CD4+8+TCRalpha/betaF cells was increased.
T105 399656-399829 Sentence denotes The relative number of CD8+ PBL was decreased; while that of CD4+ cells remained unaffected (although the percentage of CD4+25+ PBL was reduced) in propranolol-treated rats.
T106 399830-400003 Sentence denotes Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system in which it is widely accepted that autoimmunity plays a significant role.
T107 400004-400154 Sentence denotes The animal model equivalent of MS, experimental autoimmune encephalomyelitis (EAE), implicates an autoimmune T cell response as the initiating factor.
T108 400155-400313 Sentence denotes There is now substantial evidence that other components of the immune system are recruited in MS and in EAE to cause myelin damage and neuronal/axonal injury.
T109 400314-400421 Sentence denotes The complement (C) system has been implicated as a myelinolytic agent in both man and experimental animals.
T110 400422-400528 Sentence denotes The fluid-phase fragment C5a is chemotactic for phagocytic cells and activating for many other cell types.
T111 400529-400714 Sentence denotes We here describe a study of the effects of C5aR blockade using AcF- [OPdChaWR] in the well-documented Lewis rat models of EAE and an antibody-mediated demyelinating form of EAE (ADEAE).
T112 400715-400794 Sentence denotes Disease was monitored clinically and by using multiple pathological parameters.
T113 400795-400972 Sentence denotes AcF-[OPdChaWR] treatment had no effect on the clinical course or pathological outcome in either the primarily inflammatory EAE model or the profoundly demyelinating ADEAE model.
T114 400973-401099 Sentence denotes IL-12 is a heterodimeric cytokine which plays an important role in driving the differentiation of T helper type 1 (Th1) cells.
T115 401100-401255 Sentence denotes Such cells have been considered a key factor in the initiation of autoimmune inflammatory demyelination in experimental autoimmune encephalomyelitis (EAE).
T116 401256-401418 Sentence denotes However, recent evidence showed that IL-12 is dispensable in the pathogenesis of, and that severe EAE can develop in the absence of IL-12 or IL-12 responsiveness.
T117 401419-401514 Sentence denotes These data raised the possibility of an immunomodulatory action of IL-12 in this disease model.
T118 401515-401648 Sentence denotes The object of this study was to test the ability of exogenous IL-12 to modulate chronic EAE induced by MOG35-55 in the C57BL/6 mouse.
T119 401649-401817 Sentence denotes We used T-cell proliferation assays, ELISA, flow cytometry, real-time PCR, and histopathology to characterize the autoimmune response in IL-12-treated and control mice.
T120 401818-401949 Sentence denotes We found that IL-12 suppressed EAE clinically and pathologically when administered during the early induction phase of the disease.
T121 401950-402101 Sentence denotes The suppression of EAE was accompanied by induction of IFNgamma and TNF-alpha and inhibition of MOG-induced T cell proliferation in IL-12 treated mice.
T122 402102-402165 Sentence denotes IFN-gamma-deficient mice were resistant to disease suppression.
T123 402166-402241 Sentence denotes IL-12 also inhibited mRNA expression of the proinflammatory cytokine IL-17.
T124 402242-402416 Sentence denotes We conclude that exogenous IL-12 inhibits EAE by a premature induction of autoreactive effector Th1 cells and that increased IFN-gamma has an inhibitory effect on such cells.
T125 402417-402495 Sentence denotes In addition, anti-inflammatory effects may be mediated by inhibition of IL-17.
T126 402496-402616 Sentence denotes Disruption of the TGF-beta-signaling pathway in the macrophage compartment and its impact on immune-mediated diseases U.
T127 402617-402633 Sentence denotes Malipiero a , F.
T128 402634-402650 Sentence denotes Ackermann a , S.
T129 402651-402666 Sentence denotes Karlsson b , K.
T130 402667-402680 Sentence denotes Buerki a , U.
T131 402681-402696 Sentence denotes Koedel c and A.
T132 402697-402840 Sentence denotes Fontana a a University Hospital Zurich, Zurich, Switzerland; b Lund University, Lund, Sweden; c Ludwig-Maximillians-University, Munich, Germany
T133 402841-403125 Sentence denotes The TGF-beta family of proteins are secreted molecules with potent immunoregulatory properties and they control many activities of macrophages such as expression of MHCII, chemotaxis, production of cytokines and their receptors, production of reactive oxygen species and nitric oxide.
T134 403126-403284 Sentence denotes Activation and infiltration of macrophages is seen in various disease models including experimental allergic encephalomyelitis (EAE) and bacterial meningitis.
T135 403285-403320 Sentence denotes The latter are blocked by TGF-beta.
T136 403321-403449 Sentence denotes The current study investigates the role of TGF-beta on the macrophage compartment in inflammatory and autoimmune disease models.
T137 403450-403659 Sentence denotes In order to interrupt the TGF-beta-signaling pathway in macrophages, we delete the TRII by breeding floxed TRII mice with mice expressing Cre recombinase under the macrophage-specific mouse lysozymeM promoter.
T138 403660-403792 Sentence denotes Cultured bone marrow cells from mice devoid of TRII in macrophage/monocyte lineage cells show a deletion of exon 4 in the TRII gene.
T139 403793-403891 Sentence denotes The LPS-induced production of TNFalpha is not inhibited by TGF-beta in Cre-expressing macrophages.
T140 403892-403999 Sentence denotes Macrophages of wildtype animals show a 50-80% reduction of TNF-alpha secretion in the presence of TGF-beta.
T141 404000-404077 Sentence denotes The results show disruption of the TGF-beta-signaling pathway in macrophages.
T142 404078-404269 Sentence denotes TGF-beta macrophage receptor knockout mice are currently tested in EAE and bacterial meningitis to analyze disease progression with disturbed TGF-beta-signaling in the macrophage compartment.
T143 404270-404396 Sentence denotes 2002; Bechtold et al, Ann Neurol, 2004, in press ) have led us to question whether such agents might affect T cell activation.
T144 404397-404608 Sentence denotes In vitro, rat lymph node cells stimulated with phytohemagglutinin in the presence of flecainide, lamotrigine and phenytoin (5 Ag/ml) exhibited a 20-30% reduction in the proportion of ICAM+ CD4+ and CD8+ T cells.
T145 404609-404762 Sentence denotes In the same culture conditions lamotrigine also caused a 35% decrease in cell proliferation: this decrease was not observed with flecainide or phenytoin.
T146 404763-404938 Sentence denotes The effects of flecainide on T cell activation were also examined following its subcutaneous injection in animals with EAE induced by immunisation with spinal cord homogenate.
T147 404939-405177 Sentence denotes Administration of flecainide (30 mg/kg/day) between 7 and 12 days post-immunisation did not alter the percentage of T cells positive for CD44 or CD62L, but it did result in a 20% reduction in the proportion of ICAM+ CD4+ and CD8+ T cells.
T148 405178-405291 Sentence denotes In summary, the results show that sodium channel blocking agents can affect T cell function in vitro and in vivo.
T149 405292-405532 Sentence denotes Myelin-specific T cell receptor transgenic T cells Vaccination with DNA encoding myelin oligodendrocyte glycoprotein (MOG)-peptide 91-108, pMOG91-108, suppresses experimental autoimmune encephalomyelitis (EAE) induced with the same peptide.
T150 405533-405661 Sentence denotes EAE is an animal model for multiple sclerosis (MS) and can be actively induced by immunization with myelin proteins or peptides.
T151 405662-405760 Sentence denotes The CpG DNA content of the plasmid DNA backbone is necessary for efficient DNA vaccination to EAE.
T152 405761-405856 Sentence denotes Recently, we demonstrated that the suppressive mechanism involves induction of interferon-beta.
T153 405857-405947 Sentence denotes These data are of great interest, since interferon-beta is used as a MS-therapy in humans.
T154 405948-406116 Sentence denotes Here, we study the transcription of over 6000 genes using cDNA microarrays in spleens from DNA vaccinated LEW.1AV1 rats relative to control rats during peak of disease.
T155 406117-406278 Sentence denotes Plasmacytoid dendritic cell (pDC)-associated genes, as defined in mice and human pDCs, were differentially expressed in DNA-vaccinated rats compared to controls.
T156 406279-406520 Sentence denotes In contrast to human systemic lupus erythematosus (SLE)-where pDCs have been suggested to be involved in the pathogenesis-our data may indicate that pDCs can mediate protection from EAE, possibly via endogenous production of interferon-beta.
T157 406521-406578 Sentence denotes Th1-cell activation is crucial in EAE and MS development.
T158 406579-406713 Sentence denotes TIRC7 is a membrane molecule expressed early in lymphocyte activation and anti-TIRC7 therapy inhibits Th1-cell antigen-responsiveness.
T159 406714-406802 Sentence denotes Here, we studied the role of TIRC7 and therapeutic potential of TIRC7 mAb in EAE and MS.
T160 406803-407098 Sentence denotes We used mAb to characterize cell-type specific TIRC7-expression in MS lesions. mAb effects on EAE in mice immunized with peptide (PLP139-151) were studied by comparing clinical signs, brain immunohistochemistry, lymphocyte proliferation, and cytokine levels in mAb-treated and untreated animals.
T161 407099-407187 Sentence denotes TIRC7-positive T-cells were the dominant cell-type in both acute and chronic MS lesions.
T162 407188-407373 Sentence denotes At 28 days, 5 mAb-pretreated EAE mice had a lower mean clinical score of 0.6F0.6 (S.E.M.) compared with 12 EAE controls (1.75F0.58; p=0.19) suggesting mAb inhibition of EAE development.
T163 407374-407550 Sentence denotes In addition, mAb halted the clinical progression of established EAE: at 14 days, mAb-treated mice scores were 0.5F0.5 (n=4) compared with 1.7F0.73 ( p=0.08) for controls (n=5).
T164 407551-407744 Sentence denotes Clinical improvements were typically accompanied by reduced mononuclear cell infiltration in EAE lesions in mAb-treated compared with untreated mice. mAb effects were immunologically-selective.
T165 407745-407865 Sentence denotes Treated mice had lower splenocyte IFN-gamma and IL-6 expression and reduced T-cell proliferation compared with controls.
T166 407866-408047 Sentence denotes These pilot data suggest that TIRC7 is involved in the pathogenesis of EAE, and possibly of MS, and that TIRC7 mAb is a potential MS therapy with selective immunomodulatory effects.
T167 408048-408117 Sentence denotes Phenotype and kinetics of CSF B cells in inflammatory CNS diseases S.
T168 408118-408127 Sentence denotes Cepok, F.
T169 408128-408137 Sentence denotes Vogel, V.
T170 408138-408149 Sentence denotes Grummel, S.
T171 408150-408164 Sentence denotes Hofmann and B.
T172 408165-408438 Sentence denotes Hemmer Clinical Neuroimmunology Group, Department of Neurology, Philipps University, Marburg, Germany B cells are frequently found in the cerebrospinal fluid (CSF) of patients with neuroinflammatory diseases like multiple sclerosis (MS) and various infectious CNS diseases.
T173 408439-408695 Sentence denotes The objective of the present study was to characterize the phenotype and kinetics of B cell subpopulations in the CSF and blood of patients with MS and infectious diseases in order to dissect differences between chronic and acute inflammatory CNS diseases.
T174 408696-408886 Sentence denotes For this purpose, we performed serial analyses of CSF and blood cells by flow-cytometry in patients with MS and acute infectious diseases such as lyme meningoradiculitis or viral meningitis.
T175 408887-408991 Sentence denotes Plasma cells and B cells were detected in most patients with MS or acute infectious diseases in the CNS.
T176 408992-409106 Sentence denotes In contrast to peripheral blood, most of the B cells in the CSF showed a memory phenotype with expression of CD27.
T177 409107-409180 Sentence denotes CSF B cells also downregulated several B cell marker, like CD21 and CD22.
T178 409181-409247 Sentence denotes Plasma cells upregulated LFA-1 compared to peripheral plasmacells.
T179 409248-409393 Sentence denotes Interestingly, as determined by serial analysis a differential kinetic pattern in MS patients was observed compared to acute infectious diseases.
T180 409394-409529 Sentence denotes In MS patients, more than 30% of CD19+ cells were plasma cells, which remained stable over years accompanied by a stable IgG synthesis.
T181 409530-409646 Sentence denotes In contrast, in infectious diseases the plasmacells dropped immediately within weeks after the pathogen was removed.
T182 409647-409749 Sentence denotes The data demonstrate that in MS a permanent and stable activation of the humoral immune system occurs.
T183 409750-409952 Sentence denotes Multiple sclerosis (MS) is characterized by increased intrathecal synthesis of immunoglobulins of unknown specificity and by the presence of B-cell clonal expansions in the central nervous system (CNS).
T184 409953-410176 Sentence denotes Because ectopic lymphoid tissue developing at sites of chronic inflammation is thought to sustain local immune processes, we have investigated whether abnormal B-cell follicles could be identified in the CNS of MS patients.
T185 410177-410445 Sentence denotes Sections from post-mortem MS brains and spinal cords were examined by immunohistochemistry for the presence of CD20+ B cells, CD138+ plasma cells, CD3+ T cells and CD21+, CD35+ follicular dendritic cells, and for expression of the lymphoid chemokines CXCL13 and CCL21.
T186 410446-410727 Sentence denotes Lymphoid follicle-like structures containing B cells, T cells, plasma cells and follicular dendritic cells producing CXCL13 were observed in the cerebral meninges of two out of three patients with secondary progressive MS, but not in relapsing-remitting and primary progressive MS.
T187 410728-410852 Sentence denotes Proliferating B cells were detected in intrameningeal follicles, a finding which is suggestive of germinal center formation.
T188 410853-411000 Sentence denotes Despite accumulation of numerous B cells and plasma cells around blood vessels, no folliclelike structures were identified in white matter lesions.
T189 411001-411164 Sentence denotes The formation of ectopic lymphoid follicles in the meninges of patients with MS could play a role in maintaining humoral (auto)immunity and in disease progression.
T190 411165-411348 Sentence denotes A full maturation process of B cells into the CSF suggests the existence of an intrathecal lymphoid-like compartment in subjects with MS and other inflammatory disorders of the CNS A.
T191 411349-411363 Sentence denotes Uccelli a , S.
T192 411364-411378 Sentence denotes Casazza a , E.
T193 411379-411394 Sentence denotes Ferretti b , D.
T194 411395-411408 Sentence denotes Giunti a , E.
T195 411409-411422 Sentence denotes Zappia a , A.
T196 411423-411438 Sentence denotes Pistorio b , C.
T197 411439-411455 Sentence denotes Gambini c , G.L.
T198 411456-411473 Sentence denotes Mancardi a and V.
T199 411474-411607 Sentence denotes Pistoia c a Neuroimmunology Unit, Department of Neurosciences, Ophthalmology and Genetics, Genoa, Italy; b Laboratory of Oncology, G.
T200 411608-411670 Sentence denotes Gaslini Institute, Genoa, Italy; c Laboratory of Pathology, G.
T201 411671-411702 Sentence denotes Gaslini Institute, Genoa, Italy
T202 411703-411883 Sentence denotes Clonally expanded populations of hypermutated B cells have been detected in the CNS of MS subjects suggesting that a process of B cell affinity maturation may occur inside the CNS.
T203 411884-412057 Sentence denotes We have characterized by flow cytometry the B cell subsets identified within the CSF of MS patients and of individuals with other inflammatory neurological disorders (OIND).
T204 412058-412245 Sentence denotes CD19+CD38+CD77+, Ki67+, Bcl-2À centroblasts, a subset exclusively represented within lymphoid organs, were detected in the CSF, but not in peripheral blood (PB), from both patient groups.
T205 412246-412373 Sentence denotes CD27+IgDÀ memory B cells, which represent hypermutated B cells, were significantly increased in the CSF vs PB from both groups.
T206 412374-412521 Sentence denotes Memory B cells expressed high level of CD80 and CD86 costimulatory molecules and up-regulated CCR1, CCR2 and CCR4 suggesting their activated state.
T207 412522-412741 Sentence denotes Lymphotoxin-alpha, CXCL12 and CXCL13, key players in lymphoid neogenesis, were present in the CSF from MS and OIND patients and expressed in MS brain tissue providing a favourable microenvironment for B cell maturation.
T208 412742-412959 Sentence denotes This study suggests that a compartimentalized B cell response occurs within the CNS during an ongoing inflammatory reaction, evolving through all stages of B cell differentiation observed in secondary lymphoid organs.
T209 412960-413158 Sentence denotes BAFF production in human brain by astrocytes: the The brain in multiple sclerosis (MS) provides a long-term survival niche for B cells and plasma cells, which give rise to persisting oligoclonal Ig.
T210 413159-413249 Sentence denotes B cell activating factor of the TNF family (BAFF) plays a crucial role in B cell survival.
T211 413250-413348 Sentence denotes We report that BAFF is expressed in the normal human brain and is produced by astrocytes in vitro.
T212 413349-413469 Sentence denotes BAFF transcripts found in gray and white matter amounted to about 9% of that in lymphatic tissue (tonsils and adenoids).
T213 413470-413595 Sentence denotes The splice variant delta-BAFF was expressed at a lower level than the full-length variant in both brain and lymphatic tissue.
T214 413596-413728 Sentence denotes BAFF was a regular component of the normal spinal fluid, and was demonstrated in brain astrocytes by double-fluorescence microscopy.
T215 413729-413876 Sentence denotes Cultured human astrocytes secreted high amounts of BAFF after stimulation with IFNgamma and TNF-alpha, which was mediated by a furin-like protease.
T216 413877-413979 Sentence denotes The quantity of BAFF secreted per astrocyte was manifold higher than that of monocytes or macrophages.
T217 413980-414162 Sentence denotes In MS lesions, the expression of BAFF was elevated as seen by quantitative PCR; BAFF was localized on astrocytes, and the BAFF receptor BAFF-R was found on infiltrating immune cells.
T218 414163-414285 Sentence denotes This study establishes, we believe for the first time that a non-immune cell type can produce substantial amounts of BAFF.
T219 414286-414380 Sentence denotes BAFF production in the CNS might contribute to the long term survival of B cells in MS brains.
T220 414381-414472 Sentence denotes A panel of novel candidate antigens in multiple sclerosis revealed by phage cDNA display V.
T221 414473-414483 Sentence denotes Somers, C.
T222 414484-414495 Sentence denotes Govarts, J.
T223 414496-414507 Sentence denotes Raus and P.
T224 414508-414629 Sentence denotes Stinissen Biomedisch Onderzoeksinstituut (BIOMED), Limburgs Universitair Centrum, University Limburg, Diepenbeek, Belgium
T225 414630-414812 Sentence denotes Cerebrospinal fluid (CSF) of patients with clinically definite multiple sclerosis (MS) is characterized by the presence of oligoclonal antibodies, which is used as a diagnostic test.
T226 414813-414892 Sentence denotes However, despite intensive research, the antibody specificities remain unknown.
T227 414893-415079 Sentence denotes To identify immunogenic targets recognized by the humoral immune response in MS, we focus on a novel method called bserological antigen selection (SAS)Q, which is based on phage display.
T228 415080-415372 Sentence denotes First, we constructed a cDNA display library by cloning a normalized cDNA library prepared from active chronic MS plaques, with varying degrees of demyelination and inflammatory activity (Soares et al, 1994) for expression as a fusion protein with a filamentous phage minor coat protein, pVI.
T229 415373-415475 Sentence denotes This cDNA display library was then enriched on pooled CSF (n=10) from relapsing-remitting MS patients.
T230 415476-415550 Sentence denotes We identified a panel of nine different clones reactive with the CSF pool.
T231 415551-415744 Sentence denotes A detailed serological analysis of the nine different antigens on a large panel of individual patient and control CSF showed exclusive reactivity to MS patient CSF for eight different antigens.
T232 415745-415825 Sentence denotes Sequence analysis revealed that these clones have never been associated with MS.
T233 415826-416050 Sentence denotes In conclusion, our findings demonstrate that this novel molecular approach is useful to identify novel candidate antigens in MS that can be used as disease markers, and can be used to study the humoral immune response in MS.
T234 416051-416140 Sentence denotes An approach to the identification of targets of autoantibodies in multiple sclerosis E.T.
T235 416141-416154 Sentence denotes Littleton, J.
T236 416155-416168 Sentence denotes Palace and A.
T237 416169-416206 Sentence denotes Vincent Oxford University, Oxford, UK
T238 416207-416449 Sentence denotes The finding in multiple sclerosis (MS) patients of oligoclonal IgG bands upon isoelectric focusing of cerebrospinal fluid and the partial clinical response to immunosuppressive drugs support the theory of a role for antibodies in the disease.
T239 416450-416619 Sentence denotes However, previously employed candidate antigen-based approaches, usually involving ELISA assays, have failed to identify pathologically relevant antibodies and antigens.
T240 416620-416764 Sentence denotes We hypothesise that the antigenic target(s) for a relevant antibody would be located on the cell membrane of neuronal or oligodendroglial cells.
T241 416765-416997 Sentence denotes We have developed an approach that can be used to identify target antigens, first applying it to demonstrate that muscle-specific kinase (MuSK) is a muscle cell target in myasthenia gravis, and then applying it in the context of MS.
T242 416998-417293 Sentence denotes Using immunocytochemistry with flow cytometry we showed that myasthenia gravis patients' sera, containing antibodies against MuSK, bind MuSK-expressing TE 671 rhabdomyosarcoma cells, and that MuSK can be immunoprecipitated from TE 671 cell extracts by these sera and identified on Western blots.
T243 417294-417479 Sentence denotes Applying the same approach, we found that about 10% of relapsing-remitting and secondary progressive MS patients' sera contained IgG antibodies, which bound SK-N-SH neuroblastoma cells.
T244 417480-417684 Sentence denotes We then used these neuronal antibody-containing MS sera to immunoprecipitate antigens from biotin-labelled SK-N-SH cell extracts, isolating the antigens through Western blotting of the immunoprecipitates.
T245 417685-417756 Sentence denotes Immunoprecipitated antigens are being identified by protein sequencing.
T246 417757-417907 Sentence denotes Guillain-Barré syndrome (GBS) is a post infectious polyradiculoneuropathy characterized by demyelination and axonal degeneration of peripheral nerves.
T247 417908-418010 Sentence denotes Phagocytes and glycolipid (ganglioside)-specific antibodies, are thought involved in the pathogenesis.
T248 418011-418148 Sentence denotes We recently documented the inflammatory capacity of GBS-associated anti-GM1 IgG, as measured by leukocyte degranulation and phagocytosis.
T249 418149-418399 Sentence denotes Additional experiments showed that sera containing GM1-IgG (n=41), GQ1b-IgG (n=32), GD1a-IgG (n=5) and GM2-IgG (n=2) induced leukocyte activation as measured by degranulation in 59%, 84%, 80%, and 100%, respectively, of the patient sera investigated.
T250 418400-418524 Sentence denotes Leukocyte activation was IgG-receptor (FcgammaR) dependent, as shown by blocking studies using FcgammaR-specific antibodies.
T251 418525-418683 Sentence denotes The addition of pooled gammaglobulin (IVIg), used as treatment for GBS, reduced ganglioside-specific IgG-induced leukocyte activation in a dose-dependent way.
T252 418684-418815 Sentence denotes These results indicate that gangliosidespecific IgG contains pro-inflammatory activity, and that IVIg may reduce its functionality.
T253 418816-418873 Sentence denotes New genes-new targets for therapy of myasthenia gravis M.
T254 418874-418890 Sentence denotes Souroujon a , T.
T255 418891-418906 Sentence denotes Feferman b , A.
T256 418907-418921 Sentence denotes Revital b , P.
T257 418922-418934 Sentence denotes Maiti b , S.
T258 418935-418956 Sentence denotes Berrih-Aknin c and S.
T259 418957-419321 Sentence denotes Fuchs b a The Open University of Israel, Tel Aviv, Israel; b Weizmann Institute of Science, Rehovot, Israel; c Centre National de la Recherche Scientifique, UMR-8078, IPSC, Hopital Marie Lannelongue, Le Plessis Robinson, France New genes involved in the pathogenesis of experimental autoimmune myasthenia gravis (EAMG) were identified by DNA microarray technology.
T260 419322-419573 Sentence denotes Out of the differentially expressed genes associated with myasthenia we focused on genes coding for phosphodiesterases (PDE) and chemokines-which are, respectively, involved in lymphocyte activation, differentiation and migration to the target tissue.
T261 419574-419747 Sentence denotes Microarray analysis supported by real time RT-PCR revealed a significant increase in mRNA levels of specific PDE subtypes in lymph node cells and muscles of myasthenic rats.
T262 419748-419946 Sentence denotes Pentoxifylline (PTX), a general PDE inhibitor suppressed ongoing EAMG and led to downregulation of PDE subtypes 1, 4 and 7, TNF-alpha, IL-12 and IL-10 with no effect on IL-4, IFN-gamma and TGF-beta.
T263 419947-420071 Sentence denotes These results suggest that PTX may in the future serve as a potential drug for immunotherapy of myasthenia gravis in humans.
T264 420072-420219 Sentence denotes The mRNA levels of the chemokines IP-10 and Mig and of their receptor CXCR3 were upregulated in myasthenic rats and reduced after EAMG suppression.
T265 420220-420339 Sentence denotes A significant increase in IP-10 and CXCR3 mRNA levels was also observed in thymuses and muscles of myasthenic patients.
T266 420340-420450 Sentence denotes These results suggest that IP-10/CXCR3 signaling is a potential target for immunotherapy of myasthenia gravis.
T267 420451-420540 Sentence denotes Deletion of Fc-receptor-gamma abrogates encephalitogenicity of effector T cells in EAE E.
T268 420541-420553 Sentence denotes Urich and B.
T269 420554-420649 Sentence denotes Becher Department of Neurology, Neuroimmunology Unit, University of Zurich, Zurich, Switzerland
T270 420650-420771 Sentence denotes The role of B-lymphocytes and auto-antibodies in experimental autoimmune encephalomyelitis (EAE) remains heavily debated.
T271 420772-420941 Sentence denotes While some have reported that B cells are irrelevant for the development of EAE using B cell-deficient mice, others have shown that antibodies are a central requirement.
T272 420942-421039 Sentence denotes Furthermore, mice deficient in Fc-receptors (FcR) have been shown to be resistant to develop EAE.
T273 421040-421198 Sentence denotes FcRs recognize immunoglobulins and thus the requirement of FcRs to develop EAE is in apparent conflict with the findings obtained using B cell-deficient mice.
T274 421199-421367 Sentence denotes To determine the underpinnings of this paradox, we used B cell-and FcR-gamma-deficient mice to establish the functional role of these molecules in the induction of EAE.
T275 421368-421539 Sentence denotes We confirmed that B cell deficient mice are fully susceptible to the development of MOG-induced EAE regardless of whether peptides or recombinant MOG was used to immunize.
T276 421540-421630 Sentence denotes In contrast to these findings, mice deficient in FcR-gamma were shown to be EAE-resistant.
T277 421631-421786 Sentence denotes Preliminary data indicate that by combining both mutations, the FcR-gamma phenotype is dominant and that B-cell/FcR-gamma deficient mice are EAE-resistant.
T278 421787-421992 Sentence denotes Our data further show that the FcR-gamma chain is recruited into the TcR complex of effector T cells and that the ablation of FcR-gamma lesions the T cell compartment rather than Fc-receptor bearing cells.
T279 421993-422183 Sentence denotes Taken together, our data dismiss any involvement of humoral immunity in MOG-induced EAE and demonstrate that FcR-gamma-deletion affects T lymphocytes rather than FcR-bearing accessory cells.
T280 422184-422296 Sentence denotes Induction and effector phase of experimental allergic encephalomyelitis are independent of the Fc gamma chain E.
T281 422297-422309 Sentence denotes Breij a , D.
T282 422310-422324 Sentence denotes Heijnen a , R.
T283 422325-422337 Sentence denotes Vloet a , J.
T284 422338-422471 Sentence denotes Van Immunoglobulin (IgG) receptors (FcgammaR) have been implicated in the induction of experimental allergic encephalomyelitis (EAE).
T285 422472-422535 Sentence denotes We addressed the role of FcgammaR in the effector phase of EAE.
T286 422536-422721 Sentence denotes Using the MOG35-55 induction protocol, we were able to reproducibly induce chronic EAE in C57BL/6 FcR gamma-chainÀ/À mice, lacking both stimulatory Fcgam-maRs FcgammaRI and FcgammaRIII.
T287 422722-422804 Sentence denotes Disease incidence and severity were similar to EAE in wild type C57BL/6 (wt) mice.
T288 422805-422955 Sentence denotes However, disease onset was significantly delayed, suggesting a role for FcR gamma-chain signalling in the early immunological events resulting in EAE.
T289 422956-423115 Sentence denotes The model we used is B-cell independent, therefore interactions between myelinspecific antibodies and FcgammaR are unlikely to contribute to disease induction.
T290 423116-423202 Sentence denotes The FcR gamma-chain is involved in a number of antibodyindependent signaling pathways.
T291 423203-423376 Sentence denotes We propose that delayed onset of EAE in FcR gamma-chainÀ/À mice results from disturbance of one of these pathways, rather than from deficient antibody-FcgammaR interactions.
T292 423377-423453 Sentence denotes Subsequently, we investigated the role of FcgammRs in antibody-enhanced EAE.
T293 423454-423546 Sentence denotes The monoclonal anti-MOG antibody Z12 (mAb Z12) was previously shown to enhance clinical EAE.
T294 423547-423663 Sentence denotes EAE was induced in wt and FcR gamma-chainÀ/À mice, and both groups were injected with 1 mg mAb Z12 at disease onset.
T295 423664-423805 Sentence denotes In both wt and FcRg amma-chainÀ/À mice, mAb severely enhanced EAE, as revealed by clinical scores and immunocytochemical analysis of the CNS.
T296 423806-423918 Sentence denotes Our results demonstrate that anti-myelin antibodies can enhance clinical EAE in absence of stimulatory FcgammaR.
T297 423919-424095 Sentence denotes Discriminant patterns of IgG self reactivity against brain antigens have been described in multiple sclerosis (MS) patients, highlighting the possibility of B cell involvement.
T298 424096-424280 Sentence denotes To define the sequence of humoral events involved, self-reactive IgG repertoires were sequentially compared in experimental autoimmune encephalomyelitis (EAE) mice and in control mice.
T299 424281-424368 Sentence denotes EAE was induced by immunizing SJL/J mice with proteolipid protein (PLP139-151), (n=37).
T300 424369-424497 Sentence denotes Control groups comprised either mice receiving complete Freund adjuvant (CFA) and Pertussis toxin (n=18) or healthy mice (n=19).
T301 424498-424598 Sentence denotes Sera were collected weekly and tested by immunoblotting assays using healthy mice brain homogenates.
T302 424599-424806 Sentence denotes With statistical procedures a linear discriminant analysis indicated that a selfreactive IgG repertoire was significantly different in each group of mice at day 14 (k=0.942), and more so at day 28 (k=0.974).
T303 424807-424975 Sentence denotes Characterization of the discriminant antigens involved might provide new tools for understanding the mechanisms underlying the initiation and progression of EAE and MS.
T304 424976-425136 Sentence denotes Intracerebral expression of CXCL13 and BAFF and formation of Bfollicle-like structures in the meninges of mice with experimental autoimmune encephalomyelitis S.
T305 425137-425156 Sentence denotes Columba-Cabezas, R.
T306 425157-425170 Sentence denotes Magliozzi, B.
T307 425171-425186 Sentence denotes Serafini and F.
T308 425187-425281 Sentence denotes Aloisi Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
T309 425282-425602 Sentence denotes Given the abnormalities in B-cell activity occurring in the central nervous system (CNS) of multiple sclerosis patients, we investigated whether autoimmunity triggers CNS expression of molecules regulating the development and functional organization of lymphoid follicles, the sites where B-cell responses are initiated.
T310 425603-425887 Sentence denotes We found that gene expression of CXCL13, a chemokine facilitating B-cell recruitment into follicles, and BAFF, a regulator of B-cell survival, is markedly upregulated in the CNS of SJL mice with PLP 139-151-induced, relapsing-remitting experimental autoimmune encephalomyelitis (EAE).
T311 425888-426110 Sentence denotes Using immunohistochemistry, follicle-like structures containing B cells and a reticulum of CD35+, FDC-M1+ and CXCL13+ follicular dendritic cells were identified in the brain stem meninges of a proportion of relapsing mice.
T312 426111-426183 Sentence denotes Ki67+ proliferating B cells were also detected in the inflamed meninges.
T313 426184-426455 Sentence denotes Intracisternal injection of the lymphotoxin-beta receptor-Ig fusion protein which blocks the action of lymphotoxin alpha/beta, a key cytokine in lymphoid organ development, either delayed or completely suppressed EAE relapses, and reduced B-cell proliferation in the CNS.
T314 426456-426622 Sentence denotes In line with our recent observations in MS, these findings indicate that the less immune privileged meningeal compartment might promote autoreactive B-cell responses.
T315 426623-426824 Sentence denotes They also suggest that local targeting of molecules involved in B-cell immunity or lymphoid tissue development should be considered as a possible therapeutic strategy to control CNS autoimmune disease.
T316 426825-426836 Sentence denotes Background:
T317 426837-426989 Sentence denotes Mast cells and other elements of allergic immune responses can participate in the regulation of the immune response associated with pathogenesis of EAE.
T318 426990-427190 Sentence denotes We have shown in a previous study that patterns of self-IgG reactivity could model pathological processes underlying the various forms of multiple sclerosis and the sequence of events involved in EAE.
T319 427191-427298 Sentence denotes In this work, we evaluate the incidence of anti-allergic drugs on IgG reactivity against brain homogenates.
T320 427299-427369 Sentence denotes Method: EAE was induced by immunization of SJL/J mice with PLP139-151.
T321 427370-427592 Sentence denotes One group of mice (n=8) were treated daily after immunization with pyrilamine, an histamine receptor 1 (HR1) antagonist and an other group of mice (n=8) with CV6209, a platelet activating factor receptor (PAFR) antagonist.
T322 427593-427630 Sentence denotes Control EAE group (n=6) received PBS.
T323 427631-427796 Sentence denotes Sera were collected weekly and sequential IgG immunoreactivity profiles were performed by western blots on brain homogenate and analyzed with statistical procedures.
T324 427797-427805 Sentence denotes Results:
T325 427806-427909 Sentence denotes As expected, clinical signs of EAE were delayed and reduced in mice treated with pyrilamine and CV6209.
T326 427910-428008 Sentence denotes Analysis of antibody patterns shows that they evolved distinctly between the three groups of mice.
T327 428009-428139 Sentence denotes Moreover, discriminant analysis indicates that a self-reactive antibody repertoire differed significantly from each group of mice.
T328 428140-428151 Sentence denotes Conclusion:
T329 428152-428218 Sentence denotes Pyrilamine and CV6209 reduced significantly clinical signs of EAE.
T330 428219-428386 Sentence denotes Our data show analysis of the immune profiles could be an indicative marker for evaluation of disease progression or disease resolution in autoimmune disorders as EAE.
T331 428387-428550 Sentence denotes To study the nature of oligoclonal IgG, single-cell RT-PCR was used to characterize Ig repertoires of both CD19+ B-lymphocytes and CD138+ plasma cells from MS CSF.
T332 428551-428760 Sentence denotes Sequence analysis of amplified heavy-and light-chain variable (V)-regions identified rearranged germline segments, extent of somatic mutation, and clonal relationships within and between both cell populations.
T333 428761-428894 Sentence denotes Expanded B-lymphocyte and plasma cell clones were detected in each CSF, including CSF examined during a clinically isolated syndrome.
T334 428895-429114 Sentence denotes Comparison of CD138+ and CD19+ repertoires in each CSF showed that CD138+ repertoires were more restricted and contained larger numbers of clones that shared little sequence overlap with corresponding CD19+ repertoires.
T335 429115-429329 Sentence denotes To identify putative antigenic targets of MS oligoclonal IgG, we developed a transient mammalian expression system to produce recombinant antibodies that utilize rearranged V-region sequences of plasma cell clones.
T336 429330-429514 Sentence denotes Recombinant IgG will be used in various immunoassays, including screening of cDNA expression libraries and random peptide libraries to identify potential targets of MS oligoclonal IgG.
T337 429515-429605 Sentence denotes Antibodies to native myelin-oligodendrocyte-glycoprotein in multiple sclerosis patients S.
T338 429606-429636 Sentence denotes Gaertner, K.L. de Graaf and R.
T339 429637-429709 Sentence denotes Weissert Hertie Institute for Clinical Brain Research, Tübingen, Germany
T1 429710-429862 Sentence denotes The best characterized autoantigen for autoantibody mediated myelin destruction in multiple sclerosis (MS) is myelin-oligodendrocyte-glycoprotein (MOG).
T2 429863-429974 Sentence denotes MOG is a glycoprotein (218 aa) of the immunoglobulin superfamily expressed on the surface of the myelin sheath.
T3 429975-430051 Sentence denotes Native MOG was purified from MOG-transfected cells by affinity purification.
T4 430052-430151 Sentence denotes IgM and IgG MOG-specific antibodies from sera of MS patients and controls were determined by ELISA.
T5 430152-430272 Sentence denotes IgM antibodies to native MOG were elevated in patients with a first demyelinating event compared to controls ( Pb0.001).
T6 430273-430443 Sentence denotes We detected high anti-MOG IgG responses in patients with acute disease exacerbations ( Pb0.001) and secondary chronic progressive disease compared to controls ( P=0.001).
T7 430444-430521 Sentence denotes In contrast, patients in remission did not have elevated IgG antibody titers.
T8 430522-430672 Sentence denotes Thess data underscore the relevance of conformation and glycosylation of MOG for recognition of the full repertoire of MOG-specific Ig in MS patients.
T9 430673-430815 Sentence denotes We propose that antibodies against native MOG may have a potential as a diagnostic test for MS and as a possible surrogate marker for therapy.
T10 430816-431012 Sentence denotes We have determined the three-dimensional structure of the extracellular domain of MOG (MOGex) and of MOGex in complex with the antigen binding fragment (Fab) of 8-18C5 using X-ray crystallography.
T11 431013-431190 Sentence denotes 8-18C5 is a demyelinating monoclonal mouse antibody that recognises a purely conformationdependent epitope as the vast majority of other demyelinating MOGspecific antibodies do.
T12 431191-431372 Sentence denotes The complex structure, the first structure of a classical hidden autoantigen complexed with an antibody, reveals the highly discontinuous epitope at the membrane-distal side of MOG.
T13 431373-431473 Sentence denotes Homologues of MOG are expressed outside the central nervous system, able to induce B-cell tolerance.
T14 431474-431570 Sentence denotes Interestingly, those residues bound by 8-18C5 are least conserved between MOG and its relatives.
T15 431571-431652 Sentence denotes Despite of the epitope's discontinuity one loop of MOG dominates the interaction.
T16 431653-431898 Sentence denotes The conformation of the amino acids that form this loop, however, is very strained and maintained by surrounding loops of the structure providing a simple explanation for the failure to detect this region by peptide mapping with linear peptides.
T17 431899-432041 Sentence denotes It is widely accepted that an autoimmune response to myelin components plays an important role in the pathogenesis of multiple sclerosis (MS).
T18 432042-432133 Sentence denotes The aim of the current project is to find new myelin antigens, which are immunogenic in MS.
T19 432134-432261 Sentence denotes We purified human myelin glycoproteins by sucrose gradient centrifugation and subsequent lentil-lectin affinity chromatography.
T20 432262-432346 Sentence denotes Sera from MS patients and controls were screened in ELISA and 1D western blots (WB).
T21 432347-432462 Sentence denotes In addition, immunoadsorption eluates from 5 MS and 2 control patients were used for screening of 2D western blots.
T22 432463-432596 Sentence denotes In the ELISA experiments, we found an increased reactivity against human myelin glycoproteins in MS patients versus control patients.
T23 432597-432704 Sentence denotes In 1D WB, a series of proteins with different molecular weights was recognized by MS patients and controls.
T24 432705-432802 Sentence denotes In the 2D WB, 2-3 protein spots were recognized by the immunoadsorption eluates from MS patients.
T25 432803-432880 Sentence denotes The identity of these protein spots could be identified by mass spectrometry.
T26 432881-433007 Sentence denotes Thus, by using a proteomic approach, we could identify some novel candidate autoantigens of the humoral immune response in MS.
T27 433008-433134 Sentence denotes Ongoing studies with recombinant proteins will clarify if these proteins are predominant targets of the immune response in MS.
T28 433135-433229 Sentence denotes Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous (CNS) system.
T29 433230-433425 Sentence denotes Increasing evidence, both from studies in experimental autoimmune encephalomyelitis (EAE) and MS suggests an involvement of autoreactive antibodies in the immunopathogenesis of CNS demyelination.
T30 433426-433644 Sentence denotes To further our understanding of the involvement of CNSreactive autoantibodies, we are studying immunoglobulin gene rearrangements and the respective antigen specificities of individual B-and plasma cells in MS lesions.
T31 433645-433928 Sentence denotes Immunoglobulin heavy (H) and light (L) chain genes of individual microdissected cells will be amplified by RT-PCR and rearranged H and L chain genes cloned into vector systems suitable for the expression of recombinant antibodies, which then will be screened for antigen specificity.
T32 433929-434067 Sentence denotes In order to identify conformation-dependent epitopes, we are currently establishing eukaryotic expression libraries of human brain tissue.
T33 434068-434286 Sentence denotes Using highly purified mRNA of different CNS regions we have generated cDNA libraries containing between 1.9 and 3.9Â10 7 independent clones with a high proportion of full-length cDNA inserts ranging from 0.4 to 5.6 kb.
T34 434287-434412 Sentence denotes These cDNA-libraries will be cloned into a viral vector system for the surface expression of CNS antigens on mammalian cells.
T35 434413-434703 Sentence denotes Providing the correct folding and glycosylation, these eukaryotic expression libraries should provide an essential tool to screen for the identification of novel target autoantigens in multiple sclerosis and further our understanding of the role of autoantibodies in the pathogenesis of MS.
T36 434704-434902 Sentence denotes The structure-based designed glycopeptide CSF114(Glc) is able to recognize specific auto-Abs in sera of an important subgroup (37%) of MS patients (250), but not in other autoimmune conditions (90).
T37 434903-435003 Sentence denotes Auto-Abs can be detected only using glycosylated antigens (Ags) recognizing conformational epitopes.
T38 435004-435261 Sentence denotes Glycopeptide libraries (based on amino-acid and structural diversity) screened by competitive ELISA, in MS patients' sera and controls, demonstrated that the relevant epitope should contain the Asn(Glc) moiety exposed on the tip of a beta-hairpin structure.
T39 435262-435345 Sentence denotes Moreover, the amino-acid sequence is important for a correct epitope accessibility.
T40 435346-435485 Sentence denotes Isolated anti-CSF114(Glc) Abs recognized myelin and oligodendrocyte Ags, and are instrumental for isolation of the corresponding native Ag.
T41 435486-435603 Sentence denotes A proteomic approach based on high-resolution mass spectrometry will lead to its characterisation at molecular level.
T42 435604-435845 Sentence denotes The value of CSF114(Glc) appeared in a longitudinal study of untreated MS patients (40) We report preliminary data from an ongoing trial of rituximab in relapsing multiple sclerosis (MS) patients with suboptimal response to standard therapy.
T43 435846-435938 Sentence denotes Rituximab is a chimeric monoclonal antibody that depletes circulating CD20-positive B cells.
T44 435939-435950 Sentence denotes Objectives:
T45 435951-436018 Sentence denotes Assess safety and effects on B cells and antibodies in MS patients.
T46 436019-436116 Sentence denotes Number of enhancing lesions on MRI (primary endpoint) is still blinded and will not be presented.
T47 436117-436125 Sentence denotes Results:
T48 436126-436222 Sentence denotes Of 11 patients treated, two discontinued drug: one due to fever and one for shortness of breath.
T49 436223-436309 Sentence denotes Nine patients were treated with four doses of 375 mg/m 2 without serious side effects.
T50 436310-436516 Sentence denotes At 20 weeks post-treatment, no changes in cerebrospinal fluid (CSF) oligoclonal band number, IgG concentration, or serum antibodies to myelin oligodendrocyte glycoprotein and myelin basic protein were seen.
T51 436517-436641 Sentence denotes The proportion of B cells in CSF was reduced in six of eight patients and CSF IgG synthetic rate decreased in five of eight.
T52 436642-436839 Sentence denotes Two patients had detectable neutralizing antibodies to beta interferons; the titer decreased in one (from 1:72 at baseline to b1:20) and became positive in one (from b1:20 to 1:64) after treatment.
T53 436840-436949 Sentence denotes In eight patients reaching week 24, 25-ft timed walk was improved in four, stable in three, and worse in one.
T54 436950-436961 Sentence denotes Conclusion:
T55 436962-437128 Sentence denotes Rituximab appears safe in MS patients, and depleted circulating B cells with less robust effects on CSF B cells and IgG synthesis. [supported by NMSS USA, Genentech].
T56 437129-437230 Sentence denotes Turner syndrome associated with Guillain-Barré syndrome and a complex autoimmune serological profile.
T57 437231-437247 Sentence denotes A case report S.
T58 437248-437259 Sentence denotes Losi a , S.
T59 437260-437271 Sentence denotes Matà b , S.
T60 437272-437283 Sentence denotes Lori a , R.
T61 437284-437298 Sentence denotes Salti a and S.
T62 437299-437331 Sentence denotes Stagi a a Ospedale Pediatrico A.
T63 437332-437405 Sentence denotes Meyer, Florence, Italy; b Azienda Ospedaliera di Careggi, Florence, Italy
T64 437406-437593 Sentence denotes Turner syndrome (TS) is associated with autoimmune disorders, such as thyroiditis, celiac disease, inflammatory bowel disease, juvenile rheumatoid arthritis, and type I diabetes mellitus.
T65 437594-437758 Sentence denotes Celiac disease, in turn, is associated with several autoimmune disorders, and with neurological diseases, in particular peripheral neuropathy and cerebellar ataxia.
T66 437759-437839 Sentence denotes We report a young female patient diagnosed in 1998 with a TS (karyotype 45, X0).
T67 437840-438055 Sentence denotes Subsequent laboratory examinations revealed the presence of serum antibodies against gliadin, endomisium and tissue transglutaminase (2001), nucleus and smooth muscle (2002) and microsomal and thyroglobulin (2003) .
T68 438056-438102 Sentence denotes HLA analysis revealed the presence of HLA-DQ8.
T69 438103-438230 Sentence denotes In February 2002, a duodenal biopsy showed increased intraepithelial lymphocytes, and a potential celiac disease was diagnosed.
T70 438231-438265 Sentence denotes She had a normal thyroid function.
T71 438266-438373 Sentence denotes In August 2002, she was admitted to the hospital for a 2-week history of increasing weakness of four limbs.
T72 438374-438607 Sentence denotes On the basis of laboratory and electrophysiological examination, she was diagnosed with an acute motor axonal neuropathy (AMAN), a pure motor axonal variant of the Guillain-Barré syndrome, and treated with intravenous immunoglobulin.
T73 438608-438752 Sentence denotes She had high titers of anti GD1a, sulfatide and phosphatidylinositol antibodies, and serological evidence of recent coxsackie B virus infection.
T74 438753-438885 Sentence denotes This is the first description of an association between TS and AMAN in a patient with a complex serological profile of autoimmunity.
T75 438886-439149 Sentence denotes 316 Acetylcholinesterase used to screen drug treating patients should be from human brain It has been proved that the anionic subsite of acetylcholinesterase (AchE) from Torpedo constructs a part of conformational epitope directed by McAb 3F3 against this enzyme.
T76 439150-439363 Sentence denotes In this paper, the cross immunoactivity between McAb 3F3 and AchEs (bovine erythrocyte AchE, human erythrocyte AchE and human brain AchE) was detected by enzyme-linked immunosorbent assay and dot-blot immunoassay.
T77 439364-439502 Sentence denotes The results showed that each AchE reacted well with antibody against itself but McAb 3F3 did not react with any AchEs except Torpedo AchE.
T78 439503-439708 Sentence denotes It suggests that the anionic subsite of AchE from bovine erythrocyte, human brain and erythrocyte are different from that of Torpedo AchE although all their esteric subsites contain the same active serine.
T79 439709-439952 Sentence denotes Thus, it is recommended that the AchE from human brain should be used as mark enzyme when it is applied to select a drug to treat patient with Alzheimer's disease or with organophosphate poisoning, in order to get a more effective drug in man.
T80 439953-440039 Sentence denotes Natural autoantibodies against neurofilament protein alpha-internexin in human sera K.
T81 440040-440054 Sentence denotes Teesalu a , T.
T82 440055-440072 Sentence denotes Rajasalu a , P.A.
T83 440073-440088 Sentence denotes Janmey b and R.
T84 440089-440350 Sentence denotes Uibo a a University of Tartu, Tartu, Estonia; b University of Pennsylvania, Philadelphia, USA Serum autoantibodies (AAbs) to pituitary antigens have been associated with autoimmune hypophysitis, idiopathic hypopituitarism, and other autoimmune endocrinopathies.
T85 440351-440541 Sentence denotes The aim of the present study was to characterize the main AAb reactivities against pituitary antigens in patients with idiopathic hypopituitarism and type 1 diabetes using immunoblot method.
T86 440542-440669 Sentence denotes Sera from six patients with idiopathic hypopituitarism, 60 patients with type 1 diabetes, and 74 healthy controls were studied.
T87 440670-440884 Sentence denotes Frequent patient serum IgG reactivity was observed against a 60-kDa human pituitary antigen, and the cross-reactive 62 kDa protein from rat brain was identified as alpha-internexin (alpha-INX) by proteomic methods.
T88 440885-441316 Sentence denotes By using alpha-INX containing cytoskeletal extracts for AAb screening, IgG and IgM AAbs to this neuron-specific type IV intermediate filament (IF) protein were found in most patient sera as well as in healthy subjects with no significant differences in frequencies between the groups, but the levels of IgM alpha-INX AAbs were higher in patients with hypopituitarism as compared to healthy controls ( p=0.032, Mann-Whitney U-test).
T89 441317-441575 Sentence denotes In addition to the first demonstration of common occurrence of alpha-INX AAbs in human sera, AAbs were also frequently found against neurofilament heavy subunit (NF-H), a known target of natural AAbs, and relatively rarely against other neuronal IF proteins.
T90 441576-441702 Sentence denotes We conclude that alpha-INX AAbs belong to the natural AAb repertoire and their physiologic function needs further elucidation.
T91 441703-441756 Sentence denotes Mechanism of immune responses in myasthenic thymus I.
T92 441757-441768 Sentence denotes Kamo a , H.
T93 441769-441784 Sentence denotes Tomoyasu b , T.
T94 441785-441800 Sentence denotes Yamamoto c , M.
T95 441801-441818 Sentence denotes Kusakabe d and A.
T96 441819-441860 Sentence denotes Kikuchi e a School of Medicine Toho Univ.
T97 441861-442150 Sentence denotes Sagamihara, Japan; b Ohmori Red Cross Hospital, Ohmori, Japan; c Institute of Medical Science, Univ. of Tokyo, Tokyo, Japan; d ANB Tsukuba Institute, Tsukuba, Japan; e National Institute of Neuroscience, Tokyo, Japan MG is an autoimmune disease induced by autoantibodies against self-AChR.
T98 442151-442269 Sentence denotes Thymectomy results in clinical effectiveness, suggesting that this thymus plays a central role in antibody production.
T99 442270-442353 Sentence denotes However, the immunopathological mechanism of effectiveness has not been elucidated.
T100 442354-442392 Sentence denotes We aimed to understand this mechanism.
T101 442393-442601 Sentence denotes MG thymi were used for immunohisthochemical staining against B-cell marker, IL-2, IL-4 and IFNgamma, an 80-and 100-kDa haemopoietic factor and nude mouse splenocytes for in vitro immune response against SRBC.
T102 442602-442733 Sentence denotes Hyperplastic MG thymi commonly contain many IL-2 producing cells, B-cells, but essentially lack IL-4 and INF-gamma producing cells.
T103 442734-442833 Sentence denotes MG thymi also contain many myoid lineage cells that produce the 80-and 100-kDa haemopoietic factor.
T104 442834-442889 Sentence denotes Thus, in MG thymi, a new cytokine network is developed.
T105 442890-443047 Sentence denotes We designed in vitro immune response system consisting of nude mouse splenocytes and soluble factors to mimic the microenvironment of hyperplastic MG thymus.
T106 443048-443124 Sentence denotes IL-2 alone induced very small numbers of anti-SRBC-antibody producing cells.
T107 443125-443254 Sentence denotes However, when myoid cell 80-and 100-kDa haemopoietic factor, were added together, many anti-SRBC producing B-cells were detected.
T108 443255-443315 Sentence denotes IgG subclasses were also induced in the secondary responses.
T109 443316-443438 Sentence denotes These results suggest that hyperplastic MG thymus generates a new B-cell stimulatory mechanism not found in the periphery.
T110 443439-443520 Sentence denotes Anti-MOG autoantibodies in sera of patients with myasthenia gravis and thymoma C.
T111 443521-443536 Sentence denotes Cappelletti, P.
T112 443537-443552 Sentence denotes Cristaldini, P.
T113 443553-443567 Sentence denotes Bernasconi, F.
T114 443568-443581 Sentence denotes Andreetta, O.
T115 443582-443595 Sentence denotes Simoncini, F.
T116 443596-443605 Sentence denotes Baggi, F.
T117 443606-443621 Sentence denotes Cornelio and R.
T118 443622-443692 Sentence denotes Mantegazza National Neurological Institute bCarlo BestaQ, Milan, Italy
T119 443693-443793 Sentence denotes Thymomas are neoplasms of thymic epithelial origin, commonly associated with myasthenia gravis (MG).
T120 443794-444026 Sentence denotes All MG patients with thymoma have antibodies against postsynaptic nicotinic acetylcholine receptors; anti-titin and anti-ryanodine receptor antibodies have an 84% and 74% positive predictive value of thymoma detection, respectively.
T121 444027-444164 Sentence denotes It seems that autoantibodies are not produced within thymoma; nevertheless, antibodies to different antigens are associated with thymoma.
T122 444165-444241 Sentence denotes We tested by anti-human recombinant MOG antibody-specific ELISA, 49 MG sera:
T123 444242-444346 Sentence denotes 39 positive for anti-AChR antibody (10 with thymic hyperplasia and 10 with thymoma) and 10 seronegative.
T124 444347-444530 Sentence denotes Ten out of 49 (20.4%) patients were positive for anti-MOG antibody; when the positive ones were stratified according to thymus histology, six patients (60%) were positive for thymoma.
T125 444531-444606 Sentence denotes We then analyzed MOG-specific transcript expression in MG thymus specimens.
T126 444607-444793 Sentence denotes A positive signal was found in the different pathological thymic alterations (hyperplasia, involuted and thymoma) with variable intensity, differently from data previously reported (Eur.
T127 444794-444796 Sentence denotes J.
T128 444797-444805 Sentence denotes Immunol.
T129 444806-444889 Sentence denotes 2002; 32:2737) ; no MOG expression was observed in non-pathological young thymuses.
T130 444890-445085 Sentence denotes These results further suggest that a thymoma-associated immune dysregulation underlies the generation of antibodies towards different self antigens, whose pathogenetic role remains to be defined.
T131 445086-445428 Sentence denotes Measurement of autoantibodies to a muscle specific tyrosine kinase receptor (MuSK) may be useful in the assessment and management of patients with acetylcholine receptor antibody (AChRAb) negative myasthenia gravis (MG), and we have developed a new and convenient assay for MuSKAb measurement based on 125I-labelled purified recombinant MuSK.
T132 445429-445510 Sentence denotes In addition, the use of rat or human recombinant MuSK in this assay was assessed.
T133 445511-445682 Sentence denotes In the assay serum samples (5 Al) were incubated with 50 Al of 125I-MuSK (rat or human) and any immune complexes formed precipitated with anti-human IgG (100 microlitres).
T134 445683-445796 Sentence denotes MuSKAb were detected in 8/33 (24%; range 1.1-1.4 nmol/l MuSK bound) sera from AChRAbnegative MG patients studied.
T135 445797-446072 Sentence denotes In contrast, no MuSKAb were detected in 53 AChRAb-positive MG patient sera and furthermore, 0/18 Lambert-Eaton myasthenic syndrome sera, 0/5 non-MG neuromuscular disease sera, 0/95 control autoimmune disease sera and 0/50 healthy blood donor sera contained detectable MuSKAb.
T136 446073-446336 Sentence denotes Inter-assay coefficients of variation (CV, n=5) were 6.8%, 5.9% and 4.1% for samples with MuSKAbs at 0.73, 0.32 and 0.11 nmol/l, respectively; and intra-assay CV (n=12) were 2.1%, 4.3% and 7.3% for samples with MuSKAbs at 0.77, 0.32 and 0.11 nmol/l, respectively.
T137 446337-446405 Sentence denotes Similar results were obtained with 125I-labelled rat and human MuSK.
T138 446406-446544 Sentence denotes Overall, the 125I-MuSK immunoprecipitation assay we have developed provides a simple, specific and precise procedure for detecting MuSKAb.
T139 446545-446703 Sentence denotes In continuation of our attempts for antigen-specific suppression of the immune system (Urbatsch, I.L., Sterz, R.K.M., Peper, K., and Trommer, W.E. (1993) Eur.
T140 446704-446706 Sentence denotes J.
T141 446707-446715 Sentence denotes Immunol.
T142 446716-446911 Sentence denotes 23, 774-779) a fusion protein composed of amino acids 4-181 of the extracellular domain of the human acetylcholine receptor from human muscle and the plant toxin gelonin was expressed in E. coli.
T143 446912-446982 Sentence denotes Gelonin is a potent single chain type I ribosome-inactivating protein.
T144 446983-447066 Sentence denotes Due to lack of the B chain of type II toxins it is not active against intact cells.
T145 447067-447195 Sentence denotes The recombinant gelonin was not glycosylated and was about twice as active in an in vitro translation assay as the native toxin.
T146 447196-447304 Sentence denotes The fusion protein formed inclusion bodies but could be solubilized in the presence of guanidinium chloride.
T147 447305-447397 Sentence denotes It exhibited a native structure as shown by antibodies recognizing a conformational epitope.
T148 447398-447542 Sentence denotes Half maximal inhibition of translation was achieved at 46 ng/ml as compared to 4.6 ng/ml for native gelonin and 2.4 for the recombinant product.
T149 447543-447656 Sentence denotes Its use as therapeutic agent for the treatment of myasthenia gravis is currently investigated in myasthenic rats.
T150 447657-447725 Sentence denotes Autoimmune agrypnia is due to autoantibody against GABAB receptor G.
T151 447726-447738 Sentence denotes Frisullo, G.
T152 447739-447754 Sentence denotes Della Marca, M.
T153 447755-447768 Sentence denotes Mirabella, M.
T154 447769-447781 Sentence denotes Caggiula, G.
T155 447782-447793 Sentence denotes Mennuni, P.
T156 447794-447809 Sentence denotes Tonali and A.P.
T157 447810-447875 Sentence denotes Batocchi Institute of Neurology, Catholic University, Rome, Italy
T158 447876-448093 Sentence denotes We have described the clinical feature of a woman with several relapsingremitting episodes of agrypnia and continuous 9-11 Hz activity pattern in EEG recording, dysautonomic symptoms and nocturnal respiratory failure.
T159 448094-448229 Sentence denotes Plasma exchange and high-doses of corticosteroid treatment induced a remission of clinical symptoms and recovery of REM and NREM sleep.
T160 448230-448390 Sentence denotes Immunohistochemistry showed, after incubation with patient serum and CSF, an intense immunoreactivity over brainstem, hippocampus and cerebellum granular layer.
T161 448391-448498 Sentence denotes Using Western blotting, patient IgG recognized a 108 KDa protein on mouse cerebellum, cortex and brainstem.
T162 448499-448610 Sentence denotes Immunohistochemical analysis of patient purified IgG showed a binding on GABAergic synapse-rich neuronal cells.
T163 448611-448775 Sentence denotes Preincubation of mouse cerebellum sections with patient IgG completely abolished the staining obtained with the antiGABABR1 antibody but not using antiGAD antibody.
T164 448776-448967 Sentence denotes To evaluate the pathogenicity of patient antibodies, her purified IgG, at different concentration, was injected into the cisterna magna of C57BL/6 mice, pre-implanted with two EEG electrodes.
T165 448968-449238 Sentence denotes We observed, 12-20 h after injection, a severe respiratory failure followed by death in the mice injected with high dose, a severe ataxia followed by breathing depression in mice injected with middle dose, and a progressive truncal ataxia in mice injected with low dose.
T166 449239-449288 Sentence denotes These symptoms disappeared completely after 12 h.
T167 449289-449406 Sentence denotes EEG showed a strong reduction of delta EEG activity that started after 1 h of IgG injection and persisted along 14 h.
T168 449407-449493 Sentence denotes The mice injected with IgG from healthy subject did not show any neurological symptom.
T169 449494-449571 Sentence denotes Our study demonstrated that anti-GABABR1 antibody causes autoimmune agrypnia.
T170 449572-449739 Sentence denotes Antibodies against glutamic acid decarboxylase (GAD) have been described in a number of autoimmune and some neurological diseases (e.g., stiffperson syndrome, ataxia).
T171 449740-449956 Sentence denotes The observation that sera from 4/5 patients with stiff-person syndrome, in our study, had circulating anti-gliadin antibodies led us to investigate the relationship between anti-GAD antibodies and gluten sensitivity.
T172 449957-450198 Sentence denotes Using ELISA, we investigated the prevalence and levels of anti-GAD antibodies in patients with gluten ataxia (the most common neurological manifestation of gluten sensitivity) and patients with coeliac disease only in comparison to controls.
T173 450199-450252 Sentence denotes The effect of gluten-free diet was also investigated.
T174 450253-450463 Sentence denotes The prevalence of anti-GAD antibodies in patients with gluten ataxia and patients with coeliac disease only, not on gluten-free diet, was 56% and 59%, respectively, which was higher than healthy controls (10%).
T175 450464-450565 Sentence denotes Antibody levels of both groups were significantly reduced after the introduction of gluten-free diet.
T176 450566-450632 Sentence denotes Confirmation of ELISA results was achieved using Western blotting.
T177 450633-450781 Sentence denotes GAD is an important antigen in gluten sensitivity-related diseases and may provide the link between gluten sensitivity and neurological dysfunction.
T178 450782-450930 Sentence denotes Elimination of anti-GAD antibodies by gluten-free diet may have important therapeutic implications in other anti-GAD-associated autoimmune diseases.
T179 450931-451013 Sentence denotes Gluten ataxia is the most common neurological manifestation of gluten sensitivity.
T180 451014-451130 Sentence denotes In common with other forms of gluten sensitivity, gluten ataxia is believed to have an immune-mediated pathogenesis.
T181 451131-451340 Sentence denotes All patients possess circulating anti-gliadin antibodies (IgG and/or IgA) and a significant proportion also possess antibodies directed against tissue transglutaminase and/or glutamic acid decarboxylase (GAD).
T182 451341-451458 Sentence denotes In addition, we have previously reported the presence of circulating anti-Purkinje cell antibodies in these patients.
T183 451459-451594 Sentence denotes Identification of the proteins targeted by these antibodies may facilitate further understanding of the pathogenesis of this condition.
T184 451595-451887 Sentence denotes The aim of the current study was to investigate the avidity and cerebellar target(s) of these antibodies using sodium thiocyanate elution assays, 2D gel electrophoresis, Western blotting and mass spectrometry in comparison to patients with coeliac disease only and appropriate control groups.
T185 451888-452022 Sentence denotes Preliminary results have suggested no apparent difference in the avidity of either anti-gliadin or anti-GAD antibodies between groups.
T186 452023-452202 Sentence denotes Sera from patients with gluten ataxia appeared to react more frequently with proteins within certain molecular weight ranges (24-28 kDa and 56-59 kDa) than sera from other groups.
T187 452203-452275 Sentence denotes Analysis of these proteins by MALDI-TOF will allow their identification.
T188 452276-452440 Sentence denotes The use of GlycoChip(R) microarray technology for identification of anti Glc(alpha 1,4)Glc(alpha)-serum antibodies as a specific biomarker for multiple sclerosis M.
T189 452441-452455 Sentence denotes Schwarz a , L.
T190 452456-452470 Sentence denotes Spector a , M.
T191 452471-452485 Sentence denotes Gortler a , L.
T192 452486-452505 Sentence denotes Glass-Marmor b , A.
T193 452506-452518 Sentence denotes Karni c , N.
T194 452519-452533 Sentence denotes Dotan a and A.
T195 452534-452658 Sentence denotes Miller b a Glycominds Ltd., Lod, Israel; b Carmel Medical Center, Haifa, Israel; c Sorarsky Medical Center, Tel Aviv, Israel
T196 452659-452833 Sentence denotes There is an unmeet need to develop specific biomarkers for multiple sclerosis (MS) to improve the management of patients and the monitoring of the effectiveness of treatment.
T197 452834-452917 Sentence denotes Our objective was to identify anti glycans antibodies that can serve as biomarkers.
T198 452918-453360 Sentence denotes We have screened serum from 107 patients with relapsing-remitting MS (RRMS) against a library of glycans on a glycan chip, and have found significantly higher levels of IgM anti-Glc(alpha 1,4)Glc(alpha) antibodies (anti-Ga4Ga antibodies) than in 77 control patients suffering from other neurological diseases ( pb0.001) and other autoimmune diseases ( p=0.03), and higher levels than in 20 patients with primary progressive MS (PPMS, p=0.06).
T199 453361-453518 Sentence denotes We suggest that the level of anti-Ga4Ga antibodies is a specific biomarker for RRMS, with potential clinical utility for MS prognosis and disease management.
T200 453519-453530 Sentence denotes Background:
T201 453531-453675 Sentence denotes Several recent reports identified high titres of anti-glutamic acid decarboxylase autoantibodies (GAD-Ab) in association with cerebellar ataxia.
T202 453676-453796 Sentence denotes The aetiological link remains unclear, as well as the frequency and level of GAD-Abs in an unselected ataxic population.
T203 453797-453927 Sentence denotes We have explored their significance in a population-based, idiopathic LOCA (ILOCA) patients in South Wales and provide phenotypes.
T204 453928-453950 Sentence denotes Methods and materials:
T205 453951-453994 Sentence denotes Sera of 84 patients (mean disease duration:
T206 453995-454012 Sentence denotes 7.8 years; range:
T207 454013-454097 Sentence denotes 1 to 35) were analysed for anti-GAD Ab using a commercial GAD-65Ab radioimmunoassay.
T208 454098-454212 Sentence denotes Results were interpolated in the standard curve constructed using dilutions of standard controls and healthy sera.
T209 454213-454221 Sentence denotes Results:
T210 454222-454375 Sentence denotes Three patients (3.6%) showed highly elevated Ab titre with background history of type I diabetes mellitus (DM) and type II DM, n=1 and n=2, respectively.
T211 454376-454468 Sentence denotes Three other ILOCA patients with co-morbid DM (both types I and II) showed a normal Ab titre.
T212 454469-454591 Sentence denotes Clinically, all patients showed relatively pure cerebellar syndrome with few extra-cerebellar neurological manifestations.
T213 454592-454676 Sentence denotes There were no significant phenotypic differences observed with other ILOCA patients.
T214 454677-454688 Sentence denotes Discussion:
T215 454689-454767 Sentence denotes Up to 4% amongst our population-based ILOCA patients were positive for GAD-Ab.
T216 454768-454967 Sentence denotes Our data emphasise the need for a routine screening of GAD-Ab in patients with ILOCA as it improves the diagnostic accuracy for ILOCA cases as well creating opportunity for therapeutic interventions.
T217 454968-455092 Sentence denotes Circulating specific CD8+ T cell responses are unknown in autoimmune diseases with central nervous system (CNS) involvement.
T218 455093-455654 Sentence denotes Twenty-five HLA-A2 patients (13 with relapsing-remitting MS, 4 with a clinically isolated syndrome (CIS) at high risk for MS, 2 neurolupus and 3 SLE without CNS involvement, 3 healthy volunteers) were labelled on blood with PE-HLA-A*0201 tetramers loaded with myelin specific peptides according to previously published CD8+ T-cell responses to human myelin protein-derived peptides (iTAg, Beckman Coulter, Europe): MBP110-118: SLSRFSWGA; PLP80-88: FLYGALLLA; MAG556-564: VLFSSDFRI; along with CD3-FITC and CD8-PerCP antibodies, and analysed on a flow cytometer.
T219 455655-456215 Sentence denotes CD3+CD8+ T-cells specific for myelin epitopes were expanded in 6 (35%) of HLA-A2 patients with MS or CIS and in both patients with clinically active neurolupus: two CIS and one MS patient specific for MBP only (respectively, 0.13%, 0.30%, 0.58% of CD3+CD8+ T cells), one (MS) for MBP (0.38%) and PLP (0.35%), one (CIS) for MBP (0.76%) and MAG (0.36%), one MS and both neurolupus for MBP (respectively 0.53%, 6.97%, 2.01%), PLP (0.40%, 2.39%, 0.20%) and MAG (1.15%, 3.81%, 0.41%) and none of the healthy volunteers or SLE patients devoid of neurolupus (b0.15%).
T220 456216-456340 Sentence denotes MBP110-118 seems the main peptide targeted by the class I-restricted cellular response against myelin specific determinants.
T221 456341-456491 Sentence denotes Early events in the development of MS lesions are the formation of cellular infiltrates, consisting of monocyte-derived macrophages and T lymphocytes.
T222 456492-456659 Sentence denotes Sequencing of cDNA from MS brain lesions and control brains has revealed that osteopontin (OPN) is the most abundant cytokine-encoding transcript unique to MS plaques.
T223 456660-456785 Sentence denotes OPN induces chemotaxis of immune cells and promotes the induction of Th1 cytokines and inhibits the release of Th2 cytokines.
T224 456786-456959 Sentence denotes Previous studies demonstrated that an imbalance between Th1 and Th2 type cytokine mRNA level in PBMC of RR MS patients preceded the occurrence of increased disease activity.
T225 456960-457195 Sentence denotes To determine whether OPN may contribute to this phenomenon, the relation between OPN serum levels and disease activity was investigated in a longitudinal study of sixteen RR MS patients undergoing monthly clinical and MRI examinations.
T226 457196-457343 Sentence denotes A trend was observed for OPN serum levels in relation to clinical exacerbations with elevated levels 2 months prior to the occurrence of a relapse.
T227 457344-457611 Sentence denotes Moreover, OPN protein levels were significantly elevated 1 month prior to increase of lesion number with a median increase of 30% compared to baseline levels, whereas no relation was observed between OPN levels and increase in gadolinium (Gd)-enhancing lesion volume.
T228 457612-457702 Sentence denotes These data indicate that OPN plays a role in increased disease activity in RR MS patients.
T229 457703-457816 Sentence denotes Systemic vs. central nervous system cellular immunity with relevance to relapsing-remitting multiple sclerosis M.
T230 457817-457827 Sentence denotes Matsui, S.
T231 457828-457840 Sentence denotes Araya, H.-Y.
T232 457841-457849 Sentence denotes Wang, K.
T233 457850-457862 Sentence denotes Ozawa and T.
T234 457863-457906 Sentence denotes Saida Utano National Hospital, Kyoto, Japan
T235 457907-458297 Sentence denotes To clarify which disturbances in cell-mediated immunity in blood and the central nervous system (CNS) are associated with the active phase of multiple sclerosis (MS), paired peripheral blood and cerebrospinal fluid (CSF) samples were obtained from 36 patients with relapsing-remitting MS (RRMS), and examined for the percentages of lymphocyte subsets and levels of soluble immune mediators.
T236 458298-458469 Sentence denotes Active RRMS patients (n=27) were characterized by an increase in CD4 + CXCR3 + Th1 cells in blood, which was inversely correlated with plasma levels of IL-10 and IL-12p70.
T237 458470-458715 Sentence denotes Further, an increase in CD4 + CD25 + cells and a decrease in CD8 + CD11ahigh cells were found in the CSF of those patients, while CSF CD4 + CD25 + cells showed a positive correlation with leukocyte counts as well as to albumin and CXCL10 levels.
T238 458716-458854 Sentence denotes In addition, CSF CD8 + CD11a high cells showed a negative correlation with CSF cell count and a positive correlation with CSF IL-4 levels.
T239 458855-459123 Sentence denotes We also studied the clinical relevance of these cellular immune parameters by determining their percentages in another group of 31 non-treated inactive RRMS patients, and found that an increase in CSF CD4 + CD25 + cells predicted an exacerbation of MS within 3 months.
T240 459124-459346 Sentence denotes These findings suggest that flow cytometric analysis of CSF CD4 + CD25 + cells provides a good measure of ongoing inflammation in the CNS as well as indication of aberrant immunity leading to MS relapse in the near future.
T241 459347-459483 Sentence denotes Probing the specificity of recombinant antibodies generated from multiple sclerosis cerebrospinal fluid with a random peptide library X.
T242 459484-459490 Sentence denotes Yu, G.
T243 459491-459500 Sentence denotes Owens, M.
T244 459501-459512 Sentence denotes Burgoon, A.
T245 459513-459524 Sentence denotes Ritchie, K.
T246 459525-459537 Sentence denotes Keays and D.
T247 459538-459711 Sentence denotes Gilden University of Colorado Health Science Center, Denver, USA Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS).
T248 459712-459875 Sentence denotes The most common laboratory abnormality associated with MS is the intrathecal synthesis of oligoclonal immunoglobulin (Ig) G in brain and cerebrospinal fluid (CSF).
T249 459876-459928 Sentence denotes The specificity of oligoclonal IgG in MS is unknown.
T250 459929-460088 Sentence denotes To determine its specificity, single cell RT-PCR was used for the amplification of IgG heavy-and light-chain V-regions (VH and VL) from plasma cells of MS CSF.
T251 460089-460210 Sentence denotes The paired VH and VL regions from over-represented IgG sequences were selected to generate recombinant antibodies (rABs).
T252 460211-460323 Sentence denotes The specificity of the rABs was probed by panning a phage-displayed random peptide library with 12-mer peptides.
T253 460324-460454 Sentence denotes After three rounds of panning, affinity-selected peptides were identified, and ELISA confirmed the binding specificity to MS rABs.
T254 460455-460619 Sentence denotes Sequence alignments to the Swiss-Prot database revealed a plethora of putative targets, including some peptides that are highly homologous to proteins of pathogens.
T255 460620-460786 Sentence denotes To refine the many potential antigens under study, alanine scanning is being used to identify the amino acids in each peptide that are important for antibody binding.
T256 460787-460907 Sentence denotes Phage-displayed random peptide libraries have the potential to identify continuous epitopes or mimotopes of MS antigens.
T257 460908-461054 Sentence denotes Reliable, and easy to measure, immunological markers able to denote disease characteristics in multiple sclerosis (MS) patients are still lacking.
T258 461055-461327 Sentence denotes We applied a multivariate statistical analysis on results obtained by measuring-by real-time RT-PCR-mRNA levels of 25 immunological relevant molecules (e.g., cytokines, chemokines and chemokine receptors) in peripheral blood mononuclear cells (PBMCs) from 198 MS patients.
T259 461328-461490 Sentence denotes The combined measurement of mRNA levels of IL-1beta, TNF-alpha, TGFbeta, CCL20 and CCR3 was able to distinguish MS patients from healthy individuals (MS pattern).
T260 461491-461683 Sentence denotes CXCR5, CCL5, and CCR3 combined mRNA levels identify primary progressive MS patients (PP-MS pattern) while TNF-alpha, IL-10, CXCL10 and CCR3 differentiate relapsing MS patients (RR-MS pattern).
T261 461684-461865 Sentence denotes Finally, a significant correlation was found between mRNA levels of CCR3, CCR4, CCR7, and TNF-alpha measured in PBMCs and in mononuclear cells obtained from the cerebrospinal fluid.
T262 461866-462052 Sentence denotes On the other hand, we did not find any correlation between immunological markers and gadolinium-enhancing magnetic resonance imaging (MRI)detectable lesions or T1 and T2 MRI lesion load.
T263 462053-462308 Sentence denotes Our results indicate that multi-parametric analysis of mRNA levels of immunological relevant molecules in PBMCs may represent a successful strategy for the identification of putative peripheral markers of disease state and disease activity in MS patients.
T264 462309-462485 Sentence denotes The frequency of anti-GM1 ganglioside antibodies in neuropathies and other neurological and inflammatory diseases varies considerably and largely depends on the technique used.
T265 462486-462637 Sentence denotes In our study, we extended the validation of the standardized ELISA developed by the European Inflammatory Neuropathy Cause and Treatment (INCAT) group.
T266 462638-462746 Sentence denotes Anti-GM1 IgG and IgM antibodies were determined by the INCAT-ELISA in large groups of patients and controls.
T267 462747-462899 Sentence denotes Correlation of variance (CV%) was calculated by determining standard deviation divided by the mean of optical densities in 48 wells of one serum sample.
T268 462900-462988 Sentence denotes Using a positive control sample the CV% was 4% for anti-GM1 IgG and 7% for anti-GM1 IgM.
T269 462989-463080 Sentence denotes The variation could be attributed to variation between wells, plates, days and technicians.
T270 463081-463538 Sentence denotes Anti-GM1 antibodies were found in 97 (21%) of 462 patients with Guillain-Barré syndrome (GBS), 2 (5%) of 41 chronic demyelinating inflammatory polyneuropathy, 5 (50%) of 10 multifocal motor neuropathy, 9 (6%) of 143 inflammatory polyneuropathy (I-PNP), 2 (3%) of 72 noninflammatory polyneuropathy (NI-PNP), 7 (9%) of 78 motor neuron disease, none of 20 multiple sclerosis, 3 (2%) of 142 other forms of autoimmune diseases and 3 (2%) of 124 healthy controls.
T271 463539-463609 Sentence denotes IgG antibodies were only found in patients with GBS, I-PNP and NI-PNP.
T272 463610-463761 Sentence denotes In conclusion, the INCAT-ELISA has a good reproducibility and the presence of IgG anti-GM1 antibodies is almost specific for inflammatory neuropathies.
T273 463762-463769 Sentence denotes Object:
T274 463770-463921 Sentence denotes To correlate the lymphocyte network in the peripheral blood, with neurological status (EDSS) and MRI activity in newly diagnosed untreated MS patients.
T275 463922-463930 Sentence denotes Methods:
T276 463931-464038 Sentence denotes Twenty patients presenting with a first CNS inflammatory event suggestive of MS were enrolled in the study.
T277 464039-464180 Sentence denotes Every 45 days, for 1 year, they underwent clinical and MRI evaluation, and flow cytometry analysis of a broad-spectrum of lymphocyte subsets.
T278 464181-464189 Sentence denotes Results:
T279 464190-464251 Sentence denotes Twelve patients showed MRI activity throughout the follow-up.
T280 464252-464365 Sentence denotes Most of the patients had a significant reduction of blood CD8+ alpha-beta T cells compared to reference subjects.
T281 464366-464588 Sentence denotes Concomitant with MRI activity, we observed a decreased frequency of the following lymphocyte subsets: CD4+CD25high and CD8+CD28À alpha-beta T cells; CD4+CCR5+ CXCR3+ T cells; NKT cells, NK-like T cells and CD8dim NK cells.
T282 464589-464738 Sentence denotes In a subgroup of patients, we observed increased CD8dim gamma-delta T cells and CD8+CD45RA+CCR7À alpha-beta T cells at the beginning of MRI activity.
T283 464739-464751 Sentence denotes Conclusions:
T284 464752-464947 Sentence denotes Newly diagnosed MS patients display, concomitantly with MRI activity, increased terminally differentiated CD8+ alpha-beta T cells in presence of a reduction of defined regulatory T cells subsets.
T285 464948-465149 Sentence denotes These preliminary data indicate that the assessment of peripheral immunophenotype traits, consisting of the above pattern of lymphocyte subsets, may be useful in the clinical management of MS patients.
T286 465150-465313 Sentence denotes Understanding the mechanisms that sustain the effects of disease modifying drugs in MS may help refine current therapies and our knowledge of disease pathogenesis.
T287 465314-465497 Sentence denotes We investigated gene expression, by microarrays, in peripheral blood mononuclear cells (PBMC) of 7 MS patients at baseline, and after 1 and 3 months of interferon-beta (Rebif 44 mcg).
T288 465498-465585 Sentence denotes Blood sampling and gadolinium-enhanced MRI were obtained 36 h after the last injection.
T289 465586-465817 Sentence denotes The influence of IFN-beta on gene expression was more pronounced after one than after 3 months of therapy, involving genes of immunological significance and others related to energy metabolism, cell cycle and cytoskeleton dynamics.
T290 465818-465910 Sentence denotes Genes validated by RT-PCR included IL-10, FILAMIN-B (increased) and IL-16, RAB7 (decreased).
T291 465911-466033 Sentence denotes RAB7 represents a novel finding and was further investigated given its role as modulator of class-II antigen presentation.
T292 466034-466299 Sentence denotes In accord with previous reports on a reduced expression of HLA-DR on PBMC in MS and in other autoimmune diseases, RT-PCR showed that RAB7 was decreased in untreated MS patients compared to healthy controls (including three disease discordant monozygotic twin sets).
T293 466300-466411 Sentence denotes The global impact of IFN-beta treatment on gene expression tends to decrease after the first months of therapy.
T294 466412-466553 Sentence denotes The decreased expression of RAB7 may contribute to the downregulation of MHC class II, one of the known immunomodulatory actions of IFN-beta.
T295 466554-466707 Sentence denotes In vivo cell imaging by magnetic resonance (MR) may be a powerful tool to reveal the pathogenic events of cell migratory processes in multiple sclerosis.
T296 466708-466824 Sentence denotes For this purpose, cells have to be isolated, labeled ex vivo with MR contrast agents and reintroduced into the body.
T297 466825-466911 Sentence denotes In this study, we aimed to develop an efficient method for labeling primary monocytes.
T298 466912-467037 Sentence denotes As suitable contrast agents we used two differently sized ultra small particles of iron oxide (USPIO's), Sinerem and Endorem.
T299 467038-467151 Sentence denotes Beneficial effects of preincubation with transfection agents (TA's; Poly-L, Fugene and Superfect) were evaluated.
T300 467152-467239 Sentence denotes Labeling efficiency was determined by T2-relaxation time MRI and Perls' stain for iron.
T301 467240-467294 Sentence denotes Cell viability and function were constantly monitored.
T302 467295-467382 Sentence denotes Incubation of monocytes with Endorem resulted in a labeling efficiency higher than 80%.
T303 467383-467422 Sentence denotes T2-relaxation time decreased up to 40%.
T304 467423-467494 Sentence denotes Superfect was the only TA that further increased the uptake of endorem.
T305 467495-467594 Sentence denotes In conclusion, endorem preincubated with Superfect is most efficient in labeling primary monocytes.
T306 467595-467702 Sentence denotes Currently, we are planning experiments to track primary monocytes in an animal model of multiple sclerosis.
T307 467703-467809 Sentence denotes Multiple sclerosis (MS) is a demyelinating disease characterized by inflammation in brain and spinal cord.
T308 467810-467911 Sentence denotes There is a wide variability in symptoms, disease course, progression rate, and areas of CNS involved.
T309 467912-468093 Sentence denotes Based on the autoimmune nature of MS and migration of immune cells to and from the brain, we reasoned that an imprint of the disease would be present in peripheral blood (PB) cells.
T310 468094-468399 Sentence denotes In order to identify molecular differences between relapsing-remitting (RR) MS patients and healthy controls (HC) and RRMS patients in different phases of disease, we investigated gene-expression profiles in whole blood from HC and RRMS patients, using cDNA micro arrays with a complexity of 43,000 cDNAs.
T311 468400-468488 Sentence denotes A total of 1201 genes differed significantly in expression between RRMS patients and HC.
T312 468489-468573 Sentence denotes The differentially expressed genes represent several distinct functional categories.
T313 468574-468704 Sentence denotes Most interestingly, a large number of genes reflect differences in the activity of G protein signaling between MS patients and HC.
T314 468705-469020 Sentence denotes These preliminary data revealed indications for important molecular and biological variation between RRMS patients and HC, and RRMS patients in different phases of the disease that provide a lead to relevant biological pathways and could ultimately lead to identification of novel criteria for (sub) classification.
T315 469021-469114 Sentence denotes Immune-mediated mechanisms play a crucial role in the patogenesis of multiple sclerosis (MS).
T316 469115-469252 Sentence denotes Though neurodegeneration with axonal loss is an early event in MS, the therapeutic approach remains restricted to antiinflammatory drugs.
T317 469253-469317 Sentence denotes Responsivness of the patients to all available drugs is limited.
T318 469318-469513 Sentence denotes To detect if this responsiveness is generated by the shift in cytokine production, we studied a group of MS patients with monthly pulse methylprednisolone (MP) and cyclophosphamide (CPA) therapy.
T319 469514-469535 Sentence denotes Patients and methods:
T320 469536-469756 Sentence denotes 40 progressive MS patients (27 females, 13 males, age 46.9F9.2 yrs, duration of MS 14F6.9 yrs) were divided into two groups according to clinical response (7 good responders, 19 stable patients versus 14 non-responders).
T321 469757-469832 Sentence denotes Peripheral blood was taken 14 days after 1 g MP and 1 g CPA administration.
T322 469833-469934 Sentence denotes Peripheral blood from 10 ageand sex-matched healthy controls was used to compare cytokine production.
T323 469935-469958 Sentence denotes Results and discussion:
T324 469959-470054 Sentence denotes Cytokine production did not differ significantly in treatment responders versus non-responders.
T325 470055-470271 Sentence denotes Surprisingly, there was significantly higher expression of CCR5+CXCR3 on CD4 lymphocytes of responders which may be explained by the theory that immunosuppression is effective only where inflammation is still active.
T326 470272-470575 Sentence denotes Strikingly significant difference (pN0.000001) was detected in production of IFN gamma, TNF alpha, IL2, IL10 and IL12 between MS patients and healthy controls suggesting that the immune hyperactivation is present in the disease even in the second decade of its duration and despite aggressive treatment.
T327 470576-470580 Sentence denotes Aim:
T328 470581-470689 Sentence denotes To investigate interactions between immunological changes and vertebral syndrome in multiple sclerosis (MS).
T329 470690-470711 Sentence denotes Patients and methods:
T330 470712-470861 Sentence denotes 30 patients with definite MS were examined, mean age (Fsigma) was 31.3F10.5 years; Kurtzke Expanded Disability Status Scale (EDSS) score was 4.4F1.7.
T331 470862-470870 Sentence denotes Results:
T332 470871-470929 Sentence denotes Chronic back and neck pain was present in 80% of patients.
T333 470930-471026 Sentence denotes The mean age of onset of vertebral pain was 25.8F9.4 years, mean duration of pain 6.8F4.8 years.
T334 471027-471124 Sentence denotes The impairment of vertical spinal balance (scoliosis, kyphosis) was diagnosed in 70% of patients.
T335 471125-471525 Sentence denotes There were correlations (r=0.5-0.7; pb0,05) between the following vertebral signs and immunological indices: (1) high tonus of paravertebral muscles and high level of circulating immune complexes (CIC), CD8+, CD25+ T-lymphocytes; (2) presense of muscle trigger points in thoracic girdle and high levels of CIC, anti-nDNA antibodies, CD4+, CD HLADR+; (3) pronounced spondyloarthrosis and level of CIC.
T336 471526-471623 Sentence denotes These relationships may be explained by immune aggression against muscle and cartilaginous cells.
T337 471624-471718 Sentence denotes Correlation with the level of anti-nDNA antibodies confirms the fact of polyclonal activation.
T338 471719-471826 Sentence denotes Plaques in cervical part of spinal cord were visualised by magnetic resonance imaging in 56.7% of patients.
T339 471827-472034 Sentence denotes Vertebral signs (neck pain, scoliosis, high tonus of paravertebral muscles, trigger muscle points) and the level of CD8+ were more pronounced in this group versus patients without cervical lesions ( pb0.01).
T340 472035-472047 Sentence denotes Conclusions:
T341 472048-472171 Sentence denotes Immunological changes and cervical plaques have an influence on the developing of vertebral syndrome in multiple sclerosis.
T342 472172-472217 Sentence denotes CSF change in IFN beta-treated MS patients K.
T343 472218-472268 Sentence denotes Yokoyama Juntendo University, Tokyo, Japan Object:
T344 472269-472358 Sentence denotes Interferon (IFN) beta is pleiotrophic molecules with complex immunoregulatory activities.
T345 472359-472390 Sentence denotes It is commonly used world wide.
T346 472391-472487 Sentence denotes However, a valid definition of therapeutic response is needed for individual treatment decision.
T347 472488-472573 Sentence denotes We have collected the CSF samples from MS and other neurological diseases as control.
T348 472574-472690 Sentence denotes We assessed the clinical response and the mechanism of IFN beta in multiple sclerosis (MS) patients by CSF analysis.
T349 472691-472699 Sentence denotes Methods:
T350 472700-472826 Sentence denotes The CSF from 14 relapsing-remitting MS patients and 30 other neurological diseases (OND) were collected with informed consent.
T351 472827-472898 Sentence denotes Nitric oxide (NO) metabolites and 41 amino acids were measured by HPLC.
T352 472899-472945 Sentence denotes IgG index was also calculated in each patient.
T353 472946-473072 Sentence denotes The change of those measures in relation to clinical disease severity (expanded disability status score; EDSS) were evaluated.
T354 473073-473165 Sentence denotes We could measure and compare CSF change before and after IFN beta treatment in two patients.
T355 473166-473174 Sentence denotes Summary:
T356 473175-473266 Sentence denotes In relapsing MS patient with severe EDSS worsening showed increased some amino acids level.
T357 473267-473416 Sentence denotes NO metabolites do not change drastically in acute phase of the disease but IFN beta treatment decreased the concentration of NO as well as IgG index.
T358 473417-473429 Sentence denotes Conclusions:
T359 473430-473520 Sentence denotes The IFN beta treatment might influence the NO and IgG synthesis in the CSF of MS patients.
T360 473521-473635 Sentence denotes Serial measurement of IgG index might be useful as a surrogate marker for the effectiveness of IFN beta treatment.
T361 473636-473754 Sentence denotes During neuroinflammatory diseases of the CNS, immune cells infiltrate both CNS parenchyma and the cerebrospinal fluid.
T362 473755-473962 Sentence denotes Although these two populations may be distinct regarding their phenotype and functions, it is currently assumed that CSF cells resemble more closely parenchymainfiltrating cells than their blood counterpart.
T363 473963-474136 Sentence denotes Thus, as far as CNS biopsies remains an invasive procedure, analyzing CSF immune cells represent a unique tool for understanding the pathophysiology of neuroimmune diseases.
T364 474137-474302 Sentence denotes The development of techniques allowing gene array analysis from a small amount of RNA prompted us to evaluate the feasibility of analyzing gene profile of CSF cells.
T365 474303-474407 Sentence denotes Our results indicate that 1 to 3 ng of mRNA can be extracted from 1 ml of CSF obtained from MS patients.
T366 474408-474481 Sentence denotes This theoretically allows performing up to 40 RT-PCR from one CSF sample.
T367 474482-474635 Sentence denotes However, the RNA quality as assessed by analyzing the ratio of ribosomal bands depends primarily on the time elapsed from CSF sampling to CSF processing.
T368 474636-474738 Sentence denotes Indeed, only CSF cells that are immediately treated for RNA extraction display unaltered RNA profiles.
T369 474739-474858 Sentence denotes Moreover, once good quality samples are selected, an amplification step is required in order to perform assay analysis.
T370 474859-475356 Sentence denotes We studied by ELISA cerebrospinal fluid (CSF) and serum levels of classical soluble HLA-I (sHLA-I) and non-classical soluble HLA-G (sHLA-G) molecules in 69 relapsing-remitting (RR), 21 secondary progressive (SP) and 13 primary progressive (PP) multiple sclerosis (MS) patients, grouped according to clinical and Magnetic Resonance Imaging (MRI) evidence of disease activity, and 183 patients with other inflammatory neurological disorders (OIND) and non-inflammatory neurological disorders (NIND).
T371 475357-475722 Sentence denotes An intrathecal production of sHLA-I and sHLA-G was more frequent in MS than in OIND and NIND ( pb0.001), with more consistent values in clinically and MRI active than in clinically and MRI inactive MS for sHLA-I ( pb0.02 and pb0.001, respectively) and in clinically and MRI stable than in clinically and MRI active MS for sHLA-G ( pb0.01 and pb0.001, respectively).
T372 475723-475911 Sentence denotes A decrease in sHLA-I and an increase in sHLA-G levels were detected in serum of clinically active MS, while MRI active MS showed high and low CSF levels of sHLA-I and sHLA-G, respectively.
T373 475912-476034 Sentence denotes Our results seems to indicate that CSF and serum sHLA-I/ sHLA-G balance could modulate MS activity in opposite directions.
T374 476035-476173 Sentence denotes T cell immunoglobulin-and mucin-domain-containing molecules (TIMs) comprise a recently described family of molecules expressed on T cells.
T375 476174-476349 Sentence denotes TIM-3 has been shown to be expressed on murine T-helper (Th) 1 cell clones and has been implicated in the pathogenesis of Th1-driven experimental autoimmune encephalomyelitis.
T376 476350-476463 Sentence denotes In contrast, association of TIM-1 polymorphisms to Th2-related airway hyperreactivity has been suggested in mice.
T377 476464-476547 Sentence denotes The TIM molecules have not been investigated in human Th1-or Th2-mediated diseases.
T378 476548-476704 Sentence denotes Using real-time (TaqMan) RT-PCR, we show that human Th1 lines expressed higher TIM-3 mRNA levels, while Th2 lines demonstrated a higher expression of TIM-1.
T379 476705-476892 Sentence denotes Analysis of cerebrospinal fluid mononuclear cells (CSF-MC) obtained from patients with multiple sclerosis (MS) revealed significantly higher mRNA expression of TIM-1 compared to controls.
T380 476893-477014 Sentence denotes Moreover, higher TIM-1 expression was associated with clinical remissions and low expression of IFN-gamma mRNA in CSF-MC.
T381 477015-477112 Sentence denotes In contrast, expression of TIM-3 correlated well with high expression of IFN-gamma and TNF-alpha.
T382 477113-477299 Sentence denotes These data imply the differential expression of human TIM molecules by Th1 and Th2 cells and may suggest their differential involvement in different phases of a human autoimmune disease.
T383 477300-477356 Sentence denotes Cerebrospinal fluid tau protein in multiple sclerosis E.
T384 477357-477360 Sentence denotes Pal
T1 477361-477454 Sentence denotes Multiple sclerosis is an immune-mediated demyelinating disease of the central nervous system.
T2 477455-477576 Sentence denotes However, not only myelin, but axonal-neuronal damage also develops in the advanced stage, but in the early stage as well.
T3 477577-477635 Sentence denotes It may be finally responsible for irreversible disability.
T4 477636-477785 Sentence denotes Soluble markers, such as microtubule-associated protein, tau are suitable for detection of axonal damage and evaluation of neurodegeneration in vivo.
T5 477786-477914 Sentence denotes CSF tau level was determined by enzyme-linked immunosorbent assay (ELISA) in 20 MS, 6 viral encephalitis and 7 control patients.
T6 477915-477994 Sentence denotes Tau level was elevated both in MS and encephalitis cases comparing to controls.
T7 477995-478063 Sentence denotes In MS group tau level correlated with disease duration and severity.
T8 478064-478157 Sentence denotes Therefore, we concluded that CSF tau would be a probable marker for detection of axonal loss.
T9 478158-478314 Sentence denotes The effective use of neuroimmunological tests for diagnostic and research purposes requires standardization of methods and external quality control schemes.
T10 478315-478442 Sentence denotes These two requirements guarantee accuracy and reliability in diagnostic routine, and data reproducibility in research settings.
T11 478443-478558 Sentence denotes AINI promoted an unprecedented consensus-based program for procedure and method standardization in neuroimmunology.
T12 478559-478605 Sentence denotes Twenty-six Italian centres joined the program.
T13 478606-478888 Sentence denotes Four areas were identified (approximate total number of exams/year in brackets): cerebrospinal fluid examination (7000); diagnostics for paraneoplastic neurological syndromes (1700); diagnostics for peripheral disimmune neuropathies (2500), diagnostics for myasthenia gravis (4000).
T14 478889-479050 Sentence denotes A questionnaire-based survey, which was prepared by expertise-based selected centres, revealed interlaboratory variability in procedures and assay methodologies.
T15 479051-479173 Sentence denotes Attempts to uniform procedures and methods were made by internet contacts and in two AINI workshops during [2002] [2003] .
T16 479174-479257 Sentence denotes Contemporarily, quality assurance schemes was, and will be in the future, promoted.
T17 479258-479360 Sentence denotes The results of this program were summarized in four internet-available documents (http://www.aini.it).
T18 479361-479534 Sentence denotes The documents, which will be yearly updated, report tests' indications and limits, agreed common protocols, instructions for result interpretation, and essential references.
T19 479535-479647 Sentence denotes They should improve diagnostic performances, and represent a premise for clinical guidelines in neuroimmunology.
T20 479648-479804 Sentence denotes However, there is lack of data concerning OCB during disease-modifying drugs (DMD) therapy and changes of their pattern were not reported in the literature.
T21 479805-479917 Sentence denotes The aim was to assess OCB in CSF of patients with relapsingremitting multiple sclerosis (RRMS) treated with DMD.
T22 479918-479939 Sentence denotes Patients and Methods:
T23 479940-480074 Sentence denotes Set of 22 RRMS patients consisted of 17 females (aged 26-51 years, average age 37.8) and 5 males (aged 19-44 years, average age 29.8).
T24 480075-480241 Sentence denotes CSF samples were taken 0-42 (average 13.5) months before and 1-16 (average 6.2) months after initiation of DMD (interferon beta 1b, 1a or glatiramer acetate) therapy.
T25 480242-480327 Sentence denotes The number of alkaline OCB in CSF was assessed by the method of isoelectric focusing.
T26 480328-480400 Sentence denotes Paired samples test was applied when assessing statistical significance.
T27 480401-480409 Sentence denotes Results:
T28 480410-480644 Sentence denotes In 18 (81.8%) patients reduction of the number of OCB by 1-23 (average 7.8) was observed, in 2 (9.1%) patients the number of OCB increased by 1 and 3 (average 2) and no changes of the OCB number were present also in 2 (9.1%) patients.
T29 480645-480701 Sentence denotes Results differed statistically significantly ( p=0.001).
T30 480702-480714 Sentence denotes Conclusions:
T31 480715-480817 Sentence denotes Our results document the immunomodulation effect of DMD in the decreased intrathecal synthesis of IgG.
T32 480818-480942 Sentence denotes Characterization of immunorelevant human brain antigens of multiple sclerosis patients by two-dimensional electrophoresis Z.
T33 480943-481009 Sentence denotes Adwan Swaida Neuroimmunology Institution, Swaida, Syria Objective:
T34 481010-481102 Sentence denotes To identify and characterize new immunorelevant antigens associated with multiple sclerosis.
T35 481103-481114 Sentence denotes Background:
T36 481115-481293 Sentence denotes Currently, none of the myelin-associated antigen targets conclusively discriminates between the immune response observed in multiple sclerosis (MS) patients and healthy subjects.
T37 481294-481536 Sentence denotes A recent study in our laboratory found that the analysis of global IgG immune profiles to whole brain self-antigens discriminated MS subjects from healthy subjects, and could also differentiate between the three clinical forms of the disease.
T38 481537-481687 Sentence denotes Indeed, respectively, 17 and 29 brain antigens, defined according to their molecular weight, were described to support a discriminant immune response.
T39 481688-481703 Sentence denotes Design/Methods:
T40 481704-481911 Sentence denotes The protein identification of these discriminant bands was performed by one-dimensional and two-dimensional immunoblotting using MS patient sera, followed by mass spectrometry analysis and a database search.
T41 481912-481920 Sentence denotes Results:
T42 481921-482008 Sentence denotes By this approach, a total of 29 different immunorelevant antigenic bands were detected.
T43 482009-482108 Sentence denotes These bands were broken up in more than 40 spots, further selected for mass spectrometric analysis:
T44 482109-482135 Sentence denotes 21 of them were annotated.
T45 482136-482148 Sentence denotes Conclusions:
T46 482149-482266 Sentence denotes Serological proteome analysis (SERPA) may constitute a new tool for the identification of new MS-associated antigens.
T47 482267-482332 Sentence denotes Leptin levels in subgroups of patients with multiple sclerosis A.
T48 482333-482342 Sentence denotes Kurne, M.
T49 482343-482372 Sentence denotes Arsava, B.I. Ç ikrikci and R.
T50 482373-482450 Sentence denotes Karabudak Hacettepe University Medical Faculthy, Ankara, Turkey Introduction:
T51 482451-482574 Sentence denotes Leptin is primarily synthesized in the adipose tissue and is responsible for the control of appetite and energy metabolism.
T52 482575-482688 Sentence denotes Apart from the effects on metabolism, leptin has been shown to play an important role in inflammatory conditions.
T53 482689-482699 Sentence denotes Objective:
T54 482700-482846 Sentence denotes To measure serum leptin levels among different subgroups of patients with multiple sclerosis, a predominantly Th1 mediated inflammatory condition.
T55 482847-482855 Sentence denotes Methods:
T56 482856-483122 Sentence denotes Fourteen recently diagnosed relapsing-remitting multiple sclerosis (RRMS) patients, ten (10) RRMS patients on immunomodulatory drug therapy and thirteen primary progressive multiple sclerosis patients and age-matched nine control subjects were included in the study.
T57 483123-483177 Sentence denotes Body mass index (BMI) was calculated for each patient.
T58 483178-483223 Sentence denotes Serum leptin levels were measured with ELISA.
T59 483224-483232 Sentence denotes Results:
T60 483233-483407 Sentence denotes The mean leptin level were 2.9, 3.0, 3.1 and 3.9 ng/ml in controls, newly diagnosed RRMS, RRMS on immunomodulatory treatment and primary progressive MS patients respectively.
T61 483408-483533 Sentence denotes There was no statistically significant difference among the study groups, after adjustment for height, weight and BMI values.
T62 483534-483545 Sentence denotes Conclusion:
T63 483546-483663 Sentence denotes Leptin is a peptide influencing immune system modulation and has a crucial role in triggering the acute inflammation.
T64 483664-483761 Sentence denotes There is no sufficient data on its role in central nervous system inflammation and demyelination.
T65 483762-483898 Sentence denotes In our study, no difference was detected in serum leptin levels neither between the control and MS patients, nor among the MS subgroups.
T66 483899-484104 Sentence denotes The disruptiom of the blood-brain barrier, which is composed of endothelial cells, accompanied by infiltration of macrophages and T lymphocytes is implicated in the pathogenesis of multiple sclerosis (MS).
T67 484105-484298 Sentence denotes Vascular-endothelial cadherin (VE-cadherin), a major protein component of interendothelial adherens junctions, has an important barrier function regulating leukocyte transendothelial migration.
T68 484299-484419 Sentence denotes We determined serum levels of VE-cadherin to investigate the significance of VE-cadherin in the formation of MS lesions.
T69 484420-484501 Sentence denotes The subjects were 38 patients with relapsingremitting MS and 32 healthy controls.
T70 484502-484567 Sentence denotes Serum concentrations of VEcadherin were measured by ELISA method.
T71 484568-484819 Sentence denotes We measured plasma activities of von Willebrand factor (vWF) and serum levels of soluble thrombomodulin (sTM) as markers for endothelial injury and plasma levels of hepatocyte growth factor (HGF) as a marker for endothelial repair in patients with MS.
T72 484820-485020 Sentence denotes Serum VE-cadherin levels tended to be higher in MS patients during exacerbation than in the age-matched controls or MS patients during remission, but were not significantly different among the groups.
T73 485021-485244 Sentence denotes Serum VE-cadherin levels had a tendency to be associated with plasma HGF levels in MS patients, while serum VE-cadherin levels were not significantly associated with plasma vWF activities and serum sTM levels in MS patient.
T74 485245-485439 Sentence denotes The findings suggest that serum concentration of VEcadherin may increase as a reflection of the endothelial repair and adherens junction formation in the blood-brain barrier in patients with MS.
T75 485440-485447 Sentence denotes Object:
T76 485448-485567 Sentence denotes To evaluate the gene expression profiles of PBMC in newly diagnosed untreated MS patients compared to healthy subjects.
T77 485568-485576 Sentence denotes Methods:
T78 485577-485703 Sentence denotes Twenty patients with a first event of MS underwent clinical and MRI evaluation, and PBMC collection every 45 days, for 1 year.
T79 485704-485818 Sentence denotes RNA was extracted from PBMC of nine MS patients with no MRI activity and ten sex and age-matched healthy subjects.
T80 485819-486005 Sentence denotes Fluorescent cDNA probes were prepared by reverse transcription and hybridised to cDNA arrays of 6000 human genes prepared using a Lucidea Microarray Spotter (Amersham-Pharmacia Biotech).
T81 486006-486152 Sentence denotes Array included genes involved in apoptosis, cell proliferation and inflammation. cDNA reference consisted of a mRNA pool from 10 human cell lines.
T82 486153-486221 Sentence denotes After normalisation, sample-to-reference log ratios were calculated.
T83 486222-486347 Sentence denotes Only spot signals above the background in at least 90% of the samples in each group were considered for statistical analysis.
T84 486348-486356 Sentence denotes Results:
T85 486357-486474 Sentence denotes Following RNA integrity test, probe preparation and chip hybridisation, high-quality fluorescent spots were obtained.
T86 486475-486577 Sentence denotes Ten percent of evaluated genes showed differential expression upon comparison between MS and controls.
T87 486578-486590 Sentence denotes Conclusions:
T88 486591-486822 Sentence denotes Although statistical analysis is still in progress, our preliminary observations support the use of cDNA microarray technology for detection of altered gene expression profiles in the periphery of MS patients during active disease.
T89 486823-486965 Sentence denotes Multiple sclerosis is widely believed to be an autoimmune disease driven by a relative dominance of Th1 cells over Th2 and regulatory T cells.
T90 486966-487142 Sentence denotes We sought to identify lineage and activation markers of human Th subtypes that might serve as biomarkers of disease activity, diagnostic aids or guides to therapeutic efficacy.
T91 487143-487229 Sentence denotes We tested murine T cell subset markers, derived from SAGE libraries, in human systems.
T92 487230-487365 Sentence denotes Polarised Th1, Th2 and Tr1 PBMC cultures were produced in vitro by defined cytokine cocktails and validated by ELISA and real time PCR.
T93 487366-487506 Sentence denotes The putative marker genes from SAGE included GM2 ganglioside activator protein, and integrin(E)beta(7) (CD103) for regulatory T cells (Tr1).
T94 487507-487623 Sentence denotes Differentially expressed genes for Th1 were two proteins with four transmembrane domains related to the CD20 family.
T95 487624-487666 Sentence denotes GATA 3 was used as a marker for Th2 cells.
T96 487667-487776 Sentence denotes We found that GM2 was expressed by Tr1 cells and GATA3 was induced by PMA stimulation of Th2 and Tr1 subsets.
T97 487777-487905 Sentence denotes Most marked was the specific expression on activated Th1 cells of a four transmembrane protein previously identified as Chandra.
T98 487906-488014 Sentence denotes We are currently testing expression of these molecules as markers of disease activity in multiple sclerosis.
T99 488015-488025 Sentence denotes Objective:
T100 488026-488133 Sentence denotes To correlate MxA and IL-10 production with the response to treatment, dose of IFN-beta, and NAb occurrence.
T101 488134-488142 Sentence denotes Methods:
T102 488143-488324 Sentence denotes After 6 months of IFN-beta-1b 250 mcg treatment, patients with persisting disease activity were randomized to either continue on 250 mcg dose or receive an increased dose (375 mcg).
T103 488325-488462 Sentence denotes MxA was determined by immunochemiluminescence in whole blood samples; IL-10 by ELISA in PBMC supernatant; NAb by the MxA-induction assay.
T104 488463-488471 Sentence denotes Results:
T105 488472-488527 Sentence denotes We present the preliminary data concerning 34 patients.
T106 488528-488651 Sentence denotes MxA production peaked at month 3 of treatment ( pb0.001), with a greater increase in patients who responded well ( p=0.01).
T107 488652-488743 Sentence denotes Also, IL-10 peaked at month 3, remaining higher than baseline only in responders ( p=0.02).
T108 488744-488841 Sentence denotes The increase of the IFN-beta dose was associated with a renewed MxA and IL-10 increase ( p=0.03).
T109 488842-488872 Sentence denotes NAb occurred in four patients.
T110 488873-488961 Sentence denotes NAb positivity was associated with a decrease in MxA but no changes in IL-10 production.
T111 488962-488974 Sentence denotes Conclusions:
T112 488975-489053 Sentence denotes MxA and IL-10 levels correlated well with treatment response and IFNbeta dose.
T113 489054-489142 Sentence denotes Laser microdissection and single-cell RT-PCR analysis of IgG repertoire in SSPE brain M.
T114 489143-489154 Sentence denotes Burgoon, K.
T115 489155-489166 Sentence denotes Keays, G.P.
T116 489167-489176 Sentence denotes Owens, A.
T117 489177-489191 Sentence denotes Ritchie, X.-L.
T118 489192-489203 Sentence denotes Yu and D.H.
T119 489204-489476 Sentence denotes Gilden University of Colorado Health Sciences Center, Denver, CO, USA A prominent immunologic feature of subacute sclerosing panencephalitis (SSPE), a chronic fatal measles virus encephalitis, is the presence of increased IgG and oligoclonal bands (OGBs) in brain and CSF.
T120 489477-489540 Sentence denotes The oligoclonal IgG is antibody directed against measles virus.
T121 489541-489837 Sentence denotes To determine the fine specificity of individual immune cells in SSPE brain, and to develop techniques to analyze IgG repertoires in other chronic inflammatory CNS diseases, we microdissected individual plasma cells from SSPE brain and identified the specific IgG sequences expressed by each cell.
T122 489838-489948 Sentence denotes Plasma cells were identified in frozen 7-micron sections of postmortem SSPE brain by immunostaining for CD138.
T123 489949-490184 Sentence denotes Individual cells were microdissected with a nondestructive infrared laser. cDNA was synthesized and the sequences of the specific IgG heavy/light chain pairs expressed by each plasma cell were determined by nested RT-PCR amplification.
T124 490185-490369 Sentence denotes A repertoire of 50-70 plasma cells from a single SSPE brain revealed features of antigen-driven selection and affinity maturation, including clonal expansion and somatic hypermutation.
T125 490370-490505 Sentence denotes The variable region sequences can be inserted into expression vectors to produce large quantities of functional recombinant IgG (rIgG).
T126 490506-490697 Sentence denotes Studies of specific rIgG reactivities have the potential to identify the antigens in other chronic inflammatory CNS diseases of unknown cause, such as multiple sclerosis and Behcet's disease.
T127 490698-490798 Sentence denotes Neuro-Behcet's disease (n-BD) is a chronic inflammatory disease of the central nervous system (CNS).
T128 490799-490985 Sentence denotes Although the exact etiology of n-BD is unknown, it is generally accepted that autoimmunity is involved and that the auto antigen(s) probably reside in CNS, the target of immune response.
T129 490986-491124 Sentence denotes Current studies argue for some protein, especially Heat shock protein (HSP)-60, as an initiating or enhancing factor for Behcet's disease.
T130 491125-491300 Sentence denotes In this regard, levels of HSP-60 and TNF-alpha, which is one of the important cytokine in neuroimmune disorders, in cerebrospinal fluids (CSF) with n-BD patients was examined.
T131 491301-491406 Sentence denotes The CSFs were collected from n-BD patients, acute and chronic states at St. Marianna university Hospital.
T132 491407-491496 Sentence denotes HSP-60 and TNF-alpha were analyzed at the message and protein levels by RT-PCR and ELISA.
T133 491497-491612 Sentence denotes There was a relationship between HSP-60 and TNF-alpha in acute and chronic states CSFs obtained from n-BD patients.
T134 491613-491713 Sentence denotes Thus, these results indicated that HSP-60 may be one of the initiating or enhancing factor for n-BD.
T135 491714-491793 Sentence denotes Unexplained cases of CNS disorders with evidence of Chlamydia pneumoniae DNA C.
T136 491794-491808 Sentence denotes Contini a , S.
T137 491809-491824 Sentence denotes Seraceni a , R.
T138 491825-491840 Sentence denotes Cultrera a , M.
T139 491841-491859 Sentence denotes Castellazzi a , E.
T140 491860-491875 Sentence denotes Fainardi b , D.
T141 491876-491894 Sentence denotes Marchetti c and E.
T142 491895-491951 Sentence denotes Granieri a a University of Ferrara, Ferrara, Italy; b S.
T143 491952-492277 Sentence denotes Anna Hospital, Ferrara, Italy; c Bellaria Hospital, Bologna, Italy Chlamydia (C.) pneumoniae has been linked to a number of CNS chronic diseases including MS, and to few individually described cases of neurologic disorders such as encephalitis, meningoencephalitis, Guillain-Barré syndrome and lumbosacral meningoradiculitis.
T144 492278-492286 Sentence denotes Methods:
T145 492287-492628 Sentence denotes Cerebral spinal fluid (CSF) and serum specimens, collected from 48 patients with undefined meningitis, or meningoencephalitis without respiratory symptoms and neurological and magnetic resonance imaging abnormalities, were retrospectively analysed by a n-PCR btouchdownQ with specific primers for C. pneumoniae 16sRNA, MOMP and HsP 70 genes.
T146 492629-492691 Sentence denotes The specific IgG/IgA antibody response was evaluated by ELISA.
T147 492692-492700 Sentence denotes Results:
T148 492701-492843 Sentence denotes 6/48 (12.5%) patients were positive by C. pneumoniae PCR in either CSF or serum for MOMP gene (8, 17%), 16S RNA (11, 23%) and HSP-70 (5, 10%).
T149 492844-492911 Sentence denotes An anti-Chlamydial IgG antibody response was found in two patients.
T150 492912-492967 Sentence denotes Serological tests for bacteria and virus were negative.
T151 492968-493119 Sentence denotes C. pneumoniae infection should be included in the differential diagnosis of meningoencephalitis, even if there are not associated respiratory symptoms.
T152 493120-493470 Sentence denotes Of interest, the high quote of PCR positivity for Hsp-70 gene (a primary immunogen which elicits the inflammatory response during chlamydial disease) in these patients and previously demonstrated in MS disease (Contini et al., Multiple Sclerosis, in press) may be interpreted as a part of a stress response which can trigger an autoimmune reactivity.
T153 493471-493652 Sentence denotes Studies to quantitate relative transcript levels of Endogenous vasoactive neuropeptides act as hormones, neurotransmitters, and immune modulators and they have neurotrophic actions.
T154 493653-493707 Sentence denotes They are readily catalysed to small peptide fragments.
T155 493708-493822 Sentence denotes They and their binding sites are immunogenic and are known to be associated with a range of autoimmune conditions.
T156 493823-493953 Sentence denotes This theoretical paper describes a biologically plausible mechanism for chronic fatigue syndrome and sudden infant death syndrome.
T157 493954-494124 Sentence denotes Most utilised anti-gliadin antibodies (Ab) using such methods and patients were considered to have gluten sensitivity (gluten ataxia) leading to dietary treatment regime.
T158 494125-494259 Sentence denotes We have explored its significance amongst ILOCA patients in our populationbased study using both ELISA and an alternative immunoassay.
T159 494260-494279 Sentence denotes Methods/ Materials:
T160 494280-494323 Sentence denotes Sera of 84 patients (mean disease duration:
T161 494324-494341 Sentence denotes 7.8 years; range:
T162 494342-494466 Sentence denotes 1 to 35) were analysed using Western blotting (WB) for anti-gliadin IgA/IgG Ab, followed by quantitation using densitometer.
T163 494467-494619 Sentence denotes Results of assay were compared with a group of sex-and age-matched elderly in-patients as a non-neurological control group as well as positive controls.
T164 494620-494628 Sentence denotes Results:
T165 494629-494758 Sentence denotes In the initial WB step, 23/84 (27%) ILOCA, 6/34 (18%) elderly and 9/12 (75%) CD sera showed probable immunoreactivity to gliadin.
T166 494759-494920 Sentence denotes Further validation of these findings on quantitative densitometer revealed 8/9 CD, 2/23 ILOCA and none amongst elderly control with significant immunoreactivity.
T167 494921-494932 Sentence denotes Discussion:
T168 494933-495021 Sentence denotes Our data suggests that anti-gliadin Ab detection may be dependent on the assay employed.
T169 495022-495220 Sentence denotes In our WB/densitometer approach, 8% ILOCA patients showed significant levels of anti-gliadin IgA/IgG Ab and may have gluten ataxia, contrary to previous reports suggesting levels up to 40% on ELISA.
T170 495221-495298 Sentence denotes A study on serum autoantibodies in post-infectious acute cerebellar ataxia A.
T171 495299-495314 Sentence denotes Uchibori a , M.
T172 495315-495328 Sentence denotes Sakuta a , S.
T173 495329-495346 Sentence denotes Kusunoki b and A.
T174 495347-495548 Sentence denotes Chiba a a Kyorin University, Tokyo, Japan; b Kinki University, Osaka, Japan Acute cerebellar ataxia (ACA) is characterised by an acute onset of selflimiting ataxia following a systemic viral infection.
T175 495549-495699 Sentence denotes An autoimmune process has been suggested and some anti-neuronal antibodies were reported in ACA, but their antigen molecules have not been identified.
T176 495700-495871 Sentence denotes We searched for serum antibodies in patients with ACA by Western blot (W/B) using a total protein fraction extracted from the cerebellar tissue with 2% SDS as the antigen.
T177 495872-495958 Sentence denotes We found an IgM antibody that strongly reacted with a protein of approximately 28 kDa.
T178 495959-496166 Sentence denotes The cerebellar cortex showed the strongest antigenicity among various nervous and non-nervous tissues based on the same amount of protein, and the strongest reaction was detected in the cytoplasmic fraction.
T179 496167-496273 Sentence denotes The antigen protein was separated by 2D-electrophoresis and subjected to N-terminal amino acid sequencing.
T180 496274-496404 Sentence denotes The sequence of 11 amino acid residues was shown to be identical with the N-terminal sequence of triose phosphate isomerase (TPI).
T181 496405-496511 Sentence denotes Further, in 8 of 23 serum samples from patients with ACA, bands of the same mobility were detected by W/B.
T182 496512-496767 Sentence denotes Anti-TPI IgM antibody titers were measured quantitatively using ELISA and the same 8 patients showed a significantly high antibody titer above mean +3SD of healthy controls (n=45), which decreased over time in patients checked in a time course evaluation.
T183 496768-496844 Sentence denotes These findings suggest that the anti-TPI IgM antibody may be related to ACA.
T184 496845-497137 Sentence denotes Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS) refers to a proposed subgroup of childhood onset Obsessive Compulsive Disorder (OCD) and/or Tourette Syndrome, in which onset or exacerbations of illness are triggered by Group A Streptococcal pharyngitis.
T185 497138-497375 Sentence denotes These children present with sudden and dramatic symptoms of OCD, have an episodic or sawtooth course of illness, and often show subtle neurological signs such as tics, choreiform movements, sudden clumsiness and worsening of handwriting.
T186 497376-497579 Sentence denotes This presentation will update current research comparing general immune function, cellular markers, and autoantibodies in children presenting with OCD/tic exacerbation to those children that are healthy.
T187 497580-497703 Sentence denotes A correlation of immune findings in the PANDAS subtype will be made to those children with OCD/tics without PANDAS subtype.
T188 497704-497866 Sentence denotes Increased concentrations of several inflammatory cytokines have been observed in brain tissue and cerebrospinal fluid (CSF) of several neurodegenerative diseases.
T189 497867-497968 Sentence denotes They include Alzheimer disease, Down syndrome, epilepsy, Parkinson's disease, and multiple sclerosis.
T190 497969-498144 Sentence denotes Whether these inflammatory molecules are causal in the neurodegenerative process or secondary to it and which is their role in neuronal survival and damage is still not known.
T191 498145-498284 Sentence denotes One distinctive feature of these immune molecules is that they act in cascade stimulating and inhibiting one another production and action.
T192 498285-498446 Sentence denotes A crucial question concerns the initial stimuli triggering the production of different cytokines that are simultaneously present in neurodegenerative conditions.
T193 498447-498514 Sentence denotes IL-6 was measured by highly sensitive sandwich enzyme immunoassays.
T194 498515-498573 Sentence denotes IL-6 was detectable in serum from control and PD patients.
T195 498574-498675 Sentence denotes The concentration of IL-6 in serum from patients with PD was higher than those from control patients.
T196 498676-498833 Sentence denotes These results agree with previous reports, in which the cytokine levels were elevated in the striatal dopaminergic region of the brain from patients with PD.
T197 498834-499059 Sentence denotes Because cytokines play an important role as mitogens and neurotrophic factors in the brain, the increases in cytokines as a compensatory response may occur in the brain of patients PD during the progress of neurodegeneration.
T198 499060-499195 Sentence denotes Increase in cytokines may contribute not only as a compensatory response but as a primary initiating trigger for the neurodegeneration.
T199 499196-499234 Sentence denotes Acute brain ischemia and inflammation.
T200 499235-499254 Sentence denotes An outcome study S.
T201 499255-499268 Sentence denotes Sotgiu a , B.
T202 499269-499287 Sentence denotes Marchetti b , M.L.
T203 499288-499299 Sentence denotes Fois a , G.
T204 499300-499311 Sentence denotes Arru a , B.
T205 499312-499324 Sentence denotes Zanda a , A.
T206 499325-499338 Sentence denotes Pirisi a , A.
T207 499339-499353 Sentence denotes Sanna a and G.
T208 499354-499501 Sentence denotes Rosati a a Istituto di Clinica Neurologica, University of Sassari, Sassari, Italy; b Dipartimento di Neurofarmacologia, OASI (IRCCS), Troina, Italy
T209 499502-499723 Sentence denotes Although numerous examples of failed surrogate markers are provided in literature, metalloproteinases, adhesion molecules and IL-6 serum levels seem to predict neurological deterioration in patients after ischemic stroke.
T210 499724-499923 Sentence denotes Accumulating evidences suggest however that inflammation includes both detrimental and protective components thus contributing to both neurotoxicity and neuroprotection in the central nervous system.
T211 499924-500270 Sentence denotes With the aim of investigating this issue we evaluated a series of 49 consecutive patients with acute ischemic stroke, and, within 24 h from stroke onset, the serum concentrations of a panel of different biomarkers previously reported to be associated with stroke: TNF-alpha, IL-1beta, IL-6, IL-8, MCP-1, sVCAM-1, sICAM-1, MMP-1, MMP-2/9 and BDNF.
T212 500271-500395 Sentence denotes Neurological impairment was scored by using GCS, GOS and NIH scales, both at stroke onset and after a three month follow-up.
T213 500396-500614 Sentence denotes TNFalpha, BDNF and VCAM-1 and particularly ICAM-1 ( pb0.0001) and MMP-2/9 ( pb0.001) were associated with the clinical severity of the ischemic stroke, showing a linear correlation with the initial and final NIH scale.
T214 500615-500814 Sentence denotes On the contrary, and in contrast to previous reports, IL-6 showed a significant inverse correlation ( pb0.001) being up-regulated in patients who developed a milder severity score after three months.
T215 500815-500976 Sentence denotes We suggest that IL-6 may have neuroprotective actions in patients with ischemic brain injury in the context of the complex cascade of a proinflammatory response.
T216 500977-501081 Sentence denotes It has been implied that inappropriate haemostasis contributes to ischemic damage in a number of issues.
T217 501082-501185 Sentence denotes It is not known if the risk factors for developing vascular dementia differ from those found in stroke.
T218 501186-501318 Sentence denotes Because vascular dementia (VaD) is a preventable type of dementia, the determination of risk factors for VaD is extremely important.
T219 501319-501608 Sentence denotes To evaluate the role of humoral parameters in the genesis of VaD in elderly patients, we investigated a group of 30 patients with VaD and compared the results with those of 30 cerebrovascular non-demented patients (VaND) and 30 healthy controls subjects without cerebral ischemic episodes.
T220 501609-502241 Sentence denotes A significant increase of Hcy, Fg, CRP, slCAM-I, SvCAM-I, IL-Ib, IL-6 and IL-10 was observed in VaD patients compared to that found in cerebrovascular ischemic patients and controls, respectively (56.5F22.4 mmol/l, 415F68.5 mg/dl, 6.7F2.55 mg/l, 315F75 mg/l, 975F125 mg/l, 2.05F1.15 pg/ml, 1.75F1.25 pg/ml and 1.45F1.05 pg/ml vs 26.5F12.5 mmol/l, 385F70.5 mg/dl, 3.7F2.35 mg/l, 275F75 mg/l, 635F105 mg/l, 1.50F1.35 pg/ml, 1.25F1.05 pg/ml and 1.15F1.11 pg/ml vs 7.5F3.5 mmol/l, 224F64.5 mg/ dl, 0.85F0.60 mg/l, 157F39 mg/l, 637F99 mg/l, 1.04F0.65 pg/ml, 0.75F0.55 pg/ml and 0.45F0.60 pg/ml respectively; pb0.001 Mann Whitney U-test).
T221 502242-502383 Sentence denotes Our findings demonstrate that Hcy and humoral inflammatory factors are very elevated in individuals suffering from VaD after ischemic stroke.
T222 502384-502520 Sentence denotes Our study confirm that an increased systemic levels of proinflammatory and immunoregulating cytokines may be found in patients with VaD.
T223 502521-502620 Sentence denotes Prognostic significance of antibodies to acetylcholine receptor (AchR) in myasthenia gravis (MG) G.
T224 502621-502632 Sentence denotes Galassi, P.
T225 502633-502648 Sentence denotes Faglioni and A.
T226 502649-502656 Sentence denotes Ariatti
T227 502657-502721 Sentence denotes Objective: to evaluate significance of antibodies to AchR in MG.
T228 502722-502730 Sentence denotes Methods:
T229 502731-502807 Sentence denotes A retrospective study was conducted on 67 MG patients (mean age 63.9 years):
T230 502808-502859 Sentence denotes 30 males, mean age 59.1, 37 females, mean age 59.6.
T231 502860-502901 Sentence denotes Mean duration of illness was 66.9 months.
T232 502902-503017 Sentence denotes At time of diagnosis,19 patients were AchR antibody negative whereas 48 patients had detectable antibodies to AchR.
T233 503018-503207 Sentence denotes Disease severity (Osserman's classification) was graded I in 11 AchR antibody positive and in 13 seronegative, IIa in 21 seropositive and in 6 seronegative, IIb in 16 seropositive patients.
T234 503208-503250 Sentence denotes No subjects were classified as III and IV.
T235 503251-503381 Sentence denotes With regard to actual severity, among 48 patients AchR antibody positive 7 were asymptomatic; 11 were graded I, 23 IIa and 7 II b.
T236 503382-503445 Sentence denotes Among 19 seronegative subjects, 14 were classified I and 5 IIa.
T237 503446-503542 Sentence denotes Degrees of improvement was computed in AchR antibody positive (N=48) and in seronegative (N=19).
T238 503543-503554 Sentence denotes Results:1).
T239 503555-503763 Sentence denotes At time of diagnosis, percentages of AchR antibody positive patients were significantly higher among subjects IIa (78%) and IIb (100%) as compared to those graded I (46%), Chi square(2)=14.70; exact P=0.0004.
T240 503764-503767 Sentence denotes 2).
T241 503768-503975 Sentence denotes Percentages of AchR antibody positive patients was significantly higher among patients who showed clinical improvement (94%) as compared to those either unchanged or worse, Chi square(1)=4.279; exact pb0.03.
T242 503976-503979 Sentence denotes 3).
T243 503980-504144 Sentence denotes Degrees of improvement between baseline and actual severity did not differ significantly between AchR antibody positive and seronegative subjects; Chi square (2)b1.
T244 504145-504302 Sentence denotes Immunosuppressive treatment modifies both the number and phenotype of circulating but not of intrathymic CD4+CD25+ T regulatory cells in myasthenia gravis A.
T245 504303-504317 Sentence denotes Fattorossi, A.
T246 504318-504331 Sentence denotes Battaglia, F.
T247 504332-504344 Sentence denotes Ciaraffa, C.
T248 504345-504358 Sentence denotes Di Schino, G.
T249 504359-504373 Sentence denotes Scambia and A.
T250 504374-504412 Sentence denotes Evoli Catholic University, Rome, Italy
T251 504413-504486 Sentence denotes We analyzed immunosuppressive CD4+CD25+ T (Treg) cells in 42 MG patients.
T252 504487-504663 Sentence denotes The number of Treg cells in the peripheral blood of untreated patients was significantly lower than in healthy subjects (HS) and increased after immunosuppressive (IS) therapy.
T253 504664-504782 Sentence denotes IS therapy-induced Treg cells expressed less HLA-DR which is indicative of an expansion of newly generated Treg cells.
T254 504783-504960 Sentence denotes The increase in Treg cell number following IS therapy was lowered but not suppressed by thymectomy, suggesting that the thymus contributes to the peripheral pool of these cells.
T255 504961-505183 Sentence denotes The number of circulating Treg cells did not differ in patients with thymomatous and nonthymomatous thymuses, but the enhancing effect of IS therapy was considerably more prominent in patients with a non-neoplastic thymus.
T256 505184-505292 Sentence denotes This suggests that normal thymic epithelium can be relevant in maintaining peripheral Treg cell homeostasis.
T257 505293-505477 Sentence denotes Thymus function, however, appeared dispensable in governing the peripheral pool of Treg cells, as thymectomized patients had a number of circulating Treg cells within the normal range.
T258 505478-505583 Sentence denotes Intrathymic Treg cell frequency was not related to thymus histology and was not influenced by IS therapy.
T259 505584-505677 Sentence denotes Moreover, there was no correlation between intrathymic and circulating Treg cell frequencies.
T260 505678-505970 Sentence denotes Collectively, these findings are consistent with the possibility that Treg cell deficiency has a role in MG development and that up-modulation of these cells contributes to the therapeutic effect of IS treatment. (veab) , and 2 main clinical presentations: ocular (oMG) and generalised (gMG).
T261 505971-505982 Sentence denotes Objectives.
T262 505983-506141 Sentence denotes To compare age/sex distributions of all MG variants by onset of symptoms rather than ab positivity, and determine the age specific incidence of AChR ab+ve MG.
T263 506142-506150 Sentence denotes Methods.
T264 506151-506212 Sentence denotes We studied 141 patients with clinically validated gMG or oMG.
T265 506213-506265 Sentence denotes All were tested for AChR and, if negative, MuSK abs.
T266 506266-506274 Sentence denotes Results.
T267 506275-506417 Sentence denotes 58% had AChR abs (gMG [75%], 24m 36f; oMG [25%], 12m 8f), 42% were ab-ve (gMG [36%], 1m 20f; oMG [64%] 15m 24f), and 1 gMG man was MuSK ab+ve.
T268 506418-506620 Sentence denotes Here, age/sex distribution and specific incidence for all AChR ab+ve MG increased with age with two main peaks at the fourth and ninth decades caused respectively by younger gMG women and older oMG men.
T269 506621-506660 Sentence denotes Ab-ve gMG started in women at all ages.
T270 506661-506743 Sentence denotes Ab-ve oMG increased steadily to peak in the eighth decade and affected both sexes.
T271 506744-506756 Sentence denotes Conclusions.
T272 506757-506867 Sentence denotes Ab -ve MG is probably a pathogenetically-heterogeneous disorder and our data suggests it is relatively common.
T273 506868-506968 Sentence denotes It presents as generalized weakness in women of all ages and ocular weakness in older women and men.
T274 506969-507072 Sentence denotes Our AChRab+ve MG data is similar and representative to those reported for AChR ab positivity in the UK.
T275 507073-507339 Sentence denotes To clarify the distinct immune balance in the cerebrospinal fluid (CSF) compartment, we investigated intra-and extracellular levels of various cytokines and chemokines in CSF in chronic inflammatory demyelinating polyneuropathy (CIDP) and vasculitic neuropathy (VN).
T276 507340-507771 Sentence denotes Sixteen cytokines, IL-1h, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17, IFN-gamma, TNF-alpha, G-CSF, MCP-1 and MIP-1beta, in CSF supernatant were measured by a multiplexed fluorescent-bead based immunoassay; and intracellular cytokine production of IFN-gamma and IL-4 in CSF CD4+ T cells by flowcytometry, in 14 patients with CIDP, 8 patients with VN and 24 other non-inflammatory neurologic diseases (OND).
T277 507772-508028 Sentence denotes In the CSF supernatant, significant increases of IL-8 and IL-17 and significant decreases of IL-4, IL-5, IL-6 and IL-7 were detected in pretreated CIDP as compared with OND; whereas significant increases of IL-6, IL-8 and IL-10 were found in pretreated VN.
T278 508029-508268 Sentence denotes In CSF CD4+ T cells, IFN-gamma+ IL-4cell percentages were markedly elevated in CIDP compared with OND, but not in VN, resulting in a significant increase of intracellular IFN-gamma/IL-4 ratio in CIDP even in the absence of CSF pleocytosis.
T279 508269-508466 Sentence denotes Non-responders to intravenous immunoglobulins showed significantly lower IFN-gamma-IL-4+ CD4+ T cell percentages and tended to have higher intracellular IFNgamma/IL-4 ratios in CSF than responders.
T280 508467-508605 Sentence denotes Upregulation of Th1 and downregulation of Th2 cytokines are pathognomonic for CIDP, while some Th2 cytokines are upregulated in CSF in VN.
T281 508606-508722 Sentence denotes Allergic bronchial asthma induced in NGF-antibody producing rats: evidence for a non pro-inflammatory role of NGF B.
T282 508723-508744 Sentence denotes Stampachiacchiere, A.
T283 508745-508755 Sentence denotes Micera, S.
T284 508756-508769 Sentence denotes Bonini and L.
T285 508770-508987 Sentence denotes Aloe National Research Council (CNR), Rome, Italy Both in animal models and humans allergic bronchial asthma (ABA) can increase Nerve growth factor (NGF) levels in the blood serum and bronchial alveolar lavage (BALF).
T286 508988-509059 Sentence denotes The NGF inflammatory role in ABA is not clear and matter of discussion.
T287 509060-509238 Sentence denotes In the present study, we used an animal model of ABA with and without circulating levels of NGF antibodies (Ab-NGF) to investigate the role of NGF in neuroinflammatory disorders.
T288 509239-509334 Sentence denotes ABA was induced in adult female rats by ovaalbumina (OVA) immunization as previously described.
T289 509335-509425 Sentence denotes Rats with circulating Ab-NGF were obtained by injecting purified NGF in Freund's adjuvant.
T290 509426-509517 Sentence denotes NGF, TNF-alpha and IgE were measured in the serum, BALF and lung tissues, using ELISA kits.
T291 509518-509660 Sentence denotes OVA treated rats revealed significant increase in IgE, TNF-alpha levels, mast cells in the lung and eosinophils in both BALF and lung tissues.
T292 509661-509740 Sentence denotes These animals showed also an increase in circulating NGF in the serum and BALF.
T293 509741-509870 Sentence denotes NGF administration in normal adult rats did not lead to an increase in eosinophils and IgE in the BALF and lung of allergic rats.
T294 509871-510093 Sentence denotes This findings suggest that NGF does not stimulate ABA or inflammatory response and that the increase in NGF during allergic responses may be associated with regulation of neuroallergic and/or neuroimmuno protective action.
T295 510094-510315 Sentence denotes The study's aim was to evaluate whether serum levels of the matrix metalloproteinase MMP-9 and its inhibitor TIMP-1 correlate with symptomatic versus asymptomatic carotid stenosis, and restenosis following endarterectomy.
T296 510316-510468 Sentence denotes Serum from patients (n=48; 26 symptomatic) with severe carotid stenosis, confirmed by duplex, was collected pre endarterectomy, and a year post-surgery.
T297 510469-510513 Sentence denotes CRP, MMP-9, and TIMP-1 levels were measured.
T298 510514-510621 Sentence denotes Pre endarterectomy levels of CRP, MMP-9, and TIMP-1 were similar in symptomatic and a-symptomatic patients.
T299 510622-510666 Sentence denotes CRP levels did not change following surgery.
T300 510667-510765 Sentence denotes Overall, MMP 9 levels decreased (-26.5%) a year post surgery, and TIMP 1 levels increased (+9.8%).
T301 510766-510960 Sentence denotes When patients were stratified according to presence or absence of concomitant ischemic heart disease (IHD) a significant decrease in MMP 9 levels was observed (33.6%) only in the IHD-free group.
T302 510961-511103 Sentence denotes In asymptomatic patients, a trend for a decline in MMP-9 levels (-50%) was observed, and in parallel, a significant increase in TIMP-1 (+14%).
T303 511104-511205 Sentence denotes Similar changes were observed in symptomatic patients, but failing to reach statistical significance.
T304 511206-511388 Sentence denotes In eleven patients that developed restenosis, MMP-9 was significantly decreased (-50%), while in the no-restenosis group a significant increase in TIMP-1 levels was observed (+9.9%).
T305 511389-511498 Sentence denotes The results of our study indicate that a year post-carotid endarterectomy, the MMP 9/TIMP 1 ratio is reduced.
T306 511499-511628 Sentence denotes Further studies are required to support the use of these enzymes as bio-markers of atherosclerotic activity and impending stroke.
T307 511629-511710 Sentence denotes Vesicle shedding mediates IL1-beta release from ATP stimulated microglia cells F.
T308 511711-511724 Sentence denotes Bianco a , E.
T309 511725-511742 Sentence denotes Pravettoni a , U.
T310 511743-511756 Sentence denotes Schenk a , M.
T311 511757-511774 Sentence denotes Matteoli b and C.
T312 511775-511968 Sentence denotes Verderio a a CNR-Institute of Neuroscience, Milan, Italy; b University of Milan, Milan, Italy ATP has been indicated as a primary factor in microglial response to brain injury and inflammation.
T313 511969-512103 Sentence denotes By means of different P2 receptors, ATP is known to induce chemotaxis and stimulate the release of several cytokines from these cells.
T314 512104-512246 Sentence denotes The activation of P2 receptors in microglia can be triggered either by ATP deriving from dying cells, at sites of brain injury (Ferrari et al.
T315 512247-512408 Sentence denotes 1997a) , or by ATP released from astrocytes to mediate cell-to-cell signaling, in the absence of cell damage (Verderio and Matteoli, 2001; Shipke et al., 2002) .
T316 512409-512641 Sentence denotes By the use of a biochemical approach integrated with videomicroscopy experiments, we investigated the functional consequence triggered in microglia by ATP released from mechanically stimulated astrocytes, in mixed glial co-cultures.
T317 512642-512744 Sentence denotes Astrocyte-derived ATP induced in nearby microglia the formation and the shedding of membrane vesicles.
T318 512745-512845 Sentence denotes Vesicle formation was inhibited by the ATP-degrading enzyme apyrase or by P2X7 receptor antagonists.
T319 512846-513054 Sentence denotes Shed vesicle isolation, followed by IL-1beta evaluation by a specific ELISA assay revealed the presence of the cytokine inside the vesicular organelles and its subsequent efflux into the extracellular medium.
T320 513055-513287 Sentence denotes IL-1beta efflux from shed vesicles was enhanced by ATP stimulation and inhibited by pre-treatment with the P2X7 antagonist oATP, thus indicating a crucial involvement of the pore-forming P2X7 receptor in the release of the cytokine.
T321 513288-513407 Sentence denotes Toll-like receptors (TLRs) have evolved as conserved pattern-recognition receptors that are central to innate immunity.
T322 513408-513480 Sentence denotes Signaling through TLRs may also regulate endogenous responses to injury.
T323 513481-513561 Sentence denotes In the central nervous system (CNS), microglia respond rapidly to axonal injury.
T324 513562-513801 Sentence denotes Transection of axons in the entorhinal cortex causes anterograde axonal degeneration and induces microglial reactivity in the hippocampus, accompanied by local cytokine and chemokine production and later macrophage and T cell infiltration.
T325 513802-514003 Sentence denotes TLR2 and the LPS-receptor CD14 were induced in the lesionreactive hippocampus within 3 h of injury, coincident with glial cytokine and chemokine responses, but before detectable leukocyte infiltration.
T326 514004-514060 Sentence denotes TLR1 and TLR4 were not significantly induced until 24 h.
T327 514061-514164 Sentence denotes Induction of MyD88 and IkBa transcripts suggested signal transduction via TLRs in reactive glial cells.
T328 514165-514237 Sentence denotes Macrophage and T cell infiltration were reduced in MyD88-deficient mice.
T329 514238-514318 Sentence denotes T cell infiltration was delayed following axonal lesions in TLR2-deficient mice.
T330 514319-514453 Sentence denotes The microglial expansion that occurs 5 days post-lesion was reduced in TLR2-deficient mice, although macrophage influx was unaffected.
T331 514454-514578 Sentence denotes No inhibition of leukocyte infiltration or microglial expansion was observed following axonal lesions in TLR4deficient mice.
T332 514579-514784 Sentence denotes Our findings suggest that induction of and signaling through TLRs is an early innate response to CNS axonal injury that selectively regulates later cellular responses implicated in regeneration and repair.
T333 514785-514944 Sentence denotes In contrast to other tissues, the central nervous system (CNS) is essentially devoid of MHC expression and shielded from antibodies by the blood-brain barrier.
T334 514945-515068 Sentence denotes Therefore, a rapid local innate immune response by resident brain cells is required to effectively fight infectious agents.
T335 515069-515177 Sentence denotes The recognition of microbial infections is mediated by invariant receptors called Toll-like receptors (TLR).
T336 515178-515305 Sentence denotes Upon ligand binding, immune cells mount a direct response to the pathogen and additionally activate the adaptive immune system.
T337 515306-515397 Sentence denotes This study analyzed the expression of the ten TLRs by quantitative PCR in human astrocytes.
T338 515398-515514 Sentence denotes Only TLR3, the receptor responsible for the recognition of viral double-stranded RNA, had a constitutive expression.
T339 515515-515580 Sentence denotes Its levels could be enhanced by IFN-gamma, IL-1beta and IFN-beta.
T340 515581-515633 Sentence denotes The other TLRs were barely detectable and inducible.
T341 515634-515800 Sentence denotes The TLR3 ligand poly (I: C) triggered production of the cytokines IL-6 and TNF-alpha, and of the chemokines CCL5/RANTES, CXCL10/IP-10, CCL20/MIP-3alpha and CCL2/MCP1.
T342 515801-515923 Sentence denotes The TLR adapter molecules MyD88 (full length and short isoform), TIRAP/Mal, and TICAM-1/TRIF were expressed by astrocytes.
T343 515924-516108 Sentence denotes In summary, human astrocytes may sense viral infections and respond with a proinflammatory activation program that will be amplified by the recruitment of immune cells into the tissue.
T344 516109-516222 Sentence denotes Hydroxychloroquine (HQ), an anti-malarial agent, is used as an immunomodulator in lupus and rheumatoid arthritis.
T345 516223-516332 Sentence denotes It interferes with antigen processing and inhibits cytokine production by peripheral blood mononuclear cells.
T346 516333-516593 Sentence denotes We studied the effect of HQ on cultured microglia, the activation of which is thought to be crucial to the pathogenesis of multiple sclerosis (MS), and on the course of mice afflicted with experimental autoimmune encephalomyelitis (EAE), an animal model of MS.
T347 516594-516711 Sentence denotes Human fetal and adult microglia were pretreated with HQ followed by lipopolysaccharide (LPS), a monocytoid activator.
T348 516712-516810 Sentence denotes The overnight culture medium was then collected and subjected to cytokine measurement using ELISA.
T349 516811-517031 Sentence denotes HQ (3-15 microM) significantly decreased TNF-alpha and IL-10 levels and was superior to minocycline, a known microglia modulator, in inhibiting TNF-alpha production; a pretreatment period was more effective than without.
T350 517032-517138 Sentence denotes Using U937 cells, the effect of HQ on transcripts encoding matrix-metalloproteinases (MMPs) was evaluated.
T351 517139-517237 Sentence denotes HQ reduced the mRNA for MMP-1, 9 and 12, which are incriminated in the pathogenesis of MS and EAE.
T352 517238-517458 Sentence denotes Finally, we tested HQ in monophasic EAE and found that 100 mg/kg given as a pretreatment completely prevented the development of disease; this was correlated with lack of signs of microglia activation in treated animals.
T353 517459-517603 Sentence denotes We conclude that by interfering with microglia activity and MMPs, HQ deserves to be tested further as a disease modifying therapy in EAE and MS.
T354 517604-517815 Sentence denotes Dept. of Pharmacology, University of Washington, Seattle, USA Cells produce endocannabinoids that activate cannabinoid receptors, the molecular target for marijuana's bioactive ingredient 9-tetrahydrocannabinol.
T355 517816-517946 Sentence denotes The molecular mechanism underlying the production of the most abundant endocannabinoid, 2-arachidonoylglycerol (2-AG), is unclear.
T356 517947-518142 Sentence denotes Here we show that ATP increases 2-AG production by mouse microglial cells in culture, a response mediated by phosphatidylinositol-specific phospholipase C (PI-PLC) and diacylglycerol (DG) lipase.
T357 518143-518268 Sentence denotes However, efficacious activation of metabotropic P2Y purinergic receptors coupled to PI-PLC does not increase 2-AG production.
T358 518269-518424 Sentence denotes This suggests that ionotropic, and not metabotropic, purinergic receptors control 2-AG production at an unexpected enzymatic step of its metabolic pathway.
T359 518425-518594 Sentence denotes We show that activation of P2X7 ionotropic receptors, which are highly permeable to calcium, is necessary and sufficient to increase 2-AG production in microglial cells.
T360 518595-518828 Sentence denotes We also show that the sustained rise in intracellular calcium induced by activation of P2X7 receptors directly increases DG-lipase activity while inhibiting the activity of monoacylglycerol (MG) lipase, the enzyme that degrades 2-AG.
T361 518829-518974 Sentence denotes This inverse sensitivity of DG-lipase and MG-lipase to calcium constitutes an original and efficient modality for sustained accumulation of 2-AG.
T362 518975-519087 Sentence denotes Finally, overnight activation of microglial cell with interferon-gamma disrupts the ATP-induced 2-AG production.
T363 519088-519373 Sentence denotes Because prolonged increases in 2-AG amounts in brain parenchyma are thought to orchestrate neuroinflammation, the enzymatic steps involved in 2-AG synthesis and degradation by microglial cells constitute appealing targets for therapy aimed at controlling exacerbated neuroinflammation.
T364 519374-519588 Sentence denotes Nicotinic acetylcholine receptors are a family of ligand-gated pentameric ion channels whose main function is to transmit signals for the neurotransmitter acetylcholine in the peripheral and central nervous system.
T365 519589-519696 Sentence denotes Recently, the nicotinic acetylcholine receptor alpha7 subunit (alpha7) was found in peripheral macrophages.
T366 519697-519805 Sentence denotes Its interaction with specific agonists strongly reduced the release of the cytokines IL-1beta and TNF-alpha.
T367 519806-520033 Sentence denotes Epidemiological studies showed that nicotine may be protective in some neurodegenerative pathologies, such as Alzheimer and Parkinson diseases, in which chronic inflammation, sustained by microglial cells, plays a crucial role.
T368 520034-520157 Sentence denotes In the present study, we investigated the expression of alpha7 and its functional role in purified rat microglial cultures.
T369 520158-520231 Sentence denotes RT-PCR analysis revealed the presence of alpha7 mRNA in microglial cells.
T370 520232-520382 Sentence denotes Strong binding on microglial surface of FITC-alpha-bungarotoxin, which specifically binds to alpha 7 subunits, confirmed the presence of the receptor.
T371 520383-520590 Sentence denotes Nicotine slightly reduced the release of nitric oxide and IL-10 by LPS activated microglia, whereas COX-2 mRNA and synthesis of PGE2, a lipid mediator with potential anti-inflammatory effects, were enhanced.
T372 520591-520857 Sentence denotes Our study is in line with the hypothesis of an anti-inflammatory effect of nicotine and suggests that the development of molecules able to stimulate the alpha7 receptor represent potential therapeutic tools for the treatment of several inflammatory neuropathologies.
T373 520858-520884 Sentence denotes Supported by ISS, grant n.
T374 520885-520890 Sentence denotes C3A4.
T375 520891-520993 Sentence denotes Adaptive immunity instructs microglia to protect against aggregated Bamyloid and glutamate toxicity O.
T376 520994-521008 Sentence denotes Butovsky, E.A.
T377 521009-521021 Sentence denotes Talpalar, K.
T378 521022-521039 Sentence denotes Ben-Yaakov and M.
T379 521040-521242 Sentence denotes Schwartz Weizmann Institute of Science, Revohot, Israel bProtective autoimmunityQ refers to the well-controlled T-cell-mediated anti-self response that helps the body resist neurodegenerative disorders.
T380 521243-521381 Sentence denotes We show that this response, through the cytokines interferon (IFN)-gamma (Th1) and interleukin (IL)-4 (Th2), renders microglia protective.
T381 521382-521518 Sentence denotes Relative to microglial activation by IFN-gamma, IL-4-elicited activation was delayed and was effective over a wider concentration range.
T382 521519-521709 Sentence denotes Microglia responded to disease-associated self-compounds (aggregated beta-amyloid, glutamate) as aggressively as if they were bacteria (e.g., bacterial cell wall-derived lipopolysaccharide).
T383 521710-521826 Sentence denotes Their cytotoxicity down-regulated MHC-II expression through the MHC class-II transactivator and the invariant chain.
T384 521827-521962 Sentence denotes Partial protection was achieved by down-regulation of TNF-alpha and upregulation of insulin-like growth factor (IGF-I) induced by IL-4.
T385 521963-522223 Sentence denotes These findings suggest that whether the local immune response in the damaged CNS will be beneficial or harmful depends on how the microglia interpret the threat, and that a well-regulated T-cell-mediated response serves as a self-contained mechanism of repair.
T386 522224-522305 Sentence denotes Microglia are the resident tissue macrophage of the central nervous system (CNS).
T387 522306-522389 Sentence denotes Their activation is an early and common feature of nearly all CNS neuropathologies.
T388 522390-522544 Sentence denotes We and others have demonstrated that microglia are phenotypically and functionally distinct from other tissue and CNS-infiltrating macrophage populations.
T389 522545-522614 Sentence denotes Here, we sought to define microglial phenotypes on a molecular level.
T390 522615-522835 Sentence denotes Using an open profiling method (TOGA) to screen gene expression, we have detected over 19,000 novel and known molecules expressed in microglia (adult and neonatal), several populations of macrophages and dendritic cells.
T391 522836-523138 Sentence denotes From these studies, we have identified patterns of gene expression that 1) distinguish microglia from other myeloid populations, 2) reveal microglia are highly heterogeneous in the healthy CNS, and 3) indicate microglial responses to pathologic stimuli are heterogeneous even within a single pathology.
T392 523139-523294 Sentence denotes We are currently examining to what extent these multiple microglial phenotypes are a consequence of different lineages versus different environmental cues.
T393 523295-523381 Sentence denotes Oligodendrocyte recruitment in multiple sclerosis (MS): a role for CXC chemokines K.M.
T394 523382-523394 Sentence denotes Omari a , G.
T395 523395-523410 Sentence denotes John b and C.S.
T396 523411-523641 Sentence denotes Raine a a Albert Einstein College of Medicine, NY, USA; b Mount Sinai School of Medicine, NY, USA Subsequent to demyelination in MS, oligodendrocytes initially retain the capacity to remyelinate but this diminishes as lesions age.
T397 523642-523789 Sentence denotes To further elucidate factors affecting oligodendrocyte recruitment, we investigated expression of CXC chemokines and their receptors in MS lesions.
T398 523790-523953 Sentence denotes Chemokines were detected by immunohistochemistry and western blotting with antibodies against CXCL1, CXCL8 and CXCL10, and their receptors, CXCR1, CXCR2 and CXCR3.
T399 523954-524132 Sentence denotes CXCL1, CXCL8 and CXCL10 were found to be strongly induced on hypertrophic astrocytes at the edge of active MS lesions, weakly expressed in silent lesions, and absent in controls.
T400 524133-524258 Sentence denotes Interestingly, specific expression of the corresponding receptors was found on oligodendrocytes in both MS and non-MS tissue.
T401 524259-524324 Sentence denotes Human astrocytes and oligodendrocytes were also studied in vitro.
T402 524325-524504 Sentence denotes Chemokines were measured by sandwich ELISAs in astrocyte supernatants after stimulation, RNA by northern blots and quantitative-PCR, and chemokine receptors by immunofluorescence.
T403 524505-524633 Sentence denotes At protein and RNA levels, IL-1beta strongly induced CXCL1 and CXCL8 by astrocytes, while IL-1beta and IFN-gamma induced CXCL10.
T404 524634-524711 Sentence denotes Astrocytes in culture media alone produced limited amounts of CXC chemokines.
T405 524712-524837 Sentence denotes Moreover, immature (A2B5+) and more mature (CNPase+) oligodendrocytes displayed surface expression of CXCR1, CXCR2 and CXCR3.
T406 524838-525086 Sentence denotes Based on the concurrent expression of these chemokines on hypertrophic astrocytes, and their receptors on oligodendrocytes at lesion margins, we propose that CXC chemokines play an important role in recruitment of oligodendrocytes to lesions in MS.
T407 525087-525186 Sentence denotes ATP regulates oligodendrocyte progenitor migration and proliferation via P2Y receptor activation C.
T408 525187-525203 Sentence denotes Agresti a , M.E.
T409 525204-525221 Sentence denotes Meomartini b , S.
T410 525222-525235 Sentence denotes Amadio b , E.
T411 525236-525252 Sentence denotes Ambrosini a , B.
T412 525253-525268 Sentence denotes Serafini a , C.
T413 525269-525283 Sentence denotes Volonté b , S.
T414 525284-525301 Sentence denotes Visentin a and F.
T415 525302-525587 Sentence denotes Aloisi a a Istituto Superiore di Sanità , Rome, Italy; b CNR-Fondazione Santa Lucia, Rome, Italy ATP released in high amounts during inflammation may influence cell function as well as damage and repair processes via the activation of ionotropic (P2X) and metabotropic (P2Y) receptors.
T416 525588-525851 Sentence denotes To better understand the consequences of purinergic receptor stimulation in oligodendrocytes, we have investigated the expression of P2X and P2Y receptor subtypes and their functional activity in oligodendrocyte progenitors (OPs) purified from rat brain cultures.
T417 525852-525951 Sentence denotes Using western blot analysis, we demonstrate that OPs express several P2X and P2Y receptor subtypes.
T418 525952-526146 Sentence denotes Analysis of Ca2+ transients induced by P2 agonists and by the specific antagonists oxATP and MRS2179 revealed that Ca2+ signalling in OPs is mediated mainly by P2X7 and P2Y1 receptor activation.
T419 526147-526302 Sentence denotes As a functional correlate of these findings, we show that ATP, ADP and the more selective P2Y1 receptor agonist ADPbetaS, but not UTP, induce OP migration.
T420 526303-526464 Sentence denotes Moreover, ATP and ADP, but not UTP, are able to inhibit OP proliferation induced by plateletderived growth factor and to promote oligodendrocyte differentiation.
T421 526465-526571 Sentence denotes The effects of ATP and ADP on OP migration and proliferation are prevented by the P2Y1 antagonist MRS2179.
T422 526572-526698 Sentence denotes By confocal laser scanning microscopy, we also show that P2Y1 receptors are expressed in NG2+ OPs in the developing rat brain.
T423 526699-526900 Sentence denotes Our results suggest that ATP, by regulating OP mobilization and differentiation, could affect remyelination in inflammatory demyelinating diseases of the central nervous system like multiple sclerosis.
T1 526901-527080 Sentence denotes There is interest in Schwann cells (SC) as a possible source of myelinating cells for transplantation into the CNS of patients with multiple sclerosis (MS) and spinal cord injury.
T2 527081-527209 Sentence denotes Migration of SC into the CNS is limited, but even when injected directly CNS glia may interfere with SC survival and maturation.
T3 527210-527373 Sentence denotes To investigate the effects of CNS glia on SC, we cultured neonatal rat SC and exposed them to serum free supernatants (Sup) obtained from rat mixed glial cultures.
T4 527374-527492 Sentence denotes Sup from 1 and 3 day glial cultures induced proliferation of SC assayed at 5 days in a concentration dependent manner.
T5 527493-527685 Sentence denotes Sup did not induce SC differentiation as measured by induction of surface expression of galactolipids (GalL) as assessed by indirect immunofluorescence (IF) with a monoclonal antibody to GalL.
T6 527686-527756 Sentence denotes Sup did not inhibit cyclic AMP (cAMP)-induction of SC differentiation.
T7 527757-527808 Sentence denotes Sup had no apparent effect on SC viability at 48 h.
T8 527809-527979 Sentence denotes We previously demonstrated that incubation of SC with transforming growth factor-beta (TGF-beta) + tumor necrosis factor-alpha (TNF-alpha) induces SC death via apoptosis.
T9 527980-528031 Sentence denotes Sup inhibited TGF-beta+TNF-alpha -induced SC death.
T10 528032-528199 Sentence denotes Our data suggest that soluble products of CNS glia have the potential to alter SC functions and may effect the outcome of SC transplantation or migration into the CNS.
T11 528200-528326 Sentence denotes The chemokines SDF-1 alpha and IL-8 stimulate oligodendrocyte precursor proliferation and enhance myelin formation in vitro L.
T12 528327-528338 Sentence denotes Kadi a , R.
T13 528339-528355 Sentence denotes Selvaraju a , P.
T14 528356-528369 Sentence denotes De Lys a , A.
T15 528370-528386 Sentence denotes Proudfoot a , T.
T16 528387-528399 Sentence denotes Wells b , Y.
T17 528400-528418 Sentence denotes Chvatchko a and U.
T18 528419-528541 Sentence denotes Boschert a a Serono Pharmaceutical Research Institute, Geneva, Switzerland; b Serono International SA, Geneva, Switzerland
T19 528542-528717 Sentence denotes Chemokines are a group of cytokines involved in immune system signaling, which have recently been postulated to regulate central nervous system (CNS) development and function.
T20 528718-528835 Sentence denotes In particular, chemokines may play a role in regulating oligodendrocytes, the cells myelinating axons within the CNS.
T21 528836-528968 Sentence denotes Here we have chosen to study the role of several chemokines in mediating myelination, the process that leads to axonal ensheathment.
T22 528969-529111 Sentence denotes We have used a mouse oligodendrocyte precursor-like cell line, Oli-neu, to assess the activities of chemokines on oligodendrocyte development.
T23 529112-529262 Sentence denotes The recombinant human chemokines GRO-alpha, IL-8, and SDF-1alpha dose-dependently increased proliferation of mouse Oli-neu cells, while MCP-1 did not.
T24 529263-529438 Sentence denotes Oli-neu cells express CXCR4, the receptor for SDF-1alpha, and SDF-1alpha-mediated induction of proliferation could be inhibited by addition of an anti-CXCR4 blocking antibody.
T25 529439-529606 Sentence denotes The activities of GRO-alpha, IL-8, and SDF-1alpha were also studied using primary mixed cortical cultures from embryonic mouse brain, an in vitro model of myelination.
T26 529607-529803 Sentence denotes Treatment with these chemokines stimulated myelin basic protein (MBP) synthesis in a dose-dependent manner, and also enhanced myelin segment formation, visualized via anti-MBP immunocytochemistry.
T27 529804-529966 Sentence denotes In keeping with the results obtained using Oli-neu cells, these chemokines were shown to stimulate proliferation of various cell types in mixed cortical cultures.
T28 529967-530182 Sentence denotes These cultures were shown to contain a sub-population of cells expressing both the CXCR4 receptor and markers of oligodendrocyte precursor cells (OPCs) such as platelet-derived growth factor receptor alpha (PDGFaR).
T29 530183-530361 Sentence denotes Several clinical and experimental lines of evidence indicate that glycolipids (GL) may serve as autoantigens in demyelinating autoimmune disease of the peripheral nervous system.
T30 530362-530663 Sentence denotes In multiple sclerosis (MS), both humoral and cellular immune mechanisms directed to GL have been suggested to be play a pathogenetic role; however, the cellular distribution of GL on glial cells in situ has not been clearly assessed, thus hampering pathogenetic correlations with autoimmune responses.
T31 530664-530889 Sentence denotes The aim of this study was to assess the pattern of expression in situ of GL on glial cells in adult normal central nervous system (CNS) and in chronic MS lesions, focusing on mature oligodendrocytes and their precursors (OP).
T32 530890-531030 Sentence denotes We performed double staining with specific glial cell markers and mAbs for GM1, GM2, GD2, GD3, GD1a, GD1b, A2B5 and GT1b on frozen sections.
T33 531031-531181 Sentence denotes In normal conditions, most GL were preferentially expressed on astrocytes, with the exception of GD2 being present on oligodendrocytes and GD1a on OP.
T34 531182-531294 Sentence denotes In MS lesions, most gangliosides were diffusely down-regulated on astrocytes and upregulated on NG2-positive OP.
T35 531295-531504 Sentence denotes In particular, at the edge of MS lesions, OP showed high levels of expression with mAb A2B5 and for GD1a and GT1b, while GD2 and GD3 were present on oligodendrocytes and myelin in the surrounding white matter.
T36 531505-531633 Sentence denotes These results may provide interesting insights on the pathogenic role of GL as autoantigens in MS and in CNS autoimmune disease.
T37 531634-531788 Sentence denotes Sonic Hedgehog (SHH) and downstream molecules Olig1 and Olig2 may be dysregulated in MS, a disease in which selective depletion of oligodendroglia occurs.
T38 531789-532010 Sentence denotes In this study, MS lesions at different stages and CNS tissue from normal and disease controls were evaluated for the expression of SHH, its receptor Patched (PTC), Olig1, and Olig2 by immunocytochemistry and Western blot.
T39 532011-532115 Sentence denotes Oligodendrocytes at the edge of chronic active MS lesions were intensely immunoreactive for SHH and PTC.
T40 532116-532212 Sentence denotes Westerns confirmed increased SHH and PTC levels in expanding, and decreased levels in silent MS.
T41 532213-532385 Sentence denotes In contrast, Olig1 stained oligodendrocytes in normal-appearing white matter (NAWM), and cells with both astrocytic and oligodendroglial features at the active lesion edge.
T42 532386-532433 Sentence denotes Westerns showed no difference among the groups.
T43 532434-532501 Sentence denotes Olig2 selectively stained oligodendrocytes in all tissues examined.
T44 532502-532659 Sentence denotes In active MS, a gradient in immunoreactivity was seen, with oligodendrocytes in NAWM staining most intensely, and those near the lesion edge, less intensely.
T45 532660-532739 Sentence denotes Interestingly, Westerns revealed markedly increased Olig2 in chronic active MS.
T46 532740-532883 Sentence denotes Upregulation of SHH and Olig2 in oligodendrocytes around chronic active lesions suggests these genes to be active during ongoing demyelination.
T47 532884-533032 Sentence denotes Downregulation of SHH and Olig2 may explain progression from chronic active to chronic silent lesions. (Supported by NS 07098 and NMSS CA 1022-A-1).
T48 533033-533097 Sentence denotes Adult human oligodendrocytes proliferate in long-term culture A.
T49 533098-533114 Sentence denotes Boullerne a , D.
T50 533115-533128 Sentence denotes Frim b and B.
T51 533129-533146 Sentence denotes Arnason c a Dept.
T52 533147-533290 Sentence denotes Neurology, University of Chicago, Chicago, USA; b Section of Neurosurgery and the Brain Research Institute, University of Chicago, USA; c Dept.
T53 533291-533565 Sentence denotes Neurology and the Brain Research Institute, University of Chicago, Chicago, USA Human oligodendrocytes (OLG) were isolated from resection specimens of epilepsy patients and maintained in primary culture to assess their proliferative capacities in various culture conditions.
T54 533566-533654 Sentence denotes Immunostaining of cell preparations showed that all surviving cells were of OLG lineage.
T55 533655-533767 Sentence denotes At the time of isolation, staining for the OLG progenitor marker NG2 showed between 5% and 20% progenitor cells.
T56 533768-533872 Sentence denotes Co-labeling with the microglia marker CD11b was negative confirming that the NG2 labeled cells were OLG.
T57 533873-534068 Sentence denotes At several time points over two months in culture, continuous evidence of cell division by bromodeoxyuridine incorporation along with an increased cell density was documented by confocal imaging.
T58 534069-534257 Sentence denotes Proliferative capacity of OLG from adult brains was found to be dependent upon a low insulin concentration (15 Ag/ml) inhibitory at 50 Ag/ml insulin despite the presence of growth factors.
T59 534258-534315 Sentence denotes The maximum proliferation rate of OLG progenitors was 9%.
T60 534316-534453 Sentence denotes OLG maintained on laminin, an extracellular matrix protein of axons in the central nervous system, retained their proliferative capacity.
T61 534454-534607 Sentence denotes These findings are relevant for the development of therapeutic strategies to promote remyelination in human central nervous system degenerative diseases.
T62 534608-534852 Sentence denotes Lymphocytes are present within ethidium-bromide (EB)-demyelinating lesions in the Central Nervous System (CNS) and the possibility of their participation in possible immune-mediated responses to the detached myelin sheaths can not be ruled out.
T63 534853-535048 Sentence denotes This study aimed to investigate the consequences of lymphocytic interference with the immunosuppressive agents cyclophosphamide (Cy) and cyclosporine (CsA) in CNS repair after local EB injection.
T64 535049-535136 Sentence denotes Adult Wistar rats received 10 microlitres of 0.1% EB solution into the cisterna pontis.
T65 535137-535331 Sentence denotes Some were treated intraperitoneally with Cy (50 and 30 mg/kg, twice a week, group I) or Csa (10 mg/kg/day, group II) during the experimental period; others were not immunosuppressed (group III).
T66 535332-535448 Sentence denotes Three animals from each group were perfused with 4% glutaraldehyde at 7,11,15,21 and 31 days following EB injection.
T67 535449-535540 Sentence denotes Brainstem slices were collected and processed for transmission electron microscopy studies.
T68 535541-535714 Sentence denotes Rats from group I showed greater amounts of myelin-derived membranes than non-immunosuppressed rats, suggesting a delay in the macrophage activity of removing myelin debris.
T69 535715-535743 Sentence denotes Rare lymphocytes were found.
T70 535744-535853 Sentence denotes Oligodendrocyte remyelinating activity also showed a delayed pattern, with clear predominance of naked axons.
T71 535854-535947 Sentence denotes Although neovascularization was decreased, astrocytic reaction did not appear to be affected.
T72 535948-536096 Sentence denotes In rats from group II, the most important finding was the presence of a higher density of oligodendrocytes near remyelinated axons at the periphery.
T73 536097-536128 Sentence denotes Lymphocytes were still present.
T74 536129-536246 Sentence denotes Results from group II suggest that IL-2 suppression by CsA had a proliferative effect on oligodendrocyte progenitors.
T75 536247-536549 Sentence denotes Tumour necrosis factor (TNF) is a major immunomodulatory proinflammatory cytokine that's been identified as having a pathogenic role in a number of inflammatory diseases within the central nervous system including multiple sclerosis and the animal model experimental autoimmune encephalomyelitis (EAE).
T76 536550-536633 Sentence denotes TNF is synthesised as a membrane bound protein that is cleaved into a soluble form.
T77 536634-536743 Sentence denotes The proteinase responsible for this cleavage has been identified as TNFa-converting enzyme (TACE or ADAM-17).
T78 536744-536870 Sentence denotes We've shown ADAM-17 to be expressed by both the endothelial and astrocyte cells in white matter of normal human control brain.
T79 536871-537095 Sentence denotes Here we report the distribution and level of ADAM-17 expression within spinal cord white matter of naRve Lewis rats as well as in rats with EAE assessed by immunocytochemistry, western blotting and realtime RT-PCR (qRT-PCR).
T80 537096-537313 Sentence denotes ADAM-17 is associated with the blood vessel endothelium in the naRve and pre-disease spinal cords, whereas there is an abundance of astrocytic and inflammatory cells expressing ADAM-17 at peak-disease and in recovery.
T81 537314-537511 Sentence denotes This apparent up-regulation of ADAM-17 protein is coupled with a four-fold decrease in mRNA levels of its natural inhibitor TIMP3 (tissue inhibitor of metalloproteinase 3) as determined by qRT-PCR.
T82 537512-537625 Sentence denotes The Coxsackie Adenovirus receptor expressed by ependymal cells is a key component of the brain stem cell niche M.
T83 537626-537636 Sentence denotes Hauwel, C.
T84 537637-537650 Sentence denotes Canova and P.
T85 537651-537657 Sentence denotes Gasque
T86 537658-537757 Sentence denotes In the adult vertebrate brain, the subventricular zone (SVZ) is one of the rare neurogenesis areas.
T87 537758-537894 Sentence denotes Progenitors from the SVZ actively proliferate to generate neuronal precursors that migrate to the olfactory bulb and to sites of injury.
T88 537895-538010 Sentence denotes The ependymal cells, which cover the inside of the ventricles, are in direct contact with neural stem cells (NSCs).
T89 538011-538196 Sentence denotes Interestingly they express specifically the Coxsackie-Adenovirus Receptor (CAR), a 46 kDa transmembrane protein member of the immunoglobulin super family whose function remains unknown.
T90 538197-538315 Sentence denotes CAR is abundantly expressed in the brain during embryogenesis but is restricted to ependymal cells in the adult brain.
T91 538316-538420 Sentence denotes We found that CAR immunoreactivity was significantly modified following a broad range of brain infarcts.
T92 538421-538600 Sentence denotes Mass spectrometry analysis and co-immunoprecipitation of CAR from new born SVZ cell lysate revealed several associated proteins which may be involved in stem cell differentiation.
T93 538601-538702 Sentence denotes Furthermore, the proliferation of NSCs in vitro was modified by the presence of CAR in the substrate.
T94 538703-538816 Sentence denotes In conclusion, CAR is expressed by ependymal cells in the SVZ as an element of regulation of the NSCs activation.
T95 538817-538949 Sentence denotes Ependymal cells create a micro-environment in the SVZ maintaining the pluripotentiality of NSCs and controlling their proliferation.
T96 538950-538960 Sentence denotes Objective:
T97 538961-539045 Sentence denotes To investigate the mechanisms of human NSC (hNSCs) migration to sites of CNS injury.
T98 539046-539054 Sentence denotes Methods:
T99 539055-539107 Sentence denotes Migration studies were performed in Boyden chambers.
T100 539108-539264 Sentence denotes For in vivo studies, hNSCs were labeled with fluorescent cell tracker and injected in the ventricle of stroke animals that were euthanized 2-10 weeks later.
T101 539265-539385 Sentence denotes 3D Confocal reconstructions were used to correlate the migration of hNSCs to foci of pathology with expression of SDF-1.
T102 539386-539573 Sentence denotes In vitro, we measured the directional development of chain migration from neurospheres in the presence of ischemic and normal rat brain organotypical explant and with anti-CXCR4 antibody.
T103 539574-539709 Sentence denotes Results: hNSCs proliferate and migrate incrementally to in vitro addition of hSDF-1alpha ( pb0.001) and express cxcr4 mRNA and protein.
T104 539710-539813 Sentence denotes Exposure of hNSCs to hSDF-1alpha triggers phosphorylation of p38MAPK, p90RSK, ERK, IkappaB and Paxilin.
T105 539814-539978 Sentence denotes In vivo, hNSCs implanted in periventricular areas migrated towards the stroke regions, where astrocytes and endothelium upregulate SDF-1alpha (r=+0.6079, pb0.0001).
T106 539979-540067 Sentence denotes In vitro, neurospheres elaborate chains of nestin+cells with no apparent directionality.
T107 540068-540368 Sentence denotes When co-cultured with ischemic brain explants, 80% of the neurospheres elaborated, robust migratory chains of nestin+NSCs directed towards and into the explant compared with only 12% of the neurospheres co-cultured with non-ischemic explant and this directionality was inhibited by blockade of CXCR4.
T108 540369-540381 Sentence denotes Conclusions:
T109 540382-540577 Sentence denotes Our data implicate SDF-1/CXCR4 as a chemoattractant pathway for mammalian neural stem cells migration and provide new insights into the signals that activate neural stem cells molecular programs.
T110 540578-540716 Sentence denotes Bone marrow transfer experiments have shown that microglia is constantly renewed by precursor cells belonging to the hematopoietic system.
T111 540717-540782 Sentence denotes However, the exact identity of such precursors remains enigmatic.
T112 540783-540948 Sentence denotes We developed a culture system allowing the in vitro generation of microgliallike cells from bone marrow-derived myeloid precursors expanded in the presence of M-CSF.
T113 540949-541090 Sentence denotes We found that a subset of CD34+/CD11b+/MHC class II-cells give rise to microglial-like cells in the presence of glial cell conditioned media.
T114 541091-541245 Sentence denotes The differentiated cells present with phenotypical and morphological features of microglia as assessed by flow cytometry and scanning electron microscopy.
T115 541246-541461 Sentence denotes Interestingly, we observed that microglia derived from mixed glial cell cultures or from bone marrow myeloid precursors express CD34 (5% to 10% of cells) and the neural stem cell marker nestin (20% to 30% of cells).
T116 541462-541671 Sentence denotes Using a model of intracerebral viral infection with the canine distemper virus (CDV), we found that bone marrow derived microglial precursors are expanded in the bone marrow of infected versus control animals.
T117 541672-541839 Sentence denotes Moreover when these microglial precursors were labelled with CFSE and injected i.v. to CDV infected mice, they could be detected as isolated cells in brain parenchyma.
T118 541840-541879 Sentence denotes TREM-2 in the central nervous system C.
T119 541880-541893 Sentence denotes Buonsanti, M.
T120 541894-541905 Sentence denotes Mariani, F.
T121 541906-541917 Sentence denotes Benigni, P.
T122 541918-541930 Sentence denotes Di Lucia, S.
T123 541931-541943 Sentence denotes Smiroldo, L.
T124 541944-541958 Sentence denotes Adorini and P.
T125 541959-542155 Sentence denotes Panina-Bordignon Bioxell SpA, Milan, Italy TREM-2 is a cell surface molecule of the immunoglobulin superfamily that is expressed on monocyte-derived dendritic cells (DC) in association with DAP12.
T126 542156-542314 Sentence denotes TREM-2 cross-linking promotes DC migration and activation in vitro, suggesting that it may have a role in antigen presentation and T cell stimulation in vivo.
T127 542315-542461 Sentence denotes A genetic defect of human TREM-2 results in a rare genetic syndrome, the Nasu-Hakola disease, characterized by pre-senile dementia and bone cysts.
T128 542462-542610 Sentence denotes Furthermore, DAP12-deficient mice show decreased susceptibility to EAE induction and exhibit functional defects of oligodendrocytes and osteoclasts.
T129 542611-542761 Sentence denotes These observations have suggested that the array of myeloid cells regulated by TREM-2 may extend beyond DC, including microglial cells and osteoclats.
T130 542762-542860 Sentence denotes Here, we show that the TREM-2/DAP12 complex is selectively expressed on human and mouse microglia.
T131 542861-542958 Sentence denotes The expression of TREM-2 is down-regulated in brain upon intra-cerebral injection of LPS in mice.
T132 542959-543096 Sentence denotes Conversely, TREM-2 transcripts and protein are up-regulated in the spinal cord of mice with EAE induced by immunization with MOG peptide.
T133 543097-543199 Sentence denotes Work is in progress to evaluate the effect of TREM-2 blockade during EAE and LPS-induced encephalitis.
T134 543200-543385 Sentence denotes Staining with a soluble form of TREM-2 has revealed that both primary astrocytes and astrocytoma cell lines, either of mouse or human origin, express detectable levels of TREM-2 ligand.
T135 543386-543646 Sentence denotes Current data suggest that TREM-2 might modulate differentiation and activation of microglial cells, possibly by modulating responsiveness to certain cytokines or reinforcing signalling pathways triggered by cytokine receptors, integrins or chemokine receptors.
T136 543647-543770 Sentence denotes Evidence for distinct expression of pro-and anti-inflammatory cytokines within subsets of activated brain macrophages C.-F.
T137 543771-543780 Sentence denotes Calvo, E.
T138 543781-543794 Sentence denotes Amigou and J.
T139 543795-544084 Sentence denotes Glowinski INSERM U114, College de France, Paris, France The brain macrophage (BM) cell population already considered heterogeneous in terms of phenotype expression pattern also exert, upon activation, dual functions resulting in either beneficial or detrimental effects on neuron survival.
T140 544085-544272 Sentence denotes Our interest was to further characterize BM functional heterogeneity, by trying to show that production of pro-and anti-inflammatory cytokines would segregate in distinct BM cell subsets.
T141 544273-544564 Sentence denotes BM isolated from newborn (P1) mouse brain cell cultures were examined under bacterial lipopolysaccharide stimulation by intracellular immunofluorescence staining with specific antibodies to TNFalpha and IL10, as candidates of the proand anti-inflammatory families of cytokines, respectively.
T142 544565-544737 Sentence denotes By confocal microscopy, we showed that only 8% of the total cell population produced both cytokines, whereas 35% and 8% produced exclusively TNFalpha or IL10, respectively.
T143 544738-544879 Sentence denotes Using specific MAP kinase inhibitors, we showed by immunofluorescence and ELISA that these cell populations could be regulated independently.
T144 544880-545102 Sentence denotes Indeed, inhibition of the p38 MAP kinase by SB203580 inhibited both TNFalpha and IL10 production, while blockade of the p42/44 MAPK pathway by U0126 abolished the TNFalpha production but was without effect on that of IL10.
T145 545103-545227 Sentence denotes Altogether, these results show that BM response to a given stimulus represents the sum of independent cell subset responses.
T146 545228-545391 Sentence denotes We therefore postulate that the neurotrophic or neurotoxic function of BM is supported by the inflammatory nature of cytokines secreted by distinct subpopulations.
T147 545392-545494 Sentence denotes Microglial cells are bone marrow-derived antigen presenting cells involved in CNS immune surveillance.
T148 545495-545689 Sentence denotes Microglial function in the brain microenvironment comprises a wide range of activities from phagocytosis of apoptotic/necrotic cells to antigen processing and presentation to patrolling T cells.
T149 545690-546012 Sentence denotes Secreted cytokines can tune the functional capability of microglial cells by shaping them in fully competent antigen presenting cells through a bclassical activationQ or inducing a phenotype mostly associated with antiinflammatory process, healing and induction of tolerance which is often called balternative activationQ.
T150 546013-546184 Sentence denotes GM-CSF is a growth factor present only during inflammatory conditions in the adult brain which is also known to regulate the antigen presenting cell function of microglia.
T151 546185-546339 Sentence denotes In the current study, the regulation by GM-CSF of several proteins associated with either classical or alternative microglial activation was investigated.
T152 546340-546581 Sentence denotes Our results show that in murine microglia, GM-CSF induces not only primarily markers of classical activation but also some molecules involved with alternative activation, underlining its unique involvement in both pathways of APC activation.
T153 546582-546663 Sentence denotes Influence of PPAR-gamma agonists on prion-protein induced microglia activation S.
T154 546664-546674 Sentence denotes Wagner, R.
T155 546675-546686 Sentence denotes Mfssner, S.
T156 546687-546700 Sentence denotes Walter and K.
T157 546701-546936 Sentence denotes Fassbender University of Göttingen, Göttingen, Germany A pathophysiological hallmark of prion disease is chronic microglial activation, which is considered to contribute to progressive neuronal injury by release of neurotoxic products.
T158 546937-547196 Sentence denotes In Alzheimer's disease, also characterized by a microglial-induced proinflammatory response, the use of agonists to peroxisome proliferator-activated receptor gamma (PPARgamma) has been shown to reduce amyloid-beta stimulated cytokine expression by microglia.
T159 547197-547355 Sentence denotes We therefore analyzed the effect of drugs of the thiazolidindione class like rosiglitazone and troglitazone on the prionprotein-induced microglial activation.
T160 547356-547457 Sentence denotes Murine microglia or peritoneal macrophages were stimulated with fibrillar Prion protein (PrP)106-126.
T161 547458-547528 Sentence denotes The fibrillarity of the peptide was controlled by electron microscopy.
T162 547529-547622 Sentence denotes Control experiments consisted of stimulation with non-fibrillar PrP106-126 and PrP scrambled.
T163 547623-547914 Sentence denotes Stimulation of the cells with fibrillar PrP106-126 resulted in strong induction of expression of the pro-inflammatory cytokines interleukin 6 (IL-6) and tumor-necrose-factor alpha (TNFalpha) as measured by ELISA, whereas non-fibrillar and scrambled peptide had no effect on microglial cells.
T164 547915-548093 Sentence denotes Using PPAR-gamma agonists like Troglitazone, we were able to reduce up to 60% the PrP-induced expression of IL-6 and TNF-alpha by macrophages/microglia in a dosedependent manner.
T165 548094-548231 Sentence denotes These results indicate the use of PPAR-gamma agonists as a potential new therapeutic approach in prion-protein induced neuroinflammation.
T166 548232-548308 Sentence denotes Early cytoskeletal rearrangements occurring in activated microglial cells C.
T167 548309-548321 Sentence denotes Gallotti, L.
T168 548322-548336 Sentence denotes Grandbarbe, E.
T169 548337-548349 Sentence denotes Morga and P.
T170 548350-548360 Sentence denotes Heuschling
T171 548361-548552 Sentence denotes After stimulation with pro-inflammatory signals, microglia, the brain endogenous myeloid cell population, rapidly change their cell morphology in order to adopt the shape of phagocytic cells.
T172 548553-548774 Sentence denotes Using a cell line as well as primary rodent microgliocytes, we have studied the early modifications occurring in vitro at the level of the actin cytoskeleton, on actin-binding proteins, as well as on focal adhesion spots.
T173 548775-548888 Sentence denotes Morphometric analysis documents the rapid change in cell morphology over the first 6 h after activation with LPS.
T174 548889-549026 Sentence denotes Actin-fiber bundles as well as the actin-associated proteins l-plastin and alpha-actinin have been studied under fluorescence microscopy.
T175 549027-549123 Sentence denotes A link between cell morphology and the intracellular distribution of these proteins is observed.
T176 549124-549231 Sentence denotes The focal adhesion spotassociated proteins integrin beta1 and alpha6 as well as vinculin have been studied.
T177 549232-549405 Sentence denotes The disposition of adhesion spots changes after activation. lplastin, its phosphorylated form, and alpha-actinin are seen in close association with the focal adhesion spots.
T178 549406-549513 Sentence denotes Immuno-blot-analysis as well as RT-PCR has been used to study the kinetics of expression of these proteins.
T179 549514-549789 Sentence denotes The synthesis of l-plastin and especially its phosphorylation are tightly regulated during the first 30 min after activation, indicating that l-plastin and its post-translational changes are key elements during the morphological changes occurring after microglial activation.
T180 549790-549927 Sentence denotes Ischemia/reperfusion injury is associated with inflammatory responses that may play both deleterious and benefic role in neuronal damage.
T181 549928-550146 Sentence denotes FK506 (Tacrolimus) is an immunosuppressant that blocks an activation of immune system cells and exerts neuroprotective and neurotrophic action in traumatic brain injury, sciatic nerve injury, focal and global ischemia.
T182 550147-550388 Sentence denotes We found that neuroprotectant FK506 administered at 1 mg/kg, 60 min after MCAo (induced in male Wistar rats using the suture model) produced a significant reduction of IL-1beta, IL-6, and TNFalpha mRNA levels observed 12 h after reperfusion.
T183 550389-550506 Sentence denotes It was associated with a significant down-regulation of IL-1beta protein expression in microglia in the injured side.
T184 550507-550623 Sentence denotes We studied the influence of FK506 on microglia morphology and cytokine expression in LPS-activated microglial cells.
T185 550624-550709 Sentence denotes LPS-induced changes in microglia morphology were completely inhibited by 20 AM FK506.
T186 550710-550830 Sentence denotes Cultured microglia constitutively express cytokines; a basal level of cytokine mRNAs was observed in untreated cultures.
T187 550831-550995 Sentence denotes However, stimulation with LPS induced an expression of studied cytokines at 6 h and the most evident changes were observed in the levels of TNFalpha and IL-6 mRNAs.
T188 550996-551084 Sentence denotes Addition of 10 or 20 AM FK506 blocked the LPS-induced increases in cytokine mRNA levels.
T189 551085-551246 Sentence denotes Our findings suggest that microglial cells are targets for FK506 and modulation of inflammation may be a mechanism of FK506-mediated neuroprotection in ischemia.
T190 551247-551538 Sentence denotes In most neurodegenerative disorders, including multiple sclerosis, Parkinson's disease, and Alzheimer's disease, a massive neuronal cell death occurs as a consequence of an uncontrolled inflammatory response, where activated microglia and its cytotoxic agents play a crucial pathologic role.
T191 551539-551726 Sentence denotes Activated microglia secrete inflammatory mediators such as cytokines and chemokines, which contribute to the pathophysiological changes associated with several neuroimmunologic disorders.
T192 551727-551845 Sentence denotes Vasoactive intestinal peptide (VIP) is neuropeptide that function as potent anti-inflammatory factor in the periphery.
T193 551846-551928 Sentence denotes We investigated the effects of VIP on chemokine production by activated microglia.
T194 551929-552055 Sentence denotes VIP inhibited the expression of the microglia-derived CXC chemokines MIP-2 and KC, and of the CC chemokines MCP-1, and RANTES.
T195 552056-552160 Sentence denotes The inhibition of chemokine gene expression correlates with an inhibitory effect of VIP on NFkB binding.
T196 552161-552329 Sentence denotes The VIP inhibition of both chemokine production and of NFkB binding is mediated through the specific receptor VPAC1 and involves a cAMP-dependent intracellular pathway.
T197 552330-552589 Sentence denotes Of biological significance is the fact that the inhibition of chemokine production by VIP leads to a significant reduction in the chemotactic activity generated by activated microglia for peripheral leukocytes, i.e., neutrophils, macrophages, and lymphocytes.
T198 552590-552793 Sentence denotes VIP has a clear neuroprotective effect on inflammatory conditions by inhibiting the production of microglia-derived proinflammatory factors (tumor necrosis factor alpha, interleukin-1beta, nitric oxide).
T199 552794-553073 Sentence denotes Therefore, VIP represents an important factor in the control of inflammation in the central nervous system and emerges as a valuable neuroprotective agent for the treatment of pathologic conditions of the central nervous system where inflammationinduced neurodegeneration occurs.
T200 553074-553161 Sentence denotes Microglial cells are the intrinsic immunocompetent cells of the central nervous system.
T201 553162-553273 Sentence denotes Following brain injury, these cells are rapidly activated and transform from a resting into an activated state.
T202 553274-553496 Sentence denotes It is widely believed that substances released from damaged cells within the brain trigger this process and consequently lead to the long-term changes of microglial gene expression and reorganization of the cell phenotype.
T203 553497-553570 Sentence denotes Here, we have investigated how immunoglobulins activate microglial cells.
T204 553571-553681 Sentence denotes We found that immunoglobulins trigger dose-dependent microglial proliferation as well as nitric oxide release.
T205 553682-553802 Sentence denotes Furthermore, immunoglobulins led to cytokine release (TNF-alpha, IL-6) as well as changes in surface antigen expression.
T206 553803-553933 Sentence denotes Immunoglobulins are found in high concentrations in serum and could enter the CNS during periods of blood-brain barrier breakdown.
T207 553934-554089 Sentence denotes Microglia are innately refractory to nitric oxide-inducing stimuli, but acquire responsiveness following differentiation by colony-stimulating factors C.A.
T208 554090-554106 Sentence denotes Brannan and M.R.
T209 554107-554365 Sentence denotes Roberts Department of Microbiology and Medicine, University of Virginia, Charlottesville, VA, USA Microglia are the immunoregulatory cells of the central nervous system (CNS), and share many characteristics with resident macrophages in extracerebral tissues.
T210 554366-554566 Sentence denotes Macrophages secrete nitric oxide (NO) following NF-kappaB/IFN-dependent transcriptional activation of the NO synthase gene (NOS2) by stimuli elicited during a T cell response or by microbial products.
T211 554567-554732 Sentence denotes NO plays a key role in regulating both adaptive and innate immune responses, including inhibition of T cell proliferation and elimination of intracellular pathogens.
T212 554733-554804 Sentence denotes Regulation of NO production by microglia is poorly understood, however.
T213 554805-555020 Sentence denotes We find that microglia from healthy adult mice produce negligible amounts of NO compared to resident macrophages during restimulation of peptide-specific CD8 T cells, and therefore cannot block T cell proliferation.
T214 555021-555188 Sentence denotes The impaired NO response extends to all other NOS2-inducing stimuli, including cytokines, CD40 ligation, and lipopolysaccharide, and operates at the level of NOS2 RNA.
T215 555189-555344 Sentence denotes Microglia do produce proinflammatory cytokines in response to these stimuli however, and therefore possess a relatively selective block in NOS2 expression.
T216 555345-555460 Sentence denotes Furthermore, microglia acquire profound responsiveness to NO-inducers following differentiation by GM-CSF or M-CSF.
T217 555461-555614 Sentence denotes These factors are constitutively required for differentiation of macrophage populations in vivo, and increase in the CNS during inflammation and disease.
T218 555615-555827 Sentence denotes We therefore propose that microglia in the healthy adult brain exist in an bNO-incompetentQ state that may be reversed in the setting of CNS disease, thus facilitating temporal modulation of CNS immune responses.
T219 555828-555952 Sentence denotes There is increasing evidence that inflammatory activation of microglia has pathogenic influence on Alzheimer's disease (AD).
T220 555953-556210 Sentence denotes According to in vitro studies, microglia activated by amyloid-beta (Abeta) peptides have been reported to damage or kill neurons by the release of neurotoxic molecules such as tumor necrosis factor-alpha (TNF-alpha), nitric oxide or reactive oxygen species.
T221 556211-556402 Sentence denotes Whereas it has been reported that phagocytes which engulf apoptotic cells actively suppress the inflammatory response by releasing anti-inflammatory mediators such as prostaglandin E2 (PGE2).
T222 556403-556553 Sentence denotes Thus, it is tempting to speculate that activated microglia may change from proinflammatory to anti-inflammatory after phagocytosis of apoptotic cells.
T223 556554-556710 Sentence denotes In this study, we have attempted to elucidate effects of PS-liposomes, mimicking apoptotic cells, on the inflammatory response of Abeta-activated microglia.
T224 556711-556885 Sentence denotes Pretreatment of PS-liposomes significantly inhibited the release of both TNF-alpha and NO from microglial cells activated by Abeta combined with interferon-gamma (IFN-gamma).
T225 556886-556992 Sentence denotes PS-liposomes also reduced the expression of mRNA encoding TNF-alpha in Abeta/IFNgamma-activated microglia.
T226 556993-557254 Sentence denotes Furthermore, pretreatment of PS liposomes substantially decreased the generation of superoxide radicals associated with microglia activated by lipopolysaccharide (LPS) combined with phorbol 12-myristate 13-acetate (PMA) in electron spin resonance (ESR) spectra.
T227 557255-557342 Sentence denotes These results strongly suggest that PS-liposomes can be applied to the treatment of AD.
T228 557343-557543 Sentence denotes The stress hormones, glucocorticoids (GCs), and the key reproductive hormone, estrogen (E2), play a central role in neuroendocrine-immune crosstalk and have a major impact in astroglial cell function.
T229 557544-557845 Sentence denotes In the context of innate inflammatory mechanisms, a dysfunction of the astroglial cell compartment is believed to contribute to the selective degeneration of DA neurons in the substantia nigra pars compacta (SN) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's like syndrome.
T230 557846-558000 Sentence denotes Here, we show a chief role of hormonal programming of glial response to inflammation and oxidative stress in MPTP-induced loss of DA neuron functionality.
T231 558001-558262 Sentence denotes Studies carried out in transgenic (Tg) mice constitutively expressing a GR antisense RNA from early embryonic life establish a link between GRs and iNOS-derived NO and demonstrate that lack of GR regulation of NO exacerbates experimentally induced parkinsonism.
T232 558263-558818 Sentence denotes Studies carried out in female mice deprived of endogenous ovarian hormones show exacerbation of MPTPinduced loss of DA neuron function preceded by a strong astroglial activation and iNOS expression, resulting in massive death of astrocytes and neurons, whereas E2 replacement therapy sharply inhibits iNOS expression, counteracts astrocyte apoptosis and restores neurochemical parameters of DA neuron functionality, pointing to endogenous steroid hormones as prime modulators of iNOS inducibility and crucial checkpoints in MPTP-induced neuroinflammation.
T233 558819-558960 Sentence denotes The Notch pathway is a fundamental cell interaction mechanism that influences cell fate decision by interactions between cellular neighbours.
T234 558961-559119 Sentence denotes In recent years, it has been shown that the Notch signaling plays a crucial role in the differentiation process of monocytes, macrophages and dendritic cells.
T235 559120-559194 Sentence denotes In the normal brain tissue, microglial cells are found as quiescent cells.
T236 559195-559335 Sentence denotes Upon appropriate stimulation though, they continue the previously halted differentiation process to become immunocompetent phagocytic cells.
T237 559336-559431 Sentence denotes In the present study, we examine the involvement of Notch pathway in the microglial activation.
T238 559432-559610 Sentence denotes Modulation of Notch signaling by a soluble form of ligand (Jagged1) indicates that Notch signaling is functional in a murine microglial cell line as well as in primary microglia.
T239 559611-559719 Sentence denotes Our data show that Notch activation modulates the expression of proinflammatory cytokines such as TNF-alpha.
T240 559720-559962 Sentence denotes Moreover, in an attempt to modulate these neurotoxic properties of activated microglial cells, we have undertaken the characterization of pharmacological properties of hybrid compounds combining an alkanol structure and an antioxidant moiety.
T241 559963-560063 Sentence denotes This compound modulates, via the Notch pathway, the pro-inflammatory activation of microglial cells.
T242 560064-560172 Sentence denotes Together, these results suggest that Notch signaling, has important immunomodulatory functions in the brain.
T243 560173-560243 Sentence denotes Regulation of astrocytic cell response by P2Y2 nucleotide receptors N.
T244 560244-560259 Sentence denotes Chorna a , G.A.
T245 560260-560278 Sentence denotes Weisman b and A.F.
T246 560279-560530 Sentence denotes Gonzalez a a University of Puerto Rico, San Juan, Puerto Rico, USA; b University of Missouri-Columbia, Missouri, USA Immuno-regulatory properties of astrocytes and glial cells and their role in neurogenesis in response to tissue damage remain unknown.
T247 560531-560836 Sentence denotes It is recognized that activation of G-protein coupled P2Y2 nucleotide receptors by ATP or UTP upon injury or inflammation stimulate intense signaling between astrocytes, microglia, oligodendrocytes, and neurons (Neary et al., 1996 (Neary et al., , 1999 Burnstock and Williams, 2000; Chorna et al., 2003) .
T248 560837-561093 Sentence denotes We found that activation of P2Y2 receptors in 1321N1 astrocytoma cells transfected with human P2Y2 receptor, coupled to the p38 and ERK1/2dependent phosphorylation of CREB kinase triggered CRE-dependent upregulation of cell survival genes bcl-2 and bcl-xL.
T249 561094-561363 Sentence denotes Additionally, using cDNA microarray analysis and RT-PCR, P2Y2 receptors were found to up-regulate the expression of genes for neurotrophins, neuropeptides and growth factors including nerve growth factor-2; neurotrophins 3,4,5 and glia-derived neurite-promoting factor.
T250 561364-561500 Sentence denotes Moreover, conditioned media from UTP-treated 1321N1 cells expressing P2Y2 receptors stimulated the outgrowth of neurites in PC-12 cells.
T251 561501-561763 Sentence denotes Nucleotides mediated release of neurotrophins and activation of CRE-dependent cell survival response may be assumed as a solid rationale for the possible use of P2Y2 receptors in the development of new therapeutic strategies in immune and neurological disorders.
T252 561764-561841 Sentence denotes The calcium channel TRPC4 co-localizes with ZO-1 in human fetal astrocytes X.
T253 561842-561850 Sentence denotes Song, Y.
T254 561851-561864 Sentence denotes Zhao and C.F.
T255 561865-562178 Sentence denotes Brosnan Albert Einstein College of Medicine, New York, USA Members of the mammalian transient receptor potential (TRP) family form cation-permeable channels at the plasma membrane implicated in capacitative calcium influx following activation by either second-messengermediated pathways and/or by store depletion.
T256 562179-562326 Sentence denotes We now show by RT-PCR, Western blotting and immunohistochemistry that resting astrocytes express TRPC4, particularly at sites of cell-cell contact.
T257 562327-562503 Sentence denotes By confocal imaging and immunoelectron microscopy, we detected co-localization of TRPC4 with the junctional protein ZO-1 and demonstrated association by co-immunoprecipitation.
T258 562504-562653 Sentence denotes It has been proposed that the targeting of TRPC4 to the cell membrane is dependent upon the interaction of the C-terminal TRL motif with PDZ domains.
T259 562654-562887 Sentence denotes Using transfection of astrocytes with myc-tagged TRPC4 or TRL-motif truncated TRPC4 (deltaTRL), we found that deltaTRL localized to a juxtanuclear compartment, whereas the wild-type channel showed prominent cell surface distribution.
T260 562888-563008 Sentence denotes Deletion of the TRL motif also reduced plasma membrane expression as assessed by cell surface biotinylation experiments.
T261 563009-563167 Sentence denotes Using GST fusion proteins, we found that TRPC4 interacted with the PDZ1 domain of ZO-1 and that this interaction was lost in constructs missing the TRL motif.
T262 563168-563285 Sentence denotes Thus, our data demonstrate that the PDZ-interacting domain of TRPC4 controls its localization and surface expression.
T263 563286-563501 Sentence denotes Since ZO-1 also interacts with the gap junction protein 43, these data implicate TRPC4 as part of the signaling complex that forms between astrocytes and which is lost in astrocytes activated with the cytokine IL-1.
T264 563502-563577 Sentence denotes Characterisation of the Jagged-Notch-Hes pathway on activated astrocytes E.
T265 563578-563587 Sentence denotes Morga, L.
T266 563588-563602 Sentence denotes Grandbarbe, K.
T267 563603-563616 Sentence denotes Hemmer and P.
T268 563617-563676 Sentence denotes Heuschling Université du Luxembourg, Luxembourg, Luxembourg
T269 563677-563841 Sentence denotes It has been shown that the Jagged-Notch-Hes pathways are implicated in many aspects of the CNS development and functions, including differentiation and myelination.
T270 563842-563945 Sentence denotes During development Jagged1 is down-regulated, oligodendrocyte precursors mature and myelination begins.
T271 563946-564040 Sentence denotes Human oligodendrocyte maturation is blocked in the presence of cells transfected with Jagged1.
T272 564041-564184 Sentence denotes In inflamed MS tissue, Jagged1 is expressed by reactive astrocytes whereas astrocytes in myelinated areas do not show Jagged1 immunoreactivity.
T273 564185-564346 Sentence denotes In an attempt to modulate the expression of Jagged1 on astrocytes, we have undertaken the characterization of different elements of the Jagged-Notch-Hes pathway.
T274 564347-564462 Sentence denotes In this part of our work, we studied the expression of these different elements after activation of the astrocytes.
T275 564463-564575 Sentence denotes To induce the activation of the astrocytes, we used LPS or a simultaneous incubation of IFN-gamma and TNF-alpha.
T276 564576-564729 Sentence denotes LPS induces an up-regulation of ligands like Jagged1 and DeltaII but down-regulates the expression of Notch1, interestingly LPS also down-regulates Hes1.
T277 564730-564830 Sentence denotes In the presence of IFN-gamma and TNF-alpha astrocytes inhibit their expression of Notch1 and Notch2.
T278 564831-564937 Sentence denotes The simultaneous incubation with these two cytokines does not induce a clear up-regulation of the ligands.
T279 564938-564995 Sentence denotes IFN-gamma+TNF-alpha also inhibits the expression of Hes1.
T280 564996-565119 Sentence denotes Taken together, these preliminary results could have interesting issues on the understanding of this pathway on astrocytes.
T281 565120-565235 Sentence denotes In fact, a better understanding of the expression of Notchligands can be a helpful tool for demyelinating diseases.
T282 565236-565368 Sentence denotes Dexamethasone increases astrocyte immunoreactivity to GFAP following ethidium bromide injection in the brainstem of Wistar rats M.A.
T283 565369-565381 Sentence denotes Lallo and E.
T284 565382-565553 Sentence denotes Bondan Universidade Bandeirante de Sao Paulo, Sao Paulo, Brasil Ethidium bromide (EB) is a gliotoxic agent that causes focal astrocytic and oligodendroglial disappearance.
T285 565554-565821 Sentence denotes As immunosuppressive and anti-inflammatory drugs are known to modify glial expression, this study was designed to investigate astrocyte immunoreactivity to Glial Fibrillary Acidic Protein (GFAP) after EB injection in animals submitted to dexamethasone (DX) treatment.
T286 565822-565966 Sentence denotes Adult Wistar rats were injected into cisterna pontis with 0.1% EB and received DX (3 mg/kg/day, intraperitonial route-group 1) or not (group 2).
T287 565967-566069 Sentence denotes Some were injected with 0.9% saline solution and were also treated with DX (group 3) or not (group 4).
T288 566070-566204 Sentence denotes Brainstem samples were collected from 24 h to 31 days post-injection for GFAP immunohistochemical staining using avidin-biotin method.
T289 566205-566354 Sentence denotes In groups 1 and 2, extensive lesions were seen in the pons and mesencephalon, with astrocyte disappearance from the central area 24 h post-injection.
T290 566355-566439 Sentence denotes Macrophagic infiltration and peripheral astrocytic reaction were noted after 3 days.
T291 566440-566578 Sentence denotes Marginal astrocytes presented increased immunoreactivity to GFAP and DX-treated animals presented a greater number of GFAP-positive cells.
T292 566579-566749 Sentence denotes In groups 3 and 4, discrete pontine lesions were observed, showing central astrocyte preservation and a peripheral GFAP staining less intense comparing to groups 1 and 2.
T293 566750-566843 Sentence denotes No difference was found in GFAP immunostaining between groups 3 and 4 after saline injection.
T294 566844-566983 Sentence denotes Astrocytes from the edges of the EB-induced lesions presented increased immunoreactivity to GFAP and DX seemed to increase this expression.
T295 566984-567053 Sentence denotes Changes in gene expression induced by activation of P2X7 receptors C.
T296 567054-567075 Sentence denotes Santos-Berrios a , N.
T297 567076-567089 Sentence denotes Chorna a , G.
T298 567090-567106 Sentence denotes Weisman b and F.
T299 567107-567425 Sentence denotes Gonzalez a a University of Puerto Rico, San Juan, Puerto Rico; b University of Missouri, Missouri, USA Activated lymphocytes, macrophages, microglia, and platelets, as well as cells undergoing necrosis or apoptosis, release high concentrations of nucleotide diphosphates and triphosphates into the extracellular space.
T300 567426-567543 Sentence denotes Astrocytes respond to extracellular nucleotides that are released upon nerve stimulation or from damaged brain cells.
T301 567544-567608 Sentence denotes P2 receptors mediate the responses to extracellular nucleotides.
T302 567609-567747 Sentence denotes From this family of receptors, two subtypes are known-the G protein-coupled P2Y receptors and the ligand-gated ion channels P2X receptors.
T303 567748-567927 Sentence denotes In this study, we tested the hypothesis that activation of P2X7 receptors with BzATP, an analog of ATP, leads to the modulation of the expression of genes related to inflammation.
T304 567928-568020 Sentence denotes Our results show a time-and dose-dependent increase in the expression for cox and cfos mRNA.
T305 568021-568165 Sentence denotes Studies made with cDNA microarrays before and after activation of P2X7 receptors revealed additional genes that were modulated by this receptor.
T306 568166-568381 Sentence denotes Our findings will help us better understand the role of nucleotide receptors in inflammatory responses in the nervous system, information that is bound to have pharmacological applications and clinical significance.
T307 568382-568457 Sentence denotes ADAMTS-1, -4 and -5 are members of the ADAMTS family of metalloproteinases.
T308 568458-568644 Sentence denotes ADAMTS substrates include extracellular matrix (ECM) components, aggrecan, versican and brevican, which form part of CNS ECM, therefore these enzymes may have a role in CNS ECM turnover.
T309 568645-568694 Sentence denotes ADAMTS-1 and -4 exhibit anti-angiogenic activity.
T310 568695-568794 Sentence denotes Tissue inhibitor of metalloproteinase-3 (TIMP-3) is a naturally occurring inhibitor of the ADAMTSs.
T311 568795-569003 Sentence denotes The involvement of ADAMTSs in the pathology of multiple sclerosis (MS) and stroke may include a role in ECM breakdown, demyelination, and prevention of remyelination and in stroke, prevention of angiogenesis.
T312 569004-569177 Sentence denotes The expression of ADAMTS-1, -4 and -5 was studied in primary human astrocytes at the mRNA and protein level using real time RT-PCR, western blotting and immunocytochemistry.
T313 569178-569275 Sentence denotes Cells were untreated or treated with pro-inflammatory cytokines IL-1-beta, TNF-alpha and TGFbeta.
T314 569276-569363 Sentence denotes Increased expression of ADAMTS-1 was seen following treatment with all three cytokines.
T315 569364-569423 Sentence denotes ADAMTS-4 expression was increased by TGFbeta and TNF-alpha.
T316 569424-569457 Sentence denotes TIMP-3 was increased by TGF-beta.
T317 569458-569670 Sentence denotes This data indicates that during inflammation there is an imbalance in ADAMTS and TIMP3 expression, which could cause increased enzyme activity resulting in breakdown of the CNS ECM and prevention of angiogenesis.
T318 569671-569714 Sentence denotes This work was funded by the Wellcome Trust.
T319 569715-569852 Sentence denotes Neuroinflammation and oxidative stress up-regulate and translocate multidrug resistance-associated protein 1 (Mrp1) in mouse astroglia F.
T320 569853-569867 Sentence denotes Gennuso a , C.
T321 569868-569881 Sentence denotes Tirolo a , N.
T322 569882-569894 Sentence denotes Testa a , S.
T323 569895-569910 Sentence denotes Caniglia a , F.
T324 569911-569930 Sentence denotes L'Episcopo a , M.C.
T325 569931-569944 Sentence denotes Morale a , C.
T326 569945-569960 Sentence denotes Fernetti b , L.
T327 569961-569975 Sentence denotes Pascolo b , D.
T328 569976-569989 Sentence denotes Ostrow c , C.
T329 569990-570008 Sentence denotes Tiribelli b and B.
T330 570009-570342 Sentence denotes Marchetti a,d a Neuropharmacology, OASI, Troina, Italy; b Biochemistry, University of Trieste, Trieste, Italy; c Washington University, Seattle, USA; d Pharmacology, University of Sassari, Sassari, Italy Multidrug resistance associated proteins (MRPs) are ATP-driven export pumps that mediate the export of organic anions from cells.
T331 570343-570480 Sentence denotes Various MRP family members including Mrp1 are expressed in enriched astrocytes, microglia, oligodendrocytes and neuronal rodent cultures.
T332 570481-570728 Sentence denotes Mrp1 is also expressed in two CNS barriers, the endothelial cells of brain microvessels and the epithelial cells of the choroid plexus and its importance in preventing CNS accumulation of various xenobiotics has been demonstrated in knockout mice.
T333 570729-570870 Sentence denotes The Golgi apparatus has been recently shown to represent a key station involved in the intracellular trafficking of Mrp1 in mouse astrocytes.
T334 570871-571176 Sentence denotes Here, we report that Mrp1 is differentially expressed in resting vs. activated astrocytes and microglia and that exposure to oxidative/nitrosative stress, such as serum deprivation and lipopolysaccharide (LPS), time-and dose-dependently up-regulate Mrp1 expression and induce extensive membrane targeting.
T335 571177-571479 Sentence denotes At a functional level, this effect is accompanied by enhanced Fluo-3-extruding activity and reduction of intracellular reactive oxygen species accumulation, whereas exposure to Mrp1 inhibitor MK571 sharply impaired such phenomena, implicating glial Mrp1 as a key redox sensor during brain inflammation.
T336 571480-571546 Sentence denotes Receptor machinery involved in MBP-induced astrocyte activation R.
T337 571547-571562 Sentence denotes Businaro a , L.
T338 571563-571579 Sentence denotes Fumagalli a , S.
T339 571580-571596 Sentence denotes Leone b and G.M.
T340 571597-571678 Sentence denotes Lauro b a University La Sapienza, Rome, Italy; b University Roma TRE, Rome, Italy
T341 571679-571936 Sentence denotes The object of the present study is to identify the receptor(s) involved in myelin basic protein (MBP) uptake and to evaluate their role in the subsequent MBP processing and presentation by human astroglial cells: central events in the demyelinating process.
T342 571937-572160 Sentence denotes Our study deals with cultured astroglial cells, stimulated with MBP or its peptide fragments in order to evaluate heme oxygenase-1 (HO-1) and HLA class II antigen expression by cytometric analysis, RT-PCR and Western blots.
T343 572161-572329 Sentence denotes Our attention was focused on the role of bFGF receptors, GM1 ganglioside and low-density lipoprotein receptor-related protein (LRP), detected into astroglial membranes.
T344 572330-572574 Sentence denotes Our experiments, performed in the presence or in the absence of specific inhibitors of the above-mentioned putative receptors, suggest that MBP, carried by alpha2-macroglobulin, binds to LRP, undergoing subsequent receptor-mediated endocytosis.
T345 572575-572687 Sentence denotes This mechanism may represent the first step of antigen processing and presentation function in astrocytic cells.
T346 572688-572801 Sentence denotes Monocarboxylates like lactate are provided by astrocytes and can be used as fuel by neurons and oligodendrocytes.
T347 572802-573050 Sentence denotes In primary Lewis rat astrocytes, coculture with MHC class II-restricted myelin basic protein (MBP)-specific T cells resulted in a marked upregulation of the astrocytic lactate transporter MCT1 that is to export lactate into the extracellular space.
T348 573051-573148 Sentence denotes It was evident that the increase in MCT1 was triggered by T cells in an antigen-dependent manner.
T349 573149-573241 Sentence denotes The glial isoform of the glucose transporter GLUT1 was not regulated under these conditions.
T350 573242-573393 Sentence denotes T cell blasts that had been pre-activated by antigen and splenic antigen presenting cells (APCs) beforehand also led to an increase in astrocytic MCT1.
T351 573394-573544 Sentence denotes Even resting T cells stimulated the expression of MCT1 when anti-MHC class II-, but not when anti-MHC class I-antibodies were added to the co-culture.
T352 573545-573655 Sentence denotes Therefore, complexation of MHC class II molecules on astrocytes might be mandatory for the regulation of MCT1.
T353 573656-573834 Sentence denotes Consistent with the in vitro-experiments, an upregulation of MCT1 was observed in the spinal cord of autoimmune encephalitic rats while GLUT1 expression appeared to be unchanged.
T354 573835-574035 Sentence denotes This T cell-mediated regulation of MCT1 might contribute to a compensatory or protective mechanism in order to guarantee substrate pools for neurons and oligodendrocytes under inflammatory conditions.
T355 574036-574238 Sentence denotes While we have recently described that contact with astrocytes induces development of regulatory T cells, in the present study we investigated the mechanisms responsible for their suppressive properties.
T356 574239-574458 Sentence denotes Pre-incubation with astrocytes rendered rat T cells completely unresponsive to mitogenic stimuli, which coincided with the block in G0/G1 phase of the cell cycle and the increase in number of subdiploid apoptotic cells.
T357 574459-574633 Sentence denotes These anergic cells completely prevented mitogen-or antigen-induced growth of T lymphocytes, with the suppressive activity residing in both CD4+ and CD8+ T cell compartments.
T358 574634-574799 Sentence denotes The observed inhibitory effect was not mediated by the immunosuppressive factors released from apoptotic cells, but apparently required metabolically active T cells.
T359 574800-575074 Sentence denotes Heat-sensitive and protein synthesis inhibition-sensitive soluble T cell factors, not including TGF-beta or IL-10, were solely responsible for the observed suppression, which did not depend either on nitric oxide production, prostaglandin release, or tryptophan consumption.
T360 575075-575313 Sentence denotes Interestingly, the soluble T cell products induced by contact with astrocytes were also able to transfer the suppressive activity to bnormalQ T cells, which could explain the extremely high potency of astrocyte-induced suppressor T cells.
T361 575314-575518 Sentence denotes Finally, the cells with suppressive properties were readily generated upon contact of astrocytes and human T lymphocytes, indicating their potential therapeutic value in the treatment of CNS autoimmunity.
T362 575519-575652 Sentence denotes Inhibition of calpain activity and expression by interferon-beta in rat astrocytes: implications for MS pathogenesis and treatment T.
T363 575653-575669 Sentence denotes Latronico a , V.
T364 575670-575684 Sentence denotes Piscopo a , A.
T365 575685-575698 Sentence denotes Fasano a , P.
T366 575699-575716 Sentence denotes Riccio b and M.G.
T367 575717-575853 Sentence denotes Liuzzi a a Department of Biochemistry and Molecular Biology, University of Bari, Bari, Italy; b University of Basilicata, Potenza, Italy
T1 575854-576129 Sentence denotes Calpains are a family of calcium-activated proteases that have been recently implicated in multiple sclerosis (MS) pathogenesis for both their ability to degrade myelin proteins and for their presence, at increased levels, in activated glial/inflammatory cells of MS plaques.
T2 576130-576280 Sentence denotes Aim of this study was to investigate whether interferon-beta (IFN-beta), could modulate the activity and/or the expression of m-calpain in astrocytes.
T3 576281-576387 Sentence denotes Rat astrocyte cultures were activated with LPS and simultaneously treated with different doses of IFNbeta.
T4 576388-576633 Sentence denotes Culture supernatants and cellular extracts collected from astrocytes were subjected to casein-zymography and the presence of m-calpain activity was determined, after scanning densitometry, by the extent of casein degradation compared to control.
T5 576634-576736 Sentence denotes Total RNA was extracted from glial cells and subjected to RT-PCR using primers specific for m-calpain.
T6 576737-576906 Sentence denotes Increased activity of m-calpain was observed in cellular extracts from LPStreated astrocytes in comparison with cellular extracts from non-treated cells (control cells).
T7 576907-577038 Sentence denotes On the contrary, dose-dependent inhibition of mcalpain activity was observed in cellular extracts from IFN-beta-treated astrocytes.
T8 577039-577186 Sentence denotes RT-PCR revealed that the expression of m-calpain was increased in LPS-activated astrocytes and was dose-dependently inhibited by IFNbeta treatment.
T9 577187-577414 Sentence denotes These results suggest that IFN-beta could modulate the expression of calpains in astrocytes and this effect could represent an additional mechanism by which IFN-beta decreases the development of new CNS lesions in course of MS.
T10 577415-577566 Sentence denotes Within the central nervous system (CNS) in multiple sclerosis (MS), increased expression of two key chemokines, CXCL10 and CCL2, has been demonstrated.
T11 577567-577719 Sentence denotes These chemoattractants are involved in the recruitment into the CNS of T cells and monocytes, which express the corresponding receptors, CXCR3 and CCR2.
T12 577720-577843 Sentence denotes In the cerebrospinal fluid (CSF) of MS patients at times of relapse, there is an increase in CXCL10 and a decrease in CCL2.
T13 577844-578049 Sentence denotes To further understand these in vivo findings, we have investigated the expression of CXCL10 and CCL2 by primary adult human astrocytes in vitro following treatment with pro-and anti-inflammatory cytokines.
T14 578050-578213 Sentence denotes Secreted chemokine was measured by ELISA, cell-associated chemokine was visualised by immunofluorescent confocal microscopy and mRNA was measured by real-time PCR.
T15 578214-578339 Sentence denotes Interferon gamma (10 ng/ml) induced the secretion of CXCL10 and CCL2 at 24 h with levels of 205 and 1853 pg/ml, respectively.
T16 578340-578440 Sentence denotes TNF alpha (10 ng/ml) had no effect on CXCL10 expression but increased release of CCL2 to 1313 pg/ml.
T17 578441-578478 Sentence denotes Increases in mRNA were also observed.
T18 578479-578526 Sentence denotes TGF beta had no effect on chemokine expression.
T19 578527-578666 Sentence denotes The fine control of chemokine expression by cytokines may explain the different chemokine expression profiles in the CSF in people with MS.
T20 578667-578749 Sentence denotes Expression and functional role of Toll-like receptors (TLR) on human astrocytes M.
T21 578750-578763 Sentence denotes Bsibsi a , C.
T22 578764-578783 Sentence denotes Persoon-Deen a , R.
T23 578784-578917 Sentence denotes Ravid b and H. van Noort a a TNO Prevention and Health, Leiden, The Netherlands; b Netherlands Brain Bank, Amsterdam, The Netherlands
T24 578918-578929 Sentence denotes Background:
T25 578930-579122 Sentence denotes Toll-like receptors play key roles in the recognition of invariant pathogen-associated molecules by the innate immune system and generally mediate pro-inflammatory responses to these agonists.
T26 579123-579300 Sentence denotes We previously showed expression of various TLR family members on glial cells in the human central nervous system (CNS) and elevated levels of these TLR during neuroinflammation.
T27 579301-579379 Sentence denotes Yet the functional significance of TLR in the CNS is still largely unexplored.
T28 579380-579390 Sentence denotes Objective:
T29 579391-579547 Sentence denotes To investigate regulation of TLR expression on cultured human astrocytes, and to evaluate the functional response of astrocytes to appropriate TLR agonists.
T30 579548-579556 Sentence denotes Methods:
T31 579557-579673 Sentence denotes Human astrocytes were isolated from post-mortem brains of healthy donors and treated with cytokines or TLR agonists.
T32 579674-579751 Sentence denotes To monitor TLR expression, TLR-encoding mRNA was quantified by real-time PCR.
T33 579752-579914 Sentence denotes To monitor functional responses, levels of mRNA encoding 268 genes for cytokines, chemokines, growth factors and their receptors were monitored using cDNA arrays.
T34 579915-579939 Sentence denotes Results and conclusions:
T35 579940-580010 Sentence denotes Selective TLR induction was observed in astrocytes by various stimuli.
T36 580011-580190 Sentence denotes Surprisingly, activation of inducible TLR on astrocytes led to induction of several chemotactic factors along with a variety of mediators with known functions in repair processes.
T37 580191-580272 Sentence denotes TLR activation in general did not activate a polarized pro-inflammatory response.
T38 580273-580392 Sentence denotes Together, these data suggest that astroglial TLR play a role in repair functions rather than in promoting inflammation.
T39 580393-580537 Sentence denotes MoMuLV-ts1-mediated neuronal degeneration in mice is a model for human immunodeficiency virus (HIV)-induced neurodegenerative disease in humans.
T40 580538-580740 Sentence denotes In this study, we show increased expression of cyclooxygenase-2 (COX-2), an enzyme known to be associated with inflammatory and neurodegenerative diseases, in the brainstem tissues of ts1-infected mice.
T41 580741-580879 Sentence denotes In sections of the same tissues, we find that astrocytes in areas of spongiform lesions contain increased amounts of immunoreactive COX-2.
T42 580880-581128 Sentence denotes COX-2 is also upregulated in ts1-infected cultured astrocytes, but this effect is significantly decreased by treatment of the cells with curcumin and by SP600125, both of which specifically inhibit the c-Jun N-terminal kinases (JNKs)/c-Jun pathway.
T43 581129-581297 Sentence denotes By contrast, PD98059, MG-132, ALLN, and lactacystin, which inhibit extracellular signal-regulated kinase (ERK) activation, and proteasome activity, have no such effect.
T44 581298-581421 Sentence denotes These data point to the JNK/c-Jun pathway as the mechanism by which COX-2 expression is induced in ts1-infected astrocytes.
T45 581422-581747 Sentence denotes Notably, curcumin also decreases levels of (a) CCAAT/en-hancer-binding protein (CHOP), (b) glucose-related protein 78 (GRP78) and (c) phosphorylated eukaryotic initiation factor 2a (eIF2a), all of which are markers of endoplasmic reticulum (ER) stress signaling, and are upregulated in untreated C1 cells after ts1 infection.
T46 581748-581856 Sentence denotes These findings link ER stress signaling in ts1-infected astrocytes to events that result in COX-2 induction.
T47 581857-581932 Sentence denotes Tuberculous meningitis and astrocyte derived matrix metalloproteinases J.E.
T48 581933-581945 Sentence denotes Harris, J.S.
T49 581946-582160 Sentence denotes Friedland Imperial College, London, UK Tuberculous meningitis (TBM) is the most deadly form of tuberculous infection, its pathology is characterised by extensive destruction of central nervous system (CNS) tissues.
T50 582161-582279 Sentence denotes Matrix metalloproteinase-9 (MMP-9) has been implicated in tissue destruction in a range of CNS diseases including TBM.
T51 582280-582494 Sentence denotes Astrocytes are the most populous cell-type in the CNS, therefore astrocyte-derived matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) maybe key mediators of CNS tissue destruction.
T52 582495-582660 Sentence denotes In the present study, the regulation of gene expression and secretion of MMP-9 and key TIMPs are analysed using zymography, ELISAs, western blots and northern blots.
T53 582661-582844 Sentence denotes Over 120 hours astrocytes, stimulated with conditioned media from infected monocytes secreted 6-fold more MMP-9 than controls with concentrations rising to a maximum of 1273796 units.
T54 582845-582947 Sentence denotes TIMP-1 and TIMP-2 concentrations were not significantly different from controls over the study period.
T55 582948-583174 Sentence denotes The upregulation of MMP-9 was inhibited by a combination of anti-TNF-alpha, IL-1 receptor antagonist and pertussis toxin which blocks G protein-linked processes; such inhibition was not seen in response to a single inhibitors.
T56 583175-583262 Sentence denotes TNF-alpha induced MMP-9 expression in astrocytes, while IL-1 and cholera toxin did not.
T57 583263-583493 Sentence denotes These data suggest that networks active between astrocytes and monocytes play a key role in creating a matrix degrading environment during TBM and that a combination of mediators are involved with TNFalpha, having a critical role.
T58 583494-583673 Sentence denotes Astrocyte-expressed tissue inhibitor of metalloproteinase (TIMP)-1 is an important molecule in CNS homeostasis and inflammatory diseases including HIV-1-associated dementia (HAD).
T59 583674-583787 Sentence denotes Recently, TIMP-1 has emerged as a multifunctional molecule promoting cell survival in addition to MMP regulation.
T60 583788-583871 Sentence denotes Previously, we uniquely demonstrated that HAD brains have reduced levels of TIMP-1.
T61 583872-584004 Sentence denotes Astrocyte-TIMP-1 expression is differentially regulated with elevated levels in acute and diminished levels in chronic inflammation.
T62 584005-584093 Sentence denotes These observations indicate that TIMP-1 replenishment in HAD may have therapeutic value.
T63 584094-584213 Sentence denotes Laboratory and animal model systems were used to examine mechanisms of astrocyte-TIMP-1 regulation and neuroprotection.
T64 584214-584356 Sentence denotes Human astrocytes/neurons, neurotoxins, virus/viral proteins, TIMP-1 promoter-luciferase reporter constructs and RNAi gene silencing were used.
T65 584357-584489 Sentence denotes Preliminary data confirm that acute versus chronic TIMP-1 responses in astrocytes are regulated predominantly at the promoter level.
T66 584490-584593 Sentence denotes Neurotoxicity and/or neuroprotection were measured by MTT activity, TUNEL, and DNA fragmentation ELISA.
T67 584594-584703 Sentence denotes TIMP-1 siRNA-transfected astrocytes had enhanced neurotoxicity that correlated with diminished TIMP-1 levels.
T68 584704-584776 Sentence denotes TIMP-1 treatment partially reversed neurotoxicity in challenged neurons.
T69 584777-584911 Sentence denotes In addition, TIMP-1 supported neuronal differentiation during early development suggesting that TIMP-1 may function as a neurotrophin.
T70 584912-585052 Sentence denotes TIMP-1-neuroprotection may be mediated by activation of anti-apoptotic proteins such as Bcl-2/Bcl-xL and/or through neurotrophic activities.
T71 585053-585156 Sentence denotes Our results indicate that the complex astrocyte-TIMP-1 regulation in HAD may influence neuroprotection.
T72 585157-585276 Sentence denotes These studies are relevant to glial inflammation in HAD and may unravel novel mechanisms of glialneuronal interactions.
T73 585277-585385 Sentence denotes Vagus nerve prevents systemic inflammation by inhibiting TNF transcription in the spleen via alpha7 nAChR L.
T74 585386-585395 Sentence denotes Ulloa, H.
T75 585396-585404 Sentence denotes Liao, V.
T76 585405-585415 Sentence denotes Pavlov, M.
T77 585416-585431 Sentence denotes Ochani and K.J.
T78 585432-585729 Sentence denotes Tracey North Shore University Hospital, Long Island Jewish Research Institute, Manhasset, NY, USA Endotoxin, a constituent of Gram-negative bacteria, stimulates macrophages to release pro-inflammatory cytokines including tumor necrosis factor (TNF), which can cause lethal shock and tissue injury.
T79 585730-585840 Sentence denotes We have recently discovered that vagus nerve stimulation attenuates circulating TNF levels during endotoxemia.
T80 585841-586023 Sentence denotes This mechanism was named bthe cholinergic anti-inflammatory pathwayQ because acetylcholine, the principle neurotransmitter of the vagus nerve, inhibits TNF production in macrophages.
T81 586024-586126 Sentence denotes The object of this study is to determine how vagus nerve regulates TNF production in different organs.
T82 586127-586262 Sentence denotes Here we report that stimulation of the vagus nerve prevents lethal systemic inflammation by inhibiting TNF transcription in the spleen.
T83 586263-586411 Sentence denotes Splenectomy attenuates circulating TNF levels during endotoxemia (sham=181.3F31 pg TNF/ ml serum vs. splenectomy=41.2F13.4 pg TNF/ml serum; pb0.05).
T84 586412-586509 Sentence denotes Vagus nerve stimulation fails to further attenuate circulating TNF levels in splenectomized mice.
T85 586510-586739 Sentence denotes Electrical stimulation of the vagus nerve activates a splenic neuronal network, and sectioning of the common celiac trunk of the vagus nerve, proximal to the spleen, ablates vagus nerve regulation of TNF in both spleen and serum.
T86 586740-586889 Sentence denotes Vagus nerve stimulation fails to modulate splenic or circulating TNF levels in animals deficient in the alpha7 subunit of the acetylcholine receptor.
T87 586890-587012 Sentence denotes Thus, the vagus nerve prevents endotoxin-induced lethal systemic inflammation through cholinergic signaling in the spleen.
T88 587013-587222 Sentence denotes Neuropeptide Y (NPY), is a 36aa peptide distributed throughout the body which has been implicated in the regulation of several physiological processes such as energy balance, feeding, reproduction and anxiety.
T89 587223-587321 Sentence denotes NPY actions are mediated by five G-protein coupled receptors, designated as Y1, Y2, Y4, Y5 and Y6.
T90 587322-587402 Sentence denotes We assessed the effects of NPY and its receptors in regulating immune responses.
T91 587403-587486 Sentence denotes NPY was found to inhibit the migration of B cells to chemokine CXCL12 (SDF1-alpha).
T92 587487-587568 Sentence denotes We have also shown expression of Y receptors, Y1, Y2, Y4 and Y6 in murine spleen.
T93 587569-587695 Sentence denotes Y1-deficient mice (Y1À/À) have smaller spleens, less mature B cells and more naive T cells in their secondary lymphoid organs.
T94 587696-587845 Sentence denotes Furthermore, T cell differentiation to Th1 T cells in Y1À/À mice appears to be defective as lower IgG2a and IL-12 levels are detected in their serum.
T95 587846-587979 Sentence denotes When challenged with a T-dependent or T-independent antigen, Y1À/À mice still produce significantly lower levels of IgG2a antibodies.
T96 587980-588068 Sentence denotes Response of these mice was tested in a Th1 model of delayed-type hypersensitivity (DTH).
T97 588069-588166 Sentence denotes Interestingly, Y1À/À mice had significantly reduced footpad swelling compared with wildtype mice.
T98 588167-588272 Sentence denotes Finally, macrophages lacking Y1 receptors produce less TNF-alpha following stimulation with LPS in vitro.
T99 588273-588453 Sentence denotes This data strongly suggests that the Y1 receptor is a key molecule controlling fundamental immune functions, confirming the interplay between the neuroendocrine and immune systems.
T100 588454-588507 Sentence denotes Neuropeptides generate tolerogenic dendritic cells D.
T101 588508-588522 Sentence denotes Ganea a and M.
T102 588523-588750 Sentence denotes Delgado b a Rutgers University, Newark, USA; b Institute of Parasitology and Biomedicine, Granada, Spain Dendritic cells (DC) act as potent antigen presenting cells initiating T cell activation, or as tolerance-inducing agents.
T103 588751-588860 Sentence denotes The cells/factors and molecular mechanisms controlling these opposite functions of DC are not elucidated yet.
T104 588861-589026 Sentence denotes In this study, we show that bone marrow DCs generated in the presence of the neuropeptides VIP and PACAP (VIP/PACAP-DC) induce or activate regulatory T cells (Treg).
T105 589027-589195 Sentence denotes In contrast to DCs generated in the absence of VIP or PACAP, VIP/PACAP-DC secrete high levels of IL-10, and no detectable IL-12, IL-6, or TNF upon stimulation with LPS.
T106 589196-589347 Sentence denotes LPS-stimulated VIP/ PACAP-DC induce unresponsiveness in co-cultured CD4+T cells in terms of proliferation and Th1 cytokine release (IFNgamma and IL-2).
T107 589348-589420 Sentence denotes The cocultured Ag-specific T cells secrete however high levels of IL-10.
T108 589421-589729 Sentence denotes The Treg induced by co-culture with VIP-DC inhibit the proliferation of responder T cells, and this inhibition is completely reversed by the addition of a mix of neutralizing Abs (anti-IL10+anti-TGFbeta+anti-CTLA-4) suggesting that the suppressive activity is mediated by both cellular contact and cytokines.
T109 589730-589851 Sentence denotes The VIP-DC induce Treg generation in vivo, and the in vivo-induced Treg are capable to transfer tolerance to naRve hosts.
T110 589852-590026 Sentence denotes The generation of antigenspecific Treg in vitro in a controlled environment is of high therapeutic potential for autoimmune diseases and transplantation (AI47325 & AI052306).
T111 590027-590186 Sentence denotes The endogenous cannabinoid 2-arachidonoyl glycerol as chemoattractant for dendritic cells and adjuvant for T helper cell type 1 response to soluble antigens G.
T112 590187-590446 Sentence denotes Maestroni Istituto Cantonale di Patologia, Locarno, Switzerland Toll-like receptors (TLRs) expressed in dendritic cells (DCs) alert the innate immune system to the presence of pathogens so that the appropriate response can be mounted to contain the infection.
T113 590447-590554 Sentence denotes However, the decision-making mechanisms that determine the type of effector response are poorly understood.
T114 590555-590691 Sentence denotes In the preceding work, we showed that the sympathetic nervous system may influence the antigen-presenting and Th priming ability of DCs.
T115 590692-590843 Sentence denotes Here we report that murine epidermal Langherans cells as well as lymphoid and the myeloid DCs express the mRNA coding for the cannabinoid CB2 receptor.
T116 590844-591063 Sentence denotes Intradermal injection of 2-arachydonoylglycerol (2-AG), the physiological ligand for the CB2 receptor, shifted the immune response to a soluble protein and a TLR2 agonist from the mixed Th1/Th2 type to a sheer Th1 type.
T117 591064-591263 Sentence denotes This effect evidenced by enhanced hypersensitivity response, Ig2a production and Th1 pattern of cytokine production in the draining lymph nodes was abolished by the specific CB2 antagonist SR 144528.
T118 591264-591379 Sentence denotes The mechanism of this interesting effect might be related to a CB2-mediated recruitment of lymphoid DCs precursors.
T119 591380-591456 Sentence denotes Consistently, 2-AG showed a potent chemotactic activity in vitro toward DCs.
T120 591457-591645 Sentence denotes As 2-AG production may by induced by inflammatory agents, we have identified an endogenous lipid mediator which might influence the choice of the appropriate immune response to a pathogen.
T121 591646-591808 Sentence denotes In the evolutionary scale, Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRRs) involved in the innate and adaptative immune responses.
T122 591809-591935 Sentence denotes Stimulation of TLR2 and TLR4 mediates a signalling cascade that finally leads to the expression of inflammation-related genes.
T123 591936-592132 Sentence denotes Vasoactive intestinal peptide (VIP) is an immunopeptide present in the lymphoid microenvironment that exerts a therapeutic effect in several animal models of inflammatory and autoimmune disorders.
T124 592133-592430 Sentence denotes We have demonstrated that treatment with VIP reduced the clinical and histopathological severity of TNBS-induced colitis by decreasing the inflammatory and Th1-driven autoimmune components of the disease, but nothing is known about the putative involvement of TLRs both in the disease and healing.
T125 592431-592617 Sentence denotes Our results show the constitutive expression of TLR2 and TLR4, as well as the up-regulation after TNBS-treatment at protein and mRNA levels in colon that was reduced after VIP treatment.
T126 592618-592763 Sentence denotes This behaviour is also exhibited in the expression of both receptors in macrophages, dendritic cells and lymphocytes from mesenteric lymph nodes.
T127 592764-593000 Sentence denotes The present study demonstrates that the modulation of TLR2 and TLR4 receptors is involved in the beneficial effects of VIP in an animal model of Crohn's disease, representing a new step in the design of potential therapeutic strategies.
T128 593001-593078 Sentence denotes Ghrelin is a recently identified gastric hormone with a variety of functions.
T129 593079-593244 Sentence denotes This neuroendocrine peptide is involved in the release of growth hormone (GH) and neuropeptide Y (NPY), following activation of the GH secretagogue receptor (GHS-R).
T130 593245-593360 Sentence denotes Prior studies have demonstrated that NPY would play a regulatory role in EAE by causing an immune bias towards Th2.
T131 593361-593487 Sentence denotes Here we explored if Ghrelin might also exert an immunomodulatory effect similar to NPY and protect against development of EAE.
T132 593488-593669 Sentence denotes We induced EAE in C57BL/6 mice with myelin oligodendrocyte glycoprotein (MOG)35-55 and treated the mice with subcutaneous injections of Ghrelin (0.5, 5 or 50 Ag/kg) every other day.
T133 593670-593920 Sentence denotes Our results revealed that the continuous treatment with 5 Ag/kg of Ghrelin after EAE induction (up to day 35 or to day 10) could significantly ameliorate the clinical severity of EAE, whereas treatment with an acyl-modified Ghrelin showed no effects.
T134 593921-594114 Sentence denotes Unexpectedly, IFN-gamma production of the draining lymph node (LN) cells to MOG35-55 was not affected by Ghrelin treatment, indicating a mechanism of EAE suppression that is independent of NPY.
T135 594115-594203 Sentence denotes These results indicate a novel role for Ghrelin to modulate autoimmune pathology in EAE.
T136 594204-594325 Sentence denotes Endogenous catecholamines (CA) in human peripheral blood mononuclear cells (PBMCs) modulate activation-induced apoptosis.
T137 594326-594430 Sentence denotes In multiple sclerosis (MS), PBMCs have dysregulated CA production and are less susceptible to apoptosis.
T138 594431-594577 Sentence denotes Since interferon (IFN)-beta is beneficial in MS, we investigated its effects on CA production and apoptosis in PBMCs obtained from healthy donors.
T139 594578-594657 Sentence denotes Stimulation with phytohaemagglutinin (PHA) 10 Ag/ml triggered production of CA.
T140 594658-594812 Sentence denotes Incubation with IFN-beta (500-1000 U/ml) increased CA production and efflux, an effect which was prevented by antibodies against IFN-beta or its receptor.
T141 594813-594956 Sentence denotes Percentage of apoptotic PBMCs increased after PHA, and was reduced by alpha-methyl-p-tyrosine 10 AM (which prevents PHA-induced CA production).
T142 594957-595074 Sentence denotes IFN-beta per se did not affect apoptosis but completely reverted the antiapoptotic effect of alpha-methyl-p-tyrosine.
T143 595075-595238 Sentence denotes Incubation of PBMCs with IFN-gamma (0.1-2.0 pg/ml) per se completely inhibited CA production, an effect which was reverted by coincubation with IFN-beta 1000 U/ml.
T144 595239-595318 Sentence denotes Under such experimental conditions however, IFNbeta failed to induce CA efflux.
T145 595319-595517 Sentence denotes In conclusion, in human PBMCs IFN-beta (1) induces CA production and efflux; (2) restores impaired apoptosis secondary to inhibition of CA production; (3) counteracts IFN-gammainduced effects on CA.
T146 595518-595622 Sentence denotes These findings shed new light on the mechanisms of action of IFN-beta as an immunomodulatory drug in MS.
T147 595623-595734 Sentence denotes Pregnancy represents a physiological transitory state of immune tolerance to avoid the rejection of the foetus.
T148 595735-595831 Sentence denotes Multiple sclerosis (MS) ameliorates during pregnancy, with a rebound of activity after delivery.
T149 595832-595957 Sentence denotes Alterations in CD4+CD25+ regulatory T-cells (TR) are known to cause organ-specific autoimmune disease in experimental models.
T150 595958-596033 Sentence denotes Our goal was to quantify TR during pregnancy and puerperium in MS patients.
T151 596034-596154 Sentence denotes We conducted a prospective study of 10 patients with definite MS during pregnancy, and compared with two control groups:
T152 596155-596200 Sentence denotes 12 healthy pregnant and 14 nonpregnant women.
T153 596201-596279 Sentence denotes We quantified the TR and activated (CD4+HLA-DR+CD38+) cells by flow cytometry.
T154 596280-596445 Sentence denotes During pregnancy, we observed a progressive increase in CD4+CD25+ T-lymphocytes in healthy as well as MS patients, whereas a decrease in activated T-cells was noted.
T155 596446-596647 Sentence denotes The proportion of TR cells was significantly higher in pregnant than in nonpregnant women ( p=0.01), whereas no differences were observed neither in the percentages of total nor activated CD4+ T-cells.
T156 596648-596824 Sentence denotes The CD4+CD25+ and CD4+CD25high T-cells significantly decreased when comparing the third trimester and puerperal proportions in MS patients ( P=0.01, and P=0.002, respectively).
T157 596825-596990 Sentence denotes No significant differences were noted between healthy and MS pregnant in neither activated, nor TR cells, during any of the gestational trimesters and at postpartum.
T158 596991-597170 Sentence denotes Our findings are consistent with the expansion of circulating regulatory CD4+CD25+T-cells pool during pregnancy, which may represent relevant factors in the activity course of MS.
T159 597171-597432 Sentence denotes In a post-mortem study, we investigated the relationship between multiple sclerosis (MS) lesions in the hypothalamus and the state of activity of corticotropin releasing hormone (CRH)-producing neurons that control the hypothalamus-pituitary-adrenal (HPA) axis.
T160 597433-597575 Sentence denotes A high incidence (15/16) of MS lesions was found in the hypothalamus, of which more than 50% was active, i.e. contained activated macrophages.
T161 597576-597764 Sentence denotes MS patients have increased numbers of CRH-immunoreactive neurons co-expressing vasopressin (CRH/VP neurons), a sign of chronic activation of CRH neurons, and increased CRH mRNA expression.
T162 597765-597842 Sentence denotes Active MS lesions correlated with a low number of hyperactive CRH/VP neurons.
T163 597843-597970 Sentence denotes High HLA -DR, -DP, -DQ expression, a measure for macrophage and microglial activation, correlated with low CRH mRNA expression.
T164 597971-598151 Sentence denotes The nearer the HLA expression was situated to the CRH neurons, the stronger the inhibiting effect, suggesting that activated microglial cells or macrophages suppress these neurons.
T165 598152-598325 Sentence denotes The more active MS lesions were present in the hypothalamus, the shorter was the disease duration until the moment of death, indicating an unfavorable course of the disease.
T166 598326-598570 Sentence denotes Thus, MS patients have a chronically activated CRH system, but in the subgroup of patients with active MS lesions in the hypothalamus, this activation is impaired and the disease course is worse. (Tissue provided by the Netherlands Brain Bank).
T167 598571-598713 Sentence denotes Recently, it has been found to be active in neurons, and mice lacking NF-kappaB subunits p50 or p65 show deficits in specific cognitive tasks.
T168 598714-598808 Sentence denotes Here we demonstrate a strikingly low level of anxiety-like behavior in the p50 knockout mouse.
T169 598809-598976 Sentence denotes In an open field, the mutant mice showed significantly less defecation, more rearing, and more time spent in the center compartment relative to wild type control mice.
T170 598977-599074 Sentence denotes The p50 knockout mice also spent more time investigating a novel object placed in the open field.
T171 599075-599221 Sentence denotes On the elevated plus maze, p50 knockout mice spent more time on the open arms and had increased numbers of open arm entries relative to wild type.
T172 599222-599345 Sentence denotes In tests of general health, sensorimotor function, and daily activity on a circadian rhythm, p50 knockout mice were normal.
T173 599346-599591 Sentence denotes Thus, absence of the p50 subunit of the NF-kappaB transcription factor, which results in altered NF-kappaB transcriptional activity in cells throughout the body and brain, alters neuronal circuitry underlying manifestation of emotional behavior.
T174 599592-599680 Sentence denotes The p50 subunit appears to play a role in normal expression of certain forms of anxiety.
T175 599681-599812 Sentence denotes There is evidence of an innervation of lymphoid organs by sympathetic fibers releasing noradrenaline (NA) and neuropeptide Y (NPY).
T176 599813-599921 Sentence denotes In previous work, we have observed the modulatory in vitro effect of NA and NPY on several immune functions.
T177 599922-600232 Sentence denotes The aim of the present study was to evaluate the in vitro effect of these neurotransmitters, individually and jointly, on several inflammatory parameters of peritoneal leucocytes, such as adherence to fibronectin and collagen type I, PGE2 and NO release as well as susceptibility to H 2 O 2 -induced apoptosis.
T178 600233-600350 Sentence denotes Adult female BALB/c mice have been used to obtain peritoneal suspensions containing both macrophages and lymphocytes.
T179 600351-600425 Sentence denotes The concentrations of NA and NPY were 10 À10 M for NPY and 10 À8 M for NA.
T180 600426-600611 Sentence denotes The results show an inhibitory effect of both neurotransmitters, when used jointly, on PGE2 and NO release (from 137 to 104 ng/ml, pb0.001, and from 47 to 34 AM, pb0.001, respectively).
T181 600612-600769 Sentence denotes The susceptibility to apoptosis was decreased by NPY and NE, used individually or jointly, in basal conditions as well as in the presence of H 2 O 2 (50 mM).
T182 600770-600868 Sentence denotes The adherence to fibronectin and collagen was decreased only by NPY, used individually or with NA.
T183 600869-601045 Sentence denotes These results suggest an banti-inflammatoryQ effect of the sympathetic neurotransmitters studied (NPY and NA), at physiological concentrations, on murine peritoneal leucocytes.
T184 601046-601082 Sentence denotes Work supported by FIS and CM grants.
T185 601083-601196 Sentence denotes Crohn's disease (CD) is a chronic inflammatory pathology of the colon characterized by diarrhoea and weight loss.
T186 601197-601364 Sentence denotes Vasoactive intestinal peptide (VIP), an immunoregulatory neuropeptide, has proved beneficial in a mice model of human CD: trinitrobenzene sulfonic acid (TNBS)-colitis.
T187 601365-601607 Sentence denotes The aim of the present study was to determine the molecular mechanisms of action of VIP on this model of colitis studying the time-course expression of proinflammatory and regulatory mediators implicated in the pathophysiology of the disease.
T188 601608-601812 Sentence denotes Gene array and real-time PCR analysis were performed to measure mRNA levels of several proinflammatory mediators, such as cyclooxygenase-2 (COX-2), CCR5, IL-1 beta, IL-6, IL-12, IL-18, IFN gamma and IL-4.
T189 601813-601950 Sentence denotes TNBS-mice showed an increased expression of all proinflammatory mediators studied, with a specific time course pattern for each molecule.
T190 601951-602150 Sentence denotes Besides, TNBS-treated animals showed a Th1 lymphocytic response with high levels of IFN gamma mRNA but low IL-4, correlated with a high expression of IL-12 and IL-18, two Th1 differentiating factors.
T191 602151-602312 Sentence denotes VIP downregulates the expression of all these mediators, exerting an antiinflammatory function that explains the remission of the disease in the treated animals.
T192 602313-602404 Sentence denotes VIP also favours the Th2 versus Th1 response, contributing to the remission of the disease.
T193 602405-602504 Sentence denotes The results support a potential therapeutic action of VIP for the therapy of inflammatory diseases.
T194 602505-602633 Sentence denotes Role of substance P/NK-1 receptor system in the vanilloid VR1 receptor-mediated capsaicin-induced apoptosis of rat thymocytes C.
T195 602634-602646 Sentence denotes Amantini, R.
T196 602647-602661 Sentence denotes Lucciarini, M.
T197 602662-602671 Sentence denotes Mosca, D.
T198 602672-602686 Sentence denotes Martarelli, M.
T199 602687-602698 Sentence denotes Perfumi, P.
T200 602699-602715 Sentence denotes Ballarini and G.
T201 602716-602763 Sentence denotes Santoni University of Camerino, Camerino, Italy
T202 602764-602952 Sentence denotes We investigated the involvement of the substance P/NK-1 receptor system in the regulation of the vanilloid receptor (VR1)-mediated capsaicin (CPS)-induced apoptosis in rat CD5+ thymocytes.
T203 602953-603096 Sentence denotes We evaluated by confocal laser scanner microscopy analysis the expression of substance P (SP) and its NK-1 receptor in CD5+VR1+ rat thymocytes.
T204 603097-603318 Sentence denotes We found that the NK-1 and VR1 receptors completely colocalize in the plasma membrane of CD5+ rat thymocytes, while only a moderate colocalization was detected by comparing the expression of SP in CD5+VR1+ rat thymocytes.
T205 603319-603523 Sentence denotes Evidence of the involvement of the SP/NK-1 receptor in the CPS-induced apoptosis have been provided by analyzing the capability of SP to protect CD5+ rat thymocytes from CPS-mediated apoptotic cell death.
T206 603524-603757 Sentence denotes SP inhibits in a dose-and time-dependent manner VR1-mediated CPS-induced apoptosis of rat CD5+ thymocytes, as evaluated by its ability to completely reverse the CPS-induced caspase-3 activation and oligonucleosomal DNA fragmentation.
T207 603758-603923 Sentence denotes The specific NK-1 receptor antagonist, SR140333 completely reverses the anti-apoptotic effect of SP on the VR1-mediated CPS-induced apoptosis of CD5+ rat thymocytes.
T208 603924-604163 Sentence denotes CPS markedly inhibits in a time-dependent manner the expression of SP in CD5+ rat thymocytes and a specific VR1 antagonist, capsazepine markedly blocks in a time-dependent manner the CPS-induced SP synthesis/release in CD5+ rat thymocytes.
T209 604164-604402 Sentence denotes Neuropeptide Y (NPY) is involved in the modulation of functions related to immune and inflammatory reactions such as lymphocytes proliferation, NK cell activity, immune cell trafficking, cytokine secretion and release of oxidative agents.
T210 604403-604501 Sentence denotes NPY exerts biological effects through several receptor subtypes (named from Y1 to Y5, in the rat).
T211 604502-604683 Sentence denotes We have investigated the effect of NPY and NPY-related peptides with different pharmacological profiles on NO and H 2 O 2 production in rat granulocytes obtained from rat air pouch.
T212 604684-604749 Sentence denotes Carrageenan (20 Ag/rat) was injected directly into the air pouch.
T213 604750-605136 Sentence denotes Granulocytes obtained 24 h later by lavage were treated in vitro with NPY, peptide YY (PYY), pancreatic polypeptide (PP, Y4 receptor agonist), LeuPro-NPY (Y1,5 receptor agonist), NPY13-36 (Y2,5 receptor agonist) and hAlaAib-NPY (Y5 receptor agonist) in concentrations 10 À6 -10 À12 M, and stimulated with LPS (1 Ag/ml, 48 h) for NO or zymosan (125 Ag/ml, 30 min) for H 2 O 2 production.
T214 605137-605281 Sentence denotes Both NPY and PYY stimulated basal and LPS-induced NO production in granulocytes, and LeuPro-NPY potentiated NO release from LPSstimulated cells.
T215 605282-605359 Sentence denotes NPY13-36 and hAlaAib-NPY decreased NO production in cells cultured in medium.
T216 605360-605444 Sentence denotes NPY and LeuPro-NPY decreased peroxide production in zymosan-stimulated granulocytes.
T217 605445-605619 Sentence denotes It is concluded that NPY and NPY-related peptides differentially modulated NO and H 2 O 2 production in rat granulocytes. (Supported by MSTD, Republic of Serbia, Grant 1239).
T218 605620-605764 Sentence denotes The induction of interleukin-1 (IL-1B) beta and interleukin-12 (IL-12) by substance P (SP) in human peripheral blood mononuclear cells (PBMC) M.
T219 605765-605776 Sentence denotes Braitch, M.
T220 605777-605787 Sentence denotes Chopra, A.
T221 605788-605800 Sentence denotes Fahey and C.
T222 605801-606002 Sentence denotes Constantinescu University of Nottingham, Nottingham, UK Substance P (SP), neuropeptide stored in the termini of sensory neurons, induces pro-inflammatory cytokines and mediates neurogenic inflammation.
T223 606003-606007 Sentence denotes Aim:
T224 606008-606160 Sentence denotes To examine the effects of SP on the production of interleukin-1 beta (IL-1h) and interleukin-12 (IL-12) from peripheral blood mononuclear cells (PBMCs).
T225 606161-606301 Sentence denotes Method: PBMCs were stimulated with SP alone (10 À6 -10 À12 M) and in combination with Lipopolysaccharide (LPS) or Phytohaemagglutinin (PHA).
T226 606302-606377 Sentence denotes Supernatants were analysed for IL-1h, IL-12 p40 and IL-12 p40/p70 by ELISA.
T227 606378-606386 Sentence denotes Results:
T228 606387-606500 Sentence denotes 10 À6 M SP alone and in combination with LPS and PHA induced a significant increase in IL-1h production by PBMCs.
T229 606501-606586 Sentence denotes PHA was a strong inducer but in concert with other stimuli LPS proved more effective.
T230 606587-606715 Sentence denotes After 24-h, 10 À6 M SP induced the production of IL-12 p40 and IL-12p40/p70 secretion alone and in combination with LPS and PHA.
T231 606716-606792 Sentence denotes As the concentration of SP decreased, the amount of IL-12 produced declined.
T232 606793-606846 Sentence denotes This effect was more profound after 48-h stimulation.
T233 606847-606858 Sentence denotes Conclusion:
T234 606859-607022 Sentence denotes These studies confirm the ability of SP to enhance IL-1h production by human PBMC cells and show for the first time the production of IL-12 from human PBMCs by SP.
T235 607023-607145 Sentence denotes The ability of SP to augment secretion of pro-inflammatory cytokines supports the role of SP in the inflammatory response.
T236 607146-607311 Sentence denotes SP antagonists may represent future tools for down-regulating inflammation in environment rich in SP including the peripheral nerves, gut, inflamed joints and brain.
T237 607312-607434 Sentence denotes Interactions between neuro-endocrine and immune systems in ageing: trade-off analysis by means of mathematical modeling T.
T238 607435-607451 Sentence denotes Sannikova a , A.
T239 607452-607471 Sentence denotes Romanyukha a and A.
T240 607472-607605 Sentence denotes Yashin b a Institute of Numerical Mathematics, RAS, Moscow, Russia; b Max Planck Institute for Demographic Research, Rostock, Germany
T241 607606-607720 Sentence denotes The aim of this work is to quantify the trade-offs between human immune and hormonal systems in the aging process.
T242 607721-607885 Sentence denotes For that purpose, we construct mathematical model that describes mutual influences arising during agerelated decline in functioning of immune and endocrine systems.
T243 607886-607988 Sentence denotes We suppose that this closely coordinated systems change under the allostatic and antigen load actions.
T244 607989-608094 Sentence denotes These two types of environmental pressure affect the rate of resource exhausting for each of the systems.
T245 608095-608239 Sentence denotes Neuro-endocrine and immune systems are responsible for maintenance of homeostasis of the internal milieu and intensity of the energy metabolism.
T246 608240-608365 Sentence denotes On the other hand, parameters of the machine of the energy metabolism determine the activity of immune and endocrine systems.
T247 608366-608564 Sentence denotes Dynamics of the cell concentrations, the rate of the hormonal synthesis and intensity of the energy transformation and consumption processes take place in mitochondria are modeled by the ODE system.
T248 608565-608690 Sentence denotes The results of the simulation reveal that there are explicit trade-offs between immune space and power of hormonal reactions.
T249 608691-608800 Sentence denotes Existence of the trade-offs should be taken in consideration when hormonal therapy is used in elderly people.
T250 608801-608991 Sentence denotes Maintenance of body weight around a set point requires regulatory processes as energy homeostasis and depends on tightly regulated interactions between nervous, immune and endocrine systems.
T251 608992-609161 Sentence denotes Thus, obesity may result from energy homeostasis deregulation of multiple causes; including viral infection, as association of human obesity and virus has been reported.
T252 609162-609293 Sentence denotes Our mouse model of obesity induced by brain CDV infection may give insights in how virus-induced brain damages may lead to obesity.
T253 609294-609478 Sentence denotes This negative-stranded RNA virus predominantly targets neurons located in hypothalamus, a key structure for integration of central and peripheral signals regulating energy homeostasis.
T254 609479-609705 Sentence denotes Obesity syndrome, associated with persistence of virus in hypothalamus, could be due to specific neuronal loss and/or epigenetic alteration of hypothalamic genes involved in food intake, energetic control and basal metabolism.
T255 609706-609876 Sentence denotes To identify these genes, we used differential display PCR (DDRT-PCR) and subtractive libraries and compared hypothalamic mRNA profiles from infected-lean and -obese mice.
T256 609877-610001 Sentence denotes Among the identified deregulated genes, UROP 11 was selected according to the magnitude of increase and novelty of sequence.
T257 610002-610092 Sentence denotes Its full-length sequence and cellular central and peripheral localization were determined.
T258 610093-610235 Sentence denotes The functional relevance of UROP11 in obesity was demonstrated in other obesity models (leptin deficient mice ob/ob and db/db; high fat diet).
T259 610236-610376 Sentence denotes Our data pointed out Urop11 as a new gene, implicated in emerging or maintenance of obesity status, likely regulated under a leptin control.
T260 610377-610463 Sentence denotes IL-18 modulates CRH and prostaglandin production from the rat hypothalamus in vitro G.
T261 610464-610476 Sentence denotes Tringali, M.
T262 610477-610488 Sentence denotes Vairano, G.
T263 610489-610503 Sentence denotes Pozzoli and P.
T264 610504-610587 Sentence denotes Navarra Institute of Pharmacology, Catholic University School Medicine, Rome, Italy
T265 610588-610759 Sentence denotes Interleukin-18 (IL-18) is a pro-inflammatory cytokine showing similarities with IL-1beta in structure, receptor and signalling mechanisms, as well as biological functions.
T266 610760-610959 Sentence denotes We have previously shown that IL-1beta directly stimulates corticotrophin-releasing hormone (CRH) secretion from the rat hypothalamus via a mechanism requiring an increased prostaglandins production.
T267 610960-611358 Sentence denotes Here we investigated whether: (a) IL-18 shares with IL-1beta the ability to stimulate CRH gene expression and peptide release from rat hypothalamic explants in short-term (1 and 3 h) in vitro incubations; (b) IL-18 modulates basal and IL-1beta stimulated prostaglandins production in hypothalamic explants as well as in primary cultures of rat cortical microglia and astrocytes in 24-h experiments.
T268 611359-611505 Sentence denotes CRH released in the incubation medium was evaluated by radioimmunoassay (RIA), whereas CRH mRNA levels were analysed using RNase protection assay.
T269 611506-611542 Sentence denotes PGE2 production was assessed by RIA.
T270 611543-611651 Sentence denotes We found that IL-18 decreases in a concentration-dependent manner both basal and KCl-stimulated CRH release.
T271 611652-611732 Sentence denotes These findings were paralleled by a significant decrease in CRH gene expression.
T272 611733-611862 Sentence denotes IL-18 had no effect on basal PGE2 production by hypothalamic explants but completely abolished production stimulated by IL-1beta.
T273 611863-611994 Sentence denotes Moreover, IL-18 produced a reduction in both basal and IL-1betastimulated PG2 production and release from microglia and astrocytes.
T274 611995-612183 Sentence denotes These data clearly demonstrate that IL-18 shows a profile of neuroendocrine activities in vitro that are opposed to, and even antagonizing, those of IL-1beta in the control of stress axis.
T275 612184-612357 Sentence denotes Endothelin-1 increases the release of prostaglandin (PG) E2 from the preoptic area of rat anterior hypothalamus POA in vitro without altering cytokine gene expression A.S.C.
T276 612358-612373 Sentence denotes Fabricio a , G.
T277 612374-612389 Sentence denotes Tringali a , G.
T278 612390-612408 Sentence denotes Pozzoli a , G.E.P.
T279 612409-612423 Sentence denotes Souza b and P.
T280 612424-612602 Sentence denotes Navarra a a Institute of Pharmacology, Catholic University Medical School, Rome, Italy; b University of São Paulo Faculty of Pharmaceutical Sciences, Ribeirão Preto, Brazil Aims:
T281 612603-612764 Sentence denotes We have previously shown that fever is induced in rats by injection of endothelin-1 (ET-1) into the preoptic area of rat anterior hypothalamus (POA) while i.c.v.
T282 612765-612839 Sentence denotes ET-1 induces an increase in cerebrospinal fluid prostaglandin (PG) levels.
T283 612840-613024 Sentence denotes Here we investigated if ET-1 increases the release of PGE 2 from the POA or posterior hypothalamus (PHyp) explants and if this effect is related to changes in cytokine gene expression.
T284 613025-613045 Sentence denotes Methods and results:
T285 613046-613185 Sentence denotes Male Wistar rats (250 g) had the whole hypothalamic region explanted and divided at the optic chiasm to obtain isolated POA and Phyp areas.
T286 613186-613397 Sentence denotes In 1-h incubation experiments, ET-1 induced a concentrationdependent increase in immunoreactive PGE 2 release in the incubation medium from the whole hypothalamus, with statistical significance at 10 and 100 nM.
T287 613398-613489 Sentence denotes ET-1 (100 nM) also induced an increase in PGE 2 release from the POA but not from the PHyp.
T288 613490-613662 Sentence denotes RNase protection analyses of total RNA extracted from the explants showed that 100 nM ET-1 produced no effect on interleukin (IL)-1alpha, IL-1beta and IL-6 gene expression.
T289 613663-613783 Sentence denotes Conclusion: ET-1 induces an increase of the PGE 2 release at the major thermoregulatory area in the brain, i.e. the POA.
T290 613784-613922 Sentence denotes The acute stimulatory effect of ET-1 on PGE 2 release from the POA does not appear to be related to an action on cytokine mRNA expression.
T291 613923-613986 Sentence denotes Orchidectomy affects the monoamine content in rat thymocytes B.
T292 613987-614008 Sentence denotes Vidic-Dankovic a , K.
T293 614009-614027 Sentence denotes Radojevic a and G.
T294 614028-614171 Sentence denotes Leposavic b a Institute of Immunology and Virology bTorlakQ, Belgrade, Yugoslavia; b Faculty of Pharmacy, Belgrade, Yugoslavia Object of study:
T295 614172-614318 Sentence denotes It has been shown that: (i) orchidectomy influences the intrathymic concentration of monoamines and (ii) some T-cell lines produce catecholamines.
T296 614319-614514 Sentence denotes Therefore, this study was designed to investigate: (i) whether thymocytes contain detectable level of monoamines and (ii) if so, whether orchidectomy affects the intrathymocyte monoamine content.
T297 614515-614523 Sentence denotes Methods:
T298 614524-614797 Sentence denotes The concentrations of noradrenaline (NA), dopamine (DA) and serotonin (5-HT) were estimated in the whole thymus and in thymocyte suspensions from AO rats one month post bilateral orchidectomy performed at age of either 30 or 60 days, by HPLC with electrochemical detection.
T299 614798-614806 Sentence denotes Results:
T300 614807-614932 Sentence denotes In spite of age at surgery, orchidectomy diminished the intrathymic concentration of NA and 5-HT, while increased that of DA.
T301 614933-615068 Sentence denotes The thymocytes from both orchidectomized (ORX) and control (sham-ORX) rats showed detectable levels of NA and 5-HT, but not that of DA.
T302 615069-615156 Sentence denotes Orchidectomy, in both groups of rats, increased the intrathymocyte concentration of NA.
T303 615157-615293 Sentence denotes The intrathymocyte concentration of 5-HT was increased in rats ORX at age of 60 days, but it was reduced in those ORX at age of 30 days.
T304 615294-615306 Sentence denotes Conclusions:
T305 615307-615483 Sentence denotes The results revealed detectable levels of NA and 5-HT in rat thymocytes, and showed that the intrathymocyte levels of these monoamines are influenced by gonadal hormone milieu.
T306 615484-615582 Sentence denotes Regulation of dipeptidyl peptidase IV (DPPIV/CD26) on human dermal fibroblasts by endomorphin-2 J.
T307 615583-615600 Sentence denotes Gabrilovac a , B.
T308 615601-615615 Sentence denotes Cupic a and J.
T309 615616-615866 Sentence denotes Jakic-Razumovic b a Ruder Boškovic Institute, Zagreb, Croatia; b Clinical Hospital Centre Rebro, Zagreb, Croatia DPPIV is a membrane-bound peptidase that cleaves dipeptides from Nterminal of the polypeptides if proline is at the penultimate position.
T310 615867-615987 Sentence denotes Besides the enzyme activity, DPPIV can act as an adhesive and as a costimulatory molecule transducing the growth signal.
T311 615988-616060 Sentence denotes Its expression is regulated by cytokines (IL-1-alpha, IL-12, TNF-alpha).
T312 616061-616169 Sentence denotes Neuropeptides can also regulate the expression of membrane peptidases that in turn cleave the neuropeptides.
T313 616170-616354 Sentence denotes We examined whether opioid peptide endomorphin-2 (Tyr-Pro-Phe-Phe-NH2; E-2), which is a physiological DPPIV substrate, could affect the expression of DPPIV on human dermal fibroblasts.
T314 616355-616520 Sentence denotes The role of the cleavage site in the interaction was examined by using a synthetic tetrapeptideTyr-D-Pro-Phe-Phe-NH2 (DE-2), which is resistant to cleavage by DPPIV.
T315 616521-616612 Sentence denotes The role of opioid receptors was examined by using an opioid receptor antagonist, naloxone.
T316 616613-616741 Sentence denotes DPPIV enzyme activity was measured by means of hydrolysis of fluorochrome-labeled substrate and by immunohistochemical staining.
T317 616742-616891 Sentence denotes Time-and concentration-dependent up-regulation of DPPIV with both endogenous E-2 (DPPIV sensitive) and synthetic DE-2 (DPPIV resistant) was observed.
T318 616892-617054 Sentence denotes However, naloxone abrogated or diminished only the effects of DPPIV-resistant DE-2, suggesting that E-2 and DE-2 may use different mechanisms in regulating DPPIV.
T319 617055-617233 Sentence denotes Collectively, the data show that endomorphin-2 can up-regulate DPPIV expression on dermal fibroblasts either via an interaction with the enzyme itself or via the opioid receptor.
T320 617234-617324 Sentence denotes Increased DPPIV expression on fibroblasts may affect their functional activity and growth.
T321 617325-617332 Sentence denotes ET [Br.
T322 617333-617335 Sentence denotes J.
T323 617336-617346 Sentence denotes Pharmacol.
T324 617347-617368 Sentence denotes 136 (2002) 947-955] .
T325 617369-617535 Sentence denotes The aim of the present study is to investigate the effects of ICV injections of PAT on the increased intracerebral levels of cytokines induced by ICV injection of ET.
T326 617536-617544 Sentence denotes Methods:
T327 617545-617675 Sentence denotes Several groups of rats received ICV injections of either ET only (1.5 Ag in 2 Al) or ET preceded by PAT (0.2, 1, or 5 Ag in 2 Al).
T328 617676-617881 Sentence denotes After 4 h, the brain tissues were sampled from the brainstem, diencephalon and hippocampus for the determination of the levels of tumor necrosis factor (TNF) alpha, interleukins (IL) 1 beta and 6 by ELISA.
T329 617882-617890 Sentence denotes Results:
T330 617891-617995 Sentence denotes Pretreatment with PAT produced a dose-related alteration of the increased levels of all cytokines by ET.
T331 617996-618110 Sentence denotes Injection of PAT only did not produce significant alteration of the basal concentration of cytokines in the brain.
T332 618111-618122 Sentence denotes Conclusion:
T333 618123-618260 Sentence denotes The observed results provide evidence on the potential protective role of PAT against brain tissue damage during inflammatory conditions.
T334 618261-618342 Sentence denotes Melatonin receptors in goat membranes lymphocytes: light and stress regulation G.
T335 618343-618360 Sentence denotes Carrillo and C.I.
T336 618361-618467 Sentence denotes Gutierrez Universidad Nacional Experimental bFrancisco de MirandaQ (UNEFM), Coro, Estado Falcón, Venezuela
T337 618468-618553 Sentence denotes Neuroendocrine and immunological systems are connected structurally and functionally.
T338 618554-618658 Sentence denotes There are anatomical, physiological and pharmacological evidences that supported this close interaction.
T339 618659-618873 Sentence denotes The melatonin neurohormone plays an important role in the immune system, which is also supported by the existence of melatonin-specific binding sites in lymphoid cells, central nervous system and peripheral organs.
T340 618874-619058 Sentence denotes Goats are domestic animals, widespread in Venezuela, especially in arid zones like Falcó n state; they have lower incidence of neoplasic disease and lower susceptibility to infections.
T341 619059-619223 Sentence denotes The aim of this work was to characterize melatonin receptors in membranes lymphocytes of goat's peripherical blood through binding studies with [ 3 H]iodomelatonin.
T342 619224-619337 Sentence denotes The binding was dependent of time, temperature and cellular concentration, also stable, reversible and saturable.
T343 619338-619462 Sentence denotes Saturation assays demonstrated a high-affinity binding site (K d =3.6F0.21 nM) and low capacity (B max =335.2F50.2 fmol/mg).
T344 619463-619559 Sentence denotes The affinity suggests that caprines receptors may recognize serum melatonin level physiological.
T345 619560-619758 Sentence denotes When the animals were stressed by immersion and immobilization in water, we find an increased affinity without capacity modification, but under light constant for 7 days only the capacity increased.
T346 619759-619972 Sentence denotes The results indicate that adult goats have high-affinity receptors to melatonin in lymphocytes and under different conditions vary and show the interaction and communication between pineal gland and immune system.
T347 619973-620046 Sentence denotes Regulation of secretion of nociceptin/orphanin FQ from rat splenocytes A.
T348 620047-620236 Sentence denotes Fulford University of Bristol, Bristol, UK N/OFQ mRNA is expressed by various immunocyte populations although the significance of endogenous N/OFQ in the immune system is poorly understood.
T349 620237-620322 Sentence denotes In this study, the regulation of N/OFQ secretion in rat splenocytes was investigated.
T350 620323-620433 Sentence denotes Splenocytes (5Â10 6 cells/ml) were cultured with varying concentrations of mitogens or inflammatory mediators.
T351 620434-620613 Sentence denotes Production of N/OFQ after stimulation by LPS (1 or 5 Ag/ml), Con A (1 or 5 Ag/ml) and IL-1 beta (5-20 ng/ml) was measured after 24-or 48-h incubation (37 8C in 95% O 2 /5% CO 2 ).
T352 620614-620741 Sentence denotes Additionally, splenocytes were activated with Con A (5 Ag/ml) for 24 h prior to the addition of CRF (10 À12 -10 À8 M) for 24 h.
T353 620742-620823 Sentence denotes Supernatants were harvested and retained for measurement of N/OFQ content by EIA.
T354 620824-621065 Sentence denotes LPS and Con A caused dosedependent stimulation of N/OFQ secretion confirming that B and T cells have the capacity to secrete N/OFQ (basal secretion in ng/ml) at 48 h 0.06F0.009; LPS 5 Ag/ml 0.13F0.03; Con A 5 Ag/ml 0.16F0.04, n=4/5, pb0.05).
T355 621066-621260 Sentence denotes IL-1 beta stimulation of splenocytes for 24 h also stimulated N/ OFQ secretion (basal 0.093F0.006; IL-1 beta (20 ng/ml) 0.175F0.02, n=4/ 5) although lower doses of IL-1 beta were without effect.
T356 621261-621439 Sentence denotes N/OFQ secretion from Con A-activated splenocytes was enhanced by CRF in vitro (30% increase by CRF 10 À12 M vs. Con A alone and reversible with alpha-helical CRF 10 À7 M, n=4/5).
T357 621440-621612 Sentence denotes These observations are consistent with the findings for other opioids and identify possible sources of immune-derived N/OFQ that may contribute to the inflammatory process.
T358 621613-621623 Sentence denotes Rationale:
T359 621624-621745 Sentence denotes To characterize beta2-adrenoceptor (b2AR)-mediated modulation of growth and function of human intestinal mast cells (MC).
T360 621746-621959 Sentence denotes Methods: MC were isolated from intestinal surgery specimens, purified, and subsequently cultured for 14-21 days in the presence of stem cell factor (50 ng/ml) with our without addition of adrenaline or salbutamol.
T361 621960-622084 Sentence denotes MC adhesion assays were performed using fibronectin-coated plates as well as human umbilical vein endothelial cells (HUVEC).
T362 622085-622185 Sentence denotes Cellular F-actin content was measured by flow cytometry after labeling with fluorescent phallacidin.
T363 622186-622194 Sentence denotes Results:
T364 622195-622410 Sentence denotes The b2AR agonists dose-dependently reduced the MC growth to 23.4% (salbutamol) and 25.3% (adrenaline) of control conditions (at 10 À6 M, n=5) which was mainly attributable to a strong inhibition of MC proliferation.
T365 622411-622576 Sentence denotes Moreover, the b2AR agonists (at 10 À6 M) abolished adhesion of MC to HUVEC monolayers as well as adhesion to fibronectin-coated plates following MC activation (n=5).
T366 622577-622807 Sentence denotes The cellular F-actin content decreased to 70% of basal levels following challenge of the MC with the b2AR agonists for 5 min, whereas, stimulation of the MC by IgE receptor crosslinking lead to a rapid doubling in F-actin content.
T367 622808-622926 Sentence denotes This activationinduced increase in F-actin content, however, was abrogated in the presence of the b2AR agonists (n=3).
T368 622927-622939 Sentence denotes Conclusions:
T369 622940-623141 Sentence denotes Our data show that b2AR agonists regulate human intestinal MC proliferation and interaction with HUVEC and fibronectin by mechanisms that possibly involve an alteration of cellular F-actin homeostasis.
T370 623142-623247 Sentence denotes Electrical stimulation of the mesencephalic periaqueductal gray matter in rats alters NK cell function A.
T371 623248-623261 Sentence denotes Pert a and R.
T372 623262-623375 Sentence denotes Weber b a National Institutes of Health, Bethesda, USA; b University of Illinois College of Medicine, Peoria, USA
T373 623376-623658 Sentence denotes We have previously reported [Science 245 (1989) 188-190 ) that microinjections of morphine into the periaqueductal gray matter (PAG) of the rat midbrain suppresses natural killer (NK) cell activity, thus implicating this brain region in the regulation of immune function by opioids.
T374 623659-623786 Sentence denotes The purpose of this study was to examine the effects of electrical stimulation of the PAG on natural killer cell (NK) activity.
T375 623787-623920 Sentence denotes Bipolar electrodes were introduced into various aspects of the periventricular-periaqueductal axis from its rostral to caudal extent.
T376 623921-624113 Sentence denotes One week following surgery, animals were stimulated with intermittent trains of biphasic pulses for 20 min and splenic NK cell activity was determined 3 h following termination of stimulation.
T377 624114-624341 Sentence denotes It was found that stimulation of sites rostral to the dorsal raphe nucleus was relatively ineffective in decreasing NK cell activity while 11 of the 14 sites in the caudal PAG caused significant suppression of NK cell activity.
T378 624342-624457 Sentence denotes The sites most active were found in the ventral PAG and its caudal aspect at the level of the dorsal raphe nucleus.
T379 624458-624610 Sentence denotes Studies are underway to determine the neural and peripheral circuitry through which electrical stimulation of the PAG gains access to the immune system.
T1 624611-624699 Sentence denotes Exogenous dehydroepiandrosterone replacement in humans induces regulatory T cells S.A.J.
T2 624700-624715 Sentence denotes Thompson a , S.
T3 624716-624729 Sentence denotes Curran b , A.
T4 624730-624740 Sentence denotes Cox a , K.
T5 624741-624760 Sentence denotes Chatterjee b and A.
T6 624761-624986 Sentence denotes Coles a a Department of Clinical Neurosciences, University of Cambridge, UK; b Department of Endocrinology, University of Cambridge, UK DHEA, an adrenal steroid, declines with age and has been implicated in neurodegeneration.
T7 624987-625102 Sentence denotes We took advantage of an unusual cohort of patients to study the immunological effect of exogenous DHEA replacement.
T8 625103-625298 Sentence denotes Patients with Addison's disease, autoimmune gland destruction, report persistent fatigue with reduced quality of life and cognitive abilities, despite standard corticosteroid replacement therapy.
T9 625299-625428 Sentence denotes It has been previously shown that restoration of serum DHEA levels by oral administration enhances cognition and reduces fatigue.
T10 625429-625509 Sentence denotes PBMCs were extracted from patients before, during and after treatment with DHEA.
T11 625510-625642 Sentence denotes NK and NKT cells were defined by FACS of surface cell markers CD3/CD56 and regulatory T cells identified as CD4 + CD25 hi CD45RO + .
T12 625643-625721 Sentence denotes Cytokine protein and mRNA were measured by ELISA and real-time quantification.
T13 625722-625829 Sentence denotes We found that DHEA treatment of patients with Addison's disease reduced peripheral NK and NKT cell numbers.
T14 625830-625947 Sentence denotes It also induced lymphocyte cytokine mRNA and protein expression, without a particular bias to any T helper phenotype.
T15 625948-626074 Sentence denotes CD4 + CD25 hi cell numbers and foxP3 expression was also increased, suggesting that DHEA had induced regulatory T lymphocytes.
T16 626075-626157 Sentence denotes We conclude that oral DHEA treatment has significant effects on the immune system.
T17 626158-626241 Sentence denotes Modulation of immune responses in mice exposed to toluene by noseonly inhalation H.
T18 626242-626257 Sentence denotes Fujimaki a , S.
T19 626258-626273 Sentence denotes Yamamoto a , M.
T20 626274-626289 Sentence denotes Kakeyama a , Y.
T21 626290-626305 Sentence denotes Kurokawa a , N.
T22 626306-626321 Sentence denotes Kunugita b , H.
T23 626322-626335 Sentence denotes Hori b and K.
T24 626336-626482 Sentence denotes Arashidani b a National Institute for Environmental Studies, Ibaraki, Japan; b University of Occupational and Environmental Health, Fukuoka, Japan
T25 626483-626581 Sentence denotes In this study, we examined the effect of low level toluene inhalation on immune and brain regions.
T26 626582-626729 Sentence denotes Male C3H/He mice were exposed to filtered air (control), 9 and 90 ppm toluene for 30 min by nose-only inhalation on day 1, 2, 3, 7, 14, 21, and 28.
T27 626730-626896 Sentence denotes One day after the last inhalation, mice were anesthetized by injection with Nembutal sodium, and blood, thymus, spleen, olfactory bulb and hippocampus were collected.
T28 626897-627008 Sentence denotes In spleen cells, the percentage of CD3 + and CD4 + T cells was significantly decreased in toluene-exposed mice.
T29 627009-627117 Sentence denotes However, the percentage of CD19 + cells in tolueneexposed mice was increased compared with air-exposed mice.
T30 627118-627314 Sentence denotes Mitogenic stimulation by PHA and LPS induced the production of IL-4 and IFNgamma from spleen cells of control mice, but exposure to toluene gave no significant increase in the cytokine production.
T31 627315-627396 Sentence denotes Total IgE production in plasma from toluene-exposed mice significantly decreased.
T32 627397-627515 Sentence denotes It is possible to speculate that toluene inhalation may affect immune functions in brain regions via olfactory system.
T33 627516-627672 Sentence denotes In olfactory bulb and hippocampus of tolueneexposed mice, the production of nerve growth factor, TNF-alpha, and IL-1beta was equivalent to the control mice.
T34 627673-627789 Sentence denotes These things suggest that exposure of mice to low dose toluene via intranasal route may induce immune abnormalities.
T35 627790-628030 Sentence denotes Having in mind that the neuroendocrine system products might modulate intrathymic maturation of T cells, the aim of this study was to investigate whether somatostatin-14, centrally applied, alters relations between thymocyte subpopulations.
T36 628031-628205 Sentence denotes Adult male AO rats were cannulated intracerebroventriculary and treated with three doses of SRIH-14, in the concentration of 0.6Â10 À10 M per day, or saline, every other day.
T37 628206-628260 Sentence denotes Animals were sacrificed 24 h after the last treatment.
T38 628261-628431 Sentence denotes Thymuses were processed for analysis of thymocyte subpopulations and apoptosis by flow cytometry, and for evaluation of morphometric parameters by stereological analysis.
T39 628432-628658 Sentence denotes Our results showed that SRIH-14 significantly decreased volume of the thymus cortex accompanied with decrease of cellularity and the number of thymocytes, per volume unit, in it and increased the percentage of apoptotic cells.
T40 628659-628831 Sentence denotes The percentages of CD4 À CD8 À and the both single positive thymocyte subpopulations were significantly increased, while the percentage of CD4 + CD8 + cells was diminished.
T41 628832-629203 Sentence denotes The analyses of cell subsets in the relative proportion to expression of TCRah revealed increase in the percentages of the least mature CD4 À CD8 À TCRah À/low and CD4 À CD8 + TCRah À cells and the most mature CD4 À CD8 À TCRah hi , CD4 + CD8 À TCRah hi and CD4 À CD8 + TCRah hi cells, while the percentage of positively selected CD4 + CD8 + TCRah hi cells was decreased.
T42 629204-629498 Sentence denotes This increase in the percentages of the least mature and the most mature thymocyte subsets, suggest the involvement of somatostatin-14 applied intracerebroventriculary in the modulation of T cell maturation, whose consequence could be appearance of CD4 À CD8 À TCRah + regulatory T cell subset.
T43 629499-629563 Sentence denotes Thyroid hormone regulation of immune responses was demonstrated.
T44 629564-629883 Sentence denotes In addition, differential expression of protein kinase C (PKC) isoenzymes and high nitric oxide synthase (NOS) activity were described on tumor respect to normal T lymphocytes. l-Thyroxine (T4)-mediated actions on both enzymatic activities, related to T lymphocyte and BW5147 T lymphoma cell proliferation were studied.
T45 629884-630055 Sentence denotes Thyroid hormones increased tumor, but not normal, cell proliferation and potentiated mitogen-stimulation of T lymphocytes as measured by tritiated-thymidine incorporation.
T46 630056-630250 Sentence denotes Twentyfour-hour incubation with T4 induced a rise in total and membraneassociated PKC activities, as measured by [gamma-32 P]-ATP phosphorylation of a PKC specific substrate, on both cell types.
T47 630251-630393 Sentence denotes In addition, T4 potentiated mitogen-induced PKC translocation in normal T lymphocytes and lead to a rapid and transient effect on tumor cells.
T48 630394-630540 Sentence denotes T4 increased atypical PKC zeta expression on BW5147, but classical PKC isoenzymes on mitogen-stimulated normal T cells by immunoblotting analysis.
T49 630541-630671 Sentence denotes Additionally, T4 augmented NOS activity, measured by production of [U-14 C]citrulline from [U-14 C]-arginine, only on tumor cells.
T50 630672-630795 Sentence denotes These results show, for the first time, differential intracellular signals involved in T4 modulation of lymphocyte biology.
T51 630796-630873 Sentence denotes Substance P involvement in chemotactic activity of human brain endothelium C.
T52 630874-630886 Sentence denotes Cioni and P.
T53 630887-630897 Sentence denotes Annunziata
T54 630898-631051 Sentence denotes In the last few years, the mechanism underlying the recruitment of T lymphocytes through the blood-brain barrier has been receiving increasing attention.
T55 631052-631340 Sentence denotes Recently, substance P (SP), a neuropeptide with a number of proinflammatory properties, has been found to be produced and released by cytokine-stimulated brain endothelium in rodents and to mediate leakage and activation of brain endothelium cultures exposed to proinflammatory cytokines.
T56 631341-631665 Sentence denotes To test whether SP could exert chemotactic activity at the human blood-brain barrier, we analysed SP production by human brain endothelium (HBE) cultures exposed to proinflammatory cytokines (TNF-alpha, IFN-gamma) and tested whether SP may mediate the chemotactic activity of cytokine-stimulated HBE for human T lymphocytes.
T57 631666-631772 Sentence denotes Biotin-labelled T lymphocytes were seeded on the membrane and HBE cells on the bottom of a Boyden chamber.
T58 631773-631855 Sentence denotes Biotin-labelled T cells that migrated to the chamber bottom were assayed by ELISA.
T59 631856-631986 Sentence denotes SP immunoreactivity was found on the surface of cytokine-stimulated human brain endothelial cells and in the culture supernatants.
T60 631987-632162 Sentence denotes Low rate (11%) of T cells migrated through chamber membrane in the presence of unstimulated HBE, increasing up more than 50% when HBE was exposed to proinflammatory cytokines.
T61 632163-632278 Sentence denotes This percentage returned to baseline values when spantide, a SP antagonist or anti-SP polyclonal antibody was used.
T62 632279-632386 Sentence denotes These findings demonstrate that SP is involved in chemotactic activity of in vitro cytokine-stimulated HBE.
T63 632387-632397 Sentence denotes Objective:
T64 632398-632527 Sentence denotes To analyze beta adrenergic receptor (BAR) regulation of T lymphocyte proliferation in mice according to different thyroid status.
T65 632528-632536 Sentence denotes Methods:
T66 632537-632708 Sentence denotes Specific radioligand binding assays were performed on T cells from eu-, hypothyroid (by propylthiouracil treatment) and hyperthyroid (by thyroxine-T4-administration) mice.
T67 632709-632805 Sentence denotes Beta-agonist isoproterenol effects on intracellular levels of cyclic AMP (cAMP) were determined.
T68 632806-632892 Sentence denotes Mitogeninduced T-cell proliferation was measured by tritiated-thymidine incorporation.
T69 632893-633006 Sentence denotes Protein kinase C (PKC) activity in cytosol and membrane were determined using radiolabelled enzymatic substrates.
T70 633007-633015 Sentence denotes Results:
T71 633016-633249 Sentence denotes A decrease or a not significant increase in BAR number was found, respectively, on T cells from hypo-and hyperthyroid and ISO-stimulation of cAMP was lower in hypothyroid and higher in hyperthyroid T lymphocytes, respect to controls.
T72 633250-633357 Sentence denotes T-selective mitogen-induced proliferation was increased in hyperthyroidism but decreased in hypothyroidism.
T73 633358-633425 Sentence denotes BAR was downregulated during the proliferation peak in all animals.
T74 633426-633514 Sentence denotes A higher or a lower decrease was observed respectively in hyper-and hypothyroid T cells.
T75 633515-633633 Sentence denotes A higher translocation of PKC activity in hyperthyroid cells, and a lower one in hypothyroid lymphocytes was observed.
T76 633634-633646 Sentence denotes Conclusions:
T77 633647-633890 Sentence denotes Intracellular signals triggered by mitogen activation would be related to differential BAR down-regulation in T lymphocytes depending on the thyroid status, contributing to the distinct proliferative responses found in hypo-or hyperthyroidism.
T78 633891-634011 Sentence denotes Endogenous catecholamines (CA) in peripheral blood mononuclear cells (PBMCs) contribute to activation-induced apoptosis.
T79 634012-634185 Sentence denotes PBMCs from multiple sclerosis (MS) patients are less susceptible to apoptosis and we previously showed dysregulated CA production under phytohaemagglutinin (PHA)stimulation.
T80 634186-634421 Sentence denotes Since interferon (IFN)-beta positively modifies MS course, we investigated CA production, expression of mRNA for tyrosine hydroxylase (TH, the limiting enzyme in CA synthesis), and apoptosis in PBMCs from patients undergoing treatment.
T81 634422-634585 Sentence denotes So far, 38 relapsing-remitting MS patients were included: data are presently available from 27, 23, 13, 6 patients with 1, 3, 6, 12 months follow-up, respectively.
T82 634586-634665 Sentence denotes TH mRNA increased during the first 3 months, then decreased to baseline levels.
T83 634666-634769 Sentence denotes CA production and efflux increased similarly in the first quarter, then maintained high plateau levels.
T84 634770-634947 Sentence denotes The capacity of IFN-gamma added in vitro to inhibit CA production decreased progressively and the antagonistic effect of IFN-beta in vitro increased consistently with treatment.
T85 634948-635119 Sentence denotes Pharmacological inhibition of CA production significantly reduces apoptosis in healthy subjects: this effect was not observed in MS patients, even during IFN-beta therapy.
T86 635120-635293 Sentence denotes Our results suggest that IFN-beta treatment antagonises IFN-gamma on TH mRNA expression and CA production, but its relevance on activation-induced apoptosis remains unclear.
T87 635294-635407 Sentence denotes A longer follow-up is warranted to assess possible differences between responders and non-responders to IFN-beta.
T88 635408-635563 Sentence denotes EAE is a animal chronic inflammatory demyelinating disease of the central nervous system (CNS) serving as a useful model for human multiple sclerosis (MS).
T89 635564-635687 Sentence denotes Previous studies have shown that the severity of MS and EAE is reduced by increased level of sex hormones during pregnancy.
T90 635688-635854 Sentence denotes In this study, we demonstrate that estrogen treatment led to the induction of a novel subpopulation of regulatory cells, which also occurs naturally in pregnant mice.
T91 635855-636052 Sentence denotes These previously uncharacterized cells display a low level expression of CD45 (CD45 dim ), and no detectable expression of many cell surface markers related to TCR signaling, including CD3 and TCR.
T92 636053-636103 Sentence denotes However, these cells retained expression of VLA-4.
T93 636104-636250 Sentence denotes Several lines of evidence suggest that these novel cells defined as CD45 dim VLA-4 + may play a role in the protective effects of estrogen on EAE.
T94 636251-636347 Sentence denotes Injection of purified CD45 dim VLA-4 + cells conferred protection from spontaneous EAE (Sp-EAE).
T95 636348-636454 Sentence denotes CD45 dim VLA-4 + cells also suppressed antigen-specific proliferation of primed lymphocytes in co-culture.
T96 636455-636695 Sentence denotes A better understanding of how CD45 dim VLA-4 + cells suppress harmful immune response of EAE may explain the induction of immune tolerance during pregnancy and lead to novel therapeutic approaches to combat MS and other autoimmune diseases.
T97 636696-636806 Sentence denotes Effects of exposure to formaldehyde and NO 2 on neurotransmitterrelated mRNAs expression in the mouse brain M.
T98 636807-636822 Sentence denotes Kakeyama a , Y.
T99 636823-636838 Sentence denotes Kurokawa a , S.
T100 636839-636854 Sentence denotes Yamamoto a , R.
T101 636855-636866 Sentence denotes Hojo a , N.
T102 636867-636882 Sentence denotes Kunigita b , H.
T103 636883-636894 Sentence denotes Hori b , K.
T104 636895-636914 Sentence denotes Arashidani b and H.
T105 636915-637103 Sentence denotes Fujimaki a a Environmental Health Sciences Division, National Institute for Environmental Studies, Tsukuba, Japan; b University of Occupational and Environmental Health, Kita-Kyushu, Japan
T106 637104-637280 Sentence denotes Effects of low-dose exposure to two types of air pollutants, formaldehyde (FA) and nitrogen dioxide (NO 2 ) on the brain neural transmitter-related mRNAs were examined in mice.
T107 637281-637695 Sentence denotes Female C3H/He mice (10 weeks old) were exposed to 400 ppb of FA for 12 weeks (16-h daily, 5 days/week), or 1 ppm of NO 2 for 3 weeks and levels of expression of glutamate receptor subunits (GluR1, GluR2, epsilon1 and epsilon2), dopamine receptors (D1) and serotonin receptors (5-HT1A) mRNAs were semi-quantified by RT-PCR in the neocortex (NC), the hippocampus (HIP), the amygdala (AMG), and the hypothalamus (HT).
T108 637696-637902 Sentence denotes Exposure to FA resulted in the increase in epsilon1 mRNA levels in the NC and HIP, epsilon1, epsilon2 and D1 mRNAs in the AMG, and 5-HT1A mRNA in the HT, and reduced epsilon 2 mRNA levels in the NC and HIP.
T109 637903-637995 Sentence denotes On the other hand, exposure to NO 2 caused a reduction of these all mRNAs in NC, HIP and HT.
T110 637996-638133 Sentence denotes These results indicate that the brain neurotransmitter-related mRNAs can be a sensitive marker for effects of exposure to air pollutants.
T111 638134-638342 Sentence denotes In addition, there arise a possibility that difference between patterns of changes in neurotransmitter-related mRNAs after exposure to FA or NO 2 reflects the difference in neurotoxicity between FA and NO 2 .
T112 638343-638353 Sentence denotes Rationale:
T113 638354-638519 Sentence denotes Cyclosporin A (CsA) attenuates antinociceptory effects of morphine, development and expression of morphine-induced tolerance and dependency via nitric oxide pathway.
T114 638520-638531 Sentence denotes Objectives:
T115 638532-638699 Sentence denotes In our study, the effect of systemic CsA on the morphine-induced conditioned place preference (CPP) and the probable involvement of nitric oxide were assessed in mice.
T116 638700-638708 Sentence denotes Methods:
T117 638709-638889 Sentence denotes The effect of morphine (0.5-10 mg/kg), CsA (5, 10, 20 mg/kg) and N G -nitro-l-arginine methyl ester, l-NAME, (2.5, 5, 10 mg/kg) administration on the induction of CPP was assessed.
T118 638890-639062 Sentence denotes The effects of CsA, l-NAME and also co-administration of CsA (1, 2.5, 5 mg/ kg) and l-NAME (2.5 mg/kg) on the acquisition of CPP induced by morphine (5 mg/kg) were studied.
T119 639063-639071 Sentence denotes Results:
T120 639072-639217 Sentence denotes Our data showed that administration of morphine significantly increased the time spent in the drug-paired compartment in a dose-dependent manner.
T121 639218-639362 Sentence denotes CsA (5, 10 mg/kg) and l-NAME (2.5, 5, 10 mg/kg) did not induce either CPP or conditioned place aversion (CPA), while CsA (20 mg/kg) induced CPA.
T122 639363-639534 Sentence denotes Both CsA (10, 20 mg/kg) and l-NAME (5, 10 mg/kg), in combination with morphine (5 mg/kg) during conditioning, significantly suppressed acquisition of morphine-induced CPP.
T123 639535-639720 Sentence denotes Lower and per se non-effective doses of CsA (1, 2.5, 5 mg/kg) and l-NAME (2.5 mg/kg), while coadministered, exerted a significant potentiating inhibitory effect on morphine-induced CPP.
T124 639721-639733 Sentence denotes Conclusions:
T125 639734-639785 Sentence denotes CsA attenuates the reinforcing effects of morphine.
T126 639786-639852 Sentence denotes This effect is potentiated by inhibition of nitric oxide synthase.
T127 639853-639979 Sentence denotes Cortisol, cytokines and symptom severity in patients with schizophrenia during treatment with risperidone and haloperidol X.Y.
T128 639980-640018 Sentence denotes Zhang Peking University, Beijing, P.R.
T129 640019-640037 Sentence denotes China Backgrounds:
T130 640038-640250 Sentence denotes The aim of this study was to investigate the inter-relationships among cortisol, cytokines and symptoms in schizophrenia, and to compare the effects of typical and atypical antipsychotic drugs on these variables.
T131 640251-640259 Sentence denotes Methods:
T132 640260-640421 Sentence denotes Seventy-eight schizophrenia were randomly assigned to 12 weeks of treatment with 6 mg/day of risperidone or 20 mg/day of haloperidol using a double-blind design.
T133 640422-640467 Sentence denotes Clinical efficacy was determined using PANSS.
T134 640468-640604 Sentence denotes Serum cortisol and IL-2 was assayed by RIA, and serum IL-6 by quantitative ELISA, as compared to 30 sex-and age-matched normal subjects.
T135 640605-640613 Sentence denotes Results:
T136 640614-640698 Sentence denotes Serum levels of cortisol, IL-2 and IL-6 were elevated in schizophrenia (all pb0.05).
T137 640699-640814 Sentence denotes The elevated cortisol was associated with the increased IL-2 and IL-6 in schizophrenia, respectively (both pb0.01).
T138 640815-640914 Sentence denotes Cortisol was associated with negative symptoms ( pb0.05) and IL-2 with positive symptoms ( pb0.05).
T139 640915-641135 Sentence denotes As compared with haloperidol, risperidone decreased the elevated cortisol and improved negative symptoms significantly (both pb0.05), but had similar effects on IL-2 and IL-6 as well as on positive symptoms (all pN0.05).
T140 641136-641252 Sentence denotes The improvement of negative symptoms of schizophrenia was related to the change in cortisol (r=0.34, df=69, pb0.01).
T141 641253-641265 Sentence denotes Conclusions:
T142 641266-641478 Sentence denotes Schizophrenia may have hypothalamic-pituitary-adrenal (HPA) axis and cytokines dysregulation, which may be implicated in clinical symptoms of schizophrenia, and further in the response to antipsychotic treatment.
T143 641479-641713 Sentence denotes The aim of this study was to investigate perceived stress, neuroimmune function, Th1/Th2 cytokine balance and allergy symptoms in medical students, with and without atopy, during a calm and stressful (exam) period of academic studies.
T144 641714-641870 Sentence denotes Among several studied parameters, results from questionnaires, phenotyping of white blood cells, cytokine assays, urine cortisol measurements are presented.
T145 641871-641995 Sentence denotes Participants perceived elevated stress in response to examination, which was accompanied with an increase in urine cortisol.
T146 641996-642106 Sentence denotes The CD4/CD8 ratio was increased in both groups during stress, while the total number of T cells was unaltered.
T147 642107-642173 Sentence denotes The number of NK cells decreased in atopic subjects during stress.
T148 642174-642247 Sentence denotes Interestingly, regulatory T cells increased during stress in both groups.
T149 642248-642385 Sentence denotes The cytokine profiles in atopic subjects reflected a Th2-like predominance in response to stress, which was not seen in healthy subjects.
T150 642386-642538 Sentence denotes We conclude that perceived stress, Th1/Th2 cytokine profiles and important immunoregulatory lymphocyte subsets were observed in response to examination.
T151 642539-642695 Sentence denotes Some immune parameters, such as NK cell numbers and cytokine profiles were differentially regulated in atopic and healthy individuals in response to stress.
T152 642696-642827 Sentence denotes However, other parameters, such as the CD4/CD8 ratio and the number of regulatory T cells, were similarly regulated in both groups.
T153 642828-642947 Sentence denotes Our results indicate that healthy and atopic subjects share certain features of a stress response but differ in others.
T154 642948-643106 Sentence denotes The autoimmune sialadenitis developed by NOD mice is a suitable model to study the ethiopathogenic mechanisms leading to sicca symptoms in Sjfgren's syndrome.
T155 643107-643433 Sentence denotes As both nitric oxide and vasoactive intestinal peptide (VIP) are common messengers to nervous and immune systems mediating secretory and inflammatory responses, we examined nitric oxide synthase activity with special focus on VIP-mediated effects in salivary glands of NOD mice and Th1/Th2 cytokine balance in sera and glands.
T156 643434-643662 Sentence denotes We measured NOS by the conversion of l-[U-14 C]arginine to citruline in submandibular and parotid glands of NOD and BALB/c mice and the levels of cytokines in sera, supernatants of splenocytes and homogenates of salivary glands.
T157 643663-643828 Sentence denotes We found a decreased NOS activity and NO-mediated signaling in salivary glands of NOD mice that starts at 12 weeks coincident with the onset of salivary dysfunction.
T158 643829-644000 Sentence denotes The increase of IL-12, TNF-alpha and IFN-gamma levels in sera was detected 3 weeks later and at this time no changes in cytokine levels could be stated in salivary glands.
T159 644001-644080 Sentence denotes Infiltrates in the glands appeared at 20 weeks as well as histological lesions.
T160 644081-644271 Sentence denotes Our results support the hypothesis of an impaired NO production and signaling in salivary glands as early events to take place in NOD glands and these events precede the autoimmune response.
T161 644272-644378 Sentence denotes Autoantibodies to the brain opiate and glutamate receptors as putative biomarkers of morphine addiction O.
T162 644379-644395 Sentence denotes Granstrem a , W.
T163 644396-644410 Sentence denotes Adriani b , D.
T164 644411-644432 Sentence denotes Giannakopoulou b , S.
T165 644433-644449 Sentence denotes Dambinova c , G.
T166 644450-644468 Sentence denotes Izykenova c and G.
T167 644469-644781 Sentence denotes Laviola b a IP Pavlov's State Medical University, St. Petersburg, Russia; b Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità , Rome, Italy; c Emory University, Atlanta, USA Knowledge on the pathophysiological changes, underlying loss of control over drug intake, is still rather limited.
T168 644782-644986 Sentence denotes We have recently developed a novel approach based on the hypothesis that autoimmune responses, which are well documented for several nervous-system disorders, may also occur in the drug-addicted organism.
T169 644987-645077 Sentence denotes Human heroin addicts present elevated levels of autoantibodies (aAbs) to opioid receptors.
T170 645078-645173 Sentence denotes In the present study, SD rats were administered morphine (5 mg/kg s.c.) once daily for 2 weeks.
T171 645174-645366 Sentence denotes The levels of aAbs to mu-delta opioid (MDOR) and glutamate (GluR1 AMPA and NR2A/B NMDA) receptors in the rat serums were determined with synthetic peptides as antigens (0.5 ng per ELISA well).
T172 645367-645548 Sentence denotes Confirming previous reports, morphine treatment increased significantly serum titers of autoantibodies against opioid and AMPA glutamate receptors, but not NMDA glutamate receptors.
T173 645549-645642 Sentence denotes It is possible to hypothesize that an autoimmune response to repeated drug exposure occurred.
T174 645643-645794 Sentence denotes The relationship between presence in the plasma of autoantibodies to these neuroreceptors and pathological changes in brain function is so far unknown.
T175 645795-645892 Sentence denotes Circulating autoantibodies may functionally affect the AMPA glutamatergic input within the brain.
T176 645893-646001 Sentence denotes Noteworthy, AMPA receptors have been very recently implicated in drug-seeking behavior and addictive habits.
T177 646002-646012 Sentence denotes Objective:
T178 646013-646237 Sentence denotes To determine if neuropsychiatric manifestations in patients with systemic lupus erythematosus (SLE) are influenced by anti-DNA antibodies cross-reacting with the human N-methyl-d-aspartate (NMDA) receptor types NR2a or NR2b.
T179 646238-646246 Sentence denotes Methods:
T180 646247-646443 Sentence denotes A decapeptide was synthesized containing a sequence motif present in the extra-cellular ligand-binding domain of NMDA receptors NR2a and NR2b, bound by the monoclonal murine anti-DNA antibody R4A.
T181 646444-646699 Sentence denotes In an ELISA-assay with the murine monoclonal R4v as positive control, plasma samples of 57 patients with SLE were examined for the anti-peptide (anti-NR2) antibody after the patients had been subjected to comprehensive psychological and cognitive testing.
T182 646700-646708 Sentence denotes Results:
T183 646709-646836 Sentence denotes Seven out of 31 neuropsychological variables were associated with elevated levels of anti-NR2 antibody in a correlation matrix.
T184 646837-646950 Sentence denotes These candidate variables were entered into a MANOVA statistical model with anti-NR2 as the independent variable.
T185 646951-647291 Sentence denotes Poor performance on the Visual Paired Associates Test (immediate), the Grooved Pegboard Test, as well as high scores on the Beck Depression Inventory, and scales D-2 (Depression), Pd-4 (Psychopathic deviate), Sc-8 (Schizophrenia), and Ma-9 (Hypomania) of the MMPI-2 were significantly associated with elevated levels of anti-NR2 antibodies.
T186 647292-647303 Sentence denotes Conclusion:
T187 647304-647459 Sentence denotes Findings in several domains indicate an association between anti-NR2 antibodies and depressed mood in addition to decreased short time memory and learning.
T188 647460-647575 Sentence denotes Antibodies to NMDA-receptors may represent one of several mechanisms for cerebral dysfunction in patients with SLE.
T189 647576-647680 Sentence denotes It has been suggested that schizophrenia and affected disorders may be associated with viral infections.
T190 647681-647793 Sentence denotes However, search for viral nucleic acids in the brain of patients with schizophrenia revealed a paucity of virus.
T191 647794-647986 Sentence denotes We hypothesized that T cells found in the CSF of patients with schizophrenia may contain populations of T cells that initially responded to the virus (although the virus is no longer present).
T192 647987-648268 Sentence denotes Using the NPA-PCR/V betaspecific PCR, we demonstrated high proportions of identical beta-chain TCR transcripts in the CSF of seven out of seven patients with schizophrenia or affective disorders, suggesting the presence of antigen(s)-driven clonally expanded population of T cells.
T193 648269-648363 Sentence denotes These T cell clonal expansions may be the only remaining trace of the initial viral infection.
T194 648364-648502 Sentence denotes Alternatively, these T cells may be generated in response to reactivation of a viral infection, or molecular mimicry or epitope spreading.
T195 648503-648578 Sentence denotes In contrast, TCR transcripts from the CSF of normal donors were polyclonal.
T196 648579-648757 Sentence denotes It is unknown whether clonally expanded T cells in the CSF of patients with schizophrenia and affective disorders contribute to brain tissue loss and mental/cognitive impairment.
T197 648758-648837 Sentence denotes Psycho-immunological evaluation of stress preventive intervention programmes U.
T198 648838-648846 Sentence denotes Sack, K.
T199 648847-648856 Sentence denotes Meier, K.
T200 648857-648869 Sentence denotes Bauer and M.
T201 648870-648915 Sentence denotes Stqck University of Leipzig, Leipzig, Germany
T202 648916-649127 Sentence denotes We aimed to examine immunological and psychological parameters reflecting stress management capabilities, particularly the correlation between self-regulative therapeutic stimuli and immunoglobuline A in saliva.
T203 649128-649362 Sentence denotes As part of the integrative stress management training-concept for schools, a 10-week stress management training as well as the intervention method Biodanza, based on motions, emotions, and body contact, were carried out with teachers.
T204 649363-649460 Sentence denotes It was the aim of this intervention to enable teachers to better cope with their daily pressures.
T205 649461-649567 Sentence denotes The effects of both intervention methods were to be determined in an accompanying processevaluation study.
T206 649568-649826 Sentence denotes For this purpose, health-psychological (stress-relevant psychological variables; work-related behavioural and experience patterns) as well as psychological (blood pressure, skin resistance) and immunological variables (immunoglobulin A in saliva) were taken.
T207 649827-649925 Sentence denotes Twenty-four teachers were investigated before and after the sessions of both intervention studies.
T208 649926-649992 Sentence denotes Parallel to this, different emotional parameters were ascertained.
T209 649993-650081 Sentence denotes For both methods, overwhelming effects in improving stress resistance could be verified.
T210 650082-650189 Sentence denotes In saliva, increase of immunoglobulin A could be found in persons with a positive response to our training.
T211 650190-650338 Sentence denotes Furthermore, a significant positive correlation between the subjective sensation of relaxation or other health parameters and IgA could be measured.
T212 650339-650430 Sentence denotes Both procedures could be shown to be effective in improving stress management capabilities.
T213 650431-650530 Sentence denotes Psychological and subjective parameters correlated well with saliva immunoglobulin A concentration.
T214 650531-650686 Sentence denotes Therefore, measurement of this simple immunological parameter could be proved to be a reliable indicator for stress resistance as well as training effects.
T215 650687-650750 Sentence denotes Changes of immune and endocrine parameters in PTSD over time A.
T216 650751-650765 Sentence denotes Vidovic a , K.
T217 650766-650780 Sentence denotes Gotovac a , M.
T218 650781-650795 Sentence denotes Vilibic b , A.
T219 650796-650814 Sentence denotes Sabioncello a , S.
T220 650815-650829 Sentence denotes Rabatic a , V.
T221 650830-650855 Sentence denotes Folnegovic-Smalc b and D.
T222 650856-650955 Sentence denotes Dekaris a a Institute of Immunology, Zagreb, Croatia; b Vrapce Psychiatry Hospital, Zagreb, Croatia
T223 650956-651256 Sentence denotes Our study performed on post traumatic stress disorder (PTSD) patients within 8 years from traumatic event revealed elevated plasma cortisol level and lower glucocorticoid receptors (GRs) expression in examined lymphocyte populations opposite to studies performed decades following exposure to trauma.
T224 651257-651432 Sentence denotes We assumed that more time is needed for reversal of hormone and its receptor expression to take place due to hyperactivity of hypothalamic-pituitary-adrenocortical (HPA) axis.
T225 651433-651546 Sentence denotes Participants were 18 Croatian war veterans with PTSD and 10 age-matched civilian controls retested 5 years later.
T226 651547-651707 Sentence denotes Proportions of main lymphocyte populations and their activated subpopulations, as well as GRs expression in these populations were determined by flow cytometry.
T227 651708-651766 Sentence denotes Cortisol levels were determined by RIA (radioimmunoassay).
T228 651767-651821 Sentence denotes NK cell activity was measured by 51 Cr-release assays.
T229 651822-651995 Sentence denotes Platelet activation status was determined by flow cytometry according to expression of CD63 activation marker and proportion of leukocyte-platelet aggregates in circulation.
T230 651996-652186 Sentence denotes We found decreased percentages of Tc and total memory cells but did not reveal significant changes over time in GRs expression on total T, B and NK cells in this preliminary follow-up study.
T231 652187-652287 Sentence denotes Brain atrophy and aberrant behaviour are common complications of systemic lupus erythematosus (SLE).
T232 652288-652453 Sentence denotes Considering that their etiology is unknown, we use aberrant behaviour in lupus-prone MRL-lpr mice to reveal pathogenic mechanisms of autoimmunity-induced CNS damage.
T233 652454-652569 Sentence denotes We previously documented profound damage in the dopaminergic system, both in human and animal forms of the disease.
T234 652570-652729 Sentence denotes The present study explores the course of self-injurious behaviour (SIB) after sustained pharmacological challenge with quinpirole (QNP), a D2-receptor agonist.
T235 652730-652828 Sentence denotes The MRL-lpr mice and congenic controls were injected with QNP (i.p., 0.5 mg/kg) daily for 15 days.
T236 652829-652944 Sentence denotes This treatment gradually decreased grooming frequency, but increased duration of grooming episodes in both strains.
T237 652945-653088 Sentence denotes However, these effects were less profound in the MRL-lpr group with 60% of these animals showing advanced SIB with repeated QNP administration.
T238 653089-653253 Sentence denotes This was not seen in the age-matched, nonautoimmune CD1 strain of mice, suggesting that autoimmunity is required for emergence of the aberrant behavioural response.
T239 653254-653422 Sentence denotes We presently examine whether SIB is associated with excessive damage of the dopaminergic system and whether SIB can be induced before autoimmune manifestations develop.
T240 653423-653621 Sentence denotes Currently, obtained results support the hypothesis that chronic inflammation and autoimmunity damage dopaminergic neurons and increase the sensitivity of their cognate receptors thus underlying SIB.
T241 653622-653673 Sentence denotes This work was supported by funds from the NIH to B.
T242 653674-653738 Sentence denotes Sakic, who is a recipient of the FSORC career development award.
T243 653739-653741 Sentence denotes S.
T244 653742-653796 Sentence denotes Chun is a recipient of the NSERC Graduate Scholarship.
T245 653797-653973 Sentence denotes There is evidence of a bidirectional communication between Central Nervous System (CNS) and Immune System (IS), and that opioids exert a modulatory role on the immune response.
T246 653974-654308 Sentence denotes Our main goal was to study: (1) the influence of acute and chronic d-amphetamine treatment on ConAinduced lymphocyte proliferation in rats, (2) the participation of dopaminergic and opioidergic systems in these effects, (3) the amphetamineinduced effects on proenkephalin and derived peptides in immune organs and different CNS areas.
T247 654309-654486 Sentence denotes Wistar rats received chronic (1 or 2 mg/kg/day for 5 days IP) or acute (2.5 or 5 mg/kg IP) amphetamine; 4 days after the last injection, the proliferative response was assessed.
T248 654487-654658 Sentence denotes Since similar immunosuppressive effects were observed following acute and chronic treatments, Naloxone, SCH-23390 and Sulpiride were given only before 5 mg/kg amphetamine.
T249 654659-654778 Sentence denotes Since all antagonists abolished the amphetamine-induced effects on IS, dopamine and opioid systems seem to be involved.
T250 654779-654886 Sentence denotes The proenkephalin and derived peptides levels in the CNS and IS were studied following 5 mg/kg amphetamine.
T251 654887-654989 Sentence denotes An increase in Met-enkephalin was observed in spleen, thymus, nucleus accumbens and prefrontal cortex.
T252 654990-655205 Sentence denotes These changes in Met-enkephalin point out that it could be used as a common biological marker of pertinent stimuli (i.e. psychostimulant drug) acting at SI and SNC, and reflect the functional changes at both levels.
T253 655206-655289 Sentence denotes Morphofunctional characteristics of the rat thymus exposed to forced swim stress A.
T254 655290-655299 Sentence denotes Rakin, I.
T255 655300-655312 Sentence denotes Zivkovic, D.
T256 655313-655335 Sentence denotes Petrovic-Djergovic, D.
T257 655336-655348 Sentence denotes Kosec and M.
T258 655349-655354 Sentence denotes Micic
T259 655355-655573 Sentence denotes Having in mind recent studies about the effects of stress on the immune system, we investigated whether chronic stress, induced by the forced swimming procedure, alters the morphofuncional parameters in the rat thymus.
T260 655574-655716 Sentence denotes For this purpose, adult male rats were exposed to the forced swimming during 21 days, on the first day 15 min and in the following days 5 min.
T261 655717-655936 Sentence denotes The experimental and control animals were sacrificed by decapitation, the thymuses were processed for morphometric and flow cytometry analysis and blood samples were taken for measurement of corticosterone level by RIA.
T262 655937-656245 Sentence denotes Our results showed that every day treatment with the same stimulus leads to reduction of (i) the thymus mass and cellularity, (ii) the volume of thymus cortex and medulla, (iii) numerical density of thymocytes in the inner cortex and medulla and (iv) the number of thymocytes in the both thymus compartments.
T263 656246-656350 Sentence denotes However, the percentage of apoptotic cells and the level of corticosterone were significantly increased.
T264 656351-656494 Sentence denotes The phenotypic analysis of thymocyte subpopulations showed significantly decreased percentage of the least mature CD4 + CD8 À TCR À thymocytes.
T265 656495-656618 Sentence denotes On the other hand, the percentages of CD4 À CD8 À TCR low/high and CD4 À CD8 + TCR-thymocytes were significantly increased.
T266 656619-656776 Sentence denotes These results show that in adult rat recurred swimming procedure induces thymus hypotrophy, through change of the thymus compartments volume and cellularity.
T267 656777-656919 Sentence denotes Additionally, elevated percentage of CD4 À CD8 À TCR + cells suggests that chronic stress is involved in the modulation of T cells maturation.
T268 656920-657032 Sentence denotes The influence of restraint stress and beta-endorphin on inflammatory edema and macrophage function in AO rats K.
T269 657033-657045 Sentence denotes Mitic a , M.
T270 657046-657065 Sentence denotes Dimitrijevic a , V.
T271 657066-657078 Sentence denotes Vujic b , V.
T272 657079-657107 Sentence denotes Kovacevic-Jovanovic a and S.
T273 657108-657319 Sentence denotes Stanojevic a a Immunology Research Center bBranislav JankovicQ, Institute of Immunology and Virology bTorlakQ, Belgrade, Serbia; b Institute of Chemistry, University of Belgrade, Medical School, Belgrade, Serbia
T274 657320-657516 Sentence denotes The influence of i.pl. treatment with beta-Endorphin (beta-End, 0.01-10 Ag) and restraint stress (RS) on Concanavalin A (Con A)-induced paw edema were investigated in male Albino Oxford (AO) rats.
T275 657517-657788 Sentence denotes Besides, peritoneal macrophages obtained from intact and stressed rats of this strain were additionally in vitro treated with beta-End (10 À12 -10 À8 M) and tested for capacity to produce reactive oxygen species and reduce nitro blue tetrazolium salts (NBT) to formazans.
T276 657789-658012 Sentence denotes Results showed that Con-A-induced paw edema was suppressed by i.pl. treatment with 10 Ag of beta-End, which was antagonized by naltrindole and nor-binaltorphimine, suggesting involvement of delta and kappa opioid receptors.
T277 658013-658232 Sentence denotes Quite the opposite, 2 h of RS applied after but not before inflammation induction significantly increased diameter of inflamed paws in AO rats, but did not influence the NBT reduction capacity of peritoneal macrophages.
T278 658233-658555 Sentence denotes The NBT reduction was influenced by beta-End in such way that beta-End potentiated reactive oxygen radical production in unstimulated macrophages from animals exposed to RS, while dose-dependently increased and decreased NBT reduction in cells stimulated with phorbol myristate acetate in both intact and stressed animals.
T279 658556-658682 Sentence denotes It could be concluded that RS and beta-End exerted opposite effects on in vivo and in vitro inflammatory responses in AO rats.
T280 658683-658837 Sentence denotes The proinflammatory cytokine interleukin-1 beta (IL-1 beta) influences neuroendocrine activity and promotes central effects such as anxiety and anhedonia.
T281 658838-659074 Sentence denotes The melanocortin neuropeptides, like alpha melanocyte stimulating hormone (alpha-MSH), antagonize many actions of IL-1, including fever, anorexia and HPA axis activation through specific melanocortin receptors in central nervous system.
T282 659075-659154 Sentence denotes However, it is unknown if melanocortins can modulate IL-1 beta-induced anxiety.
T283 659155-659325 Sentence denotes The objective of the present study was to establish the effect of MSH peptides on IL-1 beta-induced anxiety-like behavior and the type of melanocortin receptors involved.
T284 659326-659618 Sentence denotes The present study evaluated the effects of intracerebroventricular (i.c.v.) administration of IL-1 beta (30 ng) and melanocortin receptor agonists: alpha-MSH, an MC3/MC4-R agonist (0,2 Ag) and gamma-MSH an MC3-R agonist (2 Ag) or HS014, an MC4-R antagonist (2 Ag), on elevated plus-maze test.
T285 659619-659748 Sentence denotes Injection of IL-1 beta induced an axiogenic-like response, as indicated by reduced open arms entries and time spent on open arms.
T286 659749-659816 Sentence denotes The administration of alpha-MSH reversed IL-1 beta-induced anxiety.
T287 659817-659877 Sentence denotes Coadministration of HS014 inhibited the effect of alpha-MSH.
T288 659878-659966 Sentence denotes The associated treatment with gamma-MSH did not affect the anxiety response to IL-1beta.
T289 659967-660088 Sentence denotes These data suggest that melanocortins, through central MC4-R can modulate the anxiety-like behavior induced by IL-1 beta.
T290 660089-660138 Sentence denotes Expression of Toll-like receptors in MG thymus P.
T291 660139-660156 Sentence denotes Bernasconi a , M.
T292 660157-660172 Sentence denotes Barberis b , M.
T293 660173-660187 Sentence denotes Cannone b , F.
T294 660188-660200 Sentence denotes Baggi a , E.
T295 660201-660215 Sentence denotes Arnoldi a , C.
T296 660216-660234 Sentence denotes Cappelletti a , F.
T297 660235-660252 Sentence denotes Cornelio a and R.
T298 660253-660535 Sentence denotes Mantegazza a a National Neurological Institute bCarlo BestaQ, Milan, Italy; b MultiMedica, Milan, Italy Myasthenia gravis (MG) is often associated with thymic alterations (hyperplasia, thymoma and thymitis); however, the aetiopathological basis of this association is still unknown.
T299 660536-660656 Sentence denotes Intercellular signals as well as surface molecules may represent key factors characterizing the thymic microenvironment.
T300 660657-660749 Sentence denotes Elements of innate immunity are emerging as contributors to the development of autoimmunity.
T301 660750-660906 Sentence denotes We studied, by semi-quantitative RT-PCR, the expression of Toll-like receptors (TLR) 2-5 in 38 myasthenic thymuses and in 4 non-pathological young thymuses.
T302 660907-660990 Sentence denotes TLR transcripts were found not differently expressed among groups, except for TLR4.
T303 660991-661164 Sentence denotes By realtime PCR, TLR4 mRNA expression was significantly higher in thymitis than in hyperplastic ( p=0.002), non-pathological young thymuses ( p=0.03) and thymoma ( p=0.048).
T304 661165-661299 Sentence denotes By immunohistochemistry, the protein was detected in all thymic subgroups analysed, but the extent of positivity was greatly variable.
T305 661300-661529 Sentence denotes In thymitis and hyperplastic thymuses, a strong TLR4 positivity was detected in correspondence of cytokeratin-positive cells within the thymic medulla, surrounding cortex and at the borders between cortical and medullary regions.
T306 661530-661614 Sentence denotes In thymoma and in young non-pathological thymuses, TLR4 protein was rarely detected.
T307 661615-661847 Sentence denotes These findings suggest a possible involvement of the innate immunity in thymus alterations characterized by an abnormal cell proliferation, and evoke the possibility that antigen mimicry might play a crucial role in MG pathogenesis.
T308 661848-661914 Sentence denotes In early-onset MG (EOMG), thymic infiltration is well established.
T309 661915-662130 Sentence denotes However, the thymus and its muscle-like myoid cells have not been well studied in patients without anti-AChR autoantibodies (seronegative MG)i.e. those with (MuSK Ab + ) or without (MuSK Ab À ) anti-MuSK antibodies.
T310 662131-662262 Sentence denotes The histopathology is usually reported as normal or involuted, and these patients are rarely thymectomised, unlike those with EOMG.
T311 662263-662477 Sentence denotes We compared thymic histology in patients with EOMG, MuSK Ab + and MuSK Ab À SNMG, labelling paraffin sections for mature T cells and germinal centres (GC), and for markers of inflammation and complement activation.
T312 662478-662559 Sentence denotes In most MuSK Ab + and 70% MuSK Ab À SNMG cases, the thymus appears normalfor-age.
T313 662560-662681 Sentence denotes B cells express only CD20 and are mainly in the medullary epithelial areas (MEA), near the apparently normal myoid cells.
T314 662682-662785 Sentence denotes Interestingly, in about 30% of MuSK Ab À cases, we see mild infiltration, very similar to that in EOMG.
T315 662786-662885 Sentence denotes B cells and follicular dendritic cells in GC express receptors for activated complement components.
T316 662886-663008 Sentence denotes Some of myoid cells are very close to, or within, the infiltrates where they appear to be under immune attack, as in EOMG.
T317 663009-663080 Sentence denotes We conclude that the thymus is normal or bburnt-outQ in MuSK Ab + SNMG.
T318 663081-663241 Sentence denotes By contrast, MuSK Ab À SNMG is heterogeneous; in one form, the target antigen may be expressed by thymic myoid cells, which seem to be involved in pathogenesis.
T319 663242-663350 Sentence denotes The target organ of myasthenia gravis (MG) is the postsynaptic membrane of the neuromuscular junction (NMJ).
T320 663351-663487 Sentence denotes The primary autoantigen, the acetylcholine receptor (AChR), is clustered and anchored in the postsynaptic membrane of the NMJ by rapsyn.
T321 663488-663636 Sentence denotes Previously, we found that a naturally increased rapsyn concentration in aged rats correlates with a resistance to experimental autoimmune MG (EAMG).
T322 663637-663777 Sentence denotes Here, we report that the overexpression of rapsyn by in vivo electroporation confers resistance to EAMG in treated legs of susceptible rats.
T323 663778-663873 Sentence denotes The rapsyn overexpression increased the level of AChR in muscles 2 weeks after electroporation.
T324 663874-663973 Sentence denotes In EAMG rats, rapsyn-overexpressing muscles showed no loss of AChR, in contrast to control muscles.
T325 663974-664158 Sentence denotes Repetitive nerve stimulation showed no decrement of the compound muscle action potential of the rapsynoverexpressing muscles, whereas sham-treated muscles of the same EAMG animals did.
T326 664159-664389 Sentence denotes Electron microscopic examination showed that endplates of rapsyn-overexpressing muscles of EAMG rats had a normal morphology of the postsynaptic folds, while endplates of sham-treated muscles of the same animals had damaged folds.
T327 664390-664540 Sentence denotes Rapsyn overexpression was effective to increase AChR levels in ongoing disease of chronic EAMG in the presence of high titers of anti-AChR antibodies.
T328 664541-664700 Sentence denotes These results suggest an important role for rapsyn in the susceptibility to EAMG and show a new promising therapeutic for treating myasthenia gravis in humans.
T329 664701-664828 Sentence denotes Induction of experimental autoimmune myasthenia gravis by an acetylcholine receptor peptide conjugated to lipopolysaccharide I.
T330 664829-664843 Sentence denotes Wirguin a , C.
T331 664844-664857 Sentence denotes Sicsic b , M.
T332 664858-664876 Sentence denotes Bersudsky a and T.
T333 664877-664993 Sentence denotes Brenner b a Ben-Gurion University, Beer-Sheva, Israel; b Hadassah University Hospital, Jerusalem, Israel Background:
T334 664994-665233 Sentence denotes Molecular mimicry is implicated in causing autoimmune disorders, such as Guillain-Barré syndrome which is attributed to crossreactivity between carbohydrate epitopes in Campylobacter jejuni lipopolysaccharides (LPS) and nerve gangliosides.
T335 665234-665328 Sentence denotes We showed that covalent bonding of LPS to gangliosides enhances immunity to self-gangliosides.
T336 665329-665339 Sentence denotes Objective:
T337 665340-665432 Sentence denotes To test the hypothesis that LPS-bound antigens could overcome tolerance to protein antigens.
T338 665433-665441 Sentence denotes Methods:
T339 665442-665619 Sentence denotes The decapeptide WNPDDYGGVK, [the main immunogenic region (MIR) of the chain of acetylcholine receptor (AChR)], was conjugated to Salmonella Re-LPS by heterodimeric crosslinking.
T340 665620-665766 Sentence denotes Lewis rats subcutaneously presented by Torpedo AChR or by MIR (days 1 and 21), received intraperitoneally 10 Ag of the MIR-LPS conjugate (day 28).
T341 665767-665808 Sentence denotes Control rats received MIR or Re-LPS only.
T342 665809-665934 Sentence denotes Animals were tested by repetitive nerve stimulation, by treadmill exercise tolerance and by immunoassays for AChR antibodies.
T343 665935-665943 Sentence denotes Results:
T344 665944-666072 Sentence denotes 15/25 LPS-MIR injected rats showed pathological decrements to repetitive nerve stimulation at 3 Hz compared to 2/25 of controls.
T345 666073-666177 Sentence denotes 4/12 MIR-LPS injected rats failed to complete 10 min of treadmill exercise compared to 1/13 of controls.
T346 666178-666281 Sentence denotes Rat AChR antibodies were detected by RIA in 3 of the MIR-LPS injected rats and in none of the controls.
T347 666282-666358 Sentence denotes Conclusion: MIR-LPS conjugates can induce EAMG without additional adjuvants.
T348 666359-666491 Sentence denotes The molecular bond of the LPS to the antigen appears to play an important role in overcoming tolerance to selfantigens such as AchR.
T349 666492-666693 Sentence denotes The expression level of interleukin-10 is related to the polymorphisms À1082 (G/A), À819 (T/C) and À592 (A/C) in the promotor region of the IL-10 gene constituting three haplotypes (GCC, ATA, and ACC).
T350 666694-666878 Sentence denotes The haplotype combination GCC/GCC is associated with high IL-10 expression, whereas GCC/ATA and GCC/ACC are associated with medium and ATA/ATA, ATA/ACC and ACC/ACC with low expression.
T351 666879-667046 Sentence denotes The distribution of these polymorphisms was analysed in 64 myasthenia gravis patients and 87 controls to determine whether they could influence disease susceptibility.
T352 667047-667128 Sentence denotes We found a different genotype distribution in MG patients compared with controls.
T353 667129-667193 Sentence denotes ACC/ACC and ATA/ATA were more frequent in MG patients ( p=0.02).
T354 667194-667369 Sentence denotes This was reflected in a higher frequency of ACC/ACC (21.4% vs. 3.4%) in thymoma MG patients ( p=0.05) and titin antibody positive MG patients (regardless of thymus pathology).
T355 667370-667545 Sentence denotes Early-onset MG patients and titin antibody negative MG patients (regardless of age of onset or thymus pathology) had a higher frequency of ATA/ATA (19.2% vs. 3.4%), ( p=0.05).
T356 667546-667646 Sentence denotes There were no differences between MG patients and controls for high, medium or low IL-10 expression.
T357 667647-667754 Sentence denotes Conclusions: MG patients with thymoma and thymus hyperplasia are associated with different IL-10 genotypes.
T358 667755-667928 Sentence denotes MG patients with titin antibodies are similar to thymoma patients while titin antibody negative patients are similar to early onset MG patients in regard to IL-10 genotypes.
T359 667929-668025 Sentence denotes The functional plasticity of dendritic cells (DC) makes them ideal targets for immuno-therapies.
T360 668026-668173 Sentence denotes From cancer immunology, we learn how the plasticity of DC function is ensured by capability of DC to both produce and respond to certain cytokines.
T361 668174-668294 Sentence denotes For example, melanomas or breast cancers are able to produce large amounts of IL-10, which modulate tumor-associated DC.
T362 668295-668362 Sentence denotes Such IL-10-modulated immature DC (IL-10-DC) induce anergic T cells.
T363 668363-668434 Sentence denotes However, cytokine-matured DC can induce effector T cells against tumor.
T364 668435-668522 Sentence denotes Here, we investigated therapeutic potentials of DC from EAMG rats modulated with IL-10.
T365 668523-668656 Sentence denotes Effects of IL-10-DC and LPS-matured DC on autologous T cell responses in MG compared to healthy controls (HC) were also investigated.
T366 668657-668739 Sentence denotes DC derived from EAMG rats, modulated in vitro with IL-10, ameliorate ongoing EAMG.
T367 668740-668832 Sentence denotes This was associated with suppression of both Th1 and Th2 cytokines, and of B cell responses.
T368 668833-668988 Sentence denotes Surprisingly, IL-10-DC from human MG, like mature DC, increased CD4 + CD25 + T cells expressing CD69, i.e. activated T cells, compared to IL-10-DC from HC.
T369 668989-669128 Sentence denotes IL-10-DC induced IL-10 and IL-4 production by T cells from MG patients, but only IL-10 production from HC, without affecting Th1 cytokines.
T370 669129-669456 Sentence denotes Conclusions: (a) IL-10-DC differently affect EAMG vs. MG in terms of T cell activation, and Th1/Th2 cytokine production; (b) IL-10-DC in MG have pronounced costimulatory capacity for Th2 cells, reflected by increased CD4 + CD25 + T cells expressing CD69 and increased production of IL-10 and IL-4, compared to IL-10-DC from HC.
T1 669457-669570 Sentence denotes The Lambert-Eaton myasthenic syndrome has a more progressive course in patients with small cell lung carcinoma P.
T2 669571-669580 Sentence denotes Wirtz, A.
T3 669581-669595 Sentence denotes Wintzen and J.
T4 669596-669874 Sentence denotes Verschuuren Leiden University Medical Centre, Leiden, The Netherlands HLA studies suggest a major difference in immunopathogenesis between HLA-B8-associated LEMS with small cell lung cancer (SCLC-LEMS) and non-HLA-associated LEMS without associated tumour (non-tumour, NT-LEMS).
T5 669875-670072 Sentence denotes In contrast, there is no known difference in the neurological signs and symptoms between SCLC-LEMS and NT-LEMS patients, but some reports suggest a more progressive course of disease for SCLC-LEMS.
T6 670073-670181 Sentence denotes We assessed in detail the chronology in which symptoms developed in 38 LEMS patients, of which 13 with SCLC.
T7 670182-670286 Sentence denotes Patients were interviewed using a structured checklist, backed up by a review of their clinical records.
T8 670287-670366 Sentence denotes We compared the frequency and time scale of symptoms during the course of LEMS.
T9 670367-670556 Sentence denotes In SCLC-LEMS patients, proximal leg weakness, dry mouth and impotence (in males) were the first symptoms, followed by proximal arm weakness, double vision, hand weakness and slurred speech.
T10 670557-670644 Sentence denotes In at least 50% of the SCLC-LEMS patients, all these symptoms occurred within 6 months.
T11 670645-670701 Sentence denotes All NT-LEMS patients started with proximal leg weakness.
T12 670702-670825 Sentence denotes A dry mouth was the only symptom that occurred in at least 50% of patients within 6 months after start of the leg weakness.
T13 670826-670981 Sentence denotes Symptoms in SCLC-LEMS patients developed within a shorter timeframe than in NT-LEMS patients, indicating a more progressive course of disease in SCLC-LEMS.
T14 670982-671101 Sentence denotes Therefore, in a patient with an aggressive course of LEMS one should be extra alerted for an underlying lung carcinoma.
T15 671102-671299 Sentence denotes Experimental autoimmune neuritis (EAN) is an inflammatory autoimmune demyelinating disease of peripheral nervous system (PNS) and represents an animal model of Guillain-Barré syndrome (GBS) in man.
T16 671300-671385 Sentence denotes The inflammatory cell infiltrating into the PNS is a prerequisite for developing EAN.
T17 671386-671558 Sentence denotes To explore the role of CC chemokine receptor 5 (CCR5) in the inflammatory process of EAN, we induced EAN in CCR5 deficient (CCR5 À/À ) mice with P0 protein peptide 180-199.
T18 671559-671849 Sentence denotes We found that CCR5 À/À mice showed a similar EAN clinical course and severity as well as profile of infiltrating macrophage and T cells in cauda equina (CE) of EAN and the same levels of spleen mononuclear cell (MNC) response to antigen and mitogen when compared with CCR5 +/+ control mice.
T19 671850-671946 Sentence denotes However, increased IP-10 and MIP-1alpha production in sciatic nerves were seen in CCR5 À/À mice.
T20 671947-672050 Sentence denotes These results suggest that CCR5 deficiency does not prevent P0 peptide 180-199 immunized mice from EAN.
T21 672051-672196 Sentence denotes Increased MIP-1alpha and IP-10 in sciatic nerves may compensate the CCR5 deficiency and contribute to inflammatory cells infiltrating to the PNS.
T22 672197-672347 Sentence denotes Guillain-Barré syndrome (GBS) is a post infectious polyradiculoneuropathy characterized by demyelination and axonal degeneration of peripheral nerves.
T23 672348-672499 Sentence denotes Inflammatory cells, predominantly macrophages and T cells, and humoral factors, including autoantibodies, have been implicated in disease pathogenesis.
T24 672500-672688 Sentence denotes We recently documented the capacity of GBS-associated anti-GM1 IgG to induce IgG receptor (FcgammaR)-mediated leukocyte activation, as measured by leukocyte degranulation and phagocytosis.
T25 672689-672822 Sentence denotes To investigate the association between antibody functionality and disease development, we used a recently described GBS rabbit model.
T26 672823-672935 Sentence denotes Immunization of rabbits with ganglioside mixtures results in the formation of high anti-GM1 IgG antibody titers.
T27 672936-673056 Sentence denotes Nevertheless, only GM1 specific antibodies from rabbits with clinical overt GBS induced leukocyte activation ( p=0.002).
T28 673057-673161 Sentence denotes Next, the phagocyte activating capacity of sequentially drawn sera from GBS-affected rabbits was tested.
T29 673162-673260 Sentence denotes Maximal phagocyte activation was detected 1 week before or at the occurrence of clinical symptoms.
T30 673261-673381 Sentence denotes Increased functionality may be explained by both the increase in specific antibody titer and increased antibody avidity.
T31 673382-673638 Sentence denotes Taken together, these data suggest that functionality of anti-ganglioside antibodies, as measured by in vitro assays, is associated with the presence of GBS clinical symptoms in rabbits, thus providing additional evidence for their pathogenic role in vivo.
T32 673639-673731 Sentence denotes Gangliosides are implicated as target antigens in various autoimmune neurological disorders.
T33 673732-673846 Sentence denotes IgM antibodies against b-series gangliosides including GD1b are associated with chronic sensory ataxic neuropathy.
T34 673847-673931 Sentence denotes Animal model of sensory ataxic neuropathy can be induced by sensitization with GD1b.
T35 673932-674049 Sentence denotes However, it has yet to be clarified whether GD1b is expressed on proprioceptive neurons of dorsal root ganglia (DRG).
T36 674050-674216 Sentence denotes Genetically engineered mice lacking in b-series gangliosides, immunologically naRve to GD1b, were immunized with GD1b to generate anti-GD1b monoclonal antibody (mAb).
T37 674217-674453 Sentence denotes Generation of anti-ganglioside antibodies upon immunization with GD1b was greatly enhanced, exhibited class switching to IgG isotypes and immunological memory, indicating that tolerance to self-gangliosides is a major regulatory factor.
T38 674454-674553 Sentence denotes Six clones with anti-GD1b IgG activity were obtained, three of which reacted exclusively with GD1b.
T39 674554-674648 Sentence denotes One of the monospecific anti-GD1b mAb preferentially stained the large cell bodies in rat DRG.
T40 674649-674801 Sentence denotes Immunohistochemical studies showed that GD1b co-localized with parvalbumin, but not with calcitonin gene-related peptide, substance P, and somatostatin.
T41 674802-674877 Sentence denotes This indicates that GD1b is expressed on proprioceptive neurons in rat DRG.
T42 674878-675069 Sentence denotes These results support the concept that anti-GD1b antibodies may cause selective injury to proprioceptive sensation of primary afferent neurons, and development of sensory ataxic neuropathies.
T43 675070-675163 Sentence denotes Effective prevention and treatment of experimental autoimmune neuritis with rapamycin T.Y.-H.
T44 675164-675174 Sentence denotes Lin and J.
T45 675175-675235 Sentence denotes Spies The University of Sydney, Sydney, Australia Objective:
T46 675236-675451 Sentence denotes To determine whether rapamycin, a relatively new immunosuppressive agent effective in preventing transplant rejection, is effective treatment for EAN, an animal model for human inflammatory demyelinating neuropathy.
T47 675452-675463 Sentence denotes Background:
T48 675464-675662 Sentence denotes Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) responds to immunomodulatory therapy but long term immunosuppressive therapy is often required, with significant associated toxicity.
T49 675663-675786 Sentence denotes Rapamycin has a more favorable side effect profile than agents such as cyclosporine which are currently used to treat CIDP.
T50 675787-675914 Sentence denotes Methods: EAN was induced in Lewis rats by immunization with peripheral nerve myelin or passive transfer of P2-specific T cells.
T51 675915-676099 Sentence denotes Rapamycin or placebo was administered daily by intraperitoneal injection commencing just prior to the expected onset of paralysis (prevention) or at the first signs of EAN (treatment).
T52 676100-676146 Sentence denotes Clinical grade and weight were recorded daily.
T53 676147-676234 Sentence denotes Neurophysiology and histological examination were performed at predetermined intervals.
T54 676235-676243 Sentence denotes Results:
T55 676244-676466 Sentence denotes Rapamycin given prior to the onset of disease prevented the development of significant paralysis in both EAN (mean clinical grade 0.1 vs. 3.4; pb0.00001) and adoptive transfer EAN (mean clinical grade 0 vs. 2.2; pb0.0002).
T56 676467-676677 Sentence denotes Rapamycin given at the onset of clinical weakness effectively reduced the severity (mean clinical grade 0.5 vs. 3.7; pb0.00001) and hastened recovery of clinical weakness and electrophysiological abnormalities.
T57 676678-676689 Sentence denotes Conclusion:
T58 676690-676869 Sentence denotes Rapamycin is effective in prevention and treatment of EAN and adoptive transfer EAN in Lewis rats and may be an effective and less toxic alternative treatment for refractory CIDP.
T59 676870-677041 Sentence denotes Based on the evidence that ONO-2506 suppresses S-100 protein production, preventive and therapeutic effects of this agent on immunemediated neuropathy were studied in EAN.
T60 677042-677309 Sentence denotes As to the preventive effect, neurological symptoms were remarkably lessened and the duration of disease was clearly shortened in the group receiving intraperitoneally ONO-2506 (10 mg/kg/day) every day after inoculation, as compared with the non-treated control group.
T61 677310-677692 Sentence denotes As to the therapeutic effect, a remarkable suppressive effects on the neurological symptoms and a clear shortening of the duration of disease were also noted in both the early phase-treated group receiving ONO-2506 for 7 days from the onset of limp tail and active phase-treated group receiving the agent for 7 days from the onset of paraparesis, as compared with non-treated group.
T62 677693-678109 Sentence denotes In the pathological observation at 30 days after antigen inoculation, remarkable demyelination and fibrosis were found in the non-treated group, whereas only a mild perivascular cell infiltration was noted in the preventively treated group, mild cellular infiltration and demyelination in the early phase-treated group and moderate cellular infiltration, demyelination and fibrosis in the active phase-treated group.
T63 678110-678198 Sentence denotes The above results suggested ONO-2506 to exert preventive and therapeutic effects on EAN.
T64 678199-678295 Sentence denotes Campylobacter jejuni-derived LPS abrogates oral tolerance to experimental autoimmune neuritis S.
T65 678296-678307 Sentence denotes Jung a , J.
T66 678308-678319 Sentence denotes Voss a , M.
T67 678320-678333 Sentence denotes Frosch b , H.
T68 678334-678346 Sentence denotes Karch b , K.
T69 678347-678361 Sentence denotes Toyka c and S.
T70 678362-678597 Sentence denotes Sch7fer c a Department of Neurology, University of the Saarland, Homburg, Germany; b Institute of Hygiene and Microbiology, University of Würzburg, Würzburg, Germany; c Department of Neurology, University of Würzburg, Würzburg, Germany
T71 678598-678824 Sentence denotes The inflammatory form of the Guillain-Barré syndrome (GBS) is an acute polyradiculoneuritis mediated by T lymphocytes, macrophages, and antibodies and is associated with a recent infection by Campylobacter jejuni in about 30%.
T72 678825-678950 Sentence denotes The animal model of GBS, experimental autoimmune neuritis (EAN) of Lewis rats can be induced by immunization with PNS myelin.
T73 678951-679108 Sentence denotes Immunization with antigen preparations of various C. jejuni strains derived from GBS patients did not induce clinical or histopathological signs of neuritis.
T74 679109-679186 Sentence denotes Nevertheless, animals generated high titers of C. jejuni-specific antibodies.
T75 679187-679425 Sentence denotes Subsequent injection of P2-specific T cells caused typical neuritis and opened the blood-nerve barrier, but clinical disease course or nerve histopathology were not aggravated in C. jejuniimmunized rats compared to CFA-sensitized animals.
T76 679426-679553 Sentence denotes Signs of active EAN induced by immunization with PNS-myelin could be mitigated by precedent feeding of myelin (oral tolerance).
T77 679554-679740 Sentence denotes By adding pronase-digested LPS prepared from C. jejuni to the enterally applied myelin, tolerance induction was completely prevented and rats developed an accelerated course of neuritis.
T78 679741-679783 Sentence denotes Feeding of LPS alone did not modulate EAN.
T79 679784-679911 Sentence denotes The findings demonstrate that C. jejuni-derived LPS can disturb natural immunoregulation by the gut-associated lymphoid tissue.
T80 679912-679922 Sentence denotes Objective:
T81 679923-680133 Sentence denotes To determine whether human immunoglobulin (Ig) is effective and its mechanism of action in the treatment of experimental allergic neuritis (EAN), an animal model for human inflammatory demyelinating neuropathy.
T82 680134-680145 Sentence denotes Background:
T83 680146-680354 Sentence denotes Administration of high-dose intravenous immunoglobulins (IVIg) has become one of the most successful therapies for inflammatory demyelinating neuropathies, yet the mechanism of action is not fully understood.
T84 680355-680363 Sentence denotes Methods:
T85 680364-680492 Sentence denotes We induced EAN in Lewis rats and administered human Ig or albumin intravenously commencing at the onset of neurological deficit.
T86 680493-680539 Sentence denotes Clinical grade and weight were recorded daily.
T87 680540-680631 Sentence denotes Neurophysiological and histological examinations were performed at predetermined intervals.
T88 680632-680640 Sentence denotes Results:
T89 680641-680731 Sentence denotes IgG treatment effectively reduced the severity and fastened recovery of clinical weakness.
T90 680732-680841 Sentence denotes This improvement was associated with an accelerated rate of recovery from electrophysiological abnormalities.
T91 680842-680853 Sentence denotes Conclusion:
T92 680854-680911 Sentence denotes Human Ig is an effective treatment for EAN in Lewis rats.
T93 680912-681054 Sentence denotes Further investigations are underway to determine whether the Fc or Fab component of IVIg is responsible for the observed therapeutic efficacy.
T94 681055-681142 Sentence denotes Anti-ganglioside antibodies and intrathecal IgG synthesis in Guillain-Barré syndrome S.
T95 681143-681151 Sentence denotes Matà, E.
T96 681152-681161 Sentence denotes Galli, A.
T97 681162-681174 Sentence denotes Amantini, F.
T98 681175-681184 Sentence denotes Pinto, S.
T99 681185-681197 Sentence denotes Sorbi and F.
T100 681198-681254 Sentence denotes Lolli University of Florence, Florence, Italy Objective:
T101 681255-681403 Sentence denotes To investigate the relationship between clinical, electrophysiological, immunological findings and CSF changes in the Guillain-Barré syndrome (GBS).
T102 681404-681415 Sentence denotes Background:
T103 681416-681597 Sentence denotes Increased anti-ganglioside antibody titers are a frequent finding in GBS patients and, to a lesser extent, in patients with chronic inflammatory demyelinating polyneuropathy (CIDP).
T104 681598-681769 Sentence denotes Another frequent feature of these diseases is a dysfunction of blood-brain barrier (BBB), whereas the intrathecal synthesis of immunoglobulins is still a matter of debate.
T105 681770-681821 Sentence denotes The relationship between these findings is unknown.
T106 681822-681830 Sentence denotes Methods:
T107 681831-682001 Sentence denotes The authors studied a cohort of GBS patients examined by standard EMG, by ELISA for anti-ganglioside antibodies, and by standard laboratory procedure for CSF examination.
T108 682002-682076 Sentence denotes We used four formulas for the calculation of intrathecal synthesis of IgG:
T109 682077-682175 Sentence denotes IgG Index, Reiber and Felgenhauer's formula, Blennow et al.'s formula and IgG/total protein ratio.
T110 682176-682307 Sentence denotes Controls consisted of patients with non-dysimmune polyneuropathy, inflammatory and non-inflammatory CNS disorders and blood donors.
T111 682308-682316 Sentence denotes Results:
T112 682317-682446 Sentence denotes Thirty-eight percent (28/73) of GBS patients and 28% of CIDP patients had detectable serum titers of anti-ganglioside antibodies.
T113 682447-682595 Sentence denotes In both patient groups, the anti-ganglioside reactivity was associated with high incidence of motor conduction block and prolonged F wave latencies.
T114 682596-682730 Sentence denotes In GBS patients, there was a clear association between anti-ganglioside antibody and high value of intrathecal IgG production indexes.
T115 682731-682742 Sentence denotes Conclusion:
T116 682743-682913 Sentence denotes The association between anti-ganglioside antibodies and high CSF IgG production indexes value in GBS patients suggests a pathogenetic relationship between these findings.
T117 682914-682924 Sentence denotes Objective:
T118 682925-683017 Sentence denotes Campylobacter jejuni (Cj) is the leading cause of Guillain-Barré syndrome (GBS) in Japanese.
T119 683018-683101 Sentence denotes Recently, we cloned and characterized the iron-binding protein Dps from Cj (C-Dps).
T120 683102-683197 Sentence denotes The aim of this study was to determine whether or not C-Dps contributes to pathogenesis of GBS.
T121 683198-683206 Sentence denotes Methods:
T122 683207-683398 Sentence denotes Anti-C-Dps antibody in sera was determined by ELISA in 40 patients with GBS, 11 patients with Cj enteritis, 139 patients with other inflammatory neurological diseases and 61 healthy controls.
T123 683399-683474 Sentence denotes Binding of C-Dps to various glycolipids and rat neural tissues was studied.
T124 683475-683589 Sentence denotes Furthermore, PC12 cells were exposed to various concentrations of C-Dps and LDH release was measured at 1 h later.
T125 683590-683598 Sentence denotes Results:
T126 683599-683966 Sentence denotes We found that (a) anti-C-Dps antibody was only present in GBS patients with preceding Cj infection (38.9%) and those with Cj enteritis (18.2%), (b) C-Dps bound to neurons in rat spinal cord and myelin sheath in rat peripheral nerves, (c) C-Dps bound specifically to sulfatide, (d) in vitro, C-Dps bound to PC12 cell surface and induced the LDH release from the cells.
T127 683967-684074 Sentence denotes This LDH release was inhibited by heart-inactivation and co-incubation with anti-C-Dps monoclonal antibody.
T128 684075-684172 Sentence denotes Conclusions: C-Dps is considered to bind to neural cell body and myelin sheath through sulfatide.
T129 684173-684297 Sentence denotes After binding, C-Dps exerts direct neuro-toxicity, which may contribute to axonal damage in GBS with preceding Cj infection.
T130 684298-684394 Sentence denotes This paper updates the Cochrane systematic reviews of immunotherapy for Guillain-Barré syndrome.
T131 684395-684483 Sentence denotes The primary outcome was the change in a sevenpoint disability grade scale after 4 weeks.
T132 684484-684568 Sentence denotes Plasma exchange was tested against no exchange in five trials with 606 participants.
T133 684569-684702 Sentence denotes The weighted mean difference was 0.89 (95% CI 0.64 to 1.15, pb0.00001) of a grade more improvement with plasma exchange than without.
T134 684703-684806 Sentence denotes Intravenous immunoglobulin was compared with plasma exchange in five trials involving 536 participants.
T135 684807-685029 Sentence denotes There was 0.04 of a grade more improvement with intravenous immunoglobulin than with plasma exchange (95% CI 0.26 more improvement to 0.19 less improvement, p=0.74) so that these treatments have been considered equivalent.
T136 685030-685274 Sentence denotes One trial involving 249 participants compared plasma exchange followed by intravenous immunoglobulin with plasma exchange alone: the sequentially treated group had 0.20 (95% CI: À0.14 to 0.54, p=0.24) of a grade more improvement than the other.
T137 685275-685347 Sentence denotes Five trials with 567 participants compared corticosteroids with placebo.
T138 685348-685642 Sentence denotes Despite marginally significant results in one trial seeking a synergistic effect with intravenous immunoglobulin, the synthesis of all the trials showed no significant difference (weighted mean difference only 0.05, 95% CI À0.16 to 0.25 more in the corticosteroid treated participants, p=0.66).
T139 685643-685819 Sentence denotes This synthesis shows that intravenous immunoglobulin and plasma exchange have equivalent efficacy in Guillain-Barré syndrome but the effect of corticosteroids alone is neutral.
T140 685820-685830 Sentence denotes Objective:
T141 685831-685997 Sentence denotes To determine if there is a neuropathic process selectively affecting small-diameter epidermal nerve fibers (ENFs) in patients with systemic lupus erythematosus (SLE).
T142 685998-686006 Sentence denotes Methods:
T143 686007-686085 Sentence denotes Sixty patients, age 43.2F13.5 years, were subjected to a clinical examination.
T144 686086-686334 Sentence denotes Neuropathy Impairment Score (NIS) and Neuropathy Symptom and Change Score (NSC) with emphasis on sensory symptoms were obtained as quantitative estimations of neurological deficits and symptoms of both small and large-diameter nerve fiber function.
T145 686335-686514 Sentence denotes In two punch biopsies taken from the distal part of the leg, ENFs were visualized staining with a rabbit polyclonal antibody to the panaxonal marker anti protein gene product 9.5.
T146 686515-686647 Sentence denotes The density of ENFs was considered abnormal when the number of ENFs was less than the 2.5th percentile for controls (3.4 fibers/mm).
T147 686648-686778 Sentence denotes Nerve conduction velocity studies (NCV) were performed for an evaluation of the presence of large-diameter nerve fiber neuropathy.
T148 686779-686787 Sentence denotes Results:
T149 686788-686859 Sentence denotes The density of ENFs was 7.5F3.8, and 12.4F4.6/mm in controls, P=0.0001.
T150 686860-686909 Sentence denotes Eight patients (13%) had less than 3.4 fibers/mm.
T151 686910-687067 Sentence denotes Thirty-seven patients (62%) had an abnormal NIS score, 53 patients (88%) an abnormal NSC subscore for sensory symptoms, and 7 patients (12%) an abnormal NCV.
T152 687068-687166 Sentence denotes No associations were found between reduced number of ENFs and symptoms, clinical findings, or NCV.
T153 687167-687178 Sentence denotes Conclusion:
T154 687179-687266 Sentence denotes A selective pathological process affecting only ENFs is prevalent in patients with SLE.
T155 687267-687412 Sentence denotes Motor nerve fibers blocking dynamic variations along the first month after intravenous immunoglobulin treatment in multifocal motor neuropathy A.
T156 687413-687425 Sentence denotes Villa a , G.
T157 687426-687441 Sentence denotes Sandoval b , R.
T158 687442-687455 Sentence denotes Saizar a , M.
T159 687456-687472 Sentence denotes Di Egidio a , A.
T160 687473-687487 Sentence denotes Morillo b , O.
T161 687488-687501 Sentence denotes Garcea a , G.
T162 687502-687516 Sentence denotes Nores c and R.
T163 687517-687712 Sentence denotes Sica a a Ramos Mejia Hospital, Buenos Aires, Argentina; b Hospital Aleman, Buenos Aires, Argentina; c Facultad de Ciencias Quimicas, Universidad Nacional de Cordoba, Cordoba, Argentina Objective:
T164 687713-687840 Sentence denotes To examine the effects on nerve conduction studies (NCS) after the administration of 1 g/kg of IVIg in a patient suffering MMN.
T165 687841-688033 Sentence denotes Material and methods: NCS were performed in a patient affected by MMN, with high titers of IgM anti-GM1, before the treatment and at days 7th,14th, 21st and 28th after the IVIg administration.
T166 688034-688185 Sentence denotes Multisegmental motor nerve conduction studies were performed by measuring the compound muscle action potential (CMAP) and the conduction velocity (CV).
T167 688186-688194 Sentence denotes Results:
T168 688195-688267 Sentence denotes The neurophysiological changes were first seen at the 7th day post-IVIg.
T169 688268-688447 Sentence denotes Proximal conduction block (CB) sites CAMP amplitudes and areas increased more than 50%; simultaneously, motor nerve conduction velocities values across the CB sites became faster.
T170 688448-688558 Sentence denotes After day 21st post-IgIV, there was a progressive decline in CMAP amplitudes and areas, while CVs slowed down.
T171 688559-688676 Sentence denotes The M wave amplitude increased 50% of its original value at the 7th day after treatment, but declined after day 21st.
T172 688677-688688 Sentence denotes Discussion:
T173 688689-688772 Sentence denotes Our findings showed reversible changes of the CMAP characteristics at the CB sites.
T174 688773-689010 Sentence denotes This fact suggest that the axons ion channels, modify, somehow, their permeability properties due to the activity of a pathogenic factor, possible IgM anti-GM1 antibodies, signaling a dynamic modification rather than a structural change.
T175 689011-689113 Sentence denotes Rituximab in the treatment of multifocal motor neuropathy with anti-GM1 antibodies: a case report R.F.
T176 689114-689131 Sentence denotes Bunyan a and M.R.
T177 689132-689252 Sentence denotes Swenson b a King Faisal University, Al-Khobar, Saudi Arabia; b University of Louisville, Louisville, KY, USA Objectives:
T178 689253-689348 Sentence denotes Rituxamab is a chimeric anti-CD20 monoclonal antibody used in the treatment of B cell lymphoma.
T179 689349-689429 Sentence denotes There is new evidence of its efficacy in antibody-mediated autoimmune disorders.
T180 689430-689611 Sentence denotes Multifocal motor neuropathy is an uncommon progressive autoimmune neuropathy often associated with anti-GM1 antibodies and poorly responds to conventional immunosuppressive therapy.
T181 689612-689709 Sentence denotes We describe a case of multifocal motor neuropathy with anti-GM1 antibody responsive to Rituximab.
T182 689710-689718 Sentence denotes Methods:
T183 689719-689855 Sentence denotes A 45-year-old Caucasian gentleman developed generalized progressive motor weakness of 2-year duration predominantly involving the hands.
T184 689856-689916 Sentence denotes He complained of a cold sensation of the distal extremities.
T185 689917-689974 Sentence denotes He had neither bulbar symptoms nor sphincter disturbance.
T186 689975-690126 Sentence denotes Clinical examination revealed generalized loss of muscle bulk, weakness of the appendicular and axial muscles, areflexia, and distal loss of sensation.
T187 690127-690181 Sentence denotes Electrodiagnostic studies revealed a motor neuropathy.
T188 690182-690263 Sentence denotes Laboratory studies showed anti-GM1 IgM antibody titers of 1:6400 (Normal b1:800).
T189 690264-690310 Sentence denotes Other laboratory and CSF analyses were normal.
T190 690311-690319 Sentence denotes Results:
T191 690320-690389 Sentence denotes Initial treatment with intravenous immunoglobulin was not of benefit.
T192 690390-690501 Sentence denotes Rituximab was initiated with four weekly doses of 375 mg/m 2 followed by a 375 mg/m 2 monthly maintenance dose.
T193 690502-690583 Sentence denotes This resulted in objective clinical improvement of motor power and hand function.
T194 690584-690641 Sentence denotes He did not suffer any adverse effects from the treatment.
T195 690642-690849 Sentence denotes Conclusions: (1) Rituximab was useful in this patient with multifocal motor neuropathy associated with anti-GM1 antibodies. (2) Maintenance therapy resulted in progressive improvement and no adverse effects.
T196 690850-691104 Sentence denotes Detection of auto-antibodies to gangliosides is routinely carried out in our laboratory by immunostaining on thin-layer chromatography (ITLC) using gangliosides purified by partition of total lipids extracted from human peripheral nerves and spinal cord.
T197 691105-691316 Sentence denotes A significant number of sera taken from patients with peripheral neuropathy showed staining of lipids that were identified as phospholipids (PL) recovered in the upper phase of partition along with gangliosides.
T198 691317-691392 Sentence denotes Such sera were further tested by ITLC on a panel of standard phospholipids.
T199 691393-691587 Sentence denotes The results show that the antiphospholipid antibodies reacted mostly with phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidylglycerol (PG) and less frequently with cardiolipin (CL).
T200 691588-691778 Sentence denotes For the patients that also showed autoantibodies to glycosphingolipids, the presence of antibodies to PL was most often associated with reactivity to SGPG, and in rare cases to GM1 and GD1a.
T201 691779-691904 Sentence denotes The antibodies binding SGPG and PL were always of the same isotype, mostly IgM, but IgG antibodies were sometimes prevailing.
T202 691905-692157 Sentence denotes The presence of antiphospholipid antibodies in the antiphospholipid syndrome is generally associated with prominent clinical manifestations of neurologic disorders that are predominantly related to focal central nervous system thrombo-occlusive events.
T203 692158-692281 Sentence denotes However, none of the patients with peripheral neuropathy tested in our study had any history of thrombo-occlusive problems.
T204 692282-692443 Sentence denotes There is no comprehensive study about antecedent infection in Fisher syndrome (FS) and therefore mechanism of anti-GQ1b IgG antibody production is still unclear.
T205 692444-692714 Sentence denotes We conducted a prospective case-control serological study about five antecedent infections (Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus, Mycoplasma pneumoniae, and Haemophilus influenzae) in 73 FS patients and 73 sex-and age-matched hospital controls (HC).
T206 692715-692864 Sentence denotes In FS patients, serological evidences of recent infection with C. jejuni (21%) and H. influenzae (8%) were found significantly more often than in HC.
T207 692865-692995 Sentence denotes Anti-GQ1b IgG antibody was detected in all 15 FS patients with C. jejuni infection and most patients with H. influenzae infection.
T208 692996-693212 Sentence denotes TLC with immunostaining showed that FS-related C. jejuni strains (n=20) had the GQ1b-like lipo-oligosaccharide (LOS) more often (50%) than did Guillain-Barré syndrome (GBS)-and enteritis-related strains (7% and 20%).
T209 693213-693349 Sentence denotes Some FS-related strains also had GM1 or GD1a epitopes (both 20%), but the frequencies were lower than GBS-related strains (74% and 57%).
T210 693350-693515 Sentence denotes GQ1b epitope was detected in 40% of the 10 FSrelated H. influenzae strains, but in none of the strains from patients with GBS or uncomplicated respiratory infection.
T211 693516-693702 Sentence denotes These findings provide further evidence that C. jejuni and H. influenzae are causal agents in FS and that production of anti-GQ1b autoantibody is mediated by bacterial GQ1bmimicking LOS.
T212 693703-693841 Sentence denotes Synchronized immunomodulatory combination therapy as an initial treatment for chronic inflammatory demyelinating polyradiculoneuropathy J.
T213 693842-693854 Sentence denotes Ikeda a , A.
T214 693855-693868 Sentence denotes Harada a , T.
T215 693869-693885 Sentence denotes Kohriyama b , M.
T216 693886-693899 Sentence denotes Higaki b , S.
T217 693900-693917 Sentence denotes Katayama b and M.
T218 693918-694151 Sentence denotes Matsumoto b a Hiroshima Prefectural Hospital, Hiroshima, Japan; b Hiroshima University Hospital, Hiroshima, Japan Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) responds to treatment with immunomodulatory therapies.
T219 694152-694311 Sentence denotes However, plasma exchange and intravenous immunoglobulin therapy (IVIg) have short-term clinical benefits and some patients may need these therapies repeatedly.
T220 694312-694431 Sentence denotes Many patients relapse when the dose of steroids is reduced and fewer patients had complete remission with no treatment.
T221 694432-694583 Sentence denotes This study was performed to investigate whether synchronized immunomodulatory combination therapy (SICT) in CIDP lead to short-and long-term remission.
T222 694584-694682 Sentence denotes Seven patients at Hiroshima Prefectural Hospital from 2000 to present were included in this study.
T223 694683-694779 Sentence denotes SICT was designed by immuno-adsorption therapy (IAT), methylprednisolone pulse therapy and IVIg.
T224 694780-694858 Sentence denotes Maintaining 30 mg of prednisolone every other day was given orally after SICT.
T225 694859-694963 Sentence denotes Clinical symptoms were evaluated by neurological disability score (NDS) and modified Rankin scale (mRS).
T226 694964-695157 Sentence denotes Serum tumor necrosis factor (TNF)-alpha, interferon-gamma, interleukin (IL)-4, IL-10 and macrophage-colony stimulating factor (M-CSF) were measured by enzyme-linked immunosorbent assay (ELISA).
T227 695158-695240 Sentence denotes Six patients showed improvement by decreased NDS and mRS after one course of SICT.
T228 695241-695315 Sentence denotes Oral prednisolone was gradually reduced and discontinued in four patients.
T229 695316-695359 Sentence denotes Remission has been observed in these cases.
T230 695360-695420 Sentence denotes TNF-alpha, M-CSF and IL-10 were changed greatly during SICT.
T231 695421-695478 Sentence denotes No response to all therapies was observed in one patient.
T232 695479-695524 Sentence denotes SICT is useful for initial treatment of CIDP.
T233 695525-695600 Sentence denotes Fluctuation of cytokines may reflect favorable response to immunotherapies.
T234 695601-695707 Sentence denotes A case of chronic inflammatory demyelinating polyradiculoneuropathy presenting external ophthalmoplegia M.
T235 695708-695723 Sentence denotes Sugawara a , T.
T236 695724-695736 Sentence denotes Imota b , K.
T237 695737-695749 Sentence denotes Obara a , S.
T238 695750-695767 Sentence denotes Watanabe a and I.
T239 695768-695877 Sentence denotes Toyoshima a a Akita University School of Medicine, Akita, Japan; b Akita City Hospital, Akita, Japan Patient:
T240 695878-696040 Sentence denotes We are presenting a 33-year-old man who developed an external ophthalmoplegia during a course of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).
T241 696041-696112 Sentence denotes He reported right ankle weakness after running when he was 7 years old.
T242 696113-696162 Sentence denotes He became slow at running, and easy to fall down.
T243 696163-696206 Sentence denotes He had been diagnosed as CIDP in age of 20.
T244 696207-696253 Sentence denotes Nerve biopsy revealed segmental demyelination.
T245 696254-696385 Sentence denotes Corticosteroid pulse therapy followed by oral corticosteroid and cyclosporin A resulted in only a mild improvement of muscle power.
T246 696386-696498 Sentence denotes He was admitted to our hospital due to the aggravation of the weakness of legs and the external ophthalmoplegia.
T247 696499-696601 Sentence denotes Bilateral blepharoptosis, complete palsy in horizontal gaze and vertical gaze limitation were present.
T248 696602-696661 Sentence denotes Cranial nerves V, VII, VIII, IX, X, XI and XII were intact.
T249 696662-696673 Sentence denotes Antibodies:
T250 696674-696744 Sentence denotes Anti-GM1, GM2, GM3, GD1a, GD1b, and GQ1b antibodies were not detected.
T251 696745-696777 Sentence denotes Anti-AchR antibody was positive.
T252 696778-696803 Sentence denotes Thymoma was not detected.
T253 696804-696815 Sentence denotes Management:
T254 696816-696976 Sentence denotes Four times of double-filtration plasmapheresis resulted in complete disappearance of external ophthalmoplegia but no improvement of the weakness of extremities.
T255 696977-697139 Sentence denotes High dose injection of immunoglobulin (IVIg) improved muscle power of the patient remarkably and promptly, but the effect did not continue for more than 2 months.
T256 697140-697271 Sentence denotes Muscle power of his limbs was maintained and the external ophthalmoplegia never occurred after the intermittent IVIg every 3 month.
T257 697272-697283 Sentence denotes Conclusion:
T258 697284-697457 Sentence denotes This case suggests that the patient with CIDP produced a wide diversity of antibodies, causing muscle weakness and external ophthalmoplegia, and maintained recovery by IVIg.
T259 697458-697517 Sentence denotes CIDP associated with lung cancer: a paraneoplastic disease?
T260 697518-697520 Sentence denotes R.
T261 697521-697529 Sentence denotes Fazio S.
T262 697530-697561 Sentence denotes Raffaele Hospital, Milan, Italy
T263 697562-697675 Sentence denotes We described a 65-year-old smoker male followed for 5 years for a pure motor demyelinating peripheral neuropathy.
T264 697676-697809 Sentence denotes The patient had a monthly motor relapse with severe weakness that restricted him to wheelchair, so he monthly needed high dose Ig ev.
T265 697810-697924 Sentence denotes On EMG, the MCV were very slow (30 m/ s) without evidence of conduction blocks while SCV were in the normal range.
T266 697925-697960 Sentence denotes CSF disclosed a high protein level.
T267 697961-698127 Sentence denotes Laboratory findings did not reveal any other abnormality except for the presence of monoclonal gammopathy IgMk and high-titer anti-GD1a serum IgM antibodies (1:5000).
T268 698128-698267 Sentence denotes On March 2003, he had the most severe relapse with flaccid tetraplegia and so severe respiratory failure that required ventilatory support.
T269 698268-698347 Sentence denotes A total body CT scan revealed a nodular lung lesion with diffuse lymphangiitis.
T270 698348-698427 Sentence denotes Biopsy disclosed a lung adenocarcinoma with a severe infiltration of CD8 cells.
T271 698428-698493 Sentence denotes Surgical eradication of the tumor caused the last severe relapse.
T272 698494-698576 Sentence denotes At the moment, the patient is relapse-free and no more treatment was administered.
T273 698577-698789 Sentence denotes The clinical course of the motor demyelinating relapsing neuropathy suggests a possible paraneoplastic pathogenesis of the neurological illness also supported by the severe inflammatory infiltration of the tumor.
T274 698790-698908 Sentence denotes Immunomodulation of TGF-beta1 as possible antifibrotic therapy in muscular dystrophy: data from murine animal model F.
T275 698909-698922 Sentence denotes Andreetta, P.
T276 698923-698937 Sentence denotes Bernasconi, P.
T277 698938-698947 Sentence denotes Ferro, E.
T278 698948-698959 Sentence denotes Arnoldi, L.
T279 698960-698969 Sentence denotes Oliva, F.
T280 698970-698982 Sentence denotes Cornelio, R.
T281 698983-699000 Sentence denotes Mantegazza and P.
T282 699001-699049 Sentence denotes Confalonieri National Neurological Institute bC.
T283 699050-699070 Sentence denotes BestaQ, Milan, Italy
T284 699071-699273 Sentence denotes Irreversible connective tissue proliferation in muscle is a pathological hallmark of Duchenne muscular dystrophy (DMD), and focal release of TGF-beta1 is considered a key factor in fibrosis development.
T285 699274-699453 Sentence denotes Murine muscular dystrophy (mdx) is genetically homologous to DMD and histopathological alterations comparable to DMD limb muscle have been reported in diaphragm of older mdx mice.
T286 699454-699726 Sentence denotes To investigate the early development of fibrosis and TGF-beta1 involvement in murine disease, we evaluated diaphragms of 6-to 36-week-old mdx and C57BL6 mice by morphometric analysis, immunohistochemistry for collagens, and TGF-beta1 expression by real-time PCR and ELISA.
T287 699727-699883 Sentence denotes A significant increase of extracellular matrix and TGF-beta1 expression was found in the 6-12week-old mdx mice, with deposition of type I and III collagens.
T288 699884-700080 Sentence denotes On the basis of these data, we treated mdx mice with either a neutralizing monoclonal antibody against TGF-beta1 or nonimmune murine IgG for 6 weeks, with alternate-day intraperitoneal injections.
T289 700081-700238 Sentence denotes Morphometric analysis showed at 12 weeks of age a significant decrease of fibrosis and TGFbeta-1 mRNA levels in the group treated with anti-TGFbeta antibody.
T290 700239-700497 Sentence denotes Our study describes for the first time the early and progressive development of fibrosis with overexpression of TGF-beta1 in mdx diaphragm, and suggests the immunomodulation of this fibrogenic cytokine as a promising therapeutic approach for muscle fibrosis.
T291 700498-700571 Sentence denotes Granulysin expression in infiltrating cells in inflammatory myopathies K.
T292 700572-700585 Sentence denotes Ikezoe a , S.
T293 700586-700599 Sentence denotes Oshima a , M.
T294 700600-700615 Sentence denotes Osoegawa a , K.
T295 700616-700628 Sentence denotes Ogawa b , K.
T296 700629-700644 Sentence denotes Nagata b and J.
T297 700645-700721 Sentence denotes Kira a a Kyushu University, Fukuoka, Japan; b BML, Kawagoe, Japan Objective:
T298 700722-700821 Sentence denotes Granulysin is an effector molecule present in cytolytic granules of NK cells and cytotoxic T cells.
T299 700822-701020 Sentence denotes The aim of this study is to clarify the difference of expression of granulysin in infiltrating cells in various inflammatory myopathies and the correlation of its expression with steroid resistance.
T300 701021-701028 Sentence denotes Method:
T301 701029-701214 Sentence denotes We analyzed the expression of granulysin and perforin in muscles from 10 cases of polymyositis (PM), 3 dermatomyositis (DM), and 5 inclusion body myositis (IBM) by immunohistochemistry.
T302 701215-701293 Sentence denotes We also carried out the double staining of granulysin with CD4, CD8, and CD56.
T303 701294-701302 Sentence denotes Results:
T304 701303-701408 Sentence denotes In PM and IBM, most infiltrating cells with granulysin were found in endomysium and CD8 or CD56 positive.
T305 701409-701458 Sentence denotes These results were the same as those of perforin.
T306 701459-701663 Sentence denotes The ratio of the number of granulysin positive cells to that of CD8-positive cells (G/CD8 ratio) in steroid responsive PM (0.30) was lower than that of steroid-resistant PM (0.50) (Mann-Whitney, p=0.081).
T307 701664-701697 Sentence denotes In IBM, the G/CD8 ratio was 0.17.
T308 701698-701755 Sentence denotes In DM, there were few infiltrating cells with granulysin.
T309 701756-701767 Sentence denotes Conclusion:
T310 701768-701848 Sentence denotes There is a possibility that granulysin is concerned in steroid resistance in PM.
T311 701849-701918 Sentence denotes In IBM, steroid resistance is based on factors other than granulysin.
T312 701919-701981 Sentence denotes In DM, granulysin is not participating in muscle fiber damage.
T313 701982-702123 Sentence denotes Sporadic inclusion body myositis: immunotherapy downregulates inflammation and beta-amyloid associated factors in repeated muscle biopsies J.
T314 702124-702135 Sentence denotes Schmidt, J.
T315 702136-702138 Sentence denotes G.
T316 702139-702147 Sentence denotes Voss, R.
T317 702148-702159 Sentence denotes Raju and M.
T318 702160-702162 Sentence denotes C.
T319 702163-702406 Sentence denotes Dalakas National Institutes of Health, Bethesda, MD, USA To investigate effects of high dose prednisone (PRED) and intravenous immune globulin (IVIG) on chemokines, cytokines and beta-amyloid associated proteins, crucial for sIBM-pathogenesis.
T320 702407-703018 Sentence denotes IVIG and PRED are ineffective in sIBM, although proven beneficial in other inflammatory muscle disorders. mRNA was extracted from 10 sIBM muscle biopsies before and 4 months after treatment with IVIG+PRED or PRED. cDNA was analyzed by quantitative (real-time) PCR in relation to GAPDH-expression, using sequence specific primers for chemokine-ligand CXCL9, CCL3, CCL4, interferon (IFN)-gamma, tumor-necrosis-factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-10, transforming-growth-factor (TGF)-beta, inducible-costimulator (ICOS) and -ligand (ICOS-L), perforin, amyloidprecursor-protein (APP) and ubiquitin.
T321 703019-703098 Sentence denotes After IVIG+PRED or PRED, we observed a 3-12-fold downregulated mRNA-expression:
T322 703099-703197 Sentence denotes The strongest decrease was noted for CXCL9, CCL3, CCL4, followed by IFN-gamma, TGF-beta and IL-10.
T323 703198-703268 Sentence denotes In most patients, IL-1beta, APP and ubiquitin were clearly diminished.
T324 703269-703334 Sentence denotes TNF-alpha, IL-6, ICOS, ICOS-L and perforin were modestly reduced.
T325 703335-703420 Sentence denotes Immunohistochemical greyscale-analysis confirmed downregulation at the protein-level.
T326 703421-703543 Sentence denotes In sIBM, IVIG+PRED or PRED drastically reduced the expression of proinflammatory chemokines, cytokines, APP and ubiquitin.
T327 703544-703767 Sentence denotes Our results suggest that a stronger downregulation of these molecules may be necessary to achieve clinical efficacy, or that other factors are more relevant for the immunological-degenerative interplay in sIBM-pathogenesis.
T328 703768-703814 Sentence denotes The RAGE pathway in inflammatory myopathies M.
T329 703815-703830 Sentence denotes Haslbeck a , U.
T330 703831-703843 Sentence denotes Fries b , E.
T331 703844-703861 Sentence denotes Schleicher b , A.
T332 703862-703877 Sentence denotes Bierhaus c , B.
T333 703878-703897 Sentence denotes Neundfrfer a and D.
T334 703898-704114 Sentence denotes Heuss a a Department of Neurology, University Erlangen-Nürnberg, Germany; b Department of Medicine IV, University Tübingen, Tübingen, Germany; c Department of Medicine I, University of Heidelberg, Heidelberg, Germany
T335 704115-704251 Sentence denotes Oxidative stress and NF-kB activation are linked to the pathogenesis of many metabolic, degenerative, and chronic inflammatory diseases.
T336 704252-704451 Sentence denotes Activation of the receptor for advanced glycation end products (RAGE) by its specific ligand Ne-(Carboxymethyl)lysine (CML) results in activation of NF-kB and production of proinflammatory cytokines.
T337 704452-704768 Sentence denotes In order to determine, whether an engagement of RAGE might contribute to the pathogenesis of inflammatory myopathies, we studied the presence of CML, RAGE, and activated NF-kB by immunohistochemistry in muscle biopsies of patients with polymyositis (PM, n=8), dermatomyositis (DM, n=8) and in eight healthy controls.
T338 704769-704912 Sentence denotes In inflammatory myopathies CML, RAGE and NF-kB was detected in mononuclear cells, regenerating muscle fibers and in degenerating muscle fibers.
T339 704913-705025 Sentence denotes Colocalisation of CML, RAGE and NF-kB was seen in infiltrating mononuclear cells and regenerating muscle fibers.
T340 705026-705163 Sentence denotes Our data suggest that the CML-RAGE-NF-kB pathway is an evident proinflammatory pathomechanism in mononuclear effector cells in PM and DM.
T341 705164-705267 Sentence denotes RAGE-mediated NF-kB expression may play a role in muscle fiber regeneration in inflammatory myopathies.
T342 705268-705442 Sentence denotes Autoimmune T cells in myasthenia gravis (MG) recognize several regions of the human muscle acetylcholine receptor (AChR), most of them presented by HLA class II DR molecules.
T343 705443-705618 Sentence denotes By TEPITOPE analysis, we have identified eight synthetic AChR sequences and tested T cell responses in PBMC of 74 MG patients and 51 healthy controls in proliferation studies.
T344 705619-705782 Sentence denotes The overall reactivity observed among patients was significantly higher than healthy controls but the frequency of response varied with specific HLA-DR phenotypes.
T345 705783-705935 Sentence denotes Sequences p6-24, p36-52 and p131-147 were poorly recognized by HLA-DR5 + MG patients whereas p35-53 was strongly recognized by HLA-DR1 + MG individuals.
T346 705936-706055 Sentence denotes HLA binding assays of these peptides revealed varied capacity of binding to the eight tested HLA-DR class II molecules.
T347 706056-706196 Sentence denotes Female MG subjects, mainly with severe disease, displayed significantly higher responses against p36-52, p131-147 and p133-145 than male MG.
T348 706197-706293 Sentence denotes Patients between 25 and 40 years showed strong reactivity against p36-52, p131-147 and p195-212.
T349 706294-706428 Sentence denotes Reactivity against p8-22 was significantly higher in non-thymectomized patients as well as in patients with short duration of disease.
T350 706429-706535 Sentence denotes These findings may have important implications in designing future therapeutic strategies for the disease.
T351 706536-706569 Sentence denotes Supported by FAPESP (00/11889-9).
T352 706570-706636 Sentence denotes Immunology of ryanodine receptor and FK506 in myasthenia gravis M.
T353 706637-706707 Sentence denotes Takamori Neurological Center, Kanazawa-Nishi Hospital, Kanazawa, Japan
T354 706708-707077 Sentence denotes To study the implication of anti-striational antibodies in muscle contraction fatigue in myasthenia gravis (MG), antibodies to ryanodine receptor (RyR, essential for excitation-contraction coupling in muscle) were measured in sera from 33 MG patients, 18 with thymoma and 15 without thymoma, by use of three synthetic peptides deduced from the RyR1 amino acid sequence.
T355 707078-707333 Sentence denotes One region, close to the N-terminus, implicates in inactivation at high cytoplasmic calcium concentration; the other two peptides, C-terminal transmembrane region and C-terminal tail, are from the region responsible for functional calcium release channel.
T356 707334-707449 Sentence denotes Antibodies were more frequently positive against the two C-terminal peptides, particularly in thymomaassociated MG.
T357 707450-707509 Sentence denotes The N-terminal peptide antibodies were uncommonly detected.
T358 707510-707812 Sentence denotes In 7 patients selected from 33 MG patients based on the authorized criteria for therapeutic trail, the treatment was designed to give FK506 which is an immunosuppressant acting as calcineurin inhibitor and also affects RyR-related muscle contraction through an accelerated sarcoplasmic calcium release.
T359 707813-707983 Sentence denotes The efficacy was estimated by the reductions in disease severity score, prednisone dosage and anti-acetylcholine receptor antibody titers at 1-week and 1-year medication.
T360 707984-708095 Sentence denotes Results showed early and sustained benefit of FK506 in patients positive for antibodies to C-terminal peptides.
T361 708096-708247 Sentence denotes An early effect of FK506 may reflect its action as an enhancer of RyR-related sarcoplasmic calcium release and its effects on the RyR Nterminal region.
T362 708248-708347 Sentence denotes Myasthenia gravis patient sera exhibit cytotoxic effects on human primary muscle cell cultures S.P.
T363 708348-708361 Sentence denotes Luckman, G.O.
T364 708362-708371 Sentence denotes Skeie, G.
T365 708372-708390 Sentence denotes Helgeland and N.E.
T366 708391-708644 Sentence denotes Gilhus Haukeland University Hospital, Bergen, Norway Myasthenia gravis (MG) is caused primarily by autoantibodies directed against the nicotinic acetylcholine receptor (AChR), with additional antimuscle autoantibodies being detected in some MG patients.
T367 708645-708706 Sentence denotes The role of non-AChR autoantibodies remains to be elucidated.
T368 708707-708885 Sentence denotes In order to investigate the role(s) of these autoantibodies in MG, primary human muscle cell cultures have been exposed to MG patient sera and the morphological effects observed.
T369 708886-708933 Sentence denotes Cell death in these cultures was also examined.
T370 708934-709161 Sentence denotes Cultured human muscle cells were exposed to MG patient or control sera (normal donor, systemic lupus erythematosus, or Sjogren's syndrome patient sera) for 1-4 days, and observed by crystal violet staining and light microscopy.
T371 709162-709442 Sentence denotes Sera from the most severe MG patients (MG crisis patients), induced a dramatic change in cell morphology, leading to multinucleated cell clusters (as opposed to the elongated multinucleated myotubes observed in control cultures), with obvious inclusion body and vesicle formation.
T372 709443-709534 Sentence denotes A dramatic reduction in total cell number was also observed, indicating a cytotoxic effect.
T373 709535-709611 Sentence denotes These effects were dose-and time-dependent and were not complement-mediated.
T374 709612-709711 Sentence denotes The cytotoxic effects of the MG patient sera do not appear to be due to the induction of apoptosis.
T375 709712-709924 Sentence denotes These studies demonstrate a direct cytotoxic effect of MG patient sera against normal human muscle cells in culture, with sera from the most severely affected patients demonstrating the greatest cytotoxic effect.
T376 709925-710417 Sentence denotes In order to know whether acetylcholinesterase (AChE) autoimmune plays a role in both myasthenia gravis (MG), which is associated with antibodies directed against the nicotinic acetylcholine receptor (AChR) in 85% of patients, and Graves' disease (GD), we analysed by ELISA the ability of sera from 22 patients with MG without antibodies against AChR, 116 with GD having the antibodies against thyreoglobulin (Tg), and 50 healthy controls (CR) to react with AChE from human brain and human Tg.
T377 710418-710658 Sentence denotes Results showed that significantly increased anti-AChE activity was exhibited by a high proportion of MG (50%) and nearly unchanged anti-AchE activity was observed in GD (1%) sera, being similar with CR, which no anti-AChE activity detected.
T378 710659-710746 Sentence denotes Anti-Tg activity was detected in both MG patients (25% positive) and CR (22% positive).
T379 710747-710859 Sentence denotes It is suggested that AChE autoimmune should be another important reason resulting in MG but plays no role in GD.
T380 710860-710895 Sentence denotes Tg autoimmune may be ignored in MG.
T381 710896-710961 Sentence denotes The in vivo role of complement activation in myasthenia gravis F.
T382 710962-710972 Sentence denotes Romi, E.K.
T383 710973-710992 Sentence denotes Kristoffersen, J.A.
T384 710993-711007 Sentence denotes Aarli and N.E.
T385 711008-711072 Sentence denotes Gilhus Haukeland University Hospital, Bergen, Norway Background:
T386 711073-711189 Sentence denotes Antibodies to the acetylcholine receptor (AChR), titin, and the ryanodine receptor (RyR) occur in myasthenia gravis.
T387 711190-711265 Sentence denotes These antibodies have been found capable of complement activation in vitro.
T388 711266-711389 Sentence denotes The involvement of the complement system should theoretically cause consumption of complement components such as C3 and C4.
T389 711390-711412 Sentence denotes Materials and methods:
T390 711413-711692 Sentence denotes Complement components C3 and C4 were assayed in sera from 78 AChR antibody positive MG patients (48 titin antibody positive of whom 20 were also RyR antibody positive; 30 titin and RyR antibody negative of whom 15 had early-onset MG and 15 late-onset MG) and 52 healthy controls.
T391 711693-711888 Sentence denotes Results: MG patients with AChR antibody concentrations above the median had significantly lower mean C3 and C4 concentrations compared to those with AChR antibody concentrations below the median.
T392 711889-712073 Sentence denotes Titin antibody positive MG patients, titin antibody negative early-onset MG patients, titin antibody negative late-onset MG patients, and controls had similar C3 and C4 concentrations.
T393 712074-712154 Sentence denotes Nor did mean C3 and C4 concentrations differ in MG patients with RyR antibodies.
T394 712155-712247 Sentence denotes Patients with severe MG had similar C3 and similar C4 levels compared to those with mild MG.
T395 712248-712259 Sentence denotes Conclusion:
T396 712260-712443 Sentence denotes There is serological evidence of increased C3 and C4 consumption in MG in vivo in patients with high AChR antibody concentration, unrelated to MG severity and other muscle antibodies.
T397 712444-712572 Sentence denotes This study does not exclude, however, the role of complement activation in the pathophysiology of other muscle antibodies in MG.
T398 712573-712659 Sentence denotes Modulation of antigen specific responses against AChR by recombinant erythropoietin F.
T399 712660-712673 Sentence denotes Ubiali a , S.
T400 712674-712685 Sentence denotes Nava a , C.
T401 712686-712700 Sentence denotes Antozzi a , P.
T402 712701-712714 Sentence denotes Ghezzi b , C.
T403 712715-712733 Sentence denotes Cappelletti a , F.
T404 712734-712749 Sentence denotes Cornelio a , R.
T405 712750-712769 Sentence denotes Mantegazza a and F.
T406 712770-712814 Sentence denotes Baggi a a National Neurological Institute C.
T407 712815-712902 Sentence denotes Besta, Milan, Italy; b Mario Negri Institute for Pharmacological Research, Milan, Italy
T408 712903-713122 Sentence denotes Recombinant erythropoietin (rEPO) treatment alters the number of circulating T-cells and CD4/CD8 ratio; these effects might influence immune responses pathways such as antigen presentation and/or recognition by T cells.
T409 713123-713291 Sentence denotes The aim of this study was to evaluate rEPO effect on a T-cell line specific for peptide p97-116 of rat-AChR alpha-subunit, a myasthenogenic T-cell epitope in Lewis rat.
T410 713292-713452 Sentence denotes T-cells were challenged with ConA and p97-116 in the presence of rEPO (50, 100, 200 ng/ml), and specific responses were measured by 3 H-thymidine incorporation.
T411 713453-713624 Sentence denotes Proliferative responses (ConA 20012F936 cpm; p97-116 16171F1176 cpm) were significantly reduced by spleen cells (conventional APC) preincubated with rEPO (100 ng/ml, 3 h):
T412 713625-713690 Sentence denotes ConA 9232F812 cpm ( p=0.0012); p97-116 11366F670 cpm ( p=0.0069).
T413 713691-713805 Sentence denotes Similar results were obtained by preincubation with 200 ng/ ml of rEPO (ConA 7114F1044 cpm; p97-116 8289F945 cpm).
T414 713806-714228 Sentence denotes These experiments were repeated using as APC bone marrow-derived DCs, differentiated with GM-CSF and IL-4. p97-116-specific responses (8493F832 cpm) were reduced (5199F1819 cpm) when rEPO was directly added to wells; this result was enhanced by DCs pre-incubation (3 h) with rEPO (4846F933 cpm, p=0.043). rEPO was also tested on TAChR-specific responses from lymph node cells (LNC) derived from TAChR-immunized Lewis rats.
T415 714229-714331 Sentence denotes LNC proliferations were reduced by rEPO (added to cultured LNC), confirming its modulatory properties.
T416 714332-714437 Sentence denotes These results suggest that rEPO might be implicated in the regulation of the autoimmune response to AChR.
T417 714438-714532 Sentence denotes Use of ELISPOTS to monitor cloning of AChR-specific T-cells from myasthenia gravis patients W.
T418 714533-714542 Sentence denotes Zhang, I.
T419 714543-714552 Sentence denotes Leite, U.
T420 714553-714564 Sentence denotes Kishore, P.
T421 714565-714577 Sentence denotes Water and N.
T422 714578-714853 Sentence denotes Willcox Neurosciences Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK Autoimmune CD4 T-cells that recognise peptides from the acetylcholine receptor (AChR) play an important role in the initiation and progression of Myasthenia Gravis (MG).
T423 714854-715073 Sentence denotes Because of the complexity of the AChR molecule, difficulties in purifying its subunits and the low frequency of AChR-specific T-cells in the peripheral blood lymphocytes (PBL), cloning them is laborious and inefficient.
T424 715074-715166 Sentence denotes We have modified a specific ELISPOTS assay and used it to monitor our recent T-cell cloning.
T425 715167-715335 Sentence denotes This assay has enabled us to determine precisely whether patient's' PBL have responded specifically to one round of in vitro stimulation with AChR subunits or peptides.
T426 715336-715468 Sentence denotes It also makes it quicker and easier to define the epitope(s) being recognised and to estimate frequencies of the responding T-cells.
T427 715469-715524 Sentence denotes We have now identified two promising lines for cloning.
T428 715525-715564 Sentence denotes MuSK antibodies in myasthenia gravis N.
T429 715565-715576 Sentence denotes Desai, M.E.
T430 715577-715589 Sentence denotes Farrugia, J.
T431 715590-715607 Sentence denotes McConville and A.
T432 715608-715831 Sentence denotes Vincent Oxford University, Oxford, UK Antibodies to the receptor tyrosine kinase, MuSK, are found in up to 70% of patients with generalised myasthenia gravis without acetylcholine receptor antibodies (bseronegativeQ, SNMG).
T433 715832-715988 Sentence denotes Here we describe the characteristics of the antibodies, and their frequency in myasthenia gravis patients kindly provided by neurologists from 17 countries.
T434 715989-716144 Sentence denotes The antibodies are very high affinity (kDs around 100 pM), are predominantly of IgG subclass 4, with some IgG1 and IgG2, and titres range from 1 to 200 nM.
T435 716145-716252 Sentence denotes Patients with MuSK-antibody positive MG are most frequently female and tend to have marked bulbar weakness.
T436 716253-716355 Sentence denotes The age at onset is mainly under 40 years, but older patients are relatively common in some countries.
T437 716356-716584 Sentence denotes Altogether, antibodies to MuSK have been detected in a total of 128 out of 358 SNMG patients, representing 0-46% of SNMG patients from different centres, including nine in Europe, three in North America and five in the Far East.
T438 716585-716687 Sentence denotes The highest prevalence was in patients originating from countries between 358 and 508N of the equator.
T439 716688-716902 Sentence denotes The high affinities of the antibodies, and their variable frequency in SNMG patients from different geographical locations, raise the possibility that the antibodies are induced by a specific environmental antigen.
T440 716903-717110 Sentence denotes Myasthenia Gravis (MG) with autoantibodies against Muscle Specific Kinase (MuSK) is an autoimmune disorder of neuromuscular transmission characterised by fluctuating weakness of predominantly bulbar muscles.
T441 717111-717239 Sentence denotes We studied the epidemiology of anti-MuSK(+) MG in a distinct area in the province of South Holland with 1.6 million inhabitants.
T442 717240-717311 Sentence denotes We reviewed charts of all patients diagnosed with MG in nine hospitals.
T443 717312-717431 Sentence denotes In two hospitals without registration of diagnosis, we examined charts of all patients tested for anti-AChR antibodies.
T444 717432-717512 Sentence denotes Between January 1st 1990 and January 1st 2004, MG was diagnosed in 246 patients.
T445 717513-717651 Sentence denotes Anti-AChR antibodies were negative in 57 of whom 40 had their first symptoms within this period, an incidence of 1.8 per million per year.
T446 717652-717737 Sentence denotes Among them, two patients were anti-MuSK(+), an incidence of 0.1 per million per year.
T447 717738-717884 Sentence denotes The prevalence of anti-MuSK(+) MG on January 1st 2004 was 1.9 per million, based on 3 patients in a group of 52 anti-AChR(À) patients being alive.
T448 717885-717999 Sentence denotes Among the 27 patients with generalised anti-AChR(À) MG, 3 of 20 patients tested for anti-MuSK were positive (15%).
T449 718000-718100 Sentence denotes When restricting this group to EMG confirmed MG, the proportion of anti-MuSK(+) MG increased to 25%.
T450 718101-718236 Sentence denotes In the Netherlands until now, we have found 82 patients with generalised anti-AChR(À) MG, 13 being anti-MuSK(+) out of 55 tested (24%).
T451 718237-718347 Sentence denotes In this population-based study, the prevalence of anti-MuSK(+) MG is lower than suggested by previous reports.
T452 718348-718423 Sentence denotes Analysis of LIF, IL-6, TGF-beta1 and oncostatin M in myasthenic thymuses E.
T453 718424-718435 Sentence denotes Arnoldi, P.
T454 718436-718450 Sentence denotes Bernasconi, F.
T455 718451-718460 Sentence denotes Baggi, F.
T456 718461-718476 Sentence denotes Cornelio and R.
T457 718477-718522 Sentence denotes Mantegazza National Neurological Institute C.
T458 718523-718542 Sentence denotes Besta, Milan, Italy
T1 718543-718682 Sentence denotes Thymus is a crucial tissue in the pathogenesis of myasthenia gravis (MG) and is thought to be the site of loss of tolerance in the disease.
T2 718683-718791 Sentence denotes Thymic abnormalities are often found in MG patients, including abnormal presence of B cell germinal centers.
T3 718792-718965 Sentence denotes We investigated the transcription levels of cytokines involved in thymopoiesis and B cell function: leukemia inhibitory factor (LIF), oncostatin M (OSM), IL-6 and TGF-beta1.
T4 718966-719098 Sentence denotes By real time-PCR, we studied the expression of these cytokines in 29 myasthenic thymuses (10 involuted, 11 hyperplastic, 8 thymoma).
T5 719099-719240 Sentence denotes IL-6 and OSM transcript levels were higher in 55% of cases with hyperplastic thymuses and in 50% of thymoma cases than in involuted thymuses.
T6 719241-719417 Sentence denotes LIF and TGF-beta1 expression was higher in hyperplastic thymuses than in involuted thymuses, while in all thymoma cases we did not observe an increase of the expression levels.
T7 719418-719554 Sentence denotes These data suggest that the expression of the analyzed cytokines might be related to the presence of intrathymic cellular proliferation.
T8 719555-719645 Sentence denotes A correlation between cytokine levels and serum anti-AChR antibody titers was not evident.
T9 719646-719656 Sentence denotes Objective:
T10 719657-719779 Sentence denotes To describe development and treatment of myasthenic syndrome after local botulinum-toxin injections for cervical dystonia.
T11 719780-719788 Sentence denotes Methods:
T12 719789-719937 Sentence denotes A 62-year-old male suffering from cerebral palsy (tetraparesis and dystonia) presented with severe cervical pain secondary to spasmodic torticollis.
T13 719938-720027 Sentence denotes He was treated with several local injections of botulinum toxin type A with good results.
T14 720028-720166 Sentence denotes He reported long-lasting (12 months) bilateral proximal brachial paresis after the last treatment and injections were stopped for 2 years.
T15 720167-720222 Sentence denotes Pain became severe and the patient asked for treatment.
T16 720223-720274 Sentence denotes Botulinum-toxin type B was administered four times.
T17 720275-720363 Sentence denotes A rapidly evolving progressive tetraparesis presented 3 days after the fourth injection.
T18 720364-720372 Sentence denotes Results:
T19 720373-720479 Sentence denotes Myasthenic syndrome (facilitation on EMG and increase titter of antibodies for Ca channels) was diagnosed.
T20 720480-720589 Sentence denotes Other studies (including nerve conduction velocities and SF analysis) were normal and no neoplasia was found.
T21 720590-720687 Sentence denotes Immunoglobulin was administered intravenously and the progression of paresis immediately stopped.
T22 720688-720765 Sentence denotes The patient quickly improved and steroids were given later with good results.
T23 720766-720778 Sentence denotes Conclusions:
T24 720779-720907 Sentence denotes The causal relationship between administration of Botulinum toxin and development of myasthenic syndrome warrants consideration.
T25 720908-721099 Sentence denotes It is impossible to know whether toxin causally participated in the immunologic response against the neural structures or simply both toxins A and B unmasked pre-existing myasthenic syndrome.
T26 721100-721161 Sentence denotes The response to treatment with immunoglobulin was remarkable.
T27 721162-721239 Sentence denotes Prognostic significance of thymectomy in autoimmune myasthenia gravis (MG) A.
T28 721240-721266 Sentence denotes Ariatti, P Faglioni and G.
T29 721267-721274 Sentence denotes Galassi
T30 721275-721285 Sentence denotes Objective:
T31 721286-721325 Sentence denotes To verify efficacy of thymectomy in MG.
T32 721326-721334 Sentence denotes Methods:
T33 721335-721482 Sentence denotes A retrospective study was conducted on 72 MG patients (32 males, mean age 65.7; 40 females, mean age 63.4; range 17-84 years, mean age 64.0 years).
T34 721483-721532 Sentence denotes Mean duration of patient illness was 69.9 months.
T35 721533-721593 Sentence denotes Severity was defined according to Osserman's classification.
T36 721594-721657 Sentence denotes Asymptomatic patients were scored b0Q for statistical purposes.
T37 721658-721789 Sentence denotes At time of diagnosis, 26 patients were graded I, 29 as grade IIa, 17 as grade IIb; no patients were classified in grade III and IV.
T38 721790-721990 Sentence denotes According to actual severity, 27 patients were included in grade I, 30 in grade IIa, 8 in grade IIb; no patients were graded as III and IV; 7 patients were asymptomatic at time of clinical evaluation.
T39 721991-722160 Sentence denotes Clinical outcome was evaluated in patients who underwent surgery either, for thymoma (N=14), for non-neoplastic thymus (N=11) and in those not treated surgically (N=47).
T40 722161-722372 Sentence denotes Results: (1) Percentages of subjects that improved were 21% and 55% among thymectomized patients either for thymoma, or hyperplastic thymus, respectively; 17% of patients who improved did not undergo thymectomy.
T41 722373-722422 Sentence denotes (2) The three percentages differed significantly:
T42 722423-722597 Sentence denotes Chi square (2)=7.00, Pb0.03; (3) decomposition of total Chi square revealed that thymectomy raised chances of improvement (17% vs. 36%; Chi square (1)=3.30 Pb0.04 one tailed.
T43 722598-722745 Sentence denotes Furthermore, hyperplastic thymus benefited from thymectomy more often than neoplastic thymus (55% vs. 21%; Chi square (1)=3.75; Pb0.05 one tailed).
T44 722746-722858 Sentence denotes Paraneoplastic Neurological Syndromes (PNS) are immune-mediated, nonmetastatic disorders associated with cancer.
T45 722859-722943 Sentence denotes They start before tumor's evidence and involve central or peripheral nervous system.
T46 722944-723034 Sentence denotes The role of antineuronal antibodies is uncertain but they are important for the diagnosis.
T47 723035-723132 Sentence denotes Myasthenia gravis (MG) is an autoimmune neuromuscular disorder sometimes associated with thymoma.
T48 723133-723187 Sentence denotes Combination of MG with Hodgkin's Disease (HD) is rare.
T49 723188-723283 Sentence denotes We report a case of 52-year-old female with generalized MG and radiological suspect of thymoma.
T50 723284-723406 Sentence denotes Anti-acetylcholinereceptor (AChR) antibodies resulted positive but anti-titine and antiryanodine antibodies were negative.
T51 723407-723475 Sentence denotes After neurological therapy, the patient was submitted to thymectomy.
T52 723476-723544 Sentence denotes A nodular-sclerosing syncizial HD plus thymic atrophy was diagnosed.
T53 723545-723620 Sentence denotes Oncological screening confirmed a clinically II A HD with mediastinal bulk.
T54 723621-723696 Sentence denotes Neurological treatment was stopped and chemo plus radiotherapy was started.
T55 723697-723825 Sentence denotes Successive 9 years of follow up revealed complete remission of both MG and HD with progressive decrease of anti-AChR antibodies.
T56 723826-723979 Sentence denotes Combination of seropositive MG, thymic atrophy and HD may suggest that myasthenic symptoms could be triggered by immunological alterations underlying HD.
T57 723980-724213 Sentence denotes Stable and complete resolution of MG after HD remission as well as progressive decrease of anti-AChR antibodies may reinforce this hypothesis and suggests a pathogenetic role of these antibodies in paraneoplastic MG associated to HD.
T58 724214-724273 Sentence denotes Autoimmune diseases (AID) are known to cluster in families.
T59 724274-724499 Sentence denotes We studied the frequency and nature of additional AID in patients with the Lambert-Eaton myasthenic syndrome (LEMS) and their family members, in both small cell lung carcinoma (SCLC) related and non-tumour (NT)-related cases.
T60 724500-724611 Sentence denotes Additional AID in patients with LEMS were assessed by interviewing the patient and studying the medical record.
T61 724612-724735 Sentence denotes Family histories up to second-degree family members were established by interviewing patients, controls and family members.
T62 724736-724813 Sentence denotes Forty-four patients with LEMS were assessed, of whom eighteen (41%) had SCLC.
T63 724814-724913 Sentence denotes In the NT group, seven patients (27%) had an additional AID, in the SCLC group two (11%) ( p=0.20).
T64 724914-725027 Sentence denotes Thyroid disorder (five patients) and insulin-dependent diabetes mellitus (two patients) were the most common AID.
T65 725028-725192 Sentence denotes AID were significantly more frequent in families of patients with NT-LEMS (64%) than in control families (27%, p=0.002), or in families of SCLC-LEMS patients (36%).
T66 725193-725291 Sentence denotes Affected family members were linked to the NT-LEMS patient through the maternal line in all cases.
T67 725292-725424 Sentence denotes In conclusion, AID were more frequently found in NT-LEMS patients and their families, than in SCLC-LEMS patients and their families.
T68 725425-725501 Sentence denotes This suggests that NT-LEMS shares immunological risk factors with other AID.
T69 725502-725692 Sentence denotes This finding and the remarkable preponderance of maternal inheritance, which was reported previously in myasthenia gravis, might help to identify the responsible mechanism or genes involved.
T70 725693-725825 Sentence denotes Daily versus alternate day plasmapharesis for induction of remission in patients with severe myasthenia gravis a randomised trial S.
T71 725826-725835 Sentence denotes Singh, I.
T72 725836-725846 Sentence denotes Trikha, V.
T73 725847-725856 Sentence denotes Goyal, G.
T74 725857-725867 Sentence denotes Shukla, T.
T75 725868-725882 Sentence denotes Srivastava, R.
T76 725883-725896 Sentence denotes Bhasin and M.
T77 725897-725973 Sentence denotes Behari All India Institute of Medical Sciences, New Delhi, India Objectives:
T78 725974-726119 Sentence denotes To assess the comparative efficacy of daily versus alternate day Plasmapharesis for inducing remission in patients with severe myasthenia gravis.
T79 726120-726128 Sentence denotes Methods:
T80 726129-726292 Sentence denotes Thirty-three patients with myasthenia gravis, Osserman's stage IIb and III were randomly allocated to receive alternate day (n=17) or daily plasma exchange (n=16).
T81 726293-726425 Sentence denotes Myasthenia gravis disease scale (MGDS) score was compared before and after the procedure and for subjective improvement in symptoms.
T82 726426-726548 Sentence denotes Time taken for weaning off ventilator, removal of nasogastric tube and total duration of hospital stay were also assessed.
T83 726549-726557 Sentence denotes Results:
T84 726558-726689 Sentence denotes Four to five sessions of plasma exchange were carried on each patient and about 20-25 ml/kg plasma was removed during each session.
T85 726690-726859 Sentence denotes No statistically significant difference was found in daily vs. alternate day group with regards to change in MGDS score and percentage change in MGDS score at discharge.
T86 726860-727024 Sentence denotes The total duration of stay in hospital was less in the daily group as compared to the alternate day group, which almost reached statistical significance ( p=0.054).
T87 727025-727075 Sentence denotes Complications in the two groups were also similar.
T88 727076-727087 Sentence denotes Conclusion:
T89 727088-727268 Sentence denotes We conclude that daily and alternate day plasma pharesis are similar in their efficacy and complication rates, the duration of hospital stay is less with the daily plasma pharesis.
T90 727269-727404 Sentence denotes Hence, it can be the preferred method of performing plasma exchange in patients with myasthenia gravis to induce remission of symptoms.
T91 727405-727525 Sentence denotes Various mutants of the human anti-human-acetylcholine receptor (AChR) antibody IgG1-637 were produced and characterised.
T92 727526-727702 Sentence denotes These included two mutants with changes in the complement-binding site, two mutations for generating bispecific antibodies and a mutation deleting the affinity for the antigen.
T93 727703-727802 Sentence denotes Moreover, a His6 and a Flag tag were added for analysis and purification of different heavy chains.
T94 727803-727907 Sentence denotes A transient expression system using HEK293 cells was successfully used for production of up to 30 Ag/ml.
T95 727908-728095 Sentence denotes The non-complement-binding antibody IgG1-637-C1q was tested in a passive transfer EAMG model with Rhesus monkeys for its ability to compete with the pathogenic parental antibody IgG1-637.
T96 728096-728241 Sentence denotes A drug candidate for treatment of myasthenia gravis: efficacy of a novel immunosuppressant FTY720 in experimental autoimmune myasthenia gravis T.
T97 728242-728254 Sentence denotes Kohno a , K.
T98 728255-728270 Sentence denotes Hirayama a , R.
T99 728271-728286 Sentence denotes Iwatsuki a , M.
T100 728287-728300 Sentence denotes Hirose a , K.
T101 728301-728314 Sentence denotes Watabe a , H.
T102 728315-728331 Sentence denotes Yoshikawa b , A.
T103 728332-728348 Sentence denotes Matsumoto c , T.
T104 728349-728361 Sentence denotes Kohno c , T.
T105 728362-728377 Sentence denotes Fujita c and M.
T106 728378-728744 Sentence denotes Hayashi d a Faculty of Phamaceutical Sciences, Setsunan University, Osaka, Japan; b Kanazawa University, Ishikawa, Japan; c Research Institute for Production and Development, Kyoto, Japan; d Uwajima City Hospital, Ehime, Japan FTY720 was discovered by chemical modification of ISP-I, a metabolite of the fungus Isaria sinclairii, by Fujita who is one of the authors.
T107 728745-728907 Sentence denotes The efficacy of FTY720 had been well established in preclinical transplantation models and has recently proven to be effective in renal transplantation in humans.
T108 728908-729064 Sentence denotes In this study, the efficacies of FTY720 were examined, in preventing experimental autoimmune myasthenia gravis (EAMG) development, and in treatment of EAMG.
T109 729065-729219 Sentence denotes Eight mice out of 12, which had been immunized three times with torpedo californica acetylcholine receptor (AChR) and received water, were developed EAMG.
T110 729220-729389 Sentence denotes In six mice, which had been immunized and received FTY720 continuously (1 mg/kg, orally, three times a week), starting before immunization, no EAMG symptom was observed.
T111 729390-729587 Sentence denotes The eight EAMG mice were divided into a placebo group (n=4), which had been received water, and a treatment group (n=4), which had been received FTY720 described as above after development of EAMG.
T112 729588-729677 Sentence denotes The holding time in inverted grid test was significantly improved in the treatment group.
T113 729678-729779 Sentence denotes These findings show FTY720 is effective not only in the prevention but also in the treatment of EAMG.
T114 729780-730046 Sentence denotes In addition, to clarify the mechanisms of pharmacological actions of FTY720, cytokine mRNA levels, anti-AChR IgG levels (ELISA using mouse AChR as an antigen), and AChR in muscle (fluorescence microscopic detection using FITC-labeled bungarotoxin) had been examined.
T115 730047-730124 Sentence denotes Pyridostigmine 2-4-6 induction regimen is effective in myasthenia gravis R.S.
T116 730125-730140 Sentence denotes Nicholas a , M.
T117 730141-730155 Sentence denotes Roberts b , J.
T118 730156-730170 Sentence denotes Sussman b , J.
T119 730171-730187 Sentence denotes Winer c and I.K.
T120 730188-730320 Sentence denotes Hart a a The Walton Centre, Liverpool, UK; b Hope Hospital, Manchester, UK; c Queen Elizabeth Hospital, Birmingham, UK Introduction:
T121 730321-730391 Sentence denotes Pyridostigmine is the first-line treatment for myasthenia gravis (MG).
T122 730392-730531 Sentence denotes However, there are few studies of its optimum use and neurologists often see patients on subtherapeutic doses or with drug adverse effects.
T123 730532-730536 Sentence denotes Aim:
T124 730537-730658 Sentence denotes To study in 50 MG patients, the pyridostigmine 2-4-6 induction regimen developed from the drug's pharmacokinetic profile.
T125 730659-730667 Sentence denotes Methods:
T126 730668-730764 Sentence denotes Patients entered an open-label study of the 2-4-6 regimen and worked up to the most useful dose:
T127 730765-730899 Sentence denotes 30 mg twice/day for 2 days; 30 mg five times/day for 4 days; 60/ 30/60/30/60 mg per day for 6 days; 60 mg five times/day maximum dose.
T128 730900-731035 Sentence denotes Patients and their neurologists ranked the disease symptoms by severity (0-5) on entry, and at 1 month along with drug adverse effects.
T129 731036-731044 Sentence denotes Results:
T130 731045-731092 Sentence denotes These are preliminary results from 18 patients:
T131 731093-731226 Sentence denotes 7 ocular MG (oMG; average 1.6 symptoms), 6 oculobulbar MG (obMG; average 3.7 symptoms), 5 generalised MG (gMG; average 3.4 symptoms).
T132 731227-731281 Sentence denotes 16/18 (89%) patients improved and completed the trial.
T133 731282-731561 Sentence denotes The severest oMG symptom (ptosis 4, diplopia 3) fell 1.1F1.2 grades (meanFS.D., pb0.05), the severest obMG symptom (dysphagia 3, ptosis 2, diplopia 1) fell 3.3F1 grades ( pb0.001), and the severest gMG symptom (weakness 3, dysarthria 2, diplopia 1) fell 1.6F1.1 grades ( pb0.04).
T134 731562-731643 Sentence denotes 12/18 patients reported adverse effects but in only 2 was pyridostigmine stopped.
T135 731644-731655 Sentence denotes Conclusion:
T136 731656-731827 Sentence denotes The 2-4-6 pyridostigmine induction regimen is well tolerated and effective in MG. (This work was supported by an unrestricted research grant from Valeant Pharmaceuticals).
T137 731828-731913 Sentence denotes Cyclosporin: a treatment in myasthenia gravis patients with anti-MuSK antibodies D.M.
T138 731914-731929 Sentence denotes Bonifati a , R.
T139 731930-731943 Sentence denotes Padoan a , A.
T140 731944-731958 Sentence denotes Vincent b , E.
T141 731959-731976 Sentence denotes Pegoraro a and C.
T142 731977-732070 Sentence denotes Angelini a a University of Padua, Padua, Italy; b University of Oxford, Oxford, UK Objective:
T143 732071-732174 Sentence denotes To evaluate treatment of myasthenic patients presenting antireceptor tyrosine kinase (MuSK) antibodies.
T144 732175-732186 Sentence denotes Background:
T145 732187-732308 Sentence denotes Recently, antibodies to the MuSK have been identified in 40% of seronegative generalised myasthenia gravis (MG) patients.
T146 732309-732376 Sentence denotes They often present with bulbar weakness and are difficult to treat.
T147 732377-732392 Sentence denotes Design/methods:
T148 732393-732490 Sentence denotes In a large population of MG patients, we screened seronegative patients for anti-MuSK antibodies.
T149 732491-732594 Sentence denotes We retrospectively evaluated both the efficacy of thymectomy and choice of immunosuppressive treatment.
T150 732595-732603 Sentence denotes Results:
T151 732604-732657 Sentence denotes Four patients were positive for anti-MuSK antibodies.
T152 732658-732911 Sentence denotes A 38-year-old man, affected by class IIB myasthenia, at 28 years an atrophic thymus was removed, surgery worsened his condition and he required plasmapheresis, he was refractory to steroid therapy and then he was treated with cyclosporin A 300 mg daily.
T153 732912-732977 Sentence denotes A 44-year-old woman presented since age 42 a class IV myasthenia.
T154 732978-733070 Sentence denotes She was treated with IVIg and then with cyclosporin A 250 mg daily, with marked improvement.
T155 733071-733221 Sentence denotes A 39year-old woman had bulbar myasthenia, after thymectomy she needed several plasmapheresis cycles, steroids and azathioprine were used with benefit.
T156 733222-733403 Sentence denotes A 25-year-old patient with ocular myasthenia at 23 underwent thymectomy, but after 2 months presented a relapse with upper limb weakness, she was treated with steroids with benefit.
T157 733404-733415 Sentence denotes Conclusion:
T158 733416-733578 Sentence denotes Two of our patients with anti-MuSK antibodies responded well to cyclosporin A that might be therefore an effective treatment in this group of myasthenic patients.
T159 733579-733627 Sentence denotes Thymectomy did not seem to benefit all patients.
T160 733628-733706 Sentence denotes Dramatic response of ocular symptoms to IVIG treatment in myasthenia gravis A.
T161 733707-733718 Sentence denotes Kurne, E.M.
T162 733719-733732 Sentence denotes Arsava and T.
T163 733733-733791 Sentence denotes Dalkara Hacettepe University, Ankara, Turkey Introduction:
T164 733792-733893 Sentence denotes Myasthenia gravis is an autoimmune disorder characterized by ocular, bulbar and generalized weakness.
T165 733894-734005 Sentence denotes Ninety percent of myasthenic patients suffer from ocular involvement sometime during the course of the disease.
T166 734006-734132 Sentence denotes Ocular symptoms of patients with myasthenia gravis respond incompletely to anticholinesterase and immunosuppressive therapies.
T167 734133-734143 Sentence denotes Objective:
T168 734144-734363 Sentence denotes We report six myasthenic patients whose ocular symptoms dramatically responded to intravenous immunoglobulin (IvIg) therapy and were generally refractory to anticholinesterase and immunosuppressive treatment modalities.
T169 734364-734377 Sentence denotes Case reports:
T170 734378-734457 Sentence denotes Characteristics of patients and treatment features are summarized in the table.
T171 734458-734590 Sentence denotes We propose that the IvIg should be considered in myasthenic patients whose ocular symptoms do not respond to conventional therapies.
T172 734591-734723 Sentence denotes Future studies may disclose whether all patients with ocular symptoms or only a subset of patients dramatically respond to the IvIg.
T173 734724-734853 Sentence denotes Pyridostigmine, Corticosteroid NGF regulates CGRP expression in human monocytes: effects on B7 expression and IL-10 production L.
T174 734854-734876 Sentence denotes Bracci-Laudiero a , L.
T175 734877-734888 Sentence denotes Aloe a , C.
T176 734889-734903 Sentence denotes Caroleo b , P.
T177 734904-734917 Sentence denotes Buanne c , N.
T178 734918-734930 Sentence denotes Costa d , G.
T179 734931-734947 Sentence denotes Starace a and T.
T180 734948-735331 Sentence denotes Lundeberg e a CNR Institute of Neurobiology and Molecular Medicine, Rome, Italy; b University of Calabria, Cosenza, Italy; c University of L'Aquila, L'Aquila, Italy; d University of bMagna GreciaQ, Catanzaro, Italy; e Karolinska Institutet, Stockholm, Sweden Administration of Nerve Growth Factor (NGF) in EAE models delays the onset and prevents the full development of EAE lesions.
T181 735332-735674 Sentence denotes In line with this anti-inflammatory activity of NGF are our recent results on the autocrine NGF synthesis in B lymphocytes, which directly regulate in these cells the expression of calcitonin gene-related peptide (CGRP), a neuropeptide which is a potent inhibitor of T cell proliferation and antigen presentation by macrophages and monocytes.
T182 735675-735907 Sentence denotes Using cultures of human monocytes we investigated by RT-PCR, immunofluorescence and flow cytometry analysis whether NGF can regulate the expression of CGRP also in these cells and influence the expression of B7.1 and B7.2 and IL-10.
T183 735908-736052 Sentence denotes Our data indicate that monocytes synthesise basal levels of NGF but, after LPS stimulation, upregulate NGF expression in dose-dependent fashion.
T184 736053-736204 Sentence denotes When the cultures are deprived of endogenous NGF, CGRP expression in resting cells decreases and the up-regulation of CGRP induced by LPS is prevented.
T185 736205-736404 Sentence denotes In addition, we observed that endogenous NGF reduction affects co-stimulatory molecule expression and IL-10 synthesis, and these effects can be partially mimicked by using CGRP receptor I antagonist.
T186 736405-736681 Sentence denotes Our findings indicate that endogenous synthesis of NGF in monocytes has a functional role and, by influencing B7.2 expression and IL-10 production, contributes to the downregulation of the immune response and strongly support the newly found anti-inflammatory activity of NGF.
T187 736682-736693 Sentence denotes Background:
T188 736694-736844 Sentence denotes Myasthenia gravis (MG) is caused by autoantibodies directed to the acetylcholine receptor (AChR) at neuromuscular junction leading to muscle weakness.
T189 736845-736971 Sentence denotes Dendritic cells (DC), usually regarded as antigen-presenting cells involved in T cell activation, also affect B cell function.
T190 736972-737037 Sentence denotes Immature DC may induce tolerance while mature DC induce immunity.
T191 737038-737124 Sentence denotes The presence of IL-10 during maturation of DC inhibits their terminal differentiation.
T192 737125-737254 Sentence denotes We explored potential of IL-10-modulated-DCbased immunotherapy in experimental autoimmune myasthenia gravis (EAMG) in Lewis rats.
T193 737255-737262 Sentence denotes Method:
T194 737263-737520 Sentence denotes Splenic DC were isolated from onset of EAMG on day 39 post immunization (p.i.), exposed in vitro to IL-10, and then injected intraperitoneally (i.p.) into ongoing EAMG rats at a dose of 1,000,000 cells/rat on day 5 p.i. with AChR+complete Freund's adjuvant.
T195 737521-737529 Sentence denotes Results:
T196 737530-737844 Sentence denotes Lower clinical scores, less body weight loss, lower numbers of anti-AChR IgG antibody secreting cells and lower affinity of anti-AChR antibodies were observed in rats receiving IL-10-modified DC, accompanied with lower expression of CD80 and CD86 and lower lymphocyte proliferation compared with control EAMG rats.
T197 737845-738009 Sentence denotes Lower levels of IL-10 and IFN-gamma were also found in the supernatants of AChR-stimulated lymph node mononuclear cell cultures in rats receiving IL-10-modified DC.
T198 738010-738212 Sentence denotes Conclusion: IL-10-modified DC induce hypo-responsiveness by down-regulating co-stimulatory molecules, and reducing the production of anti-AChR antibodies possibly by inhibiting IL-10 production in EAMG.
T199 738213-738281 Sentence denotes Immature and mature dendritic cells in multiple sclerosis lesions B.
T200 738282-738297 Sentence denotes Serafini a , B.
T201 738298-738316 Sentence denotes Rosicarelli a , R.
T202 738317-738333 Sentence denotes Magliozzi a , E.
T203 738334-738350 Sentence denotes Capello b , G.L.
T204 738351-738368 Sentence denotes Mancardi b and F.
T205 738369-738659 Sentence denotes Aloisi a a Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità , Rome, Italy; b University of Genova, Genova, Italy Dendritic cells (DC) accumulating in target organs during autoimmune disease are thought to have a key role in the stimulation of autoreactive T cells.
T206 738660-738894 Sentence denotes To address the functional relevance of DC in multiple sclerosis (MS), we evaluated the degree of DC infiltration in MS brain using immunohistochemical techniques and a panel of antibodies recognizing DC subsets and maturation markers.
T207 738895-738964 Sentence denotes All MS lesions examined were of the chronic active and inactive type.
T208 738965-739137 Sentence denotes The C-type lectin DC-SIGN that is present on immature myeloid DC was expressed by cells accumulating around inflamed blood vessels, predominantly in chronic active lesions.
T209 739138-739173 Sentence denotes No CD1a+ immature DC were detected.
T210 739174-739366 Sentence denotes Markers of mature DC, like CD83 and DC-lysosomeassociated membrane protein (DC-LAMP) were expressed by a few, isolated cells in the perivascular space and parenchyma of chronic active lesions.
T211 739367-739490 Sentence denotes CCR7, a chemokine receptor typical of mature DC, was detected on numerous cells at the edge of some chronic active lesions.
T212 739491-739652 Sentence denotes Most of these cells were tentatively identified as microglia due to their ramified morphology, scattered intraparenchymal distribution and coexpression of Iba-1.
T213 739653-739720 Sentence denotes In normal brain, only DC-SIGN+ cells were detected in the meninges.
T214 739721-739991 Sentence denotes The presence of immature and mature DC in chronic active MS lesions suggests that abnormal presentation of myelin antigens by these potent antigen presenting cells could break immune tolerance toward CNS antigens and allow continuous stimulation of autoimmune responses.
T215 739992-740159 Sentence denotes Upon stimulation by microbial products through Toll-like receptors (TLR), dendritic cells (DC) can prime naive T cells and initiate a pro-inflammatory immune response.
T216 740160-740334 Sentence denotes Recently, we have shown that APC within the CNS of MS patients contain peptidoglycan (PGN), a major cell wall component of Gram-positive bacteria, which signals through TLR2.
T217 740335-740485 Sentence denotes We report here that Staphylococcus aureus PGN as a single component can replace whole Mycobacterium tuberculosis in Freund's complete adjuvant in EAE.
T218 740486-740591 Sentence denotes Mice immunized with and encephalitogenic MOG-peptide in incomplete Freund's adjuvant did not develop EAE.
T219 740592-740714 Sentence denotes In contrast, addition of PGN to the emulsion was sufficient for priming of auto-reactive Th1 cells and development of EAE.
T220 740715-740915 Sentence denotes In vitro studies demonstrated that PGN stimulates DC-mediated processes, reflected by increased antigen uptake, DC maturation, Th1 cell expansion, activation, and pro-inflammatory cytokine production.
T221 740916-741078 Sentence denotes These data indicate that PGN-mediated interactions result in pro-inflammatory stimulation of antigen specific effector functions important for development of EAE.
T222 741079-741223 Sentence denotes These PGN-mediated processes may occur both within the peripheral lymph nodes as well as in the CNS and likely involve recognition by TLR on DC.
T223 741224-741307 Sentence denotes As such, PGN signaling pathways may serve as novel targets for the treatment of MS.
T224 741308-741439 Sentence denotes Dendritic cells (DC) are the key regulators of tolerance and immunity to the self-antigens that they sample and present to T cells.
T225 741440-741572 Sentence denotes Depending on their maturation state, DC either induce regulatory T cells (immature DC) or autoreactive T helper 1 cells (mature DC).
T226 741573-741675 Sentence denotes DC maturation is controlled by the balance of C-type lectin receptors (CLR), and Toll receptors (TLR).
T227 741676-741863 Sentence denotes TLR recognize pathogen-associated molecular patters and induce DC maturation (Yang), while the CLR recognition of carbohydrate structures on self-antigens antagonizes DC maturation (Yin).
T228 741864-741999 Sentence denotes As essentially all extracellular proteins are glycosylated, it can be envisaged that self glycoproteins can maintain tolerance to self.
T229 742000-742053 Sentence denotes In a healthy individual, Yin and Yang are in balance.
T230 742054-742212 Sentence denotes We have hypothesized that a lack of Yin by disturbance of the normal glycosylation of self glycoproteins affects the capacity of CLR to inhibit DC maturation.
T231 742213-742311 Sentence denotes As a consequence, DCs will mature and induce autoreactive Th1 cells to the defective glycoprotein.
T232 742312-742441 Sentence denotes We will discuss new data from nonhuman primate models of experimental autoimmune encephalomyelitis which support this hypothesis.
T233 742442-742552 Sentence denotes Modulation of experimental autoimmune encephalomyelitis with the infectious agent Trypanosoma brucei brucei M.
T234 742553-742570 Sentence denotes Wållberg and R.A.
T235 742571-742616 Sentence denotes Harris Karolinska Insitute, Stockholm, Sweden
T236 742617-742826 Sentence denotes The protozoan parasite Trypanosoma brucei brucei (Tbb) causes African sleeping sickness in cattle and also experimentally in mice, with human forms of the parasite causing disease throughout equatorial Africa.
T237 742827-743211 Sentence denotes Mice harbouring a Tbb infection do not develop Experimental autoimmune encephalomyelitis (EAE), an animal model for human disease multiple sclerosis (MS), upon immunisation with recombinant myelin oligodendrocyte glycoprotein (rMOG) in complete Freund's adjuvant (CFA), and mice that are infected with the parasites at the time of immunisation or a week later develop less severe EAE.
T238 743212-743390 Sentence denotes Protected mice display a markedly diminished rMOG-specific proliferation and IFN-gamma production in lymph node cells, and have correspondingly low titres of serum anti-rMOG IgG.
T239 743391-743633 Sentence denotes Antigen presenting cells (APC) from spleens of Tbb infected mice present rMOG less efficiently to rMOG specific T cells in vitro than APC from control spleens, and can also inhibit antigen specific proliferations in control in vitro cultures.
T240 743634-743765 Sentence denotes Transfer of splenic APC from Tbb infected mice into mice immunised with rMOG-CFA 7 days previously abrogated disease significantly.
T241 743766-743891 Sentence denotes Visualization of peracute antigen presentation/T cell activation in spleen following high-dose soluble antigen application F.
T242 743892-743903 Sentence denotes Odoardi, Z.
T243 743904-743910 Sentence denotes Li, N.
T244 743911-743923 Sentence denotes Kawakami, W.
T245 743924-743936 Sentence denotes Klinkert, J.
T246 743937-743946 Sentence denotes Bauer, H.
T247 743947-743959 Sentence denotes Lassmann, H.
T248 743960-744265 Sentence denotes We studied the mechanisms of intravenous high dose soluble MBP application (HSM) in adoptive transfer experimental autoimmune encephalomyelitis (tEAE) of the Lewis rat using gene engineered myelin basic protein specific T cells, which express the green fluorescent protein (TMBP-GFP cells) as marker gene.
T249 744266-744462 Sentence denotes HSM prevented CNS inflammation and clinical disease if applied few hours before entry of encephalitogenic T cells into the brain by trapping of the effector T cell in the peripheral immune organs.
T250 744463-744606 Sentence denotes In lymph nodes, live-imaging showed a dramatically reduced motility of TMBP-GFP cells, which formed stable aggregates with resident phagocytes.
T251 744607-744708 Sentence denotes In the spleen, HSM treatment induced redistribution of TMBP-GFP cells from the red to the white pulp.
T252 744709-744905 Sentence denotes The morphological changes were associated with fast T cell activation: increase in cytokines mRNA expression was observed within 1 h and membrane phenotype rearrangement 2 h after HSM application.
T253 744906-745058 Sentence denotes T cell activation was blocked by anti-MHC II antibodies indicating rapid antigen processing and T cell recognition process underlying these HSM effects.
T254 745059-745184 Sentence denotes Twenty-four hours after HSM application, the entire TMBP-GFP cell population was eliminated by activation induced cell death.
T255 745185-745412 Sentence denotes In conclusion, HSM treatment elucidates the crucial role of CNS-infiltration by autoreactive CD4+ T cells in CNS autoimmunity and serves as ideal model system to visualize peracute antigen processing/T cell recognition in vivo.
T256 745413-745566 Sentence denotes Matrix metalloproteinase (MMP)-12 is involved in the immunopathogenesis of multiple sclerosis (MS) and implicated in the active process of demyelination.
T257 745567-745722 Sentence denotes MMPs may contribute to demyelination by cleaving myelin proteins, and consequently propagate the immune response by generating new immunodominant epitopes.
T258 745723-745894 Sentence denotes Little is known about the role of MMPs influencing MHC class II related peptide presentation of dominant myelin epitopes, thus influencing epitope spreading or limitation.
T259 745895-746048 Sentence denotes Here we show that a principal human HLA-DR2-restricted epitope-amino acids 85-99 of myelin basic protein, MBP(85-99)-contains a cleavage site for MMP-12.
T260 746049-746220 Sentence denotes Presentation of this epitope by antigen presenting cells was completely abolished in the presence of MMP-12 as demonstrated by using MBP(80-99) specific TCR-transfectants.
T261 746221-746302 Sentence denotes In contrast, myelin oligodendrocyte glycoprotein (MOG) was not cleaved by MMP-12.
T262 746303-746471 Sentence denotes By immunohistochemistry, MMP-12 could be detected in active MS lesions, predominantly expressed by CD68+ cells, indicative of macrophages and activated microglia cells.
T263 746472-746581 Sentence denotes Moreover, proteolytic activity of MMP-12 was measurable in the CSF from patients with MS but not in controls.
T264 746582-746805 Sentence denotes Our data demonstrate that MMP-12, found in MS patients, exhibits a novel function: by destroying an immunodominant MBP-epitope, this protease could directly influence the cascade of MBP-specific T-cell autoreactivity in MS.
T265 746806-747021 Sentence denotes These findings are not only of considerable relevance for a deeper understanding of mechanisms amplifying or limiting local CNS autoreactivity but also for general considerations on central and peripheral tolerance.
T266 747022-747078 Sentence denotes The criteria for definition of driver T cell clones J.S.
T267 747079-747090 Sentence denotes Menezes, A.
T268 747091-747120 Sentence denotes Ametani, P. van den Elzen, E.
T269 747121-747134 Sentence denotes Maverakis, V.
T270 747135-747149 Sentence denotes Kumar and E.E.
T271 747150-747341 Sentence denotes Sercarz Torrey Pines Institute for Molecular Studies, San Diego, CA, USA Driver T cells (DTC) can be defined as necessary and sufficient for the induction of EAE or other autoimmune diseases.
T272 747342-747559 Sentence denotes We have recently reported that in the B10.PL mouse, a very small group of clones is responsible for the causation of EAE and when this clone is down-regulated no further disease occurs and the animal enters remission.
T273 747560-747621 Sentence denotes Thus, the disease course follows the life history of the DTC.
T274 747622-747686 Sentence denotes In fact, this becomes one of the criteria in defining bdriversQ.
T275 747687-748251 Sentence denotes We have spent considerable effort in the B10.PL model to derive a set of criteria which might be used to define such clones: (a) a high affinity for antigen, which underlies the successful competitive performance of drivers in becoming dominant members of the repertoire; (b) DTC should appear very early in the lymph nodes, and by the end of the second week, they have migrated to the spinal cord and spleen; (c) a characteristic of drivers is their sequential appearance in these central lymphoid organs; (d) their publicity and (e) their proinflammatory nature.
T276 748252-748366 Sentence denotes DTC are likely to be public clones, present in each individual, and they are also usually Th1 in cytokine pattern.
T277 748367-748522 Sentence denotes We now call clones fitting all of these criteria driver T cell clones and they have been found in mouse EAE as well as in the NOD model of type I diabetes.
T278 748523-748633 Sentence denotes Immunization with myelin antigens leads to the development of experimental autoimmune encephalomyelitis (EAE).
T279 748634-748790 Sentence denotes Auto-aggressive T lymphocytes migrate into the CNS where they recognize their cognate antigen and initiate an inflammatory cascade leading to tissue damage.
T280 748791-748946 Sentence denotes The T cells need to re-encounter their cognate antigen in the context of an MHCII bearing antigen presenting cell (APC) in order to recognize their target.
T281 748947-749114 Sentence denotes Whether the antigen presenting cell (APC) that mediates T cell entry into the CNS is located within the CNS or the systemic immune compartment remains heavily debated.
T282 749115-749329 Sentence denotes To determine the contribution of the systemic immune compartment in guiding auto-aggressive T cells into the CNS, splenectomized alymphoplasia (aly) mice, which do not have secondary lymphoid structures, were used.
T283 749330-749509 Sentence denotes We demonstrate that these mice are fully susceptible to EAE indicating that encephalitogenic T cells do not need to home into secondary lymphoid tissues prior to CNS infiltration.
T284 749510-749686 Sentence denotes In order to assess the capacity of CNS residents (microglia) to present Ag in vivo, mice with an MHCII-deficient CNS parenchyma were used as recipients of MOG-reactive T cells.
T285 749687-749778 Sentence denotes Surprisingly, these mice are fully susceptible to develop EAE induced by adoptive transfer.
T286 749779-749923 Sentence denotes Finally, we demonstrate that transgenic mice expressing MHCII molecules exclusively on dendritic cells develop EAE induced by adoptive transfer.
T287 749924-750093 Sentence denotes Our data clearly show that CD11c+ dendritic cells are sufficient to present Ag to auto-reactive T cells thus mediating CNS inflammation and clinical disease development.
T288 750094-750182 Sentence denotes Multiple sclerosis: impaired phenotype and maturation of plasmacytoid dendritic cells M.
T289 750183-750199 Sentence denotes Stasiolek a , A.
T290 750200-750212 Sentence denotes Bayas b , N.
T291 750213-750227 Sentence denotes Kruse c , K.V.
T292 750228-750240 Sentence denotes Toyka b , R.
T293 750241-750254 Sentence denotes Gold d and K.
T294 750255-750479 Sentence denotes Selmaj a a Medical University, Lodz, Poland; b University of Würzburg, Würzburg, Germany; c University of Gfttingen, Göttingen, Germany Dendritic cell (DC) subtypes possess strong but diversified immunoregulatory properties.
T295 750480-750602 Sentence denotes Plasmacytoid DCs (pDCs) demonstrate pronounced ability to prime regulatory T cells or the Th2 type of the immune response.
T296 750603-750801 Sentence denotes Considering the putative immunoregulatory function of pDCs in multiple sclerosis (MS), we assessed the phenotype of pDCs isolated from the blood of MS patients and the maturation of pDCs in culture.
T297 750802-751037 Sentence denotes Blood samples from 32 untreated RR-MS patients and 22 healthy controls were included in ex vivo phenotypic analysis performed by flow cytometry. pDCs were assessed for the expression of maturation antigens and co-stimulatory molecules.
T298 751038-751193 Sentence denotes In maturation experiments, pDCs isolated magnetically from leucapheresis material (18 MS patients, 12 controls) were cultured for 96 h with IL3 and sCD40L.
T299 751194-751378 Sentence denotes Every 24 h cultured pDCs were analysed for the expression of maturation markers and co-stimulatory molecules. pDCs in MS showed immature phenotype compared to pDCs of healthy subjects.
T300 751379-751646 Sentence denotes The expression of co-stimulatory molecules CD86 and 4-1BBL on pDCs was significantly lower in MS samples than in controls. pDCs of MS patients also showed impaired maturation as demonstrated by significantly lower or delayed up-regulation of CD86, 4-1BBL, CD40, CD83.
T301 751647-751773 Sentence denotes The observed abnormalities in ex vivo phenotype and maturation process may contribute to the immunoregulatory imbalance in MS.
T302 751774-751864 Sentence denotes Serum of patients with multiple sclerosis induce activation of antigen presenting cells A.
T303 751865-751877 Sentence denotes Karni a , D.
T304 751878-751891 Sentence denotes Azulai a , A.
T305 751892-751908 Sentence denotes Korczyn a and H.
T306 751909-752111 Sentence denotes Weiner b a Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; b Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MS, USA Objective:
T307 752112-752233 Sentence denotes To study the effect of serum from patients with multiple sclerosis (MS) on activation of antigen presenting cells (APCs).
T308 752234-752242 Sentence denotes Methods:
T309 752243-752418 Sentence denotes Peripheral mononuclear cells (PBMCs) from healthy donors were incubated with 25% serum of healthy controls (HC, n=12) or MS patients during remission (n=25) or relapse (n=11).
T310 752419-752567 Sentence denotes The production of IL-12 and TNF-alpha in dendritic cells (DCs) and monocytes and the expression of HLA-DR, CD80 and CD40 measured by flow cytometry.
T311 752568-752576 Sentence denotes Results:
T312 752577-752794 Sentence denotes An increased percentages of IL-12 producing DCs detected after incubation with serum of secondary progressive (SP) MS (3.5F2.4%) compared to relapsing-remitting (RR) MS (1.3F1.0%, p=0.04) and to HC (0.8F0.7%, p=0.02).
T313 752795-752912 Sentence denotes We searched the serum of MS patients for cytokines known to activate DCs and only IFNgamma was consistently detected.
T314 752913-753033 Sentence denotes PBMCs were incubated with eight serum from SP-MS in the presence of anti-IFN-gamma blocking antibody or isotype control.
T315 753034-753141 Sentence denotes IFN-gamma blockade decreased the percentages of IL-12 producing DCs from 3.14F2.15% to 0.84F0.79%, p=0.008.
T316 753142-753450 Sentence denotes In a comparison with serum of patients in remission, the serum of the same patients during relapse induced increased expression of HLA-DR on monocytes (mean florescence intensity 2732F409 vs. 1171F355, p=0.05), increased percentages of TNF-alpha producing cells (2.5F0.9% vs. 1.5F0.5%, p=0.04, respectively).
T317 753451-753463 Sentence denotes Conclusions:
T318 753464-753520 Sentence denotes Serum of MS patients include factors that activate APCs.
T319 753521-753572 Sentence denotes Serum IFN-gamma appears to be one of these factors.
T320 753573-753669 Sentence denotes This serum effect may provide a proinflammatory signal via APCs for myelin autoreactive T cells.
T321 753670-753750 Sentence denotes CNS microvascular pericyte polarization to alternatively activated phenotypes P.
T322 753751-753768 Sentence denotes Dore-Duffy a , R.
T323 753769-753787 Sentence denotes Balabanov b and J.
T324 753788-754055 Sentence denotes Williams a a Wayne State University, School of Medicine, Detroit Medical Center, Detroit, USA; b University of Chicago, Chicago, USA CNS microvascular pericytes are thought to be highly complex regulatory cells important to tissue homeostasis and vascular hemostasis.
T325 754056-754140 Sentence denotes We have previously shown that rat primary capillary pericytes have immune potential.
T326 754141-754239 Sentence denotes They present antigen to sensitized leukocytes and drive naRve T cells to the TH1 or TH2 phenotype.
T327 754240-754404 Sentence denotes Pericytes may therefore function as a CNS antigen presenting cell (APC) and undergo TH1 or TH2-like polarization associated with alternatively activated phenotypes.
T328 754405-754473 Sentence denotes To test this hypothesis, we examined freshly isolated rat pericytes.
T329 754474-754584 Sentence denotes Pericytes were found to be primed to the APC phenotype and produce high levels of IL-12 and low levels of PGE.
T330 754585-754646 Sentence denotes Seven-day-old primary pericytes constitutively release IL-18.
T331 754647-754710 Sentence denotes They adhere CD4+ cells of the TH1 cytokine secreting phenotype.
T332 754711-754791 Sentence denotes In the presence of IFN gamma, they express class II antigen and process antigen.
T333 754792-754969 Sentence denotes In the presence of stress stimuli such as low oxygen or TH2 cytokines (IL-4), IL-12 production is decreased, eicosanoid synthesis is increased and pericytes synthesize TGF beta.
T334 754970-755064 Sentence denotes During this stage of differentiation, pericytes are poor APC and selectively adhere TH2 cells.
T335 755065-755152 Sentence denotes They express vascular endothelial cell growth factor (VEGF) and stimulate angiogenesis.
T336 755153-755268 Sentence denotes These data suggest that pericytes have multiple states of activation/differentiation comparable to traditional APC.
T337 755269-755343 Sentence denotes It is likely that pericyte APC have an important role in CNS inflammation.
T338 755344-755440 Sentence denotes Perivascular macrophages (PVM) are a subpopulation of macrophages in the central nervous system.
T339 755441-755649 Sentence denotes Based on animal studies and on the strategic location of the PVM at the interface between circulation and brain parenchyma, it has been postulated that PVM play a role in antigen recognition and presentation.
T340 755650-755772 Sentence denotes Here we show that the hemoglobinhaptoglobin scavenger receptor, CD163, can be used as a marker for PVM in the human brain.
T341 755773-756006 Sentence denotes By means of double immunofluorescence stainings in normal control brain tissue and in sections of several multiple sclerosis (MS) lesion stages, it appeared that CD163+ PVM express DC-SIGN, MHC II and several costimulatory molecules.
T342 756007-756147 Sentence denotes Furthermore, we observed an increased number of CD163+ DC-SIGN+ macrophages as well as expression of CD163 and DC-SIGN on foamy macrophages.
T343 756148-756321 Sentence denotes These double stainings suggest that PVM have the necessary tools for antigen recognition and presentation and supposedly play a role as antigen-presenting cell of the brain.
T344 756322-756436 Sentence denotes Further studies are required to establish which immune regulatory role these cells exert upon antigen recognition.
T345 756437-756572 Sentence denotes Multiple sclerosis (MS) has a relapsing-remitting nature in 85-90% of the patients, in which periods of disease and recovery alternate.
T346 756573-756656 Sentence denotes This implies that there is a balance between detrimental and protective mechanisms.
T347 756657-756726 Sentence denotes Cervical lymph nodes (CLN) are a major site of drainage of the brain.
T348 756727-756853 Sentence denotes It has been shown that brain-derived myelin components are present in antigen presenting cells (APC) within the CLN during MS.
T349 756854-756960 Sentence denotes We hypothesize that these APC play an important role in regulating the peripheral immune system during MS.
T350 756961-757160 Sentence denotes Immunohistochemistry revealed that APC in the cervical lymph nodes not only contain myelin components, but also other central nervous system (CNS) components such as astrocytic and neuronal proteins.
T351 757161-757261 Sentence denotes Immunohistochemistry was also used to determine the immunophenotype of CNS antigen-containing cells.
T352 757262-757404 Sentence denotes MOG-containing cells express the anti-inflammatory molecules IL-1ra and TGF-beta, but did not express the pro-inflammatory cytokine TNF-alpha.
T353 757405-757594 Sentence denotes To determine the antigenpresenting capacity of myelin-laden cells in vitro, monocyte-derived macrophages were pulsed with myelin and co-incubated with T cells in a mixed leukocyte reaction.
T354 757595-757679 Sentence denotes Preliminary data demonstrate that pulsed macrophages increased T cell proliferation.
T355 757680-757799 Sentence denotes In addition, IFN-gamma production by T cells paralleled T cell proliferation, suggesting enhanced antigen presentation.
T356 757800-757904 Sentence denotes Our data suggest that phagocytic APC in CLN may display regulatory functions in the periphery during MS.
T357 757905-758101 Sentence denotes Accumulating evidence suggests that, apart from clonal deletion and anergy, T cell mediated control of self-reactive T cells contributes to the maintenance of natural immunological self-tolerance.
T358 758102-758297 Sentence denotes For example, expansion of CD25+CD4+ T cells, which constitute 5-10% of peripheral CD4+ T cells in rodents and humans, prevents autoimmunity by suppressing the activation of self-reactive T cells.
T359 758298-758407 Sentence denotes It has been observed that dendritic cells (DC) can prime CD25+CD4+ T cells to acquire suppressive properties.
T360 758408-758755 Sentence denotes In this context, gene expression analysis in murine models of autoimmunity revealed a functional role for the glucocorticoid-induced TNF receptor (GITR) in CD25+CD4+ T cells and recently it was shown in humans that a forced expression of the Foxp3 gene, which encodes a transcription repressor gene, can convert CD4+ T cells to T suppressor cells.
T361 758756-758932 Sentence denotes In a preliminary analysis using real time PCR, we could not observe any significant differences in FOXP3 and GITR mRNA expression levels between MS patients and healthy donors.
T362 758933-759148 Sentence denotes Therefore, we now extend our study employing gene expression microarray technology to assess gene expression differences in CD25+CD4+ T cells and DC between Multiple Sclerosis (MS) patients and young healthy donors.
T363 759149-759324 Sentence denotes Differentially expressed genes in these key cells of immunological tolerance may further our understanding of the molecular pathogenesis of MS and provide new disease markers.
T364 759325-759379 Sentence denotes Brain dendritic cells: origin, maturation, function G.
T365 759380-759396 Sentence denotes Reichmann a , A.
T366 759397-759412 Sentence denotes Mausberg a , S.
T367 759413-759426 Sentence denotes Jander a , D.
T368 759427-759446 Sentence denotes Schlqter b and H.G.
T369 759447-759548 Sentence denotes Fischer a a Heinrich-Heine-University, Düsseldorf, Germany; b University Mannheim-Heidelberg, Germany
T370 759549-759687 Sentence denotes It is generally accepted that DC are lacking in the normal brain, however, DC appear at intracerebral sites under inflammatory conditions.
T371 759688-759865 Sentence denotes In the absence of a brain-directed T cell response as in cerebral ischemia, these DC remain immature, whereas in pathogen-induced neuroinflammation brain DC functionally mature.
T372 759866-759997 Sentence denotes Intracerebral DC maturation precedes histopathology as evident by the early induction of CD83 and ex vivo allostimulatory activity.
T373 759998-760384 Sentence denotes A contribution of microglia to the intracerebral DC population was delineated from the amyloid-related phenotype brain DC exhibit, the microglia-like morphology of cells expressing DC markers at parenchymal sites where any cellular infiltrate is lacking features that microglia share with immature DC, and the finding that microglia purified from adult brain can generate functional DC.
T374 760385-760552 Sentence denotes Final proof that microglia constitute a portion of the DC population was obtained by sorting of donor versus host-type DC from inflamed brains of bone marrow chimeras.
T375 760553-760745 Sentence denotes Distinct stages in microgliato-DC differentiation were demonstrated in vitro: GM-CSF drives microglia to acquire an immature DC-like phenotype while CD40 ligation triggers terminal activation.
T376 760746-760888 Sentence denotes Since an inflammatory neural environment is a likely source of both stimuli, microglia must be regarded as an organotypic reservoir of pre-DC.
T377 760889-761070 Sentence denotes Antigen presentation by brain DC in situ was substantiated by the finding that DC from the brains of mice with toxoplasmosis spontaneously activate pathogenspecific T cells ex vivo.
T378 761071-761167 Sentence denotes The object of this study was to evaluate the effect of simvastatin on microglia immune function.
T379 761168-761324 Sentence denotes We treated primary mouse and human microglia with simvastatin and evaluated the membrane expression of several immune regulatory molecules by FACS analysis.
T380 761325-761437 Sentence denotes Next, we subjected simvastatin treated primary human microglia to a chemotaxis assay towards various chemokines.
T381 761438-761604 Sentence denotes Finally, we evaluated the impact of simvastatin treatment on the subcellular structure of human microglia by cytoskeleton staining and structural electron microscopy.
T382 761605-761793 Sentence denotes We show that simvastatin is able to reduce in primary microglia the expression of MHC class II, the costimulatory molecule CD86, the adhesion molecule CD40 and the chemokine receptor CCR5.
T383 761794-761929 Sentence denotes In addition, we demonstrate that simvastatin reduces the capacity of microglia to migrate towards the chemokines RANTES and MIP-1alpha.
T384 761930-762031 Sentence denotes Finally, we show that simvastatin treatment results in an altered subcellular structure of microglia.
T385 762032-762244 Sentence denotes Together, these data suggest that simvastatin is able to reduce the capacity of microglia to migrate and interact with their environment by disturbing the metabolism of several important membrane-bound molecules.
T386 762245-762309 Sentence denotes Supported by the Dutch MS Research Foundation (Grant 00-407 MS).
T387 762310-762405 Sentence denotes Inflammation of the CNS is usually locally limited to avoid otherwise devastating consequences.
T388 762406-762471 Sentence denotes Critical players implicated in this process are microglial cells.
T389 762472-762583 Sentence denotes The B7 family of ligands and their receptors are recognized as pathways for the regulation of immune responses.
T390 762584-762696 Sentence denotes Human and murine microglial cells were analyzed for the expression of B7-H1 and other B7costimulatory molecules.
T391 762697-762783 Sentence denotes Functional relevance and expression of B7-H1 during MOG-induced EAE were investigated.
T392 762784-762865 Sentence denotes Human and mouse microglial cells constitutively expressed B7-H1 mRNA and protein.
T393 762866-762975 Sentence denotes Under inflammatory conditions, a significant upregulation of B7-H1 mRNA and cell surface protein was notable.
T394 762976-763088 Sentence denotes Microglial expression levels of B7-H1 protein were substantially higher as compared to astrocytes and monocytes.
T395 763089-763356 Sentence denotes Coculture experiments of the different APC with T cells demonstrated the functional consequences of B7-H1 expression: the production of inflammatory cytokines (IFN-gamma and IL-2) by T cells was markedly enhanced in the presence of a neutralizing anti-B7-H1 antibody.
T396 763357-763476 Sentence denotes This effect was clearly more pronounced when microglia cells were used as the APC, compared to monocytes or astrocytes.
T397 763477-763621 Sentence denotes B7-H1 was highly upregulated during the course of MOG-induced EAE in vivo and expression was predominantly located to the areas of inflammation.
T398 763622-763845 Sentence denotes Taken together, our data point to microglial B7-H1 as an important immune-inhibitory molecule that downregulates T cell activation in the CNS and would contribute to the regulation of local levels of inflammatory responses.
T399 763846-763939 Sentence denotes Regulation of immunoproteasome and MHC class I expression by human brain endothelial cells H.
T400 763940-763960 Sentence denotes Lau, M. van Zwam, K.
T401 763961-763971 Sentence denotes Liu and K.
T402 763972-764069 Sentence denotes Dorovini-Zis Vancouver General Hospital and the University of British Columbia, Vancouver, Canada
T403 764070-764256 Sentence denotes Proteasome is a multi-subunit protease responsible for the breakdown of misfolded and regulatory proteins into small peptides which posses anchor sites for MHC class I molecules (MHC I).
T404 764257-764372 Sentence denotes Completely folded MHC Ipeptide complexes are then delivered to the cell surface and presented to CD8+ T cells (TC).
T405 764373-764474 Sentence denotes Recent studies suggest that proteasomes play an important role in leukocyte-endothelial interactions.
T406 764475-764620 Sentence denotes In inflammatory CNS diseases, TC subsets cross the blood-brain barrier (BBB) to initiate immune responses by mechanisms presently poorly defined.
T407 764621-764955 Sentence denotes In this study, regulation of proteasome expression and its role on MHC I expression by HBMEC was investigated in an in vitro BBB model. mRNA and protein expression of the constitutive subunit alpha5 and the inducible beta1i (LMP2) and beta5i (LMP7) subunits by HBEMC was investigated by RT-PCR and ELISA and MHC I expression by ELISA.
T408 764956-765035 Sentence denotes Unstimulated HBMEC express alpha5 and low levels of beta1i and beta5i subunits.
T409 765036-765138 Sentence denotes Both subunits were upregulated following treatment with IFN-gamma (200 U/ml) and TNF-alpha (100 U/ml).
T410 765139-765293 Sentence denotes MHC I expression on HBMEC was significantly upregulated after treatment with IFN-gamma for 48 h and downregulated by the proteasome inhibitor lactacystin.
T411 765294-765538 Sentence denotes These results indicate that cytokine-induced upregulation of immunoproteasome subunits is required for MHC I upregulation on HBMEC and suggest that the proteasome may influence antigen processing and presentation at the BBB in CNS inflammation.
T412 765539-765596 Sentence denotes Peptide motif for the rat MHC class II molecule RT1.Da H.
T413 765597-765606 Sentence denotes Duyar, J.
T414 765607-765633 Sentence denotes Dengjel, K.L. de Graaf, S.
T415 765634-765651 Sentence denotes Stevanovic and R.
T416 765652-765835 Sentence denotes Weissert University of Tübingen, Tübingen, Germany MOG-induced EAE in DA rats (RT1av1) is a model of multiple sclerosis (MS) that reproduces major aspects of this detrimental disease.
T417 765836-765944 Sentence denotes So far, no MHC class II peptide binding motif for the DA rat RT1.Ba and RT1.Da molecules has been described.
T418 765945-766006 Sentence denotes We were interested to obtain an RT1.Da peptide binding motif.
T419 766007-766105 Sentence denotes This will allow subsequent functional studies in rat models of autoimmune and infectious diseases.
T420 766106-766318 Sentence denotes Sequence alignment of the beta-chain of the rat MHC class II molecule RT1.Da with human HLA class II molecules revealed strong similarity in the residues of the peptide binding groove of RT1.Da and HLA-DRB1*1501.
T421 766319-766472 Sentence denotes According to the putative peptide binding pockets of RT1.Da after comparison with the pockets of HLA-DRB1*1501, we predicted the peptide motif of RT1.Da.
T422 766473-766713 Sentence denotes To verify the predicted motif, naturally processed peptides were eluted by acidic treatment from immunoaffinity-purified RT1.Da molecules in lymphoid tissue of MOG immunized DA rats and subsequently analyzed by ESI tandem mass spectrometry.
T423 766714-766822 Sentence denotes The identified peptides were aligned to the peptide binding pockets according to the putative peptide motif.
T424 766823-766942 Sentence denotes Additionally, we performed binding studies with nonameric combinatorial peptide libraries to purified RT1.Da molecules.
T425 766943-767018 Sentence denotes Based on these studies, we could define a peptide binding motif for RT1.Da.
T426 767019-767137 Sentence denotes The peptide motif of RT1.Da will allow epitope predictions for analysis of peptides, relevant for autoimmune diseases.
T1 767138-767192 Sentence denotes Searching for autoimmunizing cell types in thymomas Y.
T2 767193-767206 Sentence denotes Kadota a , M.
T3 767207-767219 Sentence denotes Jones b , T.
T4 767220-767235 Sentence denotes Meager c and N.
T5 767236-767492 Sentence denotes Willcox a a Neuroscience WIMM; b Cellular Science, University of Oxford, Oxford, UK; c National Institute Biological Standards and Control, London, UK Thymomas are neoplasms of thymic epithelial cells (TEC), often generating abundant developing thymocytes.
T6 767493-767626 Sentence denotes Around 30% of thymoma patients develop myasthenia gravis (MG), with antibodies against the muscle acetylcholine receptor (anti-AChR).
T7 767627-767876 Sentence denotes We recently also found high titre neutralising auto-antibodies against Interferon-alpha (IFN-alpha) in N70% of thymoma patients at diagnosis, regardless of histology or HLAtype; titres increase sharply when thymomas recur, unlike those against AChR.
T8 767877-768035 Sentence denotes Cultured thymoma cells spontaneously produce anti-IFN-alpha but not anti-AchR, again suggesting more direct autoimmunization against IFN-alpha in the tumours.
T9 768036-768192 Sentence denotes To identify autoimmunizing cells, we labelled paraffin sections from 21 MG patients with thymomas; 15 with WHO type-B1-2, 5 with type-AB, and 1 with type-A.
T10 768193-768263 Sentence denotes Anti-IFN-alpha titres were high in 10, medium in 5, low/negative in 6.
T11 768264-768392 Sentence denotes IFN-alpha expression appeared strong in 6 (mostly with high serum anti-IFN-alpha), intermediate in 5, and low or negative in 10.
T12 768393-768456 Sentence denotes Most IFN-alpha+ cells appeared large with dendritic morphology.
T13 768457-768542 Sentence denotes They were consistently positive for CD68, and negative for Cytokeratin, CD20 and CD3.
T14 768543-768645 Sentence denotes Conversely, CD68+ cells were also seen in 8 of the 10 thymomas with weak/negative IFN-alpha labelling.
T15 768646-768698 Sentence denotes Most IFN-alpha+ cells were also CD14+ and HLA-DRint.
T16 768699-768755 Sentence denotes We are currently labelling for co-stimulatory molecules.
T17 768756-768911 Sentence denotes In conclusion, the most obvious autoimmunizing cells appear to be IFN-alpha+ macrophages rather than TEC, but unusual dendritic subsets cannot be excluded.
T18 768912-768922 Sentence denotes Objective:
T19 768923-769065 Sentence denotes To investigate the expression and role of the novel B7 family members ICOSL and B7-H1 in cultured muscle cells and in inflammatory myopathies.
T20 769066-769074 Sentence denotes Methods:
T21 769075-769235 Sentence denotes Expression and regulation of B7-H1 and ICOSL was analyzed in cultured myoblasts and muscle biopsy specimens by QRT-PCR, flow cytometry and immunohistochemistry.
T22 769236-769324 Sentence denotes Functional relevance was investigated by coculture experiments of myoblasts and T cells.
T23 769325-769333 Sentence denotes Results:
T24 769334-769405 Sentence denotes Cultured human muscle cells constitutively express ICOSL but not B7-H1.
T25 769406-769471 Sentence denotes Stimulation with IFN-gamma strongly upregulates B7-H1 expression.
T26 769472-769787 Sentence denotes Coculture experiments of MHC-class I/II-positive myoblasts with CD4 and CD8 T cells in the presence of antigen demonstrated the functional consequences of muscle-related B7-H1 and ICOSL expression: whereas ICOSL provided stimulated T cells, B7-H1 was a strong inhibitor of T cell cytokine production and activation.
T27 769788-769866 Sentence denotes Muscle fibers showed constitutive expression of ICOSL, but not B7-H1, in vivo.
T28 769867-770072 Sentence denotes Importantly, both molecules were upregulated in specimens from patients with polymyositis, dermatomyositis and inclusion body myositis and were predominantly located in the areas of strongest inflammation.
T29 770073-770084 Sentence denotes Conclusion:
T30 770085-770174 Sentence denotes Cultured muscle cells and muscle fibers in vivo express the B7-molecules ICOSL and B7-H1.
T31 770175-770465 Sentence denotes Whereas ICOSL provides an augmentatory signal for muscle immune cell interactions, inducible expression of the immune inhibitory molecule B7-H1 provides evidence for the capability of muscle to promote immunoprotective mechanisms putatively involved in the regulation of local inflammation.
T32 770466-770670 Sentence denotes The recently discovered inducible costimulator (ICOS), a CD28 like molecule interacting with its B-7 like ligand ICOS-L on antigen-presenting cells (APC), is expressed preferentially by activated T cells.
T33 770671-770799 Sentence denotes Recent data indicate that ICOS and ICOS-L represent an important pathway in the regulation of autoimmune or infectious diseases.
T34 770800-771180 Sentence denotes To define the expression of ICOS and ICOS-L in inflammatory demyelination of the PNS, we studied their expression and distribution patterns in sural nerve biopsies from patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and, for comparison, various non-inflammatory neuropathies (NIN) by RT-PCR and immunohistochemistry.
T35 771181-771285 Sentence denotes In patients diagnosed as GBS and CIDP but not in NIN, a significant upregulation of ICOS mRNA was found.
T36 771286-771422 Sentence denotes T cells were identified as the primary cellular source expressing ICOS in the inflamed PNS thus corroborating their state of activation.
T37 771423-771568 Sentence denotes Similarly, significantly increased mRNA expression levels of its ligand, ICOS-L, were found in GBS and CIDP samples, but not in the NIN controls.
T38 771569-771653 Sentence denotes Macrophages were deciphered as the cellular source of ICOS-L within the endoneurium.
T39 771654-771693 Sentence denotes Schwann cells were negative for ICOS-L.
T40 771694-771922 Sentence denotes Our data show that ICOS and its ligand ICOS-L are expressed in immune-mediated peripheral neuropathies and might play an important role in the augmentation of cellular immune responses in inflammatory peripheral nerve disorders.
T41 771923-772053 Sentence denotes The surface unit of MSRV envelope protein activates innate immunity through TLR4/CD14 receptors and promotes Th1 like responses A.
T42 772054-772068 Sentence denotes Rolland a , E.
T43 772069-772089 Sentence denotes Jouvin-Marche a , C.
T44 772090-772102 Sentence denotes Viret a , H.
T45 772103-772120 Sentence denotes Perron b and P.N.
T46 772121-772198 Sentence denotes Marche a a CEA/INSERM, Grenoble, France; b bioMerieux, Marcy l'étoile, France
T47 772199-772336 Sentence denotes Multiple Sclerosis (MS) is a pro-inflammatory autoimmune disease causing lesions in the white matter of the central nervous system (CNS).
T48 772337-772457 Sentence denotes Its etiology is not understood but appears to involve both genetic and environmental factors including viral infections.
T49 772458-772664 Sentence denotes MSRV is a retroviral element previously isolated in cell cultures from MS patients and bearing pro-inflammatory properties characterized by the induction of proinflammatory cytokines in human PBMC cultures.
T50 772665-772838 Sentence denotes It is increasingly clear that pattern recognition receptors are of primary importance for innate immune responses to viral components and for the initiation of inflammation.
T51 772839-772991 Sentence denotes CD14 and Toll like receptor 4 (TLR4) are two members of this receptor group with the ability to sense microbial products from both bacteria and viruses.
T52 772992-773184 Sentence denotes We report here that the surface unit of MSRV envelope protein (ENV-SU) specifically induces human monocytes to produce major pro-inflammatory cytokines through a TLR4/CD14 dependent mechanism.
T53 773185-773318 Sentence denotes ENV-SU also induced dendritic cell maturation and conferred them the capacity to support a T helper 1 type of T cell differentiation.
T54 773319-773559 Sentence denotes Thus, it appears that MSRV through the pro-inflammatory properties of its surface envelope protein could constitute an upstream event in the immunopathological cascade leading to autoimmunity and/or neuroinflammation in diseases such as MS.
T55 773560-773656 Sentence denotes Encephalitogenic and beneficial roles of amyloid beta-specific T cells in Alzheimer's disease A.
T56 773657-773673 Sentence denotes Monsonego a , V.
T57 773674-773685 Sentence denotes Zota a , S.
T58 773686-773701 Sentence denotes Petrovic a , J.
T59 773702-773716 Sentence denotes Imitola a , T.
T60 773717-773729 Sentence denotes Owens b , D.
T61 773730-773747 Sentence denotes Selkoe a and H.L.
T62 773748-774055 Sentence denotes Weiner a a Harvard Institute of Medicine, Brigham and Women's Hospital, Center for Neurologic Diseases, Boston, MA, USA; b Montreal Neurological Institute, Montreal, Canada Amyloid beta (Ab) vaccination of patients with Alzheimer's disease (AD) resulted in encephalitis observed in about 5% of the patients.
T63 774056-774281 Sentence denotes Recently, we have shown that a significantly higher portion of healthy elderly and AD subjects had strong Ab-reactive T-cell responses than occurred in middleaged adults, strongly dependent on certain HLA-DR class II alleles.
T64 774282-774418 Sentence denotes We then examined in a mouse model of AD whether Ab-specific T cells can migrate to sites of Ab plaques and affect disease pathogenicity.
T65 774419-774582 Sentence denotes We show that a single immunization with a dominant Ab T-cell epitope induced agedependent transient meningoencephalitis only if IFN-gamma was expressed in the CNS.
T66 774583-774718 Sentence denotes Immune infiltrates were targeted to sites of Ab plaques in the brain associated with enhanced microglia activation and clearance of Ab.
T67 774719-774984 Sentence denotes Overall, we demonstrate that accumulation of Ab in the CNS, MHC genetic background, and inflammatory signal such as IFN-gamma are required to induce Ab-specific T-cell responses in the brain of APP-Tg mice similar to that observed in Ab-vaccinated patients with AD.
T68 774985-775137 Sentence denotes These T-cell responses in the CNS to Ab are dependent on the local milieu and may be beneficial or detrimental depending on the type of T-cell response.
T69 775138-775226 Sentence denotes It is widely accepted that cytotoxic T cells play a dominant role in viral encephalitis.
T70 775227-775369 Sentence denotes The aim of this study is to determine the role of the various cytotoxic pathways used by CD8+ T cells in acute and chronic viral encephalitis.
T71 775370-775545 Sentence denotes We investigated the distribution of GrB+CD8+ T cells in virus infected brains, the patterns of activation, cytotoxicity mechanisms and induction of cell death in target cells.
T72 775546-775843 Sentence denotes We used immunohistochemical and confocal fluorescence double labeling techniques on formalin-fixed, paraffin embedded sections from selected viral encephalitis brains (cytomegalovirus encephalitis (CMV, n=7), tick borne encephalitis (TBE, n=5) and subacute sclerosing panencephalitis (SSPE, n=2)).
T73 775844-775945 Sentence denotes Results show a predominance of CD8+ T cells in the inflammatory infiltrate of all encephalitis cases.
T74 775946-776157 Sentence denotes In CMV cases, the percentage of GrB+ cells remains high during the studied course of disease (4-20 weeks) whereas in TBE we found a gradual decrease in percentage of GrB+ cells during disease course (1-9 weeks).
T75 776158-776302 Sentence denotes Preliminary studies performed with a confocal laser scanning microscope revealed a close contact between CD8+ cells and CMV infected astrocytes.
T76 776303-776407 Sentence denotes In TBE and SSPE, we also found close apposition of GrB+ cells to neurons in the early course of disease.
T77 776408-776543 Sentence denotes These results indicate that especially during the early stage of disease, GrB-mediated cytotoxicity is important in viral encephalitis.
T78 776544-776615 Sentence denotes This work was supported by a grant from the Austrian FWF (P-16063-B02).
T79 776616-776720 Sentence denotes Autoimmune responses against axonal proteins during experimental autoimmune encephalomyelitis (EAE) H.G.
T80 776721-776733 Sentence denotes Huizinga, A.
T81 776734-776745 Sentence denotes Jagessa, P.
T82 776746-776755 Sentence denotes Smith, N.
T83 776756-776771 Sentence denotes Heijmans and S.
T84 776772-776849 Sentence denotes Amor Biomedical Primate Research Centre, Rijswijk, The Netherlands Objective:
T85 776850-776987 Sentence denotes Axonal pathology plays an important role in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE).
T86 776988-777052 Sentence denotes The mechanism of axonal degeneration, however, is not yet known.
T87 777053-777152 Sentence denotes We hypothesise that immune responses against axonal proteins contribute to axonal pathology in EAE.
T88 777153-777284 Sentence denotes Therefore, we investigated whether autoimmune responses against axonal proteins develop in EAE and correlate with clinical disease.
T89 777285-777433 Sentence denotes In addition, we studied the encephalitogenic potential of neuronal antigens, derived from newborn spinal cord in which myelination is just starting.
T90 777434-777442 Sentence denotes Methods:
T91 777443-777526 Sentence denotes Biozzi ABH mice were immunised with newborn and adult spinal cord homogenate (SCH).
T92 777527-777645 Sentence denotes T-cell and antibody responses against neurofilaments (heavy and light) were measured during various stages of disease.
T93 777646-777724 Sentence denotes Cervical lymph nodes were isolated to study presentation of neuronal antigens.
T94 777725-777841 Sentence denotes Results: T-cell and antibody responses to both neurofilament light and heavy were observed in adult SCH-induced EAE.
T95 777842-777929 Sentence denotes Antibody levels, however, did not correlate necessarily with disease stage or severity.
T96 777930-778078 Sentence denotes Neurofilament staining was observed in cervical lymph nodes of mice with EAE, indicating that neuronal antigens can be presented in the lymph nodes.
T97 778079-778206 Sentence denotes Although newborn SCH-immunisation induced T-cell and antibody responses to SCH and neurofilaments, animals did not develop EAE.
T98 778207-778219 Sentence denotes Conclusions:
T99 778220-778346 Sentence denotes Our data indicate that both T-cell and antibody responses against neurofilaments develop during chronic relapsing EAE in mice.
T100 778347-778426 Sentence denotes However neuronal antigens, as in newborn SCH, was not encephalitogenic in mice.
T101 778427-778477 Sentence denotes The relevance of these findings will be discussed.
T102 778478-778557 Sentence denotes Inflammation plays an important role in the pathophysiology of ischemic stroke.
T103 778558-778777 Sentence denotes We mucosally administered myelin oligodendrocyte glycoprotein (MOG) (35-55) peptide to C57BL/6 mice prior to middle cerebral artery occlusion (MCAO) to induce an anti-inflammatory T-cell response directed at CNS myelin.
T104 778778-778911 Sentence denotes We found that nasal and oral administration of MOG (35-55) peptide decreased ischemic infarct size at 24 and 72 h after MCAO surgery.
T105 778912-779087 Sentence denotes Nasal MOG (35-55) peptide was most efficacious and reduced ischemic infarct size by 70% at 24 h and by 50% at 72 h ( pb0.0001 vs. control) as well as improving behavior score.
T106 779088-779231 Sentence denotes Immunohistochemistry demonstrated increased IL-10 and reduced IFN-gamma in the area surrounding the ischemic infarct following nasal treatment.
T107 779232-779303 Sentence denotes Nasal MOG did not reduce ischemic infarct size in IL-10 deficient mice.
T108 779304-779545 Sentence denotes Adoptive transfer of CD4+ T-cells from nasally tolerized mice to untreated mice prior to MCAO surgery significantly decreased stroke size ( pb0.001 vs. control) whereas, CD4+ T-cells from nasally tolerized IL-10 deficient mice had no effect.
T109 779546-779678 Sentence denotes Furthermore, our results demonstrate that IL-10 secreting CD4+ T cells induced by nasal MOG reduce ischemic injury following stroke.
T110 779679-779828 Sentence denotes Modulation of cerebral inflammation by mucosal tolerance to myelin antigens may improve outcome after stroke and enhance mechanisms of self-recovery.
T111 779829-779907 Sentence denotes T helper cells type 2 stimulate axonal outgrowth and attract cortical axons S.
T112 779908-779924 Sentence denotes Müller-Röver, S.
T113 779925-779936 Sentence denotes Sallach, C.
T114 779937-779947 Sentence denotes Brandt, D.
T115 779948-779959 Sentence denotes Lqdecke, D.
T116 779960-779973 Sentence denotes Schwanzar, E.
T117 779974-779988 Sentence denotes Kwidzinski, B.
T118 779989-780004 Sentence denotes Heimrich and R.
T119 780005-780176 Sentence denotes Nitsch Charité University Hospital, Berlin, Germany After mechanical lesions of the nervous system, activated T cells have been suggested to exert neuroprotective effects.
T120 780177-780237 Sentence denotes However, the structural basis of these effects is not clear.
T121 780238-780323 Sentence denotes Stimulation of axonal outgrowth by T cells might be a key mechanism for regeneration.
T122 780324-780494 Sentence denotes Therefore, we have investigated the effects of activated T helper cells type 1 (Th1) and type 2 (Th2) on neuronal outgrowth in murine organotypic brain explants in vitro.
T123 780495-780626 Sentence denotes In these T cell/ explant co-cultures, Th2 cells stimulated axonal outgrowth and attracted axons of cortical explants significantly.
T124 780627-780796 Sentence denotes Since T helper cell subtypes might exert neuroregenerative effects by secreting neurotrophins, we analyzed their neurotrophin expression patterns using RT-PCR and ELISA.
T125 780797-781124 Sentence denotes We have compared the expression patterns of nerve growth factor (NGF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), and brain-derived neurotrophic factor (BDNF) as well as interferon-gamma (IFNgamma), interleukin-1beta (IL-1beta), IL-2, IL-4, IL-10, and transforming growth factor-beta 1 (TGFbeta 1) between TH1 and TH2 cells.
T126 781125-781246 Sentence denotes Both subtypes expressed mRNA of all investigated factors except IFNgamma mRNA expression, which was limited to TH1 cells.
T127 781247-781373 Sentence denotes On the protein level, TH2 cells secreted significantly higher levels of IL-4, IL-10, NGF, NT-3 and NT-4 compared to TH1 cells.
T128 781374-781524 Sentence denotes The application of functionally inhibiting antibodies against NGF, NT-3 and NT-4 substantially reduced axonal outgrowth in T cell/explant co-cultures.
T129 781525-781684 Sentence denotes These data suggest that one important structural element of bprotective autoimmunityQ is the stimulation of neurotrophin-dependent axon outgrowth by Th2 cells.
T130 781685-781751 Sentence denotes The etiology of neurodegenerative disorders is at present unknown.
T131 781752-781874 Sentence denotes Although a small percentage of these disorders are familial cases linked to specific genetic defects, most are idiopathic.
T132 781875-781987 Sentence denotes Thus environmental factors are thought to play an important role in the onset and progression of such disorders.
T133 781988-782176 Sentence denotes We have determined the effect of an exposure (4 h, 5 days per week for 2 weeks) to concentrated airborne particulate matter on brain inflammatory indices in cortical tissue of BALB/c mice.
T134 782177-782303 Sentence denotes Animals were divided into three exposure groups: filtered air (control), ultrafine particles, or fine and ultrafine particles.
T135 782304-782524 Sentence denotes The levels of proinflammatory cytokines interleukin-1 alpha (IL-1alpha) and tumor necrosis factor alpha (TNFalpha) were increased in cortical tissue of mice exposed to particulate matter compared to that of control mice.
T136 782525-782689 Sentence denotes Levels of the immune-related transcription factor NF-kB were also found to be substantially elevated in the brain of exposed groups compared with the control group.
T137 782690-782813 Sentence denotes These data indicate that components of inhaled particulate matter may trigger a proinflammatory response in nervous tissue.
T138 782814-783028 Sentence denotes Since inflammatory events may contribute to the pathogenesis of neurodegenerative disorders, results suggest that environmental exposure to particulate matter may enhance pathogenic processes within nervous tissue.
T139 783029-783183 Sentence denotes Induction of antiphospholipid syndrome exacerbates amyloid and plaque deposition as well as memory impairment in an animal model of Alzheimer's disease A.
T140 783184-783196 Sentence denotes Katzav, C.G.
T141 783197-783205 Sentence denotes Pick, Y.
T142 783206-783222 Sentence denotes Shoenfeld and J.
T143 783223-783268 Sentence denotes Chapman Tel Aviv University, Tel Aviv, Israel
T144 783269-783466 Sentence denotes Immune and inflammatory mechanisms may be involved in the pathogenesis of neurodegenerative diseases and immune mediated diseases of the central nervous system lead eventually to neurodegeneration.
T145 783467-783643 Sentence denotes The antiphospholipid syndrome (APS) is associated with dementia and can be induced experimentally in mice by immunization with the autoantigen beta2-glycoprotein I (beta2-GPI).
T146 783644-783766 Sentence denotes We investigated the effects of APS induction on the course of neurodegeneration in an animal model of Alzheimer's disease.
T147 783767-784005 Sentence denotes Transgenic mice with the pathogenic betaAPP mutation were immunized with beta2-GPI at the age of 4-5 and 4.5 months later were tested for hyperactivity on a staircase apparatus and for cognitive function in a swim T-maze alternation test.
T148 784006-784055 Sentence denotes Brains were examined for mature plaque formation.
T149 784056-784206 Sentence denotes There were significant differences in behavior between the APP transgenic mice compared to the controls in both tests and in total h-amyloid staining.
T150 784207-784284 Sentence denotes The induction of APS had significantly reduced hyperactivity in the APP mice.
T151 784285-784361 Sentence denotes Cognitive impairment and mature plaques were found only in the APP-APS mice.
T152 784362-784470 Sentence denotes Induction of APS results in more rapid onset of amyloid deposition and cognitive impairment in betaAPP mice.
T153 784471-784540 Sentence denotes Similar mechanisms may be involved in patients with APS and dementia.
T154 784541-784612 Sentence denotes The LPS receptor CD14 links Alzheimer's disease with innate immunity K.
T155 784613-784819 Sentence denotes Fassbender University of Göttingen, Göttingen, Germany A pathophysiological hallmark of Alzheimer's disease (AD) is chronic neuroinflammation that appears to contribute to progressive neuronal injury in AD.
T156 784820-784935 Sentence denotes The lipopolysaccharide receptor, CD14, is the key cellular receptor for components of gram-negative microorganisms.
T157 784936-785174 Sentence denotes Here, co-immunoprecipitation experiments and studies in CD14 deficient microglia and monocytes demonstrate that CD14 recognizes Alzheimer's amyloid peptide, thereby mediating microglial and monocytic activation and release of neurotoxins.
T158 785175-785345 Sentence denotes Further, we show that expression of CD14 is increased in brains of AD patients in correlation with senile plaques, suggesting a clinical relevance of this receptor in AD.
T159 785346-785484 Sentence denotes Thus, CD14 mediated microglial activation by amyloid peptide may explain chronic neuroinflammation and subsequent neurodegeneration in AD.
T160 785485-785657 Sentence denotes We hypothesize that a structural mimicry between amyloid fibrils and microbial components may underlie the mechanism of chronic neuroinflammation mediated by CD14 ligation.
T161 785658-785779 Sentence denotes The lipopolysaccharide receptor, CD14, may, thus represent a novel therapeutic target in prevention of progression of AD.
T162 785780-785890 Sentence denotes Axonal injury at the onset of murine experimental autoimmune encephalomyelitis (EAE): a role for astrocytes D.
T163 785891-785902 Sentence denotes Wang a , M.
T164 785903-785915 Sentence denotes Ayers b , D.
T165 785916-785930 Sentence denotes Catmull a , L.
T166 785931-785947 Sentence denotes Hazelwood a , C.
T167 785948-785964 Sentence denotes Bernard a and J.
T168 785965-786065 Sentence denotes Orian a a La Trobe University, Melbourne, Australia; b University of Melbourne, Melbourne, Australia
T169 786066-786245 Sentence denotes Recent data have changed the view of Multiple Sclerosis (MS) from a primary inflammatory demyelinating disease to one in which cumulative axonal damage drives disease progression.
T170 786246-786393 Sentence denotes Concurrently, studies of axonglia and glia-glia communication have emphasized the importance of interactivity between central nervous system cells.
T171 786394-786554 Sentence denotes From this perspective, we studied axonal damage in the context of inflammation and glial responses in preclinical stages of murine EAE, an established MS model.
T172 786555-786854 Sentence denotes We report several major findings: (1) we provide evidence of axonal injury before significant parenchymal T-cell entry, (2) we demonstrate an association between axonal injury and astrocyte responses from presymptomatic stages and (3) differences in astrocytic responses in two forms of the disease.
T173 786855-787019 Sentence denotes Our data clearly show that mechanisms additional to those mediated by T cells are operating in early stages and strongly implicate astrocytes in disease initiation.
T174 787020-787181 Sentence denotes In common with data from a growing number of neurodegenerative conditions, we show that murine EAE is characterized by early active contribution from astrocytes.
T175 787182-787364 Sentence denotes These observations mark a change in the understanding of the role of astrocytes in disease pathogenesis and have important implications for development of neuroprotective strategies.
T176 787365-787454 Sentence denotes Neurodegeneration and inflammation are fundamental aspects of many neurological diseases.
T177 787455-787677 Sentence denotes Numerous molecular pathways that regulate these processes have been identified in recent years, but knowledge of how aspects of neurodegeneration and CNS inflammation are regulated on a genomic level is still very limited.
T178 787678-787886 Sentence denotes We are currently dissecting these features using a standardized nerve trauma model in adult rats, ventral root avulsion (VRA), in combination with experimental genetic protocols to unravel genetic influences.
T179 787887-788090 Sentence denotes In an F2 intercross between DA and PVG rats four quantitative trait loci (QTLs) controlling nerve cell death, expression of MHC class II on microglia and/or T cell infiltration after VRA were identified.
T180 788091-788245 Sentence denotes These findings have now been extended in an advanced intercross line (F8(PVG.1AV1xDA)) reproducing the QTLs regulating MHC class II and neurodegeneration.
T181 788246-788352 Sentence denotes Further fine mapping of the genomic regions are currently performed in the F10 generation of the same AIL.
T182 788353-788447 Sentence denotes In parallel, congenic strains are being bred to allow for mechanistic studies in other models.
T183 788448-788616 Sentence denotes Preliminary experiments performed in the founder strains reproduce considerable phenotypic differences also in experimental spinal cord and cortical contusion injuries.
T184 788617-789009 Sentence denotes The demonstration that polymorphic genes in different loci control neurodegeneration and CNS inflammation has implications for various experimental rodent nervous system paradigms and this approach may lead to the identification of evolutionary conserved genetic polymorphisms in key controlling genes, which can serve as prime candidates for association studies in several human CNS disease.
T185 789010-789185 Sentence denotes Multiple Sclerosis is a chronic inflammatory disease of the CNS leading to focal destruction of myelin, still the earliest changes that lead to lesion formation are not known.
T186 789186-789306 Sentence denotes We have studied the gene-expression pattern of 12 samples of normal-appearing white matter from 10 postmortem MS brains.
T187 789307-789493 Sentence denotes Microarray analysis revealed upregulation of genes involved in maintenance of cellular homeostasis, and in neural protective mechanisms known to be induced upon ischemic preconditioning.
T188 789494-789702 Sentence denotes This is best illustrated by the upregulation of transcription factors such as HIF-1alpha and associated PI3K/Akt signalling pathways, as well as the upregulation of their target genes such as VEGF receptor 1.
T189 789703-789789 Sentence denotes In addition, a general neuroprotective reaction against oxidative stress is suggested.
T190 789790-789900 Sentence denotes These molecular changes might reflect an adaptation of cells to the chronic progressive pathophysiology of MS.
T191 789901-790059 Sentence denotes Alternatively, they might also indicate the activation of neural protective mechanisms allowing preservation of cellular and functional properties of the CNS.
T192 790060-790201 Sentence denotes Our data introduce novel concepts of the molecular pathogenesis of MS with ischemic preconditioning as a major mechanism for neuroprotection.
T193 790202-790405 Sentence denotes An increased understanding of the underlying mechanisms may lead to the development of new more specific treatment to protect resident cells and thus minimize progressive oligodendrocyte and axonal loss.
T194 790406-790474 Sentence denotes Heavy metals and free radicals have been related to MS pathogenesis.
T195 790475-790575 Sentence denotes Serum levels of 26 elements were compared within 10 couples of disease discordant monozygotic twins.
T196 790576-790873 Sentence denotes We developed a reliable method for the simultaneous quantification of Al, Ba, Be, Bi, Ca, Cd, Co, Cr, Cu, Fe, Hg, Li, Mg, Mn, Mo, Ni, Pb, Sb, Si, Sn, Sr, Tl, V, W, Zn and Zr using Sector Field Inductively Coupled Plasma Mass Spectrometry (SF-ICP-MS) and ICP Atomic Emission Spectrometry (ICP-AES).
T197 790874-791003 Sentence denotes We carried out a similar comparison by photometric assay for the serum oxidant status (SOS) and serum antioxidant capacity (SAC).
T198 791004-791259 Sentence denotes No significant differences emerged-at a p=0.05, nonparametric test-for the elements under study as well as for parameters relating oxidative stress, with the exception of Mg (median values of 19,213 for patients and 17,881 ng/ml for controls at a p=0.03).
T199 791260-791523 Sentence denotes In affected twins, we observed a decreasing trend for Al, Co and Sr, especially in the case of Co (medians, 0.15 vs. 0.37 ng/ml, at a p=0.06) and a tendency to higher concentrations for Zn (medians, 883 vs. 818 ng/ml, p=0.10) and Be (0.48 vs. 0.40 ng/ml, p=0.18).
T200 791524-791581 Sentence denotes Results on a larger series of patients will be presented.
T201 791582-791697 Sentence denotes The role of plasminogen activators in experimental allergic encephalomyelitis: inflammation and axonal pathology E.
T202 791698-791706 Sentence denotes East, D.
T203 791707-791716 Sentence denotes Baker, G.
T204 791717-791728 Sentence denotes Pryce, M.L.
T205 791729-791742 Sentence denotes Cuzner and D.
T206 791743-792020 Sentence denotes Gveric Institute of Neurology, University College London, London, UK Entry of fibrin, normally excluded from the CNS and upregulation of urokinase plasminogen activator (PA) receptor (uPAR) and PA inhibitor-1 (PAI-1) are one of the earliest signs of inflammatory demyelination.
T207 792021-792226 Sentence denotes Concentrations of tissue PA (tPA), the key fibrinolytic enzyme, are decreased in the CNS due to higher amounts of its inhibitor PAI-1, thus ensuring that fibrin entering the CNS is not efficiently removed.
T208 792227-792346 Sentence denotes In addition to its proteolytic activity with uPA, uPAR is involved in the migration and adhesion of inflammatory cells.
T209 792347-792418 Sentence denotes The roles of tPA and uPAR were investigated in EAE using knockout mice.
T210 792419-792573 Sentence denotes Both tPAÀ/À and wild type mice experienced an acute disease lasting 7 days; however, tPAÀ/À animals incurred a significant degree of neurological deficit.
T211 792574-792684 Sentence denotes In contrast, uPARÀ/À mice had a prolonged acute phase of disease, the peak of which was significantly delayed.
T212 792685-792746 Sentence denotes This was accompanied by a decrease in leucocyte infiltration.
T213 792747-792926 Sentence denotes Loss of neurofilament, an indicator of axonal integrity, was observed early on in all groups of mice indicating that axonal loss is an early feature of EAE and multiple sclerosis.
T214 792927-793083 Sentence denotes High levels of CNS fibrin persisted in tPAÀ/À animals during acute and chronic phases of disease and deposits of fibrin could be localised on damaged axons.
T215 793084-793187 Sentence denotes In conclusion, these data enforce the concept of the involvement of the PA system in neuroinflammation.
T216 793188-793308 Sentence denotes Neuroinflammatory conditions may disrupt the normal function of adrenomedullin (ADM) at the blood-brain barrier (BBB) E.
T217 793309-793324 Sentence denotes Liverani a , A.
T218 793325-793337 Sentence denotes Woods a , C.
T219 793338-793353 Sentence denotes Bolton b and C.
T220 793354-793526 Sentence denotes Paul a a University of the West of England, Bristol, UK; b William Harvey Research Institute, London, UK ADM appears intimately involved in the maintenance of BBB function.
T221 793527-793718 Sentence denotes In vitro studies have clearly shown ADM capable of regulating key features of the BBB including transendothelial electrical resistance (TEER), permeability and p-glycoprotein pump activation.
T222 793719-793883 Sentence denotes The BBB forms a highly selective barrier between the peripheral circulation and the central nervous system, which is, in part, under the control of glucocorticoids.
T223 793884-794000 Sentence denotes Loss of normal BBB integrity is an integral feature of the neuroinflammatory process during multiple sclerosis (MS).
T224 794001-794200 Sentence denotes Neurovascular function is intimately linked to glutamate-mediated events and we have shown that restoration of normal BBB permeability is associated with an improved clinical outcome in models of MS.
T225 794201-794376 Sentence denotes We have examined the effect of glutamate and glucocorticoids on ADM function in vitro using ECV304 human endothelial cells and C6 rat astroglioma cells alone and in coculture.
T226 794377-794520 Sentence denotes Our preliminary immunocytochemistry studies indicate that receptor-activity modifying protein-2 (RAMP-2) is normally expressed on ECV304 cells.
T227 794521-794616 Sentence denotes However, on exposure to 0.1 mM glutamate, RAMP-2 expression is significantly reduced ( pb0.05).
T228 794617-794798 Sentence denotes Additionally, TEER measurements in the co-culture BBB model are significantly elevated in the presence of co-administered ADM and dexamethasone compared to control values ( pb0.05).
T229 794799-794888 Sentence denotes The data suggests that glutamate affects endothelial expression of ADM receptor proteins.
T230 794889-795007 Sentence denotes Furthermore, the results indicate that steroidal compounds can influence ADM control of neuroendothelial permeability.
T231 795008-795100 Sentence denotes The role of inflammation in central nervous system (CNS) damage and repair is controversial.
T232 795101-795185 Sentence denotes Inflammation is considered a major cause of neurodegeneration in most CNS disorders.
T233 795186-795307 Sentence denotes In contrast, autoreactive immune responses induced by injury were found to be part of the physiological repair mechanism.
T234 795308-795438 Sentence denotes Thus, controlled boosting of protective immunity is proposed as a means of attenuating neurodegeneration and facilitating healing.
T235 795439-795697 Sentence denotes Implantation of educated macrophages, produced from monocytes co-incubated with peripheral tissue (skin or sciatic nerve) but not with central tissue (optic nerve), was shown to improve functional recovery following optic nerve or spinal cord injury in rats.
T236 795698-795956 Sentence denotes Since incubation conditions influence the activity of the resulting macrophages, skin-coincubated macrophages were characterized and compared to macrophages activated by lipopolysaccharide (bclassical activationQ) or interleukin-4 (balternative activationQ).
T237 795957-796080 Sentence denotes The incubated cells were analyzed for morphological characteristics, expression of membrane markers and cytokine secretion.
T238 796081-796293 Sentence denotes Activation with skin or lipopolysaccharide increased significantly the number and size of cytoplasmic granules and secretion of proinflammatory cytokines, in contrast with interleukin-4 that had opposite effects.
T239 796294-796445 Sentence denotes Only lipopolysaccharide activation induced secretion of tumor necrosis factor alpha, as well as elevated expression of a co-stimulatory molecule, CD80.
T240 796446-796511 Sentence denotes Interleukin-12 secretion was unaffected by any of the activators.
T241 796512-796656 Sentence denotes Skin-co-incubated macrophages thus represent a unique cellular phenotype, distinct from bclassically'Q or balternatively-activatedQ macrophages.
T242 796657-796798 Sentence denotes We propose that this phenotype promotes an immune response that supports neuronal cell survival and repair, resulting in functional recovery.
T243 796799-796883 Sentence denotes Effect of inflammatory mediators on axonal transport of synaptic vesicle proteins M.
T244 796884-796893 Sentence denotes Stagi, N.
T245 796894-796906 Sentence denotes Frank and H.
T246 796907-797114 Sentence denotes Neumann European Neuroscience Institute, Göttingen, Germany Axonal transport disturbance is an early sign of most inflammatory brain diseases, but the molecular mechanism of this dysfunction remains elusive.
T247 797115-797305 Sentence denotes Activated microglial cells are found to be in close proximity to dystrophic neurites and release nitric oxide (NO) and inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha).
T248 797306-797584 Sentence denotes Confocal microscopy of fluorescence recovery after photobleaching (FRAP) was performed to analyze the axonal transport of the synaptic vesicle precursor protein synaptophysin tagged with green fluorescent protein (synaptophysin-EGFP) in transfected cultured hippocampal neurons.
T249 797585-797748 Sentence denotes Microglia, pre-stimulated by inflammatory cytokines to produce NO and TNF-alpha, focally suppressed the axonal motility of synaptophysin-EGFP at the contact point.
T250 797749-797898 Sentence denotes Direct application of TNF-alpha or short-term NO donor to cultured hippocampal neurons inhibited axonal motility of synaptophysin-EGFP within 10 min.
T251 797899-798102 Sentence denotes Inhibition of axonal transport by this inflammatory mediator significantly increased the immobile fraction of synaptophysin-EGFP and was dependent on phosphorylation of c-jun NH(2)-terminal kinase (JNK).
T252 798103-798170 Sentence denotes In particular, TNFalpha stimulated phosphorylation of JNK in axons.
T253 798171-798320 Sentence denotes Reduced motility of synaptophysin-EGFP after TNF-alpha treatment was dependent on phosphorylation of JNK as determined by the JNK inhibitor SP600125.
T254 798321-798574 Sentence denotes Thus, overt production of TNF-alpha and reactive NO by activated microglial cells blocks the motility of synaptic vesicle precursor via phosphorylation of JNK and may cause axonal and synaptic dysfunction in inflammatory and degenerative brain diseases.
T255 798575-798693 Sentence denotes Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegeneration disease involving upper and lower motor neurons.
T256 798694-799019 Sentence denotes Although microglia activation is a prominent feature of ALS and the mechanisms by which microglia contribute to motor neuron degeneration remain unknown, the supernatant derived from LPS-activated microglial cells (BV-2) induce death of a motor neuron hybridoma cell line (NSC-34 cells) through a TNF alpha dependent pathway.
T257 799020-799301 Sentence denotes In this study, we have used both a cDNA superarray and real time PCR and observed a significant increase in the mRNA levels of the TNF receptor superfamily, including TNFR1, DR3, DR6 and the death ligand LT-beta following exposure of NSC-34 cells to LPS-activated BV-2 supernatant.
T258 799302-799534 Sentence denotes In the presence of cycloheximide, LPSactivated BV-2 supernatant induced NSC-34 apoptosis (caspase 3 activation and PARP cleavage) with caspase 9 activation, suggesting a role for mitochondria in microglial-mediated NSC-34 apoptosis.
T259 799535-799682 Sentence denotes In order to determine whether this was due to TNF alpha, recombinant murine TNF alpha was applied to NSC-34 cells in the presence of cycloheximide.
T260 799683-799764 Sentence denotes The results were identical to those obtained with LPS-activated BV-2 supernatant.
T261 799765-799990 Sentence denotes These findings suggest that LPS activated microglial BV-2 supernatant can induce NSC-34 motor neuron cell apoptosis through a mitochondria-dependent signaling pathway and that TNF alpha is a major contributor to this process.
T262 799991-800063 Sentence denotes Research supported by the Scottish Rite Charitable Foundation of Canada.
T263 800064-800207 Sentence denotes Glutamate stimulates peroxynitrite production in a brain-derived endothelial cell line via N-methyl-d-aspartate (NMDA) receptor activation S.R.
T264 800208-800220 Sentence denotes Bowman, G.S.
T265 800221-800233 Sentence denotes Scott and C.
T266 800234-800399 Sentence denotes Bolton The William Harvey Research Institute, London, UK There is compelling evidence indicating a role for glutamate in the pathogenesis of multiple sclerosis (MS).
T267 800400-800620 Sentence denotes Studies in experimental allergic encephalomyelitis (EAE), the model of MS, demonstrate that pharmacological inhibition of specific glutamate receptors suppresses symptoms and prevents blood-brain barrier (BBB) breakdown.
T268 800621-800716 Sentence denotes The mechanisms through which glutamate influences BBB function during disease remain undefined.
T269 800717-800843 Sentence denotes Glutamate is known to trigger the production of nitric oxide and superoxide, which can lead to the formation of peroxynitrite.
T270 800844-800939 Sentence denotes Recent studies have implicated peroxynitrite in the loss of neurovascular integrity during EAE.
T271 800940-801032 Sentence denotes We propose that glutamate contributes to BBB breakdown through the actions of peroxynitrite.
T272 801033-801243 Sentence denotes The current study aims to determine whether glutamate induces peroxynitrite formation in a brain-derived endothelial cell line (b.End3). b.End3 cells were incubated with glutamate (1 AM to 20 mM) for 1 to 24 h.
T273 801244-801339 Sentence denotes The production of peroxynitrite was assessed by quantitating the oxidation of dihydrorhodamine.
T274 801340-801449 Sentence denotes Results showed a concentration-and timedependent increase in peroxynitrite levels in glutamate-treated cells.
T275 801450-801584 Sentence denotes Furthermore, glutamate-induced changes were suppressed by the peroxynitrite decomposition catalyst FeTPPS and the inhibitor uric acid.
T276 801585-801713 Sentence denotes In addition, glutamate-mediated generation of peroxynitrite from b.End3 cells was reduced by the NMDA receptor antagonist MK801.
T277 801714-801926 Sentence denotes The study reconfirms the importance of glutamate in the loss of neuroendothelial integrity and highlights the deleterious effects of the molecule through the actions of peroxynitrite and NMDA receptor activation.
T278 801927-802089 Sentence denotes Developmental morphological changes were found in the cerebellar cortex after a single injection of the cytostatic drug cisplatin (5 Ag/g b.w.) to 10-dayold rats.
T279 802090-802322 Sentence denotes One day after treatment (PD11), the external granular layer in the vermis showed several apoptotic cells; recovery of proliferating activity and ectopic granule cells were found in the lobules VI-VIII on PD17 and PD30, respectively.
T280 802323-802471 Sentence denotes Purkinje cells slowed their differentiation and at the end of histogenesis they had changed/reoriented dendrite branches (Calbindin immunoreaction).
T281 802472-802568 Sentence denotes However, degeneration of Purkinje cells has also been described (Scherini and Bernocchi, 1994) .
T282 802569-802765 Sentence denotes Autofluorescence, depending on nature, amount, distribution of endogenous fluorophores, and on optical properties can provide information on structure and metabolic activity of biological tissues.
T283 802766-802878 Sentence denotes Autofluorescence potentials for diagnosis of cerebellum structural changes during development were investigated.
T284 802879-803031 Sentence denotes The pattern profile was analysed by nonlinear regression to estimate the depth of tissue involved (mm at which the signal is 1/e of the incident light).
T285 803032-803194 Sentence denotes In neocerebellar lobules VI-VIII, this was 0.75, 0.37, 0.23 mm for control rats of 10, 17 and 30 days, and 2.22, 1.63, 0.51 mm for the corresponding treated rats.
T286 803195-803274 Sentence denotes Paleocerebellum showed neither structural alterations nor depth values changes.
T287 803275-803369 Sentence denotes Microspectrofluorometry and spectral fitting analysis indicated an increase in oxidised state.
T288 803370-803546 Sentence denotes Results show a great influence of structural organization, and thus of optical properties, on autofluorescence emission, in addition to biochemical composition (Research Grant:
T289 803547-803580 Sentence denotes Cofin 2002 to G.B., MIUR-Italy) .
T290 803581-803653 Sentence denotes Junction between tubulin and Na,K-ATPase in calf brain stem neurons N.M.
T291 803654-803671 Sentence denotes Vladimirova, E.N.
T292 803672-803686 Sentence denotes Sautkina, T.V.
T293 803687-803708 Sentence denotes Ovchinnikova and N.A.
T294 803709-803819 Sentence denotes Potapenko Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
T295 803820-803900 Sentence denotes The function of Na,K-ATPase in the brain is poorly studied and least understood.
T296 803901-804102 Sentence denotes It was shown that in the brain, in addition to conventional functions, Na,K-ATPase is involved in intercellular interaction between the neurons and glial cells and the binding to cytoskeleton proteins.
T297 804103-804181 Sentence denotes In brain cells, all known isoforms of both Na,K-ATPase subunits are expressed.
T298 804182-804364 Sentence denotes The goal of this study was the isolation, structural characterization, and search for structural peculiarities of isozymes of Na,K-ATPase that really function in various brain cells.
T299 804365-804532 Sentence denotes Glial cells were shown to contain mainly Na,K-ATPase of the alpha1beta1 type and minor amounts of isozymes of the alpha2 beta2 (beta1) and the alpha3beta1(beta2) type.
T300 804533-804592 Sentence denotes The axolemma contains alpha2beta1 and alpha3beta1 isozymes.
T301 804593-804713 Sentence denotes An enhanced sensitivity of the alpha3 catalytic subunit of Na,K-ATPase from neurons to endogenous proteolysis was found.
T302 804714-804983 Sentence denotes The presence of the cytoskeleton protein tubulin (beta3 isoform) in the high-molecular-weight complex of Na,K-ATPase alpha3beta1 isozyme from brain stem axolemma and the junction between Na,K-ATPase alpha3 subunit and tubulin beta3 subunit are shown for the first time.
T303 804984-805078 Sentence denotes It should be noted that dysfunction of Na,K-ATPase leads to set of neurodegenerative diseases.
T304 805079-805136 Sentence denotes This enzyme is trigger of some apoptotic ways of neurons.
T305 805137-805343 Sentence denotes The finding of connection between the Na,K-ATPase and cytoskeleton protein may lead to the discovery of the novel functions of the sodium pump in the brain and understanding of the reasons of some diseases.
T306 805344-805437 Sentence denotes The inflammatory response contributes to the evolution of brain ischemia/ reperfusion injury.
T307 805438-805686 Sentence denotes We studied the effect of helper-dependent adenoviral vector (Ad) engineered with the anti-inflammatory cytokine interleukin (IL)-4 gene and with the green fluorescent protein (GFP) as a reporter gene, in a model of transient focal ischemia in mice.
T308 805687-805892 Sentence denotes Ischemia was induced in 129SV mice by occlusion of the middle cerebral artery (MCA) using a nylon monofilament introduced into the internal carotid artery and advanced so as to block the origin of the MCA.
T309 805893-805977 Sentence denotes At the end of 10 min ischemia, the filament was removed and reperfusion was allowed.
T310 805978-806156 Sentence denotes The vectors expressing IL-4 (Ad-IL-4-GFP) or the reporter gene alone (Ad-GFP) were infused intracerebroventricularly at the dose of 8Â10 6 PFU/5 Al at the end of ischemic period.
T311 806157-806317 Sentence denotes Five days later, general and focal neurological deficits were significantly improved in mice receiving IL-4 gene compared to those receiving the control vector.
T312 806318-806395 Sentence denotes Mice treated with IL-4 had also significantly reduced infarct volume (Ad-GFP:
T313 806396-806422 Sentence denotes 18.8F5 mm 3 ; Ad-IL-4-GFP:
T314 806423-806438 Sentence denotes 5.2F1.3 mm 3 ).
T315 806439-806530 Sentence denotes Thus IL-4 gene delivery using Ad vectors induces protection in ischemia/reperfusion injury.
T316 806531-806679 Sentence denotes Identification of signaling pathways associated with rat strain-dependent susceptibility to nerve injury by microarray-based expression profiling M.
T317 806680-806692 Sentence denotes Swanberg, K.
T318 806693-806705 Sentence denotes Duvefelt, J.
T319 806706-806717 Sentence denotes Hillert, T.
T320 806718-806728 Sentence denotes Olsson, F.
T321 806729-806741 Sentence denotes Piehl and O.
T322 806742-806853 Sentence denotes Lidman Karolinska Institute, Stockholm, Sweden Axonal damage is a common feature of many neurological diseases.
T323 806854-807045 Sentence denotes Although certain regulators of the retrograde axotomy reaction have been identified, information about the regulation of this process on a global genome-wide transcriptional level is limited.
T324 807046-807124 Sentence denotes It is not known to what extent the genetic background influences the response.
T325 807125-807317 Sentence denotes Global gene expression pattern was examined after ventral root avulsion (VRA), a well-characterized model of nerve injury-induced neurodegeneration and inflammation, in two inbred rat strains.
T326 807318-807454 Sentence denotes Gene expression was analysed with Affymetrix arrays in spinal cord tissue sampled from naRve DA and PVG rats at 5 and 14 days after VRA.
T327 807455-807626 Sentence denotes Regulation was shown in both strains for 359 of 8000 studied transcripts; 104 transcripts significantly differed between strains at one or more of the studied time points.
T328 807627-807861 Sentence denotes The DA rat displays a higher degree of neuronal loss and more intense glial activation than the PVG strain and this was associated with higher levels of several mRNAs coding for proteins known to be involved in inflammatory reactions.
T329 807862-808013 Sentence denotes Principal component analysis revealed that the segregation between the strains was almost of the same magnitude as that between naRve and injured rats.
T330 808014-808210 Sentence denotes These results suggest a common VRA response pattern significantly modified by the genetic background and underscore the importance of a strict control of genetic background in experimental design.
T331 808211-808292 Sentence denotes Age-related response of brain cells to pro-inflammatory cytokines in the mouse M.
T332 808293-808308 Sentence denotes Bentivoglio, A.
T333 808309-808324 Sentence denotes Sadki and X.-H.
T334 808325-808658 Sentence denotes Deng University of Verona, Verona, Italy Neurological diseases show a well known age-dependent prevalence; e.g. multiple sclerosis prevails in young and middle age and neurodegenerative diseases increase with aging, indicating that the response to inflammatory and neuronal death-inducing processes varies in the CNS during lifetime.
T335 808659-808818 Sentence denotes Recent evidence also indicates that aging is characterized by low-grade chronic inflammatory activity, with increased production of pro-inflammatory cytokines.
T336 808819-808903 Sentence denotes On this basis, we are investigating the brain response to an inflammatory challenge.
T337 808904-809140 Sentence denotes Intracerebroventricular (i.c.v.) stereotaxic injections of a mixture of recombinant interferon-gamma and tumor necrosis factor-alpha were made in young (2-3.5 months) and old (18-20 months) C57BL/6J mice; saline was injected as control.
T338 809141-809290 Sentence denotes We examined neuronal activation using Fos as marker, expression of the anti-apoptotic protein Bcl-2, and the glial response with immunocytochemistry.
T339 809291-809520 Sentence denotes Cytokine injections resulted in Fos induction in neurons at several brain sites, such as the piriform cortex, midline thalamus, hypothalamic structures including the suprachiasmatic nucleus which plays a role of biological clock.
T340 809521-809670 Sentence denotes At these sites, Fos induction was even more robust after i.c.v. cytokine injection in old mice than in young ones, with some subregional differences.
T341 809671-809856 Sentence denotes After cytokine treatment, marked activation of astrocytes and microglia, and Bcl-2 induction in neurons and some glial cells, were seen in both age groups, with age-related differences.
T342 809857-810004 Sentence denotes The data point out that the brain cell response to an inflammatory challenge is age-dependent and involves gene expression in different cell types.
T343 810005-810222 Sentence denotes Supported by EC Grant QLRT-2001 QLRT- -2258 Advanced glycation and glyco-oxidation conditionate the loss of neuroprotective growth factors and the increased production of neurotoxic cytokines in Alzheimer's disease M.
T344 810223-810240 Sentence denotes Fioravanti a , A.
T345 810241-810257 Sentence denotes Lapolla b , S.B.
T346 810258-810624 Sentence denotes Solerte a a Department of Internal Medicine and Geriatrics, University of Pavia, Pavia, Italy; b Department of Metabolic Sciences and Metabolism, University of Padova, Padova, Italy Advanced glycation end products (AGEs) and glyco-oxidative mechanisms could induce a pro-inflammatory burst of cytokines from immune and microglial cells and a loss of neuroprotection.
T347 810625-810725 Sentence denotes Within this context, AGEs and Pentosidine were studied in 27 subjects with Alzheimer's disease (AD).
T348 810726-810866 Sentence denotes We also measured TNF-alpha, IFN-gamma and Vascular endothelial growth factor (VEGF) released in the supernates of natural killer (NK) cells.
T349 810867-810972 Sentence denotes Both cytokines and VEGF were evaluated after exposure with LPS (1 Ag/ml), beta-amyloid 1-42 (A-beta 1-42:
T350 810973-811051 Sentence denotes 5 Ag/ml), and LPS/A-beta co-incubated with Glycated human serum albumin (GHSA:
T351 811052-811062 Sentence denotes 20 Ag/ml).
T352 811063-811142 Sentence denotes TNF-alpha and IFN-gamma were also determined after GHSA at 5, 10, 20, 50 Ag/ml.
T353 811143-811312 Sentence denotes AGEs and Pentosidine were significantly increased in AD than in healthy subjects (15F3 Ag/ml and 190F40 pmol/ml vs. 8F2.5 Ag/ml and 115F28 pmo/ml respectively; pb0.001).
T354 811313-811422 Sentence denotes A significant dose response increase of TNF-alpha and IFN-gamma was demonstrated in AD after GHSA ( pb0.001).
T355 811423-811517 Sentence denotes Moreover, GHSA amplified the overproduction of both cytokines after LPS and A-beta ( pb0.001).
T356 811518-811710 Sentence denotes Finally, a significant reduction of VEGF was found in AD subjects compared to healthy subjects ( pb0.001); while the co-incubation of NK cells with GHSA determined a further reduction of VEGF.
T357 811711-811795 Sentence denotes In summary, advanced glycation and glyco-oxidation are significantly enhanced in AD.
T358 811796-811939 Sentence denotes These mechanisms could conditionate the overexpression of neurotoxic cytokines, also inducing an impairment of neuroprotection induced by VEGF.
T359 811940-812012 Sentence denotes Innate immunity receptor TLR4 plays a key role in Alzheimer's disease S.
T360 812013-812250 Sentence denotes Walter University of Gfttingen, Göttingen, Germany A pathophysiological hallmark of Alzheimer's disease is chronic microglial activation, which is considered to contribute to progressive neuronal injury by release of neurotoxic products.
T361 812251-812398 Sentence denotes The Toll-like-receptor 4, TLR4, is localized on the surface of microglia and has recently been shown to play a key role in innate immune responses.
T362 812399-812624 Sentence denotes Here, we show in studies with murine tlr4 mutant microglia, peritoneal macrophages and human monocytes that TLR4 is crucial for microglial and monocytic activation and that it can contribute to microglial toxicity to neurons.
T363 812625-812831 Sentence denotes Further, investigations in HEK293 cells demonstrate interaction and define a trimolecular receptor complex consisting of TLR4, MD-2 and CD14, necessary for full cellular response to amyloid peptide fibrils.
T364 812832-813032 Sentence denotes Suggesting a clinical relevance of TLR4 in AD pathology in vivo, we observed that expression of TLR4 is upregulated in APP transgenic mice, the animal model of AD, in close association with microglia.
T365 813033-813221 Sentence denotes Together these observations provide first evidence for a role of the key innate immune receptor TLR4 in neuroinflammation in AD pathophysiology as a new potential therapeutic target in AD.
T1 813222-813312 Sentence denotes Oxidative stress in rat brain induced by amyloid-beta under continuous light conditions S.
T2 813313-813331 Sentence denotes Rosales-Corral, G.
T3 813332-813341 Sentence denotes Ortiz, M.
T4 813342-813489 Sentence denotes Valdivia-Velázquez Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, Mexico The brain is especially sensitive to oxidative damage.
T5 813490-813760 Sentence denotes On the other hand, the chief secretory product of the pineal gland, melatonin, may reduce tissue destruction during inflammatory responses by scavenging free radicals and, indirectly, by lowering the production of cell damaging agents (cytokines and adhesion molecules).
T6 813761-813869 Sentence denotes With the age, changes in both the amplitude and timing of the melatonin rhythm have been reported in humans.
T7 813870-814050 Sentence denotes We used male, adult Wistar rats, separated into two groups: (a) continuous light (during 5 days); and (b) continuous darkness, besides an only surgically manipulated control group.
T8 814051-814119 Sentence denotes Fibrillar amyloid-beta (4 Ag) was intracerebrally injected onto CA1.
T9 814120-814183 Sentence denotes Hydrogen peroxide-injected rats were used as positive controls.
T10 814184-814350 Sentence denotes During 5 days of continuous light, melatonin levels in serum decreased significantly compared with the observed concentrations in animals housed in light/dark cycles.
T11 814351-814432 Sentence denotes This phenomenon was related with an increase in brain lipoperoxides and nitrites.
T12 814433-814682 Sentence denotes On the other hand, increased serum levels of melatonin, either by exogenous administration or an increment in the endogenous production due to continuous darkness, was related with a significant reduction in oxidative stress induced by amyloid-beta.
T13 814683-814821 Sentence denotes Even the highly significant production of lipoperoxides and nitrites induced by hydrogen peroxide injection was also reduced by melatonin.
T14 814822-814968 Sentence denotes Microglial activity, as assessed by immunohistochemistry, showed a marked increase in hippocampus, around the amyloid-beta deposits in CA1 region.
T15 814969-815192 Sentence denotes Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL, Nasu-Hakola disease) is a recessively inherited disease characterized with the unusual combination of bone cysts and early-onset dementia.
T16 815193-815312 Sentence denotes Our group has recently established the molecular background of PLOSL by identifying mutations in DAP12 and TREM2-genes.
T17 815313-815507 Sentence denotes The encoded proteins form an activating signal transduction complex in immune cells, but their function in the target tissues of PLOSL, central nervous system (CNS) and bone, is largely unknown.
T18 815508-815710 Sentence denotes As a starting point for understanding how loss of function of this activating signaling complex leads to dementia and loss of myelin, we have analyzed the expression of DAP12 and TREM2 in the mouse CNS.
T19 815711-815867 Sentence denotes Analyses of transcripts in the mouse CNS show that DAP12 and TREM2 are expressed from embryonic stage to adulthood with a highly similar expression pattern.
T20 815868-815986 Sentence denotes In addition, microglial cells and oligodendrocytes are identified as the major DAP12/TREM2 producing cells in the CNS.
T21 815987-816118 Sentence denotes Consequently, microglial cells and oligodendrocytes can be considered as the predominant cell types involved in PLOSL pathogenesis.
T22 816119-816259 Sentence denotes The myeloid origin of both microglial cells and osteoclasts provides a biological link between the CNS and bone pathology in PLOSL patients.
T23 816260-816438 Sentence denotes Further, the expression of DAP12/TREM2 in oligodendrocytes, the myelin producing cells of the CNS, agrees well with the histopathological and clinical findings of PLOSL patients.
T24 816439-816626 Sentence denotes These findings provide a basis for the study of the molecular mechanisms behind this inherited dementia and new evidence for the involvement of the immune system in neuronal degeneration.
T25 816627-816783 Sentence denotes It is known that stress induces increase of chemotaxis, which may contribute to increase migration and recruitment of immune cells to sites of inflammation.
T26 816784-816828 Sentence denotes Chemokines play a role in neuroinflammation.
T27 816829-816973 Sentence denotes CXCR4 is a chemokine receptor, which binds to its ligand SDF 1 (stromal cell-derived factor), while CX3CR1 is the only receptor for fractalkine.
T28 816974-817090 Sentence denotes In this study, we have focused whether these two chemokines systems are involved in stressinduced neurodegeneration.
T29 817091-817200 Sentence denotes For this purpose, rats were submitted to a chronic stress consistent of daily restraint for 6 h, for 3 weeks.
T30 817201-817349 Sentence denotes Levels of CXCR4/SDF and CX3CR1/fractalkine were measure in homogenates from several brain structures, and chemokines were quantified by ELISA assay.
T31 817350-817433 Sentence denotes Protein levels of CXCR4/SDF and CX3CR1/fractalkine were reduced in the hippocampus.
T32 817434-817516 Sentence denotes However, upregulated CXCR4 levels were found in the cerebellum and olfactory bulb.
T33 817517-817666 Sentence denotes Interestingly, SDF was significantly increased in the hypothalamus and olfactory bulb whereas fractalkine was only upregulated in the olfactory bulb.
T34 817667-817756 Sentence denotes Control groups showed a high negative correlation between SDF and hippocampal Bax levels.
T35 817757-817890 Sentence denotes All together, these data suggest that hippocampal SDF 1 decreased levels might reduce neuroprotection under chronic restraint stress.
T36 817891-817969 Sentence denotes By contrast, differential chemokine modulation was found in other brain areas.
T37 817970-818000 Sentence denotes Funded by a UNED Grant, Spain.
T38 818001-818137 Sentence denotes In Alzheimer's disease (AD), amyloid plaques within the brain are surrounded by activated microglia, astrocytes and dystrophic neurites.
T39 818138-818322 Sentence denotes Elevated levels of the pro-inflammatory cytokines IL-1beta and IL-6 have been found in AD brains at early stages of the disease, implying that the inflammation is an early event in AD.
T40 818323-818410 Sentence denotes This inflammation is regulated, at least in part, by the transcription factor NFkappaB.
T41 818411-818550 Sentence denotes The mechanisms of amyloid-beta (Abeta)-mediated neurotoxicity are unknown but it has been suggested that oxidative stress plays a key role.
T42 818551-818698 Sentence denotes Although Abeta may act directly on neuronal cells, the increased levels of oxidative stress due to activation of glial cells may be more important.
T43 818699-818865 Sentence denotes Upon activation, glial cells produce pro-inflammatory cytokines and putatively neurotoxic factors including superoxide anion, hydroxyl radicals and nitric oxide (NO).
T44 818866-818999 Sentence denotes The reactive oxygen species (ROS) can cause great damage by lipid peroxidation and oxidation of proteins that may lead to cell death.
T45 819000-819190 Sentence denotes The aim of this study was to investigate the effect of Abeta and the proinflammatory cytokine IL-1beta on glial activation and the production of ROS in rat primary mixed glial cell cultures.
T46 819191-819274 Sentence denotes We investigated NFkappaB activation and the mRNA levels of IL-1beta, IL-6 and iNOS.
T47 819275-819408 Sentence denotes NO and H 2 O 2 , secreted into the medium, were analysed in the absence or presence of the anti-oxidant alpha-tocopherol (Vitamin E).
T48 819409-819499 Sentence denotes Parkinson's disease (PD) is an age-related neurodegenerative disorder of unknown etiology.
T49 819500-819581 Sentence denotes The involvement of immune mechanisms in the etiopathogenesis of PD is documented.
T50 819582-819670 Sentence denotes The neuroinflammation is regulated by numerous signal molecules, including nitric oxide.
T51 819671-819878 Sentence denotes The nitric oxide-synthesizing enzyme nitric oxide synthase (NOS) is present in the CNS in three different isoforms: two constitutive enzymes (neuronal-nNOS, and endothelial-eNOS) and inducible enzyme (iNOS).
T52 819879-820087 Sentence denotes In the present study, we examined nNOS, eNOS and iNOS gene expression in the striatum of C57BL/6 male mice (12 month old) in a murine model of PD induced by 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP).
T53 820088-820168 Sentence denotes The animals were sacrificed on 6 h, on 1, 3, 7, 14 days after MPTP intoxication.
T54 820169-820218 Sentence denotes The levels of mRNA were assayed by RT-PCR method.
T55 820219-820596 Sentence denotes We observed the increased nNOS gene expression from 1 up to 14 days with the peak within 3-14 days. eNOS mRNA expression showed increase at 24 h and it was continued to 3 days and peaked in this time point. iNOS mRNA expression rapidly increased as early as at 6 h after MPTP intoxication; peaked at 24 h; significantly decreased at 3 days, and was observed until the 14th day.
T56 820597-820830 Sentence denotes In conclusion, this work extend our knowledge about the potential role of NOS isoforms in neurodegenerative disorders and may become in the future a target for therapeutic interventions in patients suffering from Parkinson's disease.
T57 820831-820968 Sentence denotes Characterization of mononuclear cells isolated from bone marrow for potential transplantation in an animal model of Huntington Disease T.
T58 820969-821059 Sentence denotes Serrano-Sanchez Centro Internacional de Restauración Neurológica, CIREN, Havana City, Cuba
T59 821060-821127 Sentence denotes Huntington Disease (HD) is an inherited neurodegenerative disorder.
T60 821128-821226 Sentence denotes The intrastriatal administration of neurotoxic has served as the most frequent animal model of HD.
T61 821227-821308 Sentence denotes Animal models have allowed extensive research into therapeutic strategies for HD.
T62 821309-821374 Sentence denotes Recently, the cellular source has demonstrated an important role.
T63 821375-821489 Sentence denotes The bone marrow cells are easily accessible in the adult rat and it is a rich source of stem and progenitor cells.
T64 821490-821665 Sentence denotes A growing number of recent publications have shown that adult stem cells from the bone marrow are able to exhibit neural phenotypes in vitro and in vivo after transplantation.
T65 821666-821804 Sentence denotes This study was based on immunocytochemical technique for obtaining these descriptive phenotypic markers available for cell identification.
T66 821805-821933 Sentence denotes In this report, we have performed the isolation of cells, antibody titration and characterization of cells from rat bone marrow.
T67 821934-822022 Sentence denotes The phenotype of the cells comprising mononuclear cells system is present in the marrow.
T68 822023-822090 Sentence denotes This population was characterized as CD3+, CD45+, CD90+, and CD38+.
T69 822091-822297 Sentence denotes Our results showed the different contribution in the percentage each marker given a major comprehension to the real contribution of each one of this population cells in the effectiveness of transplantation.
T70 822298-822381 Sentence denotes Gluten sensitivity is an alterated immunological responsiveness to ingested gluten.
T71 822382-822510 Sentence denotes Extraintestinal organs, such as cerebellum, might be the unique target of this disease as occurs in gluten ataxia (GA) syndrome.
T72 822511-822637 Sentence denotes We report a 76-year-old patient with ataxia yielding antigliadin antibodies (AGA), who developed a Ramsay Hunt syndrome (RHS).
T73 822638-822797 Sentence denotes Instrumental exams, biochemical, genetic and histological analyses excluded vascular, inflammatory, metabolic or heredodegenerative ataxia and coeliac disease.
T74 822798-822969 Sentence denotes Mild limb ataxia with severe gait ataxia, cognitive impairment, bladder dysfunction and high values of AGA without any intestinal involvement, resembled the pattern of GA.
T75 822970-823067 Sentence denotes The patient showed a temporary clinical improvement to gluten free diet, and AGA became negative.
T76 823068-823127 Sentence denotes Five months later, her clinical condition rapidly worsened.
T77 823128-823219 Sentence denotes The patient became bedridden, confused and developed myoclonus and pseudo-absence episodes.
T78 823220-823332 Sentence denotes Serial EEGs showed a progressive slowing of background activity and multifocal, periodic, epileptiform activity.
T79 823333-823373 Sentence denotes AGA titer was higher than that at onset.
T80 823374-823392 Sentence denotes RHS was suggested.
T81 823393-823520 Sentence denotes Throughout the last 2 months her clinical and electrophysiological conditions improved once again and AGA test became negative.
T82 823521-823636 Sentence denotes RHS has been previously reported with coeliac disease, but never with GA, considered a mild and monophasic disease.
T83 823637-823734 Sentence denotes We report an association between AGA and RHS, and between clinical severity of RHS and AGA titer.
T84 823735-823827 Sentence denotes AGA have also been found in healthy controls and in patients with heredodegenerative ataxia.
T85 823828-823901 Sentence denotes The significance of their presence and fluctuation needs to be clarified.
T86 823902-823962 Sentence denotes The role of anti-ganglioside antibodies in nerve injury M.A.
T87 823963-823977 Sentence denotes David a , J.M.
T88 823978-823992 Sentence denotes Spies a , J.D.
T89 823993-824007 Sentence denotes Pollard a , G.
T90 824008-824022 Sentence denotes Zhang b , P.J.
T91 824023-824038 Sentence denotes Armati a and K.
T92 824039-824157 Sentence denotes Sheikh b a The University of Sydney, Sydney, Australia; b John Hopkins University, Baltimore, Maryland, USA Objective:
T93 824158-824243 Sentence denotes To determine whether anti-GM1 and anti-GD1a antibodies directly mediate nerve injury.
T94 824244-824255 Sentence denotes Background:
T95 824256-824410 Sentence denotes Chronic inflammatory demyelinating polyradiculoneuropathy and Guillain-Barre Syndrome (GBS) are both considered to be organ specific autoimmune disorders.
T96 824411-824495 Sentence denotes Antibodies have long been suspected of mediating nerve damage in these neuropathies.
T97 824496-824675 Sentence denotes Antibodies to the major gangliosides GM1 and GD1a are strongly associated with the acute motor axonal neuropathy variant of GBS, implicating these gangliosides as target antigens.
T98 824676-824809 Sentence denotes Until recently, attempts to develop animal models of anti-ganglioside antibody mediated nerve injury have given inconsistent results.
T99 824810-824969 Sentence denotes The recent availability of high affinity monoclonal anti-ganglioside antibodies has enabled the development of new animal models to further clarify this issue.
T100 824970-824978 Sentence denotes Methods:
T101 824979-825079 Sentence denotes Monoclonal IgG anti-GM1 or anti-GD1a antibodies or control IgG were injected into rat sciatic nerve.
T102 825080-825311 Sentence denotes Motor nerve conduction studies, stimulating proximal and distal to the site of injection and recording the compound muscle action potential (CMAP) from the foot muscles, were performed before and at 2-day intervals after injection.
T103 825312-825320 Sentence denotes Results:
T104 825321-825471 Sentence denotes Injection of anti-GD1a and anti-GM1 IgG caused a significant (40%) decrease in proximal CMAP amplitude with relative preservation of distal amplitude.
T105 825472-825557 Sentence denotes Preliminary pathological studies show mild axonal degeneration without demyelination.
T106 825558-825569 Sentence denotes Conclusion:
T107 825570-825647 Sentence denotes These findings suggest that anti-GM1 and antiGD1a do cause nerve dysfunction.
T108 825648-825735 Sentence denotes Whether this is via axonal degeneration or conduction failure remains to be determined.
T109 825736-825797 Sentence denotes The buckthorn (Karwinskia humboldtiana) is a poisonous shrub.
T110 825798-825892 Sentence denotes Ingestion produces distal, ascending, symmetric flaccid paralysis with slow recovery or death.
T111 825893-825960 Sentence denotes Buckthorn polyneuropathy is frequently misdiagnosed as GBS or CIDP.
T112 825961-826045 Sentence denotes Histologically, the peripheral nerve presents demyelination and axonal degeneration.
T113 826046-826127 Sentence denotes The mechanisms implicated and the participation of the immune system are unknown.
T114 826128-826220 Sentence denotes We developed a new experimental neuropathy model, which resembles human intoxication stages.
T115 826221-826353 Sentence denotes Rats were classified in four groups: (1) before the onset of paresis, (2) weakness in limbs, (3) paralysis, (4) paralysis recovered.
T116 826354-826527 Sentence denotes Sciatic nerves histopathological studies and statistic analyses were performed (hematoxylin-eosin, Toluidine-blue, Klqver-Barrera, Marsland-Glees and Erickson silver stains.
T117 826528-826565 Sentence denotes CD4+Lymphocyte immunohistochemistry).
T118 826566-826620 Sentence denotes IgG and IgM-anti-myelin were searched by Western-Blot.
T119 826621-826776 Sentence denotes Sciatic nerves of treated rats showed demyelination, axonal degeneration, an important increment of mast cells and lymphocytes in comparison with controls.
T120 826777-826804 Sentence denotes Many lymphocytes were CD4+.
T121 826805-826913 Sentence denotes Groups 2 and 3 showed great degranulated mast cells at endoneurium and perineurim, shrunken or broken axons.
T122 826914-827102 Sentence denotes All sera including controls presented IgM-antibodies against four myelin proteins, in contrast only IgG-antibodies of treated animals reacted with such proteins but none IgG from controls.
T123 827103-827221 Sentence denotes We propose that mast cells, lymphocytes and immunoglobulins participate in the Buckthorn polyneuropathy demyelination.
T124 827222-827314 Sentence denotes Our model can be useful for pathogenic mechanism studies in this and other polyneuropathies.
T125 827315-827339 Sentence denotes Grants: CONACYT, PAICYT.
T126 827340-827500 Sentence denotes The aim of the present study was to investigate cytokine changes after peripheral nerve injury in the rat sciatic nerve and the corresponding sensory ganglions.
T127 827501-827614 Sentence denotes The left sciatic nerves of 26 male rats were transacted at the level of hip joint under pentobarbital anesthesia.
T128 827615-827824 Sentence denotes Samples for TaqMan PCR studies were collected proximally and distally from the point of transection as well as from the contralateral intact sciatic nerve 12 h and 3, 7, 14, 35 and 49 days post-operation (PO).
T129 827825-827881 Sentence denotes The corresponding sensory ganglions were also collected.
T130 827882-827919 Sentence denotes Non-operated rats served as controls.
T131 827920-828000 Sentence denotes Studied cytokine RNAs were: IL-1beta, IL-10, IFN-gamma, TNF-alpha and TGF-beta1.
T132 828001-828128 Sentence denotes IL-1beta, TNF-alpha and IL-10 were markedly expressed during the first week after transection in the distal and proximal areas.
T133 828129-828208 Sentence denotes The expressions in the sensory ganglions correlated partly with these findings.
T134 828209-828311 Sentence denotes TGF-beta1 was upregulated in almost all the samples taken from the injured side between days 3 and 49.
T135 828312-828370 Sentence denotes The most prominent expressions were between 3 and 14 days.
T136 828371-828457 Sentence denotes Contralateral sciatic nerve showed increased expression of TNF-alpha up to 49 days PO.
T137 828458-828552 Sentence denotes The contralateral ganglions showed marked expression of IL-10 and TNFalpha in all time points.
T138 828553-828703 Sentence denotes The expressions patterns of the cytokines IL-1beta, TNF-alpha and IL-10 were similar in the sciatic nerve and in the ganglions of the transected side.
T139 828704-828826 Sentence denotes The noted strong expression of TGF-beta1 could be related to its property to increase axonal growth or to induce fibrosis.
T140 828827-828945 Sentence denotes Effect of nordihydroguairetic acid on thermal hyperalgesia and cold allodynia in STZ-induced diabetic rats and mice M.
T141 828946-828963 Sentence denotes Anjaneyulu and K.
T142 828964-829227 Sentence denotes Chopra Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India Although pain is experienced by many patients with diabetic neuropathy, the pathophysiology of painful diabetic neuropathy is not fully understood.
T143 829228-829484 Sentence denotes Thus study was designed to examine the effect of an antioxidant and lipoxygenase inhibitor, Nordihydroguairetic acid (NDGA), on thermal nociception in streptozotocin (STZ)-induced diabetic rats and mice assessed by tail-immersion and paw withdrawal assays.
T144 829485-829586 Sentence denotes Diabetes was induced in rats and mice by single injection of STZ (65 and 200 mg/kg/i.p respectively).
T145 829587-829689 Sentence denotes After 4 weeks of STZ, diabetic rats and mice were subjected to tailimmersion and paw withdrawal assay.
T146 829690-829806 Sentence denotes Diabetic rats exhibited significant decrease in tail-immersion and paw withdrawal latencies as compared to controls.
T147 829807-829899 Sentence denotes Similarly in diabetic mice, significant decreases in tail-immersion latencies were observed.
T148 829900-830047 Sentence denotes In an acute study in mice after 4 weeks of STZ, NDGA (1, 2 and 5 mg/kg/s.c), dose dependently attenuated tail-immersion latencies in diabetic mice.
T149 830048-830256 Sentence denotes Where as chronic treatment of NDGA (5 and 10 mg/kg/s.c) for 4 weeks starting from 4th week after STZ, a significant attenuation of both tail-immersion and paw withdrawal leniencies were absorbed in diabetics.
T150 830257-830316 Sentence denotes NDGA did not show any change in control animals' latencies.
T151 830317-830583 Sentence denotes These results emphasize that role of oxidative stress in the development of significant hyperalgesia and cold allodynia in diabetic animals and points towards the potential of NDGA as a complementary therapy for the prevention/treatment of diabetic neuropathic pain.
T152 830584-830631 Sentence denotes Regulatory cells and human malignant gliomas A.
T153 830632-830647 Sentence denotes Waziri a , R.C.
T154 830648-830665 Sentence denotes Anderson a , J.N.
T155 830666-830682 Sentence denotes Bruce a and D.E.
T156 830683-830790 Sentence denotes Anderson b a Columbia-Presbyterian Medical Center, New York, USA; b Harvard Medical School, Boston, MA, USA
T157 830791-830944 Sentence denotes We have isolated and analyzed both tumor cells and tumor infiltrating lymphocytes (TILs) present in ex vivo central nervous system (CNS) tumor specimens.
T158 830945-831174 Sentence denotes We used flow cytometry to examine immunologically important cell surface molecules on glioblastoma multiformae (GBM) tumor cells prior to any culturing in vitro, and screened supernatants from ex vivo GBMs for secreted cytokines.
T159 831175-831341 Sentence denotes Tumor cells expressed moderate to high levels of both HLA class I and class II molecules, suggesting that tumor cells could directly interact with and influence TILs.
T160 831342-831456 Sentence denotes In addition, a majority of the GBMs examined (n=10) secreted high amounts of the immunosuppressive cytokine IL-10.
T161 831457-831664 Sentence denotes Based on these observations, we hypothesize that GBM tumor cells promote the differentiation and/or expansion of IL-10secreting type 1 T regulatory (Tr1) cells, which in turn suppress tumor immunity in situ.
T162 831665-831919 Sentence denotes Consistent with this hypothesis, additional preliminary observations suggest that a CD25+ population of CD4+ TILs, which appear to represent effector cells activated in situ, infiltrates GBMs and that these cells are notable for their secretion of IL-10.
T163 831920-832037 Sentence denotes In contrast, CD4+ TILs lacking CD25 expression are notable for their secretion of IFN-gamma and the absence of IL-10.
T164 832038-832206 Sentence denotes These data suggest a novel mechanism by which the tumor microenvironment influences the function of TILs and hinders their ability to mount an effective tumor response.
T165 832207-832404 Sentence denotes To determine whether the T-cells infiltrating brain tumors are comprised of oligoclonal T-cell populations, we amplified, cloned and sequenced betachain TCR transcripts from tumor biopsy specimens.
T166 832405-832651 Sentence denotes In one patient with glioblastoma multiforme, we identified the presence of multiple identical copies of beta-chain TCR transcripts after NPA-PCR amplification, cloning and sequencing, suggesting the presence of oligoclonal populations of T cells.
T167 832652-832832 Sentence denotes The non-palindromic adaptor (NPA)-PCR method was developed in our laboratory to sequence transcripts with unknown or variable 5Vends, such as those of the immunoglobulins and TCRs.
T168 832833-833028 Sentence denotes Vbeta13-specific PCR amplification followed by cloning and sequencing revealed the presence of a strong clonal expansion, which accounted for 7 of 20 (35%) of the betachain transcripts sequenced.
T169 833029-833258 Sentence denotes Similarly, Vbeta22-specific and Vbeta21specific PCR amplification followed by cloning and sequencing revealed clonal expansions accounting for 6 of 14 (35%) and 6 of 21 (28%) of the beta-chain transcripts sequenced, respectively.
T170 833259-833480 Sentence denotes Oligoclonal expansions of beta-chain TCR transcripts were also identified in two other patients (one with recurring glioblastoma multiforme and one with recurrent malignant astrocytoma) using two-sided Vbeta-specific PCR.
T171 833481-833713 Sentence denotes The presence of these oligoclonal T-cell populations indicates that the T cells may have undergone antigen-driven proliferation and clonal expansion in situ at the site of the tumor in response to an as yet unknown tumor antigen(s).
T172 833714-833862 Sentence denotes Increased IFN gamma secretion from restimulated lymphocytes in patients immunized with autologous glioma cells correlates with prolonged survival P.
T173 833863-833876 Sentence denotes Siesjf and E.
T174 833877-833926 Sentence denotes Visse Lund University, Lund, Sweden Introduction:
T175 833927-834116 Sentence denotes In order to monitor the immune response of patients immunized with IFN gamma secreting tumor cells, peripheral blood leucocytes were assayed after restimulation for 5 days with tumor cells.
T176 834117-834125 Sentence denotes Methods:
T177 834126-834213 Sentence denotes Blood samples were collected during the immunizations and PBL were isolated and frozen.
T178 834214-834288 Sentence denotes After thawing PBL, were restimulated with tumor cells in vitro for 5 days.
T179 834289-834470 Sentence denotes The restimulated, cells were then assayed for cytokine production by flow cytometry and ELIspot, proliferation by thymidine incorporation and lymphocyte subset distribution by FACS.
T180 834471-834479 Sentence denotes Results:
T181 834480-834616 Sentence denotes Samples from five patients were analyzed and compared with survival data, immune infiltration and DTH reactions at the vaccination site.
T182 834617-834723 Sentence denotes No correlation or discernable pattern could be observed from proliferation and lymphocyte subset analyses.
T183 834724-834842 Sentence denotes Increased IFN gamma levels measured by flow cytometry and ELIspot were seen in 2/5 patients with a prolonged survival.
T184 834843-834915 Sentence denotes A decrease in IFN gamma production was observed during tumor recurrence.
T185 834916-835009 Sentence denotes Detectable levels of IL-10 were observed displaying a weak association with shorter survival.
T186 835010-835128 Sentence denotes Lymphocyte cytokine production correlated with lymphocyte infiltration but not DTH reactions at the immunization site.
T187 835129-835307 Sentence denotes Conclusions: IFN gamma secretion from restimulated lymphocytes and lymphocyte infiltration at the immunization site were more prominent in 2/5 patients with a prolonged survival.
T188 835308-835425 Sentence denotes The results underscore the importance of using relevant parameters in the evaluation of immunotherapy against tumors.
T189 835426-835618 Sentence denotes Patients with glioblastoma, the most common and lethal intrinsic human brain tumor, are reported here to show decreased expression of the activating immunoreceptor NKG2D in CD8 T and NK cells.
T190 835619-835724 Sentence denotes A soluble factor released by glioma cells down-regulates NKG2D expression in CD8 T and NK cells in vitro.
T191 835725-835877 Sentence denotes Unexpectedly, this soluble factor is not a soluble NKG2D ligand, but transforming growth factor-beta (TGF-beta) which inhibits NKG2D gene transcription.
T192 835878-836101 Sentence denotes Moreover, TGF-beta inhibits the transcription of the NKG2D ligand MICA and promotes the release of matrix metalloproteinases (MMP) by glioma cells which in turn mediate the shedding of MICA from the surface of glioma cells.
T193 836102-836311 Sentence denotes Interference with TGFbeta synthesis by siRNA technology in glioma cells prevents the downregulation of NKG2D on immune cells and suppresses MMP expression and strongly enhances MICA expression in glioma cells.
T194 836312-836405 Sentence denotes Furthermore, TGF-beta knock-down leads to a decreased migratory and invasive tumor phenotype.
T195 836406-836572 Sentence denotes Altogether, the knock-down of TGF-beta results in a glioma cell phenotype which is less motile, more sensitive to immune cell lysis, and non-tumorigenic in nude mice.
T196 836573-836672 Sentence denotes Identification of a novel neuroblastoma-associated molecule that protects from NK-mediated lysis R.
T197 836673-836690 Sentence denotes Castriconi a , A.
T198 836691-836705 Sentence denotes Dondero a , C.
T199 836706-836722 Sentence denotes Bottino b and A.
T200 836723-836853 Sentence denotes Moretta a a Dipartimento di Medicina Sperimentale, University of Genova, Genova, Italy; b Istituto Giannina Gaslini, Genova, Italy
T201 836854-837172 Sentence denotes In order to identify novel markers useful for specific recognition of Neuroblastoma cells, we immunized mice with a Neuroblastoma cell line and after cell fusion, an mAb termed 5B14 was selected that stained all Neuroblastoma cell lines tested as well as tumors of different origin, including melanomas and carcinomas.
T202 837173-837315 Sentence denotes Importantly, in bone marrow aspirates derived from stage 4 patients, infiltrating Neuroblastoma cells were selectively recognized by 5B14 mAb.
T203 837316-837438 Sentence denotes The molecule recognized by the 5B14 mAb has a molecular mass of approximately 100 kDa (thereafter termed NBp100 molecule).
T204 837439-837598 Sentence denotes Protein purification followed by in-gel tryptic digestion, liquid chromatography and tandem mass spectrometry allowed the identification of the NBp100 protein.
T205 837599-837741 Sentence denotes Purified neuroblastoma cells were used as target cells in cytotoxicity assays in which effector cells were represented by polyclonal NK cells.
T206 837742-837867 Sentence denotes These experiments demonstrated that NBp100 molecules play an important role in protecting tumor cells from NK-mediated lysis.
T207 837868-837945 Sentence denotes Indeed NK cell-mediated killing was inhibited by the interaction with NBp100.
T208 837946-838009 Sentence denotes This inhibition was reversed by mAb-mediated masking of NBp100.
T209 838010-838148 Sentence denotes This observation is reminiscent of the effect of anti-HLA class I mAb that can reverse the NK-mediated lysis of HLA class I+ target cells.
T210 838149-838335 Sentence denotes Thus it appears conceivable that NK cells may be equipped with specific inhibitory receptors that upon interaction with this new ligand transduce signals that down-regulate cytotoxicity.
T211 838336-838502 Sentence denotes Eradication of murine brain tumors by direct inoculation of concentrated high titer-recombinant retrovirus harboring the herpes simplex virus thymidine kinase gene K.
T212 838503-838517 Sentence denotes Shimizu a , T.
T213 838518-838531 Sentence denotes Yawata a , T.
T214 838532-838549 Sentence denotes Tsuchiya a , K.C.
T215 838550-838561 Sentence denotes Park a , S.
T216 838562-838577 Sentence denotes Toyonaga a , S.
T217 838578-838591 Sentence denotes Yamada a , H.
T218 838592-838610 Sentence denotes Nakabayashi a , E.
T219 838611-838623 Sentence denotes Nakai a , N.
T220 838624-838638 Sentence denotes Ikawa a and K.
T221 838639-838903 Sentence denotes Ikenaka b a Kochi Medical School, Nankoku City, Japan; b National Institute for Physiological Sciences, Okazaki, Japan Implantation of retrovirus-producing cells within a tumor has been demonstrated to eliminate malignant brain tumors effectively in animal models.
T222 838904-839052 Sentence denotes In our previous study, the implantation of high-titer retrovirusproducing fibroblasts into tumors resulted in highly efficient transduction in vivo.
T223 839053-839184 Sentence denotes The transduced glioma cells migrated far from the implantation site, potentiating the induction of the remarkable bystander effect.
T224 839185-839329 Sentence denotes It is also possible, however, that the implantation of murine fibroblast-derived virusproducing cells may induce an immune response in patients.
T225 839330-839599 Sentence denotes In this study, we prepared retroviruses carrying the herpes simplex virus thymidine kinase (HTK) gene with titers of 1.4-2.5Â10 11 colony-forming units (c.f.u.)/ml, and stereotactically inoculated only 3 Al of the HTK-bearing retroviruses into the brain tumors of mice.
T226 839600-839732 Sentence denotes Following repetitive ganciclovir (GCV) intraperitoneal injection, effective killing of glioma cells in the mouse brain was observed.
T227 839733-839865 Sentence denotes The transduction efficiency was nearly as high as that observed for the implantation of high-titer retrovirus-producing fibroblasts.
T228 839866-840003 Sentence denotes Eighty percent of brain tumor-bearing mice were completely cured by our treatment protocol using concentrated HTK-harboring retroviruses.
T229 840004-840202 Sentence denotes Our results suggest that repeated inoculations of high-titer retroviruses carrying the HTK gene followed by GCV treatment may be a promising strategy for the clinical treatment of malignant gliomas.
T230 840203-840305 Sentence denotes Delivery of interleukin 4 to experimental gliomas by viral vectors and neural stem-progenitor cells P.
T231 840306-840319 Sentence denotes Tunici and G.
T232 840320-840442 Sentence denotes Finocchiaro Laboratory of Experimental Neuro-Oncology and Gene Therapy, Istituto Nazionale Neurologico Besta, Milan, Italy
T233 840443-840783 Sentence denotes In previous experiments, we showed that retroviral delivery of IL-4 restrains the growth of C6 and 9L malignant gliomas in rats and, subsequently, that the injection of rat-immortalized or murine primary neural stem progenitor cells (NSPC) overexpressing IL-4 could be even more effective for the treatment of C6 or GL261 malignant gliomas.
T234 840784-841018 Sentence denotes MLVderived retroviral vectors, used in these experiments to deliver the IL-4 cDNA to brain tumors or NSPC, have limitations because they only transduce dividing cells and because LTR-driven expression of the transgene can be silenced.
T235 841019-841195 Sentence denotes To test if lentiviral vectors could be more effective, we prepared a lentiviral vector for IL-4 gene delivery (plasmids were obtained from the laboratory of Dr. Luigi Naldini).
T236 841196-841330 Sentence denotes The lentiviral preparation contained 50 ng/Al of p24 and NSPC transduced by 1 Al of lenti-IL-4 produced 90 ng/10 6 cells/24 h of IL-4.
T237 841331-841501 Sentence denotes We injected 2Â10 4 GL261 glioblastoma cells into the striatum of C57Bl6J mice (seven for each experimental group) and after 5 days 3 Al of lenti IL-4 or 2Â10 5 NSPC-IL-4.
T238 841502-841561 Sentence denotes Lenti GFP or NSPC-GFP, respectively, were used as controls.
T239 841562-841679 Sentence denotes Only mice injected with NSPC-IL-4 cells survived significantly longer than controls ( p=0.006, log-rank, Mantel-Cox).
T240 841680-841754 Sentence denotes This effect, however, decreased if more GBM cells (5Â10 4 ) were injected.
T241 841755-841853 Sentence denotes These experiments confirmed that NSPC-IL-4 cells have a significant anti-tumor effects on gliomas.
T242 841854-842036 Sentence denotes However, NSPC transduced by lentivirus did not appear more effective than NSPC transduced by MLV-derived retrovirus and IL-4 delivery by lentivirus did not yield anti-tumor activity.
T243 842037-842126 Sentence denotes Cancers can be partially attributed to defects in the regulation of apoptotic cell death.
T244 842127-842304 Sentence denotes Failure to trigger the cellular suicide program not only predisposes to development of malignancies, but also increases resistance of tumors to anticancer drugs and irradiation.
T245 842305-842505 Sentence denotes From the recent observation that taurolidine, an antibacterial drug, displayed a potent antineoplastic effect on several tumor cell lines, we decided to test taurolidine on human ex vivo glioma cells.
T246 842506-842612 Sentence denotes We performed cytotoxicity and colony formation assays and found a high susceptibility of the glioma cells.
T247 842613-842727 Sentence denotes From the high activity of taurolidine in both assays, we elucidated the mechanism(s) of its antineoplastic effect.
T248 842728-842971 Sentence denotes The results of our studies revealed that taurolidine induces programmed cell death through the generation of intracellular ROI which was prevented by the radical scavenger N-acetylcysteine (NAC), but not by the pan-caspase inhibitor z-VAD-fmk.
T249 842972-843125 Sentence denotes By confocal laser scanning confocal microscopy, we identified apoptosis-inducing factor (AIF) as the major player in this caspase-independent cell death.
T250 843126-843290 Sentence denotes Interestingly, taurolidine suppressed the constitutive VEGF production of glioma cells displaying thus an antiangiogenic effect besides its antineoplastic activity.
T251 843291-843504 Sentence denotes Taken together, taurolidine treatment of glioblastoma cells results in a caspase-independent programmed cell death which was preceded by ROI generation, mitochondrial dysfunction and AIF release from mitochondria.
T252 843505-843716 Sentence denotes Interestingly, taurolidine-induced cell death is also initiated at the lysosomal level leading to mitochondrial dysfunction and programmed cell death either directly or through autophagy of damaged mitochondria.
T253 843717-843794 Sentence denotes Multifunctional fusion cytokines for breaking cancer-induced immune anergy S.
T254 843795-843832 Sentence denotes Paul Transgene SA, Strasbourg, France
T255 843833-844251 Sentence denotes The idea that tumors must bescapeQ from immune recognition contains the implicit assumption that tumors can be destroyed by immune responses either spontaneously or as the result of immunotherapeutic intervention. bNatural selectionQ of heterogeneous tumor cells results in the survival and proliferation of variants that happen to possess genetic and epigenetic traits that facilitate their growth and immune evasion.
T256 844252-844461 Sentence denotes Several mechanisms have been developed by tumor cells which enable them to escape host immunity due to reduction in antigen presentation by tumor cells or due to a local or general decline in patient immunity.
T257 844462-844603 Sentence denotes Previous work has shown that cytokine immune effectors can enhance host's immunity, and thus overcome a tumor-induced state of immune anergy.
T258 844604-844769 Sentence denotes More recently, many studies with both mouse and human tumor models have shown the importance of cytokine combinations in the development of optimal immune responses.
T259 844770-844913 Sentence denotes Here we described novel fusion proteins also called bFusokineTMQ, that are useful for enhancing both nonspecific and specific immune responses.
T260 844914-845128 Sentence denotes The murine fusokine IL-2/IL-18 provide high rate of tumor rejection after intratumoral delivery of encoding adenoviral vectors in various animal models, with evidence of immunostimulation and very limited toxicity.
T261 845129-845262 Sentence denotes The antitumoral effect of IL-2/IL-18 murine fusokine is correlated with the activation of both CTLs, NK and antigen presenting cells.
T262 845263-845321 Sentence denotes Microglia and gliomas may have a symbiotic relationship M.
T263 845322-845338 Sentence denotes Graeber a and A.
T264 845339-845447 Sentence denotes Flqgel b a Imperial College London, London, UK; b Max-Planck-Institute of Neurobiology, Martinsried, Germany
T265 845448-845550 Sentence denotes The number of microglial glial cells/brain macrophages in malignant astrocytomas is surprisingly high.
T266 845551-845692 Sentence denotes Based on in vitro findings, it has been speculated that brain macrophages derived from microglial cells may exert tumour cytotoxic functions.
T267 845693-845816 Sentence denotes However, the biological bsuccessQ of malignant astrocytomas strongly suggests that this potential is not exploited in vivo.
T268 845817-846033 Sentence denotes We have tested the effect of both native microglia that were isolated from neonatal Lewis rat brain and kept in primary culture for 14 days and of supernatant taken from these cells on C6 glioma cells grown in vitro.
T269 846034-846246 Sentence denotes We did not use a conventional cell death assay but determined the absolute number of tumour cells which carried the bgreen fluorescent proteinQ (GFP) marker gene using a fluorescence-activated cell sorter (FACS).
T270 846247-846298 Sentence denotes There was no significant cytotoxicity of microglia.
T271 846299-846382 Sentence denotes Instead, our experiments showed a clear growth promoting effect on C6 glioma cells.
T272 846383-846704 Sentence denotes The fact that supernatant alone derived from unstimulated microglia which had not been in contact with tumour cells was sufficient to promote survival of neoplastic cells suggests that there is no need for complicated microglia-tumour interactions to explain survival of glioma cells in the presence of microglia in vivo.
T273 846705-846776 Sentence denotes The molecular basis for the observed effect is currently being studied.
T274 846777-846912 Sentence denotes Symbiosis between microglia and a glial tumour seems a distinct possibility as gliomas are known to stimulate microglial proliferation.
T275 846913-847001 Sentence denotes Vascular endothelial growth factor (VEGF) and interleukin-10 (IL-10) in brain tumours R.
T276 847002-847016 Sentence denotes Kumar a,b , L.
T277 847017-847030 Sentence denotes Madden a , K.
T278 847031-847043 Sentence denotes Hills b , D.
T279 847044-847057 Sentence denotes Crooks b , J.
T280 847058-847075 Sentence denotes Greenman a and D.
T281 847076-847318 Sentence denotes O'Brien b a University of Hull, Hull, UK; b Hull and East Yorkshire Hospitals, Hull, UK IL-10 is an immunosuppressive cytokine produced by T-lymphocytes, and is reported to be a regulatory molecule for angiogenesis primarily mediated by VEGF.
T282 847319-847424 Sentence denotes The aim of this work was to investigate the relationship between VEGF and IL-10 in brain tumour patients.
T283 847425-847568 Sentence denotes A prospective analysis to compare levels in serum, cyst and tumour expression of VEGF and IL-10 in patients with newly diagnosed brain tumours.
T284 847569-847666 Sentence denotes Immunohistochemistry was performed for VEGF, its receptors and IL-10; 71 patients were recruited.
T285 847667-847738 Sentence denotes Serum samples were obtained prior to surgery and cyst fluid at surgery.
T286 847739-847806 Sentence denotes Serum and cyst, VEGF and IL-10 were measured by Quantitative ELISA.
T287 847807-847886 Sentence denotes Patients were divided into benign, low grade, high grade and metastatic groups.
T288 847887-847984 Sentence denotes Patients with benign and low grade tumours had a median serum VEGF levels of 211.4 and 274 pg/ml.
T289 847985-848093 Sentence denotes The median serum VEGF levels in the high grade and metastatic group were 279.9 and 288.3 pg/ml respectively.
T290 848094-848152 Sentence denotes Serum IL-10 was only detected in 54 patients at 2.0 pg/ml.
T291 848153-848192 Sentence denotes Immunohistochemistry results to follow.
T292 848193-848331 Sentence denotes There is a trend towards higher serum VEGF levels with advancing tumour grade, with the highest levels being seen in the metastatic group.
T293 848332-848383 Sentence denotes Serum IL-10 was detectable in only 76% of patients.
T294 848384-848428 Sentence denotes There was no relationship with tumour grade.
T295 848429-848483 Sentence denotes There was no association between serum VEGF and IL-10.
T296 848484-848586 Sentence denotes There was a significant increase of cyst fluid VEGF ( p=0.002) and IL-10 ( p=0.015) compared to serum.
T297 848587-848771 Sentence denotes Here a pilot study is presented comparing the levels of a panel of cytokines in intracavitary cyst fluid from patients with brain tumours against their serum and normal serum controls.
T298 848772-848779 Sentence denotes Design:
T299 848780-848900 Sentence denotes A prospective analysis of cyst fluid VEGF, TNF alpha, IL-6, IL-8 and IL-10 levels in patients with brain tumours (n=12).
T300 848901-848988 Sentence denotes Serum was obtained prior to surgery and cyst fluid was obtained at the time of surgery.
T301 848989-849006 Sentence denotes Outcome measures:
T302 849007-849086 Sentence denotes Quantitative ELISA was used to measure intracavitary cytokine and serum levels.
T303 849087-849127 Sentence denotes All samples were analysed in duplicates.
T304 849128-849205 Sentence denotes All cytokine levels were compared with serum values and normal serum control.
T305 849206-849214 Sentence denotes Results:
T306 849215-849344 Sentence denotes The levels for all these cytokines were significantly higher in intracavitary cyst fluid compared with patients and normal serum.
T307 849345-849728 Sentence denotes The level of VEGF was approximately 480-fold higher than normal serum (mean 131,805 vs. 271 pg/ml); TNFalpha concentration was approximately 2-fold lower (3 vs. 6.7 pg/ml); IL-6 concentration was approximately 6500-fold higher (325 vs. 0.05 pg/ml); IL-8 concentration was approximately 10-fold higher (127 vs. 12.5 pg/ml) and IL-10 was approximately 3-fold higher (6.52 vs. 2 pg/ml).
T308 849729-849741 Sentence denotes Conclusions:
T309 849742-849821 Sentence denotes Except for TNFalpha, there was a significant increase in all cytokines studied.
T310 849822-849937 Sentence denotes The significance of such increases in cytokine levels will require further analysis in a larger series of patients.
T311 849938-850068 Sentence denotes Expression of novel B7 molecules by human glioma cells in vitro and in vivo: B7-H1 as a potential mechanism of immune paralysis S.
T312 850069-850085 Sentence denotes Wintterle a , B.
T313 850086-850102 Sentence denotes Schreiner a , M.
T314 850103-850122 Sentence denotes Mitsdoerffer a , D.
T315 850123-850139 Sentence denotes Schneider a , L.
T316 850140-850151 Sentence denotes Chen b , R.
T317 850152-850168 Sentence denotes Meyermann a , M.
T318 850169-850184 Sentence denotes Weller a and H.
T319 850185-850369 Sentence denotes Wiendl a a University of Tübingen,Tübingen, Germany; b Mayo Clinic, Rochester, MN, USA Human glioblastoma is a highly lethal tumor that is known for its immune inhibitory capabilities.
T320 850370-850494 Sentence denotes B7-H1 is a recently identified homolog of B7.1/2 (CD80/86) described to exert costimulatory and immune regulatory functions.
T321 850495-850633 Sentence denotes We investigated the expression and the functional activity of novel B7 costimulatory molecules in human glioma cells in vitro and in vivo.
T322 850634-850739 Sentence denotes While lacking B7.1/2 (CD80/86), all 12 glioma cell lines constitutively expressed B7-H1 mRNA and protein.
T323 850740-850797 Sentence denotes Exposure to IFN-gamma strongly enhanced B7-H1 expression.
T324 850798-850982 Sentence denotes Immunohistochemical analysis of malignant glioma specimens revealed strong B7-H1 expression in all 10 samples examined whereas no B7-H1 expression was detected on normal brain tissues.
T325 850983-851156 Sentence denotes To elucidate the functional significance of glioma cell-related B7-H1 expression, we performed coculture experiments of glioma cells with alloreactive CD4+ and CD8+ T cells.
T326 851157-851455 Sentence denotes Glioma-related B7-H1 was identified as a strong inhibitor of CD4+ as well as CD8+ T cell activation as assessed by increased cytokine production (IFN-gamma, IL-2, IL-10) and expression levels of the T cell activation marker (CD69) in the presence of a neutralizing antibody against B7-H1 (mAb 5H1).
T327 851456-851648 Sentence denotes B7-H1 expression may thus significantly influence the outcome of T cell tumor cell interactions and represents a novel mechanism by which glioma cells evade immune recognition and destruction.
T328 851649-851806 Sentence denotes Microglia, in response to brain pathology, undergo an activation process and become capable of phagocytosis, antigen presentation, and lymphocyte activation.
T329 851807-851966 Sentence denotes Recent studies suggest that microglia accumulation in glial tumors may reflect participation of these cells in supporting and promoting the invasive phenotype.
T330 851967-852047 Sentence denotes Mutual interactions between microglia and glioma cells are not well established.
T331 852048-852196 Sentence denotes We therefore studied the effects of soluble factors released by rat microglial cells on proliferation and signaling pathways in rat C6 glioma cells.
T332 852197-852335 Sentence denotes LPS treated microglia-conditioned medium has a weak activatory effect on C6 glioma proliferation as determined using MTT metabolism assay.
T333 852336-852583 Sentence denotes In the presence of conditioned medium from resting and LPS-activated microglia cultures, we did not observed changes in the activation of p38 MAPK, Erk and JNK kinases in glioma cells, as analysed by Western blot analysis with specific antibodies.
T334 852584-852656 Sentence denotes However, a significant activation of Akt signaling pathway was observed.
T335 852657-852807 Sentence denotes PI-3K/Akt kinase signaling pathway regulates many cellular processes, including survival, proliferation, differentiation, chemotaxis and angiogenesis.
T336 852808-852894 Sentence denotes Furthermore, we studied the effects of glioma-conditioned medium on resting microglia.
T337 852895-852992 Sentence denotes We found an activation of morphological changes and stimulation of some MAP kinases in microglia.
T338 852993-853150 Sentence denotes Our results suggest that glioma cells may activate microglial cells that further exert an activatory effect on glioma cells contributing to glioma pathology.
T339 853151-853183 Sentence denotes Supported by PBZ-MIN/001/P05/10.
T340 853184-853267 Sentence denotes Gene immunotherapy in the brain: looking for anti-tumour activities of microglia A.
T341 853268-853280 Sentence denotes Abschütz, R.
T342 853281-853294 Sentence denotes Geibig and A.
T343 853295-853366 Sentence denotes Régnier-Vigouroux Deutsches Krebsforschungszentrum, Heidelberg, Germany
T344 853367-853516 Sentence denotes Common strategies for tumour gene therapy mainly focus at inducing cell death or stimulating the immune system in order to eliminate the tumour mass.
T345 853517-853649 Sentence denotes In case of brain tumours, new therapies are desperately needed due to poor prognosis of patients and failure of classical therapies.
T346 853650-853805 Sentence denotes Microglia represent a potential, though poorly exploited arm of defense which antitumour activity could be triggered by tumour-targeted gene immunotherapy.
T347 853806-854094 Sentence denotes Autonomous parvovirus-based vectors are promising tools for delivery of therapeutical genes into the brain, given the natural oncotropism of these viruses, their oncosuppressive activity in vivo and their capacity for selective delivery of toxic/immunostimulatory genes into tumour cells.
T348 854095-854190 Sentence denotes We first investigated the permissiveness of primary mouse glial cells to the murine parvovirus.
T349 854191-854312 Sentence denotes Astrocytes, but not microglia, readily take up the virus and about 10% of the cells express viral or transduced proteins.
T350 854313-854389 Sentence denotes Nevertheless, the viral life cycle is not completed and cells are not lysed.
T351 854390-854460 Sentence denotes Second we started to characterize anti-tumour capacities of microglia.
T352 854461-854643 Sentence denotes We show that microglia can (i) kill glioma cells via soluble compounds after stimulation with lipopolysaccharide and IFN-gamma and (ii) phagocytose living and apoptotic glioma cells.
T353 854644-854871 Sentence denotes Taken together, our data suggest that microglia do have the potential to fight against brain tumours and that immunostimulatory molecules produced by virally transduced tumour cells and astrocytes could regulate this potential.
T354 854872-855053 Sentence denotes Glioma cells stimulated with proinflammatory cytokines produce high amount of nitric oxide (NO), a highly reactive free radical with both anticancer and cancer-promoting properties.
T355 855054-855232 Sentence denotes Aloe-emodin (AE), an herbal compound with tumoricidal activity, strongly down-regulated NO synthesis in rat astrocytoma C6 cells stimulated with IL-1beta, IFN-gamma and TNFalpha.
T356 855233-855395 Sentence denotes AE affected the expression of both transcription and translation products of NO-producing enzyme inducible NO synthase (iNOS), rather than its enzymatic activity.
T357 855396-855573 Sentence denotes Treatment with AE significantly reduced cytokine-triggered expression of important iNOS transcription factor IRF-1 in C6 cells, while activation of NF-kappaB remained unaltered.
T358 855574-855782 Sentence denotes Furthermore, AE partially interfered with the activation of mitogen-activated protein kinase (MAPK) pathway, as activation of ERK1/2, but not c-Jun Nterminal or and p38 MAPK, was suppressed upon AE treatment.
T359 855783-856021 Sentence denotes In conclusion, AE-mediated down-regulation of IRF-1 and ERK pathways, with subsequent inhibition of iNOS transcription and NO synthesis in glioma cells, might have important implications for potential therapeutic use of this antraquinone.
T360 856022-856117 Sentence denotes Aloe-emodin (AE) is a naturally occurring compound with wide spectrum of biological properties.
T361 856118-856240 Sentence denotes This antraquinone induces apoptosis in several tumor cell lines with special affinity to tumors of neuroectodermal origin.
T362 856241-856333 Sentence denotes High amounts of nitric oxide (NO) released by activated macrophages induce tumor cell death.
T363 856334-856444 Sentence denotes Therefore, we explored the capacity of AE to modulate macrophage NO-mediated killing of glioma cells in vitro.
T364 856445-856625 Sentence denotes Interestingly, while AE markedly suppressed NO release from macrophages alone, it significantly potentiated NO production in cocultures of macrophages and rat astrocytoma C6 cells.
T365 856626-856743 Sentence denotes Accordingly, the viability of C6 cells cocultivated with macrophages was significantly reduced in the presence of AE.
T366 856744-856940 Sentence denotes The contrasting AE-imposed effects on macrophage NO release were closely related to macrophage density, as its increase readily converted the observed inhibition into potentiation of NO synthesis.
T367 856941-857170 Sentence denotes Stimulation of NO synthesis in high density macrophages culture by AE was not affected by transcription or translation inhibitors, indicating that enzymatic activity, rather than gene expression, was a target for the drug action.
T368 857171-857245 Sentence denotes Accordingly, the expression of iNOS in macrophages was not affected by AE.
T369 857246-857431 Sentence denotes Therefore, the capacity of AE to modulate macrophage NO release and survival of glioma cells might considerably depend on the contact between macrophages or macrophages and tumor cells.
T370 857432-857527 Sentence denotes Expression of CCR7 in the central nervous system (CNS) and its implications for CNS immunity P.
T371 857528-857540 Sentence denotes Kivis7kk, D.
T372 857541-857555 Sentence denotes Mahad and R.M.
T373 857556-857698 Sentence denotes Ransohoff Cleveland Clinic Foundation, Cleveland, OH, USA It is unclear how immune cells traffic between the lymphoid compartment and the CNS.
T374 857699-857990 Sentence denotes We defined the expression of trafficking determinants on T cells and dendritic cells (DCs) in the cerebrospinal fluid (CSF) and brain parenchyma as well as on endothelial cells from different compartments within the CNS to gain insight into pathways for immune cell trafficking to the brain.
T375 857991-858165 Sentence denotes Ninety percent of CSF T cells from patients with multiple sclerosis (MS) or noninflammatory neurological diseases (NIND) were CD4+/CD45RO+/CD27+/CCR7+ central-memory T cells.
T376 858166-858280 Sentence denotes In contrast, all CD4+ T cells in parenchymal MS lesions lacked CCR7, consistent with an effector-memory phenotype.
T377 858281-858491 Sentence denotes Postcapillary venules of the choroid plexus and subarachnoid space, but not brain parenchymal microvessels, in autopsy sections from NIND patients expressed adhesion molecules supporting recruitment of T cells.
T378 858492-858767 Sentence denotes These findings suggest that immune surveillance of the non-inflamed CNS immunity is executed by centralmemory T cells, which enter CSF directly from the systemic circulation, retaining the capacity to differentiate into effector-memory cells upon local antigen restimulation.
T379 858768-858881 Sentence denotes Inflamed MS lesions contained numerous CCR7+ cells with phenotypic features of mature DCs or activated microglia.
T380 858882-858936 Sentence denotes CCR7+ DCs were identified in the CSF from MS patients.
T381 858937-859088 Sentence denotes These findings indicate that the efferent limb of CNS immunity is comprised in part of DCs, which migrate to deep cervical lymph nodes through the CSF.
T382 859089-859168 Sentence denotes The nature of CCR7+ myeloid cells in the CNS parenchyma is under investigation.
T383 859169-859262 Sentence denotes Identification of putative trigger agents in multiple sclerosis using an unbiased approach M.
T384 859263-859278 Sentence denotes Sospedra a , Y.
T385 859279-859290 Sentence denotes Zhao a , P.
T386 859291-859304 Sentence denotes Muraro a , S.
T387 859305-859320 Sentence denotes Jacobson a , C.
T388 859321-859337 Sentence denotes Pinilla b and R.
T389 859338-859536 Sentence denotes Martin a a National Institutes of Health, Bethesda, USA; b Torrey Pines Institute, San Diego, USA Multiple sclerosis (MS) is a T cell-mediated autoimmune disease of the central nervous system (CNS).
T390 859537-859678 Sentence denotes Viral infections often precede exacerbations, and hence infectious agents have been considered as triggers, although their nature is unknown.
T391 859679-859822 Sentence denotes Molecular mimicry provides an elegant framework as to how similarities between foreign agents and autoantigens can trigger autoimmune diseases.
T392 859823-860063 Sentence denotes In this study, we determined the specificity of cerebrospinal fluid (CSF)-infiltrating T cells from a patient with RR-MS in exacerbation using an unbiased approach in order to identify foreign agents that might have activated these T cells.
T393 860064-860119 Sentence denotes CSF T cells were cloned by limiting dilution using PHA.
T394 860120-860271 Sentence denotes Subsequently, we analyzed the TCR expression and by CDR3 spectratyping we identified which of these T cell clones (TCC) were clonally expanded in vivo.
T395 860272-860528 Sentence denotes In vivo expanded TCC were then tested with synthetic combinatorial peptide libraries (ps-SCL), and a recently described search algorithm applied to predict peptides from the entire bacterial-and viral protein databases that might be recognized by each TCC.
T396 860529-860606 Sentence denotes Interesting peptides were synthesized and their stimulatory potential tested.
T397 860607-860692 Sentence denotes Several stimulatory natural peptides originating from foreign agents were identified.
T398 860693-860822 Sentence denotes Interestingly, two out of five TCC recognized multiple peptides from related organisms, mainly human herpes viruses and TT-virus.
T399 860823-860923 Sentence denotes Our data strongly indicate that ubiquitous viral agents can activate CSF-infiltrating T cells in MS.
T400 860924-861008 Sentence denotes Similar low frequency of anti-MOG IgG and IgM in MS patients and healthy subjects V.
T401 861009-861025 Sentence denotes Lampasona a , D.
T402 861026-861043 Sentence denotes Franciotta b , R.
T403 861044-861057 Sentence denotes Furlan a , S.
T404 861058-861073 Sentence denotes Zanaboni a , R.
T405 861074-861086 Sentence denotes Fazio a , E.
T406 861087-861103 Sentence denotes Bonifacio a , G.
T407 861104-861117 Sentence denotes Comi a and G.
T408 861118-861214 Sentence denotes Martino a a San Raffaele Scientific Institute, Milan, Italy; b University of Pavia, Pavia, Italy
T1 861215-861434 Sentence denotes Anti-MOG antibodies induce extensive demyelination in T cell-mediated experimental autoimmune encephalomyelitis (EAE), and bind to disintegrating myelin in acute multiple sclerosis (MS) and in the marmoset model of EAE.
T2 861435-861573 Sentence denotes These observations motivate the search for anti-MOG antibodies in MS, in which increased MOG-specific T and B cell responses are reported.
T3 861574-861779 Sentence denotes Reported data have had a negligible impact on patient care, but Berger et al. showed that serum anti-MOG IgM strongly predicted the early conversion of first demyelinating events to clinically definite MS.
T4 861780-861952 Sentence denotes We used a liquidphase radiobinding assay to measure serum anti-MOG IgG in 87 multiple sclerosis patients (MS), in 12 encephalomyelitis patients, and in 47 healthy subjects.
T5 861953-862058 Sentence denotes Anti-MOG IgM were determined in samples obtained at onset from 40 of the 87 MS patients, and in controls.
T6 862059-862189 Sentence denotes The frequency of positive samples with low titers of anti-MOG IgG (=5.7%) and IgM (=8.3%) was similar in all the groups/subgroups.
T7 862190-862268 Sentence denotes Binding competition experiments showed that these antibodies had low affinity.
T8 862269-862314 Sentence denotes Anti-MOG antibodies are not disease-specific.
T9 862315-862476 Sentence denotes Interactions between complement, immunoglobulins (IgG) and IgGreceptors (FcgammaR) could contribute to inflammation and demyelination in multiple sclerosis (MS).
T10 862477-862599 Sentence denotes MS lesions were recently classified into four subtypes, one of which is characterized by deposition of complement and IgG.
T11 862600-862677 Sentence denotes Expression of FcgammaR in active lesions has been described in another study.
T12 862678-862773 Sentence denotes We investigated the presence of complement, IgG and FcgammaR in different stages of MS lesions.
T13 862774-862878 Sentence denotes Immunohistochemistry was performed on 55 lesions from 30 patients, derived from frozen autopsy material.
T14 862879-862994 Sentence denotes We stained for complement, IgG, MHC class II, myelin proteins and FcgammaR (FcgammaRI, FcgammaRII and FcgammaRIII).
T15 862995-863042 Sentence denotes Immunopositivity was scored semiquantitatively.
T16 863043-863187 Sentence denotes Lesions with MHC class IIpositive macrophages containing intracellular myelin debris (PLP+ macrophages) were classified as active demyelinating.
T17 863188-863285 Sentence denotes C1q and C3d, but not C4d, C5b-9 and IgG, were detected on astrocytes in MS lesions of all stages.
T18 863286-863408 Sentence denotes In contrast, presence of C1q, C3b, C5b-9 and IgG on and within macrophages was restricted to active demyelinating lesions.
T19 863409-863456 Sentence denotes Complement and IgG colocalized intracellularly.
T20 863457-863574 Sentence denotes In contrast to earlier publications, complement and IgG deposition were observed in all active demyelinating lesions.
T21 863575-863743 Sentence denotes Enhanced expression of FcgammaRI, FcgammaRII and FcgammaRIII was observed on both PLP+ and PLPÀ macrophages, always associated with enhanced expression of MHC class II.
T22 863744-863910 Sentence denotes This suggests that the presence of complement in macrophages is associated with active demyelination, whereas expression of FcgammaRs is associated with inflammation.
T23 863911-864020 Sentence denotes Double stainings to co-localize complement, IgG and FcgammaR within PLP+ macrophages are currently performed.
T24 864021-864119 Sentence denotes New antigenic candidates in multiple sclerosis: identification by serological proteome analysis D.
T25 864120-864134 Sentence denotes Lefranc a , L.
T26 864135-864149 Sentence denotes Almeras a , H.
T27 864150-864179 Sentence denotes Drobecq b , J. de Seze c , S.
T28 864180-864196 Sentence denotes Dubucquoi a , P.
T29 864197-864215 Sentence denotes Vermersch c and L.
T30 864216-864384 Sentence denotes Prin a a Department of Immunology, CHRU of Lille, Lille, France; b Biological Institute of Lille, Lille, France; c Department of Neurology, CHRU of Lille, Lille, France
T31 864385-864516 Sentence denotes Myelin antigen targets that are clearly associated with pathogenic events in multiple sclerosis (MS) patients remain to be defined.
T32 864517-864759 Sentence denotes We recently demonstrated that the analysis of global IgG antibody response against human brain antigens using one-dimensional immunoblotting, allowed us to discriminate MS patients from controls (both healthy subjects and Sjfgren's syndrome).
T33 864760-864851 Sentence denotes Additionally, this approach also differentiated the three clinical forms of the MS disease.
T34 864852-864973 Sentence denotes Indeed, 42 brain antigenic bands (26 in healthy brain and 16 in MS brain) showed these discriminant IgG immune responses.
T35 864974-865077 Sentence denotes The aim of our study was to characterize the 26 discriminant antigenic bands detected on healthy brain.
T36 865078-865273 Sentence denotes Protein identification was successively performed by one-dimensional (1-D) and two-dimensional (2-D) immunoblottings using sera from 18 MS patients, followed by MS analysis and a database search.
T37 865274-865384 Sentence denotes One hundred and two antigenic spots were then detected on 2-D immunoblots, with MS sera against healthy brain.
T38 865385-865603 Sentence denotes Sixty-four spots successfully matched with 2-D coomassie brilliant blue (CBB) stained gels, which were further selected for MS analysis and annotated leading to the identification of 14 of the 26 discriminant antigens.
T39 865604-865807 Sentence denotes Thus, serological proteome analysis (SERPA) may provide a useful tool for the identification of potentially new MS-associated antigens, whose relevance to physiopathological events remains to be defined.
T40 865808-865920 Sentence denotes Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the central nervous system (CNS).
T41 865921-866058 Sentence denotes Disease mechanisms in MS at the molecular level remain poorly understood and no reliable proteinaceous disease markers are available yet.
T42 866059-866177 Sentence denotes The goal of the present study is the construction of a protein database of cerebrospinal fluid (CSF) from MS patients.
T43 866178-866359 Sentence denotes Proteomic approaches are particularly suitable for a molecular dissection of disease phenotypes of the CNS that is largely inaccessible to meaningful mRNA expression based analysis.
T44 866360-866484 Sentence denotes CSF is a secretion product of several CNS structures and its protein profile can be affected by several diseases of the CNS.
T45 866485-866578 Sentence denotes Proteomic analysis of CSF could provide more insight into the pathogenesis of these diseases.
T46 866579-866779 Sentence denotes CSF proteins from relapsingremitting MS patients were sampled and analyzed by means of twodimensional (2-D) gel electrophoresis and 2-D liquid chromatography, both coupled to tandem mass spectrometry.
T47 866780-866893 Sentence denotes The use of these two complementary techniques resulted in the identification of more than 150 different proteins.
T48 866894-866973 Sentence denotes The majority of these proteins have been analyzed already in other CSF studies.
T49 866974-867037 Sentence denotes However, some of these proteins have not been described so far.
T50 867038-867150 Sentence denotes Further investigation will provide additional information on whether they are implicated in the MS pathogenesis.
T51 867151-867250 Sentence denotes The constructed CSF database will be used in our future study on differentially expressed proteins.
T52 867251-867356 Sentence denotes Important applications are the identification of diagnostic, paragnostic and theranostic protein markers.
T53 867357-867415 Sentence denotes The role of the HLA-DR2 haplotype in multiple sclerosis K.
T54 867416-867431 Sentence denotes Kawamura a , L.
T55 867432-867447 Sentence denotes Fugger b and T.
T56 867448-867878 Sentence denotes Forsthuber a a Institute of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; b Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK Multiple sclerosis (MS) is an autoimmune disease strongly associated with the MHC class II genes HLA-DRB1*1501, HLA-DRB5*0101 and HLA-DQB1*0602 which are almost always inherited together as the bHLA-DR2 haplotypeQ.
T57 867879-868109 Sentence denotes The reason for the association of the HLA-DR2 haplotype with MS is unknown, but it has been postulated that these MHC class II genes could be deficient in their ability to induce central or peripheral tolerance to myelin antigens.
T58 868110-868261 Sentence denotes Indeed, T cell responses to myelin antigens are readily detectable in MS patients, indicating that self-tolerance or regulatory mechanisms have failed.
T59 868262-868477 Sentence denotes To understand the role of the HLA-DR2 complex in the induction of tolerance to MBP, we have generated mice that express each of the HLA-DR2 haplotype MHC molecules and are deficient for MBP (MBPÀ/À) or not (MBP+/+).
T60 868478-868682 Sentence denotes The MBP+/+ or MBPÀ/À mice were immunized with human MBP protein and epitope mapping of MBP was performed by cytokine ELISPOT assay with overlapping sets of MBP peptides spanning the complete MBP sequence.
T61 868683-868809 Sentence denotes The epitope mapping showed that MBP84-102 was the immunodominant epitope for MBPdeficient HLA-DRB1*1501 and DRB5*0101 Tg mice.
T62 868810-869024 Sentence denotes Surprisingly, MBP+/+ HLA-DR transgenic mice were tolerant to MBP84-102, suggesting that these MHC class II molecules were not deficient in their ability to induce central or peripheral tolerance to myelin antigens.
T63 869025-869121 Sentence denotes We will suggest an alternative mechanism to account for the role of the HLA-DR2 haplotype in MS.
T64 869122-869175 Sentence denotes Microarrays provide a global view of gene expression.
T65 869176-869351 Sentence denotes In multifactorial diseases with uncertain etiology, they represent a powerful method to disclose unknown causative factors and to place known alterations in the right context.
T66 869352-869455 Sentence denotes However, microarrays are subjected to many variables that complicate the interpretation of the results.
T67 869456-869579 Sentence denotes We tried to limit these variables by studying monozygotic twins (four sets; F/M=3/1, mean age 36.25F3.9) discordant for MS.
T68 869580-869638 Sentence denotes The affected twin was free of immunomodulatory treatments.
T69 869639-869768 Sentence denotes Following leukapheresis, CD4+ and CD8+ T cells were separated and studied by microarrays (Agilent Human 1A Oligo Microarray Kit).
T70 869769-869957 Sentence denotes In the affected co-twins, 10 genes were over-while 22 were underexpressed in CD4+ cells; in CD8+ cells, expression was increased in 74 genes and decreased in 62 (fold change N1.3, pb0.05).
T71 869958-870145 Sentence denotes Differentially expressed genes included transcripts of immunological significance, genes involved in cell structural remodelling and in the regulation of the cellular electrolyte balance.
T72 870146-870225 Sentence denotes Experiments are in progress, on the same material, with an Affymetrix platform.
T73 870226-870345 Sentence denotes So far, the results show that differentially expressed genes CD8+ T cells numerically exceed those of CD4+ lymphocytes.
T74 870346-870395 Sentence denotes Results on the validated genes will be presented.
T75 870396-870448 Sentence denotes Functional genomic analysis in multiple sclerosis J.
T76 870449-870463 Sentence denotes Wuerfel a , A.
T77 870464-870476 Sentence denotes Weber a , J.
T78 870477-870496 Sentence denotes Kraetzschmar b , T.
T79 870497-870515 Sentence denotes Prozorovski a , J.
T80 870516-870538 Sentence denotes Bellmann-Strobl a , O.
T81 870539-870553 Sentence denotes Aktas a , C.S.
T82 870554-870574 Sentence denotes Stuerzebecher b , F.
T83 870575-870588 Sentence denotes Zipp a and C.
T84 870589-870694 Sentence denotes Infante-Duarte a a Institute of Neuroimmunology, Charité, Berlin, Germany; b Schering AG, Berlin, Germany
T85 870695-870886 Sentence denotes Multiple sclerosis (MS) is a complex multifactorial disease characterized by an enormous variability in its clinical presentation and course, in which clear diagnostic parameters are lacking.
T86 870887-871225 Sentence denotes In order to identify a gene expression pattern in peripheral immune cells from MS patients with potential diagnostic and prognostic implications, we performed a largescale gene expression analysis using DNA-microarrays (12,000 genes) in relapsing-remitting (RRMS) and primary progressive (PPMS) patients as well as in healthy individuals.
T87 871226-871348 Sentence denotes The most representative genes differentially regulated in MS were selected according to very stringent selection criteria.
T88 871349-871482 Sentence denotes Ten genes out of these were subsequently used to confirm the array data by real-time rtPCR in an extended control and patient cohort.
T89 871483-871801 Sentence denotes By this approach, we defined an MS expression profile which is characterized by an increased expression of genes involved in cellular activity, chemotaxis, adhesion processes and transendothelial migration, and by a diminished expression of factors related to regulation of B-cell response and response to interferons.
T90 871802-871896 Sentence denotes No factors distinguishing between RRMS and PPMS were detected applying our selection criteria.
T91 871897-872171 Sentence denotes The identified expression profile indicates important aspects of the MS pathophysiology, highlighting the role of transendothelial migration as well as B-cell and IFN-related processes in MS immunopathology and offers a basis for the development of diagnostic markers in MS.
T92 872172-872261 Sentence denotes Human endogenous retrovirus-W envelope abundance and infectivity in multiple sclerosis J.
T93 872262-872275 Sentence denotes Antony a , M.
T94 872276-872287 Sentence denotes Izad b , K.
T95 872288-872300 Sentence denotes Zhang a , K.
T96 872301-872314 Sentence denotes Warren c , M.
T97 872315-872332 Sentence denotes Vodjgani b and C.
T98 872333-872487 Sentence denotes Power a a University of Calgary, Calgary, AB, Canada; b Tehran University of Medical Sciences, Tehran, Iran; c University of Alberta, Edmonton, AB, Canada
T99 872488-872618 Sentence denotes Human endogenous retroviruses (HERVs) constitute 8% of the human genome yet their role (s) in health and disease remain uncertain.
T100 872619-872831 Sentence denotes To determine if disease status is associated with HERV-W envelope (env) abundance, we developed an HERV-W env PCR-based viral load assay for quantitation of provirus and viral RNA copy numbers in brain and blood.
T101 872832-873074 Sentence denotes Proviral copy number in blood (9.9F8.3 log10 copies/mg DNA) and brain (8F7.3 log10 copies/mg DNA) was significantly increased ( pb0.05) in MS patients (n=33) compared to controls (n=31) (8.6F7.8 and 7.11F6.7 log10 copies/mg DNA respectively).
T102 873075-873230 Sentence denotes In addition, viral RNA levels in brain of MS patients (n=7) (7.9F7.1 log10 copies/mg RNA) were higher than in controls (n=3) (7.6F6.7 log10 copies/mg RNA).
T103 873231-873467 Sentence denotes Whether this increased HERV-W env copy number reflected increased infectivity of neural cells was examined by infection of human brain-derived cells by a pseudotyped virus consisting of the HERV-W envelope and an envelope-deleted HIV-1.
T104 873468-873614 Sentence denotes Pseudotyped virus infected only astrocytes and macrophages but not neurons despite expression of the putative HERV-W receptor, ASCT2 in all cells.
T105 873615-873853 Sentence denotes These data indicate both HERV-W env provirus and viral RNA levels are increased in MS patients, which may reflect infectivity mediated by HERV-W envelope in astrocytes and macrophages, likely driven by concurrent innate immune activation.
T106 873854-873984 Sentence denotes Expression and modulation by cytokines of multiple sclerosis (MS)associated retrovirus (MSRV): epiphenomenon or pathogenic factor?
T107 873985-873987 Sentence denotes C.
T108 873988-874000 Sentence denotes Serra a , G.
T109 874001-874014 Sentence denotes Mameli a , G.
T110 874015-874026 Sentence denotes Arru b , V.
T111 874027-874040 Sentence denotes Astone a , S.
T112 874041-874056 Sentence denotes Sotgiu b and A.
T113 874057-874238 Sentence denotes Dolei a a Section of Microbiology, Department of Biomedical Sciences, University of Sassari, Sassari, Italy; b Institute of Clinical Neurology, University of Sassari, Sassari, Italy
T114 874239-874370 Sentence denotes Multiple sclerosis (MS) has unknown etiology and debated, immunemediated pathogenesis, including genetic and environmental factors.
T115 874371-874567 Sentence denotes Several viruses were suggested to be involved, particularly HHV-6 and MSRV, a member of the HERV-W family of human endogenous retroviruses, with gliotoxic, fusogenic and superantigenic properties.
T116 874568-874682 Sentence denotes Extracellular MSRV is detectable in plasma of 100% MS patients from Sardinia, Italian island at very high MS risk.
T117 874683-874815 Sentence denotes Patients with MSRV-free CSF remain stable, whereas those with MSRV-positive CSF disclose a more severe, treatment-requiring disease.
T118 874816-875074 Sentence denotes We selected MSRV(+) and MRSV(À) healthy volunteers to evaluate the effects on MSRV release by cultured PBMC exerted by cytokines supposed to have detrimental or beneficial effects on MS immunopathogenesis, evaluating virionic RNAs by semiquantitative RT-PCR.
T119 875075-875223 Sentence denotes Data show that cultured PBMC from MSRV(+) donors spontaneously release MSRV that accumulates with time and with mitogens, and is cytokine-sensitive.
T120 875224-875350 Sentence denotes The highest effects are seen with the MS-detrimental TNF-alpha and IFN-gamma cytokines, while IFN-beta is strongly inhibitory.
T121 875351-875445 Sentence denotes PBMC from MSRV(À) individuals do not release MSRV, neither spontaneously nor after treatments.
T122 875446-875628 Sentence denotes Although MSRV role in MS is still not defined, an intriguing parallelism between the effects of the above cytokines on MSRV production in vitro and on MS disease in vivo is observed.
T123 875629-875738 Sentence denotes Multiple sclerosis associated retrovirus (MSRV) seems to be the important candidate for viral etiology of MS.
T124 875739-875819 Sentence denotes The aim of the study was to analyze MSRV pol sequences in MS and control groups.
T125 875820-875898 Sentence denotes In the serum RNA MSRV pol sequences have been identified in 31/32 MS patients.
T126 875899-876068 Sentence denotes MSRV pol sequences were detected in serum cDNA of 9/17 myasthenia gravis patients, 7/16 with Parkinson's disease, 10/21 migraine patients, and 13/27 healthy individuals.
T127 876069-876272 Sentence denotes MSRV pol sequences were observed also in RNA from lymphocytes of all MS patients, 12/17 myasthenia gravis patients, 9/16 with Parkinson's disease, 14/21 migraine patients and 18 out of 27 healthy donors.
T128 876273-876340 Sentence denotes In genomic DNA of all studied cases, MSRV pol sequences were found.
T129 876341-876472 Sentence denotes The pattern of fiber-FISH signals suggests the presence of multiple copies of MSRV pol sequences, tandemly dispersed in the genome.
T130 876473-876664 Sentence denotes It can be concluded that MSRV pol sequences are endogenous, widespread in lymphocytes DNA and transcribed into RNA of MS patients as well as of other studied patients and healthy individuals.
T131 876665-876882 Sentence denotes However, more frequent expression of MSRV sequences detected in lymphocytes RNA, as well as their presence in higher frequency in serum of MS patients may suggest the involvement of MSRV in the etiopathogenesis on MS.
T132 876883-877007 Sentence denotes Clonally expanded CD8 populations have been identified in brain specimens, peripheral blood and the CSF of patients with MS.
T133 877008-877140 Sentence denotes Although their antigen-specificity is unknown to date, genuine CNS autoantigen(s) or viral antigens are the most obvious candidates.
T134 877141-877251 Sentence denotes Notably, disease onset and exacerbations have been correlated to concomitant viral infections, especially EBV.
T135 877252-877343 Sentence denotes MHC-class-I tetramers were synthesized for dominant epitopes of EBV and CMV herpes viruses.
T136 877344-877572 Sentence denotes Antigen-specific T cells were analyzed by multicolour flow-cytometry in the peripheral blood of MS patients and controls; 28 MS patients were compared with 24 healthy donors (HD) using an HLA-B7 EBV peptide (RPPIFIRRL) tetramer.
T137 877573-877695 Sentence denotes Whereas 93% of the MS patients showed reactivity to this dominant EBV epitope, only 15 out of 24 HD (62.5%) were positive.
T138 877696-877816 Sentence denotes Additionally, frequency of EBVreactive CD8-cells in the MS group was higher than in controls (mean 0.52% against 0.12%).
T139 877817-877941 Sentence denotes EBV-specific CD8-T cells predominantly belonged to the effector memory phenotype as assessed by costaining with CD45RA/CCR7.
T140 877942-878073 Sentence denotes Overall, MS patients showed a significant downregulation of CD28 in EBVreactive CD8-cells suggesting a chronic in vivo stimulation.
T141 878074-878213 Sentence denotes In two out of seven patients with acute relapses, the majority of EBV-reactive T-cells consisted of CD45RA+/CCR7À cytotoxic effector cells.
T142 878214-878320 Sentence denotes In contrast to EBV, CMV-specific CD8-T cells did not show significant differences between MS and controls.
T143 878321-878500 Sentence denotes Taken together, EBV-specific CD8-T cells in MS patients differ from HD in their frequency and phenotype further corroborating their putative involvement in the immunopathogenesis.
T144 878501-878668 Sentence denotes CD8 T cells from acute multiple sclerosis patients display selective increase of adhesiveness in brain venules: a critical role for P-selectin glycoprotein ligand-1 L.
T145 878669-878682 Sentence denotes Piccio a , L.
T146 878683-878700 Sentence denotes Battistini c , B.
T147 878701-878713 Sentence denotes Rossi a , S.
T148 878714-878725 Sentence denotes Bach a , L.
T149 878726-878741 Sentence denotes Ottoboni a , E.
T150 878742-878757 Sentence denotes Scarpini b , G.
T151 878758-878777 Sentence denotes Borsellino c and G.
T152 878778-879021 Sentence denotes Constantin a a University of Verona, Verona, Italy; b University of Milan, Milan, Italy; c IRCCS Santa Lucia Foundation, Rome, Italy Lymphocyte migration into the brain represents a critical step in the pathogenesis of multiple sclerosis (MS).
T153 879022-879138 Sentence denotes CD4 and CD8 T cells were obtained from healthy donors and relapsing-remitting (RR) MS patients at the relapse onset.
T154 879139-879199 Sentence denotes Adhesion molecules expression was studied by flow cytometry.
T155 879200-879273 Sentence denotes Intravital microscopy studies and in vitro rolling assays were performed.
T156 879274-879437 Sentence denotes In patients with RRMS CD8, but not CD4, T cells display increased rolling and arrest in inflamed murine brain venules and increased rolling on P-selectin in vitro.
T157 879438-879535 Sentence denotes Anti-l-selectin antibodies block the recruitment of CD8 and CD4 T cells from MS patients in vivo.
T158 879536-879678 Sentence denotes Anti-P-selectin glycoprotein ligand-1 (PSGL-1) antibodies dramatically inhibit the recruitment of CD8 cells from MS patients in brain vessels.
T159 879679-879808 Sentence denotes Moreover, vascular cell adhesion molecule-1 (VCAM-1), but not PSGL-1, is critical for the adhesion of CD4 cells from MS patients.
T160 879809-879940 Sentence denotes FACS analysis and functional data indicate that a large fraction of CD8 cells from MS patients display a memory-effector phenotype.
T161 879941-880093 Sentence denotes Our results show that CD8, but not CD4, T cells from MS patients in the acute phase display increased ability to be recruited in inflamed brain venules.
T162 880094-880163 Sentence denotes PSGL-1 is a key molecule mediating CD8 cell migration into the brain.
T163 880164-880353 Sentence denotes The dichotomy in the adhesion mechanisms of CD8 versus CD4 lymphocytes provides important information for the selective blocking of the recruitment of lymphocyte subpopulations in acute MS.
T164 880354-880421 Sentence denotes Dopamine fails to regulate T cell activation in multiple sclerosis.
T165 880422-880444 Sentence denotes Effects of IFN beta M.
T166 880445-880457 Sentence denotes Giorelli, P.
T167 880458-880471 Sentence denotes Livrea and M.
T168 880472-880575 Sentence denotes Trojano Department of Neurological and Psychiatric Sciences, University of Bari, Bari, Italy Objective:
T169 880576-880692 Sentence denotes To assess whether the dopamine network of lymphocytes is involved in the pathophysiology of Multiple Sclerosis (MS).
T170 880693-880701 Sentence denotes Methods:
T171 880702-880980 Sentence denotes Peripheral blood mononuclear cells (PBMCs) were isolated from 14 stable relapsing-remitting MS patients, 6 relapsing MS patients, 13 IFNbeta-1a (8) or IFNbeta-1b (5) treated MS patients, 6 patients affected from Other Inflammatory Neurological Diseases, and 11 healthy controls.
T172 880981-881187 Sentence denotes We assessed the expression of dopamine receptors (D3R, D5R), and investigated the dopamine (0.001-1 Ag/ml) capability to regulate T cell proliferation, expression of IFN gamma, MMP-9, and Th1/Th2 cytokines.
T173 881188-881196 Sentence denotes Results:
T174 881197-881295 Sentence denotes The D5R was reduced in PBMCs from both stable and IFNbeta treated MS patients ( pb0.0001 to 0.05).
T175 881296-881458 Sentence denotes The D3R was expressed at normal levels in PBMCs from stable MS patients, but it was reduced in PBMCs from MS patients undergoing to IFNbeta treatment ( pb0.0001).
T176 881459-881595 Sentence denotes Dopamine inhibited T cell proliferation, MMP-9 expression, and enhanced T1/Th2 cytokines mRNA in PBMCs from HD but not from MS patients.
T177 881596-881699 Sentence denotes Differently, the regulatory effects of dopamine were renewed in PBMCs from IFNbeta treated MS patients.
T178 881700-881712 Sentence denotes Conclusions:
T179 881713-881924 Sentence denotes Differential expression of the dopamine receptors subtypes D5R and D3R underlies the loss of the inhibitory effects of dopamine on T cell proliferation, expression of MMP-9 mRNA and secretion of IFN gamma in MS.
T180 881925-882059 Sentence denotes Availability of agonists/antagonists for dopamine receptors and effects of IFNbeta might open novel paths to therapeutic intervention.
T181 882060-882307 Sentence denotes In humans, T cells that utilize a Vdelta2Vgamma9 T cell receptor respond to phosphate antigens found in pathogens such as Mycobacterium tuberculosis by rapidly producing large amounts of proinflammatory cytokines, chemokines and cytotoxic factors.
T182 882308-882544 Sentence denotes For this reason, they have been implicated as contributors to inflammatory diseases, and depletion of gamma-delta T cells in mice delays or protects against experimental autoimmune encephalomyelitis, a model for multiple sclerosis (MS).
T183 882545-882857 Sentence denotes Using transcriptional profiling of phosphate-antigenactivated Vdelta2 cells, we observed potent upregulation of proinflammatory cytokines and cytotoxic factors, but also noted upregulation of the vitamin D receptor (VDR) and confirmed by western blotting that was dependent on the PKC and ERK signaling pathways.
T184 882858-882992 Sentence denotes The VDR has been implicated in downregulation of Th1-type cells by promoting the production of regulatory activity of dendritic cells.
T185 882993-883051 Sentence denotes Less is known about the direct effects of VitD on T cells.
T186 883052-883153 Sentence denotes We now show that VitD significantly reduced IPP-induced IFNgamma, CD25 expression and IL-2-signaling.
T187 883154-883246 Sentence denotes VitD also increased activation-induced cell death, as determined by indicators of apoptosis.
T188 883247-883388 Sentence denotes Given the recent data that support a protective effect of VitD intake on the risk of developing MS (Munger, K.L. et al., Neurology, 2004; 62:
T189 883389-883530 Sentence denotes 60) , our results suggest that effects of VitD on reducing the proinflammatory activity of gamma-delta T cells may contribute to this effect.
T190 883531-883694 Sentence denotes Spreading of autoreactivity from antigens present in the thyroid gland to the spinal cord or vice versa: an alternative pathogenic mechanism in multiple sclerosis?
T191 883695-883699 Sentence denotes J.M.
T192 883700-883714 Sentence denotes Greer and M.P.
T193 883715-883767 Sentence denotes Pender University of Queensland, Brisbane, Australia
T194 883768-883893 Sentence denotes We have identified a subgroup of patients with multiple sclerosis (MS) who have coexistent autoimmune thyroid disease (AITD).
T195 883894-883956 Sentence denotes In most patients, the AITD developed prior to the onset of MS.
T196 883957-884144 Sentence denotes All of these patients have shown predominant involvement of the spinal cord from the outset of their MS, with much less involvement of the cerebrum and optic nerves than is normally seen.
T197 884145-884252 Sentence denotes These patients also have a high prevalence of autoimmune disease (especially AITD) in their family members.
T198 884253-884498 Sentence denotes Class II HLA alleles carried by the patients are linked to the autoimmune disease that first arises in these patients, i.e. patients who develop MS first tend to carry HLA-DRB1*1501, whereas patients who first develop AITD carry DR3, DR4 or DR7.
T199 884499-884698 Sentence denotes Increased T cell and antibody reactivity can be detected in these patients against several antigens that are present predominantly, but not exclusively, in both the spinal cord and the thyroid gland.
T200 884699-884789 Sentence denotes Increased reactivity to these antigens is not found in patients with only MS or only AITD.
T201 884790-884996 Sentence denotes These findings suggest the possibility of interorgan spread of autoimmunity from the thyroid gland to the nervous system or vice versa in individuals who have a genetic susceptibility to autoimmune disease.
T202 884997-885080 Sentence denotes Expression of K+ channels by CD4+ T-lymphocytes from multiple sclerosis patients P.
T203 885081-885096 Sentence denotes Sarchielli , L.
T204 885097-885106 Sentence denotes Greco, A.
T205 885107-885122 Sentence denotes Candeliere, Ar.
T206 885123-885135 Sentence denotes Floridi, Al.
T207 885136-885150 Sentence denotes Floridi and G.
T208 885151-885202 Sentence denotes Capocchi University of Perugia, Perugia, Italy Aim:
T209 885203-885357 Sentence denotes This study was aimed to assess the expression of K+ channel Kv1.3 mRNA levels by CD4+ cells in patients with relapsing-remitting (R-R) multiple sclerosis.
T210 885358-885379 Sentence denotes Patients and methods:
T211 885380-885480 Sentence denotes 15 R-R MS patients were assessed in a stable clinical phase and 15 R-R MS patients during a relapse.
T212 885481-885547 Sentence denotes The control group consisted of 15 age-matched healthy individuals.
T213 885548-885727 Sentence denotes Expression of KTv1.3 was assessed by RT-PCR, lymphocyte proliferation assay, measurement of IL-2 and IFN-gamma by ELISA and Ca+ measurement by Fura-2 method were also carried out.
T214 885728-885885 Sentence denotes Results: RT-PCR analysis showed a higher expression of the KTv1.3 band in CD4+ Tcells of MS patients, particularly during relapses, than in healthy controls.
T215 885886-885955 Sentence denotes The higher expression of KTv1.3 band was present in MBP+ CD4+ Tcells.
T216 885956-886103 Sentence denotes K+ blockers KTXK, ShK, Shk-Dap and MgTx all inhibited mitogen-and antigen-specific proliferation of total CD4+ and MBP+CD4+ T cells in MS patients.
T217 886104-886200 Sentence denotes The same K+ blockers also reduced Ca+ intracellular levels and production of IL-2 and IFN-gamma.
T218 886201-886212 Sentence denotes Discussion:
T219 886213-886375 Sentence denotes We confirmed the expression of Kv1.3 channel by CD4+ T-cells and MBP+ encephalitogenic T cells of MS patients particularly during the active phase of the disease.
T220 886376-886517 Sentence denotes These channels can be a relevant target for immunosuppression and blockers of these channels can be putative drug candidates for treating MS.
T221 886518-886657 Sentence denotes Multiple Sclerosis is an autoimmune disorder of the Central Nervous System, in which the immune attack is directed against myelin antigens.
T222 886658-886756 Sentence denotes A role for both gamma/delta T lymphocytes and NK cells in disease pathogenesis has been suggested.
T223 886757-886941 Sentence denotes Upon exposure to phosphoantigens, human Vdelta2 T lymphocytes enter a lineage differentiation pattern that determines the generation of memory cells with a range of effector functions.
T224 886942-887160 Sentence denotes Here, we show that within the effector memory Vdelta2 population, based on expression of CD16 two distinct and complementary subsets with regard to phenotype, mode of activation and type of responses can be identified:
T225 887161-887203 Sentence denotes Vdelta2TEMh cells, and Vdelta2TEMRA cells.
T226 887204-887341 Sentence denotes The latter are refractory to phosphoantigen but respond to activation via FcgammaRIII and are highly active against tumoral target cells.
T227 887342-887432 Sentence denotes CD16+ gamma/delta cells likely represent the final differentiation step of effector cells.
T228 887433-887617 Sentence denotes Interestingly, on a cohort of 27 MS patients, we have found an expansion of the CD16+ fraction within the Vdelta2 T cell population: implications on disease pathogenesis are discussed.
T229 887618-887697 Sentence denotes Dendritic cells (DCs) are essential in orchestration of immunity and tolerance.
T230 887698-887843 Sentence denotes We investigated, if the immunoregulatory function of freshly isolated plasmacytoid dendritic cells (pDCs) is impaired in multiple sclerosis (MS).
T231 887844-887908 Sentence denotes We studied pDCs from untreated MS patients and healthy controls.
T232 887909-888178 Sentence denotes In an allogenic co-culture assay with irradiated peripheral blood mononuclear cells (PBMCs) always obtained from the same healthy donor, increasing ratios of pDCs (1:100, 1:20 and 1:10) were added to autologous PBMCs (=effector cells) that were before depleted of pDCs.
T233 888179-888240 Sentence denotes The response of effector cells was measured by proliferation.
T234 888241-888364 Sentence denotes Proliferation was calculated as stimulation index (SI) representing the x-fold increase compared to PBMCs depleted of pDCs.
T235 888365-888491 Sentence denotes We found a dose dependent increase in proliferation by adding increasing numbers of pDCs in co-cultures from healthy controls.
T236 888492-888595 Sentence denotes Increases were 1.2-fold (SDF0.3) for pDCs 1:100, 1.7 (F0.6) for pDCs 1:20 and 2.2 (F1.3) for pDCs 1:10.
T237 888596-888652 Sentence denotes In MS patients, no modulatory effects could be observed.
T238 888653-888791 Sentence denotes There was a statistically significant difference between MS and controls for the pDC ratios 1:20 and 1:10 ( pb0,007, Mann-Whitney U-test).
T239 888792-888946 Sentence denotes In co-cultures supplemented with IL3, we also found a dose dependent difference between MS patients and controls reaching significance for the 1:20 ratio.
T240 888947-889116 Sentence denotes Our results demonstrate that pDCs derived from MS patients have an altered regulatory function compared to controls that may have an influence on immune imbalance in MS.
T241 889117-889192 Sentence denotes Reactivation of immune response causes increased cerebral blood volume K.A.
T242 889193-889205 Sentence denotes Broom a , D.
T243 889206-889220 Sentence denotes Anthony b , A.
T244 889221-889235 Sentence denotes Blamire a , S.
T245 889236-889251 Sentence denotes Waters b , V.H.
T246 889252-889264 Sentence denotes Perry b , P.
T247 889265-889280 Sentence denotes Styles a and N.
T248 889281-889472 Sentence denotes Sibson a a University of Oxford, Oxford, UK; b University of Southampton, Southampton, UK It has long been postulated that environmental factors cause exacerbation of multiple sclerosis (MS).
T249 889473-889818 Sentence denotes We have used Magnetic Resonance Imaging (MRI) to investigate whether systemic inflammation, induced by peritoneal injection of bacterial cell wall products, can reactivate a quiescent CNS lesion bearing many of the hallmarks of an MS lesion; 5Â10 5 heat-killed BCG organisms/Al were injected stereotaxically into the striatum of male Lewis rats.
T250 889819-889956 Sentence denotes Additionally, 0.2 Al of BCG was deposited on the cortical surface to initiate a spontaneous delayed type hypersensitivity (DTH) response.
T251 889957-890072 Sentence denotes Once the lesion had resolved (day 42), 100 Ag/ml (i.p.) of E. coli lipopolysaccharide (LPS) endotoxin was injected.
T252 890073-890172 Sentence denotes MRI was performed throughout the acute DTH response and following LPS challenge at 6, 24, and 72 h.
T253 890173-890418 Sentence denotes The initial intracerebral injection caused an acute DTH inflammatory response, including an~8-fold increase in regional cerebral blood volume (rCBV), blood-brain barrier (BBB) breakdown, and oedema accumulation, all of which resolved by 42 days.
T254 890419-890567 Sentence denotes At 6 h after LPS challenge, a new increase in rCBV was observed throughout the injected striatum ( pb0.005 when compared with pre-challenge values).
T255 890568-890649 Sentence denotes Additionally, increased BBB permeability was observed 24-72 h post-LPS challenge.
T256 890650-890814 Sentence denotes We have shown that a systemic inflammatory response can reactivate a Th1-dominated DTH lesion in the rodent brain, by increasing rCBV and altering BBB permeability.
T257 890815-890968 Sentence denotes These findings may have implications for MS patients, and suggest that monitoring regional perfusion may be valuable in detecting early CNS inflammation.
T258 890969-891083 Sentence denotes During the course of Multiple Sclerosis (MS), the gene expression levels of some immune system genes are modified.
T259 891084-891267 Sentence denotes The aim of this study was to assess the differences in gene expression levels for a set of eight immune system genes in peripheral blood mononuclear cells (PBMCs) in patients with MS.
T260 891268-891466 Sentence denotes We assessed the gene expression levels of HLA-DQB1, HLA-DRA, IFN-gamma, IL4, TNF-alpha, IDO, soluble CTLA4 and full length CTLA4 in PBMCs from 20 MS patients and 20 healthy controls by realtime PCR.
T261 891467-891663 Sentence denotes We found that the gene expression levels of IFN-gamma were significantly lower in patients than in controls ( p=0.018) and the ratio IFNgamma/IL4 was significantly lower in MS patients ( p=0.028).
T262 891664-891849 Sentence denotes We also found a correlation between IFN-gamma and TNF-alpha expression levels in both groups ( p=0.041, r=0.46) and a reduction of the ratio IFN-gamma/ TNF-alpha in patients ( p=0.037).
T263 891850-891939 Sentence denotes Finally, IFN-gamma levels were lower in untreated than in treated MS patients ( p=0.030).
T264 891940-892009 Sentence denotes No differences were found between groups for the other studied genes.
T265 892010-892090 Sentence denotes Our results show an imbalance of Th1 cytokines in the PBMCs of patients with MS.
T266 892091-892250 Sentence denotes Whether such decrease indicates that IFN-gamma producing cells are decreased or sequestered in peripheral tissues (such as the brain) requires further studies.
T267 892251-892420 Sentence denotes Cerebrospinal fluid and serum levels and intrathecal production of active matrix metalloproteinase-9 are elevated in multiple sclerosis patients with disease activity M.
T268 892421-892436 Sentence denotes Castellazzi, T.
T269 892437-892450 Sentence denotes Bellini, M.C.
T270 892451-892465 Sentence denotes Manfrinato, E.
T271 892466-892475 Sentence denotes Baldi, E.
T272 892476-892487 Sentence denotes Paolino, E.
T273 892488-892500 Sentence denotes Granieri, F.
T274 892501-892519 Sentence denotes Dall'occhio and E.
T275 892520-892566 Sentence denotes Fainardi University of Ferrara, Ferrara, Italy
T276 892567-893090 Sentence denotes We measured cerebrospinal fluid (CSF) and serum levels of matrix metalloproteinase-9 (MMP-9) and their tissue inhibitor TIMP-1 by Activity Assay System ELISA, respectively, in 37 relapsing-remitting (RR), 15 secondary progressive (SP) and 9 primary progressive (PP) multiple sclerosis (MS) patients, stratified according to clinical and Magnetic Resonance Imaging (MRI) evidence of disease activity, and in 96 patients with other inflammatory neurological disorders (OIND) and noninflammatory neurological disorders (NIND).
T277 893091-893291 Sentence denotes Intrathecal synthesis of active MMP-9 were more frequent in MS than in NIND ( pb0.02) and in clinically and MRI active than in clinically and MRI stable MS patients ( pb0.05 and pb0.02, respectively).
T278 893292-893466 Sentence denotes Serum active MMP-9/TIMP-1 ratio were higher in MS and OIND than in NIND ( pb0.02) and in clinically and MRI active than in clinically and MRI inactive MS patients ( pb0.001).
T279 893467-893603 Sentence denotes CSF active MMP-9/TIMP-1 ratio was more elevated in MS than in NIND ( pb0.02) and in MRI active than in MRI stable MS patients ( pb0.01).
T280 893604-893800 Sentence denotes Our results suggests that an intrathecal synthesis of active form of MMP-9 could represent a sensitive marker of disease activity in MS in association with CSF and serum active MMP-9/TIMP-1 ratio.
T281 893801-893934 Sentence denotes Brain plaques from patients with multiple sclerosis (MS) of short duration contain oligoclonal populations of infiltrating T cells X.
T282 893935-893946 Sentence denotes Zhang, W.L.
T283 893947-893954 Sentence denotes Lin, C.
T284 893955-893972 Sentence denotes Platsoucas and E.
T285 893973-894017 Sentence denotes Oleszak Temple University, Philadelphia, USA
T286 894018-894279 Sentence denotes We have amplified by NPA-PCR and/or Valpha-or Vbeta-specific PCR alpha-and beta-chain TCR transcripts of T cells infiltrating acutely demyelinating brain lesions of four patients with chronic progressive MS who died within 2 to 8 years after clinical diagnosis.
T287 894280-894332 Sentence denotes The amplified transcripts were cloned and sequenced.
T288 894333-894483 Sentence denotes Sequence analysis revealed multiple identical copies of TCR transcripts, strongly suggesting the presence of clonally expanded populations of T cells.
T289 894484-894710 Sentence denotes Limited numbers (1-2) of clonally expanded T-cell clones have been found in brain plaques from patients who died 2 years after diagnosis or from patients who died of acute or severe necrotizing MS 6 to 7 years after diagnosis.
T290 894711-894951 Sentence denotes In contrast several alpha (Valpha9, Valpha22, Valpha23, and Valpha24)and beta-chain (Vbeta3, Vbeta13, Vbeta14 and Vbeta5) TCR transcripts were clonally expanded in brain plaques from a patient who died of chronic MS 8 years after diagnosis.
T291 894952-895148 Sentence denotes These results demonstrate the presence of oligoclonal populations of T cells in brain plaques from these patients with chronic progressive MS, comprised of a few numbers of expanded T-cell clones.
T292 895149-895240 Sentence denotes Multiple sclerosis is considered to predominantly affect the white matter of the human CNS.
T293 895241-895320 Sentence denotes However, demyelination of grey matter structures is prominent in some MS cases.
T294 895321-895484 Sentence denotes In the present study, we systematically analyzed cortical demyelinated plaques in a large sample of multiple sclerosis brains from different stages of the disease.
T295 895485-895686 Sentence denotes Hemispheric and double hemispheric paraffin-embedded tissue sections were examined for cortical demyelination and offered the unique opportunity to evaluate disease involvement of large cortical areas.
T296 895687-895894 Sentence denotes Demyelinated plaques-in both the cerebral and cerebellar cortex-were abundant in patients with primary or secondary progressive MS, but were virtually absent in patients with acute or relapsing-remitting MS.
T297 895895-895982 Sentence denotes The extent of demyelination in the white matter was almost the same in the four groups.
T298 895983-896210 Sentence denotes Additionally, in primary and secondary MS a characteristic pallor of the myelin of the normal appearing white matter was observed, which was associated with significant inflammation and also microglia and macrophage activation.
T299 896211-896275 Sentence denotes These pathological changes were absent in acute and RRMS brains.
T300 896276-896547 Sentence denotes Incidence and distribution of cortical lesions and diffuse white matter injury in multiple sclerosis may be pathological correlates of disease progression and suggest that fundamentally different pathological mechanisms may play a role in different stages of the disease.
T301 896548-896624 Sentence denotes In vivo dynamic neuropathology of brain new lesions in multiple sclerosis A.
T302 896625-896640 Sentence denotes Barilaro a , F.
T303 896641-896655 Sentence denotes Zellini a , F.
T304 896656-896669 Sentence denotes Caleri a , A.
T305 896670-896684 Sentence denotes Passeri a , C.
T306 896685-896701 Sentence denotes Gasperini b , C.
T307 896702-896719 Sentence denotes Pozzilli c and L.
T308 896720-896870 Sentence denotes Massacesi a a University of Florence, Florence, Italy; b San Camillo Forlanini Hospital, Rome, Italy; c University of Rome b La SapienzaQ, Rome, Italy
T309 896871-897069 Sentence denotes The present study describes in relapsing-remitting multiple sclerosis (MS) patients, the natural history of new brain lesions visualized with Gd enhanced (Gd+) MRI scans by two different Gd dosages.
T310 897070-897213 Sentence denotes Persistent lesions were evaluated monthly for 6 months and once more after 6 months; other persistent lesions were analyzed weekly for 6 weeks.
T311 897214-897326 Sentence denotes In each lesion, two different enhancing volumes were observed according to the different Gd dosage administered.
T312 897327-897488 Sentence denotes These volumes were smaller than the volume evaluated at the same time with the T2 w scan, but larger than the corresponding T2 outcome evaluated after N6 months.
T313 897489-897594 Sentence denotes Therefore, during the acute phase, tissue damaging factor(s) are present mainly in the centre of lesions.
T314 897595-897797 Sentence denotes Interpolating the volume kinetic of each lesion, with a multiparametric fitting suitable for representing diffusive expansion and contraction biological phenomena, random walk type curves were obtained.
T315 897798-897897 Sentence denotes Noteworthy kinetic of the T2 volumes was the result of two different kinetics, in part overlapping.
T316 897898-898044 Sentence denotes Correlation of the T2 outcome of each lesion with the corresponding enhancing lesion, was high provided that the zenith Gd+ volume was considered.
T317 898045-898161 Sentence denotes This correlation was usually high also in each patient, and patient specific correlation coefficients were observed.
T318 898162-898235 Sentence denotes These data indicate that brain MS lesions follow common biological rules.
T319 898236-898494 Sentence denotes In addition, these data indicate that the T2 outcome correlates with the corresponding Gd+ lesion, better than previously reported. are an effort to simplify the diagnostic process of MS and to incorporate magnetic resonance imaging (MRI) into the diagnosis.
T320 898495-898615 Sentence denotes Diagnosis continues to require two attacks separated in space and time but can utilize MRI to establish new MS activity.
T321 898616-898752 Sentence denotes Cerebrospinal fluid (CSF) analysis and evoked potentials studies may still be employed to provide paraclinical evidence of the diseases.
T322 898753-898775 Sentence denotes Materials and methods:
T323 898776-898933 Sentence denotes We measured tau protein and beta-amyloid42 concentrations in CSF in patients with MS and control group of patients and the results were statistical analysed.
T324 898934-899046 Sentence denotes Tau protein and beta-amyloid42 were measured by a double antibody sandwich ELISA (Innogenetics, Ghent, Belgium).
T325 899047-899055 Sentence denotes Results:
T326 899056-899124 Sentence denotes The outcomes of diagnostic process decided patients into two groups.
T327 899125-899224 Sentence denotes The CSF tau and beta-amyloid42 concentrations of patients with MS were not different from controls.
T328 899225-899309 Sentence denotes We did not find a correlation with age of patients and with duration of the disease.
T329 899310-899322 Sentence denotes Conclusions:
T330 899323-899453 Sentence denotes The concentrations of tau protein and beta-amyloid42 in two groups of patients with and without MS were not statistical different.
T331 899454-899536 Sentence denotes The role of immune mechanisms in multiple sclerosis (MS) patients with epilepsy D.
T332 899537-899554 Sentence denotes Kountouris and K.
T333 899555-899629 Sentence denotes Koutsobelis Neurological and Diagnostic Center, Athens, Greece Background:
T334 899630-899728 Sentence denotes The aim of this study was to check any role of the immune mechanisms in MS patients with epilepsy.
T335 899729-899736 Sentence denotes Method:
T336 899737-899965 Sentence denotes Electroencephalograms (EEG) and sleep EEGs were performed in eight MS patients (two males and six females) with epilepsy of mean disease duration 8.4F3.6 years at different stages of the disease and in a period of 1 year's time.
T337 899966-900091 Sentence denotes The partially pathological EEG findings and the immunological parameters were collected and assessed at the end of the study.
T338 900092-900144 Sentence denotes The Kurtzky EPSS were also taken into consideration.
T339 900145-900153 Sentence denotes Results:
T340 900154-900263 Sentence denotes We found a significant increase of CD8 and lymphocytes in relation to the sleep EEG and EDSS findings pb0.05.
T341 900264-900342 Sentence denotes We also noticed an analogy between the clinical symptoms and the EEG findings.
T342 900343-900354 Sentence denotes Conclusion:
T343 900355-900510 Sentence denotes The results showed that in MS patients with epilepsy, deterioration of the general clinical image and the EEG is due to occasional immunological disorders.
T344 900511-900563 Sentence denotes Therefore, treatment should be accordingly directed.
T345 900564-900627 Sentence denotes Multiple sclerosis associated with other autoimmune diseases T.
T346 900628-900649 Sentence denotes Petkovska-Boskova, V.
T347 900650-900666 Sentence denotes Bojkovski and V.
T348 900667-900706 Sentence denotes Daskalovska Clinical Centre, Skopje, R.
T349 900707-900728 Sentence denotes Macedonia Background:
T350 900729-900861 Sentence denotes Multiple sclerosis (MS) is commonly associated with other autoimmune diseases, such as: uveitis, thyreoiditis, Crohn's disease, etc.
T351 900862-900875 Sentence denotes Case history:
T352 900876-900914 Sentence denotes We present seven cases of definite MS.
T353 900915-901223 Sentence denotes Three of them, in whom the disease has been ranged 5 to 7 years, developed uveitis, one patient with relapsing-remitting (R-R) MS, presented two attacks of erythema nodosum (EN), one of them developed Crohn's disease, 3 years after diagnosing MS, another one after 10-year duration of psoriasis developed MS.
T354 901224-901307 Sentence denotes The last one presented coexistence of diabetes mellitus type 1, and R-R form of MS.
T355 901308-901355 Sentence denotes The mean disability degree was 2.0 by the EDSS.
T356 901356-901367 Sentence denotes Conclusion:
T357 901368-901466 Sentence denotes Intermediate uveitis may belong to a constellation of HLA-DR15 related disorders which include MS.
T358 901467-901640 Sentence denotes Although MS and chronic inflammatory bowel disease (IBD) may share common predisposing factors, unsufficient information is available to speculate about possible mechanisms.
T359 901641-901771 Sentence denotes If an individual has a genetic susceptibility to infections, the downregulation of an inflammation does not occur in a proper way.
T360 901772-901846 Sentence denotes This initiates the autoimmune process EN which is a self-increasing cycle.
T361 901847-902016 Sentence denotes It was found that haplotype DRB1*0401 and DQB1*0302 is linked to type1 diabetes mellitus and that is increased among patients with the primary progressive subtype of MS.
T362 902017-902204 Sentence denotes Whether patient's autoimmunity or genetics, associated MS with another disease, remains indeterminate, with a possibility that some environmental factor could bcomplicateQ this condition.
T363 902205-902274 Sentence denotes Antiphospholipid syndrome, livedo reticularis and multiple sclerosis?
T364 902275-902277 Sentence denotes C.
T365 902278-902320 Sentence denotes Dikova Medical University, Sofia, Bulgaria
T366 902321-902574 Sentence denotes In the last couple of years, patients with multiple sclerosis (MS) and antiphospholipid syndrome (APS) have been reported because of the presence of migraine, miscarriages, livedo reticularis (LR) and increased level of anticardiolipin antibodies (ACA).
T367 902575-902654 Sentence denotes We present 10 women with livedo reticularis, diagnosed with multiple sclerosis.
T368 902655-902732 Sentence denotes The purpose of this study is to find out clinical or laboratory data for APS.
T369 902733-903000 Sentence denotes Five women (50%) have elevated IgM anticardiolipin antibodies (ACA), two have elevated IgG ACA, six have miscarriages, two are migraine sufferers, two have tension type of headache, three have had deep vein thrombosis, three have had occasionally high blood pressure.
T370 903001-903046 Sentence denotes Astrocyte loss in Rasmussen's encephalitis J.
T371 903047-903059 Sentence denotes Bauer a , C.
T372 903060-903072 Sentence denotes Elgar b , T.
T373 903073-903087 Sentence denotes Pietsch b , J.
T374 903088-903102 Sentence denotes Schramm b , H.
T375 903103-903116 Sentence denotes Urbach b , H.
T376 903117-903136 Sentence denotes Lassmann a and C.G.
T377 903137-903310 Sentence denotes Bien b a Brain Research Institute, Vienna, Austria; b University of Bonn, Bonn, Germany Rasmussen's encephalitis is an inflammatory, unihemispheric epileptic brain disorder.
T378 903311-903500 Sentence denotes The current histopathological criteria include the presence of T-cell dominated inflammation, microglial activation and microglial nodules as well as neuronal loss and astrocyte activation.
T379 903501-903573 Sentence denotes Anti-GluR3 antibodies have been implied to play a pathogenic role in RE.
T380 903574-903702 Sentence denotes In mixed cell cultures, these antibodies could activate the glutamate receptor and were shown to destroy neurons and astrocytes.
T381 903703-903769 Sentence denotes This prompted us to investigate astrocyte cell loss in situ in RE.
T382 903770-903978 Sentence denotes Respective epilepsy surgery or diagnostic brain biopsies from 16 patients were studied for active degeneration (apoptosis) and loss of GFAP+ and S100+ astrocytes by fluorescence confocal and light microscopy.
T383 903979-904140 Sentence denotes Astrocyte apoptosis was found both in cortical areas, inseparable from neuronal loss, as well as in white matter areas, resulting in astrocyte deficient lesions.
T384 904141-904262 Sentence denotes Like other parenchymal cells (neurons and microglial cells), astrocytes in these tissues revealed MHC class I expression.
T385 904263-904398 Sentence denotes Furthermore, Granzyme-B positive lymphocytes were found in close apposition to astrocytes on the border of astrocyte-deficient lesions.
T386 904399-904499 Sentence denotes Granzyme-B positive granules in these lymphocytes were polarised and facing the astrocytic membrane.
T387 904500-904629 Sentence denotes We therefore suggest a specific attack by cytotoxic T lymphocytes as a possible mechanism responsible for astrocyte degeneration.
T388 904630-904879 Sentence denotes The loss of astrocytes, important in homeostatic regulation of glutamate and other neuronal transmitters, in addition to other cytotoxic mechanisms, might play a role in neuronal dysfunction, seizure induction and enhancement of neuronal cell death.
T389 904880-905032 Sentence denotes Rasmussen's encephalitis (RE) is a severe epileptic disorder that may respond transiently to immunotherapies suggesting a possible autoimmune aetiology.
T390 905033-905273 Sentence denotes Antibodies to glutamate receptor type 3 (GluR3) have been reported, but in a recent comprehensive study we failed to confirm the presence of GluR3 antibodies in sera from RE and intractable epilepsy (IE) patients (Watson et al., in press ).
T391 905274-905362 Sentence denotes Here we looked for antibodies to neuronal alpha 7 acetylcholine receptor (alpha7 nAChR).
T392 905363-905507 Sentence denotes Sera from patients with RE (n=30), IE (49) and healthy individuals (23) were tested by a range of techniques for antibodies to the alpha7 nAChR.
T393 905508-905622 Sentence denotes Two sera from patients with RE blocked the agonist-induced currents of alpha7 nAChRs expressed in Xenopus oocytes.
T394 905623-905783 Sentence denotes Additionally, these sera, and their derived IgGs, inhibited the agonist-induced calcium ion influx into an alpha7 nAChR-transfected human endothelial cell line.
T395 905784-905952 Sentence denotes To confirm that the antibodies were directed against the alpha7 nAChR, we used immunoprecipitation of 125I-alphabungarotoxin-labelled detergent extracts of these cells.
T396 905953-906102 Sentence denotes Anti-alpha7 nAChR antibodies were present during active disease, but were negative later in the disease process when the patients were in bburn-outQ.
T397 906103-906176 Sentence denotes Our results demonstrate for the first time alpha7 nAChR antibodies in RE.
T398 906177-906265 Sentence denotes These antibodies inhibit nAChR channel function and have the potential to be pathogenic.
T399 906266-906408 Sentence denotes Ongoing studies are looking for these antibodies in patients with different forms of severe epilepsy, and testing their pathogenicity in vivo.
T400 906409-906484 Sentence denotes HLA studies indicate immunogenetic susceptibility to adult Rasmussen's I.K.
T401 906485-906498 Sentence denotes Hart a and J.
T402 906499-906707 Sentence denotes Darroch b a University of Liverpool, Liverpool, UK; b Royal Liverpool University Hospital, Liverpool, UK Rasmussen's syndrome (RS) causes severe, drug resistant epilepsy and neurologic and cognitive deficits.
T403 906708-906752 Sentence denotes It can be present in childhood or adulthood.
T404 906753-906847 Sentence denotes Autoimmunity is implicated in its pathogenesis, although the crucial mechanisms are not clear.
T405 906848-906858 Sentence denotes Objective:
T406 906859-906897 Sentence denotes To study HLA associations in adult RS.
T407 906898-906906 Sentence denotes Methods:
T408 906907-906958 Sentence denotes We performed DNA based HLA typing on six RS adults.
T409 906959-907005 Sentence denotes All had responded to immunomodulatory therapy.
T410 907006-907014 Sentence denotes Results:
T411 907015-907256 Sentence denotes Compared with control data-the allele prevalencies in the general UK population-our patients had increased frequencies of HLA A2 (100% versus 24.1%,), HLA B44 (66.7% versus 10.3%), HLA DR4 (83.3% versus 12.8%), and HLA DQ8 (66.7% versus 5%).
T412 907257-907371 Sentence denotes While only 2.2% of the general population are HLA A2, B44, DR4 positive, 66.7% of our patients had this haplotype.
T413 907372-907384 Sentence denotes Conclusions:
T414 907385-907577 Sentence denotes These findings provide further evidence, albeit indirect, that autoimmunity contributes to the triggering or maintenance of adult RS and that the immune dysregulation is genetically dependent.
T415 907578-907809 Sentence denotes Further studies will establish whether HLA typing can help identify those adults presenting with focal epilepsy who are at risk of progressing to severe chronic focal autoimmune encephalitis and who may benefit from immune therapy.
T416 907810-907932 Sentence denotes Morphological and functional analysis of the effect of GAD-antibody positive sera on rat hippocampal neurons in culture M.
T417 907933-907948 Sentence denotes Vianello a , C.
T418 907949-907964 Sentence denotes Mucignat a , S.
T419 907965-907982 Sentence denotes Vassanelli a , K.
T420 907983-908003 Sentence denotes Fountzoulas a and B.
T421 908004-908160 Sentence denotes Giometto b a Department of Human Anatomy and Physiology, University of Padova, Padova, Italy; b Department of Neurology, Hospital of Treviso, Treviso, Italy
T422 908161-908282 Sentence denotes In addition to Stiff-Person Syndrome (SPS) and Ataxia, GAD-antibodies (Ab) were detected in Drug-resistant Epilepsy (EP).
T423 908283-908475 Sentence denotes We tested reactivity of sera on cultured rat hippocampal neurons and recorded post-synaptic inhibitory potentials (IPPS) in these cells to assess the pathogenetic role of these autoantibodies.
T424 908476-908591 Sentence denotes We tested sera from GAD-Ab positive patients with EP on cultured neurons using an immunohistochemical (IHC) method.
T425 908592-908720 Sentence denotes As control we tested sera from GAD-Ab positive patients with SPS, Ataxia and diabetes and GAD-Ab negative epileptic individuals.
T426 908721-908932 Sentence denotes Sera from GAD-Ab positive epileptic and diabetic patients and normal controls were selected and IPPS recorded on cultured hippocampal neurons before and after application of diluted sera, in a patch clamp study.
T427 908933-909051 Sentence denotes On IHC, a specific reactivity on the soma of neurons was detected when we applied sera from GAD-Ab epileptic patients.
T428 909052-909123 Sentence denotes Different staining was obtained with sera from SPS and ataxic patients.
T429 909124-909220 Sentence denotes No specific labelling was found in patients with GAD-Ab negative epilepsy and diabetic controls.
T430 909221-909411 Sentence denotes A significant reduction in amplitude and an increase in frequency of IPPS were observed after application of serum from the positive epileptic case, while no effect was noted using controls.
T431 909412-909560 Sentence denotes The observed morphological and functional effect on hippocampal neurons may suggest a pathogenetic role of GAD-Ab in the development of the disease.
T432 909561-909702 Sentence denotes Cytotoxic T cells in the pathogenesis of paraneoplastic encephalitis, nonparaneoplastic limbic encephalitis and Rasmussen's encephalitis C.G.
T433 909703-909714 Sentence denotes Bien a , H.
T434 909715-909732 Sentence denotes Lassmann b , C.E.
T435 909733-909747 Sentence denotes Elger a and J.
T436 909748-909840 Sentence denotes Bauer b a University of Bonn, Bonn, Germany; b Medical University of Vienna, Vienna, Austria
T1 909841-910015 Sentence denotes Recently, the immunohistochemical investigation of the immunopathology of Rasmussen's encephalitis (RE) has provided evidence for a cytotoxic T cell reaction against neurons.
T2 910016-910328 Sentence denotes In the present study, we sought to determine if the composition of inflammatory cells in patients with paraneoplastic encephalitis (PE) and nonparaneoplastic limbic encephalitis (NPLE), two other chronic encephalitic conditions that have been suggested to be T cell mediated disorders, are similar to that in RE.
T3 910329-910408 Sentence denotes We studied paraffin-embedded brain specimens from 8 PE, 5 NPLE and 21 RE cases.
T4 910409-910564 Sentence denotes Specimens were stained immunohistochemically with antibodies against CD3, CD8, Granzyme-B, CD20, CD138, immunoglobulins, C9neo, CD68, Fas, and MHC class I.
T5 910565-910705 Sentence denotes Quantitative evaluation of cell densities were performed and statistically analyzed using nonparametric and parametric tests as appropriate.
T6 910706-910825 Sentence denotes The ratios of CD8+/CD3+ and GrB+/CD3+ ratios and the frequency of Fas+ cells did not differ between the three diseases.
T7 910826-910917 Sentence denotes MHC class I+ neurons, astrocytes and oligodendrocytes were observed at similar proportions.
T8 910918-911058 Sentence denotes The PE specimens however contained significantly higher densities of T cells, B cells, plasma cells and macrophages compared to NPLE and RE.
T9 911059-911135 Sentence denotes We conclude that T cell cytotoxicity forms a bbackboneQ of these conditions.
T10 911136-911292 Sentence denotes The higher inflammatory activity and broader spectrum of inflammatory cells in PE may be an indicator of inflammatory mechanisms beyond T cell cytotoxicity.
T11 911293-911382 Sentence denotes This work was supported by a grant from the Austrian science foundation FWF (P16063-B02).
T12 911383-911555 Sentence denotes Since the first description in 1999, there have been reports on 12 patients with anti-Ma (anti-PNMA1 and PNMA2) and 27 patients with anti-Ta reactivities (anti-PNMA2 only).
T13 911556-911740 Sentence denotes Here we update the clinical information on these two reactivities with 9 additional anti-Ma and 10 additional anti-Ta positive patients whom we have identified between 12/99 and 04/04.
T14 911741-911890 Sentence denotes Sera were tested using Western-Blot analysis with semi-purified recombinant PNMA1 and PNMA2 protein, and the clinical data collected retrospectively.
T15 911891-912064 Sentence denotes The nine anti-Ma positive patients (6/9 female, mean age 62) presented with brainstem/cerebellar (6/9), limbic (5/9), extrapyramidal symptoms (2/9) and polyneuropathy (2/9).
T16 912065-912143 Sentence denotes In 6/9 tumors were identified (each twice: renal rhabdosarcoma, breast, lung).
T17 912144-912221 Sentence denotes In the patient with lung tumor, an overlapping anti-Hu antibody was detected.
T18 912222-912465 Sentence denotes The 10 anti-Tapositive patients (9/10 male, mean age 50) presented with limbic syndrome (7/10, one with obsessive-compulsive symptoms), brainstem/cerebellar symptoms (4/9), polyneuropathy (1/9) and with signs of motor neuron involvement (1/9).
T19 912466-912640 Sentence denotes In 8/10 tumors were identified including germ cell tumors (5/10, one extragonadal, one at orchiectomy, one at autopsy), and one each of melanoma, lymphoma and lung-carcinoma.
T20 912641-912706 Sentence denotes One patient has a past history of seminoma without known relapse.
T21 912707-912805 Sentence denotes Another recognized a suspicious testicular swelling which disappeared spontaneously before biopsy.
T22 912806-912944 Sentence denotes Anti-Ma and anti-Ta reactivities prove to be of high clinical relevance in patients presenting with subacute brainstem or limbic symptoms.
T23 912945-912994 Sentence denotes If present, a thorough tumor search is warranted.
T24 912995-913061 Sentence denotes Proteasome antibodies in paraneoplastic cerebellar degeneration A.
T25 913062-913075 Sentence denotes Storstein, A.
T26 913076-913092 Sentence denotes Knudsen and C.A.
T27 913093-913321 Sentence denotes Vedeler Haukeland University Hospital, Bergen, Norway Paraneoplastic neurological syndromes (PNS) are often associated with specific onconeural antibodies, but the pathogenic importance of the humoral immune response is unclear.
T28 913322-913543 Sentence denotes Activated specific T lymphocytes in paraneoplastic cerebellar degeneration (PCD) and in paraneoplastic encephalomyelitis/sensory neuropathy (PEM/SN) suggests that cellular immune responses participate in the pathogenesis.
T29 913544-913699 Sentence denotes In this study, we detected proteasome antibodies in sera from 7 of 10 patients with PCD by Western blot, but in only 1 of 8 sera from patients with PEM/SN.
T30 913700-913853 Sentence denotes Proteasome antibodies were not found in any control serum (10 blood donor sera, a serum pool of 100 blood donors and 20 patients with cancer and no PNS).
T31 913854-914071 Sentence denotes By immunohistochemistry, we found that serum antibodies from 8 of the 10 PCD patients stained cytospins of various cancer cell lines, and the staining co-localised with the proteasome-associated promyelocytic protein.
T32 914072-914157 Sentence denotes The PCD sera also stained living cancer cells, but did not affect the cell viability.
T33 914158-914264 Sentence denotes Proteasome antibodies were not detected in the cerebrospinal fluid from one PCD and three PEM/SN patients.
T34 914265-914426 Sentence denotes The proteasome is important in nonlysosomal protein degradation and in antigen processing and presentation by major histocompatibility complex class I molecules.
T35 914427-914554 Sentence denotes The proteasome antibodies in PCD may be of pathogenic importance by regulating the cellular metabolism and the immune response.
T36 914555-914672 Sentence denotes Conformational epitopes can prevent the recognition of target antigens of autoantibodies in paraneoplastic syndromes.
T37 914673-914925 Sentence denotes As such, the target antigen of anti-TR antibodies-characterizing patients with paraneoplastic cerebellar degeneration (PCD) and Hodgkin's disease (HD)-is still elusive owing to the failure of its identification using conventional proteomics approaches.
T38 914926-915156 Sentence denotes We applied new procedures, which are based on direct tissue isoelectric focusing and gradient electrophoresis in non-denaturing polyacrylamide gel, to test the hypothesis that anti-TR antibodies recognize a conformational epitope.
T39 915157-915263 Sentence denotes We studied sera of two patients with PCD and HD, using rat and human cerebellum as the source of antigens.
T40 915264-915356 Sentence denotes Both the sera recognized a sharp band of approximately 39 kDa both in rat and human tissues.
T41 915357-915490 Sentence denotes With mass spectrometry (MALDI-TOF), we identified a cytoplasmic protein of a corresponding mass that was the same in rats and humans.
T42 915491-915549 Sentence denotes This protein is a candidate ligand for anti-TR antibodies.
T43 915550-915617 Sentence denotes CRMP3 antibodies associated with limbic encephalitis and thymoma A.
T44 915618-915632 Sentence denotes Knudsen a , G.
T45 915633-915648 Sentence denotes Bredholt a , A.
T46 915649-915665 Sentence denotes Storstein a , L.
T47 915666-915680 Sentence denotes Oltedal b , S.
T48 915681-915700 Sentence denotes Davanger b and C.A.
T49 915701-915812 Sentence denotes Vedeler a a Haukeland University Hospital, Bergen, Norway; b University of Bergen, Bergen, Norway Introduction:
T50 915813-915903 Sentence denotes Paraneoplastic neurological syndromes arise as remote effects of several different tumors.
T51 915904-916020 Sentence denotes Thymoma can be associated with various antibodies such as anti-AChR, anti-titin, anti-RyR, anti-VGKC and anti-CRMP5.
T52 916021-916029 Sentence denotes Methods:
T53 916030-916112 Sentence denotes A 52-year-old patient developed limbic encephalitis with focal epileptic seizures.
T54 916113-916160 Sentence denotes Screening for occult cancer revealed a thymoma.
T55 916161-916329 Sentence denotes Paraneoplastic antibodies related to limbic encephalitis such as anti-Hu, anti-amphiphysin, anti-Ma2, anti-CRMP5 and anti-Ri and those related to thymoma were negative.
T56 916330-916505 Sentence denotes The patient serum was tested on tissue sections of rat brain and on primary cultured neurons of the hippocampus and used to screen a cDNA expression library of rat cerebellum.
T57 916506-916585 Sentence denotes A rabbit polyclonal antibody against CRMP1-4 was used to stain the hippocampus.
T58 916586-916594 Sentence denotes Results:
T59 916595-916783 Sentence denotes The patient serum stained cellular regions of the hippocampus, synaptic boutons and nuclei of cells in the dentate gyrus and similar staining was observed on the pyramidal cells i culture.
T60 916784-916834 Sentence denotes The CRMP1-4 antibody also stained the hippocampus.
T61 916835-916952 Sentence denotes Western blot of rat brain extract incubated with the patient serum revealed two bands of approximately 40 and 60 kDa.
T62 916953-917078 Sentence denotes Screening of the cDNA library identified two different clones, one coding for CRMP3, and the other for nuclear protein XAP-5.
T63 917079-917161 Sentence denotes Discussion: CRMP3 antibodies were associated with thymoma and limbic encephalitis.
T64 917162-917262 Sentence denotes CRMP3 is present in the hippocampus and may be relevant for the pathogenesis of limbic encephalitis.
T65 917263-917454 Sentence denotes Seizures involve complex neurophysiological and neurochemical events that are involved in the detrimental consequences and reoccurrence of seizures, and the establishment of chronic epilepsy.
T66 917455-917545 Sentence denotes These events include neuroinflammation, which manifests itself quickly following seizures.
T67 917546-917701 Sentence denotes Although inflammation in the brain following seizures has been well characterized, its role, which could be adaptive or detrimental, is still under debate.
T68 917702-918077 Sentence denotes In order to clarify this problem, we treated mice with corticosterone (a potent suppressor of inflammation) and characterized its effect on seizures and their associated neurological and neuroimmune consequences (in the well-established model of pilocarpine administration in mice) using in situ hybridisation, immunocytochemisty and various markers of cell death and damage.
T69 918078-918251 Sentence denotes We found that even if corticosterone was able to suppress neuroinflammation associated with seizures, these seizures and their associated neuronal cell death still occurred.
T70 918252-918486 Sentence denotes However, suppressing the immune system spared a specific population of neurons in the hippocampus, and the expression of NPY in this region (believed to be an indices of mossy fiber sprouting and neuroprotective) was greatly affected.
T71 918487-918766 Sentence denotes Thus we conclude that neuroinflammation could play a major role in the reorganization that takes place in key regions following seizures and this could have implications in possible immune interventions to prevent the detrimental events that follow seizures and lead to epilepsy.
T72 918767-918858 Sentence denotes Antiepileptogenic and anticonvulsant activity of interleukin-1B in amygdala-kindled rats M.
T73 918859-918874 Sentence denotes Sayyah a and S.
T74 918875-919078 Sentence denotes Beheshti b a Institute Pasteur of Iran, Tehran, Iran; b Tehran University, Tehran, Iran Ischaemic, excitotoxic and traumatic brain injuries have been associated with the occurrence of epileptic seizures.
T75 919079-919250 Sentence denotes Microglia, the principal immune cells in the brain, produce a variety of proinflammatory and cytotoxic factors especially interleukin-1 (IL-1) early after an acute insult.
T76 919251-919399 Sentence denotes We studied the effect of IL-1h (1 pg-10 ng/rat, i.c.v.) on seizure acquisition and on fully kindled seizures in amygdala kindling model of epilepsy.
T77 919400-919493 Sentence denotes IL-1h retarded acquisition of kindled behavioral seizures and growth of afterdischarges (AD).
T78 919494-919597 Sentence denotes IL-1h also exhibited significant anticonvulsant effect on established kindled seizures and AD duration.
T79 919598-919803 Sentence denotes Pretreatment of the kindled animals with nitric oxide synthase inhibitor, N G -nitro-l-arginine methyl ester, or cyclooxygenase inhibitor, piroxicam, completely reversed the anticonvulsant effect of IL-1h.
T80 919804-919968 Sentence denotes Although most of the previous studies indicate a proconvulsant or convulsant property of IL-1, our results support a protective and antiepileptogenic role of IL-1h.
T81 919969-920102 Sentence denotes Seizures are common sequel to brain insults in cases such as stroke, trauma and infection where there is a certain neuroinflammation.
T82 920103-920263 Sentence denotes Intracerebroventricular (i.c.v.) administration of lipopolysaccharide (LPS) induces an inflammatory state in brain that is used as a model of neuroinflammation.
T83 920264-920407 Sentence denotes We studied the effect of LPS (0.25 and 2.5 Ag/rat, i.c.v.) on development of electrical kindling of the amygdala and on fully kindled seizures.
T84 920408-920543 Sentence denotes LPS, at the doses used, had no effect on fully kindled seizures and afterdischarge (AD) duration at 0.5, 2 or 4 h after administration.
T85 920544-920641 Sentence denotes However, daily injection of LPS (2.5 Ag/rat) retarded acquisition of kindled behavioral seizures.
T86 920642-920824 Sentence denotes This antiepileptogenic effect could be due to the release of inflammatory mediators from microglia and the related morphological and functional changes in synaptic neurotransmission.
T87 920825-920893 Sentence denotes Increased serum levels of interleukin-8 in patients with epilepsy L.
T88 920894-920905 Sentence denotes Bastone, A.
T89 920906-920916 Sentence denotes Bagalà, T.
T90 920917-920928 Sentence denotes Ferraro, M.
T91 920929-920942 Sentence denotes Casaletto, N.
T92 920943-920955 Sentence denotes Romeo and L.
T93 920956-921027 Sentence denotes Crescibene Institute of Neurological Sciences, CNR, Mangone (CS), Italy
T94 921028-921158 Sentence denotes There are some evidences that inflammatory processes may be involved in clinical and neuropathological manifestations of epilepsy.
T95 921159-921349 Sentence denotes Proinflammatory cytokines (such as IL-1, IL-6, TNF-alpha) are known to have indirect or direct effects on neurons and neurotoxic neurotransmitters released during excitation or inflammation.
T96 921350-921516 Sentence denotes Studies of patients with epilepsy and animals with experimental induced seizures indicate that cytokines may influence the electrophisiological properties of neurons.
T97 921517-921648 Sentence denotes In adult rats, status epilepticus induces cytokine production by glia especially when seizures are associated with neuronal injury.
T98 921649-921730 Sentence denotes This suggests that cytokines may play a role in seizures-induced neuronal damage.
T99 921731-921875 Sentence denotes Interleukin-8 is a chemokine produced by monocytes, endothelial cells and other cells that acts as a chemotactic and activator for neutrophilis.
T100 921876-921914 Sentence denotes Its effects are manly proinflammatory.
T101 921915-922075 Sentence denotes We investigated the levels of interleukin-8 as proinflammatory cytokines in serum of normal and epileptic patients by using an enzymelinked immunosorbent assay.
T102 922076-922157 Sentence denotes We found elevated concentrations of interleukin-8 in serum of epileptic patients.
T103 922158-922225 Sentence denotes Our data support the hypothesis that cytokines groups is activated.
T104 922226-922342 Sentence denotes Whether these elevated cytokines levels have some role in the pathogenesis of epilepsy must be investigated further.
T105 922343-922456 Sentence denotes Experimental studies have demonstrated that epileptic seizures are followed by increased production of cytokines.
T106 922457-922564 Sentence denotes In human patients, increased levels of IL-6 and IL-1ra have been reported in CSF and plasma after seizures.
T107 922565-922692 Sentence denotes However, whether this increase is caused by seizures per se or some other underlying disease causing seizures is controversial.
T108 922693-922800 Sentence denotes Electroconvulsive seizures (ECS) are commonly used experimental approach in antiepileptic drug development.
T109 922801-922865 Sentence denotes ECS is also employed in treatment of drug refractory depression.
T110 922866-923018 Sentence denotes In the present study, we determined the plasma levels of cytokines IL-1h, IL-1ra and IL-6 before and at several time points after administration of ECS.
T111 923019-923136 Sentence denotes The levels of IL-1h were significantly increased at 1-3 h time points ( pb0.05) and returned to basal levels by 24 h.
T112 923137-923173 Sentence denotes The levels of IL-1ra were unchanged.
T113 923174-923290 Sentence denotes The levels of IL-6 were increased significantly at 3-6 h time points ( pb0.05) and returned to basal levels by 24 h.
T114 923291-923416 Sentence denotes Our results clearly demonstrate that ECS are followed by transient increase in systemic levels of pro-inflammatory cytokines.
T115 923417-923509 Sentence denotes This finding provides further evidence about seizure induced production of cytokines in CNS.
T116 923510-923637 Sentence denotes In addition, activation of cytokine cascade after ECS may have importance in the therapeutic effect of ECS in major depression.
T117 923638-923799 Sentence denotes Antinuclear, cytoskeletal, antineuronal antibodies and C-reactive protein levels in the sera of children with tic disorders and obsessive compulsive disorders I.
T118 923800-923810 Sentence denotes Gorker, G.
T119 923811-923826 Sentence denotes Akman-Demir, N.
T120 923827-923842 Sentence denotes Gqrel Polat, R.
T121 923843-923861 Sentence denotes Eker Ö meroglu, S.
T122 923862-923870 Sentence denotes Icoz, P.
T123 923871-923888 Sentence denotes Serdaroglu and U.
T124 923889-924056 Sentence denotes Tuzun Istanbul Medical Faculty, Istanbul, Turkey 650 Immunohistochemical analysis of serum antibodies to central nervous system antigens in antiphospolipid syndrome E.
T125 924057-924071 Sentence denotes Aykutlu a , E.
T126 924072-924084 Sentence denotes Tqzqn b , B.
T127 924085-924098 Sentence denotes Baykan a , N.
T128 924099-924117 Sentence denotes Polat-Gqrel a , S.
T129 924118-924129 Sentence denotes Icoz a , P.
T130 924130-924148 Sentence denotes Christadoss b , C.
T131 924149-924162 Sentence denotes Gqrses a , M.
T132 924163-924175 Sentence denotes Inanc a , G.
T133 924176-924196 Sentence denotes Akman-Demir a and A.
T134 924197-924533 Sentence denotes Gfkyigit a a Istanbul Medical Faculty, Istanbul, Turkey; b University of Texas Medical Branch, Galveston, TX, USA In order to detect antibodies against central nervous system (CNS) antigens in 12 patients with seizures and primary or secondary antiphospholipid (aPL) antibody syndrome, serum samples were tested by immunohistochemistry.
T135 924534-924620 Sentence denotes Four out of 12 cases (33.3%) with aPL syndrome and seizures showed binding to neurons.
T136 924621-924745 Sentence denotes The binding was predominantly nuclear in two cases with strong staining and cytoplasmic in two cases with moderate staining.
T137 924746-924875 Sentence denotes The strength of immunohistochemical staining was correlated with both the age of the patients and the duration of their seizures.
T138 924876-924927 Sentence denotes Patients with strong nuclear staining also had SLE.
T139 924928-925010 Sentence denotes Three patients had partial epilepsy, whereas one patient had generalized epilepsy.
T140 925011-925213 Sentence denotes In one of the patients with strong staining, seizures were a sequel of aPL syndrome related-cerebral infarct, whereas in the remaining three cases seizures were not related to any focal cerebral lesion.
T141 925214-925425 Sentence denotes In aPL syndrome patients, serum antibodies against CNS might have emerged due to certain antiepileptic drugs, disruption of blood-brain barrier by stroke or in certain cases, they might be playing a causal role.
T142 925426-925754 Sentence denotes Strong nuclear staining might simply be related to the anti-nuclear antibodies frequently detected in aPL syndrome or SLE patients, whereas cytoplasmic staining might be indicating the presence of CNS-specific antibodies developing either as an epiphenomenon during the course of disease or as a contributing factor to epilepsy.
T143 925755-925846 Sentence denotes Autoantibodies to central nervous system in cases with Lafora disease-late onset variant E.
T144 925847-925861 Sentence denotes Aykutlu a , E.
T145 925862-925874 Sentence denotes Tqzqn b , G.
T146 925875-925893 Sentence denotes Akman-Demir a , N.
T147 925894-925906 Sentence denotes Bebek a , S.
T148 925907-925918 Sentence denotes Icfz a , P.
T149 925919-925939 Sentence denotes Christadoss b and B.
T150 925940-926345 Sentence denotes Baykan a a Istanbul Medical Faculty, Istanbul, Turkey; b University of Texas Medical Branch, Galveston, TX, USA Sera from 4 siblings (aged 24-31 years) with Lafora disease (LD) late onset variant, diagnosed by axillary skin biopsy, who also had high titers of anti-gliadin IgG antibodies were tested by immunohistochemistry for antibodies capable of binding to mouse central nervous system (CNS) antigens.
T151 926346-926485 Sentence denotes Serum samples of three out of four patients with LD showed binding to the neurons including cerebellar Purkinje cells and cortical neurons.
T152 926486-926563 Sentence denotes No staining was observed beyond 1/800 dilution or with control serum samples.
T153 926564-926621 Sentence denotes The binding was predominantly nuclear in all three cases.
T154 926622-926771 Sentence denotes Notably, these patients also had high titers of anti-gliadin IgG antibodies, although coeliac disease could not be demonstrated by intestinal biopsy.
T155 926772-926846 Sentence denotes All four patients were treated with valproate, clonazepam and lamotrigine.
T156 926847-926968 Sentence denotes The strength of immunohistochemical staining was correlated with neither the severity nor the length of the PME syndrome.
T157 926969-927238 Sentence denotes Since one patient from the same family with a similar clinical condition did not reveal detectable amounts of antibodies against CNS, it is more likely that these autoantibodies emerged as a by-product of the ongoing disease rather than being primary or causal factors.
T158 927239-927397 Sentence denotes Coexistence of LD and coeliac disease have previously been reported and our results are providing further support that these two diseases might be associated.
T159 927398-927510 Sentence denotes Introduction: CRMP5 is an onconeural antibody that is associated with small cell lung cancer (SCLC) and thymoma.
T160 927511-927642 Sentence denotes The prevalence of CRMP5 antibodies in patients with such tumours, as well as the correlation with the prognosis is largely unknown.
T161 927643-927664 Sentence denotes Patients and Methods:
T162 927665-927894 Sentence denotes Sera from 200 patients with SCLC, 83 patients with thymoma and myasthenia gravis and from 200 healthy blood donors were examined for CRMP5 antibodies by an in vitro transcription-translation (ITT) based immunoprecipitation assay.
T163 927895-928018 Sentence denotes Positive sera were also examined by Western blot using CNS extract and recombinant CRMP5, and by a commercial dot blot kit.
T164 928019-928191 Sentence denotes Results: CRMP5 antibodies were found in 14/200 (7.5%) of the SCLC, 9/83 (10.8%) of the thymoma and in none of the healthy control sera by the ITT immunoprecipitation assay.
T165 928192-928280 Sentence denotes High CRMP5 index (N500) was found in seven of the thymoma and four of the SCLC patients.
T166 928281-928357 Sentence denotes Most of the high-index sera were also positive by Western blot and dot blot.
T167 928358-928502 Sentence denotes Conclusion: CRMP5 antibodies were detected in approximately 8% of the SCLC and 11% of the thymoma patients by the ITT immunoprecipitation assay.
T168 928503-928564 Sentence denotes This assay was more sensitive than Western blot and dot blot.
T169 928565-928576 Sentence denotes Background:
T170 928577-928738 Sentence denotes Presence of anti-neuronal autoantibodies (Abs) has been well described in association with late onset cerebellar ataxia (LOCA) as a paraneoplastic manifestation.
T171 928739-928850 Sentence denotes They are identified in the presence of certain cancers but may also rarely be seen in the absence of neoplasia.
T172 928851-928942 Sentence denotes However, the frequency of these Abs and relevance in wider LOCA population remains unclear.
T173 928943-929075 Sentence denotes We have explored their significance in a prevalent, population-based sample of patients with idiopathic LOCA (ILOCA) in South Wales.
T174 929076-929098 Sentence denotes Methods and materials:
T175 929099-929142 Sentence denotes Sera of 84 patients (mean disease duration:
T176 929143-929160 Sentence denotes 7.8 years; range:
T177 929161-929412 Sentence denotes 1 to 35) were analysed using indirect immunohistochemistry and/or Western blot (IHC/WB) for anti-Hu, Ma, Ri, Tr and Yo Abs, and using immunoprecipitation (IP) for P/Qtype voltage-gated calcium channel (VGCC) and voltage-gated potassium channel (VGKC).
T178 929413-929499 Sentence denotes Results of each assay were compared with known negative, normal and positive controls.
T179 929500-929508 Sentence denotes Results:
T180 929509-929652 Sentence denotes On IHC/WB, 11/84 sera showed staining patterns initially suggestive of anti-Yo (n=4), Hu (n=3), Ma (n=3) and Tr (n=1), but were excluded on WB.
T181 929653-929720 Sentence denotes In further 13/84 sera, these revealed batypicalQ staining patterns.
T182 929721-929778 Sentence denotes On IP, none was positive for anti-VGCC and anti-VGKC Abs.
T183 929779-929790 Sentence denotes Discussion:
T184 929791-929899 Sentence denotes No ILOCA patients were positive for the anti-neuronal Abs screened (anti-Hu, Ma, Ri, Tr, Yo, VGCC and VGKC).
T185 929900-930089 Sentence denotes However, 13/84 (15%) showed atypical staining patterns of unknown significance indicating the possibility of an undetermined immunological pathology in a significant proportion of patients.
T186 930090-930130 Sentence denotes Neuroprotection in multiple sclerosis R.
T187 930131-930139 Sentence denotes Diem, M.
T188 930140-930152 Sentence denotes Hobom and M.
T189 930153-930401 Sentence denotes B7hr Department of Neurology, University of Gfttingen, Gfttingen, Germany Long-term disability in multiple sclerosis (MS) patients is primarily caused by axonal and neuronal lesions, but up to date no neuro-or axono-protective therapy is available.
T190 930402-930571 Sentence denotes We previously demonstrated that neuronal apoptosis occurs early during myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE).
T191 930572-930704 Sentence denotes High-dosage methylprednisolone treatment has been established as the standard therapy of acute inflammation of the optic nerve (ON).
T192 930705-930865 Sentence denotes To investigate the influence of methylprednisolone therapy on the survival of retinal ganglion cells (RGCs), whose axons form the ON, we used (MOG)-induced EAE.
T193 930866-931010 Sentence denotes ON involvement was assessed by recording visual evoked potentials (VEPs), and RGC function was monitored by measuring electroretinograms (ERGs).
T194 931011-931140 Sentence denotes Methylprednisolone treatment significantly increased RGC apoptosis during MOG-EAE and did not lead to a recovery of ERGs or VEPs.
T195 931141-931291 Sentence denotes The underlying molecular mechanism of RGC death involved suppression of mitogen-activated protein kinase phosphorylation, which was calcium-dependent.
T196 931292-931381 Sentence denotes Hence we provide evidence for negative effects of steroid treatment on neuronal survival.
T197 931382-931472 Sentence denotes Thus, besides immunosuppressive strategies, neuroprotective approaches should be designed.
T198 931473-931642 Sentence denotes To that end, we could show that systemic treatment with erythropoietin of rats with MOG-EAE including severe optic neuritis reduced the clinical severity of the disease.
T199 931643-931760 Sentence denotes Moreover, survival and function of RGCs, as documented by histology and ERG measurements were significantly improved.
T200 931761-931865 Sentence denotes Neurodegeneration in multiple sclerosis: high vulnerability of neurons to Th1 but not Th2 lymphocytes F.
T201 931866-931881 Sentence denotes Giuliani a , A.
T202 931882-931899 Sentence denotes Bar-Or b and V.W.
T203 931900-932120 Sentence denotes Yong a a University of Calgary, Calgary, Canada; b McGill University, Montreal, Canada MS is considered a T cell-mediated disease of the CNS and is characterized by inflammation, demyelination, and neuronal degeneration.
T204 932121-932263 Sentence denotes The current objective is to determine whether Th1 and Th2 polarized T cells have different capacity for neurodegeneration in vitro and in EAE.
T205 932264-932335 Sentence denotes We used a coculture system of human leukocytes and human fetal neurons.
T206 932336-932433 Sentence denotes T cells were activated in an antigen-specific manner and polarized into lines of Th1 or Th2 bias.
T207 932434-932549 Sentence denotes Following a period of co-culture, neurons were stained with anti-MAP-2 antibody and counted to assess cytotoxicity.
T208 932550-932694 Sentence denotes Antigen-specific mixed Th1/Th2 populations induced 50% of neuronal death, whereas the Th1 polarized population induced 90% of death within 24 h.
T209 932695-932743 Sentence denotes Th2 polarized cells were unable to kill neurons.
T210 932744-932875 Sentence denotes EAE was further induced in C57/BL6 mice that were clinically scored on a daily basis and then sacrificed for histological analysis.
T211 932876-932991 Sentence denotes Co-localization of inflammation and axonal loss showed a significant correlation in the spinal cord of EAE animals.
T212 932992-933167 Sentence denotes Overall, these data demonstrate that Th1 cells are toxic for human neurons while Th2 lines are not, and that axonal loss occurs in vivo in EAE in areas of T cell inflammation.
T213 933168-933282 Sentence denotes We suggest that when T cells are appropriately activated, they can traffic into the CNS and induce neuronal death.
T214 933283-933363 Sentence denotes The shift of T cells towards a Th2 phenotype decreases their potential toxicity.
T215 933364-933463 Sentence denotes Direct impact of T cells on neurons as potential damage mechanism in neuroinflammatory disorders O.
T216 933464-933476 Sentence denotes Aktas a , E.
T217 933477-933488 Sentence denotes Pohl b , A.
T218 933489-933508 Sentence denotes Smorodchenko a , C.
T219 933509-933530 Sentence denotes Infante-Duarte a , R.
T220 933531-933546 Sentence denotes Nitsch b and F.
T221 933547-933730 Sentence denotes Zipp a a Institute of Neuroimmunology, Humboldt University Medical School Charité, Berlin, Germany; b Institute of Anatomy, Humboldt University Medical School Charité, Berlin, Germany
T222 933731-933892 Sentence denotes The precise mechanisms of neuronal damage in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE) are poorly understood.
T223 933893-934083 Sentence denotes Here we applied two photon laser-scanning microscopy to track the direct interactions of proteolipid protein (PLP)specific T cells within the complex cellular network of living brain tissue.
T224 934084-934355 Sentence denotes CD4+CD8-CD25+CD69+CD44+ Th-1-like T cell lines releasing high amounts of IFN-gamma and TNF-alpha (as used for induction of EAE) were labeled with red fluorescent dye CMTMR and applied on living brain slices, which had been incubated with the calcium-sensitive dye Fluo-4.
T225 934356-934513 Sentence denotes PLP-specific T cells directly contacted neurons in which they induced calcium oscillations finally resulting in a lethal increase in neuronal calcium levels.
T226 934514-934641 Sentence denotes Prevention of the calcium overload was achieved by blockade of perforin-mediated cytotoxicity of the T cells by concanamycin-A.
T227 934642-934855 Sentence denotes Wash-in experiments, in which the glutamatergic neuronal connectivity in the hippocampus was inhibited using blockers of the different glutamate receptors, further reversed the T cell-induced calcium oscillations.
T228 934856-934993 Sentence denotes The effects were independent of antigen presentation since OVA-specific T cells were also able to induce an increase in neuronal calcium.
T229 934994-935055 Sentence denotes In contrast, unstimulated T cells did not elicit this effect.
T230 935056-935327 Sentence denotes Thus, our data provide direct insight into the detrimental impact of T cells on neurons and shows that stimulation of T cells independent of their target antigen enables them to induce collateral damage in neurons via direct cell-cell contact within the brain parenchyma.
T231 935328-935479 Sentence denotes Complement activation is involved in the initiation of antibody-mediated inflammatory demyelination in experimental autoimmune encephalomyelitis (EAE).
T232 935480-935581 Sentence denotes At a sublytic dose, the C5b-9 membrane attack complex (MAC) protects oligodendrocytes from apoptosis.
T233 935582-935758 Sentence denotes Using C5-deficient mice (C5-d), we previously showed a dual role for C5: enhancement of inflammatory demyelination in acute EAE, and promotion of remyelination during recovery.
T234 935759-935840 Sentence denotes In this study, we investigated the role of C5 in apoptosis in myelin-induced EAE.
T235 935841-935999 Sentence denotes In acute EAE, C5-d and C5-sufficient (C5-s) mice had similar numbers of total apoptotic cells, whereas C5-s had significantly fewer than C5-d during recovery.
T236 936000-936161 Sentence denotes In addition, while both groups of mice displayed TUNEL+ oligodendrocytes, there were significantly fewer in C5-s than in C5-d during both acute EAE and recovery.
T237 936162-936266 Sentence denotes Gene array and immunostaining of apoptosis-related genes showed that FasL expression was higher in C5-s.
T238 936267-936405 Sentence denotes In C5-s mice, Fas+ cells were also higher than in C5-d mice in acute EAE; however, these cells were significantly reduced during recovery.
T239 936406-936587 Sentence denotes Together, these findings are consistent with the role of C5, possibly by forming the MAC, in limiting oligodendrocyte apoptosis in EAE, thus promoting remyelination during recovery.
T240 936588-936676 Sentence denotes The JNK activation is involved in TRAIL-induced death of adult human oligodendrocytes M.
T241 936677-936689 Sentence denotes Matysiak, A.
T242 936690-936702 Sentence denotes Jurewicz, S.
T243 936703-936719 Sentence denotes Andrzejak and K.
T244 936720-936853 Sentence denotes Selmaj Medical University of Lodz, Lodz, Poland TRAIL has been reported to induce apoptosis in tumour cell lines and in normal cells.
T245 936854-936972 Sentence denotes TRAIL was demonstrated on autoreactive T cells and may be involved in immune mediated apoptosis of brain target cells.
T246 936973-937152 Sentence denotes Susceptibility or resistance to TRAIL-induced death is related to differences in TRAIL receptors expression or/and differences in involvement of intracellular apoptotic molecules.
T247 937153-937264 Sentence denotes To assess death of adult human oligodendrocytes (ahOl) after TRAIL stimulation we used Annexin and PI staining.
T248 937265-937395 Sentence denotes The JNK activation after TRAIL stimulation was assessed by using antibodies against phosphorylated form of kinase in Western blot.
T249 937396-937470 Sentence denotes The c-jun phosphorylation in cell lysates was assessed by autoradiography.
T250 937471-937567 Sentence denotes Caspase pathway activation was analysed by Western blotting and using general caspase inhibitor.
T251 937568-937701 Sentence denotes The role of JNK activation in oligodendrocytes death was determined by inhibition of JNK using dominant-negative mutant of MKK-4/SEK.
T252 937702-937813 Sentence denotes TRAIL induces ahOl death, but only in condition on protein synthesis inhibition or pre-treatment with IFNgamma.
T253 937814-937875 Sentence denotes Microglia cells are resistant to TRAIL mediated cytotoxicity.
T254 937876-938007 Sentence denotes We did not detect caspase pathway activation in ahOL after TRAIL stimulation and caspase inhibitor did not prevent ahOl from death.
T255 938008-938127 Sentence denotes We have observed persistent activation of JNK in oligodendrocytes, but not in microglia cells, after TRAIL stimulation.
T256 938128-938206 Sentence denotes Inhibition of JNK activity protects oligodendrocytes from TRAIL-induced death.
T257 938207-938351 Sentence denotes These results may implicate JNK pathway involvement in TRAIL-induced selective oligodendrocytes demise in inflammatory/demyelinating conditions.
T258 938352-938584 Sentence denotes An inappropriate cross-talk between activated T lymphocytes infiltrating the central nervous system (CNS) and neural cells can sustain the onset and progression of demyelination and axonal degeneration in neuroinflammatory diseases.
T259 938585-938864 Sentence denotes To mimic this deleterious crosstalk, we designed an experimental paradigm consisting of transient cocultures of T lymphocytes chronically activated by retrovirus infection (not virus productive) with human multipotent neural precursors or primary oligodendrocytes from rat brain.
T260 938865-939049 Sentence denotes We showed that activated T lymphocytes induced apoptotic death of multipotent neural progenitors and immature oligodendrocytes after a progressive collapse of their process extensions.
T261 939050-939134 Sentence denotes These effects were reminiscent of those induced by brain semaphorin on neural cells.
T262 939135-939456 Sentence denotes Blockade by specific antibodies of soluble Sema-4D/CD100 released by activated T cells, or treatment with recombinant sSema4D/CD100, demonstrated that this immune semaphorin has the ability to collapse oligodendrocyte process extensions and to trigger neural cell apoptosis, likely through receptors of the plexin family.
T263 939457-939707 Sentence denotes The specific presence of sSema4D/CD100 in the CSF and of Sema4D/CD100 expressing-T lymphocytes in the spinal cord of patients suffering with neuroinflammatory demyelination pointed out to the potential pathological effect of sSema4D/CD100 in the CNS.
T264 939708-940006 Sentence denotes Thus, our results show that Sema4D/CD100 is a new important element in the deleterious T cellneural cell crosstalk during neuroinflammation and suggest its role in demyelination or absence of remyelination in neuroinflammatory diseases including multiple sclerosis and HTLV-1-associated myelopathy.
T265 940007-940111 Sentence denotes Proteinase-activated receptor-2 expression is neuroprotective in lentivirus-induced neuroinflammation F.
T266 940112-940129 Sentence denotes Noorbakhsh a , N.
T267 940130-940146 Sentence denotes Vergnolle a , M.
T268 940147-940162 Sentence denotes Vodjgani b , M.
T269 940163-940182 Sentence denotes Hollenberg a and C.
T270 940183-940439 Sentence denotes Power a a University of Calgary, Calgary, Canada; b Tehran University of Medical Sciences, Tehran, Iran Proteinase-activated receptors (PARs) are a family of G-protein coupled receptors that are activated by the proteolytic cleavage of their aminoterminus.
T271 940440-940551 Sentence denotes Previous studies from our group have shown a pathogenic role for PAR-1 in lentivirus-induced neuroinflammation.
T272 940552-940758 Sentence denotes To explore further the role of these receptors we analysed the role of PAR-2 in the context of lentivirus (human immunodeficiency virus-HIV, and feline immunodeficiency virus-FIV)-induced neuroinflammation.
T273 940759-940947 Sentence denotes PAR-2 mRNA and protein levels were increased in both HIV-and FIV-infected brains, with principally neuronal localization ( Pb0.05), as analysed by real-time RT-PCR and immunocytochemistry.
T274 940948-941086 Sentence denotes Treatment of human and mouse neuronal cell lines with recombinant IL-1beta or TNF-alpha increased PAR-2 mRNA and protein levels ( Pb0.05).
T275 941087-941220 Sentence denotes Overexpression of PAR-2 in neuronal cells decreased neuronal cell death induced by exposure to HIV Tat-induced neurotoxins ( Pb0.05).
T276 941221-941334 Sentence denotes Intracerebral implantation of PAR-2 activating peptide (SLIGRL) decreased the neurobehavioral effects of HIV Tat.
T277 941335-941551 Sentence denotes Indeed, PAR-2 null animals exhibited more prominent astrocytosis and neuronal loss, together with greater neurobehavioral effects than wild-type littermates, following the implantation of HIV Tat-induced neurotoxins.
T278 941552-941707 Sentence denotes These studies indicate that PAR-2 exerts a neuroprotective effect against lentivirus-induced brain disease that is augmented by pro-inflammatory cytokines.
T279 941708-941869 Sentence denotes MoMuLV-ts1-mediated neuronal death in mice is likely due both to loss of glial support and to release of cytokines and neurotoxins from ts1-infected glial cells.
T280 941870-942174 Sentence denotes We investigated whether ER stress signaling is involved in ts1mediated neuronal loss in the brain of infected mice. ts1-infected brainstems were found to show significant increases in phosphorylation of the double-stranded RNA-dependent protein kinase-like ER kinase and eukaryotic initiation factor 2-a.
T281 942175-942392 Sentence denotes In addition, increased expression of growth arrest DNA damage 153 (GADD153), glucose-regulated protein 78, and caspase-12 were accompanied by increases in processing of caspase-12 and its downstream target, caspase-3.
T282 942393-942438 Sentence denotes All of these events are markers of ER stress.
T283 942439-942587 Sentence denotes We observed that GADD153 and cleaved caspase-3 were present in degenerative neurons in the lesions of infected mice, but not in uninfected controls.
T284 942588-942791 Sentence denotes Phosphorylated calmodulin-dependent protein kinase II-a was significantly increased, and was co-expressed with GADD153 in a large proportion of neurons undergoing early and advanced degenerative changes.
T285 942792-942921 Sentence denotes Finally, neuronal degeneration in spongiform lesions was associated with increase in calcium (Ca2+) accumulation in mitochondria.
T286 942922-943128 Sentence denotes Together these results suggest that ts1 infection-mediated neuronal degeneration in mice may result from activation of ER stress signaling pathways, presumably initiated by perturbation of Ca2+ homeostasis.
T287 943129-943259 Sentence denotes Our findings highlight the importance of the ER stress signaling pathway in ts1 infection-induced neuronal degeneration and death.
T288 943260-943376 Sentence denotes The radical scavenger edaravone prevents oxidative neurotoxicity induced by peroxynitrite and activated microglia M.
T289 943377-943386 Sentence denotes Banno, T.
T290 943387-943397 Sentence denotes Mizuno, G.
T291 943398-943407 Sentence denotes Zhang, J.
T292 943408-943423 Sentence denotes Kawanokuchi, R.
T293 943424-943432 Sentence denotes Kuno, S.
T294 943433-943440 Sentence denotes Jin, H.
T295 943441-943449 Sentence denotes Kato, H.
T296 943450-943465 Sentence denotes Takeuchi and A.
T297 943466-943510 Sentence denotes Suzumura University of Nagoya, Nagoya, Japan
T298 943511-943623 Sentence denotes The free radical scavenger edaravone has been used as an anti-oxidative agent in acute ischemic brain disorders.
T299 943624-943963 Sentence denotes We examined the effect of edaravone on the production of nitric oxide (NO), reactive oxygen species (ROS) and proinflammatory cytokines by activated microglia, and we also examined its neuroprotective role in cortical neuronal cultures oxidatively stressed by the peroxynitrite donor N-morpholinosydoniamine (SIN-1) or activated microglia.
T300 943964-944116 Sentence denotes Edaravone significantly suppressed the production of NO and ROS by activated microglia, though it did not suppress production of inflammatory cytokines.
T301 944117-944278 Sentence denotes In addition, edaravone significantly suppressed neuronal cell death and dendrotoxicity induced by either SIN-1 or activated microglia in a dose dependent manner.
T302 944279-944520 Sentence denotes These results suggest that edaravone may be a useful neuroprotective agent counteracting oxidative neurotoxicity arising from activated microglia, as occurs in either inflammatory or neurodegenerative disorders of the central nervous system.
T303 944521-944574 Sentence denotes Effects of nitric oxide on adult neural stem cells R.
T304 944575-944585 Sentence denotes Covacu, M.
T305 944586-944608 Sentence denotes Aguilar-Santelises, T.
T306 944609-944622 Sentence denotes Olsson and L.
T307 944623-944676 Sentence denotes Brundin Karolinska Institutet, Stockholm, Sweden Aim:
T308 944677-944765 Sentence denotes To determine the long and short time effects of nitric oxide on adult neural stem cells.
T309 944766-944777 Sentence denotes Background:
T310 944778-944927 Sentence denotes Nitric oxide, NO, is produced in high concentrations in the CNS of multiple sclerosis patients, where it contributes to the tissue damage seen in MS.
T311 944928-944936 Sentence denotes Methods:
T312 944937-945027 Sentence denotes Adult neural stem cells (rat) were exposed to Deta-NONO:ate 0.01-2.5 mM for 2, 8 and 24 h.
T313 945028-945085 Sentence denotes NO release was calibrated using a NO sensitive electrode.
T314 945086-945173 Sentence denotes The NO-effects on cell viability and differentiation were assessed after 2, 8 and 24 h.
T315 945174-945324 Sentence denotes Necrosis and apoptosis was studied using propidium Iodide/Annexin V (flow cytometry) and JC-1 staining which also was assessed by immunocytochemistry.
T316 945325-945482 Sentence denotes The effects of NO on differentiation were assessed by immunolabeling the cells for neuronal (Tuj), oligodendrocyte-(O4) and astrocyte-(GFAP) lineage markers.
T317 945483-945491 Sentence denotes Results:
T318 945492-945612 Sentence denotes Nitric oxide administered to stem cell cultures had dose dependent effects on survival and differentiation of the cells.
T319 945613-945729 Sentence denotes There was dose dependent damage to the cells as determined by flow cytometry for annexin V/propidiumiodide and JC-1.
T320 945730-945828 Sentence denotes The levels of NO released from the donor above 1 mM is comparable to the levels found in patients.
T321 945829-945947 Sentence denotes Above 1 mM, the capacity of the stem cell to form neurons and oligodendrocytes is lost and only astrocytes are formed.
T322 945948-945994 Sentence denotes NO-depleted DETA-NONO:ate was used as control.
T323 945995-946006 Sentence denotes Conclusion:
T324 946007-946096 Sentence denotes The CSF nitric oxide levels of MS patients affect stem cell survival and differentiation.
T325 946097-946212 Sentence denotes Neurotoxicity induced by LTA-activated glial cells is mediated by nitric oxide production and caspase activation A.
T326 946213-946227 Sentence denotes Kinsner a , S.
T327 946228-946241 Sentence denotes Coecke a , T.
T328 946242-946260 Sentence denotes Hartung a,b and A.
T329 946261-946578 Sentence denotes Price a a ECVAM, European Commission Join Research Centre, Ispra (VA,) Italy; b Dept. of Biochemical Pharmacology, University of Konstanz, Konstanz, Germany In central nervous system (CNS) pro-inflammatory potential of lipoteichoic acid (LTA) derived from the Gram-positive bacterial cell wall is still controversial.
T330 946579-946847 Sentence denotes We investigated whether LTAFMDP (muramyl dipeptide) could activate rat cortical glial cells (astrocytes and/or microglia) by measuring IL-1beta, TNF-alpha and nitric oxide (NO) production that subsequently could induce neuronal cell death and if so by what mechanisms.
T331 946848-947062 Sentence denotes Indeed LTA in synergy with MDP (active principle of peptidoglycan) induced strong inflammatory response of both types of glial cells as time-and dose-dependent production of IL-1beta, TNF-alpha and NO was observed.
T332 947063-947269 Sentence denotes To study whether activated glia could induce neuronal cell death, we exposed cerebellar granule cells (CGCs) cultured in the presence of glia (~15% non-neuronal cells) to LTA (30 Ag/ml) and MDP (100 ng/ml).
T333 947270-947389 Sentence denotes After 72 h, significant neuronal cell death was observed (70-90%) as assessed by propidium iodide and Hoechst staining.
T334 947390-947613 Sentence denotes Indeed, the death of CGCs was caused by activated glia as in the absence of glia (treatment with 7.5 AM cytosine-d-arabinoside to inhibit non-neuronal cell proliferation) LTA+MDP did not cause significant cell death (~20%).
T335 947614-947880 Sentence denotes The neuronal cell death induced by LTA and MDP-activated glia was significantly blocked by iNOS inhibitor (100 AM 1400 W) and broad-spectrum caspase inhibitor (50 AM z-VAD-fmk) suggesting that neuronal cell death was mediated by NO production and caspase-activation.
T336 947881-947992 Sentence denotes This mechanism may contribute to neurodegeneration observed in CNS infections caused by Gram-positive bacteria.
T337 947993-947997 Sentence denotes Aim:
T338 947998-948137 Sentence denotes Cytotoxic T cells are involved in West Nile virus (WNV) encephalitis, and are the predominant lymphocyte population infiltrating the brain.
T339 948138-948334 Sentence denotes We aimed at determining the role of the Tc cell cytolytic pathways, granule exocytosis (mediated by perforin and granzymes) and Fas-triggered killing, in either virus clearance or immunopathology.
T340 948335-948466 Sentence denotes Methods: C57BL/6J wildtype and mutant mice defective in cytolytic effector molecules were infected i.v. with WNV (Sarafend strain).
T341 948467-948531 Sentence denotes Virus was detected by plaque titration and immunohistochemistry.
T342 948532-948598 Sentence denotes Cytotoxicity of splenocytes was measured by in vitro 51Cr-release.
T343 948599-948607 Sentence denotes Results:
T344 948608-948855 Sentence denotes Infection of CD8+ T cell-deficient mice (beta2mÀ/À) with high doses of WNV (10 8 PFU) resulted in reduced mortality with prolonged mean survival time (MST), whereas infection with low doses (10 3 PFU) led to increased mortality with prolonged MST.
T345 948856-948923 Sentence denotes Transfer of WNV-immune CD8+ T cells reduced WNV-mediated mortality.
T346 948924-949126 Sentence denotes Mice with defects in the granule exocytosis pathway of cytotoxicity are at higher risk of encephalitis and death, but perforin by itself does not play a crucial role in the recovery from WNV infections.
T347 949127-949218 Sentence denotes Deficiency of either Fas or FasL did not markedly affect the susceptibility of mice to WNV.
T348 949219-949349 Sentence denotes However, mice with deficiency in Fas and perf (perfÀ/Àgld) displayed a higher incidence of encephalitis and death after infection.
T349 949350-949362 Sentence denotes Conclusions:
T350 949363-949493 Sentence denotes Granule exocytosis as well as the Fas pathway of cytotoxicity are involved in recovery and immunopathology in mouse WNV infection.
T351 949494-949588 Sentence denotes TMEV induces, in SJL mice, early acute disease followed by late chronic demyelinating disease.
T352 949589-949676 Sentence denotes During early acute disease, the virus is partially cleared from the CNS by CD3 T cells.
T353 949677-949740 Sentence denotes These T cells express Fas, FasL and negligible levels of Bcl-2.
T354 949741-949911 Sentence denotes At 3 days post infection (dpi), but not at 8 dpi, CD3 T cells infiltrating the CNS of SJL mice express significantly higher proportions of CTLA-4 versus those in B6 mice.
T355 949912-950023 Sentence denotes In vivo labeling with BrdU revealed that 15% of CNS-infiltrating T cells is cycling during early acute disease.
T356 950024-950128 Sentence denotes Large proportion of these cells showed a phenotype of activated effector cells (CD44hi CD64lo/-, CD25+).
T357 950129-950217 Sentence denotes These T cells were undergoing AICD resulting in downsizing of the inflammatory response.
T358 950218-950300 Sentence denotes TUNEL assay revealed that 30.1% of CD3 T cells were undergoing apoptosis at 8 dpi.
T359 950301-950398 Sentence denotes In contrast, during late chronic demyelinating disease only few mononuclear cells were apoptotic.
T360 950399-950469 Sentence denotes CNS infiltrating T cells expressed high levels of Fas, FasL and Bcl-2.
T361 950470-950548 Sentence denotes 26% of these CD3 T cells were memory cells while 98.6% were arrested in G0/G1.
T362 950549-950788 Sentence denotes Lack of in situ proliferation of T cells expressing high levels of Bcl-2 in the CNS and the paucity of apoptosis are likely responsible for the accumulation of these T cells in the CNS during late chronic demyelinating disease in SJL mice.
T363 950789-950879 Sentence denotes Identification of astrocyte-derived genes that induce apoptosis of autoreactive T cells H.
T364 950880-950891 Sentence denotes Hara and T.
T365 950892-950957 Sentence denotes Tabira National Institute for Longevity Sciences, Obu City, Japan
T366 950958-951034 Sentence denotes In EAE, apoptosis of T cells is mainly seen at the site of CNS inflammation.
T367 951035-951143 Sentence denotes There are some reports that astrocytes may render T cells susceptible for induction of apoptotic cell death.
T368 951144-951296 Sentence denotes In this study, we have identified and cloned the genes derived from IFN-gamma-treated astrocyte cell line that induce apoptosis of autoreactive T cells.
T369 951297-951406 Sentence denotes We made the subtracted cDNA libraries from IFN-gamma-treated astrocyte cell line and got 100 positive clones.
T370 951407-951503 Sentence denotes All clones were sequenced and 50 genes with interest were transfected to CHO cells individually.
T371 951504-951692 Sentence denotes Activated PLP-reactive CD4+ T cell line were co-cultured with each transfected CHO cells, then, T cell were harvested and stained with Annexin V-FITC and PI and analyzed by flow cytometry.
T372 951693-951779 Sentence denotes We identified two candidate genes that induced apoptosis of PLP-reactive T cell lines.
T373 951780-951908 Sentence denotes First gene is unknown gene, named as astrocytederived immune suppressor factor (AdIF) and its length is 726 bp, 228 amino acids.
T374 951909-951976 Sentence denotes Recombinant AdIF protein was made by Drosophilae expression system.
T375 951977-952105 Sentence denotes After acute EAE was induced in C57BL6/J mice by immunization with MOG peptide plus CFA, AdIF protein was injected intravenously.
T376 952106-952216 Sentence denotes The treated group showed significant ameliorations of clinical EAE scores and pathological changes in the CNS.
T377 952217-952283 Sentence denotes This AdIF may be effective in the treatment of multiple sclerosis.
T378 952284-952381 Sentence denotes Regulation of natural killer cell stimulatory and inhibitory molecules in mouse nervous system E.
T379 952382-952402 Sentence denotes Backström a , A.F.J.
T380 952403-952416 Sentence denotes Drenth a , H.
T381 952417-952432 Sentence denotes Sjflin b , H.G.
T382 952433-952451 Sentence denotes Ljunggren c and K.
T383 952452-952903 Sentence denotes Kristensson a a Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden; b Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm, Sweden; c Center for Infectious Medicine, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden Expression of ligands for stimulatory and inhibitory natural killer (NK) cell receptors may determine whether neurons are susceptible or resistant to NK cell-mediated cytolysis.
T384 952904-953304 Sentence denotes By using real time PCR, the expression of ligands for the stimulatory receptor NKG2D as well as ligands for NK cell inhibitory receptors in dorsal root ganglia (DRG) were analyzed in vivo, after a peripheral nerve lesion, and in vitro, in DRG neuronal cultures exposed to interferon (IFN)-gamma or LPS, or infected with murine cytomegalovirus (MCMV) or a neurotropic influenza A virus strain, WSN/33.
T385 953305-953522 Sentence denotes Peripheral nerve lesions are associated with a decrease in levels of RAE1 and murine UL16-binding protein-like transcript 1 (MULT1), but an increase in levels of classical MHC class I transcripts in DRG of adult mice.
T386 953523-953707 Sentence denotes The study also shows that IFN-gamma and LPS caused a marked induction of classical and nonclassical major histocompatibility complex (MHC) class I encoding transcripts in DRG cultures.
T387 953708-953873 Sentence denotes Cultures infected with either MCMV or WSN/33 showed a significant increase in the expression of transcripts encoding RAE1 and classical and nonclassical MHC class I.
T388 953874-954016 Sentence denotes Exogenous agents as well as peripheral nerve lesions can alter the expression of NK cell stimulatory and inhibitory ligands in nervous tissue.
T389 954017-954097 Sentence denotes Mechanism of resistance of microglia to quinolinic acid-mediated cell death C.M.
T390 954098-954112 Sentence denotes Figueiredo, M.
T391 954113-954130 Sentence denotes Faria Pais and S.
T392 954131-954414 Sentence denotes Chatterjee Instituto Gulbenkian Ciência, Oeiras, Portugal Brain macrophages, microglia, respond to traumatic injury or to pathogens in Central Nervous System by migrating to the site of injury, where they may proliferate and release inflammatory cytokines, and potential neurotoxins.
T393 954415-954589 Sentence denotes In addition, microglia when activated releases a metabolite of the tryptophan-kynurenine pathway, quinolinic acid (QA), which can be implicated in neurodegenerative diseases.
T394 954590-954664 Sentence denotes QA can induce neurotoxicity through N-methyl-d-aspartate receptor (NMDAR).
T395 954665-954841 Sentence denotes NMDAR is a heteromeric complex composed of two classes of subunits, the essential NR1 and NR2A to D that potentiate NR1 activity and confer functional variability to the NMDAR.
T396 954842-955036 Sentence denotes Interestingly, unlike neurons primary microglia is resistant to QA challenge; therefore analysis of the mechanism of resistance of microglia to quinolinic acid-mediated cell death was performed.
T397 955037-955354 Sentence denotes Results from fluorescence staining with propidium iodide, calcium imaging, Western Blot and RT-PCR analysis showed that QA stimulates NMDAR primary cerebellar granule neurons but not microglia; inducing an increased Ca2+ influx and activation of the extracellular signal regulated kinase, and consequently cell death.
T398 955355-955481 Sentence denotes The two cell types possess same protein levels of NR1 subunit, but microglia did not express mRNA of the other NMDAR subunits.
T399 955482-955618 Sentence denotes A specific NR1-NR2B complex blocker, ifenprodil, rescues cell death, suggesting that QA may bind to NR2B, a subunit absent in microglia.
T400 955619-955793 Sentence denotes Characterization and functional implication of the NMDAR in microglia and in neurons in perspective of the differential response to QA will be discussed in this presentation.
T1 955794-955910 Sentence denotes Beta amyloid 1-40 peptide selectively downregulates MMP-9 production in differentiated SH-SY5Y neuronal cell line M.
T2 955911-955926 Sentence denotes Ruggieri a , F.
T3 955927-955941 Sentence denotes Roselli a , C.
T4 955942-955953 Sentence denotes Pica a , A.
T5 955954-955964 Sentence denotes Lia a , C.
T6 955965-955978 Sentence denotes Avolio b , M.
T7 955979-955995 Sentence denotes Trojano a and P.
T8 955996-956088 Sentence denotes Livrea a a University of Bari, Bari, Italy; b University of Foggia, Foggia, Italy Objective:
T9 956089-956205 Sentence denotes Neuronal Matrix Metalloproteinases (MMPs) may be involved in memory consolidation processes and synaptic plasticity.
T10 956206-956291 Sentence denotes MMP-9 expression has been detected in dentate gyrus neuron cell bodies and dendrites.
T11 956292-956430 Sentence denotes Amyloid accumulation in strategic brain areas induce memory dysfunctions, but the effect of amyloid peptides on neuronal MMPs are unknown.
T12 956431-956536 Sentence denotes We tested whether amyloid peptides could alter MMPs (or their inhibitors) production by neurons in vitro.
T13 956537-956545 Sentence denotes Methods.
T14 956546-956647 Sentence denotes SH-SY5Y human neuroblastoma cell cultures were treated with 1-40 Abeta at 0.5 and 5 AM or by vehicle.
T15 956648-956780 Sentence denotes Supernatants were collected after 24 and 48 h incubation and MMP-9, MMP-2 (activity assay) and TIMP-1, TIMP-2 (ELISA) were detected.
T16 956781-956834 Sentence denotes Cell death was evaluated by vital dye exclusion test.
T17 956835-956843 Sentence denotes Results.
T18 956844-957067 Sentence denotes MMP-9 levels were markedly reduced in both 0.5 and 5 AM Abeta treated cell supernatants versus negative controls at 24 h ( pb0.002) and 48 h ( pb0.002); no differences were detected between 0.5 and 5 AM Abeta treated cells.
T19 957068-957124 Sentence denotes MMP-2, TIMP-1 and TIMP-2 were unchanged between samples.
T20 957125-957185 Sentence denotes Vitality did not differ between treated and untreated cells.
T21 957186-957198 Sentence denotes Conclusions:
T22 957199-957259 Sentence denotes 1-40 Abeta selectively inhibits MMP-9 production in neurons.
T23 957260-957436 Sentence denotes This effect could not be due to cell toxicity because it is restricted to MMP-9, with unchanged MMP-2 and TIMPs and with unchanged cell death in treated versus untreated cells.
T24 957437-957562 Sentence denotes The down regulation of MMP-9 induced by 1-40 Abeta may play a role in age related memory impairment and in Alzheimer disease.
T25 957563-957697 Sentence denotes Immunization with myelin oligodendrocyte glycoprotein (MOG 35-55) slows down the recovery of dopaminergic neurons injured with MPTP I.
T26 957698-957726 Sentence denotes Kurkowska-Jastrzebska a , E.
T27 957727-957749 Sentence denotes Balkowiec-Iskra b , I.
T28 957750-957763 Sentence denotes Joniec b , A.
T29 957764-957784 Sentence denotes Czlonkowski b and A.
T30 957785-958027 Sentence denotes Czlonkowska a,b a Institute of Psychiatry and Neurology, Warsaw, Poland; b Medical University of Warsaw, Warsaw, Poland 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration causes an injury of nigrostriatal dopaminergic neurons.
T31 958028-958160 Sentence denotes The inflammatory reaction follows the dopaminergic neurons impairment, and is believed to contribute to neuronal death and survival.
T32 958161-958373 Sentence denotes As it is postulated that additional brain inflammation may modulate neurodegenerative process, we would like to examine an influence of immune system enhancement on the recovery after toxic insult caused by MPTP.
T33 958374-958501 Sentence denotes Male, 2 months old C57BL10 mice received 40 mg/kg MPTP i.p. and after 7 days they were immunized with MOG 35-55 peptide in CFA.
T34 958502-958649 Sentence denotes Mice receiving MPTP showed a 63% decrease of dopamine content in striatum on the 7th day following MPTP administration as compared to control mice.
T35 958650-958790 Sentence denotes From the 14th day dopamine content increased and was less than in the control by 52%, 42% and 18% on 14th, 28th, and 50th day, respectively.
T36 958791-959018 Sentence denotes In group of mice receiving additional immunization the recovery was however slower as compared to nonimmunized mice, and dopamine content decrease was less than in the control by 75%, 59% and 33% on the same days, respectively.
T37 959019-959172 Sentence denotes Thus immunization with MOG after MPTP intoxication resulted in deeper dopamine depletion and the worse recovery of dopaminergic neurons after the insult.
T38 959173-959295 Sentence denotes Tumor necrosis factor (TNF) induces apoptotic-like cell death of oligodendrocytes, cell target in multiple sclerosis (MS).
T39 959296-959439 Sentence denotes Human adult oligodendrocytes (hOLs) and microglial cells (MG) were prepared from human brain specimen obtained during neurosurgical procedures.
T40 959440-959555 Sentence denotes The cells were stimulated with TNF and cell death was detected by annexinV-FITC and PI staining and flow cytometry.
T41 959556-959877 Sentence denotes We defined that intracellular transduction pathway involved in TNF-induced death of hOLs is noncaspase dependent as evidenced by lack of generation of active subunits of caspase-8, -1 and -3 detected on Western blot as well as the lack of cleavage of fluorogenic substrates of caspase-1 and -3 measured by flow cytometry.
T42 959878-959968 Sentence denotes In addition, the general caspase inhibitor ZVAD.FMK did not prevent TNFinduced hOLs death.
T43 959969-960143 Sentence denotes Also calpain inhibitor ZLLY.FMK, serine proteases inhibitor, TPCK, and cathepsin inhibitors, ZFL and ca-074-Me, were inefficient in prevention of TNF-induced hOLs cell death.
T44 960144-960295 Sentence denotes Electrophoresis of TNF-exposed hOLs DNA revealed a large scale DNA fragmentation characteristic for apoptosis inducing factor (AIF)-induced cell death.
T45 960296-960350 Sentence denotes In TNF-stimulated hOLs AIF was translocated to nuclei.
T46 960351-960443 Sentence denotes Accordingly, hOLs death was prevented by inhibition of AIF using antisense strategy (asAIF).
T47 960444-960605 Sentence denotes Inhibition of AIF with asAIF led to significant decrease of AIF expression in hOLs but did not affect the TNF-induced change of mitochondrial membrane potential.
T48 960606-960797 Sentence denotes These results indicate that TNF-induced hOLs death depends critically on AIF activation and might have significant importance in designing new molecules to protect hOLs in multiple sclerosis.
T49 960798-960931 Sentence denotes Leukemia inhibitory factor is produced by myelin reactive T-cells and protects against cytokine induced oligodendrocyte cell death J.
T50 960932-960950 Sentence denotes Vanderlocht a , N.
T51 960951-960966 Sentence denotes Hellings a , F.
T52 960967-960986 Sentence denotes Vandenabeele a , M.
T53 960987-961001 Sentence denotes Moreels a , J.
T54 961002-961014 Sentence denotes Antel b , J.
T55 961015-961028 Sentence denotes Raus a and P.
T56 961029-961324 Sentence denotes Stinissen a a Limburgs Universitair Centrum, Diepenbeek, Belgium; b McGill University, Montreal, Canada Leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF) are members of the neuropoietic family of neurotrophins and ameliorate experimental autoimmune encephalomyelitis (EAE).
T57 961325-961464 Sentence denotes We examined whether human T-cells specific for myelin basic protein (MBP) and myelin oligodendrocyte protein (MOG) are able to secrete LIF.
T58 961465-961632 Sentence denotes 10/19 myelin reactive T-cell lines/clones (TCL) from eight multiple sclerosis (MS) patients and 5/11 TCL from five healthy controls (HC) produced LIF upon stimulation.
T59 961633-961711 Sentence denotes The mean net LIF secretion of MS TCL did not significantly differ from HC TCL.
T60 961712-961751 Sentence denotes LIF expression was confirmed by RT-PCR.
T61 961752-961860 Sentence denotes In addition, TCL specific for tetanus toxoid, monocytes, CD4+ and CD8+ Tcells, but not B-cells secreted LIF.
T62 961861-961992 Sentence denotes LIF secreting T-lymphocytes and macrophages could also be identified immunohistochemically in active and chronic active MS lesions.
T63 961993-962149 Sentence denotes We further demonstrated dose-dependent protective effects of both CNTF and LIF on TNF-alpha induced apoptosis in HOG cells and rat oligodendrocyte cultures.
T64 962150-962272 Sentence denotes At concentrations of 10-20 ng/ml both neurokines completely protected oligodendrocytes against cytokine induced apoptosis.
T65 962273-962338 Sentence denotes Post-treatment with neurokines was as effective as pre-treatment.
T66 962339-962462 Sentence denotes In conclusion, our in vitro studies indicate that LIF and CNTF are possible candidates for therapeutic interventions in MS.
T67 962463-962564 Sentence denotes Factors that enhance the production of neurotrophins by T cells may provide new tools for MS therapy.
T68 962565-962782 Sentence denotes To elucidate pathogenic circuits between immune and neuroendocrine systems, we are examining the emergence of behavioral deficits that temporally coincide with impaired dopamine catabolism in lupus-prone MRL-lpr mice.
T69 962783-962882 Sentence denotes Our hypothesis is that systemic autoimmunity affects central dopaminergic systems in diseased mice.
T70 962883-963012 Sentence denotes The functional damage of the nigrostriatal pathway was assessed from rotational behavior after a single injection of apomorphine.
T71 963013-963127 Sentence denotes Amphetamine was employed to further probe the relationship between mesolimbic damage and depressive-like behavior.
T72 963128-963258 Sentence denotes Neurodegeneration in the midbrain was estimated by Fluoro Jade B (FJB) staining and tyrosine-hydroxylase (TH) immunocytochemistry.
T73 963259-963469 Sentence denotes In comparison to young and age-matched controls, diseased MRL-lpr mice showed increased circling following an apomorphine injection and failed to increase palatable food consumption after receiving amphetamine.
T74 963470-963611 Sentence denotes Increased FJB-positive neurons and a profound reduction in TH-positive somas confirmed mesencephalon cell loss in behaviorally impaired mice.
T75 963612-963667 Sentence denotes Our study coincided with the death of a NP-SLE patient.
T76 963668-963819 Sentence denotes Neuropathologic changes observed in the patient's basal ganglia were similar to MRL-lpr neuropathology, strengthening the validity of our NP-SLE model.
T77 963820-963936 Sentence denotes In summary, results suggest that systemic autoimmunity damages dopaminergic systems and induces behavioral deficits.
T78 963937-964071 Sentence denotes Electronic microscopy is presently being employed to elucidate the mode of neuronal death and results will be reported at the meeting.
T79 964072-964127 Sentence denotes Supported by funds from NIH and CIHR to B.S. and D.A.B.
T80 964128-964186 Sentence denotes Immunoglobulins in cytotoxic CSF from autoimmune mice M.M.
T81 964187-964199 Sentence denotes Sidor and B.
T82 964200-964205 Sentence denotes Sakic
T83 964206-964350 Sentence denotes Neuropsychiatric lupus (NP-SLE) is a complex manifestation of unknown etiology that can occur during the course of systemic lupus erythematosus.
T84 964351-964427 Sentence denotes We use the lupus-prone MRL-lpr murine model to study the etiology of NP-SLE.
T85 964428-964657 Sentence denotes Our previous experiments have revealed that leukocyte infiltration into the brain, cell loss in periventricular areas, and cytotoxic cerebrospinal fluid (CSF) coincide temporally with behavioural deficits in diseased MRLlpr mice.
T86 964658-964809 Sentence denotes The presence of B-cells in the choroid plexus and toxicity of IgGrich CSF fractions suggest intrathecal synthesis of autoantibodies to neuronal tissue.
T87 964810-964920 Sentence denotes The present study examines whether cytotoxic CSF from diseased MRL-lpr mice exhibits a unique protein profile.
T88 964921-965104 Sentence denotes Western blotting has revealed distinct IgG bands in the CSF of 16-to 20-week-old MRL-lpr mice, with a 25-kDa band occurring more frequently than in age-matched controls (79% vs. b1%).
T89 965105-965153 Sentence denotes This band was absent in all asymptomatic groups.
T90 965154-965340 Sentence denotes Intensity of the IgG bands show positive correlation with splenomegaly, suggesting that progress of systemic autoimmunity and inflammation are associated with changes in the CSF content.
T91 965341-965547 Sentence denotes At the meeting we will report whether in vitro CSF toxicity is associated with presence of the 25-kDa band, whether this band is produced intrathecally, and whether it is a product or cause of brain damage.
T92 965548-965599 Sentence denotes This work was supported by funds from the NIH to B.
T93 965600-965688 Sentence denotes Sakic, recipient of the Father Sean O'sullivan Research Centre career development award.
T94 965689-965813 Sentence denotes Glatiramer acetate induces pro-apoptotic mechanisms involving Bcl-2, Bax and Cyt-c in multiple sclerosis treated patients M.
T95 965814-965829 Sentence denotes Ruggieri a , S.
T96 965830-965843 Sentence denotes Scacco a , C.
T97 965844-965855 Sentence denotes Pica a , A.
T98 965856-965866 Sentence denotes Lia a , S.
T99 965867-965878 Sentence denotes Papa a , P.
T100 965879-965892 Sentence denotes Livrea a , M.
T101 965893-965909 Sentence denotes Trojano a and C.
T102 965910-966089 Sentence denotes Avolio b a University of Bari, Bari, Italy; b University of Foggia, Foggia, Italy Apoptotic deletion of autoreactive T cells is defective in patients with Multiple Sclerosis (MS).
T103 966090-966174 Sentence denotes Glatiramer acetate (GA) may be effective to induce apoptosis of detrimental T cells.
T104 966175-966390 Sentence denotes We analyzed pro-(Bax, Cyt-c, APAF-1) and anti-(Bcl-2) apoptotic proteins in peripheral blood mononuclear cells (PBMNCs) cytosol and mitochondria membranes during GA treatment in relapsing-remitting (RR) MS patients.
T105 966391-966539 Sentence denotes Blood samples from eight RR MS patients were collected before and every 3 months during 9 months of GA treatment and from six healthy controls (HC).
T106 966540-966643 Sentence denotes PBMNCs Bcl-2, Bax, Cyt-c and APAF-1 were quantified by Western blot followed by densitometric scanning.
T107 966644-966715 Sentence denotes The percentage of apoptotic cells was assessed by a dye exclusion test.
T108 966716-966796 Sentence denotes T-cells were in vitro tested for oxigen consumption by a respirometric analysis.
T109 966797-966895 Sentence denotes A decrease ( p=0.005) in Bcl-2 and an increase ( p=0.02) in Bax during GA treatment were observed.
T110 966896-967064 Sentence denotes Cytosolic Cyt-c trended to increase ( p=0.05) during treatment, suggesting a release of Cyt-c from mitochondria membranes to cytosol, whereas APAF-1 remained unchanged.
T111 967065-967145 Sentence denotes An increase in the percentage of apoptotic PBMNCs was observed during treatment.
T112 967146-967238 Sentence denotes A reduction by 58% in oxygen consumption by T-cells was evident after GA treatment in vitro.
T113 967239-967446 Sentence denotes Our findings suggest that GA might exert a regulatory effect on peripheral T lymphocytes through pro-apoptosis mechanisms involving the downregulation of Bcl-2 and an upregulation of Bax and cytosolic Cyt-c.
T114 967447-967533 Sentence denotes Modulation of soluble Fas levels in patients with Herpes simplex encephalitis (HSE) F.
T115 967534-967543 Sentence denotes Sabri, A.
T116 967544-967559 Sentence denotes Hjalmarsson, F.
T117 967560-967571 Sentence denotes Granath, K.
T118 967572-967586 Sentence denotes Lfvgren and B.
T119 967587-967648 Sentence denotes Skfldenberg Karolinska University Hospital, Stockholm, Sweden
T120 967649-967747 Sentence denotes Herpes simplex encephalitis (HSE) is the most common cause of sporadic, severe viral encephalitis.
T121 967748-967865 Sentence denotes There is evidence of a vigorous intrathecal immune response during the acute phase of HSE and at long-term follow up.
T122 967866-968125 Sentence denotes We hypothesize that the severity and the progression of the cerebral injury resulting from HSE can be evaluated by quantitative measurement of different compartments of immune activation molecules, such as soluble Fas (sFas), a molecule involved in apoptosis.
T123 968126-968288 Sentence denotes Cerebral spinal fluid (CSF) and serum sFas levels in 242 consecutive samples from 42 HSE patients in a Vidarabine -Acyclovir trial were analyzed by capture ELISA.
T124 968289-968469 Sentence denotes Interestingly, the sFas levels in CSF were highest in HSE patients who died, and lowest in those with no or mild sequels and in-between in patients with moderate or severe outcome.
T125 968470-968584 Sentence denotes No detectable sFas found in CSF samples from 35 patients with non-HSE encephalitis or in 18 persons with headache.
T126 968585-968749 Sentence denotes The sFas levels in the last serum sample obtained were higher in HSE patients with comatose state compared to those being semicomatose or lethargic at presentation.
T127 968750-968867 Sentence denotes A similar pattern was observed in serum samples with highest sFas during disease progression in the three HSE groups.
T128 968868-969085 Sentence denotes These observations enforce the role of immune activation state, observed in serum, during the acute phase of HSE and in CSF, in particular, at disease progression, which might reflect the apoptotic state in the brain.
T129 969086-969186 Sentence denotes Oxidative stress and NF-kB activation are suggested to be linked to acute and chronic inflammations.
T130 969187-969387 Sentence denotes Recent studies showed that activation of the receptor for advanced glycated end products (RAGE) by its specific ligand (CML) results in activation of NF-kB and production of proinflammatory cytokines.
T131 969388-969646 Sentence denotes To determine the possible role of this pathway in the pathogenesis of vasculitic neuropathy we investigated the immunolocalisation of CML, RAGE, NFkB and IL6 in sural nerve biopsies of 12 patients with vasculitic neuropathy and eight controls (normal, HMSN).
T132 969647-969810 Sentence denotes CML, RAGE, NFkB and IL6 could be localized in infiltrating mononuclear cells in epineurial and endoneurial vessels and in the perineurium in vasculitic neuropathy.
T133 969811-969923 Sentence denotes Controls showed sporadic weak staining for the four antigens in vessel walls and for CML/IL6 in the perineurium.
T134 969924-970037 Sentence denotes Colocalisation studies demonstrated a CML-, RAGE-, and IL6 expession in CD4+, CD8+ and CD68+ cells in vasculitis.
T135 970038-970122 Sentence denotes Activated NFkB was expressed by CD4+, CD8+ and CD68+ mononuclear infiltrating cells.
T136 970123-970302 Sentence denotes Our data suggest that CML induced, RAGE mediated NF-kB activation resulting in elevated IL6 production is a proinflammatory mechanism in the pathogenesis of vasculitic neuropathy.
T137 970303-970581 Sentence denotes The therapeutic use of antioxidants like vitamin E, alpha-lipoic-acid or benfotiamine causing a reduction of intracellular oxidative stress and extracellular CML formation as shown in various models for late diabetic complications should be evaluated in vasculitic neuropathies.
T138 970582-970632 Sentence denotes NGF and NGF-receptor in myastenia gravis thymus L.
T139 970633-970646 Sentence denotes Aloe a , T.S.
T140 970647-970662 Sentence denotes Marinova b , D.
T141 970663-970678 Sentence denotes Petrov c and L.
T142 970679-970902 Sentence denotes Manni a a Institute of Neurobiology and Molecular Medicine, CNR, Rome, Italy; b Department of Biology, Medical University, Sofia, Bulgaria; c Department of General and Clinical Pathology, Medical University, Sofia, Bulgaria
T143 970903-971236 Sentence denotes We have previously reported that autoimmune inflammatory disorders are associated with altered levels of nerve growth factor (NGF), that immune cells produce NGF and express NGF-receptors (NGF-R), and prospected the hypothesis that these two NGF markers should be considered as signals for cell-to-cell recognition in immune systems.
T144 971237-971346 Sentence denotes We have now analyzed the distribution of NGF and NGF-R in the thymus of subjects with Myasthenia Gravis (MG).
T145 971347-971547 Sentence denotes Thymuses from healthy and MG subjects, removed in accordance with Helsinki Convention, and Ethical Medical Board consent, were used for structural, ultrastructural, biochemical and molecular analysis.
T146 971548-971777 Sentence denotes The results showed the presence of NGF and of NGF-R in thymic epithelial cells and in mast cells of control subjects, and an altered expression of these NGF markers, both at protein and gene expression levels, in the MG thymuses.
T147 971778-971960 Sentence denotes These observations and studies showing that administration of NGF in laboratory animals retards thymic cell death suggest that thymic cells regulate NGF through autocrine mechanisms.
T148 971961-972158 Sentence denotes Thus NGF represents an important biological mediator not only for nerve cells but also for immune cells and most probably for transmitting signals back and forth between nervous and immune systems.
T149 972159-972172 Sentence denotes Supported by:
T150 972173-972233 Sentence denotes Progetto di Ricerca Multicentrico Triennale, CARISBO, Italy.
T151 972234-972336 Sentence denotes Spinal neuroimmune activation induces behavioral sensitization in the animal models of chronic pain V.
T152 972337-972355 Sentence denotes Raghavendra and J.
T153 972356-972609 Sentence denotes DeLeo Anesthesiology/Pharmacology, Dartmouth-Hitchcock Medical Center, Lebanon, USA Recent evidence suggests that activation of intrinsic inflammatory immune responses in the CNS contribute to the development and maintenance of behavioral sensitization.
T154 972610-972795 Sentence denotes In this study, we examined the pattern of glial activation and proinflammatory cytokine expression at the lumbar spinal cord in a rat model of neuropathic and chronic inflammatory pain.
T155 972796-972913 Sentence denotes Further, the role of spinal neuroimmune activation in the development of allodynia and hyperlagesia was investigated.
T156 972914-973185 Sentence denotes Gene expression, studied by real-time RT-PCR, for glial markers (GFAP and S100B for astrocytes, and Mac-1, TLR4 and CD14 for microglia), and prinflammatory cytokines (IL-1beta, IL-6 and TNF-alpha) showed a differential upregulation following nerve injury or inflammation.
T157 973186-973388 Sentence denotes Protein quantification (by immunohistochemistry, ELISA and Western blot analysis) in these rats also revealed glial activation and enhanced proinflammatory cytokine expression at the lumbar spinal cord.
T158 973389-973600 Sentence denotes Central administration of dexamethasone 21-phosphate attenuated both neuroimmune activation and the development of behavioral allodynia and hyperalgesia in the animal models of neuropathic and inflammatory pain.
T159 973601-973781 Sentence denotes This study provides data to implicate a role of glia and proinflammatory cytokines in the development of behavioral hypersensitivity during peripheral nerve injury or inflammation.
T160 973782-973901 Sentence denotes Immunological mechanisms of autologous hematopoietic stem cell transplantation as a therapy for multiple sclerosis P.A.
T161 973902-973915 Sentence denotes Muraro a , K.
T162 973916-973928 Sentence denotes Chung a , D.
T163 973929-973943 Sentence denotes Douek a , H.F.
T164 973944-973962 Sentence denotes McFarland a , R.K.
T165 973963-973976 Sentence denotes Burt b and R.
T166 973977-974306 Sentence denotes Martin a a National Institutes of Health, Bethesda, MD, USA; b Northwestern University, Chicago, IL, USA High-dose immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) has shown strikingly beneficial effects on the disease course in a subset of patients with severe autoimmune diseases.
T167 974307-974377 Sentence denotes The mechanism of action of HSCT, however, has remained elusive so far.
T168 974378-974567 Sentence denotes We studied seven patients with multiple sclerosis (MS) after HSCT who had no toxicities or infectious adverse events and no signs of residual inflammatory disease activity during follow-up.
T169 974568-974661 Sentence denotes After 2 years, naRve CD4+ T cells more than doubled at the expense of central memory T cells.
T170 974662-974878 Sentence denotes T cell receptor excision circle analysis confirmed that the output of thymus-derived naRve CD4+ T cells after immune reconstitution substantially increased, reaching levels comparable to healthy age-matched controls.
T171 974879-975044 Sentence denotes Peripheral mechanisms contributing to recovery of immune tolerance included propensity of T cells to apoptosis and proliferative senescence of expanded CD8+ T cells.
T172 975045-975247 Sentence denotes Our findings demonstrate that abrogation of disease activity after HSCT is associated with a profound reconfiguration of the immune system and is not simply the effect of a protracted immunosuppression.
T173 975248-975370 Sentence denotes Intense immunosuppression followed by autologous stem cell transplantation as treatment for severe multiple sclerosis G.L.
T174 975371-975383 Sentence denotes Mancardi, A.
T175 975384-975495 Sentence denotes Uccelli and the Italian Gitmo-Neuro intergroup on ASCT for multiple sclerosis University of Genoa, Genoa, Italy
T176 975496-975762 Sentence denotes Based on studies on experimental models of autoimmunity, intense immunosuppression followed by autologous stem cell transplantation (ASCT) has been recently proposed as treatment for rapidly progressing multiple sclerosis (MS) unresponsive to conventional therapies.
T177 975763-975940 Sentence denotes It has been reported that such therapy can effect on MRI parameters of disease activity and halt disease progression in such severe MS forms, despite of relevant mortality risk.
T178 975941-976229 Sentence denotes Here we report the MRI and clinical follow up of 19 rapidly worsening MS patients with a high number of gadolinium-enhancing lesions at T0, treated with cyclophosphamide 4 g/m 2 as mobilizing regimen and BEAM (BCNU, Cytosine-Arabinoside Etoposide and Melphalan) as conditioning treatment.
T179 976230-976295 Sentence denotes The mean follow up is now 29 months, with a range of 2-54 months.
T180 976296-976340 Sentence denotes The treatment was relatively well tolerated.
T181 976341-976473 Sentence denotes More importantly, it strikingly abolished any MRI activity although it did not influence the progression of brain atrophy over time.
T182 976474-976559 Sentence denotes In most patients we observed also a clinical improvement or stabilization of disease.
T183 976560-976929 Sentence denotes The present results demonstrate that intense immunosuppression followed by ASCT has an effect on inflammation detected by MRI not comparable to any other currently available therapy, may successfully stabilize disease course and thus should be considered as therapeutic option for those MS subjects with poor prognostic factors not responding to conventional therapies.
T184 976930-977016 Sentence denotes Anti-ergotypic T cell responses in healthy controls and multiple sclerosis patients N.
T185 977017-977029 Sentence denotes Hellings, C.
T186 977030-977041 Sentence denotes Govarts, J.
T187 977042-977053 Sentence denotes Raus and P.
T188 977054-977145 Sentence denotes Stinissen Biomedisch Onderzoeksinstituut, Liburgs Universitair Centrum, Diepenbeek, Belgium
T189 977146-977301 Sentence denotes Peripheral regulatory mechanisms may prevent the expansion of autoreactive T-cells that play a role in autoimmune diseases such as multiple sclerosis (MS).
T190 977302-977430 Sentence denotes Anti-idiotypic and anti-ergotypic T-cells take part in these regulatory networks and can be boosted by T-cell vaccination (TCV).
T191 977431-977544 Sentence denotes We showed that TCV induces both long-term clonotypic and temporal antiergotypic responses (to activated T-cells).
T192 977545-977649 Sentence denotes This study aims to further characterize anti-ergotypic T-cells in MS patients and healthy controls (HC).
T193 977650-977733 Sentence denotes PBMC were stimulated with PHA-activated T-cell blasts as source of activated cells.
T194 977734-977817 Sentence denotes Proliferative anti-ergotypic responses were found in all HC and MS patients tested.
T195 977818-977985 Sentence denotes Anti-ergotypic short-term lines with a mixed CD4+/ CD8+TCRab+ phenotype produced high amounts of IFN-gamma, but no IL-4/IL-10 and were predominantly HLA-DR restricted.
T196 977986-978108 Sentence denotes Depletion experiments showed that CD4+ T-cells were mainly responsible for the observed in vitro anti-ergotypic responses.
T197 978109-978253 Sentence denotes Cytokine receptors including interleukin-2 receptor (IL-2R) have been identified as candidate targets of anti-ergotypic T-T interactions in EAE.
T198 978254-978370 Sentence denotes We tested reactivity to a peptide derived from the IL2R alpha chain containing a dominant epitope for HLA-DRB1*1501.
T199 978371-978458 Sentence denotes We were able to isolate T cell lines (TCL) specific for this IL2R peptide from four HC.
T200 978459-978574 Sentence denotes The TCL had a Th1/Th0 phenotype and proliferated strongly to activated but not resting tetanus toxoid specific TCL.
T201 978575-978704 Sentence denotes We are currently testing whether IL2R-specific TCL with similar properties can be isolated from MS patients before and after TCV.
T202 978705-978773 Sentence denotes This will help unravel their actual role in T-cell immunoregulation.
T203 978774-978937 Sentence denotes Boosting regulatory T cells in multiple sclerosis: immunogenicity and safety of a trivalent BV5S2, BV6S5 and BV13S1 CDR2 vaccine in incomplete Freund's adjuvant A.
T204 978938-978955 Sentence denotes Vandenbark a , R.
T205 978956-978976 Sentence denotes Bartholomes b and D.
T206 978977-979316 Sentence denotes Bourdette c a Veterans Affairs Medical Center, Portland, OR, USA; b Immune Response Corporation, Carlsbad, CA, USA; c Oregon Health and Science University Oregon Health and Science University, Portland, OR, USA T cell receptor (TCR) peptide vaccination represents a novel approach to boosting regulatory T cells in multiple sclerosis (MS).
T207 979317-979478 Sentence denotes Development of TCR peptide vaccination as a treatment for MS has been hindered by the relatively low immunogenicity of previously available TCR peptide vaccines.
T208 979479-979641 Sentence denotes For example, intradermal vaccination with a single CDR2 BV5S2 TCR peptide given without adjuvant induced regulatory TCR reactive T cells in 20-60% of MS subjects.
T209 979642-979915 Sentence denotes In an effort to develop a more effective vaccine, we compared intramuscular injections of a trivalent TCR vaccine containing BV5S2, BV6S5 and BV13S1 CDR2 peptides emulsified in incomplete Freund's adjuvant (IFA) with intradermal injections of the same peptides without IFA.
T210 979916-980166 Sentence denotes Six monthly injections of the trivalent/IFA vaccine induced vigorous T cell responses in 100% of subjects (9/9) and was significantly more immunogenic than the peptide/saline vaccine, which induced responses in only 20% of subjects (2/10) ( p=0.002).
T211 980167-980275 Sentence denotes Aside from injection site reactions, there were no significant adverse events attributable to the treatment.
T212 980276-980477 Sentence denotes While there were no significant clinical changes over the course of this short trial, subjects who had T cell responses to the trivalent TCR peptide vaccine showed a trend towards reduced MRI activity.
T213 980478-980645 Sentence denotes The trivalent TCR peptide in IFA vaccine represents a significant improvement over previous TCR peptide vaccines and warrants investigation of its ability to treat MS.
T214 980646-980824 Sentence denotes Atorvastatin regulates T cell anergy via the extracellular signal-related kinase pathway: a novel immunomodulatory function of 3-hydroxy-3methylglutaryl-CoA reductase inhibitors?
T215 980825-980827 Sentence denotes S.
T216 980828-980840 Sentence denotes Waiczies, C.
T217 980841-980859 Sentence denotes Infante-Duarte, T.
T218 980860-980875 Sentence denotes Prozorovski, S.
T219 980876-980888 Sentence denotes Pikol and F.
T220 980889-980999 Sentence denotes Zipp Institute of Neuroimmunology, Neuroscience Research Center, Charité, Humboldt University, Berlin, Germany
T221 981000-981197 Sentence denotes The 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoAR) inhibitors, statins, are orally administered cholesterol-lowering drugs, which have been shown to exhibit immunomodulatory properties.
T222 981198-981350 Sentence denotes We have previously reported that in vivo atorvastatin treatment could prevent and reverse disease progression in the animal model of multiple sclerosis.
T223 981351-981435 Sentence denotes However, the mechanism of immunomodulation by statins has yet to be fully clarified.
T224 981436-981577 Sentence denotes In the human system we report an influence of atorvastatin on cell cycle progression in peripheral T cells and antigen-specific T cell lines.
T225 981578-981818 Sentence denotes We could explain this by a failure of atorvastatin-treated cells to downregulate the negative cell cycle regulator p27Kip1 following a productive stimulus. p27Kip1 is specifically required for the induction and maintenance of T cell anergy.
T226 981819-981953 Sentence denotes In fact, we report here that following incubation with atorvastatin, T cells lose their capacity to respond to their specific antigen.
T227 981954-982095 Sentence denotes Anergy induction was shown to be dependent on HMG-CoAR, since we could reverse this with mevalonate, an intermediary product of this pathway.
T228 982096-982314 Sentence denotes Preliminary results also show that atorvastatin induces an unexpected activation of the extracellular signal-related kinase pathway, which we show, via blocking experiments, to be necessary for the induction of anergy.
T229 982315-982544 Sentence denotes Our results indicate that atorvastatin regulates T cell expansion via an induction of anergy and portray a novel immunomodulatory function of HMG-CoAR inhibitors in the treatment of autoimmune diseases such as multiple sclerosis.
T230 982545-982652 Sentence denotes Glatiramer acetate (Copaxone) therapy induces an oligoclonal CD8+ T cell response with cytotoxic ability R.
T231 982653-982662 Sentence denotes Mehta, S.
T232 982663-982670 Sentence denotes Yan, B.
T233 982671-982682 Sentence denotes Biegler, S.
T234 982683-982693 Sentence denotes Ortega, M.
T235 982694-982706 Sentence denotes Racke and N.
T236 982707-982919 Sentence denotes Karandikar UT Southwestern Medical Center, Dallas, TX, USA Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system with features suggestive of T-cell-mediated autoimmunity.
T237 982920-983020 Sentence denotes Treatment with glatiramer acetate (GA, Copaxone) decreases the rate of exacerbation in relapsing MS.
T238 983021-983133 Sentence denotes We have shown that GA therapy upregulates GA-specific CD8+ T-cell responses to levels found in healthy subjects.
T239 983134-983229 Sentence denotes In this study, we evaluated the functional profile and clonal complexity of GA-induced T-cells.
T240 983230-983395 Sentence denotes Sequencing of T-cell receptor-beta chains of flow-sorted GA-specific CD4+ and CD8+ T-cells revealed strikingly oligoclonal GA-reactive CD8+ responses in MS patients.
T241 983396-983521 Sentence denotes Over the course of therapy, the same dominant clones of CD8+ T-cells persisted over long periods of time in certain patients.
T242 983522-983658 Sentence denotes In contrast, GA-reactive CD4+ T-cells were polyclonal and revealed different clonal composition at different time points during therapy.
T243 983659-983801 Sentence denotes The heightened CD8+ T-cell response corresponded with the longitudinal upregulation of ex vivo cytotoxic activity of GA-specific CD8+ T-cells.
T244 983802-983898 Sentence denotes GA therapy also induced a change in functional molecular profiles of both CD4+ and CD8+ T-cells.
T245 983899-984114 Sentence denotes These results demonstrate that a few dominant clones of CD8+ T-cells contribute to the GA-induced response and may mediate its immunomodulatory effect through direct cytotoxic killing of relevant immune populations.
T246 984115-984245 Sentence denotes This also raises important questions about the immunologic effects of chronic GA therapy and the development of T-cell senescence.
T247 984246-984318 Sentence denotes Supported in part by grants from the NIH, NMSS and Wadsworth Foundation.
T248 984319-984453 Sentence denotes Effect of Rituximab on the peripheral blood and cerebrospinal fluid B cells in patients with primary progressive multiple sclerosis N.
T249 984454-984464 Sentence denotes Monson, K.
T250 984465-984475 Sentence denotes Hawker, E.
T251 984476-984490 Sentence denotes Frohman and M.
T252 984491-984553 Sentence denotes Racke UT Southwestern Medical Center, Dallas, TX, USA Context:
T253 984554-984628 Sentence denotes Rituximab is an anti-CD20 monoclonal antibody that depletes CD20+ B cells.
T254 984629-984838 Sentence denotes Whether the efficacy of Rituximab in peripheral neurological diseases can be translated to neurological diseases of the central nervous system (CNS) with possible autoimmune B cell involvement remains unknown.
T255 984839-984849 Sentence denotes Objective:
T256 984850-985084 Sentence denotes To determine what effect Rituximab has on the cerebrospinal fluid (CSF) B cell population in patients with Multiple Sclerosis (MS), a chronic inflammatory, demyelinating disease of the CNS that likely involves an autoimmune mechanism.
T257 985085-985092 Sentence denotes Design:
T258 985093-985268 Sentence denotes Four patients with Primary Progressive MS (PPMS), a subtype of MS that presents as a slow deterioration of neurological function without relapses, were treated with Rituximab.
T259 985269-985358 Sentence denotes Peripheral blood (PB) and/or CSF were collected from each patient pre-and post-Rituximab.
T260 985359-985439 Sentence denotes The PB and CSF cells were analyzed by flow cytometry to identify B cell subsets.
T261 985440-985639 Sentence denotes Results: CSF B cells were not as effectively depleted as their peripheral counterparts, most likely because the majority of CSF B cells are highly activated CD19dim advanced memory or plasma B cells.
T262 985640-985701 Sentence denotes Rituximab suppressed the activation state of the CSF B cells.
T263 985702-985799 Sentence denotes CD19dim B cells in the periphery and CSF expanded beyond their normal frequencies post-Rituximab.
T264 985800-985811 Sentence denotes Conclusion:
T265 985812-985976 Sentence denotes The effect(s) of Rituximab on the CSF B cell compartment are limited in comparison to the periphery, but will need to be confirmed in a larger group of MS patients.
T266 985977-986047 Sentence denotes Current therapies of multiple sclerosis are only moderately effective.
T267 986048-986285 Sentence denotes We have recently shown that a humanized monoclonal antibody against the interleukin-2 receptor alpha chain, Daclizumab, substantially reduces brain inflammation in MS patients with incomplete response to standard interferon beta therapy.
T268 986286-986406 Sentence denotes The aim of this study was to determine in vivo immune changes that are responsible for this profound therapeutic effect.
T269 986407-986669 Sentence denotes We prospectively analyzed the functional status of lymphocytes in patients before and during therapy with Daclizumab by evaluating surface expression of activation markers, chemokine receptors and cytokine chains, and by employing CFSE-based proliferation assay.
T270 986670-986807 Sentence denotes Additional in vitro experiments required cellular separations by magnetic beads, intracellular cytokine staining and cytotoxicity assays.
T271 986808-986972 Sentence denotes We demonstrated that Daclizumab does not act via the anticipated direct functional-and activation blockade of CD4+ T cells, a central population in MS pathogenesis.
T272 986973-987135 Sentence denotes Instead, Daclizumab therapy led to prominent expansion of immunoregulatory CD56bright natural killer (NK) cells and to a gradual decline in CD8+ and CD4+ T cells.
T273 987136-987206 Sentence denotes These changes were highly correlated to and predictive of MRI outcome.
T274 987207-987308 Sentence denotes We will describe the mechanism by which CD56bright NK cells may mediate peripheral tolerance in vivo.
T275 987309-987384 Sentence denotes Our data reveal an intriguing pathway how to manipulate cytokine circuitry.
T276 987385-987533 Sentence denotes These findings have important implications for the treatment of autoimmune diseases, transplant rejection and toward modification of tumor immunity.
T277 987534-987618 Sentence denotes Immunomodulatory effects of simvastatin in relapsing-remitting multiple sclerosis S.
T278 987619-987649 Sentence denotes Markovic-Plese a,b , X. b , S.
T279 987650-987661 Sentence denotes Giri c , D.
T280 987662-987680 Sentence denotes Sujkowski a and I.
T281 987681-987840 Sentence denotes Singh c a University of North Carolina, Chapel Hill, USA; b Yale University, New Haven, USA; c Medical University of South Carolina, Charleston, USA Objective:
T282 987841-988000 Sentence denotes To study immunomodulatory therapeutic potential of simvastatin, CNS penetrating HMG-CoA reductase inhibitor, in relapsing-remitting multiple sclerosis (RR MS).
T283 988001-988009 Sentence denotes Results:
T284 988010-988122 Sentence denotes Statins exhibit dose-dependant antiproliferative effect in activated peripheral blood mononuclear cells (PBMCs).
T285 988123-988214 Sentence denotes Simvastatin decreased IFN-gamma-inducible expression of MHC class II DR on CD14+ monocytes.
T286 988215-988465 Sentence denotes In addition to the effect on antigen presentation, simvastatin decreased surface expression of activation markers (CD25, CD69), memory and naRve subset markers (CD45RO, CD45RA), and chemokine receptor (CCR5) on the effector CD4+ and CD8+ lymphocytes.
T287 988466-988644 Sentence denotes Described effects were reversed by mevalonate, the product of HMG-CoA reductase, confirming that the effect on lymphocyte activation is specific for HMG-CoA reductase inhibition.
T288 988645-988724 Sentence denotes Treatment with simvastatin induced a shift from Th1 to Th2 cytokine production.
T289 988725-988870 Sentence denotes We measured a significantly decreased IFN-gamma, TNF-alpha and IL-2 secretion, and increased IL-4 production following in vitro PBMC stimulation.
T290 988871-989003 Sentence denotes Further analysis revealed consistently decreased expression of T-bet, transcription factor that regulates Th-1 cell differentiation.
T291 989004-989144 Sentence denotes Gene arrays were subsequently used in order to capture treatment-induced changes in the expression of multiple cytokine and chemokine genes.
T292 989145-989303 Sentence denotes We identified a significant increase in IL-1A, IL-3, and SDF1, and decrease in IL-6, IL-7, IL-8, and TNF-beta gene expression in simvastatin-treated cultures.
T293 989304-989338 Sentence denotes Findings were confirmed by RT-PCR.
T294 989339-989351 Sentence denotes Conclusions:
T295 989352-989490 Sentence denotes Due to multiple immunomodulatory mechanisms of action, statins represent a promising treatment for MS, a chronic inflammatory CNS disease.
T296 989491-989581 Sentence denotes Multiple sclerosis is a chronic inflammatory disorder of the central nervous system (CNS).
T297 989582-989716 Sentence denotes Auto-aggressive T-cells drive inflammation leading to focal myelin destruction, loss of oligodendrocytes and acute axonal transection.
T298 989717-989795 Sentence denotes Campath-1H is a monoclonal antibody that induces prolonged T-cell lymphopenia.
T299 989796-990015 Sentence denotes After Campath treatment, there is a 90% reduction in relapse rate and an initial improvement in disability (as assessed by the EDSS score), which may represent release from conduction block due to residual inflammation.
T300 990016-990101 Sentence denotes However, there is continued improvement in disability between 12-24 and 24-36 months.
T301 990102-990289 Sentence denotes Although there are many possible explanations for this, we hypothesised that immune cells, regenerated after Campath-1H, secrete growth factors which promote neuronal survival and repair.
T302 990290-990495 Sentence denotes We have shown that patients' PBMCs secrete neurotrophic factors ex-vivo in response to various stimuli and that PBMC-conditioned medium supports the survival of neurons derived from rat embryonic cortices.
T303 990496-990635 Sentence denotes At 6 months post-treatment we found an increase in ciliary neurotrophic factor (CNTF); a factor recently shown to enhance myelin formation.
T304 990636-990730 Sentence denotes Additionally, we found a dramatic reduction in insulin-like growth factor-1 (IGF-1) secretion.
T305 990731-990866 Sentence denotes IGF-1 mediates protection from Fas-induced cell death, a process essential for immune system homeostasis by clearing activated T cells.
T306 990867-990993 Sentence denotes This finding suggests that Campath's immuno-modulation may, in part, be due to the apoptotic elimination of activated T cells.
T307 990994-991152 Sentence denotes Increasing evidence indicates that the Epstein-Barr virus (EBV) has a role in the pathogenesis of many autoimmune diseases, including multiple sclerosis (MS).
T308 991153-991533 Sentence denotes We have proposed a new hypothesis that chronic autoimmune diseases occur in individuals genetically susceptible to the effects of B-cell infection by EBV, with a resultant increase in the frequency of EBV-infected autoreactive B cells, which not only produce autoantibodies but also inhibit activation-induced apoptosis of autoreactive T cells in the target organ [Trends Immunol.
T309 991534-991550 Sentence denotes 24 (2003) 584 ].
T310 991551-991711 Sentence denotes This study aims to determine whether MS patients have an increased frequency of EBV-infected immortalized autoreactive B cells leading to the development of MS.
T311 991712-991904 Sentence denotes We are using realtime PCR to measure the EBV DNA load in peripheral blood mononuclear cells (PBMCs), and ELISA and myelin opsonization-for-phagocytosis assays to measure antimyelin antibodies.
T312 991905-992272 Sentence denotes In addition to detecting EBV DNA in PBMCs of MS patients, we have found that, compared to healthy subjects and patients with other neurological diseases, MS patients have higher levels of circulating antibodies to two overlapping peptides of myelin proteolipid protein (PLP), namely PLP184-199 and PLP190-209, and increased levels of opsonizing antimyelin antibodies.
T313 992273-992517 Sentence denotes One MS patient with high circulating levels of opsonizing antimyelin antibodies and severe progressive spinal cord involvement refractory to intravenous methylprednisolone and glatiramer acetate improved following B cell depletion by rituximab.
T314 992518-992655 Sentence denotes Primary progressive multiple sclerosis converted to relapsing remitting multiple sclerosis after intensive immunosuppressive therapy E.J.
T315 992656-992673 Sentence denotes Bartholomé a , M.
T316 992674-992687 Sentence denotes Vokaer a , D.
T317 992688-992699 Sentence denotes Bron b , M.
T318 992700-992717 Sentence denotes Toungouz a and M.
T319 992718-992929 Sentence denotes Goldman a a Hô pital Erasme, Brussels, Belgium; b Hô pital Bordet, Brussels, Belgium Primary progressive multiple sclerosis (PPMS) is a devastating form of MS resulting in progressive handicap without remission.
T320 992930-993055 Sentence denotes It is less frequent than relapsing-remitting MS (RRMS) and some studies suggest it may represent a totally separated disease.
T321 993056-993155 Sentence denotes We provide evidence of conversion from PPMS to RRMS in a patient after intensive immunosuppression.
T322 993156-993209 Sentence denotes Our patient born in 1966 suffered from MS since 1986.
T323 993210-993328 Sentence denotes Clinical diagnosis of PPMS was confirmed by nuclear magnetic resonance, evoked potential and lumbar puncture findings.
T324 993329-993475 Sentence denotes Between 1998 and 2000, aggressive evolution despite corticoids, azathioprine and cyclophosphamide therapy resulted in severe handicap development.
T325 993476-993534 Sentence denotes In December 2000, the patient became wheelchair dependant.
T326 993535-993625 Sentence denotes Peripheral blood stem cell were mobilized, harvested and highly purified in February 2001.
T327 993626-993758 Sentence denotes In March 2001, the patient received 200 mg/kg Cyclophosphamide followed by autograft rescue with successful haematological recovery.
T328 993759-993823 Sentence denotes Handicap progressively recessed to stabilize by the end of 2001.
T329 993824-993881 Sentence denotes Then, the patient was able to walk alone more than 100 m.
T330 993882-993979 Sentence denotes However, the patient experienced two relapse in 2003 (optic neuritis, left arm neuropathic pain).
T331 993980-994115 Sentence denotes Both relapses were followed by partial remission over 3 months and confirmed by nuclear magnetic resonance and ophthalmologic findings.
T332 994116-994313 Sentence denotes This case proves that PPMS may convert to RRMS after intensive immunosuppression, suggesting that PPMS and RRMS are not separate entities but distinct expression of a common immunological disorder.
T333 994314-994422 Sentence denotes Identification of novel lead compounds in modulation of pathogenic immune responses in multiple sclerosis M.
T334 994423-994435 Sentence denotes Massa a , R.
T335 994436-994453 Sentence denotes Campanelli a , A.
T336 994454-994468 Sentence denotes Uccelli b , V.
T337 994469-994480 Sentence denotes Meli c , P.
T338 994481-994493 Sentence denotes Lanza c , R.
T339 994494-994509 Sentence denotes Billetta c , A.
T340 994510-994526 Sentence denotes Martini d and S.
T341 994527-994546 Sentence denotes Albani e a IRCCS S.
T342 994547-994667 Sentence denotes Matteo Hospital, Pavia, Italy; b University of Genoa, Genoa, Italy; c Androclus Therapeutics, San Diego, USA; d IRCCS G.
T343 994668-994832 Sentence denotes Gaslini Institute, Genoa, Italy; e University of California, San Diego, USA Immune responses to bacterial heat shock proteins (HSP) may play a role in autoimmunity.
T344 994833-995079 Sentence denotes By applying a computer algorithm for the identification of panHLADR binder motifs, we have defined two sets of peptides from bacterial HSP hsp60 and Escherichia coli dnaJ, which may function as relevant T cell epitopes in multiple sclerosis (MS).
T345 995080-995126 Sentence denotes A PanDR-peptide was tested as control peptide.
T346 995127-995216 Sentence denotes PBMC from 33 MS individuals were stimulated with individual proband and control peptides.
T347 995217-995401 Sentence denotes We found that peptides B1, B5, B6, B7 from E. coli dnaJ were able to induce an increased expression of CD69 ( pb0.04) or T cell proliferation ( pb0.02) compared to the control peptide.
T348 995402-995648 Sentence denotes In addition, while peptide B1 induced an increased intracellular production of IFNgamma ( p=0.04) and TNFalpha ( p=0.02) by stimulated PBMC, peptide B6 elicited bulk cultures to produce intracellular IL10 ( p=0.04) or IL10 and IFNgamma ( p=0.03).
T349 995649-995821 Sentence denotes A significantly higher percentage of IFNgamma and IL10 producing cells was also found following incubation with hsp60 derived peptides P10 or P11 than with control peptide.
T350 995822-995935 Sentence denotes Thus, HSP-derived peptides are capable of inducing both pro-inflammatory and regulatory responses in MS subjects.
T351 995936-996125 Sentence denotes These results suggest that responses to HSP peptides may play a modulating role during CNS autoimmunity and may be exploited at tailoring immunomodulatory compounds for the treatment of MS.
T352 996126-996284 Sentence denotes Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system caused by an autoimmune attack directed against CNS myelin antigens.
T353 996285-996428 Sentence denotes Vdelta2 cells form a minor component of the circulating peripheral lymphocyte pool and also home to sites of inflammation, including the brain.
T354 996429-996561 Sentence denotes It has been reported that in vitro activation of human Vdelta2T cells by nonpeptidic ligands rapidly induces production of IFNgamma.
T355 996562-996722 Sentence denotes High amounts of IFN-gamma that is produced rapidly by T cells after bacterial infection can have adverse effects for the development of intracellular pathogens.
T356 996723-996939 Sentence denotes On the other hand, gamma\delta T cells may contribute to the immunopathology associated with chronic inflammatory or autoimmune disorders through a high and sustained release of inflammatory cytokines and chemokines.
T357 996940-997129 Sentence denotes Here, we have evaluated gamma/delta T cell responses to pyrenil-pyrophosphate antigen with and without ST1959, a compound of the triazoles class of molecules, in healthy and MS individuals.
T358 997130-997242 Sentence denotes Our results show that ST1959 significantly inhibits proliferation and cytokine production in gamma/deltaT cells.
T359 997243-997326 Sentence denotes Furthermore, ST1959 efficiently interferes with antigen specific T cell activation.
T360 997327-997477 Sentence denotes We conclude that ST1959 represents a novel immunomodulatory agent in the treatment of T cell mediated autoimmune diseases, such as multiple sclerosis.
T361 997478-997573 Sentence denotes T cell-mediated action against self-antigens is implicated in a variety of autoimmune diseases.
T362 997574-997625 Sentence denotes This T cell activation is dependent on two signals:
T363 997626-997678 Sentence denotes T cell receptor (TcR) engagement and co-stimulation.
T364 997679-997811 Sentence denotes Co-stimulation is therefore a potential target for treating autoimmune diseases such as rheumatoid arthritis and multiple sclerosis.
T365 997812-998056 Sentence denotes We have previously shown that a series of small compounds, discovered at Avidex, bind exclusively to CD80 with nanomolar affinity (SPR technology) and block its interaction with CD28 (time resolved fluorescence resonance energy transfer assay).
T366 998057-998210 Sentence denotes In the current study, we demonstrate the effects of these compounds in a range of cellular assays using both transformed cells and primary human T cells.
T367 998211-998412 Sentence denotes The compounds inhibit cytokine release from Jurkat cells (interleukin-2 (IL-2)) and primary CD4+ T cells (IL-2, interferon-gamma and tumour necrosis factor-alpha) with IC50 in the sub-micromolar range.
T368 998413-998591 Sentence denotes T cell activation is therefore reduced by the presence of molecules bound to CD80 and these compounds represent promising leads for the development of novel autoimmune therapies.
T369 998592-998724 Sentence denotes Influence of estriol therapy on inflammatory responses on brain endothelial cell tight junction molecules in multiple sclerosis I.V.
T370 998725-998736 Sentence denotes Korzh, I.F.
T371 998737-998754 Sentence denotes Fedotova and V.D.
T372 998755-998808 Sentence denotes Nemtsova Kharkov Medical University, Kharkov, Ukraine
T373 998809-999005 Sentence denotes The protective effect of pregnancy on putative Th1-mediated autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis, is associated with a Th1 to Th2 immune shift during pregnancy.
T374 999006-999159 Sentence denotes The hormone estriol increases during pregnancy and has been shown to ameliorate experimental autoimmune encephalomyelitis and collagen-induced arthritis.
T375 999160-999552 Sentence denotes To elucidate mechanisms of endothelial cell (EC) dysfunction in CNS inflammatory responses and beneficial effects of oral estriol therapy in multiple sclerosis (MS), we analyzed effects of individual and combinations of soluble inflammatory mediators on the intracellular localization of the EC tight junction-associated molecules zonula occludens-1 and -2 (ZO-1 and ZO-2) in human brain ECs.
T376 999553-999751 Sentence denotes The cytoplasm in the majority of cells in control EC cultures was clear; ZO-1 and ZO-2 were localized peripherally near sites of cell contact and associated with submembranous cytoplasmic filaments.
T377 999752-999914 Sentence denotes H2O2 induced reversible time-and concentration-dependent translocation of ZO-1 and ZO-2 to a random distribution within EC cytoplasm and retraction of EC borders.
T378 999915-1000097 Sentence denotes For low concentrations, these effects were accompanied by less prominent submembranous filaments but not by evidence of cytotoxicity, increased cell death or altered amounts of ZO-1.
T379 1000098-1000173 Sentence denotes Tumor necrosis factor-beta induced similar alterations but estriol did not.
T380 1000174-1000293 Sentence denotes Co-treatment with either cytokine increased H 2 O 2 effects, whereas estriol therapy reversed H 2 O 2 -induced effects.
T381 1000294-1000387 Sentence denotes In control white matter samples, EC cytoplasm was clear and ZO-1 was located on cell borders.
T382 1000388-1000531 Sentence denotes In inflammatory/ demyelinating lesions, EC ZO-1 was diffuse, indicating that the alterations induced in vitro mimic those in active MS lesions.
T383 1000532-1000714 Sentence denotes These findings suggest that in MS patients, estriol treatment may counteract inflammatory mediator effects on CNS EC tight junction molecules, thereby preserving EC barrier function.
T384 1000715-1000866 Sentence denotes Type 1 interferons such as IFN-beta appear critical to trigger immunoregulatory mechanisms lying at the interface between innate and adaptive immunity.
T385 1000867-1001057 Sentence denotes The therapeutic effect of IFN-beta could be due to restoration of immunoregulatory mechanisms that are defective in multiple sclerosis (MS) patients such as regulatory NKT cell/CD1d pathway.
T386 1001058-1001208 Sentence denotes Aim: to analyze the NKT cell defect in patients affected by MS and to test whether treatment with IFN-b1a improves immunoregulatory NKT cell function.
T387 1001209-1001490 Sentence denotes Design: NKT cells percentages in peripheral blood lymphocytes (PBL) and secretion of cytokines (IFN-gamma, IL-4, IL-10, IL-12 and TGF-beta) by NKT cells stimulated with their model antigen agalactosylceramide were measured in RR MS patients before and after treatment with IFN-b1a.
T388 1001491-1001586 Sentence denotes Individuals affected by other neurological diseases and healthy subjects were used as controls.
T389 1001587-1001595 Sentence denotes Results:
T390 1001596-1001729 Sentence denotes Our preliminary data showed that percentages of NKT cells are reduced in MS patients prior to IFN-b1a treatment compared to controls.
T391 1001730-1001811 Sentence denotes In some patients percentage of NKT cells in PBL increased with IFNb-1a treatment.
T392 1001812-1001998 Sentence denotes Moreover, IFN-b1a increased secretion of cytokines by NKT cells of MS patients without shifting NKT cell cytokine profile from an inflammatory Th1 toward a protective IL-4secreting type.
T393 1001999-1002100 Sentence denotes Neutralizing antibodies have a higher affinity to interferon-beta than non-neutralizing antibodies P.
T394 1002101-1002110 Sentence denotes Tripp, C.
T395 1002111-1002124 Sentence denotes Gneiss and F.
T396 1002125-1002218 Sentence denotes Deisenhammer Innsbruck Medical University, Dept. of Neurology, Innsbruck, Austria Background:
T397 1002219-1002355 Sentence denotes Patients with multiple sclerosis receiving recombinant interferon-beta (IFN-beta) may develop binding antibodies (BAB) against IFN-beta.
T398 1002356-1002453 Sentence denotes Two types of BAB can be distinguished, neutralizing (NAB) and non-neutralizing antibodies (NNAB).
T399 1002454-1002563 Sentence denotes NAB are associated with greater BAB titers than NNAB, suggesting a quantitative influence on NAB development.
T400 1002564-1002698 Sentence denotes The correlation between NAB and BAB is weak and there is evidence that IFN-beta neutralization also depends on qualitative components.
T401 1002699-1002759 Sentence denotes In this study the affinity of NAB vs. NNAB was investigated.
T402 1002760-1002768 Sentence denotes Methods:
T403 1002769-1002879 Sentence denotes Thirty-eight serum samples with BAB of 27 MS patients receiving IFN-beta-1a or 1b were included in this study.
T404 1002880-1002944 Sentence denotes Of these, 21 samples were NAB-positive and 17 were NAB-negative.
T405 1002945-1003067 Sentence denotes The relative affinity values (RAV) of IFN-beta antibodies were determined using an affinity assay as described earlier [J.
T406 1003068-1003081 Sentence denotes Neuroimmunol.
T407 1003082-1003097 Sentence denotes 66 (1996) 85] .
T408 1003098-1003247 Sentence denotes The determination of RAV is based upon disrupting interactions between antibody and antigen using increasing concentrations of sodium isothiocyanate.
T409 1003248-1003367 Sentence denotes Results: RAVs were significantly higher in NAB-positive (266.6F5.884) than in NAB-negative (223.8F15.96) serum samples.
T410 1003368-1003491 Sentence denotes The amount of antibodies as measured by optical density did not differ between both groups (0.9803F0.035 vs. 0.9771F0.033).
T411 1003492-1003566 Sentence denotes No significant correlation was observed between RAV and BAB or NAB titers.
T412 1003567-1003579 Sentence denotes Conclusions:
T413 1003580-1003696 Sentence denotes After exclusion of confounding factors these results indicate that NAB have a higher affinity to IFN-beta than NNAB.
T1 1003697-1003799 Sentence denotes Evaluation of functional disability in multiple sclerosis patients during interferon beta treatment M.
T2 1003800-1003817 Sentence denotes Bošnjak Pašic, M.
T3 1003818-1003827 Sentence denotes Lisak, Z.
T4 1003828-1003843 Sentence denotes Trkanjec and V.
T5 1003844-1003921 Sentence denotes Demarin Sestre Milosrdnice University Hospital, Zagreb, Croatia Introduction:
T6 1003922-1004086 Sentence denotes Fifteen patients (10 females and 5 males) with remittingrelapsing multiple sclerosis (RRMS) were treated with interferon beta at University Department of Neurology.
T7 1004087-1004223 Sentence denotes Ten patients were treated with interferon beta 1a (6 MIU three times weekly) and five with interferon beta 1b (9,6 MIU every other day).
T8 1004224-1004232 Sentence denotes Methods:
T9 1004233-1004336 Sentence denotes We used the Expanded Disability Status Scale (EDSS) to evaluate functional disability in RRMS patients.
T10 1004337-1004460 Sentence denotes An average EDSS score was recorded before interferon beta therapy and 6 months after initiation of interferon beta therapy.
T11 1004461-1004469 Sentence denotes Results:
T12 1004470-1004592 Sentence denotes In interferon beta 1a group average EDSS score before therapy was 3.00 and after 6 months of therapy it decreased to 2.92.
T13 1004593-1004713 Sentence denotes In interferon beta 1b group an average EDSS score was 3.07, before treatment, and after 6 months of therapy it was 3.00.
T14 1004714-1004864 Sentence denotes There was no statistically significant difference between interferon beta 1a group and interferon beta 1b group, before and after 6 months of therapy.
T15 1004865-1005083 Sentence denotes The average EDSS score was slightly smaller after 6 months of treatment in both groups, but the difference was not statistically significant ( p=0.17 in interferon beta 1a group and p=0.36 in interferon beta 1b group).
T16 1005084-1005096 Sentence denotes Conclusions:
T17 1005097-1005174 Sentence denotes Results favor interferon beta therapy in these small groups of RRMS patients.
T18 1005175-1005307 Sentence denotes Further follow-ups are required to obtain data about functional status during interferon beta treatment after longer period of time.
T19 1005308-1005430 Sentence denotes IFN-beta has shown to be an effective treatment for multiple sclerosis (MS), however, some patients fail to respond fully.
T20 1005431-1005547 Sentence denotes The biological activity of IFNbeta is exerted through the IFN receptor, composed of two subunits, IFNAR1 and IFNAR2.
T21 1005548-1005634 Sentence denotes Deficiency of one or both of these subunits may lead to a loss of interferon activity.
T22 1005635-1005843 Sentence denotes To evaluate differences in IFNAR1 and IFNAR2 expression in MS patients treated with different IFN-beta molecules we quantified IFNAR1 and IFNAR2 mRNA by real-time RT-PCR in peripheral blood mononuclear cells.
T23 1005844-1005912 Sentence denotes Clinical disease activity was based on annual relapse rate and EDSS.
T24 1005913-1006076 Sentence denotes A total of 210 MS patients, 45 treated with IFN-beta1b (Betaferon), 46 with IFN-beta1a (Avonex), 68 with IFN-beta1a (Rebif) and 30 without treatment were included.
T25 1006077-1006147 Sentence denotes The results were analysed by comparisons with a healthy control group.
T26 1006148-1006327 Sentence denotes A nonparametric test showed significant decrease in patients treated with IFNbeta compared to patients without treatment and healthy controls in both IFNAR1 and IFNAR2 expression.
T27 1006328-1006435 Sentence denotes There was no difference in the IFNAR1 or IFNAR2 expression between patients with any of the treatment used.
T28 1006436-1006649 Sentence denotes We found a decrease in both IFNAR1 and IFNAR2 expression in MS patients compared to healthy controls, and also a decrease in this expression was observed in treated MS patients compared to non-treated MS patients.
T29 1006650-1006746 Sentence denotes Naturally occurring regulatory CD4+CD25+ T cells at a crossroads of neuro-immune interactions J.
T30 1006747-1006757 Sentence denotes Kipnis, M.
T31 1006758-1006768 Sentence denotes Cardon, H.
T32 1006769-1006779 Sentence denotes Avidan, S.
T33 1006780-1006793 Sentence denotes Mordechay, L.
T34 1006794-1006804 Sentence denotes Gil and M.
T35 1006805-1006941 Sentence denotes Schwartz Weizmann Institute of Science, Revohot, Israel CNS injury activates autoimmune T cells, which accumulate at the site of injury.
T36 1006942-1007038 Sentence denotes These T cells were believed to mediate processes of secondary degeneration of the neural tissue.
T37 1007039-1007223 Sentence denotes Our group has recently showed that these autoimmune T cells have a beneficial protective effect on neurons and are protecting non-damaged vulnerable to death neurons from degeneration.
T38 1007224-1007472 Sentence denotes Autoimmune T cells are kept in the periphery under tight control of naturally occurring regulatory T cells and a mechanism underlying an ability to evoke autoimmune response to CNS injury without developing an autoimmune disease is largely unknown.
T39 1007473-1007726 Sentence denotes In this study we show that certain neurotransmitters, increased after CNS injury, can preferentially act on naturally occurring CD4+CD25+ regulatory T cells through a specific receptors, expressed by these cells, and alleviate their inhibitory activity.
T40 1007727-1007887 Sentence denotes The same neurotransmitters also affect the adhesion and migration of these cells in a mild manner, namely not eliminating, but rather weakening those functions.
T41 1007888-1008147 Sentence denotes The effect of suppression is mediated through reduced expression of CTLA-4 and reduced production of TGF-beta and IL-10, however, the adhesion and migration are reduced by decrease in expression of the specific receptors for adhesion molecules and chemokines.
T42 1008148-1008239 Sentence denotes This effect on multiple functions of regulatory T cells involves ERK1/2 dependent pathways.
T43 1008240-1008391 Sentence denotes High sensitivity of regulatory T cells to neurotransmitters might represent the bmissing linkQ between the immune and the nervous systems interactions.
T44 1008392-1008538 Sentence denotes A bfine tuningQ on a level of regulatory T cells by neurotransmitters could be a promising therapy for autoimmune and neurodegenerative disorders.
T45 1008539-1008690 Sentence denotes Human CD4+CD25+ Treg cells expressing the highest levels of CD25 (2-4% CD4+ T cells) are the most efficient suppressors of CD4+CD25À T cell activation.
T46 1008691-1008988 Sentence denotes Since these Treg cells are believed to control auto-reactivity, experiments were performed to determine whether CD4+CD25high Treg cells isolated from the peripheral blood of patients with multiple sclerosis exhibited alterations in frequency or function as compared to those from healthy controls.
T47 1008989-1009167 Sentence denotes While there was no difference in the frequency of CD4+CD25high cells between patients and controls, Treg cells isolated from patients with MS were significantly less suppressive.
T48 1009168-1009403 Sentence denotes Furthermore, Treg cells from MS patients were less able to suppress responder T cells from allogeneic healthy controls, while Treg cells isolated from healthy controls could strongly inhibit responder T cells isolated from MS patients.
T49 1009404-1009577 Sentence denotes Functional analysis of non-activated CD4+CD25high cells expressing only high levels of CD62L demonstrated an even greater functional disparity between patients and controls.
T50 1009578-1009848 Sentence denotes Furthermore, two subsets within the CD4+CD25high Treg population differing by HLA-DR expression, exhibit striking temporal differences in suppression and regulation of Th2 cytokines indicating that subsets of CD4+CD25high Tregs may function through different mechanisms.
T51 1009849-1010023 Sentence denotes As skewing towards Th2 responses has important implications for many autoimmune diseases, this investigation is being expanded to Treg subsets isolated from patients with MS.
T52 1010024-1010133 Sentence denotes The central role of T cells in inflammatory reactions of the central nervous system (CNS) is well documented.
T53 1010134-1010205 Sentence denotes Much less is known about the few T cells found within the intact organ:
T54 1010206-1010442 Sentence denotes In particular, the contribution of CD4+ and CD8+ T cells to the infiltrating lymphocyte pool, their preferential target sites within the CNS, and their responses to environmental cues provided by neurodegeneration are largely undefined.
T55 1010443-1010572 Sentence denotes To address these points, we used the Lewis rat as model organism, and studied T cells in the intact and degenerative spinal cord.
T56 1010573-1010718 Sentence denotes In the intact spinal cord, T cells were preferentially located to the CNS gray matter, and CD8+ T cells were more numerous than CD4+ lymphocytes.
T57 1010719-1010824 Sentence denotes In cases of degeneration, T cells increased in numbers and preferentially infiltrated affected CNS areas.
T58 1010825-1010905 Sentence denotes These effects were more pronounced for the CD4+ than for the CD8+ T cell subset.
T59 1010906-1011078 Sentence denotes Collectively, these data provide evidence for a clear cellular and compartmental bias in immune cell infiltration and in the immune response to degeneration within the CNS.
T60 1011079-1011340 Sentence denotes To learn whether T cells recruited to sites of neurodegeneration represent single or multiple T cell clones, we are currently performing T cell receptor analysis, combining spectratyping, single cell PCR of laser microdissected T cells and immunohistochemistry.
T61 1011341-1011434 Sentence denotes Active and differential regulation of autoreactive CD4+ and CD8+ T cell responses by the CNS:
T62 1011435-1011483 Sentence denotes A threshold for autoimmunity within the CNS C.S.
T63 1011484-1011494 Sentence denotes Anglen, C.
T64 1011495-1011507 Sentence denotes Ploix and M.
T65 1011508-1011781 Sentence denotes Carson The Scripps Research Institute, La Jolla, CA, USA To define how the CNS regulates autoreactive T cell responses, we used transgenic mice expressing hemagglutinin (HA) exclusively in CNS astrocytes (GFAP-HA mice) or exclusively in pancreatic beta cells (INS-HA mice).
T66 1011782-1011988 Sentence denotes Ins-HA mice that also express CD4+ (6.5) or CD8+ (clone4) HA-specific TCRs develop spontaneous autoimmune diabetes; whereas GFAP-HA mice co-expressing either HA-specific TCR do not develop CNS autoimmunity.
T67 1011989-1012147 Sentence denotes Similarly, transfer of HA-specific CD4+ T cells into lymphopenic INS-HA mice led to autoimmune diabetes, but failed to cause CNS autoimmunity in GFAP-HA mice.
T68 1012148-1012385 Sentence denotes In transgenic mice expressing HA in both the CNS and pancreas (GFAP-HAxINS-HA mice), encounter with CNS-expressed antigen led to clonal diversion of HA-specific CD4+ T cells, decreased diabetes incidence, and infrequent CNS inflammation.
T69 1012386-1012536 Sentence denotes In contrast, co-transfer of HA-specific CD4+ and CD8+ T cells did trigger diabetes and modest signs of clinical ataxic disease in GFAP-HAxINS-HA mice.
T70 1012537-1012624 Sentence denotes Autoreactive CD4+ and CD8+ T cells also differentially responded to adjuvant challenge.
T71 1012625-1012844 Sentence denotes Co-administration of pertussis toxin (PT) with HA-specific CD4+ T cells triggered rapid lethal CNS inflammation in GFAP-HA mice, while co-administration of PT with HA-specific CD8+ T cells failed to produce CNS disease.
T72 1012845-1013030 Sentence denotes These results suggest that regulation of autoreactive T cell responses is not only tissue-specific, but that the CNS actively exerts differential regulation of CD4+ versus CD8+ T cells.
T73 1013031-1013150 Sentence denotes A paradoxical role of APCs in the induction of intravenous tolerance in experimental autoimmune encephalomyelitis G.-X.
T74 1013151-1013160 Sentence denotes Zhang, B.
T75 1013161-1013169 Sentence denotes Gran, S.
T76 1013170-1013176 Sentence denotes Yu, Y.
T77 1013177-1013183 Sentence denotes Li, E.
T78 1013184-1013198 Sentence denotes Ventura and A.
T79 1013199-1013367 Sentence denotes Rostami Thomas Jefferson University, Philadelphia, PA, USA APCs, based on their phenotypes, have been considered to be important in determining Th1/Th2 differentiation.
T80 1013368-1013500 Sentence denotes Here we define whether immunoregulatory function of T cells in the induction of antoantigen-specific tolerance is mediated via APCs.
T81 1013501-1013780 Sentence denotes Intravenous (i.v.) tolerance against experimental autoimmune encephalomyelitis (EAE) was induced by administering myelin oligodendrocyte glycoprotein (MOG) 35-55, and APCs/CD4+ T cells from MOG-i.v. or PBS-i.v . mice were purified to analyze their functions in vitro and in vivo.
T82 1013781-1013913 Sentence denotes Co-culture of purified APCs and CD4+ T cells showed that T cells, but not APCs, play a predominant role in i.v. tolerance induction.
T83 1013914-1014080 Sentence denotes In vivo, APCs of MOG-i.v. mice induced a non-specific Th1-type response in naRve mice, and were less effective in suppressing clinical EAE than APCs of PBS-i.v. mice.
T84 1014081-1014200 Sentence denotes Further, increased levels of IL-12p40, IL-23p19 and IL-23 receptor mRNA expression were found in APCs of MOG-i.v. mice.
T85 1014201-1014371 Sentence denotes We conclude that induction of i.v. tolerance is a T cell phenomenon and that APCs are not tolerized, but indeed immuno-stimulatory, upon systemic exposure to autoantigen.
T86 1014372-1014545 Sentence denotes Blocking this APC activation, therefore, would enhance the effectiveness of tolerance induction and block the potential reversal of tolerance in preventing and treating EAE.
T87 1014546-1014682 Sentence denotes Using retrovirally transduced, GFP labeled T cells we followed the fate of encephalitogenic effector cells in the clinical phase of EAE.
T88 1014683-1014767 Sentence denotes We had learned masses of the pathogenic effector T cells invade deeply into the CNS.
T89 1014768-1014888 Sentence denotes Using life-imaging techniques, we now have followed green autoreactive MBP specific T cells within the brain parenchyma.
T90 1014889-1014997 Sentence denotes Many of the cells (60-70%) cruise with unexpected speed (bmotile typeQ) and in seemingly undirected fashion.
T91 1014998-1015101 Sentence denotes Other cells (30-40%), however, attach and begin to toss around some central object (bstationary typeQ).
T92 1015102-1015315 Sentence denotes We speculate that the motile cells are in search of their brain autoantigen, and that the stationary cells just have found their autoantigen, that their arrest reflects presentation and recognition of the antigen.
T93 1015316-1015364 Sentence denotes Several observations support our interpretation.
T94 1015365-1015506 Sentence denotes First, T cells, which do not recognize brain antigens, such as ovalbumin specific T cells, move almost exclusively (98%) in a motile fashion.
T95 1015507-1015658 Sentence denotes Second, the motility pattern correlates with the local reactivation level as well as with the pathogenic potential of the transferred effector T cells.
T96 1015659-1015954 Sentence denotes Thus, T cells with a high pathogenic potential, as the MBP specific, display a relatively high proportion of stationary cells, while T cells of low pathogenic potential (e.g. specific for other brain autoantigen such as S100beta), show a significantly lower proportion of stationary cells (15%).
T97 1015955-1016130 Sentence denotes This tightly correlates with in situ activation as assessed by T cell receptor down-modulation, up-modulation of activation markers, pro-inflammatory cytokines and chemokines.
T98 1016131-1016222 Sentence denotes Impaired function of CD4+CD25high regulatory T cells in patients with multiple sclerosis J.
T99 1016223-1016234 Sentence denotes Haas a , T.
T100 1016235-1016248 Sentence denotes Vetter a , L.
T101 1016249-1016263 Sentence denotes Milkova a , A.
T102 1016264-1016279 Sentence denotes Viehfver a , A.
T103 1016280-1016290 Sentence denotes Hug a , C.
T104 1016291-1016302 Sentence denotes Falk b , E.
T105 1016303-1016320 Sentence denotes Suri-Payer c , B.
T106 1016321-1016333 Sentence denotes Fritz a , P.
T107 1016334-1016350 Sentence denotes Krammer c and B.
T108 1016351-1016522 Sentence denotes Wildemann a a Department of Neurology, University of Heidelberg, Heidelberg, Germany; b GSF-Institute of Molecular Immunology, Munich, Germany; c DKFZ, Heidelberg, Germany
T109 1016523-1016618 Sentence denotes Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS).
T110 1016619-1016875 Sentence denotes Since activation of circulating self-reactive T cells with specificity for myelin components is considered to be an important disease initiating event, effective immunoregulation of peripheral T cells may be critical to prevent autoimmunity within the CNS.
T111 1016876-1017016 Sentence denotes Immunoregulatory T cells of the CD4+CD25high phenotype (Treg) suppress T cell function and protect rodents from organ-specific autoimmunity.
T112 1017017-1017075 Sentence denotes The precise role of Treg in human autoimmunity is unclear.
T113 1017076-1017323 Sentence denotes We assessed prevalence and suppressor function of Treg isolated from peripheral blood of patients with clinically active relapsing-remitting MS and healthy controls using flow cytometry, gene expression analysis, and in vitro proliferation assays.
T114 1017324-1017647 Sentence denotes We demonstrate that the suppressive potency of patient-derived Treg is impaired, as their inhibitory effect on allogeneic and polyclonal T cell proliferative responses as well as on antigen specific T cell proliferation induced by myelin oligodendrocyte glycoprotein is significantly reduced compared to Treg from controls.
T115 1017648-1017814 Sentence denotes Number and cell surface phenotype of Treg were not altered and no differences as to the composition and activation state of CD4+CD25À responder T cells were observed.
T116 1017815-1017954 Sentence denotes These results suggest that an impaired inhibitory effect of Treg on autoreactive T cell clones might be involved in the pathogenesis of MS.
T117 1017955-1018064 Sentence denotes Identification of a novel natural regulatory CD8 T cell subset and analysis of its mechanism of regulation E.
T118 1018065-1018078 Sentence denotes Xystrakis, A.
T119 1018079-1018089 Sentence denotes Dejean, I.
T120 1018090-1018104 Sentence denotes Bernard and A.
T121 1018105-1018141 Sentence denotes Saoudi INSERM U563, Toulouse, France
T122 1018142-1018274 Sentence denotes Normal immune system contains bprofessionalQ natural regulatory T cells that control physiological as well as pathological immunity.
T123 1018275-1018428 Sentence denotes Although the suppressive function was historically attributed to CD8 T cells, most current reports about natural regulatory T cells focus on CD4 T cells.
T124 1018429-1018536 Sentence denotes In the present study, we identify a new subset of natural CD8 regulatory T cells in normal healthy animals.
T125 1018537-1018729 Sentence denotes This subset expresses low level of CD45RC at its surface (CD45RClow), produces mainly IL-4, IL-10 and IL-13 cytokines upon in vitro stimulation and is not cytotoxic against allogeneic targets.
T126 1018730-1018946 Sentence denotes In coculture experiments and after in vitro stimulation with allogeneic accessory cells, this subset suppresses the proliferation and differentiation of autologous CD4 T cells into type-1 cytokines producing T cells.
T127 1018947-1019066 Sentence denotes This regulatory subset mediates its suppression by cellcell contact and not through secretion of suppressive cytokines.
T128 1019067-1019201 Sentence denotes The regulatory activity of CD8 CD45RClow cells is also demonstrated in vivo in a rat model of CD4-dependent Graft-versus Host Disease.
T129 1019202-1019422 Sentence denotes Collectively, these data demonstrate for the first time that freshly isolated rat CD8 CD45RClow T cells contain T cells with regulatory properties, a result that enlarges the general figure of T cell mediated regulation.
T130 1019423-1019532 Sentence denotes The role of this cell subset in the regulation of central nervous system autoimmunity is under investigation.
T131 1019533-1019695 Sentence denotes Campath-1H, a monoclonal antibody used in the treatment of multiple sclerosis (MS), induces persistent T lymphopenia and remission of autoimmune disease activity.
T132 1019696-1019783 Sentence denotes During lymphocyte repopulation, a third of patients develop autoimmune thyroid disease.
T133 1019784-1019964 Sentence denotes The interaction of lymphocytes with MHC class II: self antigen complexes and cytokines such as interleukin-7 (IL-7) are critical for the maintenance of T cell number and diversity.
T134 1019965-1020111 Sentence denotes We assessed the impact of Campath on these homeostatic mechanisms and their possible involvement in the subsequent development of Graves' disease.
T135 1020112-1020254 Sentence denotes We demonstrate greater proliferation of unstimulated lymphocytes from untreated patients, suggesting increased homeostatic proliferation (HP).
T136 1020255-1020323 Sentence denotes However, IL-7 serum levels were equivalent in patients and controls.
T137 1020324-1020417 Sentence denotes Lymphopenia induced a significant increase in serum IL-7 levels, which remained at 12 months.
T138 1020418-1020558 Sentence denotes An increased percentage of unstimulated lymphocytes, from patients 1 year following treatment, proliferate when left for 10 days in culture.
T139 1020559-1020735 Sentence denotes This result is mimicked using peripheral blood mononuclear cells from controls, variably depleted ex vivo of T lymphocytes, suggesting the involvement of lymphopenia-driven HP.
T140 1020736-1020828 Sentence denotes Proliferation was prevented if the interaction between TCR and MHC: self peptide is blocked.
T141 1020829-1020894 Sentence denotes In conclusion, MS patients respond to lymphopaenia appropriately.
T142 1020895-1021061 Sentence denotes Variation in responses between patients, and the differential effect of IL-7 on various T cell subsets may predispose to the development of new autoimmune phenomenon.
T143 1021062-1021196 Sentence denotes Also, we have evidence that HP may be exaggerated in patients with MS perhaps suggesting a mechanism by which autoimmunity may arises.
T144 1021197-1021409 Sentence denotes During autoimmune inflammation of the central nervous system (CNS) as occurs in multiple sclerosis (MS), self reactive immune response is compartmentalized, and oligoclonal expansion of B cells has been observed.
T145 1021410-1021508 Sentence denotes Probably equivalent expansion occurs in T cell subpopulations because ongoing antigen stimulation.
T146 1021509-1021923 Sentence denotes In order to assess whether clonal composition of ex vivo unstimulated cerebrospinal fluid (CSF) T-cells might be related to pathogenic potential, molecular analysis of T-cell receptor (TCR) Vh transcripts of 46 functionally rearranged genes and global comparison of the complementarity-determining region 3 length distribution (CDR3-LD), was carried out ex vivo, contemporarily in unstimulated CSF cells and PBMCs.
T147 1021924-1022124 Sentence denotes The method, consisting in a twostep Multiplex RT-PCR, allowed expansion of the whole TCR Vh gene repertoire from as few as 10(5) cells, indicating that it was sensitive enough to evaluate CSF T cells.
T148 1022125-1022457 Sentence denotes As skewed usage of the TCRVh chain CDR3 segment is a marker of antigen-driven expansion, the expansions allowed identification and separation by monoclonal Abs and magnetic microbeads, of a CSF T-cell subpopulation that should be enriched of Ag specific cells and allow generation at high frequency of CNS Ag-specific T cell clones.
T149 1022458-1022581 Sentence denotes These bpathogenic relevantQ T-cells from CSF are being examined to characterize their phenotypic and functional properties.
T150 1022582-1022763 Sentence denotes Preliminary findings suggest that the strategy adopted is a powerful method for sensitive and accurate detection and characterization of the few relevant Tcells in CNS inflammation.
T151 1022764-1022914 Sentence denotes Multiple sclerosis brain-derived cDNA expression libraries allow the identification of novel autoantigens for CSF-infiltrating CD4+ T lymphocytes D.M.
T152 1022915-1022926 Sentence denotes Park a , M.
T153 1022927-1022942 Sentence denotes Sospedra a , X.
T154 1022943-1022954 Sentence denotes Wang a , J.
T155 1022955-1022968 Sentence denotes Quandt a , C.
T156 1022969-1022983 Sentence denotes Raine b , H.F.
T157 1022984-1023002 Sentence denotes McFarland a and R.
T158 1023003-1023213 Sentence denotes Martin a a National Institutes of Health, Bethesda, USA; b Albert Einstein College of Medicine, New York, NY, USA CD4+ T cells are believed to play a central role in the pathogenesis of multiple sclerosis (MS).
T159 1023214-1023411 Sentence denotes Although extensive research is aimed at characterizing myelin-reactive CD4+ T cells, it remains unknown whether myelin components are the principal or only targets of the autoimmune response in MS.
T160 1023412-1023597 Sentence denotes We therefore tried to identify MS-related autoantigens in an unbiased genetic-based approach to determine the targets of cerebrospinal fluid (CSF) infiltrating CD4+ T cell clones (TCC).
T161 1023598-1023751 Sentence denotes MS plaque tissue-derived cDNAs were cloned into an expression system designed for human leukocyte antigen (HLA) class II-restricted antigen presentation.
T162 1023752-1023842 Sentence denotes A peripheral blood derived myelin-basic protein (MBP)-specific CD4+ TCC served as control.
T163 1023843-1023992 Sentence denotes Three CSF-derived TCCs were isolated from an MS patient during exacerbation and characterized in detail with respect to HLArestriction and phenotype.
T164 1023993-1024115 Sentence denotes Each of the CSF-derived TCCs was in vivo clonally expanded as shown by complementarity determining region 3 spectratyping.
T165 1024116-1024239 Sentence denotes The MBP-specific clone recognized MBP from the plaquederived library, confirming the technical feasibility of the approach.
T166 1024240-1024327 Sentence denotes The CSF-derived clonally expanded CD4+ TCCs recognized an array of interesting targets.
T167 1024328-1024451 Sentence denotes These findings were further supported by data generated with positional scanning synthetic peptide combinatorial libraries.
T168 1024452-1024618 Sentence denotes Our data indicate that likely disease-relevant CSF-infiltrating T cells recognize a much broader range of antigens within MS brain tissue than previously anticipated.
T169 1024619-1024725 Sentence denotes Putative mechanisms of statins in multiple sclerosis-preferential inhibition of activated T lymphocytes O.
T170 1024726-1024740 Sentence denotes Neuhaus a , O.
T171 1024741-1024755 Sentence denotes Stuve a , J.J.
T172 1024756-1024776 Sentence denotes Archelos b and H.-P.
T173 1024777-1024889 Sentence denotes Hartung a a Heinrich Heine University, Düsseldorf, Germany; b Karl Franzens University, Graz, Austria Objective:
T174 1024890-1024957 Sentence denotes To investigate the effects of statins on human T and B lymphocytes.
T175 1024958-1024969 Sentence denotes Background:
T176 1024970-1025190 Sentence denotes It was recently demonstrated that statins, 3hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have immunomodulatory properties and ameliorate disease severity in experimental allergic encephalomyelitis.
T177 1025191-1025278 Sentence denotes Evidence is emerging that statins reduce MRI disease activation markers in MS patients.
T178 1025279-1025287 Sentence denotes Methods:
T179 1025288-1025470 Sentence denotes Mitogenactivated, antigen-specific, and naRve peripheral blood leukocytes obtained from patients with relapsing-remitting MS or from healthy donors were treated with various statins.
T180 1025471-1025608 Sentence denotes The proliferative responsiveness and the presence of surface markers, including activation markers and adhesion molecules were evaluated.
T181 1025609-1025617 Sentence denotes Results:
T182 1025618-1025806 Sentence denotes Statins reduced proliferative activity of mitogen-activated and antigen-stimulated T cells in a dose-dependent manner, simvastatin being most potent, followed by lovastatin and mevastatin.
T183 1025807-1025849 Sentence denotes Proliferation of B cells was not affected.
T184 1025850-1025981 Sentence denotes There was a marked alteration in the surface marker expression of activated T cells, with a decrease in the ratio of CD45RO+ cells.
T185 1025982-1026086 Sentence denotes Following statin-treatment, the phenotype of activated T cells approached that of non-activated T cells.
T186 1026087-1026099 Sentence denotes Conclusions:
T187 1026100-1026399 Sentence denotes Our results support the prevalent hypothesis regarding mechanisms of action of statins: intermediates of the cholesterol biosynthesis pathway downstream of HMG-CoA promote isoprenylation, i.e. post-translational lipid attachment of intracellular proteins that regulate the activation of lymphocytes.
T188 1026400-1026507 Sentence denotes The activation of autoreactive encephalitogenic T cells may be affected by statin treatment in MS patients.
T189 1026508-1026620 Sentence denotes The frequency of CD4(+)CD25(+) T regulatory cells is increased in the CSF but not in the blood of MS patients U.
T190 1026621-1026630 Sentence denotes Feger, C.
T191 1026631-1026641 Sentence denotes Luther, B.
T192 1026642-1026655 Sentence denotes Schreiner, A.
T193 1026656-1026665 Sentence denotes Melms, E.
T194 1026666-1026679 Sentence denotes Tolosa and H.
T195 1026680-1026863 Sentence denotes Wiendl Department of Neurology, University of Tübingen, Tübingen, Germany CD4(+)CD25(+) regulatory T cells contribute to the maintenance of peripheral tolerance by active suppression.
T196 1026864-1026969 Sentence denotes They control the reactivity of potentially harmful, self-reactive T cells and prevent autoimmune disease.
T197 1026970-1027102 Sentence denotes Multiple sclerosis (MS) is an inflammatory autoimmune disease thought to be mediated by T cells recognizing myelin protein peptides.
T198 1027103-1027413 Sentence denotes To address the question if regulatory T cells are involved in the immunopathogenesis of MS, we measured the frequency of CD4(+)CD25(+) regulatory T cells by 4-colour flow cytometry in the blood and the CSF of MS patients in comparison to healthy donors and to patients with non-autoimmune neurological disease.
T199 1027414-1027627 Sentence denotes In agreement with other studies, we did not observe any difference in the amount of blood circulating CD25À high CD4+ cells in patients with either chronic or remitting-relapsing MS in comparison to normal donors.
T200 1027628-1027797 Sentence denotes By contrast, a higher frequency of regulatory T cells was found in the CSF from the same MS patients, but not in the CSF from patients with other neurological disorders.
T201 1027798-1027969 Sentence denotes Selective elevation in the CSF compartment of MS patients therefore suggests a role of CD4(+)CD25(+) regulatory T cells in the development of autoimmune CNS demyelination.
T202 1027970-1028102 Sentence denotes Pathologic relevance of degenerate foreign and self antigen recognition by a myelin-specific HLA-DR2-restricted T cell receptor J.A.
T203 1028103-1028116 Sentence denotes Quandt a , J.
T204 1028117-1028127 Sentence denotes Huh a , D.
T205 1028128-1028139 Sentence denotes Park a , C.
T206 1028140-1028154 Sentence denotes Pinilla b , K.
T207 1028155-1028167 Sentence denotes Ito c and R.
T208 1028168-1028554 Sentence denotes Martin a a National Institutes of Health, Bethesda, USA; b Torrey Pines Institute for Molecular Studies, San Diego, USA; c University of Medicine and Dentistry of New Jersey, Piscataway, USA Degenerate antigen recognition by T cells may contribute significantly to autoimmunity through activation of auto-reactive T cells via molecular mimicry and the subsequent development of disease.
T209 1028555-1028782 Sentence denotes Two unbiased approaches were used to demonstrate the degenerate antigen recognition of a clone recognizing the immunodominant myelin basic protein (MBP) epitope restricted by a multiple sclerosis (MS)-associated HLA DR2 allele.
T210 1028783-1029052 Sentence denotes Screening of positional scanning combinatorial peptide libraries (PSCL) and an MS brain cDNA expression library with a MBP83-99 specific HLA-DR2a-restricted T cell clone have identified numerous infectious/foreign proteins as well as ubiquitous autoantigens as ligands.
T211 1029053-1029183 Sentence denotes PSCL studies predicted several bacterial and viral epitopes as well as myelin-associated proteins as molecular mimics of MBP83-99.
T212 1029184-1029374 Sentence denotes Proliferation and cytokine studies confirmed PLP, MOG and MBP epitopes previously described as HLA DR2 immunodominant epitopes as well as others to be ligands for this T cell receptor (TCR).
T213 1029375-1029565 Sentence denotes These reactivities were conserved in the humanized TCR/HLA DR2 transgenic mouse sharing this TCR, and studies are currently underway to test the pathologic relevance of these mimics in vivo.
T214 1029566-1029772 Sentence denotes Together, these studies emphasize the highly degenerate antigen recognition of autoreactive T cells implicated in MS and describe an important means to identify bnovelQ antigens relevant to MS pathogenesis.
T215 1029773-1029860 Sentence denotes IL-12 suppresses CD4+CD25+ regulatory T cells: a possible mechanism of promoting EAE I.
T216 1029861-1029874 Sentence denotes King and B.M.
T217 1029875-1029920 Sentence denotes Segal University of Rochester, Rochester, USA
T218 1029921-1030040 Sentence denotes The IL-12p40 family of monokines plays a critical role in the differentiation of T lymphocytes into Th1 effector cells.
T219 1030041-1030290 Sentence denotes We have previously demonstrated that IL-12p40 monokines are also critical for the development of relapsing-remitting experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis that is mediated by myelin-specific Th1 cells.
T220 1030291-1030469 Sentence denotes In the current study we investigated the effects of IL-12 on CD4+CD25+ regulatory T cells (Treg), a thymusderived subpopulation of CD4+ T cells with immunosuppressive properties.
T221 1030470-1030622 Sentence denotes Adoptive transfer of Treg prevents EAE in myelin-sensitized wildtype mice or mice bearing a T cell receptor transgene specific for myelin basic protein.
T222 1030623-1030715 Sentence denotes Here we show that Treg express both subunits of the IL-12 receptor (beta1 and beta2 chains).
T223 1030716-1030833 Sentence denotes Furthermore, recombinant IL-12 directly reverses Treg-mediated suppression of effector T cell proliferation in vitro.
T224 1030834-1031059 Sentence denotes Endogenous Treg appear to infiltrate the CNS during peak EAE and to persist at high levels during remissions as indicated by the upregulation of Foxp3, a Treg-specific transcription factor, in spinal cords of sensitized mice.
T225 1031060-1031193 Sentence denotes We conclude that one of the mechanisms by which IL-12 promotes EAE might be through inactivation of an endogenous population of Treg.
T226 1031194-1031321 Sentence denotes Furthermore, Treg spontaneously infiltrate the CNS during EAE, suggesting that they might participate in triggering remissions.
T227 1031322-1031471 Sentence denotes Regulation of Th1/Th2 cytokine balance and inhibition of nuclear factor kappa B (NF kappa B) activation by cannabinoid in encephalitogenic T cells A.
T228 1031472-1031489 Sentence denotes Garcia-Merino, P.
T229 1031490-1031502 Sentence denotes Gonzalez, A.
T230 1031503-1031517 Sentence denotes Arriaga and A.
T231 1031518-1031577 Sentence denotes Sanchez Puerta de Hierro University Hospital, Madrid, Spain
T232 1031578-1031848 Sentence denotes Cannabinoids have been reported to downregulate the production of T helper 1 (Th1) associated cytokines, including IL-2, IL12, interferongamma (IFN-gamma) and tumor necrosis factor-alpha, and to increase the production of Th2 associated cytokines such as IL-4 and IL-10.
T233 1031849-1031958 Sentence denotes Experimental autoimmune encephalomyelitis (EAE) of Lewis rats is a prototypic CD4+ Th1 cell-mediated disease.
T234 1031959-1032052 Sentence denotes It is unknown whether the reported effects of cannabinoids on Th profile are relevant in EAE.
T235 1032053-1032300 Sentence denotes An encephalitogenic T cell line derived from Lewis rats inoculated with guinea pig MBP, was cultured in presence of the synthetic cannabinoid R(+)-WIN 55,212-2 and analyzed by flow cytometry on a FACScanTM for detection of intracellular cytokines.
T236 1032301-1032475 Sentence denotes Compared to control encephalitogenic cells, the cannabinoid reduced IFN gamma production and increased the concentration of IL-10, suggesting a shift towards the Th2 profile.
T237 1032476-1032761 Sentence denotes Taking into account the crucial role played by the nuclear factor-kappa B (NF-kappa B) in the control of key genes involved in activation and differentiation of autoreactive T cells in vivo, we also investigated possible effects of the cannabinoid on activation of this nuclear factor.
T238 1032762-1032893 Sentence denotes Using a construct containing NF-kappa B binding sequences, we observed that R(+)-WIN 55,212-2 decreased markedly promoter activity.
T239 1032894-1032984 Sentence denotes These coordinated effects suggest a potential role of cannabinoids in autoimmune diseases.
T240 1032985-1033200 Sentence denotes The Notch receptor, its ligands of the Delta/Jagged families and downstream signaling mediators form a highly conserved functional pathway playing a central role in cellular differentiation and proliferation events.
T241 1033201-1033434 Sentence denotes Notch signalling is characterised by ligand-induced proteolytic cleavage events that release the Notch intracellular domain, which translocates to the nucleus and binds CBF1, converting it from repressor to transcriptional activator.
T242 1033435-1033601 Sentence denotes Although transcriptional regulation via CBF1 remains the bestcharacterised outcome of Notch signalling, alternative CBF1-independent pathways have also been proposed.
T243 1033602-1033798 Sentence denotes We show that Notch signalling via Delta promotes dose-dependent inhibition of murine T-cell effector cytokine production (IL-2, IL-5, IL-13, IFNgamma, TNFalpha) and upregulation of IL-4 and IL-10.
T244 1033799-1033926 Sentence denotes Using a gamma-secretase inhibitor to block Notch cleavage, we show that Delta1-induced cytokine upregulation is CBF1-dependent.
T245 1033927-1034058 Sentence denotes By contrast, Delta-mediated cytokine inhibition occurs rapidly and involves a different, cleavage-independent signalling mechanism.
T246 1034059-1034209 Sentence denotes These activities are associated with Delta1-modified differentiation of cells: inhibited Th1 development and acquisition of a shared Th2/Treg profile.
T247 1034210-1034293 Sentence denotes These effects occur even under conditions for promoting Th1 or Th2 differentiation.
T248 1034294-1034433 Sentence denotes Notch signalling may, therefore, provide a unique therapeutic approach to the treatment of autoimmune disorders such as multiple sclerosis.
T249 1034434-1034552 Sentence denotes Targeting JAK-STAT pathway by nuclear receptor agonists in the treatment of Th1 cell-mediated autoimmune diseases J.J.
T250 1034553-1034563 Sentence denotes Bright, G.
T251 1034564-1034577 Sentence denotes Muthian, H.P.
T252 1034578-1034589 Sentence denotes Raikwar, R.
T253 1034590-1034604 Sentence denotes Johnson and C.
T254 1034605-1034790 Sentence denotes Johnson Vanderbilt University Medical Center, Nashville, TN, USA Experimental allergic encephalomyelitis (EAE) is a CD4+ Th1 cellmediated autoimmune disease model of multiple sclerosis.
T255 1034791-1034940 Sentence denotes IL-12 is a proinflammatory cytokine that plays a crucial role in the differentiation of neural antigen-specific Th1 cells and pathogenesis of EAE/MS.
T256 1034941-1035102 Sentence denotes Signaling through its receptor, IL-12 induces the activation of JAK-STAT pathway in T cells and targeted disruption of this pathway inhibits Th1 differentiation.
T257 1035103-1035286 Sentence denotes In this study, we have tested the hypothesis that JAK-STAT pathway is a novel therapeutic target in the treatment of Th1 cellmediated autoimmune diseases by nuclear receptor agonists.
T258 1035287-1035501 Sentence denotes We found that in vivo treatment with specific agonists for nuclear receptors, PPARgamma, vitamin D receptor or estrogen receptor, ameliorated the clinical and pathological symptoms of EAE in SJL/J and C57BL/6 mice.
T259 1035502-1035706 Sentence denotes Treatment of neural antigen-specific T cells with nuclear receptor agonists, 15d-PGJ2, Ciglitazone, vitamin D, estrogen or quercetin inhibited antigeninduced T cell proliferation and IFN-gamma production.
T260 1035707-1035918 Sentence denotes The nuclear receptor agonists also inhibited IL-12-induced T cell proliferation and Th1 differentiation by blocking the tyrosine phosphorylation and activation of JAK2, TYK2, STAT3 and STAT4 proteins in T cells.
T261 1035919-1036104 Sentence denotes These results suggest that nuclear receptor agonists modulate JAK-STAT signaling pathway in T cells and be useful in the treatment of MS and other Th1 cell mediated autoimmune diseases.
T262 1036105-1036206 Sentence denotes Computer modeling of lymphocyte behavior in inflamed brain venules by using stochastic Pi-calculus P.
T263 1036207-1036219 Sentence denotes Lecca a , C.
T264 1036220-1036233 Sentence denotes Priami a , C.
T265 1036234-1036251 Sentence denotes Laudanna b and G.
T266 1036252-1036341 Sentence denotes Constantin b a University of Trento, Trento, Italy; b University of Verona, Verona, Italy
T267 1036342-1036551 Sentence denotes The objective of this study was to use new mathematical languages to integrate quantitative and qualitative biological data and create a predictive computer modeling of lymphocyte recruitment in brain venules.
T268 1036552-1036560 Sentence denotes Methods:
T269 1036561-1036632 Sentence denotes Intravital microscopy was performed in inflamed brain microcirculation.
T270 1036633-1036761 Sentence denotes A stochastic extension of the Pi-calculus, an ion based on the notion of naming, was used to model and simulate biological data.
T271 1036762-1036770 Sentence denotes Results:
T272 1036771-1037036 Sentence denotes Integration of interactions between PSGL-1-E-/P-selectin, VLA-4-VCAM-1 and LFA-1-ICAM-1 was required for efficient rolling of autoreactive lymphocytes, while Giprotein-linked signaling and interactions between LFA-1-ICAM-1 and VLA-4-VCAM-1 led to lymphocyte arrest.
T273 1037037-1037215 Sentence denotes These results together with the quantification of hemodynamical parameters and adhesion molecule density allowed us to model the biological data as a set of concurrent processes.
T274 1037216-1037397 Sentence denotes We created a computer model based on stochastic process algebras for mobile systems able to simulate the processes involved in lymphocyte recruitment in inflamed brain microvessels.
T275 1037398-1037615 Sentence denotes Moreover, we showed that the model predicts the percentage of rolling lymphocytes in relation to hemodynamical parameters such as vessel diameter reproducing the functional exponential behavior of the in vivo results.
T276 1037616-1037628 Sentence denotes Conclusions:
T277 1037629-1037806 Sentence denotes The usage of mathematical languages may increase our ability to predict, and thus pharmacologically manipulate, complex key phenomena in the pathogenesis of autoimmune diseases.
T278 1037807-1037871 Sentence denotes Visualising T cell activation in situ in the nervous system K.R.
T279 1037872-1037889 Sentence denotes Williams a , E.K.
T280 1037890-1037903 Sentence denotes Mathey a , A.
T281 1037904-1037919 Sentence denotes Flugel b and C.
T282 1037920-1038165 Sentence denotes Linington a a Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill Aberdeen, Scotland, UK; b Department of Neuroimmunology, Max Planck Institute of Neurobiology, Martinsried Munich, Germany
T283 1038166-1038382 Sentence denotes Recent studies using central nervous system antigen (CNS) specific T cell lines engineered to express green fluorescent protein (GFP) have demonstrated that cell activation is crucial in determining disease severity.
T284 1038383-1038701 Sentence denotes In adoptive transfer experimental autoimmune encephalomyelitis differences in activation levels of infiltrated T cells are antigen specific and determine their ability to recruit macrophages, explaining why some T cell lines are weakly pathogenic (S100beta) while others are strongly pathogenic (myelin basic protein).
T285 1038702-1038889 Sentence denotes However, very little is known about reactivation of T cells in the CNS, in particular when does it occur, where does it take place and what cell types act as the antigen presenting cells?
T286 1038890-1039130 Sentence denotes To answer these questions we have developed a retroviral construct that tags GFP to CD3zeta, a component of the T cell receptor (TCR), which is recruited to the immune synapse formed between a T cell and stimulating antigen-presenting cell.
T287 1039131-1039337 Sentence denotes We demonstrate that antigen-specific stimulation of transduced T cells in vitro results in the translocation of CD3zetaGFP to the cell surface where it co-localises with other components of the TCR complex.
T288 1039338-1039443 Sentence denotes This immune synapse forms adjacent to class II MHC expression on the surface of antigen presenting cells.
T289 1039444-1039677 Sentence denotes Analysis of autoantigen-specific CD3zetaGFP T cells after adoptive transfer reveals that immune synapses can be visualised in the CNS, enabling the identification of antigen-presenting cells in experimental autoimmune disease models.
T290 1039678-1039736 Sentence denotes VIP induces tolerogenic differentiation of immune cells J.
T291 1039737-1039747 Sentence denotes Leceta, C.
T292 1039748-1039762 Sentence denotes Martinez, M.G.
T293 1039763-1039775 Sentence denotes Juarranz, C.
T294 1039776-1039784 Sentence denotes Abad, A.
T295 1039785-1039795 Sentence denotes Arranz, F.
T296 1039796-1039809 Sentence denotes Rosignoli, M.
T297 1039810-1039825 Sentence denotes Garcia and R.P.
T298 1039826-1039928 Sentence denotes Gomariz Departamento de Biología Celular, Facultad de Biología, Universidad Complutense, Madrid, Spain
T299 1039929-1040091 Sentence denotes Vasoactive intestinal peptide (VIP) is a neuropeptide that modulates immunity through cellular signalling mediated by G protein-coupled receptors in immune cells.
T300 1040092-1040180 Sentence denotes It is a potent anti-inflammatory factor, inducing differentiation toward a Th2 response.
T301 1040181-1040277 Sentence denotes Several autoimmune diseases present an imbalance in Th1/Th2 responses, with a prevalence of Th1.
T302 1040278-1040447 Sentence denotes VIP has a protective effect in a murine experimental model of collagen type II (CII)induced arthritis (CIA), an autoimmune process similar to human rheumatoid arthritis.
T303 1040448-1040673 Sentence denotes The aim of this study was to determine the expression of cytokines, chemokines, and their receptors in joints of arthritic mice treated with VIP, as well as to check the immune response against CII of cells from treated mice.
T304 1040674-1040788 Sentence denotes Gene expression for cytokines, chemokines and their receptors were performed using mouse-targeted DNA microarrays.
T305 1040789-1040939 Sentence denotes Proliferative response and secretion of cytokines in cultures of synovial and spleen cells stimulated with CII were used to study the immune response.
T306 1040940-1041002 Sentence denotes Th1 and Th2 cytokines are expressed in the joints of CIA mice.
T307 1041003-1041105 Sentence denotes However, VIP reduces their expression more than 80%, but different cytokines are affected selectively.
T308 1041106-1041173 Sentence denotes IL-10 is the more expressed cytokine and IL-2Ra is little affected.
T309 1041174-1041361 Sentence denotes Local expression of mediators after VIP treatment indicates a shift in the cellular infiltration favouring the homing of mature dendritic cells, CD25+ cells, naive T cells, and Th2 cells.
T310 1041362-1041423 Sentence denotes VIP treatment inhibits proliferation of CII stimulated cells.
T311 1041424-1041503 Sentence denotes In conclusion, VIP biases immune response toward a Th2/T regulatory reactivity.