Epistemic_Statements  

CORD-19:932bcdd2f6c6d487386e8bf983e4874387771be1 JSONTXT 9 Projects

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Id Subject Object Predicate Lexical cue
T1 0-46 Epistemic_statement denotes 1 -18 Plenary lectures and concurrent symposia
T2 57-289 Epistemic_statement 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.
T3 462-610 Epistemic_statement denotes The relative importance of quantity versus quality of response will be considered, together with the characteristics of immunodominance hierarchies.
T4 1063-1307 Epistemic_statement 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.
T5 1626-1721 Epistemic_statement denotes I will review the experimental evidence supporting a bstem cell modelQ of immunological memory.
T6 2663-2880 Epistemic_statement 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.
T7 4382-4515 Epistemic_statement denotes Two-photon imaging reveals that many of the cells rapidly cruises through the brain parenchyma, while the others seem to be arrested.
T8 4607-4727 Epistemic_statement denotes Intra-parenchymal T cell activation seems to underlie the pathogenic inflammatory response responsible for clinical EAE.
T9 5173-5377 Epistemic_statement 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: 853-859, 2002 ).
T10 5695-5853 Epistemic_statement 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.
T11 6501-6675 Epistemic_statement 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.
T12 7293-7524 Epistemic_statement 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.
T13 8863-9049 Epistemic_statement 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.
T14 9595-9779 Epistemic_statement 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.
T15 9780-9951 Epistemic_statement 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.
T16 10136-10310 Epistemic_statement 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.
T17 10311-10462 Epistemic_statement 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.
T18 10747-10916 Epistemic_statement 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.
T19 10917-11042 Epistemic_statement denotes Manipulation of GITR/GITR-L interactions may prove to be an effective way of manipulating regulatory T cell function in vivo.
T20 11043-11323 Epistemic_statement denotes Regulatory T cells: a privileged target for the treatment of autoimmune diseases L. 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.
T21 11658-11819 Epistemic_statement 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.
T22 12407-12623 Epistemic_statement 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.
T23 12624-12758 Epistemic_statement denotes It is foreseeable that this proof of concept in autoimmune diabetes could be extended in the near future to other autoimmune diseases.
T24 12820-13028 Epistemic_statement denotes Nitsch and C. 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.
T25 13029-13407 Epistemic_statement 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.
T26 14409-14555 Epistemic_statement denotes These data show that the generation of antibodies against beta-amyloid in response to immunization can slow cognitive decline in patients with AD.
T27 14556-14699 Epistemic_statement denotes Provided that the tolerability can be improved, they suggest that vaccination against betaamyloid is a valuable option for the treatment of AD.
T28 14700-14799 Epistemic_statement denotes Prospects and limitations in the genetic analysis of common autoimmune diseases F. Cucca a and M.G.
T29 14800-15002 Epistemic_statement 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
T30 15003-15127 Epistemic_statement denotes The genetic analysis of multifactorial traits such as multiple sclerosis and type 1 diabetes is complicated by many factors.
T31 15290-15433 Epistemic_statement denotes Further complications are caused by low penetrance which may be compounded by the small individual genetic effects of most of the disease loci.
T32 15434-15631 Epistemic_statement 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.
T33 15830-15981 Epistemic_statement 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.
T34 16184-16413 Epistemic_statement 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.
T35 17211-17262 Epistemic_statement denotes Protection may be provided by Fas-670 and IL-12p40.
T36 17263-17336 Epistemic_statement denotes The course may be influenced by polymorphisms for IL-10, CNTF, and ApoE4.
T37 17422-17559 Epistemic_statement 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.
T38 17560-18229 Epistemic_statement 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.
T39 18230-18340 Epistemic_statement denotes A major part of future studies will be to resolve the question of disease heterogeneity in multiple sclerosis.
T40 18341-18432 Epistemic_statement denotes The HLA complex is associated with a large number of diseases including Multiple Sclerosis.
T41 18433-18506 Epistemic_statement denotes In the case of MS, there is a strong association with the DR15 haplotype.
T42 18507-18566 Epistemic_statement denotes It remains uncertain exactly how this translates into risk.
T43 18567-18745 Epistemic_statement 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.
T44 18746-18929 Epistemic_statement 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.
T45 19050-19151 Epistemic_statement denotes This locus is complex being characterised by cis and trans effects and a hierarchical susceptibility.
T46 19485-19651 Epistemic_statement 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).
T47 19974-20191 Epistemic_statement 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.
T48 20192-20422 Epistemic_statement 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.
T49 20536-20711 Epistemic_statement 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.
T50 20712-20909 Epistemic_statement 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.
T51 20910-21175 Epistemic_statement denotes Molecular mechanisms driving transendothelial migration of leukocytes across the blood-brain barrier B. Engelhardt Theodor Kocher-Institute, University of Bern, Bern, Switzerland Diapedesis of encephalitogenic T lymphocytes across the blood-brain barrier is unique.
T52 22364-22491 Epistemic_statement denotes Surprisingly, tyrosine-phosphorylation of endothelial ICAM-1 was not necessary for TEM of T cells nor for RhoGTPase activation.
T53 22492-22695 Epistemic_statement 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.
T54 22696-22802 Epistemic_statement denotes It is generally believed that this signal is required to open endothelial junctions for T cell diapedesis.
T55 22896-23284 Epistemic_statement 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.
T56 23661-23770 Epistemic_statement denotes In striking contrast, the actions of JNKs in the immune cells of the nervous system remains to be elucidated.
T57 24221-24457 Epistemic_statement 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.
T58 24578-24680 Epistemic_statement denotes This observation suggests that JNK2 is mainly responsible for the activation of transcription factors.
T59 25191-25358 Epistemic_statement 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.
T60 25359-25586 Epistemic_statement 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.
T61 25952-26087 Epistemic_statement denotes Excessive production and accumulation of cytotoxic forms of amyloid beta peptide (Abeta) is believed to be a pivotal abnormality in AD.
T62 26088-26312 Epistemic_statement 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.
T63 26450-26607 Epistemic_statement denotes Data suggest that cytokines may either promote or protect against neuronal degeneration, depending upon the cell type and signaling pathway(s) they activate.
T64 26608-26827 Epistemic_statement 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.
T65 27226-27400 Epistemic_statement 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.
T66 27401-27621 Epistemic_statement 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.
T67 28404-28716 Epistemic_statement 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.
T68 28717-29092 Epistemic_statement 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.
T69 29443-29673 Epistemic_statement 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).
T70 29674-29797 Epistemic_statement denotes This can occur either by antigennonspecific bystander events or through cross-reactivity between viral and self-components.
T71 29798-29994 Epistemic_statement 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.
T72 29995-30145 Epistemic_statement denotes However, recently, it has become increasingly clear that the opposite situation, prevention of autoimmunity by viral infections, might be more common.
T73 30146-30239 Epistemic_statement denotes There is accumulating evidence that viruses such as Coxsackie B or LCMV can prevent diabetes.
T74 30240-30280 Epistemic_statement denotes How can viral infections be good for us?
T75 30281-30458 Epistemic_statement 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.
T76 30459-30521 Epistemic_statement denotes The reversal of disease appears in most cases to be permanent.
T77 31517-31621 Epistemic_statement denotes Unexpectedly, genes other than S appeared to modulate events critical to viral replication and survival.
T78 31799-32010 Epistemic_statement 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.
T79 32236-32403 Epistemic_statement 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.
T80 32449-32644 Epistemic_statement 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.
T81 32891-33055 Epistemic_statement 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.
T82 33473-33658 Epistemic_statement 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.
T83 33659-33865 Epistemic_statement 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).
T84 34106-34329 Epistemic_statement 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.
T85 35416-35662 Epistemic_statement 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.
T86 35900-36021 Epistemic_statement denotes Huseby b and D. Liggitt a a University of Washington, Seattle, WA, USA; b National Jewish Medical Centre, Denver, CO, USA
T87 36022-36159 Epistemic_statement denotes The activation of immune responses to myelin antigens is believed to be one of the early steps in the pathogenesis of multiple sclerosis.
T88 36356-36531 Epistemic_statement 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.
T89 36532-36748 Epistemic_statement 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.
T90 37321-37405 Epistemic_statement denotes How regulatory T cells function in both the CNS and the periphery will be discussed.
T91 38367-38482 Epistemic_statement 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.
T92 38638-38875 Epistemic_statement 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.
T93 39169-39439 Epistemic_statement 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.
T94 39615-39897 Epistemic_statement 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?
T95 39898-40096 Epistemic_statement denotes (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?
T96 40335-40431 Epistemic_statement denotes The specificity and phenotype of CD4+ myelin-specific T cells is related to clinical phenotypes.
T97 41066-41141 Epistemic_statement denotes Here, we present evidence that the MS brain is also generating new neurons.
T98 41885-41949 Epistemic_statement denotes NeuN-positive neurons, however, are increased around MS plaques.
T99 41950-42120 Epistemic_statement 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.
T100 42121-42358 Epistemic_statement 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.
T101 42359-42599 Epistemic_statement 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.
T102 42600-42755 Epistemic_statement denotes Neurotrophic factors could be of therapeutical interest in MS as they might promote either oligodendrocyte survival, myelin formation or axonal protection.
T103 42756-42900 Epistemic_statement denotes Using a recently developed index of myelination, we have shown that synthetic neuroprotective sigma agonists could strongly enhance myelination.
T104 42901-43004 Epistemic_statement denotes We further analyzed whether some endogenous neurotrophic factors could also stimulate myelin formation.
T105 43323-43793 Epistemic_statement 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. 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.
T106 43794-44010 Epistemic_statement 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.
T107 44011-44096 Epistemic_statement denotes Therefore this new family of receptors might also be of therapeutical interest in MS.
T108 44178-44711 Epistemic_statement denotes Kotter a , W.-W. Li a , F. Molina-Holgado a , C. Zhao a , A. Setzu a,b , C. ffrench-Constant b and R.J. 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.
T109 44871-44963 Epistemic_statement denotes The environmental factors that orchestrate this process have attracted much recent interest.
T110 44964-45111 Epistemic_statement denotes A picture is emerging of a complex matrix of factors that changes with time, initially promoting OPC recruitment and then inducing differentiation.
T111 45112-45379 Epistemic_statement 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.
T112 45526-45702 Epistemic_statement 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.
T113 46048-46226 Epistemic_statement 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.
T114 46986-47174 Epistemic_statement 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.
T115 47504-47605 Epistemic_statement denotes The remaining 15% patients have either autoantibodies to Musk or to a not yet defined antigen (SNMG).
T116 48066-48145 Epistemic_statement denotes Interestingly, these changes were similarly observed in SNMG and SNPG patients.
T117 48540-48695 Epistemic_statement denotes Altogether, these data suggest the existence of a compensatory mechanism regulating the expression of several genes involved in the neuromuscular junction.
T118 48696-48841 Epistemic_statement denotes Most dysregulated genes are common between SNMG and SNPG patients, suggesting common mechanisms of autoimmune attack in these groups of patients.
T119 48842-49040 Epistemic_statement denotes Autoantibodies and the autonomic nervous system S. Vernino Mayo Clinic, Rochester, MN, USA Many cases of acute or subacute peripheral autonomic failure are associated with neurological autoimmunity.
T120 49488-49645 Epistemic_statement 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.
T121 49646-49852 Epistemic_statement 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.
T122 49853-50026 Epistemic_statement denotes Other cases of autoimmune autonomic failure or severe gastrointestinal dysmotility occur in association with small-cell lung carcinoma (paraneoplastic autonomic neuropathy).
T123 50027-50190 Epistemic_statement 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.
T124 50446-50610 Epistemic_statement denotes Since then, additional antibodies have been reported in association with PND, 12 of them currently considered clinically relevant markers of paraneoplasia (PND-Ab).
T125 50611-50838 Epistemic_statement 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.
T126 50839-50977 Epistemic_statement 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.
T127 51078-51190 Epistemic_statement denotes Among the other 50% of patients, many show signs of inflammation in the CNS or CSF suggesting immune mechanisms.
T128 51300-51586 Epistemic_statement 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.
T129 51828-52171 Epistemic_statement denotes Antibodies in demyelinating diseases C. 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.
T130 52520-52823 Epistemic_statement 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.
T131 52824-53155 Epistemic_statement 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.
T132 53156-53605 Epistemic_statement denotes Gangliosides as autoantibody targets at the neuromuscular junction in immune-mediated neuropathies H. 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.
T133 54120-54306 Epistemic_statement 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.
T134 54307-54464 Epistemic_statement denotes This talk will review our current understanding of this complex field and address new approaches to testing novel treatments for these debilitating diseases.
T135 55797-56010 Epistemic_statement 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.
T136 56451-56724 Epistemic_statement 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.
T137 56725-56867 Epistemic_statement denotes Apoptosis of autoreactive myelin specific T cells may be an important mechanism to limit the immunoinflammatory response and to abort disease.
T138 56965-57120 Epistemic_statement denotes However, the role of cytokines in immune regulation and autoimmune inflammatory neuropathies is more complex than a simple Th1-Th2 dichotomy would suggest.
T139 57121-57295 Epistemic_statement 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.
T140 57296-57546 Epistemic_statement 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.
T141 58152-58310 Epistemic_statement denotes Appropriate stimuli can differentiate DCs and render them immunogenic, whereas in the steady state, most DCs are immature and can induce peripheral tolerance.
T142 58501-58557 Epistemic_statement denotes DC function can also be studied with ex vivo approaches.
T143 58667-58778 Epistemic_statement denotes It has become apparent that DCs induce and/or expand these regulators, including CD4+ CD25+ suppressor T cells.
T144 58959-59120 Epistemic_statement 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.
T145 59364-59511 Epistemic_statement denotes However, following acute brain injury, and in immune mediated lesions, small numbers of OX62+ve dendritic cells appear in the rat brain parenchyma.
T146 60001-60329 Epistemic_statement 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.
T147 61167-61346 Epistemic_statement 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.
T148 61636-61684 Epistemic_statement denotes However, they are unable to prime naive T cells.
T149 61898-61995 Epistemic_statement denotes Thus, CNS-DC may be the key responsible for maintaining immune privilege within the inflamed CNS.
T150 62135-62396 Epistemic_statement 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.
T151 62572-62763 Epistemic_statement 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.
T152 62764-62975 Epistemic_statement 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.
T153 62976-63170 Epistemic_statement 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.
T154 63358-63432 Epistemic_statement denotes That these molecules normally regulate microglial cells in situ is likely.
T155 63749-63988 Epistemic_statement 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.
T156 65061-65278 Epistemic_statement 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.
T157 65465-65574 Epistemic_statement denotes In addition, human and animal model studies demonstrate multiple abnormalities in astroglial function in ALS.
T158 66508-66685 Epistemic_statement 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.
T159 67096-67369 Epistemic_statement 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.
T160 67370-67506 Epistemic_statement denotes However, recent data suggest that at least some of the complement components have the ability to contribute to neuroprotective pathways.
T161 67726-67943 Epistemic_statement 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.
T162 67944-68364 Epistemic_statement denotes Protective autoimmunity as a defense mechanism against destructive self-compounds: role of CD4+CD25+ regulatory T cells and prospects for therapeutic vaccination M. 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.
T163 68365-68626 Epistemic_statement 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).
T164 69213-69390 Epistemic_statement 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.
T165 70048-70243 Epistemic_statement 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.
T166 70244-70370 Epistemic_statement denotes However, the clinical decline was found much less in patients who developed antibodies to beta amyloid than those who did not.
T167 70371-70493 Epistemic_statement denotes It is interesting to know that an autopsy case who had received the vaccine suggested the disappearance of senile plaques.
T168 70775-70943 Epistemic_statement 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.
T169 71199-71260 Epistemic_statement denotes Can neurotransmitters by themselves trigger T-cell functions?
T170 72488-72900 Epistemic_statement 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.
T171 72901-73083 Epistemic_statement denotes The presentation of self in the thymus network: a novel way for prevention and cure of autoimmune diseases V. Geenen Liege University Center of Immunology, Liege-Sart Tilman, Belgium
T172 73084-73228 Epistemic_statement denotes The thymus ensures the establishment of self-tolerance by deleting selfreactive T cells and generating self-antigen specific regulatory T cells.
T173 74240-74395 Epistemic_statement 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.
T174 74735-74812 Epistemic_statement denotes Bluthé, P. Parnet and J.P. Konsman Integrative Neurobiology, Bordeaux, France
T175 74813-74954 Epistemic_statement denotes The signaling pathways that mediate the behavioral effects of interleukin-1 (IL-1) during the acute phase reaction have not yet been studied.
T176 75710-75895 Epistemic_statement 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).
T177 76802-77030 Epistemic_statement 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.
T178 77953-78144 Epistemic_statement 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.
T179 78145-78221 Epistemic_statement denotes Basic mechanistic experiments as well as clinical studies will be discussed.
T180 78247-78313 Epistemic_statement denotes Chrousos PREB, NICHD, NIH and University of Athens, Athens, Greece
T181 78314-78431 Epistemic_statement denotes Like the stress response, the inflammatory reaction of an individual is crucial for survival of the self and species.
T182 79737-79896 Epistemic_statement denotes Yet, peripheral neuronal CRH activated by stress or the inflammatory reaction, and substance P, activated by the inflammatory reaction potentiate inflammation.
T183 79897-80156 Epistemic_statement 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.
T184 80989-81162 Epistemic_statement 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.
T185 81163-81296 Epistemic_statement denotes It should be highlighted that immune activation is the only stressor that can induce a pituitary-adrenal response in the CrhÀ/À mice.
T186 81450-81656 Epistemic_statement 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.
T187 82007-82116 Epistemic_statement denotes Interestingly, CrhÀ/À mice had profound anorexia and weight loss despite their reduced inflammatory response.
T188 82117-82273 Epistemic_statement 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.
T189 82274-82385 Epistemic_statement denotes Identification of polymorphic genes regulating inflammatory diseases may unravel crucial pathogenic mechanisms.
T190 82386-82569 Epistemic_statement 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.
T191 83402-83570 Epistemic_statement 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.
T192 83571-83783 Epistemic_statement 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.
T193 83902-84121 Epistemic_statement denotes Satoh, M. Nakanishi, H. Onoue, T. Aranami and T. Yamamura National Institute of Neuroscience, Tokyo, Japan Objective: To clarify the molecular background underlying the phenotypic variability of multiple sclerosis (MS).
T194 84690-85033 Epistemic_statement denotes The patients presenting with the lesion distribution restricted in the cerebrum were clustered in the subgroup C. 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.
T195 85204-85499 Epistemic_statement denotes Conclusions: 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.
T196 85500-85709 Epistemic_statement denotes A clinical-genetic study of multiple sclerosis in a Dutch genetically isolated community R. Hintzen, E. Croes, C. van Duijn and I. Hoppenbrouwers Erasmus MC, Department of Neurology, Rotterdam, The Netherlands
T197 85710-85903 Epistemic_statement denotes Background: 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) .
T198 85904-86030 Epistemic_statement denotes Objectives: To identify MS cases within a Dutch genetically isolated population and attempt to link them to a common ancestor.
T199 86622-86706 Epistemic_statement denotes Twenty of the 48 patients could be linked to a common ancestor in 12-14 generations.
T200 87130-87182 Epistemic_statement denotes HLA-Dr2 was not specifically linked to the MS cases.
T201 87183-87296 Epistemic_statement denotes Several studies have shown that multiple sclerosis (MS) is associated with the HLA class II specificity HLA-DR15.
T202 87297-87449 Epistemic_statement 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.
T203 87450-87791 Epistemic_statement denotes Though DR15 increases the risk for OCB-positive conventional MS in Japan, it is not a risk factor for OCB-negative MS. 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.
T204 88653-88821 Epistemic_statement 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.
T205 89252-89364 Epistemic_statement denotes Results: Each of the two variants was associated with an increased risk of AD only in the presence of the other.
T206 89639-89842 Epistemic_statement denotes Conclusions: 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.
T207 89987-90428 Epistemic_statement denotes Age, parent, and season at immunization influence susceptibility to EAE E. Blankenhorn a , C. Teuscher b , J. Bunn b and P. 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.
T208 90757-90977 Epistemic_statement 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.
T209 90978-91108 Epistemic_statement denotes Surprisingly, CNS inflammation in male mice was not affected by POO, and female progeny were not influenced by POO effects at all.
T210 91398-91704 Epistemic_statement 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.
T211 91705-91846 Epistemic_statement denotes Background: Several studies demonstrated the involvement of the myelin oligodendrocyte glycoprotein (MOG) protein in multiple sclerosis (MS).
T212 92569-92755 Epistemic_statement 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).
T213 93998-94183 Epistemic_statement 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.
T214 94306-94832 Epistemic_statement denotes Identification of QTL controlling cortical motor evoked potentials in experimental autoimmune encephalomyelitis: correlation with incidence, onset and severity of disease I. Mazon a , S. Vogler a , U. Strauss b , P. Wernhoff a , A. Rolfs b and S. 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.
T215 94833-94959 Epistemic_statement denotes Previous studies have identified multiple quantitative trait loci (QTL) controlling different aspects of disease pathogenesis.
T216 94960-95067 Epistemic_statement denotes However, direct genetic control of motor-evoked potentials as a measure of demyelination was not addressed.
T217 95479-95668 Epistemic_statement 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).
T218 95725-95947 Epistemic_statement 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.
T219 96229-96351 Epistemic_statement denotes A congenic rat strain, DAc9BN-Eae4, has been established and a phenotypic effect of the isolated locus has been confirmed.
T220 96472-96784 Epistemic_statement 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.
T221 97114-97282 Epistemic_statement 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.
T222 98485-98613 Epistemic_statement denotes The smaller C4R11 interval overlaps with one of the QTLs, and C4R11 congenic rats were also less susceptible than DA to MOG-EAE.
T223 98822-98885 Epistemic_statement denotes This gene(s) may be a general regulator of autoimmune diseases.
T224 99388-99467 Epistemic_statement denotes This region overlaps with Pia4, which was also identified in the (DAÂE3) cross.
T225 100550-100697 Epistemic_statement denotes MOG-EAE like MS is complex genetic disease with contributions from major histocompatibility complex (MHC) genes and multiple unknown non-MHC genes.
T226 101418-101625 Epistemic_statement 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.
T227 101626-101805 Epistemic_statement 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.
T228 101806-101973 Epistemic_statement 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.
T229 101974-102413 Epistemic_statement denotes A novel SNP in the coding region of PSGL-1 in multiple sclerosis patients C. Fenoglio a , D. Galimberti a , R. Clerici a , M. Ronzoni a , M. De Riz a , L. Piccio a , A. Gatti a , E. Venturelli a , L. Berti a , G. Constantin b , N. Bresolin a and E. 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).
T230 102523-102658 Epistemic_statement 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.
T231 103312-103507 Epistemic_statement 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.
T232 103508-103882 Epistemic_statement denotes Analysis of the Asp299Gly polymorphism in the Toll-like receptor 4 (TLR-4) gene in patients with multiple sclerosis A. Kroner a , B. Rosche b , A. Kolb-M7urer a , N. Kruse c , K. Toyka a , B. Hemmer b , P. Rieckmann a and M. M7urer a a University of Würzburg, Würzburg, Germany; b Heinrich Heine University, Düsseldorf, Germany; c University of Göttingen, Göttingen, Germany
T233 103883-104060 Epistemic_statement denotes In multiple sclerosis, disease deterioration often occurs in association with bacterial infections, particularly with lipopolysaccharide (LPS) containing gram negative bacteria.
T234 104942-105048 Epistemic_statement denotes No association of different genotypes with MS susceptibility, subtypes or disease severity could be found.
T235 105049-105192 Epistemic_statement denotes Significantly lower proliferation rates ( p=0.023) in PBMCs derived from heterozygous individuals could be detected after stimulation with LPS.
T236 105193-105316 Epistemic_statement denotes We could not find an association between Asp299Gly genotypes and disease course of multiple sclerosis in our MS population.
T237 105317-105438 Epistemic_statement denotes However, we could confirm the functional relevance of the Asp299Gly polymorphism after exposure of immune cells with LPS.
T238 105597-105997 Epistemic_statement denotes Albergoni b , F. Ranzato a and L. 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.
T239 106694-106779 Epistemic_statement denotes An association of MS with Type 1 Diabetes Mellitus was also noticed (T1DM) ( p=0.04).
T240 106997-107212 Epistemic_statement 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.
T241 107213-107743 Epistemic_statement denotes The CD14 C(-260)T promoter polymorphism is associated with disease severity in multiple sclerosis patients A. Lutterotti a , R. Ehling a , H. Lassmann b , F. Deisenhammer a , T. Berger a and M. 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.
T242 107744-107972 Epistemic_statement 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).
T243 108539-108692 Epistemic_statement denotes We found no association between CD14-260 C-T polymorphism and susceptibility to MS. CD14 is upregulated in MS lesions, most prominently in acute lesions.
T244 108693-108908 Epistemic_statement 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.
T245 109279-109384 Epistemic_statement denotes Many unknown genetic factors lead to a set of clinical phenotypes of different intensity and periodicity.
T246 109852-109993 Epistemic_statement 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.
T247 110155-110216 Epistemic_statement denotes The interaction of genes and loci may be graphically browsed.
T248 110658-110882 Epistemic_statement 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.
T249 110883-111029 Epistemic_statement denotes Lymphocyte recruitment into the brain is a critical event in the pathogenesis of multiple sclerosis (MS), and is controlled by adhesion molecules.
T250 111599-111805 Epistemic_statement 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.
T251 111806-112048 Epistemic_statement 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.
T252 112049-112184 Epistemic_statement denotes Besides, A561C polymorphism does not seem to be a susceptibility factor for MS, although its presence could influence the age at onset.
T253 112281-112691 Epistemic_statement 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.
T254 113009-113131 Epistemic_statement 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.
T255 113262-113450 Epistemic_statement 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.
T256 113664-113732 Epistemic_statement denotes Both genetic and environmental factors play a role in its aetiology.
T257 113797-113941 Epistemic_statement denotes In MS, there is evidence from linkage studies and allelic association studies suggesting that chromosome 2q33 would harbour a predisposing gene.
T258 113942-114048 Epistemic_statement denotes We have performed a two-stage study to analyse the association of polymorphism on chromosome 2q33 with MS.
T259 114049-114192 Epistemic_statement 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.
T260 114193-114274 Epistemic_statement denotes We did not find previously reported allelic or haplotype associations with CTLA4.
T261 114377-114617 Epistemic_statement 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).
T262 114767-114874 Epistemic_statement denotes Our results provide preliminary evidence for two distinct MS susceptibility genes on 2q33 outside of CTLA4.
T263 114875-115026 Epistemic_statement denotes Background: To evaluate correlation between HLA-DRB1-DQB1 haplotype and age-at-onset in a population of multiple sclerosis (MS) patients from Sardinia.
T264 115919-116154 Epistemic_statement 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).
T265 116168-116286 Epistemic_statement denotes This results indicate that in Sardinians MS patients HLA-DRB1-DQB1 molecules contribute to early onset of the disease.
T266 116287-116384 Epistemic_statement denotes Interestingly, risk of early onset is associated with the autoimmune diabetes high-risk genotype.
T267 117499-117741 Epistemic_statement 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.
T268 117742-117994 Epistemic_statement 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.
T269 118197-118432 Epistemic_statement 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.
T270 118433-118739 Epistemic_statement 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.
T271 118740-119050 Epistemic_statement 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.
T272 119506-119660 Epistemic_statement 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.
T273 119661-119773 Epistemic_statement denotes Common viral infections have been implicated as environmental factors influencing onset and activity of disease.
T274 119882-119979 Epistemic_statement denotes Some of the genes were located in regions previously linked to MS in genome wide linkage studies.
T275 119980-120148 Epistemic_statement 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.
T276 120431-120488 Epistemic_statement denotes So far, none of the polymorphisms was associated with MS.
T277 121544-121710 Epistemic_statement 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.
T278 121957-122213 Epistemic_statement 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.
T279 123180-123271 Epistemic_statement denotes However, there were ethnic differences of C band size on Y-chromosome in middle-aged group.
T280 123825-123969 Epistemic_statement denotes This fact suggests that Y-chromosomal polymorphism variants constitute the cytogenetic markers of both individual and probably ethnic longevity.
T281 123970-124214 Epistemic_statement 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.
T282 124215-124446 Epistemic_statement 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.
T283 125010-125190 Epistemic_statement denotes Massive tissue destruction, cystic necrosis, respectively, was associated with immunohistochemically detectable inducible nitric oxide synthase (iNOS) in macrophages and microglia.
T284 125191-125394 Epistemic_statement 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.
T285 125628-125825 Epistemic_statement 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.
T286 126318-126416 Epistemic_statement denotes Therefore, FcgammaR polymorphisms could influence the vigour of antibody-induced immune responses.
T287 126833-127207 Epistemic_statement 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).
T288 127208-127295 Epistemic_statement denotes FcgammaRIIIa and FcgammaRIIIb genotypes may represent disease-modifying factors in GBS.
T289 127810-127908 Epistemic_statement denotes Interindividual differences in cytokine profiles appear related to allelic polymorphisms of genes.
T290 127909-128358 Epistemic_statement denotes Differences in the distribution of polymorphic alleles may have implications on genetic susceptibility to MG. 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).
T291 128630-128749 Epistemic_statement denotes However, an association of IL-12p40 3V UTR C allele with anti-titin antibody positivity is detected (OD=4.25, pc=0.02).
T292 130411-130502 Epistemic_statement denotes An association with HLA class II antigens and the disease was described in other countries.
T293 130503-130672 Epistemic_statement 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).
T294 130673-130849 Epistemic_statement 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.
T295 130850-130919 Epistemic_statement denotes Severe MG was associated with HLA-DR2 and HLA-DR3 ( p=0.04 for both).
T296 130920-131072 Epistemic_statement 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.
T297 131073-131228 Epistemic_statement 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.
T298 131229-131354 Epistemic_statement denotes On the other hand, an strong association between HLA DR7 and early-onset disease was found in female MG patients ( p=0.0005).
T299 131355-131531 Epistemic_statement 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.
T300 131566-131891 Epistemic_statement denotes Age-related changes in the inflammatory response to cytokines in the brain S. Campbell and D.C. 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.
T301 131892-132095 Epistemic_statement 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).
T302 132370-132519 Epistemic_statement denotes Neutrophil recruitment through vessel walls was associated with loss of the tight-junction protein claudin-1, and with blood-brain barrier breakdown.
T303 132703-132929 Epistemic_statement 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.
T304 133516-133704 Epistemic_statement 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.
T305 133705-133857 Epistemic_statement denotes However, our understanding of the consequences of activation of cytokine signaling systems in the CNS is relatively limited, especially for CNS neurons.
T306 133937-134057 Epistemic_statement denotes Therefore, we have investigated the potential involvement of this mechanism in the neuronal signaling activated by CCL2.
T307 134629-134771 Epistemic_statement denotes These modulatory effects of CCL2 on neuronal properties are likely to contribute to alter CNS function associated with CNS disease and injury.
T308 134985-135074 Epistemic_statement denotes The accumulation of ingested lipids is associated with a foamy appearance of these cells.
T309 135075-135234 Epistemic_statement denotes It is generally assumed that foamy macrophages contribute to a local pro-inflammatory environment, but this assumption is based on surprisingly scant evidence.
T310 135235-135491 Epistemic_statement 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.
T311 135961-136094 Epistemic_statement denotes Preliminary in vitro data suggest that myelin-lipid preparations decrease LPS-induced TNF production and induce IL-10 by macrophages.
T312 136095-136297 Epistemic_statement 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.
T313 136298-136394 Epistemic_statement denotes Our data suggest that phagocytic macrophages may display regulatory functions within MS lesions.
T314 136395-136932 Epistemic_statement 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. Rolland a , E. Jouvin-Marche a , M. Saresella b , P. 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.
T315 136933-137152 Epistemic_statement 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.
T316 137440-137586 Epistemic_statement 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.
T317 137587-137759 Epistemic_statement 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.
T318 137760-137908 Epistemic_statement denotes The pro-inflammatory properties of ENV-SU could be compatible with a relationship between MSRV expression, MS immunopathology and disease evolution.
T319 138659-138828 Epistemic_statement 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.
T320 139160-139329 Epistemic_statement 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.
T321 139330-139514 Epistemic_statement 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.
T322 139893-140164 Epistemic_statement 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.
T323 141200-141292 Epistemic_statement denotes Changes in DST11 levels in brain could contribute to the progression of inflammatory damage.
T324 141912-142224 Epistemic_statement 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.
T325 142225-142520 Epistemic_statement 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.
T326 142903-143107 Epistemic_statement 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.
T327 143263-143497 Epistemic_statement denotes Langel and K. 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.
T328 143596-143778 Epistemic_statement 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).
T329 143779-144034 Epistemic_statement 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.
T330 144166-144319 Epistemic_statement denotes This suggests that therapeutical strategies aimed to control the development of AD could include administration of drugs that hinder NFkappaB activation.
T331 144525-144689 Epistemic_statement denotes We also investigated the possibility to block the action of NFkappaB using double-stranded oligonucleotides containing the consensus sequences for NFkappaB binding.
T332 144907-145202 Epistemic_statement denotes Role of TNF in axonal lesion-induced microglial activation in vivo C. Fenger, N. Drbjdahl, M. Meldgaard, R. Ladeby, K. Lambertsen and B. 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.
T333 145950-146278 Epistemic_statement 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).
T334 146279-146418 Epistemic_statement denotes The data suggest that endogenously produced TNF may be redundant in terms of lesion-induced expansion of the microglial population in vivo.
T335 147202-147280 Epistemic_statement denotes However, IFN-gamma is considered to be produced exclusively by lymphoid cells.
T336 147801-148042 Epistemic_statement 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.
T337 148553-148737 Epistemic_statement 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.
T338 148738-148851 Epistemic_statement denotes In the present study, we aimed to understand their potential biological roles in the brain and myasthenic thymus.
T339 149316-149357 Epistemic_statement denotes These factors support neural cell growth.
T340 149434-149485 Epistemic_statement denotes The two factors also support the growth of B cells.
T341 149486-149633 Epistemic_statement denotes These results suggest that the two new haemopoietic factors play important physiological roles in brain and regulatory roles in autoimmune disease.
T342 150884-151132 Epistemic_statement 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.
T343 151133-151299 Epistemic_statement 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.
T344 151710-151921 Epistemic_statement 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).
T345 152909-153415 Epistemic_statement denotes Ferrari a , A.M. Depino a , F. Prada a , O. Podhajcer a , H. Perry b , D. Anthony c and F. 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.
T346 153416-153534 Epistemic_statement denotes However, the effects of long-term IL-1 expression in the brain parenchyma on CNS integrity have not been investigated.
T347 154178-154329 Epistemic_statement denotes Interestingly, at 30 days, the nervous tissue has completely recovered, appearing normal with no signs of demyelination, infiltration or BBB breakdown.
T348 154330-154601 Epistemic_statement 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.
T349 155097-155366 Epistemic_statement 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.
T350 155367-155486 Epistemic_statement 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.
T351 156497-156545 Epistemic_statement denotes The role of neuroinflammation in SCI is unclear.
T352 156546-156686 Epistemic_statement denotes The objective of this study is to examine neuroinflammation after SCI and to determine whether a particular molecule regulates this process.
T353 157254-157493 Epistemic_statement 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.
T354 157641-157773 Epistemic_statement 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.
T355 158141-158249 Epistemic_statement denotes Thus, we hypothesized that these two factors would also increase oligodendrocyte production from adult NSCs.
T356 158398-158674 Epistemic_statement 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.
T357 158675-158957 Epistemic_statement 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.
T358 158958-159076 Epistemic_statement denotes Both GM-CSF and T3 also decreased the number of TUNEL-positive cells in the CC suggesting that they reduce cell death.
T359 159077-159295 Epistemic_statement 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.
T360 159296-159558 Epistemic_statement 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.
T361 160078-160295 Epistemic_statement 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.
T362 161056-161183 Epistemic_statement denotes Conclusions: Replication-competent, avirulent alphaviral vectors may serve as vehicles for non-invasive gene delivery into CNS.
T363 161184-161395 Epistemic_statement 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.
T364 161396-161698 Epistemic_statement denotes Potential role of interleukin-15 (IL-15) in autoimmunity and impact of IGIV on IL-15 expression N. Eller, S. Inoue and D. 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.
T365 161960-162108 Epistemic_statement denotes Il-15 may be membranetethered or associated with the IL-15Ralpha subunit and very little is secreted from cells, making protein detection difficult.
T366 162109-162218 Epistemic_statement denotes IL-15 has been associated with autoimmune diseases such as multiple sclerosis (MS), and rheumatoid arthritis.
T367 162219-162337 Epistemic_statement denotes It is unclear whether IL-15 has a role in disease initiation or if it is a marker of disease and disease pathogenesis.
T368 162481-162553 Epistemic_statement denotes This method can be used to correlate IL-15 levels with clinical disease.
T369 162554-162700 Epistemic_statement denotes Immune Globulin, Intravenous (IGIV) has been shown to have immunomodulatory effects and has been used in the treatment of MS with varying results.
T370 163844-164035 Epistemic_statement 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.
T371 164036-164210 Epistemic_statement 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.
T372 164211-164653 Epistemic_statement denotes Conclusion: 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.
T373 164823-164978 Epistemic_statement denotes Kylliäinen a , K. Kimppa a,b , S. Ruohonen a , M. Tenhami a and M. Rfytt7 a a University of Turku, Turku, Finland; b Åbo Akademi University, Turku, Finland
T374 164979-165135 Epistemic_statement 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.
T375 165594-165690 Epistemic_statement denotes Sample preparations and hybridizations were performed according to Affymetrix's recommendations.
T376 165767-165895 Epistemic_statement denotes We decided that values SLRN1.5 or SLRbÀ1.5 are relevant and the expression can then be considered either increased or decreased.
T377 165896-166019 Epistemic_statement denotes Expression of many cytokines and cytokine-related genes were detected and the results correlated well to previous findings.
T378 166020-166129 Epistemic_statement denotes An interesting finding was the significant expression of IL-6 mRNA from 12 h up to 49 days after transection.
T379 166350-166645 Epistemic_statement denotes Interleukin-23 in acute inflammatory demyelination of the peripheral nervous system W. Hu, H.-P. Hartung and B. 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.
T380 166646-166782 Epistemic_statement denotes Mounting evidence suggests that IL-23 rather than IL-12 is critically involved in the pathogenesis of various immune-mediated disorders.
T381 167518-167820 Epistemic_statement 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.
T382 169372-169466 Epistemic_statement denotes This suggests that these are involved in the building up the missing part of peripheral nerve.
T383 170137-170300 Epistemic_statement 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.
T384 170301-170408 Epistemic_statement 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).
T385 170535-170600 Epistemic_statement denotes Conclusions: MCP-1 may play an important role in both GBS and FS.
T386 170601-170658 Epistemic_statement denotes Contrary the up-regulation of IL-1ra in FS was not clear.
T387 170659-170768 Epistemic_statement denotes This difference may reflect the diversity of PNS involvement area or different cytokine milieu in GBS and FS.
T388 170769-170860 Epistemic_statement denotes In GBS, IL-1ra may indicate recovery from disease although further investigation is needed.
T389 171360-171578 Epistemic_statement 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.
T390 172409-172473 Epistemic_statement denotes Decreased synthesis of IL-10 is associated with worse prognosis.
T391 173110-173205 Epistemic_statement denotes Our hypothesis is that IL-18 participates in the inflammatory response during ischaemic stroke.
T392 173206-173496 Epistemic_statement 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.
T393 173713-173820 Epistemic_statement denotes Moreover IL-18 levels correlated positively with the volume of early CT hypodense areas (r=0.82; pb0.0001).
T394 173821-173907 Epistemic_statement denotes The results suggest involvement of IL-18 in early inflammatory response during stroke.
T395 175273-175414 Epistemic_statement denotes However, Insulin action was completely blocked during exposure with 10 AM of p-38 mitogen-activated protein kinase (MAPK) inhibitor SB203580.
T396 175542-175705 Epistemic_statement denotes The normalizing effects of insulin could depend on MAPK modulation, so involving the insulin intracellular signaling pathways in immune-mediated AD neuropathology.
T397 176065-176151 Epistemic_statement denotes The higher prevalence of PD in men may suggest a link between estrogens levels and PD.
T398 176208-176314 Epistemic_statement denotes IL6 has been suggested to play a role in regulating neuronal survival in the injured nigrostriatal system.
T399 176315-176402 Epistemic_statement denotes Estrogens could modulate the immune reaction by regulating of this cytokine expression.
T400 177256-177423 Epistemic_statement 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.
T401 177997-178128 Epistemic_statement denotes In healthy individuals, IL-6 secretion increases with age, correlates with adiposity, and shows a characteristic circadian pattern.
T402 179015-179230 Epistemic_statement 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.
T403 180459-180611 Epistemic_statement 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).
T404 180612-180818 Epistemic_statement 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.
T405 181060-181171 Epistemic_statement denotes Numerous soluble mediators have been implicated but not yet convincingly documented in multiple sclerosis (MS).
T406 183996-184229 Epistemic_statement 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.
T407 184940-185099 Epistemic_statement 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.
T408 185199-185300 Epistemic_statement denotes In this aspect, our results might be important for explaining GS effects during the MS exacerbations.
T409 185872-186045 Epistemic_statement 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.
T410 186046-186202 Epistemic_statement 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.
T411 186307-186527 Epistemic_statement 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.
T412 186607-186811 Epistemic_statement 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.
T413 186812-187002 Epistemic_statement 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.
T414 187003-187388 Epistemic_statement 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. Lannes-Vieira a , V. Michailowsky a,b and R. 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
T415 187389-187584 Epistemic_statement 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.
T416 187585-187756 Epistemic_statement denotes Symptomatic meningoencephalitis rarely occurs, being more frequently found in children before 2 years of age and in immunosuppressed transplanted or HIV-infected patients.
T417 188398-188531 Epistemic_statement denotes Interestingly, the inflammatory infiltrates detected in the CNS of T. cruzi-infected IL-12KO mice were mostly devoid of CD8+ T cells.
T418 188776-188943 Epistemic_statement 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.
T419 189391-189645 Epistemic_statement 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).
T420 189852-189996 Epistemic_statement denotes In microglia maintained under basal culture conditions, TLR4 mRNA is consistently detected, while its surface expression is low to undetectable.
T421 189997-190135 Epistemic_statement denotes In contrast, although there is marked variation amongst individuals, TLR3 and TLR2 protein is more strongly expressed at the cell surface.
T422 190322-190431 Epistemic_statement denotes Notably, ligation of TLR3 results in a significantly stronger IFN-beta and IP-10 response than TLR4 ligation.
T423 190505-190686 Epistemic_statement denotes Local production of IFN-beta within the CNS may modulate the complex pro-inflammatory responses characteristic of MS. Microglia are resident semi-professional phagocytes of the CNS.
T424 190994-191118 Epistemic_statement denotes A multitude of TLRs have now been cloned, though their exact functions and tissue distributions are yet to be characterised.
T425 191119-191181 Epistemic_statement denotes Microglia have been shown to express a few of these receptors.
T426 191616-191780 Epistemic_statement 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.
T427 191928-192350 Epistemic_statement denotes Potential dual role of astrocytes in innate and autoimmune CNS responses induced by Theiler's virus infection P. Carpentier and S. 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.
T428 192594-192824 Epistemic_statement 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.
T429 193338-193612 Epistemic_statement 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.
T430 193706-193807 Epistemic_statement denotes However, virus persistence in glia is associated with sustained inflammation and ongoing myelin loss.
T431 193928-194070 Epistemic_statement denotes By contrast, infection of IFN-gamma deficient mice suggested that IFN-gamma but not perforin controlled virus replication in oligodendrocytes.
T432 194497-194570 Epistemic_statement denotes Increased R1 expression was associated with enhanced R2 chain expression.
T433 194720-194843 Epistemic_statement denotes However, virus was still recovered from the CNS of transgenic mice at day 21, while wt mice controlled infection by day 14.
T434 195900-196075 Epistemic_statement denotes Interestingly, immune priming efficiently protected perforin-deficient mice against infection with BDV, whereas no protection was seen in interferongamma-deficient (GKO) mice.
T435 196341-196592 Epistemic_statement 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.
T436 196593-196794 Epistemic_statement 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.
T437 196795-196906 Epistemic_statement denotes Moreover, interferon gamma appears to be neuroprotective in BDV-induced central nervous system immunopathology.
T438 197539-197832 Epistemic_statement 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.
T439 198407-198593 Epistemic_statement 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.
T440 198594-199072 Epistemic_statement denotes The intermediate filament GFAP is important for the control of experimental murine Staphylococcus aureus-induced brain abscess and Toxoplasma encephalitis W. Stenzel a , M. Deckert a , S. Soltek b and D. 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.
T441 199579-199764 Epistemic_statement 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.
T442 201292-201370 Epistemic_statement denotes Furthermore, many ASC of unknown specificity were associated with persistence.
T443 201622-201802 Epistemic_statement 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.
T444 202605-202797 Epistemic_statement 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.
T445 202798-203068 Epistemic_statement 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.
T446 203188-203564 Epistemic_statement 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.
T447 203782-203905 Epistemic_statement denotes These findings demonstrate the complexity of immunomodulation in the CNS with COX-2 pathway products playing diverse roles.
T448 204635-204777 Epistemic_statement denotes Reduced chemokine expression may account for the decreased inflammation in the CNS resulting in increased viral replication and dissemination.
T449 204921-205226 Epistemic_statement 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.
T450 206375-206464 Epistemic_statement denotes Regions of high nodule formation did not correlate with those of high neuronal infection.
T451 207041-207167 Epistemic_statement denotes Differential MHC-II+ cell numbers in each strain, correlating with the presence of IFN-gamma may have functional implications.
T452 207524-207597 Epistemic_statement denotes However, only 20% mortality was observed in IFN-gamma knockout mice (KO).
T453 207598-207870 Epistemic_statement 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.
T454 207871-208023 Epistemic_statement 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.
T455 208239-208468 Epistemic_statement 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.
T456 208469-208683 Epistemic_statement 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.
T457 208684-208805 Epistemic_statement denotes Alternatively, there may be a direct role played by IFN-gamma in mediating cytotoxic activity against WNV-infected cells.
T458 210003-210189 Epistemic_statement 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.
T459 210637-210833 Epistemic_statement 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).
T460 212131-212281 Epistemic_statement denotes Magnetic resonance imaging (MRI) and especially diffusionweighted MRI can improve diagnostic sensitivity and contains information of prognostic value.
T461 212282-212484 Epistemic_statement 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.
T462 213097-213262 Epistemic_statement 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.
T463 213263-213373 Epistemic_statement denotes Diffusion changes in small regions might not be displayed by our data aquisition from the whole temporal lobe.
T464 213374-213482 Epistemic_statement denotes A ROI analysis in correlation with MR-changes and clinical impairment may provide more accurate information.
T465 214744-215181 Epistemic_statement denotes Dynamics of neurotrophic factor expression in experimental herpes-simplex virus encephalitis J. Sellner a , T. Lenhard a , J. Haas a , R. von Einsiedel b and U. 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.
T466 216154-216326 Epistemic_statement denotes Our results indicate a differential expression pattern of neurotrophic factors during acute viral encephalitis, which may have impact on neuronal survival and regeneration.
T467 216327-216497 Epistemic_statement 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.
T468 216498-216964 Epistemic_statement denotes Effects of antigen-specific tolerance of CD8+ T-cells on a viral infection of the central nervous system M. Teague and S. 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.
T469 217044-217202 Epistemic_statement 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.
T470 217354-217427 Epistemic_statement denotes C57BL/6 mice, however, clear the virus and are thus resistant to disease.
T471 217428-217501 Epistemic_statement denotes The role of CD8+ T-cells in this disease has been controversial thus far.
T472 217833-217930 Epistemic_statement denotes Thus, this method can be used to assess the roles of specific CD8+ T-cells in a disease scenario.
T473 219103-219233 Epistemic_statement denotes Interestingly, C57BL/6 mice deficient in the NF-kappaB p50 subunit permit viral persistence in the CNS and clinical manifestation.
T474 219426-219509 Epistemic_statement denotes However, fewer CNS-infiltrating T cells, both CD4+ and CD8+, are specific for TMEV.
T475 219510-219638 Epistemic_statement denotes It is clear from these studies that the NF-kappaB p50 subunit is important in the resolution of CNS infection in resistant mice.
T476 219639-219830 Epistemic_statement 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.
T477 219831-220391 Epistemic_statement denotes Zinc-binding motif in leader protein of Theiler's murine encephalomyelitis virus is critical for viral persistence and demyelination K. Asakura a , H. Murayama b , T. Himeda a and Y. 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.
T478 220537-220580 Epistemic_statement denotes The function of L* is not fully understood.
T479 220581-220683 Epistemic_statement denotes L* is considered to play a key role in viral persistence though it is controversial for demyelination.
T480 220948-221070 Epistemic_statement 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.
T481 221540-221672 Epistemic_statement denotes It is well established that early life stress can induce long-lasting changes in behavioral and neuroendocrine reactivity to stress.
T482 221673-221806 Epistemic_statement denotes However, little is known about the long-term consequences of neonatal stress on susceptibility to infectious and autoimmune diseases.
T483 222973-223118 Epistemic_statement denotes These findings suggest that maternal separation has long-term effects on neuroimmune, neuroendocrine, and behavioral responses to TMEV infection.
T484 223445-223623 Epistemic_statement 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.
T485 224741-224957 Epistemic_statement denotes Aydin c a Hacettepe University, Ankara, Turkey; b Social Securitý Hospital, Ankara, Turkey; c SUCH Hospital, Ankara, Turkey Aim: Efficient treatment methods are lacking for subacute sclerosing panencephalitis (SSPE).
T486 225838-225983 Epistemic_statement denotes Conclusion: Despite the difference in the stages of the patients, the proportion tients with satisfactory outcome was higher with h-IFN1a 3/wkSC.
T487 226031-226134 Epistemic_statement denotes Randomized studies are difficult to realize in SSPE because of the clinical variability of the disease.
T488 226135-226297 Epistemic_statement 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.
T489 226826-226974 Epistemic_statement 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).
T490 227269-227374 Epistemic_statement 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).
T491 227567-227653 Epistemic_statement denotes The previously reported lower IL-12 response to measles virus seem to persist in SSPE.
T492 228085-228260 Epistemic_statement 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.
T493 229122-229372 Epistemic_statement 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.
T494 229710-229897 Epistemic_statement 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.
T495 229898-230112 Epistemic_statement 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.
T496 231425-231557 Epistemic_statement denotes The in vivo protective effect is associated with multiple biological activities of COAM, such as a reduction of plasma virus titers.
T497 231983-232268 Epistemic_statement 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.
T498 232563-232778 Epistemic_statement 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.
T499 232911-233133 Epistemic_statement 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.
T500 234097-234264 Epistemic_statement 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.
T501 234358-234435 Epistemic_statement denotes Patients often present with neurological symptoms that can progress to death.
T502 234436-234584 Epistemic_statement 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.
T503 234585-234807 Epistemic_statement 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.
T504 235745-235838 Epistemic_statement denotes Changes in the expression of chemokines may play an important role in the pathogenesis of CM.
T505 236128-236201 Epistemic_statement denotes Symptom severity is associated with the intensity of the immune response.
T506 236202-236318 Epistemic_statement denotes First, there is a long asymptomatic period where the host immunity seems to be incapable of resolving the infection.
T507 236319-236413 Epistemic_statement denotes Helminth teguments are dynamically responsive to adverse environments and can be rapidly shed.
T508 236751-236940 Epistemic_statement 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.
T509 237318-237504 Epistemic_statement 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.
T510 237505-237637 Epistemic_statement denotes Additionally, these molecules likely provide a source of persistent antigen responsible for life-long sequelae in many NCC patients.
T511 237975-238107 Epistemic_statement denotes It was suggested that sepsis activates defense mechanisms that cause cellular processes to be reduced to basic bhousekeepingQ roles.
T512 238108-238229 Epistemic_statement denotes We examined whether similar processes are induced in the peripheral nerve when the blood-nerve barrier (BNB) is breached.
T513 238357-238575 Epistemic_statement 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.
T514 238922-239157 Epistemic_statement 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.
T515 239158-239303 Epistemic_statement denotes This pathophysiological process could be involved in the pathogenesis of critical illness neuropathy in septic patients with multisystem failure.
T516 239518-239694 Epistemic_statement 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.
T517 239695-239858 Epistemic_statement 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.
T518 240679-240799 Epistemic_statement denotes These observations suggest that pharmacologic manipulation of Rho/RhoK may prevent Mo egress across the BBB during HIVE.
T519 240800-241030 Epistemic_statement 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.
T520 241437-241659 Epistemic_statement 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.
T521 241973-242101 Epistemic_statement denotes This unique infection phenotype may be a result of their ability to initially infect a much larger percentage of cultured cells.
T522 242102-242285 Epistemic_statement 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.
T523 242486-242609 Epistemic_statement denotes Although numerous potential neurotoxic molecules have been identified, the nature of the CNS disorder has remained elusive.
T524 243088-243268 Epistemic_statement 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.
T525 243471-243579 Epistemic_statement denotes The viral-host interaction occurring in the CNS environment can have profound effects on cellular processes.
T526 243580-243689 Epistemic_statement denotes The elucidation of these effects will enable the understanding of how HIV infection leads to CNS dysfunction.
T527 243690-243834 Epistemic_statement 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.
T528 243835-244044 Epistemic_statement 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.
T529 244045-244290 Epistemic_statement 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.
T530 244291-244369 Epistemic_statement denotes LPS may be a relevant antigen causing immunemediated demyelination of the PNS.
T531 245129-245248 Epistemic_statement denotes Thus, our data indicate that SCs might act as a link between innate and acquired immunity via TLRs in the inflamed PNS.
T532 246346-246530 Epistemic_statement 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.
T533 247127-247370 Epistemic_statement 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.
T534 247661-247725 Epistemic_statement denotes We could not find GM1 in C. jejuni by immunoelectron microscopy.
T535 247726-247864 Epistemic_statement denotes Further studies should be taken to clarify the role of antecedent infections of C. jejuni and the role antiganglioside antibody responses.
T536 248293-248371 Epistemic_statement denotes The mechanism(s) by which the virus persists and demyelinates remains unknown.
T537 249218-249329 Epistemic_statement denotes The above data suggest that L* has an anti-apoptotic activity in macrophages that can function in cis or trans.
T538 249330-249410 Epistemic_statement denotes The anti-apoptotic activity of L* may play an important role in TV pathogenesis.
T539 249411-249792 Epistemic_statement denotes Identification of novel markers for encephalitogenicity of effector T cells in EAE U. Boehlmann and B. 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).
T540 249793-249902 Epistemic_statement denotes We have recently shown that the TH1/TH2 paradigm cannot be used as a reliable marker for encephalitogenicity.
T541 249903-250162 Epistemic_statement 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.
T542 250163-250368 Epistemic_statement 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.
T543 250369-250451 Epistemic_statement denotes We have identified several genes which could have a potential pathogenic function.
T544 250881-251032 Epistemic_statement denotes Preliminary data clearly show that several of the newly identified genes confer encephalitogenic potential and are critical for the development of EAE.
T545 251033-251139 Epistemic_statement denotes Taken together, our approach will allow us to reliably unmask potential encephalitogenicity genes in vivo.
T546 252133-252251 Epistemic_statement denotes This study suggests that T-bet may be a viable target for therapy in Th1mediated diseases, such as multiple sclerosis.
T547 252382-252593 Epistemic_statement denotes Khoury Brigham and Women's Hospital, Harvard Medical School, Boston, USA Background: The CD200-CD200R pathway may play an important role in the regulation of immune responses in the periphery as well as the CNS.
T548 253593-253736 Epistemic_statement denotes Addition of anti-CD200 Ab to Wlds cultures abrogated protection, suggesting that neuronal protection in Wlds is related to expression of CD200.
T549 253737-253850 Epistemic_statement denotes Conclusions: Signaling through CD200R is associated with protection in EAE and increased Th2 cytokine production.
T550 254041-254166 Epistemic_statement denotes The extent to which RON and MSP are expressed in the central nervous system (CNS) and influence neuroinflammation is unknown.
T551 255661-255911 Epistemic_statement 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.
T552 256818-256892 Epistemic_statement denotes These results suggest that endogenous histamine importantly modulates EAE.
T553 257549-257879 Epistemic_statement 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.
T554 257880-258040 Epistemic_statement denotes Enhanced clinical disease in H3RKO mice is also associated with earlier disruption of the blood-brain barrier and significantly greater histopathologic disease.
T555 258041-258284 Epistemic_statement 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.
T556 258285-258583 Epistemic_statement 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.
T557 258584-258733 Epistemic_statement denotes Macrophage migration inhibitory factor (MIF) has recently been shown to regulate T cell activation, cell division and macrophage cytokine production.
T558 259907-260015 Epistemic_statement denotes Autoreactive T cells persist in rats protected against EAE and can be activated through innate immunity S.B.
T559 260311-260376 Epistemic_statement denotes However, protected rats harbor inactive encephalitogenic T cells.
T560 260377-260441 Epistemic_statement denotes We investigated whether these cells could be activated in vitro.
T561 260442-260616 Epistemic_statement 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.
T562 260617-260832 Epistemic_statement 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.
T563 261186-261593 Epistemic_statement 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.
T564 262536-262565 Epistemic_statement denotes This hypothesis is incorrect.
T565 262566-262793 Epistemic_statement 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.
T566 263387-263510 Epistemic_statement denotes The interaction between these two free radicals may regulate immune response intensity and autoimmunity, as studied in EAE.
T567 263511-263582 Epistemic_statement denotes The identity of the source(s) of NO and O 2 À in the spleen is unknown.
T568 263957-264118 Epistemic_statement 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.
T569 264375-264463 Epistemic_statement denotes These studies provide a novel way for innate immune cells to regulate adaptive immunity.
T570 264985-265117 Epistemic_statement denotes However, in multiple sclerosis (MS), this endogenous repair mechanism is inefficient and ultimately fails as the disease progresses.
T571 265118-265385 Epistemic_statement 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.
T572 265528-265611 Epistemic_statement denotes The antibody response can be assayed by Western blotting, ELISA and flow cytometry.
T573 265820-266010 Epistemic_statement 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.
T574 266826-266951 Epistemic_statement 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.
T575 267050-267251 Epistemic_statement 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.
T576 267397-267669 Epistemic_statement 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).
T577 267670-267828 Epistemic_statement 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.
T578 268149-268286 Epistemic_statement denotes Evidence will be presented to indicate that tissue levels of OSM mRNA are associated with the severity of symptoms and phases of disease.
T579 269106-269258 Epistemic_statement 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.
T580 269259-269572 Epistemic_statement denotes The role of the central dopamine depletion in regulation of experimental autoimmune encephalomyelitis in C57BL mice E. Balkowiec-Iskra a , I. Kurkowska-Jastrzebska b , I. Joniec a , A. Czlonkowska b and A. Czlonkowski a a Medical University, Warsaw, Poland; b Institute of Psychiatry and Neurology, Warsaw, Poland
T581 269573-269690 Epistemic_statement denotes Circumstantial evidence suggests the involvement of central dopaminergic system in the regulation of immune response.
T582 269691-269838 Epistemic_statement denotes The aim of our study was to investigate the influence of central dopamine depletion on experimental autoimmune encephalomyelitis (EAE) progression.
T583 270325-270411 Epistemic_statement denotes Similarly, remission of symptoms in EAE group appeared earlier than in MPTP+EAE group.
T584 270412-270473 Epistemic_statement denotes However, the disease index did not differ between the groups.
T585 270655-270741 Epistemic_statement denotes In our previous studies, MPTP has been shown to have no direct action on immune cells.
T586 270742-270845 Epistemic_statement denotes Herein, we demonstrate, that EAE induction and progression may be dependent on central dopamine action.
T587 270846-270912 Epistemic_statement denotes We suggest indirect mechanisms to be involved in reported results.
T588 271435-271664 Epistemic_statement 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;
T589 271665-271797 Epistemic_statement denotes (2) with progression, astrocyte hypertrophy occurs throughout white matter and grey matter with or without parenchymal inflammation;
T590 271798-272131 Epistemic_statement 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.
T591 272132-272349 Epistemic_statement 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.
T592 272462-272665 Epistemic_statement 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.
T593 273756-273875 Epistemic_statement denotes The localization of SHH on injured axons in early remyelination might indicate a role of SHH as axonal survival factor.
T594 273994-274037 Epistemic_statement denotes Yong University of Calgary, Calgary, Canada
T595 274038-274268 Epistemic_statement 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).
T596 274345-274562 Epistemic_statement 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.
T597 275450-275575 Epistemic_statement denotes Many environmental factors have been implicated in disease although results of studies performed to date remain inconclusive.
T598 275576-275761 Epistemic_statement 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.
T599 276635-277013 Epistemic_statement 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. Murine EAE is a well established model that recapitulates many clinical and physiopathological aspects of MS. A close examination of the earliest changes in gene expression, even those preceding inflammation, has not been reported yet.
T600 277014-277194 Epistemic_statement 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).
T601 277418-277579 Epistemic_statement denotes Supervised and unsupervised machine learning algorithms were used to identify expression signatures that correlated with disease stage and histological profiles.
T602 277699-277901 Epistemic_statement 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.
T603 277902-278013 Epistemic_statement denotes Such high frequency expression data will enable the formulation of more precise models of disease pathogenesis.
T604 279443-279534 Epistemic_statement denotes Expression of CCR7 and CX3CR1 in the spinal cord correlated well with the disease severity.
T605 279720-279922 Epistemic_statement denotes Conclusion: 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.
T606 280830-280987 Epistemic_statement 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.
T607 281395-281520 Epistemic_statement denotes Previously, we demonstrated that restoration of BBB function is associated with an improved clinical outcome in models of MS.
T608 281694-281957 Epistemic_statement denotes Therefore, ADM-mediated control of BBB function may be a viable therapeutic target for controlling the course of MS. 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.
T609 282198-282394 Epistemic_statement 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.
T610 282544-282663 Epistemic_statement denotes Hence, the receptor pathway with respect to RAMP2 and 3 expression appears intact at the cerebrovasculature during EAE.
T611 282664-282780 Epistemic_statement denotes Therefore, the potential exists to employ ADM and related agonists to restore BBB function during neuroinflammation.
T612 282910-283094 Epistemic_statement 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.
T613 283302-283638 Epistemic_statement 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.
T614 284078-284207 Epistemic_statement denotes Currently, we are investigating whether there is an interaction between MMP-12 and OPN, and their function(s) in EAE progression.
T615 285020-285131 Epistemic_statement denotes We postulate that the interaction between MMP-12 and OPN may have important roles in EAE onset and progression.
T616 285495-285608 Epistemic_statement denotes However, our knowledge on the new MMP family members expression profile in inflammatory demyelination is limited.
T617 286518-286682 Epistemic_statement 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.
T618 287036-287291 Epistemic_statement 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.
T619 287376-287505 Epistemic_statement denotes However, pathogenetic mechanisms underlying axonal injury within inflammatory diseases of the CNS remain still largely undefined.
T620 287506-287649 Epistemic_statement 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.
T621 288124-288277 Epistemic_statement denotes Acute axonal injury, identified by the accumulation of amyloid precursor protein, correlated strictly with numbers of iNOSpositive macrophages/microglia.
T622 288385-288467 Epistemic_statement denotes Our findings may have major implications for therapy of inflammatory CNS diseases.
T623 288468-288627 Epistemic_statement 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.
T624 289714-289834 Epistemic_statement denotes We proposed that these enzymes contribute to enhanced glutamate-mediated excitotoxicity of oligodendrocytes and neurons.
T625 289835-290086 Epistemic_statement 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.
T626 290811-290900 Epistemic_statement denotes COX-2 was also observed in association with iNOS both nearby and within oligodendrocytes.
T627 290901-291127 Epistemic_statement denotes Conclusion: 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.
T628 291128-291236 Epistemic_statement denotes Expression of COX-2 may then render oligodendrocytes more vulnerable to glutamatemediated excitotoxic death.
T629 291237-291523 Epistemic_statement denotes Oxidative modification alters the autoantigenicity of myelin oligodendrocyte glycoprotein-implications for induction of disease and tolerance in mice and men M. W3llberg a , J. Bergquist b and R. Harris a a Karolinska Institutet, Stockholm, Sweden; b Uppsala University, Uppsala, Sweden
T630 291524-291667 Epistemic_statement denotes Myelin antigens may become autoantigenic through modification of their structure, but this concept has received little or no attention to date.
T631 291668-291921 Epistemic_statement 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.
T632 292557-292983 Epistemic_statement 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. 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.
T633 292984-293184 Epistemic_statement 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.
T634 293185-293333 Epistemic_statement denotes In addition several peptides were non-encephalitogenic but were immunogenic in vitro suggesting that these peptides may induce regulatory responses.
T635 294040-294205 Epistemic_statement 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.
T636 295018-295161 Epistemic_statement denotes Conclusions: We demonstrate that the induction of autoimmunity by PT is associated with inhibition of apoptosis in autoreactive T helper cells.
T637 296149-296324 Epistemic_statement 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.
T638 296459-296640 Epistemic_statement 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.
T639 297000-297185 Epistemic_statement 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.
T640 297186-297322 Epistemic_statement 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.
T641 298622-298760 Epistemic_statement denotes The role of immune cell subsets, T cell specificities and antibody responses in determining the pathogenesis of disease will be discussed.
T642 298761-298939 Epistemic_statement denotes This model will elucidate immunological parameters that influence clinical disease, and may provide insight into the complex and heterogeneous pathogenesis of multiple sclerosis.
T643 298940-299166 Epistemic_statement 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.
T644 299167-299374 Epistemic_statement 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.
T645 299971-300095 Epistemic_statement denotes Interestingly, SCMNC isolated from animals in the recovery phase of EAE were unable to inhibit proliferation of naRve cells.
T646 300096-300259 Epistemic_statement denotes Further studies of the observed phenomena would contribute to the understanding of mechanisms involved in spontaneous recovery during inflammatory diseases of CNS.
T647 300260-300541 Epistemic_statement 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.
T648 300542-300704 Epistemic_statement denotes Prophylactic autoimmune tolerance can be induced by a variety of different means, yet therapeutic tolerance in established disease provides a more difficult goal.
T649 300705-301096 Epistemic_statement 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.
T650 301097-301365 Epistemic_statement 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.
T651 301366-301684 Epistemic_statement 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.
T652 301685-301792 Epistemic_statement denotes Therefore, there appears to be correlation between that observed in humans and that found in rodent models.
T653 302030-302228 Epistemic_statement 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.
T654 302769-303266 Epistemic_statement 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. 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.
T655 303618-303716 Epistemic_statement denotes At the latest time-points, MEP amplitudes significantly decreased, suggesting chronic axonal loss.
T656 304072-304407 Epistemic_statement 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.
T657 304408-304590 Epistemic_statement 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.
T658 306169-306373 Epistemic_statement 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.
T659 307244-307527 Epistemic_statement 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.
T660 307528-307623 Epistemic_statement denotes These findings suggest that the lesion during the later stage is maintained by humoral factors.
T661 307624-307716 Epistemic_statement denotes Taken together, this experimental system can serve as a model of neuromyelitis optica (NMO).
T662 308823-308899 Epistemic_statement denotes aNPCs can be successfully labelled in vitro with novel SPIOs contrast media.
T663 308900-308946 Epistemic_statement denotes This method might allow in vivo aNPC tracking.
T664 310346-310579 Epistemic_statement denotes CONCLUSIONS: 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.
T665 311018-311284 Epistemic_statement 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.
T666 311285-311477 Epistemic_statement 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.
T667 311564-311802 Epistemic_statement 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.
T668 311803-312066 Epistemic_statement 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.
T669 312868-312977 Epistemic_statement denotes We next investigated how adenoviral-mediated chronic TNF-alpha expression might affect platelet accumulation.
T670 313075-313201 Epistemic_statement denotes The chronic, adenoviral mediated expression of TNF-alpha is also associated with neuronal cell death and monocyte recruitment.
T671 313315-313515 Epistemic_statement 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.
T672 313618-313741 Epistemic_statement denotes Molecules involved in the interaction between leukocytes and endothelial cells are therefore candidate targets for therapy.
T673 313742-313889 Epistemic_statement denotes CD81 is a member of the tetraspanin familiy of small surface proteins, and it has been implicated in cellular adhesion, motility and proliferation.
T674 314717-314929 Epistemic_statement denotes Furthermore, our results provide strong support for its further exploration as a therapeutic target in MS. Understanding the mechanisms of immune cell migration into MS lesions offers great therapeutic potential.
T675 314999-315158 Epistemic_statement 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.
T676 315389-315567 Epistemic_statement 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.
T677 315644-315797 Epistemic_statement 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.
T678 317229-317302 Epistemic_statement denotes CCR2 may be a potential therapeutic target in CNS inflammatory disorders.
T679 317559-317836 Epistemic_statement 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.
T680 318180-318364 Epistemic_statement 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.
T681 318472-318673 Epistemic_statement 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.
T682 319632-319747 Epistemic_statement denotes Interestingly, we observed laminin alpha-4, beta-1 and gamma-1 chain-positive structures within perivascular cuffs.
T683 319875-319989 Epistemic_statement denotes It has already been shown that HSPGs and GAGs can bind chemokines, small proteins that control cellular migration.
T684 319990-320182 Epistemic_statement 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.
T685 320183-320296 Epistemic_statement denotes Future research is warranted to study the functional role of ECM/BM molecules in multiple sclerosis pathogenesis.
T686 320712-320829 Epistemic_statement denotes The factors that regulate the trafficking of monocytes across the blood-brain barrier (BBB) remain poorly understood.
T687 321884-322031 Epistemic_statement 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.
T688 322998-323147 Epistemic_statement 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.
T689 323384-323466 Epistemic_statement denotes The relevance of this data and implications for future research will be discussed.
T690 323949-324048 Epistemic_statement denotes However, little is known about the effects of CXCL10 on the cells of the blood-brain barrier (BBB).
T691 324646-324759 Epistemic_statement denotes However, CXCL10 led to an increase in CXCL8 and CCL2 levels in the supernatant of stimulated HBEC and astrocytes.
T692 324831-325062 Epistemic_statement 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.
T693 325063-325218 Epistemic_statement 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.
T694 325390-325679 Epistemic_statement 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.
T695 326157-326340 Epistemic_statement 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.
T696 326654-326732 Epistemic_statement denotes Modeling monocyte/macrophage migration and reverse transmigration in the brain
T697 326733-326935 Epistemic_statement 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.
T698 326936-327042 Epistemic_statement denotes In addition, HIV-1-associated dementia has been shown to correlate with macrophage abundance in the brain.
T699 327043-327291 Epistemic_statement 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.
T700 327292-327445 Epistemic_statement denotes We have developed a novel transendothelial migration model that will allow us to test the ability of chemokines to alter monocyte/macrophage trafficking.
T701 327811-327999 Epistemic_statement 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.
T702 328000-328415 Epistemic_statement 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.
T703 328416-328640 Epistemic_statement 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).
T704 329004-329109 Epistemic_statement denotes We investigated whether the antioxidant lipoic acid (LA) could inhibit monocyte migration across the BBB.
T705 329183-329408 Epistemic_statement 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.
T706 329577-329696 Epistemic_statement denotes Together, these results indicate that oxygen radicals are essential for monocyte migration in vitro as well as in vivo.
T707 329697-329844 Epistemic_statement 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.
T708 329845-329965 Epistemic_statement denotes Development of microglia from mouse embryonic stem cells and their migration into the brain parenchyma T. Tsuchiya, K.C.
T709 330225-330351 Epistemic_statement denotes Microglia function as an antigen presenting cell in several CNS diseases, but the detailed mechanism has remained obscure yet.
T710 331079-331241 Epistemic_statement 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.
T711 331349-331524 Epistemic_statement 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.
T712 331708-331839 Epistemic_statement denotes The aim of this study has been to investigate whether astrocytes produce chemokines which facilitate dendritic cell (DC) migration.
T713 332320-332583 Epistemic_statement 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.
T714 332857-332914 Epistemic_statement denotes Expression of CCL20 in MS lesions is under investigation.
T715 332915-333033 Epistemic_statement denotes These findings suggest that astrocytes may actively contribute to DC recruitment in the CNS during autoimmune disease.
T716 333358-333580 Epistemic_statement 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.
T717 333921-334038 Epistemic_statement denotes These cells were also CD11c-positive, indicating that they may be more potent APCs compared to residential microglia.
T718 334039-334144 Epistemic_statement denotes We also tested whether stem cell immigration into the CNS would be increased in neurodegenerative models.
T719 334402-334618 Epistemic_statement 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.
T720 334619-334791 Epistemic_statement denotes These results may have great clinical relevance for both immune-derived neuronal disorders and cancer patients undergoing allogeneic hematopoietic stemcell transplantation.
T721 335131-335244 Epistemic_statement denotes The relative contribution of each population during infections of the CNS has not always been clearly determined.
T722 336308-336562 Epistemic_statement 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.
T723 336563-336773 Epistemic_statement denotes Lymphomononuclear infiltration in the CNS of mice with acute GvHD after allogeneic bone marrow transplantation P. Sostak, C. S. Padovan, A. Gerbitz and A. Straube Ludwig-Maximilinans-University, Munich, Germany
T724 336774-336983 Epistemic_statement 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.
T725 336984-337146 Epistemic_statement 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.
T726 337147-337310 Epistemic_statement denotes In an animal model of chronic GvHD, we could already detect cerebral lymphomononuclear infiltrations, microglial activation and upregulation of adhesion molecules.
T727 337810-337983 Epistemic_statement 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.
T728 338268-338350 Epistemic_statement denotes The different underlying pathophysiological mechanisms need further clarification.
T729 338507-338591 Epistemic_statement denotes Marino Department of Immunology-IOC, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
T730 338592-338714 Epistemic_statement denotes Central nervous system (CNS) damage can occur during Trypanosoma cruzi infection, especially in immunosuppressed patients.
T731 338715-338950 Epistemic_statement 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.
T732 339149-339284 Epistemic_statement denotes Lastly, the reactivation of meningoencephalitis in immunosuppressed chronically infected mice was associated with VCAM-1 up-regulation.
T733 339285-339413 Epistemic_statement denotes Therefore, we hypothesize that VLA-4/VCAM-1-pathway plays a pivotal role in the establishment of T. cruzi-elicited encephalitis.
T734 340632-340866 Epistemic_statement 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.
T735 341482-341697 Epistemic_statement 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.
T736 342653-342826 Epistemic_statement 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.
T737 344098-344158 Epistemic_statement denotes These cleavages are expected to downregulate the activities.
T738 345029-345143 Epistemic_statement denotes Previous studies have shown that leukocyte infiltration into brains of MRL-lpr mice coincides with neurotoxic CSF.
T739 345144-345231 Epistemic_statement denotes The intrathecal synthesis of IgG is proposed in destruction of periventricular neurons.
T740 345770-345917 Epistemic_statement 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.
T741 345918-346042 Epistemic_statement denotes The presence of B and plasma cells provides further support for the hypothesis that toxic IgG are synthesized intrathecally.
T742 346266-346590 Epistemic_statement denotes Signaling delivered through cannabinoid receptor CB1 blocks the recruitment of encephalitogenic lymphocytes in brain venules through a PKA-dependent mechanism B. Rossi a , S. Bach a , M. Fusco b , F. Fachinetti b , A. Leon b and G. Constantin a a University of Verona, Verona, Italy; b Research and Innovation, Padova, Italy
T743 346591-346754 Epistemic_statement denotes It is known that cannabinoid treatment prevents the development of experimental autoimmune encephalomyelitis, but its mechanisms of action are not well elucidated.
T744 346755-346951 Epistemic_statement 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.
T745 347952-348186 Epistemic_statement denotes Conclusions: 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.
T746 348257-348613 Epistemic_statement denotes Furthermore, CD26 exerts unique enzymatic specificity in cleaving dipeptides from chemokines (CXC3R ligands) and neuropeptides, such as neuropeptide Y and substance P. 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.
T747 348948-349138 Epistemic_statement 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.
T748 349610-349775 Epistemic_statement 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).
T749 349776-349881 Epistemic_statement denotes The mechanisms controling the recruitment of CD8 T cells in inflamed brain venules is not yet understood.
T750 349882-350001 Epistemic_statement denotes Objective: The study proposes to compare the behavior of autoreactive CD4 versus CD8 T cells in inflamed brain venules.
T751 350730-350979 Epistemic_statement denotes Conclusions: 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.
T752 351380-351546 Epistemic_statement 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.
T753 352533-352698 Epistemic_statement 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.
T754 352699-353043 Epistemic_statement denotes Expression of cutaneous lymphocyte antigen (CLA) on activated lymphocytes is critical for efficient tethering and rolling in inflamed brain venules B. Rossi a , L. Piccio b , L. Colantonio c , E. Scarpini b , D. D'Ambrosio c and G. Constantin a a University of Verona, Verona, Italy; b University of Milan, Milan, Italy; c Bioxell, Milan, Italy
T755 353044-353204 Epistemic_statement denotes We have previously shown that endothelial selectins are expressed by the inflamed brain endothelium during EAE and experimental models of subacute inflammation.
T756 353393-353509 Epistemic_statement denotes Objective: The goal of this study was to determine the role of CLA epitope in lymphocyte recruitment into the brain.
T757 354331-354549 Epistemic_statement denotes Conclusion: 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.
T758 355878-355985 Epistemic_statement denotes Our findings have high relevance for the development of new therapies for relapsing EAE and potentially MS.
T759 356956-357065 Epistemic_statement denotes Both heme-mediated ROS formation and inflammatory processes may contribute to tissue damage in EAE/MS brains.
T760 357066-357204 Epistemic_statement 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.
T761 357405-357525 Epistemic_statement denotes We therefore hypothesize that the heme-heme oxygenase system may be involved in transendothelial migration of monocytes.
T762 357526-357624 Epistemic_statement denotes In future, we will study the effects of heme, HO activity, CO and bilirubin on monocyte migration.
T763 357625-358045 Epistemic_statement denotes Additional research is needed to further elucidate the role of the heme-HO system in the pathogenesis of MS. CCR6 expression defines the subset of CD25+ regulatory effectormemory T cells M. Kleinewietfeld a , F. Puentes a , G. Borsellino b , L. Battistini b , O. Rötzschke a and K. Falk a a Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany; b Institute of Neuroimmunology, IRCCS Santa Lucia, Rome, Italy
T764 358046-358119 Epistemic_statement denotes Regulatory CD25+ T cells are the central element of peripheral tolerance.
T765 358120-358238 Epistemic_statement denotes Little is known, however, about phenotypic and functional characteristics of regulatory T cells with regard to memory.
T766 359123-359296 Epistemic_statement 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.
T767 360089-360189 Epistemic_statement denotes Overall, these experiments identify fibrin as a potential target for therapeutic intervention in MS.
T768 360263-360491 Epistemic_statement 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.
T769 361335-361580 Epistemic_statement 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.
T770 361581-361804 Epistemic_statement 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.
T771 361912-362007 Epistemic_statement denotes Migration of monocytes across the bloodbrain barrier is crucial for disease onset and severity.
T772 362191-362376 Epistemic_statement denotes Flavonoids are naturally occurring food compounds, with anti-inflammatory properties that scavenge oxygen radicals, implying they might suppress clinical symptoms in multiple sclerosis.
T773 362678-362792 Epistemic_statement denotes The therapeutic potential of luteolin was assessed in a chronic relapsing-remitting EAE model in Dark-Agouti rats.
T774 363244-363337 Epistemic_statement denotes Our results indicate the therapeutic potential for dietary adaptations in multiple sclerosis.
T775 364021-364224 Epistemic_statement 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.
T776 364225-364316 Epistemic_statement denotes Both compounds suppressed symptoms during treatment, yet their Ig profiles vastly differed.
T777 364600-364795 Epistemic_statement 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.
T778 364796-364997 Epistemic_statement 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.
T779 365251-365394 Epistemic_statement denotes Our results are extremely promising and provide a rationale for testing the combination of atorvastatin and GA in MS. Once intravenously (i.v.)
T780 366388-366483 Epistemic_statement denotes Our results indicate that aNPCs home specifically to inflamed brain areas during EAE, once i.v.
T781 366662-366874 Epistemic_statement 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.
T782 367056-367234 Epistemic_statement 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.
T783 369086-369212 Epistemic_statement denotes EAE has been shown to cause a marked circulating and brain synthesis of NGF and a higher responsiveness of brain cells to NGF.
T784 370020-370153 Epistemic_statement denotes Our results suggest that NGF has a protective action on EAE brain, most probably acting on both damaged brain cells and immune cells.
T785 371062-371275 Epistemic_statement 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.
T786 371276-371349 Epistemic_statement denotes BMP-4)-possibly maintaining aNPCs in a quiescent state-were co-localized.
T787 371350-371388 Epistemic_statement denotes Our data indicate that aNPCs-once i.v.
T788 371389-371616 Epistemic_statement denotes 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.
T789 371617-371797 Epistemic_statement denotes Background: Although neural precursor cells remyelinate focal lesions, the mechanism of their beneficial effect in clinically relevant models of multiple sclerosis (MS) is unclear.
T790 374096-374508 Epistemic_statement denotes There is only sparse knowledge on the impact of genetic factors, timing, tissue repopulation and immuneregulatory mechanisms by BMT in MS. 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.
T791 374700-374925 Epistemic_statement 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.
T792 374926-375134 Epistemic_statement 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.
T793 375135-375257 Epistemic_statement denotes Astrocytes are able to induce regulatory T cells, which can completely abolish proliferative response of T cells in vitro.
T794 375258-375392 Epistemic_statement 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.
T795 375714-375800 Epistemic_statement denotes Alleviation of EAE symptoms correlated with the results of pathohistological analysis.
T796 376190-376336 Epistemic_statement denotes Interestingly, no protective effect was observed when the astro-LNC were administered to naive animals simultaneously with encephalitogenic cells.
T797 376337-376450 Epistemic_statement denotes Our results suggest important role of astrocyte-induced regulatory T cells in the regulation of CNS inflammation.
T798 376686-376790 Epistemic_statement denotes Interaction between encephalitogenic T cells and APC in the CNS is a crucial step in disease initiation.
T799 376791-376893 Epistemic_statement denotes Astrocytes have been suggested to play essential roles in initiating and maintaining CNS autoimmunity.
T800 377594-377776 Epistemic_statement 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.
T801 377960-378080 Epistemic_statement denotes Our findings support an important role of IFN-gamma mediated astrocyte signaling in ameliorating CNS autoimmune disease.
T802 378209-378348 Epistemic_statement denotes Sporadic repair occurs giving the appearance of dshadow plaquesT or areas of thin remyelination; however, this process is often incomplete.
T803 378524-378698 Epistemic_statement denotes We have utilized this mechanism to examine whether the presence of inflammatory cells suppresses spontaneous myelin repair in experimental autoimmune encephalomyelitis (EAE).
T804 380527-380640 Epistemic_statement denotes Recovery was associated to a significantly increased number of CNSinfiltrating CD4+CD69ÀCD25+ regulatory T cells.
T805 380859-381067 Epistemic_statement denotes Prevention of EAE by treatment with a neurotropic alphavirus vector expressing tissue inhibitor of metalloproteinase-2 P. Furu, S. Grfnberg, J. Heikkil7 and A. Hinkkanen Åbo Akademi University, Turku, Finland
T806 381068-381230 Epistemic_statement denotes Objective: In experimental autoimmune encephalomyelitis (EAE), enhanced activity of matrix metalloproteinases (MMPs), has been implicated in disease pathogenesis.
T807 381749-381915 Epistemic_statement 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.
T808 382110-382265 Epistemic_statement 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.
T809 382266-382496 Epistemic_statement denotes Conclusions: 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.
T810 382497-382607 Epistemic_statement denotes TIMPs might be candidates for novel treatment regimens in CNS autoimmune disorders such as multiple sclerosis.
T811 382816-382942 Epistemic_statement denotes In experimental autoimmune encephalomyelitis (EAE), infusions of IVIG have been shown to significantly ameliorate the disease.
T812 382943-383135 Epistemic_statement 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.
T813 383770-383949 Epistemic_statement denotes Results: 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.
T814 385015-385073 Epistemic_statement denotes Cannabinoids may alleviate symptoms of multiple sclerosis.
T815 385074-385138 Epistemic_statement denotes Furthermore, cannabinoids might also modulate neuroinflammation.
T816 385139-385384 Epistemic_statement 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.
T817 385385-385573 Epistemic_statement 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.
T818 386123-386319 Epistemic_statement 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.
T819 386320-386474 Epistemic_statement 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.
T820 386954-387005 Epistemic_statement denotes However, disease progression is largely unaffected.
T821 387073-387236 Epistemic_statement denotes Anecdotal evidence and clinical surveys suggest that many MS patients derive subjective improvements in spasticity, chronic pain and spasms from smoking marijuana.
T822 387411-387510 Epistemic_statement denotes In contrast, CB2 is expressed only peripherally, and is thought to have immunomodulatory functions.
T823 387751-387893 Epistemic_statement denotes We demonstrate that treatment with R(+)WIN55,212 at the onset of clinical symptoms can significantly inhibit disease severity and progression.
T824 387894-388041 Epistemic_statement denotes This was associated with the inhibition of myelin specific T cell proliferation, differentiation to Th1 phenotype and autoimmune humoral responses.
T825 388119-388281 Epistemic_statement denotes In conclusion, cannabinoids are potent therapeutic agents which may be beneficial in MS as a symptomatic treatment for spasticity and as immunosuppressive agents.
T826 388282-388473 Epistemic_statement denotes Rationale: Phospholipase A2 (PLA2) hydrolyzes phosphatidylcholine to lysophosphatidylcholine and arachidonic acid (AA), which can cause myelin breakdown and induce inflammation, respectively.
T827 388549-388614 Epistemic_statement denotes cPLA2 is thought to be the major form contributing to AA release.
T828 389513-389634 Epistemic_statement denotes Conclusions: These findings suggest that inhibiting cPLA2 may play an important role in the onset and progression of EAE.
T829 389635-389806 Epistemic_statement 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).
T830 389807-390064 Epistemic_statement 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.
T831 390239-390436 Epistemic_statement 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.
T832 390733-391029 Epistemic_statement 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.
T833 391422-391590 Epistemic_statement denotes Therefore, we tested whether NAC was capable of preventing MOG35-55-induced experimental autoimmune encephalomyelitis (EAE), an established model of multiple sclerosis.
T834 391780-391896 Epistemic_statement denotes This was associated with a reduction of CNS infiltrating T cells and macrophages as well as decreased demyelination.
T835 392159-392237 Epistemic_statement denotes This was probably due to an immmunosuppressive effect of NAC at the APC level.
T836 392361-392463 Epistemic_statement denotes Our data indicate that NAC can effectively interfere with the autoimmune reaction associated with EAE.
T837 392941-393086 Epistemic_statement denotes We hypothesized that Smad7 inhibition should enhance TGF-beta-signalling at sites of local inflammation such as the central nervous system (CNS).
T838 393728-393826 Epistemic_statement denotes T cell activation is a critical step in the development of an autoimmune attack against the brain.
T839 395120-395268 Epistemic_statement 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.
T840 395269-395443 Epistemic_statement 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.
T841 395444-395602 Epistemic_statement 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.
T842 395603-395905 Epistemic_statement 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).
T843 396652-396805 Epistemic_statement 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.
T844 400314-400421 Epistemic_statement denotes The complement (C) system has been implicated as a myelinolytic agent in both man and experimental animals.
T845 401256-401418 Epistemic_statement 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.
T846 401419-401514 Epistemic_statement denotes These data raised the possibility of an immunomodulatory action of IL-12 in this disease model.
T847 402417-402495 Epistemic_statement denotes In addition, anti-inflammatory effects may be mediated by inhibition of IL-17.
T848 404270-404396 Epistemic_statement denotes 2002; Bechtold et al, Ann Neurol, 2004, in press ) have led us to question whether such agents might affect T cell activation.
T849 405178-405291 Epistemic_statement denotes In summary, the results show that sodium channel blocking agents can affect T cell function in vitro and in vivo.
T850 405533-405661 Epistemic_statement denotes EAE is an animal model for multiple sclerosis (MS) and can be actively induced by immunization with myelin proteins or peptides.
T851 406279-406520 Epistemic_statement 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.
T852 406521-406578 Epistemic_statement denotes Th1-cell activation is crucial in EAE and MS development.
T853 406714-406881 Epistemic_statement denotes Here, we studied the role of TIRC7 and therapeutic potential of TIRC7 mAb in EAE and MS. We used mAb to characterize cell-type specific TIRC7-expression in MS lesions.
T854 407278-407373 Epistemic_statement denotes compared with 12 EAE controls (1.75F0.58; p=0.19) suggesting mAb inhibition of EAE development.
T855 407551-407700 Epistemic_statement denotes Clinical improvements were typically accompanied by reduced mononuclear cell infiltration in EAE lesions in mAb-treated compared with untreated mice.
T856 407866-408047 Epistemic_statement 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.
T857 409248-409393 Epistemic_statement denotes Interestingly, as determined by serial analysis a differential kinetic pattern in MS patients was observed compared to acute infectious diseases.
T858 409750-409952 Epistemic_statement 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).
T859 409953-410176 Epistemic_statement 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.
T860 410728-410852 Epistemic_statement denotes Proliferating B cells were detected in intrameningeal follicles, a finding which is suggestive of germinal center formation.
T861 410853-411000 Epistemic_statement denotes Despite accumulation of numerous B cells and plasma cells around blood vessels, no folliclelike structures were identified in white matter lesions.
T862 411001-411164 Epistemic_statement 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.
T863 411165-411455 Epistemic_statement 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. Uccelli a , S. Casazza a , E. Ferretti b , D. Giunti a , E. Zappia a , A. Pistorio b , C. Gambini c , G.L.
T864 411456-411702 Epistemic_statement denotes Mancardi a and V. Pistoia c a Neuroimmunology Unit, Department of Neurosciences, Ophthalmology and Genetics, Genoa, Italy; b Laboratory of Oncology, G. Gaslini Institute, Genoa, Italy; c Laboratory of Pathology, G. Gaslini Institute, Genoa, Italy
T865 411703-411883 Epistemic_statement 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.
T866 412374-412521 Epistemic_statement denotes Memory B cells expressed high level of CD80 and CD86 costimulatory molecules and up-regulated CCR1, CCR2 and CCR4 suggesting their activated state.
T867 412742-412959 Epistemic_statement 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.
T868 413159-413249 Epistemic_statement denotes B cell activating factor of the TNF family (BAFF) plays a crucial role in B cell survival.
T869 414163-414285 Epistemic_statement denotes This study establishes, we believe for the first time that a non-immune cell type can produce substantial amounts of BAFF.
T870 414286-414380 Epistemic_statement denotes BAFF production in the CNS might contribute to the long term survival of B cells in MS brains.
T871 414813-414892 Epistemic_statement denotes However, despite intensive research, the antibody specificities remain unknown.
T872 415745-415825 Epistemic_statement denotes Sequence analysis revealed that these clones have never been associated with MS.
T873 415826-416050 Epistemic_statement 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.
T874 416051-416140 Epistemic_statement denotes An approach to the identification of targets of autoantibodies in multiple sclerosis E.T.
T875 416155-416206 Epistemic_statement denotes Palace and A. Vincent Oxford University, Oxford, UK
T876 416207-416449 Epistemic_statement 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.
T877 416450-416619 Epistemic_statement denotes However, previously employed candidate antigen-based approaches, usually involving ELISA assays, have failed to identify pathologically relevant antibodies and antigens.
T878 416620-416764 Epistemic_statement denotes We hypothesise that the antigenic target(s) for a relevant antibody would be located on the cell membrane of neuronal or oligodendroglial cells.
T879 416765-416997 Epistemic_statement 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.
T880 416998-417293 Epistemic_statement 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.
T881 417908-418010 Epistemic_statement denotes Phagocytes and glycolipid (ganglioside)-specific antibodies, are thought involved in the pathogenesis.
T882 418011-418148 Epistemic_statement denotes We recently documented the inflammatory capacity of GBS-associated anti-GM1 IgG, as measured by leukocyte degranulation and phagocytosis.
T883 418684-418815 Epistemic_statement denotes These results indicate that gangliosidespecific IgG contains pro-inflammatory activity, and that IVIg may reduce its functionality.
T884 419947-420071 Epistemic_statement denotes These results suggest that PTX may in the future serve as a potential drug for immunotherapy of myasthenia gravis in humans.
T885 420340-420450 Epistemic_statement denotes These results suggest that IP-10/CXCR3 signaling is a potential target for immunotherapy of myasthenia gravis.
T886 420942-421039 Epistemic_statement denotes Furthermore, mice deficient in Fc-receptors (FcR) have been shown to be resistant to develop EAE.
T887 421368-421539 Epistemic_statement 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.
T888 421631-421786 Epistemic_statement 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.
T889 421787-421992 Epistemic_statement 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.
T890 422536-422721 Epistemic_statement 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.
T891 422805-422955 Epistemic_statement denotes However, disease onset was significantly delayed, suggesting a role for FcR gamma-chain signalling in the early immunological events resulting in EAE.
T892 422956-423115 Epistemic_statement denotes The model we used is B-cell independent, therefore interactions between myelinspecific antibodies and FcgammaR are unlikely to contribute to disease induction.
T893 423203-423376 Epistemic_statement 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.
T894 423454-423546 Epistemic_statement denotes The monoclonal anti-MOG antibody Z12 (mAb Z12) was previously shown to enhance clinical EAE.
T895 423806-423918 Epistemic_statement denotes Our results demonstrate that anti-myelin antibodies can enhance clinical EAE in absence of stimulatory FcgammaR.
T896 423919-424095 Epistemic_statement 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.
T897 424807-424975 Epistemic_statement denotes Characterization of the discriminant antigens involved might provide new tools for understanding the mechanisms underlying the initiation and progression of EAE and MS.
T898 424976-425281 Epistemic_statement denotes Intracerebral expression of CXCL13 and BAFF and formation of Bfollicle-like structures in the meninges of mice with experimental autoimmune encephalomyelitis S. Columba-Cabezas, R. Magliozzi, B. Serafini and F. Aloisi Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
T899 425282-425602 Epistemic_statement 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.
T900 426456-426622 Epistemic_statement 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.
T901 426623-426824 Epistemic_statement 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.
T902 426825-426989 Epistemic_statement denotes Background: Mast cells and other elements of allergic immune responses can participate in the regulation of the immune response associated with pathogenesis of EAE.
T903 426990-427190 Epistemic_statement 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.
T904 428009-428139 Epistemic_statement denotes Moreover, discriminant analysis indicates that a self-reactive antibody repertoire differed significantly from each group of mice.
T905 428219-428386 Epistemic_statement 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.
T906 429330-429514 Epistemic_statement 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.
T907 430673-430815 Epistemic_statement 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.
T908 430816-431012 Epistemic_statement 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.
T909 431191-431372 Epistemic_statement 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.
T910 431474-431570 Epistemic_statement denotes Interestingly, those residues bound by 8-18C5 are least conserved between MOG and its relatives.
T911 431571-431652 Epistemic_statement denotes Despite of the epitope's discontinuity one loop of MOG dominates the interaction.
T912 431653-431898 Epistemic_statement 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.
T913 432042-432261 Epistemic_statement denotes The aim of the current project is to find new myelin antigens, which are immunogenic in MS. We purified human myelin glycoproteins by sucrose gradient centrifugation and subsequent lentil-lectin affinity chromatography.
T914 432803-432880 Epistemic_statement denotes The identity of these protein spots could be identified by mass spectrometry.
T915 432881-433007 Epistemic_statement denotes Thus, by using a proteomic approach, we could identify some novel candidate autoantigens of the humoral immune response in MS.
T916 433008-433134 Epistemic_statement denotes Ongoing studies with recombinant proteins will clarify if these proteins are predominant targets of the immune response in MS.
T917 433230-433425 Epistemic_statement 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.
T918 434413-434703 Epistemic_statement 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.
T919 434903-435003 Epistemic_statement denotes Auto-Abs can be detected only using glycosylated antigens (Ags) recognizing conformational epitopes.
T920 435004-435261 Epistemic_statement 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.
T921 435486-435603 Epistemic_statement denotes A proteomic approach based on high-resolution mass spectrometry will lead to its characterisation at molecular level.
T922 436950-437092 Epistemic_statement denotes Conclusion: Rituximab appears safe in MS patients, and depleted circulating B cells with less robust effects on CSF B cells and IgG synthesis.
T923 437129-437230 Epistemic_statement denotes Turner syndrome associated with Guillain-Barré syndrome and a complex autoimmune serological profile.
T924 437231-437405 Epistemic_statement denotes A case report S. Losi a , S. Matà b , S. Lori a , R. Salti a and S. Stagi a a Ospedale Pediatrico A. Meyer, Florence, Italy; b Azienda Ospedaliera di Careggi, Florence, Italy
T925 437406-437593 Epistemic_statement 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.
T926 437594-437758 Epistemic_statement denotes Celiac disease, in turn, is associated with several autoimmune disorders, and with neurological diseases, in particular peripheral neuropathy and cerebellar ataxia.
T927 438103-438230 Epistemic_statement denotes In February 2002, a duodenal biopsy showed increased intraepithelial lymphocytes, and a potential celiac disease was diagnosed.
T928 438753-438885 Epistemic_statement denotes This is the first description of an association between TS and AMAN in a patient with a complex serological profile of autoimmunity.
T929 438886-439149 Epistemic_statement 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.
T930 439503-439708 Epistemic_statement 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.
T931 439709-439952 Epistemic_statement 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.
T932 440073-440350 Epistemic_statement denotes Janmey b and R. 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.
T933 440351-440541 Epistemic_statement 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.
T934 441317-441575 Epistemic_statement 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.
T935 442151-442269 Epistemic_statement denotes Thymectomy results in clinical effectiveness, suggesting that this thymus plays a central role in antibody production.
T936 442270-442353 Epistemic_statement denotes However, the immunopathological mechanism of effectiveness has not been elucidated.
T937 443125-443254 Epistemic_statement denotes However, when myoid cell 80-and 100-kDa haemopoietic factor, were added together, many anti-SRBC producing B-cells were detected.
T938 443316-443438 Epistemic_statement denotes These results suggest that hyperplastic MG thymus generates a new B-cell stimulatory mechanism not found in the periphery.
T939 444027-444164 Epistemic_statement denotes It seems that autoantibodies are not produced within thymoma; nevertheless, antibodies to different antigens are associated with thymoma.
T940 444890-445085 Epistemic_statement 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.
T941 445086-445428 Epistemic_statement 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.
T942 447196-447304 Epistemic_statement denotes The fusion protein formed inclusion bodies but could be solubilized in the presence of guanidinium chloride.
T943 449740-449956 Epistemic_statement 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.
T944 450633-450781 Epistemic_statement denotes GAD is an important antigen in gluten sensitivity-related diseases and may provide the link between gluten sensitivity and neurological dysfunction.
T945 450782-450930 Epistemic_statement denotes Elimination of anti-GAD antibodies by gluten-free diet may have important therapeutic implications in other anti-GAD-associated autoimmune diseases.
T946 451014-451130 Epistemic_statement denotes In common with other forms of gluten sensitivity, gluten ataxia is believed to have an immune-mediated pathogenesis.
T947 451459-451594 Epistemic_statement denotes Identification of the proteins targeted by these antibodies may facilitate further understanding of the pathogenesis of this condition.
T948 451595-451887 Epistemic_statement 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.
T949 451888-452022 Epistemic_statement denotes Preliminary results have suggested no apparent difference in the avidity of either anti-gliadin or anti-GAD antibodies between groups.
T950 452203-452275 Epistemic_statement denotes Analysis of these proteins by MALDI-TOF will allow their identification.
T951 452834-452917 Epistemic_statement denotes Our objective was to identify anti glycans antibodies that can serve as biomarkers.
T952 453361-453518 Epistemic_statement 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.
T953 453519-453675 Epistemic_statement denotes Background: Several recent reports identified high titres of anti-glutamic acid decarboxylase autoantibodies (GAD-Ab) in association with cerebellar ataxia.
T954 453676-453796 Epistemic_statement denotes The aetiological link remains unclear, as well as the frequency and level of GAD-Abs in an unselected ataxic population.
T955 454968-455092 Epistemic_statement denotes Circulating specific CD8+ T cell responses are unknown in autoimmune diseases with central nervous system (CNS) involvement.
T956 456960-457195 Epistemic_statement 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.
T957 457612-457702 Epistemic_statement denotes These data indicate that OPN plays a role in increased disease activity in RR MS patients.
T958 457841-457906 Epistemic_statement denotes Wang, K. Ozawa and T. Saida Utano National Hospital, Kyoto, Japan
T959 457907-458297 Epistemic_statement 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.
T960 458298-458469 Epistemic_statement 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.
T961 458470-458715 Epistemic_statement 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.
T962 458716-458854 Epistemic_statement 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.
T963 459124-459346 Epistemic_statement 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.
T964 459876-459928 Epistemic_statement denotes The specificity of oligoclonal IgG in MS is unknown.
T965 460620-460786 Epistemic_statement 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.
T966 460787-460907 Epistemic_statement denotes Phage-displayed random peptide libraries have the potential to identify continuous epitopes or mimotopes of MS antigens.
T967 460908-461054 Epistemic_statement denotes Reliable, and easy to measure, immunological markers able to denote disease characteristics in multiple sclerosis (MS) patients are still lacking.
T968 461866-462052 Epistemic_statement 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.
T969 462053-462308 Epistemic_statement 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.
T970 462747-462899 Epistemic_statement 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.
T971 462989-463080 Epistemic_statement denotes The variation could be attributed to variation between wells, plates, days and technicians.
T972 463762-463921 Epistemic_statement denotes Object: To correlate the lymphocyte network in the peripheral blood, with neurological status (EDSS) and MRI activity in newly diagnosed untreated MS patients.
T973 464948-465149 Epistemic_statement 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.
T974 465150-465313 Epistemic_statement 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.
T975 466412-466553 Epistemic_statement denotes The decreased expression of RAB7 may contribute to the downregulation of MHC class II, one of the known immunomodulatory actions of IFN-beta.
T976 466554-466707 Epistemic_statement 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.
T977 467912-468093 Epistemic_statement 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.
T978 468094-468399 Epistemic_statement 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.
T979 468574-468704 Epistemic_statement denotes Most interestingly, a large number of genes reflect differences in the activity of G protein signaling between MS patients and HC.
T980 468705-469020 Epistemic_statement 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.
T981 469021-469114 Epistemic_statement denotes Immune-mediated mechanisms play a crucial role in the patogenesis of multiple sclerosis (MS).
T982 469115-469252 Epistemic_statement denotes Though neurodegeneration with axonal loss is an early event in MS, the therapeutic approach remains restricted to antiinflammatory drugs.
T983 469253-469317 Epistemic_statement denotes Responsivness of the patients to all available drugs is limited.
T984 470055-470271 Epistemic_statement 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.
T985 470272-470575 Epistemic_statement 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.
T986 471526-471623 Epistemic_statement denotes These relationships may be explained by immune aggression against muscle and cartilaginous cells.
T987 471624-471718 Epistemic_statement denotes Correlation with the level of anti-nDNA antibodies confirms the fact of polyclonal activation.
T988 472172-472358 Epistemic_statement denotes CSF change in IFN beta-treated MS patients K. Yokoyama Juntendo University, Tokyo, Japan Object: Interferon (IFN) beta is pleiotrophic molecules with complex immunoregulatory activities.
T989 472391-472487 Epistemic_statement denotes However, a valid definition of therapeutic response is needed for individual treatment decision.
T990 473073-473165 Epistemic_statement denotes We could measure and compare CSF change before and after IFN beta treatment in two patients.
T991 473417-473520 Epistemic_statement denotes Conclusions: The IFN beta treatment might influence the NO and IgG synthesis in the CSF of MS patients.
T992 473521-473635 Epistemic_statement denotes Serial measurement of IgG index might be useful as a surrogate marker for the effectiveness of IFN beta treatment.
T993 473755-473962 Epistemic_statement 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.
T994 473963-474136 Epistemic_statement 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.
T995 474303-474407 Epistemic_statement denotes Our results indicate that 1 to 3 ng of mRNA can be extracted from 1 ml of CSF obtained from MS patients.
T996 474408-474481 Epistemic_statement denotes This theoretically allows performing up to 40 RT-PCR from one CSF sample.
T997 474482-474635 Epistemic_statement 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.
T998 475912-476034 Epistemic_statement denotes Our results seems to indicate that CSF and serum sHLA-I/ sHLA-G balance could modulate MS activity in opposite directions.
T999 476174-476349 Epistemic_statement 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.
T1000 476350-476463 Epistemic_statement denotes In contrast, association of TIM-1 polymorphisms to Th2-related airway hyperreactivity has been suggested in mice.
T1001 476464-476547 Epistemic_statement denotes The TIM molecules have not been investigated in human Th1-or Th2-mediated diseases.
T1002 476893-477014 Epistemic_statement denotes Moreover, higher TIM-1 expression was associated with clinical remissions and low expression of IFN-gamma mRNA in CSF-MC.
T1003 477113-477299 Epistemic_statement 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.
T1004 477455-477576 Epistemic_statement denotes However, not only myelin, but axonal-neuronal damage also develops in the advanced stage, but in the early stage as well.
T1005 477577-477635 Epistemic_statement denotes It may be finally responsible for irreversible disability.
T1006 477995-478063 Epistemic_statement denotes In MS group tau level correlated with disease duration and severity.
T1007 478064-478157 Epistemic_statement denotes Therefore, we concluded that CSF tau would be a probable marker for detection of axonal loss.
T1008 479648-479804 Epistemic_statement 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.
T1009 479805-479917 Epistemic_statement denotes The aim was to assess OCB in CSF of patients with relapsingremitting multiple sclerosis (RRMS) treated with DMD.
T1010 480818-481102 Epistemic_statement denotes Characterization of immunorelevant human brain antigens of multiple sclerosis patients by two-dimensional electrophoresis Z. Adwan Swaida Neuroimmunology Institution, Swaida, Syria Objective: To identify and characterize new immunorelevant antigens associated with multiple sclerosis.
T1011 481294-481536 Epistemic_statement 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.
T1012 481537-481687 Epistemic_statement denotes Indeed, respectively, 17 and 29 brain antigens, defined according to their molecular weight, were described to support a discriminant immune response.
T1013 482136-482266 Epistemic_statement denotes Conclusions: Serological proteome analysis (SERPA) may constitute a new tool for the identification of new MS-associated antigens.
T1014 482575-482688 Epistemic_statement denotes Apart from the effects on metabolism, leptin has been shown to play an important role in inflammatory conditions.
T1015 483534-483663 Epistemic_statement denotes Conclusion: Leptin is a peptide influencing immune system modulation and has a crucial role in triggering the acute inflammation.
T1016 485021-485244 Epistemic_statement 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.
T1017 485245-485439 Epistemic_statement 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.
T1018 485568-485703 Epistemic_statement denotes Methods: Twenty patients with a first event of MS underwent clinical and MRI evaluation, and PBMC collection every 45 days, for 1 year.
T1019 486578-486822 Epistemic_statement denotes Conclusions: 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.
T1020 486823-486965 Epistemic_statement 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.
T1021 486966-487142 Epistemic_statement 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.
T1022 488015-488133 Epistemic_statement denotes Objective: To correlate MxA and IL-10 production with the response to treatment, dose of IFN-beta, and NAb occurrence.
T1023 488744-488841 Epistemic_statement denotes The increase of the IFN-beta dose was associated with a renewed MxA and IL-10 increase ( p=0.03).
T1024 488873-488961 Epistemic_statement denotes NAb positivity was associated with a decrease in MxA but no changes in IL-10 production.
T1025 488962-489053 Epistemic_statement denotes Conclusions: MxA and IL-10 levels correlated well with treatment response and IFNbeta dose.
T1026 490370-490505 Epistemic_statement denotes The variable region sequences can be inserted into expression vectors to produce large quantities of functional recombinant IgG (rIgG).
T1027 490506-490697 Epistemic_statement 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.
T1028 490799-490985 Epistemic_statement 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.
T1029 491497-491612 Epistemic_statement denotes There was a relationship between HSP-60 and TNF-alpha in acute and chronic states CSFs obtained from n-BD patients.
T1030 491613-491713 Epistemic_statement denotes Thus, these results indicated that HSP-60 may be one of the initiating or enhancing factor for n-BD.
T1031 491714-492277 Epistemic_statement denotes Unexplained cases of CNS disorders with evidence of Chlamydia pneumoniae DNA C. Contini a , S. Seraceni a , R. Cultrera a , M. Castellazzi a , E. Fainardi b , D. Marchetti c and E. Granieri a a University of Ferrara, Ferrara, Italy; b S. 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.
T1032 492968-493119 Epistemic_statement denotes C. pneumoniae infection should be included in the differential diagnosis of meningoencephalitis, even if there are not associated respiratory symptoms.
T1033 493120-493470 Epistemic_statement 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.
T1034 493708-493822 Epistemic_statement denotes They and their binding sites are immunogenic and are known to be associated with a range of autoimmune conditions.
T1035 493823-493953 Epistemic_statement denotes This theoretical paper describes a biologically plausible mechanism for chronic fatigue syndrome and sudden infant death syndrome.
T1036 494921-495021 Epistemic_statement denotes Discussion: Our data suggests that anti-gliadin Ab detection may be dependent on the assay employed.
T1037 495022-495220 Epistemic_statement 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.
T1038 495549-495699 Epistemic_statement denotes An autoimmune process has been suggested and some anti-neuronal antibodies were reported in ACA, but their antigen molecules have not been identified.
T1039 496768-496844 Epistemic_statement denotes These findings suggest that the anti-TPI IgM antibody may be related to ACA.
T1040 497580-497703 Epistemic_statement denotes A correlation of immune findings in the PANDAS subtype will be made to those children with OCD/tics without PANDAS subtype.
T1041 497969-498144 Epistemic_statement 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.
T1042 498285-498446 Epistemic_statement denotes A crucial question concerns the initial stimuli triggering the production of different cytokines that are simultaneously present in neurodegenerative conditions.
T1043 498834-499059 Epistemic_statement 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.
T1044 499060-499195 Epistemic_statement denotes Increase in cytokines may contribute not only as a compensatory response but as a primary initiating trigger for the neurodegeneration.
T1045 499288-499501 Epistemic_statement denotes Fois a , G. Arru a , B. Zanda a , A. Pirisi a , A. Sanna a and G. Rosati a a Istituto di Clinica Neurologica, University of Sassari, Sassari, Italy; b Dipartimento di Neurofarmacologia, OASI (IRCCS), Troina, Italy
T1046 499502-499723 Epistemic_statement 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.
T1047 499724-499923 Epistemic_statement 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.
T1048 499924-500270 Epistemic_statement 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.
T1049 500396-500614 Epistemic_statement 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.
T1050 500615-500814 Epistemic_statement 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.
T1051 500815-500976 Epistemic_statement 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.
T1052 501082-501185 Epistemic_statement denotes It is not known if the risk factors for developing vascular dementia differ from those found in stroke.
T1053 502384-502520 Epistemic_statement denotes Our study confirm that an increased systemic levels of proinflammatory and immunoregulating cytokines may be found in patients with VaD.
T1054 504783-504960 Epistemic_statement 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.
T1055 505184-505292 Epistemic_statement denotes This suggests that normal thymic epithelium can be relevant in maintaining peripheral Treg cell homeostasis.
T1056 505293-505477 Epistemic_statement 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.
T1057 505584-505677 Epistemic_statement denotes Moreover, there was no correlation between intrathymic and circulating Treg cell frequencies.
T1058 505678-505890 Epistemic_statement 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.
T1059 506757-506867 Epistemic_statement denotes Ab -ve MG is probably a pathogenetically-heterogeneous disorder and our data suggests it is relatively common.
T1060 508606-508987 Epistemic_statement denotes Allergic bronchial asthma induced in NGF-antibody producing rats: evidence for a non pro-inflammatory role of NGF B. Stampachiacchiere, A. Micera, S. Bonini and L. 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).
T1061 508988-509059 Epistemic_statement denotes The NGF inflammatory role in ABA is not clear and matter of discussion.
T1062 509871-510093 Epistemic_statement 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.
T1063 510094-510315 Epistemic_statement 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.
T1064 511389-511498 Epistemic_statement denotes The results of our study indicate that a year post-carotid endarterectomy, the MMP 9/TIMP 1 ratio is reduced.
T1065 511499-511628 Epistemic_statement denotes Further studies are required to support the use of these enzymes as bio-markers of atherosclerotic activity and impending stroke.
T1066 512104-512246 Epistemic_statement 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.
T1067 513408-513480 Epistemic_statement denotes Signaling through TLRs may also regulate endogenous responses to injury.
T1068 514579-514784 Epistemic_statement 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.
T1069 514785-514944 Epistemic_statement 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.
T1070 515515-515580 Epistemic_statement denotes Its levels could be enhanced by IFN-gamma, IL-1beta and IFN-beta.
T1071 515924-516108 Epistemic_statement 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.
T1072 516333-516711 Epistemic_statement 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. Human fetal and adult microglia were pretreated with HQ followed by lipopolysaccharide (LPS), a monocytoid activator.
T1073 517238-517458 Epistemic_statement 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.
T1074 517816-517946 Epistemic_statement denotes The molecular mechanism underlying the production of the most abundant endocannabinoid, 2-arachidonoylglycerol (2-AG), is unclear.
T1075 518143-518268 Epistemic_statement denotes However, efficacious activation of metabotropic P2Y purinergic receptors coupled to PI-PLC does not increase 2-AG production.
T1076 518269-518424 Epistemic_statement denotes This suggests that ionotropic, and not metabotropic, purinergic receptors control 2-AG production at an unexpected enzymatic step of its metabolic pathway.
T1077 519088-519373 Epistemic_statement 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.
T1078 519806-520033 Epistemic_statement 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.
T1079 520383-520590 Epistemic_statement 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.
T1080 520591-520857 Epistemic_statement 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.
T1081 521963-522223 Epistemic_statement 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.
T1082 523139-523294 Epistemic_statement denotes We are currently examining to what extent these multiple microglial phenotypes are a consequence of different lineages versus different environmental cues.
T1083 524133-524258 Epistemic_statement denotes Interestingly, specific expression of the corresponding receptors was found on oligodendrocytes in both MS and non-MS tissue.
T1084 524838-525086 Epistemic_statement 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.
T1085 525087-525203 Epistemic_statement denotes ATP regulates oligodendrocyte progenitor migration and proliferation via P2Y receptor activation C. Agresti a , M.E.
T1086 525204-525587 Epistemic_statement denotes Meomartini b , S. Amadio b , E. Ambrosini a , B. Serafini a , C. Volonté b , S. Visentin a and F. 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.
T1087 526147-526302 Epistemic_statement 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.
T1088 526699-526900 Epistemic_statement 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.
T1089 526901-527080 Epistemic_statement 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.
T1090 527081-527209 Epistemic_statement denotes Migration of SC into the CNS is limited, but even when injected directly CNS glia may interfere with SC survival and maturation.
T1091 528032-528199 Epistemic_statement 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.
T1092 528718-528835 Epistemic_statement denotes In particular, chemokines may play a role in regulating oligodendrocytes, the cells myelinating axons within the CNS.
T1093 529263-529438 Epistemic_statement 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.
T1094 530183-530361 Epistemic_statement 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.
T1095 530362-530663 Epistemic_statement 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.
T1096 530664-530889 Epistemic_statement 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).
T1097 531505-531633 Epistemic_statement denotes These results may provide interesting insights on the pathogenic role of GL as autoantigens in MS and in CNS autoimmune disease.
T1098 531634-531788 Epistemic_statement denotes Sonic Hedgehog (SHH) and downstream molecules Olig1 and Olig2 may be dysregulated in MS, a disease in which selective depletion of oligodendroglia occurs.
T1099 532660-532883 Epistemic_statement denotes Interestingly, Westerns revealed markedly increased Olig2 in chronic active MS. Upregulation of SHH and Olig2 in oligodendrocytes around chronic active lesions suggests these genes to be active during ongoing demyelination.
T1100 532884-532986 Epistemic_statement denotes Downregulation of SHH and Olig2 may explain progression from chronic active to chronic silent lesions.
T1101 534608-534852 Epistemic_statement 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.
T1102 535541-535714 Epistemic_statement 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.
T1103 535715-535743 Epistemic_statement denotes Rare lymphocytes were found.
T1104 535854-535947 Epistemic_statement denotes Although neovascularization was decreased, astrocytic reaction did not appear to be affected.
T1105 536129-536246 Epistemic_statement denotes Results from group II suggest that IL-2 suppression by CsA had a proliferative effect on oligodendrocyte progenitors.
T1106 536634-536743 Epistemic_statement denotes The proteinase responsible for this cleavage has been identified as TNFa-converting enzyme (TACE or ADAM-17).
T1107 537096-537313 Epistemic_statement 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.
T1108 537512-537657 Epistemic_statement denotes The Coxsackie Adenovirus receptor expressed by ependymal cells is a key component of the brain stem cell niche M. Hauwel, C. Canova and P. Gasque
T1109 537658-537757 Epistemic_statement denotes In the adult vertebrate brain, the subventricular zone (SVZ) is one of the rare neurogenesis areas.
T1110 538011-538196 Epistemic_statement 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.
T1111 538421-538600 Epistemic_statement 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.
T1112 539265-539385 Epistemic_statement denotes 3D Confocal reconstructions were used to correlate the migration of hNSCs to foci of pathology with expression of SDF-1.
T1113 540717-540782 Epistemic_statement denotes However, the exact identity of such precursors remains enigmatic.
T1114 541246-541461 Epistemic_statement 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).
T1115 541756-541839 Epistemic_statement denotes to CDV infected mice, they could be detected as isolated cells in brain parenchyma.
T1116 541840-542155 Epistemic_statement denotes TREM-2 in the central nervous system C. Buonsanti, M. Mariani, F. Benigni, P. Di Lucia, S. Smiroldo, L. Adorini and P. 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.
T1117 542156-542314 Epistemic_statement 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.
T1118 542315-542461 Epistemic_statement 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.
T1119 542611-542761 Epistemic_statement denotes These observations have suggested that the array of myeloid cells regulated by TREM-2 may extend beyond DC, including microglial cells and osteoclats.
T1120 542762-542860 Epistemic_statement denotes Here, we show that the TREM-2/DAP12 complex is selectively expressed on human and mouse microglia.
T1121 543386-543646 Epistemic_statement 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.
T1122 544085-544272 Epistemic_statement 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.
T1123 544738-544879 Epistemic_statement denotes Using specific MAP kinase inhibitors, we showed by immunofluorescence and ELISA that these cell populations could be regulated independently.
T1124 545690-546012 Epistemic_statement 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.
T1125 546937-547196 Epistemic_statement 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.
T1126 548094-548231 Epistemic_statement denotes These results indicate the use of PPAR-gamma agonists as a potential new therapeutic approach in prion-protein induced neuroinflammation.
T1127 549027-549123 Epistemic_statement denotes A link between cell morphology and the intracellular distribution of these proteins is observed.
T1128 549124-549231 Epistemic_statement denotes The focal adhesion spotassociated proteins integrin beta1 and alpha6 as well as vinculin have been studied.
T1129 549292-549405 Epistemic_statement denotes lplastin, its phosphorylated form, and alpha-actinin are seen in close association with the focal adhesion spots.
T1130 549514-549789 Epistemic_statement 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.
T1131 549790-549927 Epistemic_statement denotes Ischemia/reperfusion injury is associated with inflammatory responses that may play both deleterious and benefic role in neuronal damage.
T1132 550389-550506 Epistemic_statement denotes It was associated with a significant down-regulation of IL-1beta protein expression in microglia in the injured side.
T1133 550831-550995 Epistemic_statement 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.
T1134 551085-551246 Epistemic_statement 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.
T1135 551539-551726 Epistemic_statement denotes Activated microglia secrete inflammatory mediators such as cytokines and chemokines, which contribute to the pathophysiological changes associated with several neuroimmunologic disorders.
T1136 552056-552160 Epistemic_statement denotes The inhibition of chemokine gene expression correlates with an inhibitory effect of VIP on NFkB binding.
T1137 553274-553496 Epistemic_statement 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.
T1138 553497-553570 Epistemic_statement denotes Here, we have investigated how immunoglobulins activate microglial cells.
T1139 554733-554804 Epistemic_statement denotes Regulation of NO production by microglia is poorly understood, however.
T1140 555189-555344 Epistemic_statement denotes Microglia do produce proinflammatory cytokines in response to these stimuli however, and therefore possess a relatively selective block in NOS2 expression.
T1141 555615-555827 Epistemic_statement 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.
T1142 556403-556553 Epistemic_statement denotes Thus, it is tempting to speculate that activated microglia may change from proinflammatory to anti-inflammatory after phagocytosis of apoptotic cells.
T1143 556993-557254 Epistemic_statement 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.
T1144 557255-557342 Epistemic_statement denotes These results strongly suggest that PS-liposomes can be applied to the treatment of AD.
T1145 557544-557845 Epistemic_statement 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.
T1146 558001-558262 Epistemic_statement 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.
T1147 558961-559119 Epistemic_statement 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.
T1148 559432-559610 Epistemic_statement 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.
T1149 560064-560172 Epistemic_statement denotes Together, these results suggest that Notch signaling, has important immunomodulatory functions in the brain.
T1150 560279-560530 Epistemic_statement 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.
T1151 561501-561763 Epistemic_statement 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.
T1152 562504-562653 Epistemic_statement 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.
T1153 563286-563501 Epistemic_statement 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.
T1154 563502-563676 Epistemic_statement denotes Characterisation of the Jagged-Notch-Hes pathway on activated astrocytes E. Morga, L. Grandbarbe, K. Hemmer and P. Heuschling Université du Luxembourg, Luxembourg, Luxembourg
T1155 563677-563841 Epistemic_statement 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.
T1156 564576-564729 Epistemic_statement 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.
T1157 564996-565119 Epistemic_statement denotes Taken together, these preliminary results could have interesting issues on the understanding of this pathway on astrocytes.
T1158 565120-565235 Epistemic_statement denotes In fact, a better understanding of the expression of Notchligands can be a helpful tool for demyelinating diseases.
T1159 567748-567927 Epistemic_statement 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.
T1160 568166-568381 Epistemic_statement 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.
T1161 568458-568644 Epistemic_statement 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.
T1162 568795-569003 Epistemic_statement 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.
T1163 569458-569670 Epistemic_statement 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.
T1164 570481-570728 Epistemic_statement 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.
T1165 570729-570870 Epistemic_statement denotes The Golgi apparatus has been recently shown to represent a key station involved in the intracellular trafficking of Mrp1 in mouse astrocytes.
T1166 572330-572574 Epistemic_statement 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.
T1167 572575-572687 Epistemic_statement denotes This mechanism may represent the first step of antigen processing and presentation function in astrocytic cells.
T1168 572688-572801 Epistemic_statement denotes Monocarboxylates like lactate are provided by astrocytes and can be used as fuel by neurons and oligodendrocytes.
T1169 573545-573655 Epistemic_statement denotes Therefore, complexation of MHC class II molecules on astrocytes might be mandatory for the regulation of MCT1.
T1170 573656-573834 Epistemic_statement 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.
T1171 573835-574035 Epistemic_statement 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.
T1172 575075-575313 Epistemic_statement 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.
T1173 575314-575518 Epistemic_statement 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.
T1174 576130-576280 Epistemic_statement 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.
T1175 577187-577414 Epistemic_statement 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.
T1176 577415-577566 Epistemic_statement denotes Within the central nervous system (CNS) in multiple sclerosis (MS), increased expression of two key chemokines, CXCL10 and CCL2, has been demonstrated.
T1177 578527-578666 Epistemic_statement denotes The fine control of chemokine expression by cytokines may explain the different chemokine expression profiles in the CSF in people with MS.
T1178 579301-579379 Epistemic_statement denotes Yet the functional significance of TLR in the CNS is still largely unexplored.
T1179 580011-580190 Epistemic_statement 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.
T1180 580273-580392 Epistemic_statement denotes Together, these data suggest that astroglial TLR play a role in repair functions rather than in promoting inflammation.
T1181 580538-580740 Epistemic_statement 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.
T1182 581422-581747 Epistemic_statement 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.
T1183 582161-582279 Epistemic_statement denotes Matrix metalloproteinase-9 (MMP-9) has been implicated in tissue destruction in a range of CNS diseases including TBM.
T1184 583263-583493 Epistemic_statement 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.
T1185 584005-584093 Epistemic_statement denotes These observations indicate that TIMP-1 replenishment in HAD may have therapeutic value.
T1186 584357-584489 Epistemic_statement denotes Preliminary data confirm that acute versus chronic TIMP-1 responses in astrocytes are regulated predominantly at the promoter level.
T1187 584594-584703 Epistemic_statement denotes TIMP-1 siRNA-transfected astrocytes had enhanced neurotoxicity that correlated with diminished TIMP-1 levels.
T1188 584777-584911 Epistemic_statement denotes In addition, TIMP-1 supported neuronal differentiation during early development suggesting that TIMP-1 may function as a neurotrophin.
T1189 584912-585052 Epistemic_statement denotes TIMP-1-neuroprotection may be mediated by activation of anti-apoptotic proteins such as Bcl-2/Bcl-xL and/or through neurotrophic activities.
T1190 585053-585156 Epistemic_statement denotes Our results indicate that the complex astrocyte-TIMP-1 regulation in HAD may influence neuroprotection.
T1191 585157-585276 Epistemic_statement denotes These studies are relevant to glial inflammation in HAD and may unravel novel mechanisms of glialneuronal interactions.
T1192 585432-585729 Epistemic_statement 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.
T1193 586024-586126 Epistemic_statement denotes The object of this study is to determine how vagus nerve regulates TNF production in different organs.
T1194 587013-587222 Epistemic_statement 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.
T1195 587696-587845 Epistemic_statement 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.
T1196 588069-588166 Epistemic_statement denotes Interestingly, Y1À/À mice had significantly reduced footpad swelling compared with wildtype mice.
T1197 588273-588453 Epistemic_statement 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.
T1198 588751-588860 Epistemic_statement denotes The cells/factors and molecular mechanisms controlling these opposite functions of DC are not elucidated yet.
T1199 589348-589420 Epistemic_statement denotes The cocultured Ag-specific T cells secrete however high levels of IL-10.
T1200 589421-589729 Epistemic_statement 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.
T1201 589852-590026 Epistemic_statement denotes The generation of antigenspecific Treg in vitro in a controlled environment is of high therapeutic potential for autoimmune diseases and transplantation (AI47325 & AI052306).
T1202 590027-590446 Epistemic_statement 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. 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.
T1203 590447-590554 Epistemic_statement denotes However, the decision-making mechanisms that determine the type of effector response are poorly understood.
T1204 590555-590691 Epistemic_statement denotes In the preceding work, we showed that the sympathetic nervous system may influence the antigen-presenting and Th priming ability of DCs.
T1205 591264-591379 Epistemic_statement denotes The mechanism of this interesting effect might be related to a CB2-mediated recruitment of lymphoid DCs precursors.
T1206 591457-591645 Epistemic_statement 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.
T1207 592764-593000 Epistemic_statement 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.
T1208 593245-593360 Epistemic_statement denotes Prior studies have demonstrated that NPY would play a regulatory role in EAE by causing an immune bias towards Th2.
T1209 593361-593487 Epistemic_statement denotes Here we explored if Ghrelin might also exert an immunomodulatory effect similar to NPY and protect against development of EAE.
T1210 593670-593920 Epistemic_statement 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.
T1211 594115-594203 Epistemic_statement denotes These results indicate a novel role for Ghrelin to modulate autoimmune pathology in EAE.
T1212 595239-595318 Epistemic_statement denotes Under such experimental conditions however, IFNbeta failed to induce CA efflux.
T1213 596991-597170 Epistemic_statement 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.
T1214 597171-597432 Epistemic_statement 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.
T1215 597765-597842 Epistemic_statement denotes Active MS lesions correlated with a low number of hyperactive CRH/VP neurons.
T1216 597843-597970 Epistemic_statement denotes High HLA -DR, -DP, -DQ expression, a measure for macrophage and microglial activation, correlated with low CRH mRNA expression.
T1217 597971-598151 Epistemic_statement 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.
T1218 599592-599680 Epistemic_statement denotes The p50 subunit appears to play a role in normal expression of certain forms of anxiety.
T1219 599922-600232 Epistemic_statement 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.
T1220 600869-601045 Epistemic_statement denotes These results suggest an banti-inflammatoryQ effect of the sympathetic neurotransmitters studied (NPY and NA), at physiological concentrations, on murine peritoneal leucocytes.
T1221 601365-601607 Epistemic_statement 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.
T1222 601951-602150 Epistemic_statement 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.
T1223 602405-602504 Epistemic_statement denotes The results support a potential therapeutic action of VIP for the therapy of inflammatory diseases.
T1224 604164-604402 Epistemic_statement 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.
T1225 607023-607145 Epistemic_statement denotes The ability of SP to augment secretion of pro-inflammatory cytokines supports the role of SP in the inflammatory response.
T1226 607146-607311 Epistemic_statement 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.
T1227 607312-607605 Epistemic_statement denotes Interactions between neuro-endocrine and immune systems in ageing: trade-off analysis by means of mathematical modeling T. Sannikova a , A. Romanyukha a and A. Yashin b a Institute of Numerical Mathematics, RAS, Moscow, Russia; b Max Planck Institute for Demographic Research, Rostock, Germany
T1228 607606-607720 Epistemic_statement denotes The aim of this work is to quantify the trade-offs between human immune and hormonal systems in the aging process.
T1229 608691-608800 Epistemic_statement denotes Existence of the trade-offs should be taken in consideration when hormonal therapy is used in elderly people.
T1230 608992-609161 Epistemic_statement 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.
T1231 609162-609293 Epistemic_statement denotes Our mouse model of obesity induced by brain CDV infection may give insights in how virus-induced brain damages may lead to obesity.
T1232 609479-609705 Epistemic_statement 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.
T1233 610236-610376 Epistemic_statement denotes Our data pointed out Urop11 as a new gene, implicated in emerging or maintenance of obesity status, likely regulated under a leptin control.
T1234 610760-610959 Epistemic_statement 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.
T1235 610960-611358 Epistemic_statement 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.
T1236 612409-612764 Epistemic_statement denotes Souza b and P. 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: 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.
T1237 612840-613024 Epistemic_statement 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.
T1238 613784-613922 Epistemic_statement 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.
T1239 613923-614318 Epistemic_statement denotes Orchidectomy affects the monoamine content in rat thymocytes B. Vidic-Dankovic a , K. Radojevic a and G. Leposavic b a Institute of Immunology and Virology bTorlakQ, Belgrade, Yugoslavia; b Faculty of Pharmacy, Belgrade, Yugoslavia Object of study: It has been shown that: (i) orchidectomy influences the intrathymic concentration of monoamines and (ii) some T-cell lines produce catecholamines.
T1240 614319-614514 Epistemic_statement 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.
T1241 614798-614932 Epistemic_statement denotes Results: In spite of age at surgery, orchidectomy diminished the intrathymic concentration of NA and 5-HT, while increased that of DA.
T1242 615867-615987 Epistemic_statement denotes Besides the enzyme activity, DPPIV can act as an adhesive and as a costimulatory molecule transducing the growth signal.
T1243 616061-616169 Epistemic_statement denotes Neuropeptides can also regulate the expression of membrane peptidases that in turn cleave the neuropeptides.
T1244 616170-616354 Epistemic_statement 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.
T1245 616892-617054 Epistemic_statement 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.
T1246 617055-617233 Epistemic_statement 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.
T1247 617234-617324 Epistemic_statement denotes Increased DPPIV expression on fibroblasts may affect their functional activity and growth.
T1248 617369-617535 Epistemic_statement 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.
T1249 618111-618260 Epistemic_statement denotes Conclusion: The observed results provide evidence on the potential protective role of PAT against brain tissue damage during inflammatory conditions.
T1250 619059-619223 Epistemic_statement 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.
T1251 619463-619559 Epistemic_statement denotes The affinity suggests that caprines receptors may recognize serum melatonin level physiological.
T1252 619759-619972 Epistemic_statement 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.
T1253 619973-620236 Epistemic_statement denotes Regulation of secretion of nociceptin/orphanin FQ from rat splenocytes A. 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.
T1254 621440-621612 Epistemic_statement 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.
T1255 622808-622926 Epistemic_statement denotes This activationinduced increase in F-actin content, however, was abrogated in the presence of the b2AR agonists (n=3).
T1256 622927-623141 Epistemic_statement denotes Conclusions: 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.
T1257 624700-624986 Epistemic_statement denotes Thompson a , S. Curran b , A. Cox a , K. Chatterjee b and A. 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.
T1258 625103-625298 Epistemic_statement 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.
T1259 625299-625428 Epistemic_statement denotes It has been previously shown that restoration of serum DHEA levels by oral administration enhances cognition and reduces fatigue.
T1260 625830-625947 Epistemic_statement denotes It also induced lymphocyte cytokine mRNA and protein expression, without a particular bias to any T helper phenotype.
T1261 625948-626074 Epistemic_statement denotes CD4 + CD25 hi cell numbers and foxP3 expression was also increased, suggesting that DHEA had induced regulatory T lymphocytes.
T1262 627009-627117 Epistemic_statement denotes However, the percentage of CD19 + cells in tolueneexposed mice was increased compared with air-exposed mice.
T1263 627397-627515 Epistemic_statement denotes It is possible to speculate that toluene inhalation may affect immune functions in brain regions via olfactory system.
T1264 627673-627789 Epistemic_statement denotes These things suggest that exposure of mice to low dose toluene via intranasal route may induce immune abnormalities.
T1265 627790-628030 Epistemic_statement 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.
T1266 629204-629498 Epistemic_statement 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.
T1267 630796-630897 Epistemic_statement denotes Substance P involvement in chemotactic activity of human brain endothelium C. Cioni and P. Annunziata
T1268 630898-631051 Epistemic_statement denotes In the last few years, the mechanism underlying the recruitment of T lymphocytes through the blood-brain barrier has been receiving increasing attention.
T1269 631341-631665 Epistemic_statement 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.
T1270 633634-633890 Epistemic_statement denotes Conclusions: 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.
T1271 634770-634947 Epistemic_statement 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.
T1272 635120-635293 Epistemic_statement 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.
T1273 635294-635407 Epistemic_statement denotes A longer follow-up is warranted to assess possible differences between responders and non-responders to IFN-beta.
T1274 635564-635687 Epistemic_statement denotes Previous studies have shown that the severity of MS and EAE is reduced by increased level of sex hormones during pregnancy.
T1275 636053-636103 Epistemic_statement denotes However, these cells retained expression of VLA-4.
T1276 636104-636250 Epistemic_statement 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.
T1277 636455-636695 Epistemic_statement 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.
T1278 637996-638133 Epistemic_statement denotes These results indicate that the brain neurotransmitter-related mRNAs can be a sensitive marker for effects of exposure to air pollutants.
T1279 638134-638342 Epistemic_statement 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 .
T1280 640019-640250 Epistemic_statement denotes China Backgrounds: 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.
T1281 640699-640814 Epistemic_statement denotes The elevated cortisol was associated with the increased IL-2 and IL-6 in schizophrenia, respectively (both pb0.01).
T1282 640815-640914 Epistemic_statement denotes Cortisol was associated with negative symptoms ( pb0.05) and IL-2 with positive symptoms ( pb0.05).
T1283 641253-641478 Epistemic_statement denotes Conclusions: 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.
T1284 641479-641713 Epistemic_statement 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.
T1285 642174-642247 Epistemic_statement denotes Interestingly, regulatory T cells increased during stress in both groups.
T1286 642696-642827 Epistemic_statement denotes However, other parameters, such as the CD4/CD8 ratio and the number of regulatory T cells, were similarly regulated in both groups.
T1287 642828-642947 Epistemic_statement denotes Our results indicate that healthy and atopic subjects share certain features of a stress response but differ in others.
T1288 643829-644000 Epistemic_statement 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.
T1289 644081-644271 Epistemic_statement 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.
T1290 644272-644781 Epistemic_statement denotes Autoantibodies to the brain opiate and glutamate receptors as putative biomarkers of morphine addiction O. Granstrem a , W. Adriani b , D. Giannakopoulou b , S. Dambinova c , G. Izykenova c and G. 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.
T1291 644782-644986 Epistemic_statement 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.
T1292 645549-645642 Epistemic_statement denotes It is possible to hypothesize that an autoimmune response to repeated drug exposure occurred.
T1293 645643-645794 Epistemic_statement denotes The relationship between presence in the plasma of autoantibodies to these neuroreceptors and pathological changes in brain function is so far unknown.
T1294 645795-645892 Epistemic_statement denotes Circulating autoantibodies may functionally affect the AMPA glutamatergic input within the brain.
T1295 646002-646237 Epistemic_statement denotes Objective: 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.
T1296 646700-646836 Epistemic_statement denotes Results: Seven out of 31 neuropsychological variables were associated with elevated levels of anti-NR2 antibody in a correlation matrix.
T1297 646951-647291 Epistemic_statement 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.
T1298 647292-647459 Epistemic_statement denotes Conclusion: Findings in several domains indicate an association between anti-NR2 antibodies and depressed mood in addition to decreased short time memory and learning.
T1299 647460-647575 Epistemic_statement denotes Antibodies to NMDA-receptors may represent one of several mechanisms for cerebral dysfunction in patients with SLE.
T1300 647576-647680 Epistemic_statement denotes It has been suggested that schizophrenia and affected disorders may be associated with viral infections.
T1301 647681-647793 Epistemic_statement denotes However, search for viral nucleic acids in the brain of patients with schizophrenia revealed a paucity of virus.
T1302 647794-647986 Epistemic_statement 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).
T1303 647987-648268 Epistemic_statement 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.
T1304 648269-648363 Epistemic_statement denotes These T cell clonal expansions may be the only remaining trace of the initial viral infection.
T1305 648364-648502 Epistemic_statement denotes Alternatively, these T cells may be generated in response to reactivation of a viral infection, or molecular mimicry or epitope spreading.
T1306 648579-648757 Epistemic_statement 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.
T1307 648758-648915 Epistemic_statement denotes Psycho-immunological evaluation of stress preventive intervention programmes U. Sack, K. Meier, K. Bauer and M. Stqck University of Leipzig, Leipzig, Germany
T1308 648916-649127 Epistemic_statement 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.
T1309 649363-649460 Epistemic_statement denotes It was the aim of this intervention to enable teachers to better cope with their daily pressures.
T1310 649993-650081 Epistemic_statement denotes For both methods, overwhelming effects in improving stress resistance could be verified.
T1311 650082-650189 Epistemic_statement denotes In saliva, increase of immunoglobulin A could be found in persons with a positive response to our training.
T1312 650190-650338 Epistemic_statement denotes Furthermore, a significant positive correlation between the subjective sensation of relaxation or other health parameters and IgA could be measured.
T1313 650339-650430 Epistemic_statement denotes Both procedures could be shown to be effective in improving stress management capabilities.
T1314 650431-650530 Epistemic_statement denotes Psychological and subjective parameters correlated well with saliva immunoglobulin A concentration.
T1315 650531-650686 Epistemic_statement denotes Therefore, measurement of this simple immunological parameter could be proved to be a reliable indicator for stress resistance as well as training effects.
T1316 652288-652453 Epistemic_statement 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.
T1317 652454-652569 Epistemic_statement denotes We previously documented profound damage in the dopaminergic system, both in human and animal forms of the disease.
T1318 652945-653088 Epistemic_statement denotes However, these effects were less profound in the MRL-lpr group with 60% of these animals showing advanced SIB with repeated QNP administration.
T1319 653089-653253 Epistemic_statement 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.
T1320 653254-653422 Epistemic_statement 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.
T1321 653423-653621 Epistemic_statement 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.
T1322 654659-654778 Epistemic_statement denotes Since all antagonists abolished the amphetamine-induced effects on IS, dopamine and opioid systems seem to be involved.
T1323 654990-655110 Epistemic_statement denotes These changes in Met-enkephalin point out that it could be used as a common biological marker of pertinent stimuli (i.e.
T1324 655206-655354 Epistemic_statement denotes Morphofunctional characteristics of the rat thymus exposed to forced swim stress A. Rakin, I. Zivkovic, D. Petrovic-Djergovic, D. Kosec and M. Micic
T1325 655355-655573 Epistemic_statement 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.
T1326 656246-656350 Epistemic_statement denotes However, the percentage of apoptotic cells and the level of corticosterone were significantly increased.
T1327 656777-656919 Epistemic_statement denotes Additionally, elevated percentage of CD4 À CD8 À TCR + cells suggests that chronic stress is involved in the modulation of T cells maturation.
T1328 657857-658012 Epistemic_statement denotes treatment with 10 Ag of beta-End, which was antagonized by naltrindole and nor-binaltorphimine, suggesting involvement of delta and kappa opioid receptors.
T1329 658556-658682 Epistemic_statement denotes It could be concluded that RS and beta-End exerted opposite effects on in vivo and in vitro inflammatory responses in AO rats.
T1330 659075-659154 Epistemic_statement denotes However, it is unknown if melanocortins can modulate IL-1 beta-induced anxiety.
T1331 659878-659966 Epistemic_statement denotes The associated treatment with gamma-MSH did not affect the anxiety response to IL-1beta.
T1332 659967-660088 Epistemic_statement denotes These data suggest that melanocortins, through central MC4-R can modulate the anxiety-like behavior induced by IL-1 beta.
T1333 660089-660535 Epistemic_statement denotes Expression of Toll-like receptors in MG thymus P. Bernasconi a , M. Barberis b , M. Cannone b , F. Baggi a , E. Arnoldi a , C. Cappelletti a , F. Cornelio a and R. 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.
T1334 660536-660656 Epistemic_statement denotes Intercellular signals as well as surface molecules may represent key factors characterizing the thymic microenvironment.
T1335 661530-661614 Epistemic_statement denotes In thymoma and in young non-pathological thymuses, TLR4 protein was rarely detected.
T1336 661615-661847 Epistemic_statement 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.
T1337 661915-662060 Epistemic_statement 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.
T1338 662131-662262 Epistemic_statement denotes The histopathology is usually reported as normal or involuted, and these patients are rarely thymectomised, unlike those with EOMG.
T1339 662478-662559 Epistemic_statement denotes In most MuSK Ab + and 70% MuSK Ab À SNMG cases, the thymus appears normalfor-age.
T1340 662682-662785 Epistemic_statement denotes Interestingly, in about 30% of MuSK Ab À cases, we see mild infiltration, very similar to that in EOMG.
T1341 662886-663008 Epistemic_statement denotes Some of myoid cells are very close to, or within, the infiltrates where they appear to be under immune attack, as in EOMG.
T1342 663081-663241 Epistemic_statement 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.
T1343 663488-663636 Epistemic_statement denotes Previously, we found that a naturally increased rapsyn concentration in aged rats correlates with a resistance to experimental autoimmune MG (EAMG).
T1344 663974-664158 Epistemic_statement 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.
T1345 664541-664700 Epistemic_statement 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.
T1346 665329-665432 Epistemic_statement denotes Objective: To test the hypothesis that LPS-bound antigens could overcome tolerance to protein antigens.
T1347 666282-666358 Epistemic_statement denotes Conclusion: MIR-LPS conjugates can induce EAMG without additional adjuvants.
T1348 666359-666491 Epistemic_statement denotes The molecular bond of the LPS to the antigen appears to play an important role in overcoming tolerance to selfantigens such as AchR.
T1349 666492-666693 Epistemic_statement 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).
T1350 666694-666878 Epistemic_statement 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.
T1351 666879-667046 Epistemic_statement denotes The distribution of these polymorphisms was analysed in 64 myasthenia gravis patients and 87 controls to determine whether they could influence disease susceptibility.
T1352 667647-667754 Epistemic_statement denotes Conclusions: MG patients with thymoma and thymus hyperplasia are associated with different IL-10 genotypes.
T1353 668026-668173 Epistemic_statement 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.
T1354 668363-668434 Epistemic_statement denotes However, cytokine-matured DC can induce effector T cells against tumor.
T1355 668740-668832 Epistemic_statement denotes This was associated with suppression of both Th1 and Th2 cytokines, and of B cell responses.
T1356 668833-668939 Epistemic_statement denotes Surprisingly, IL-10-DC from human MG, like mature DC, increased CD4 + CD25 + T cells expressing CD69, i.e.
T1357 669457-669874 Epistemic_statement denotes The Lambert-Eaton myasthenic syndrome has a more progressive course in patients with small cell lung carcinoma P. Wirtz, A. Wintzen and J. 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).
T1358 669875-670072 Epistemic_statement 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.
T1359 670982-671101 Epistemic_statement denotes Therefore, in a patient with an aggressive course of LEMS one should be extra alerted for an underlying lung carcinoma.
T1360 671850-671946 Epistemic_statement denotes However, increased IP-10 and MIP-1alpha production in sciatic nerves were seen in CCR5 À/À mice.
T1361 671947-672050 Epistemic_statement denotes These results suggest that CCR5 deficiency does not prevent P0 peptide 180-199 immunized mice from EAN.
T1362 672051-672196 Epistemic_statement denotes Increased MIP-1alpha and IP-10 in sciatic nerves may compensate the CCR5 deficiency and contribute to inflammatory cells infiltrating to the PNS.
T1363 672348-672499 Epistemic_statement denotes Inflammatory cells, predominantly macrophages and T cells, and humoral factors, including autoantibodies, have been implicated in disease pathogenesis.
T1364 672500-672688 Epistemic_statement 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.
T1365 672689-672822 Epistemic_statement denotes To investigate the association between antibody functionality and disease development, we used a recently described GBS rabbit model.
T1366 673261-673381 Epistemic_statement denotes Increased functionality may be explained by both the increase in specific antibody titer and increased antibody avidity.
T1367 673382-673638 Epistemic_statement 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.
T1368 673732-673846 Epistemic_statement denotes IgM antibodies against b-series gangliosides including GD1b are associated with chronic sensory ataxic neuropathy.
T1369 673847-673931 Epistemic_statement denotes Animal model of sensory ataxic neuropathy can be induced by sensitization with GD1b.
T1370 673932-674049 Epistemic_statement denotes However, it has yet to be clarified whether GD1b is expressed on proprioceptive neurons of dorsal root ganglia (DRG).
T1371 674050-674216 Epistemic_statement denotes Genetically engineered mice lacking in b-series gangliosides, immunologically naRve to GD1b, were immunized with GD1b to generate anti-GD1b monoclonal antibody (mAb).
T1372 674217-674453 Epistemic_statement 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.
T1373 674802-674877 Epistemic_statement denotes This indicates that GD1b is expressed on proprioceptive neurons in rat DRG.
T1374 674878-675069 Epistemic_statement 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.
T1375 675175-675451 Epistemic_statement denotes Spies The University of Sydney, Sydney, Australia Objective: 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.
T1376 675452-675662 Epistemic_statement denotes Background: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) responds to immunomodulatory therapy but long term immunosuppressive therapy is often required, with significant associated toxicity.
T1377 676678-676869 Epistemic_statement denotes Conclusion: 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.
T1378 677310-677692 Epistemic_statement 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.
T1379 678110-678198 Epistemic_statement denotes The above results suggested ONO-2506 to exert preventive and therapeutic effects on EAN.
T1380 678199-678597 Epistemic_statement denotes Campylobacter jejuni-derived LPS abrogates oral tolerance to experimental autoimmune neuritis S. Jung a , J. Voss a , M. Frosch b , H. Karch b , K. Toyka c and S. 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
T1381 678598-678824 Epistemic_statement 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%.
T1382 678825-678950 Epistemic_statement denotes The animal model of GBS, experimental autoimmune neuritis (EAN) of Lewis rats can be induced by immunization with PNS myelin.
T1383 679426-679553 Epistemic_statement denotes Signs of active EAN induced by immunization with PNS-myelin could be mitigated by precedent feeding of myelin (oral tolerance).
T1384 679784-679911 Epistemic_statement denotes The findings demonstrate that C. jejuni-derived LPS can disturb natural immunoregulation by the gut-associated lymphoid tissue.
T1385 679912-680133 Epistemic_statement denotes Objective: 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.
T1386 680134-680354 Epistemic_statement denotes Background: 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.
T1387 680732-680841 Epistemic_statement denotes This improvement was associated with an accelerated rate of recovery from electrophysiological abnormalities.
T1388 680912-681054 Epistemic_statement denotes Further investigations are underway to determine whether the Fc or Fab component of IVIg is responsible for the observed therapeutic efficacy.
T1389 681055-681403 Epistemic_statement denotes Anti-ganglioside antibodies and intrathecal IgG synthesis in Guillain-Barré syndrome S. Matà, E. Galli, A. Amantini, F. Pinto, S. Sorbi and F. Lolli University of Florence, Florence, Italy Objective: To investigate the relationship between clinical, electrophysiological, immunological findings and CSF changes in the Guillain-Barré syndrome (GBS).
T1390 681598-681769 Epistemic_statement 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.
T1391 681770-681821 Epistemic_statement denotes The relationship between these findings is unknown.
T1392 682447-682595 Epistemic_statement denotes In both patient groups, the anti-ganglioside reactivity was associated with high incidence of motor conduction block and prolonged F wave latencies.
T1393 682596-682730 Epistemic_statement denotes In GBS patients, there was a clear association between anti-ganglioside antibody and high value of intrathecal IgG production indexes.
T1394 682731-682742 Epistemic_statement denotes Conclusion:
T1395 682743-682913 Epistemic_statement denotes The association between anti-ganglioside antibodies and high CSF IgG production indexes value in GBS patients suggests a pathogenetic relationship between these findings.
T1396 683102-683197 Epistemic_statement denotes The aim of this study was to determine whether or not C-Dps contributes to pathogenesis of GBS.
T1397 684173-684297 Epistemic_statement denotes After binding, C-Dps exerts direct neuro-toxicity, which may contribute to axonal damage in GBS with preceding Cj infection.
T1398 685348-685642 Epistemic_statement 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).
T1399 685820-685997 Epistemic_statement denotes Objective: To determine if there is a neuropathic process selectively affecting small-diameter epidermal nerve fibers (ENFs) in patients with systemic lupus erythematosus (SLE).
T1400 687068-687166 Epistemic_statement denotes No associations were found between reduced number of ENFs and symptoms, clinical findings, or NCV.
T1401 688034-688185 Epistemic_statement denotes Multisegmental motor nerve conduction studies were performed by measuring the compound muscle action potential (CMAP) and the conduction velocity (CV).
T1402 688773-689010 Epistemic_statement 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.
T1403 689430-689611 Epistemic_statement denotes Multifocal motor neuropathy is an uncommon progressive autoimmune neuropathy often associated with anti-GM1 antibodies and poorly responds to conventional immunosuppressive therapy.
T1404 691588-691778 Epistemic_statement 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.
T1405 691905-692157 Epistemic_statement 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.
T1406 692158-692281 Epistemic_statement denotes However, none of the patients with peripheral neuropathy tested in our study had any history of thrombo-occlusive problems.
T1407 692282-692443 Epistemic_statement 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.
T1408 693516-693702 Epistemic_statement 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.
T1409 694152-694311 Epistemic_statement denotes However, plasma exchange and intravenous immunoglobulin therapy (IVIg) have short-term clinical benefits and some patients may need these therapies repeatedly.
T1410 694432-694583 Epistemic_statement denotes This study was performed to investigate whether synchronized immunomodulatory combination therapy (SICT) in CIDP lead to short-and long-term remission.
T1411 695525-695600 Epistemic_statement denotes Fluctuation of cytokines may reflect favorable response to immunotherapies.
T1412 697272-697457 Epistemic_statement denotes Conclusion: 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.
T1413 698577-698789 Epistemic_statement 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.
T1414 698790-699049 Epistemic_statement denotes Immunomodulation of TGF-beta1 as possible antifibrotic therapy in muscular dystrophy: data from murine animal model F. Andreetta, P. Bernasconi, P. Ferro, E. Arnoldi, L. Oliva, F. Cornelio, R. Mantegazza and P. Confalonieri National Neurological Institute bC.
T1415 700239-700497 Epistemic_statement 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.
T1416 700822-701020 Epistemic_statement 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.
T1417 701756-701848 Epistemic_statement denotes Conclusion: There is a possibility that granulysin is concerned in steroid resistance in PM.
T1418 703544-703767 Epistemic_statement 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.
T1419 703768-704114 Epistemic_statement denotes The RAGE pathway in inflammatory myopathies M. Haslbeck a , U. Fries b , E. Schleicher b , A. Bierhaus c , B. Neundfrfer a and D. 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
T1420 704115-704251 Epistemic_statement denotes Oxidative stress and NF-kB activation are linked to the pathogenesis of many metabolic, degenerative, and chronic inflammatory diseases.
T1421 704452-704768 Epistemic_statement 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.
T1422 705026-705163 Epistemic_statement denotes Our data suggest that the CML-RAGE-NF-kB pathway is an evident proinflammatory pathomechanism in mononuclear effector cells in PM and DM.
T1423 705164-705267 Epistemic_statement denotes RAGE-mediated NF-kB expression may play a role in muscle fiber regeneration in inflammatory myopathies.
T1424 706429-706535 Epistemic_statement denotes These findings may have important implications in designing future therapeutic strategies for the disease.
T1425 708096-708247 Epistemic_statement 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.
T1426 708645-708706 Epistemic_statement denotes The role of non-AChR autoantibodies remains to be elucidated.
T1427 709612-709711 Epistemic_statement denotes The cytotoxic effects of the MG patient sera do not appear to be due to the induction of apoptosis.
T1428 709925-710417 Epistemic_statement 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.
T1429 710747-710859 Epistemic_statement denotes It is suggested that AChE autoimmune should be another important reason resulting in MG but plays no role in GD.
T1430 710860-710895 Epistemic_statement denotes Tg autoimmune may be ignored in MG.
T1431 711266-711389 Epistemic_statement denotes The involvement of the complement system should theoretically cause consumption of complement components such as C3 and C4.
T1432 712444-712572 Epistemic_statement denotes This study does not exclude, however, the role of complement activation in the pathophysiology of other muscle antibodies in MG.
T1433 712573-712902 Epistemic_statement denotes Modulation of antigen specific responses against AChR by recombinant erythropoietin F. Ubiali a , S. Nava a , C. Antozzi a , P. Ghezzi b , C. Cappelletti a , F. Cornelio a , R. Mantegazza a and F. Baggi a a National Neurological Institute C. Besta, Milan, Italy; b Mario Negri Institute for Pharmacological Research, Milan, Italy
T1434 712903-713122 Epistemic_statement 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.
T1435 713123-713291 Epistemic_statement 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.
T1436 714332-714437 Epistemic_statement denotes These results suggest that rEPO might be implicated in the regulation of the autoimmune response to AChR.
T1437 714854-715073 Epistemic_statement 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.
T1438 715167-715335 Epistemic_statement 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.
T1439 716688-716902 Epistemic_statement 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.
T1440 718237-718347 Epistemic_statement denotes In this population-based study, the prevalence of anti-MuSK(+) MG is lower than suggested by previous reports.
T1441 718348-718542 Epistemic_statement denotes Analysis of LIF, IL-6, TGF-beta1 and oncostatin M in myasthenic thymuses E. Arnoldi, P. Bernasconi, F. Baggi, F. Cornelio and R. Mantegazza National Neurological Institute C. Besta, Milan, Italy
T1442 718543-718682 Epistemic_statement 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.
T1443 719418-719554 Epistemic_statement denotes These data suggest that the expression of the analyzed cytokines might be related to the presence of intrathymic cellular proliferation.
T1444 719555-719645 Epistemic_statement denotes A correlation between cytokine levels and serum anti-AChR antibody titers was not evident.
T1445 720766-720907 Epistemic_statement denotes Conclusions: The causal relationship between administration of Botulinum toxin and development of myasthenic syndrome warrants consideration.
T1446 720908-721099 Epistemic_statement 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.
T1447 721100-721161 Epistemic_statement denotes The response to treatment with immunoglobulin was remarkable.
T1448 722746-722858 Epistemic_statement denotes Paraneoplastic Neurological Syndromes (PNS) are immune-mediated, nonmetastatic disorders associated with cancer.
T1449 722944-723034 Epistemic_statement denotes The role of antineuronal antibodies is uncertain but they are important for the diagnosis.
T1450 723035-723132 Epistemic_statement denotes Myasthenia gravis (MG) is an autoimmune neuromuscular disorder sometimes associated with thymoma.
T1451 723133-723187 Epistemic_statement denotes Combination of MG with Hodgkin's Disease (HD) is rare.
T1452 723826-723979 Epistemic_statement denotes Combination of seropositive MG, thymic atrophy and HD may suggest that myasthenic symptoms could be triggered by immunological alterations underlying HD.
T1453 723980-724213 Epistemic_statement 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.
T1454 725193-725291 Epistemic_statement denotes Affected family members were linked to the NT-LEMS patient through the maternal line in all cases.
T1455 725425-725501 Epistemic_statement denotes This suggests that NT-LEMS shares immunological risk factors with other AID.
T1456 725502-725692 Epistemic_statement 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.
T1457 727269-727404 Epistemic_statement denotes Hence, it can be the preferred method of performing plasma exchange in patients with myasthenia gravis to induce remission of symptoms.
T1458 730392-730531 Epistemic_statement denotes However, there are few studies of its optimum use and neurologists often see patients on subtherapeutic doses or with drug adverse effects.
T1459 731036-731226 Epistemic_statement denotes Results: These are preliminary results from 18 patients: 7 ocular MG (oMG; average 1.6 symptoms), 6 oculobulbar MG (obMG; average 3.7 symptoms), 5 generalised MG (gMG; average 3.4 symptoms).
T1460 732309-732376 Epistemic_statement denotes They often present with bulbar weakness and are difficult to treat.
T1461 733404-733578 Epistemic_statement denotes Conclusion: 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.
T1462 733579-733627 Epistemic_statement denotes Thymectomy did not seem to benefit all patients.
T1463 734458-734590 Epistemic_statement denotes We propose that the IvIg should be considered in myasthenic patients whose ocular symptoms do not respond to conventional therapies.
T1464 734591-734723 Epistemic_statement denotes Future studies may disclose whether all patients with ocular symptoms or only a subset of patients dramatically respond to the IvIg.
T1465 735675-735907 Epistemic_statement 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.
T1466 735908-736052 Epistemic_statement denotes Our data indicate that monocytes synthesise basal levels of NGF but, after LPS stimulation, upregulate NGF expression in dose-dependent fashion.
T1467 736205-736404 Epistemic_statement 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.
T1468 736405-736681 Epistemic_statement 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.
T1469 736972-737037 Epistemic_statement denotes Immature DC may induce tolerance while mature DC induce immunity.
T1470 737125-737254 Epistemic_statement denotes We explored potential of IL-10-modulated-DCbased immunotherapy in experimental autoimmune myasthenia gravis (EAMG) in Lewis rats.
T1471 738010-738212 Epistemic_statement 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.
T1472 738351-738659 Epistemic_statement denotes Mancardi b and F. 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.
T1473 739721-739991 Epistemic_statement 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.
T1474 739992-740159 Epistemic_statement 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.
T1475 740335-740485 Epistemic_statement denotes We report here that Staphylococcus aureus PGN as a single component can replace whole Mycobacterium tuberculosis in Freund's complete adjuvant in EAE.
T1476 740916-741078 Epistemic_statement denotes These data indicate that PGN-mediated interactions result in pro-inflammatory stimulation of antigen specific effector functions important for development of EAE.
T1477 741079-741223 Epistemic_statement 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.
T1478 741224-741307 Epistemic_statement denotes As such, PGN signaling pathways may serve as novel targets for the treatment of MS.
T1479 741308-741439 Epistemic_statement denotes Dendritic cells (DC) are the key regulators of tolerance and immunity to the self-antigens that they sample and present to T cells.
T1480 741864-741999 Epistemic_statement denotes As essentially all extracellular proteins are glycosylated, it can be envisaged that self glycoproteins can maintain tolerance to self.
T1481 742054-742212 Epistemic_statement 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.
T1482 742312-742441 Epistemic_statement denotes We will discuss new data from nonhuman primate models of experimental autoimmune encephalomyelitis which support this hypothesis.
T1483 743391-743633 Epistemic_statement 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.
T1484 744709-744905 Epistemic_statement 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.
T1485 745185-745412 Epistemic_statement 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.
T1486 745567-745722 Epistemic_statement denotes MMPs may contribute to demyelination by cleaving myelin proteins, and consequently propagate the immune response by generating new immunodominant epitopes.
T1487 745723-745894 Epistemic_statement 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.
T1488 746303-746471 Epistemic_statement denotes By immunohistochemistry, MMP-12 could be detected in active MS lesions, predominantly expressed by CD68+ cells, indicative of macrophages and activated microglia cells.
T1489 746582-746805 Epistemic_statement 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.
T1490 747150-747341 Epistemic_statement 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.
T1491 747687-748251 Epistemic_statement 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.
T1492 748252-748366 Epistemic_statement denotes DTC are likely to be public clones, present in each individual, and they are also usually Th1 in cytokine pattern.
T1493 748947-749114 Epistemic_statement 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.
T1494 749330-749509 Epistemic_statement 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.
T1495 749687-749778 Epistemic_statement denotes Surprisingly, these mice are fully susceptible to develop EAE induced by adoptive transfer.
T1496 751647-751773 Epistemic_statement denotes The observed abnormalities in ex vivo phenotype and maturation process may contribute to the immunoregulatory imbalance in MS.
T1497 751774-752233 Epistemic_statement denotes Serum of patients with multiple sclerosis induce activation of antigen presenting cells A. Karni a , D. Azulai a , A. Korczyn a and H. 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: To study the effect of serum from patients with multiple sclerosis (MS) on activation of antigen presenting cells (APCs).
T1498 753521-753572 Epistemic_statement denotes Serum IFN-gamma appears to be one of these factors.
T1499 753573-753669 Epistemic_statement denotes This serum effect may provide a proinflammatory signal via APCs for myelin autoreactive T cells.
T1500 753670-754055 Epistemic_statement denotes CNS microvascular pericyte polarization to alternatively activated phenotypes P. Dore-Duffy a , R. Balabanov b and J. 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.
T1501 754056-754140 Epistemic_statement denotes We have previously shown that rat primary capillary pericytes have immune potential.
T1502 754240-754404 Epistemic_statement denotes Pericytes may therefore function as a CNS antigen presenting cell (APC) and undergo TH1 or TH2-like polarization associated with alternatively activated phenotypes.
T1503 754405-754473 Epistemic_statement denotes To test this hypothesis, we examined freshly isolated rat pericytes.
T1504 755153-755268 Epistemic_statement denotes These data suggest that pericytes have multiple states of activation/differentiation comparable to traditional APC.
T1505 755269-755343 Epistemic_statement denotes It is likely that pericyte APC have an important role in CNS inflammation.
T1506 755650-755772 Epistemic_statement denotes Here we show that the hemoglobinhaptoglobin scavenger receptor, CD163, can be used as a marker for PVM in the human brain.
T1507 755773-756006 Epistemic_statement 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.
T1508 756148-756321 Epistemic_statement 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.
T1509 756322-756436 Epistemic_statement denotes Further studies are required to establish which immune regulatory role these cells exert upon antigen recognition.
T1510 756727-757160 Epistemic_statement denotes It has been shown that brain-derived myelin components are present in antigen presenting cells (APC) within the CLN during MS. We hypothesize that these APC play an important role in regulating the peripheral immune system during MS. 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.
T1511 757595-757679 Epistemic_statement denotes Preliminary data demonstrate that pulsed macrophages increased T cell proliferation.
T1512 757680-757799 Epistemic_statement denotes In addition, IFN-gamma production by T cells paralleled T cell proliferation, suggesting enhanced antigen presentation.
T1513 757800-757904 Epistemic_statement denotes Our data suggest that phagocytic APC in CLN may display regulatory functions in the periphery during MS.
T1514 757905-758101 Epistemic_statement 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.
T1515 758298-758407 Epistemic_statement denotes It has been observed that dendritic cells (DC) can prime CD25+CD4+ T cells to acquire suppressive properties.
T1516 758408-758755 Epistemic_statement 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.
T1517 758756-758932 Epistemic_statement 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.
T1518 759149-759324 Epistemic_statement 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.
T1519 759447-759548 Epistemic_statement denotes Fischer a a Heinrich-Heine-University, Düsseldorf, Germany; b University Mannheim-Heidelberg, Germany
T1520 759549-759687 Epistemic_statement denotes It is generally accepted that DC are lacking in the normal brain, however, DC appear at intracerebral sites under inflammatory conditions.
T1521 759998-760384 Epistemic_statement 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.
T1522 760746-760888 Epistemic_statement denotes Since an inflammatory neural environment is a likely source of both stimuli, microglia must be regarded as an organotypic reservoir of pre-DC.
T1523 762032-762244 Epistemic_statement 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.
T1524 762310-762405 Epistemic_statement denotes Inflammation of the CNS is usually locally limited to avoid otherwise devastating consequences.
T1525 763622-763845 Epistemic_statement 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.
T1526 764373-764474 Epistemic_statement denotes Recent studies suggest that proteasomes play an important role in leukocyte-endothelial interactions.
T1527 765294-765538 Epistemic_statement 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.
T1528 766007-766105 Epistemic_statement denotes This will allow subsequent functional studies in rat models of autoimmune and infectious diseases.
T1529 766943-767018 Epistemic_statement denotes Based on these studies, we could define a peptide binding motif for RT1.Da.
T1530 767019-767137 Epistemic_statement denotes The peptide motif of RT1.Da will allow epitope predictions for analysis of peptides, relevant for autoimmune diseases.
T1531 768756-768911 Epistemic_statement denotes In conclusion, the most obvious autoimmunizing cells appear to be IFN-alpha+ macrophages rather than TEC, but unusual dendritic subsets cannot be excluded.
T1532 770671-770799 Epistemic_statement denotes Recent data indicate that ICOS and ICOS-L represent an important pathway in the regulation of autoimmune or infectious diseases.
T1533 771654-771922 Epistemic_statement denotes Schwann cells were negative for ICOS-L. 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.
T1534 772337-772457 Epistemic_statement denotes Its etiology is not understood but appears to involve both genetic and environmental factors including viral infections.
T1535 772665-772838 Epistemic_statement 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.
T1536 773185-773318 Epistemic_statement denotes ENV-SU also induced dendritic cell maturation and conferred them the capacity to support a T helper 1 type of T cell differentiation.
T1537 773319-773747 Epistemic_statement 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. Encephalitogenic and beneficial roles of amyloid beta-specific T cells in Alzheimer's disease A. Monsonego a , V. Zota a , S. Petrovic a , J. Imitola a , T. Owens b , D. Selkoe a and H.L.
T1538 774985-775137 Epistemic_statement 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.
T1539 775227-775369 Epistemic_statement 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.
T1540 776158-776302 Epistemic_statement denotes Preliminary studies performed with a confocal laser scanning microscope revealed a close contact between CD8+ cells and CMV infected astrocytes.
T1541 776408-776543 Epistemic_statement denotes These results indicate that especially during the early stage of disease, GrB-mediated cytotoxicity is important in viral encephalitis.
T1542 776988-777052 Epistemic_statement denotes The mechanism of axonal degeneration, however, is not yet known.
T1543 777153-777284 Epistemic_statement denotes Therefore, we investigated whether autoimmune responses against axonal proteins develop in EAE and correlate with clinical disease.
T1544 777285-777433 Epistemic_statement denotes In addition, we studied the encephalitogenic potential of neuronal antigens, derived from newborn spinal cord in which myelination is just starting.
T1545 777842-777929 Epistemic_statement denotes Antibody levels, however, did not correlate necessarily with disease stage or severity.
T1546 777930-778078 Epistemic_statement denotes Neurofilament staining was observed in cervical lymph nodes of mice with EAE, indicating that neuronal antigens can be presented in the lymph nodes.
T1547 778079-778206 Epistemic_statement denotes Although newborn SCH-immunisation induced T-cell and antibody responses to SCH and neurofilaments, animals did not develop EAE.
T1548 778207-778346 Epistemic_statement denotes Conclusions: Our data indicate that both T-cell and antibody responses against neurofilaments develop during chronic relapsing EAE in mice.
T1549 778347-778426 Epistemic_statement denotes However neuronal antigens, as in newborn SCH, was not encephalitogenic in mice.
T1550 778427-778477 Epistemic_statement denotes The relevance of these findings will be discussed.
T1551 779679-779828 Epistemic_statement denotes Modulation of cerebral inflammation by mucosal tolerance to myelin antigens may improve outcome after stroke and enhance mechanisms of self-recovery.
T1552 779829-780176 Epistemic_statement denotes T helper cells type 2 stimulate axonal outgrowth and attract cortical axons S. Müller-Röver, S. Sallach, C. Brandt, D. Lqdecke, D. Schwanzar, E. Kwidzinski, B. Heimrich and R. Nitsch Charité University Hospital, Berlin, Germany After mechanical lesions of the nervous system, activated T cells have been suggested to exert neuroprotective effects.
T1553 780177-780237 Epistemic_statement denotes However, the structural basis of these effects is not clear.
T1554 780238-780323 Epistemic_statement denotes Stimulation of axonal outgrowth by T cells might be a key mechanism for regeneration.
T1555 780627-780796 Epistemic_statement denotes Since T helper cell subtypes might exert neuroregenerative effects by secreting neurotrophins, we analyzed their neurotrophin expression patterns using RT-PCR and ELISA.
T1556 781125-781246 Epistemic_statement denotes Both subtypes expressed mRNA of all investigated factors except IFNgamma mRNA expression, which was limited to TH1 cells.
T1557 781525-781684 Epistemic_statement denotes These data suggest that one important structural element of bprotective autoimmunityQ is the stimulation of neurotrophin-dependent axon outgrowth by Th2 cells.
T1558 781685-781751 Epistemic_statement denotes The etiology of neurodegenerative disorders is at present unknown.
T1559 781752-781874 Epistemic_statement denotes Although a small percentage of these disorders are familial cases linked to specific genetic defects, most are idiopathic.
T1560 781875-781987 Epistemic_statement denotes Thus environmental factors are thought to play an important role in the onset and progression of such disorders.
T1561 782690-782813 Epistemic_statement denotes These data indicate that components of inhaled particulate matter may trigger a proinflammatory response in nervous tissue.
T1562 782814-783028 Epistemic_statement 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.
T1563 783197-783268 Epistemic_statement denotes Pick, Y. Shoenfeld and J. Chapman Tel Aviv University, Tel Aviv, Israel
T1564 783269-783466 Epistemic_statement 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.
T1565 783467-783643 Epistemic_statement 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).
T1566 784471-784540 Epistemic_statement denotes Similar mechanisms may be involved in patients with APS and dementia.
T1567 784541-784819 Epistemic_statement denotes The LPS receptor CD14 links Alzheimer's disease with innate immunity K. 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.
T1568 785175-785345 Epistemic_statement 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.
T1569 785346-785484 Epistemic_statement denotes Thus, CD14 mediated microglial activation by amyloid peptide may explain chronic neuroinflammation and subsequent neurodegeneration in AD.
T1570 785485-785657 Epistemic_statement denotes We hypothesize that a structural mimicry between amyloid fibrils and microbial components may underlie the mechanism of chronic neuroinflammation mediated by CD14 ligation.
T1571 785658-785779 Epistemic_statement denotes The lipopolysaccharide receptor, CD14, may, thus represent a novel therapeutic target in prevention of progression of AD.
T1572 786555-786854 Epistemic_statement 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.
T1573 787455-787677 Epistemic_statement 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.
T1574 787678-787886 Epistemic_statement 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.
T1575 788353-788447 Epistemic_statement denotes In parallel, congenic strains are being bred to allow for mechanistic studies in other models.
T1576 788617-789009 Epistemic_statement 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.
T1577 789010-789185 Epistemic_statement 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.
T1578 789703-789789 Epistemic_statement denotes In addition, a general neuroprotective reaction against oxidative stress is suggested.
T1579 789790-790059 Epistemic_statement denotes These molecular changes might reflect an adaptation of cells to the chronic progressive pathophysiology of MS. Alternatively, they might also indicate the activation of neural protective mechanisms allowing preservation of cellular and functional properties of the CNS.
T1580 790202-790405 Epistemic_statement 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.
T1581 790406-790474 Epistemic_statement denotes Heavy metals and free radicals have been related to MS pathogenesis.
T1582 792419-792573 Epistemic_statement 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.
T1583 792927-793083 Epistemic_statement 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.
T1584 793188-793324 Epistemic_statement denotes Neuroinflammatory conditions may disrupt the normal function of adrenomedullin (ADM) at the blood-brain barrier (BBB) E. Liverani a , A.
T1585 793325-793526 Epistemic_statement denotes Woods a , C. Bolton b and C. 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.
T1586 794001-794376 Epistemic_statement 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. 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.
T1587 794377-794520 Epistemic_statement denotes Our preliminary immunocytochemistry studies indicate that receptor-activity modifying protein-2 (RAMP-2) is normally expressed on ECV304 cells.
T1588 794521-794616 Epistemic_statement denotes However, on exposure to 0.1 mM glutamate, RAMP-2 expression is significantly reduced ( pb0.05).
T1589 794799-794888 Epistemic_statement denotes The data suggests that glutamate affects endothelial expression of ADM receptor proteins.
T1590 794889-795007 Epistemic_statement denotes Furthermore, the results indicate that steroidal compounds can influence ADM control of neuroendothelial permeability.
T1591 795008-795100 Epistemic_statement denotes The role of inflammation in central nervous system (CNS) damage and repair is controversial.
T1592 795308-795438 Epistemic_statement denotes Thus, controlled boosting of protective immunity is proposed as a means of attenuating neurodegeneration and facilitating healing.
T1593 796657-796798 Epistemic_statement denotes We propose that this phenotype promotes an immune response that supports neuronal cell survival and repair, resulting in functional recovery.
T1594 796799-797114 Epistemic_statement denotes Effect of inflammatory mediators on axonal transport of synaptic vesicle proteins M. Stagi, N. Frank and H. 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.
T1595 798321-798574 Epistemic_statement 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.
T1596 798694-799019 Epistemic_statement 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.
T1597 799302-799534 Epistemic_statement 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.
T1598 799535-799682 Epistemic_statement 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.
T1599 799765-799990 Epistemic_statement 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.
T1600 800717-800843 Epistemic_statement denotes Glutamate is known to trigger the production of nitric oxide and superoxide, which can lead to the formation of peroxynitrite.
T1601 800844-800939 Epistemic_statement denotes Recent studies have implicated peroxynitrite in the loss of neurovascular integrity during EAE.
T1602 800940-801032 Epistemic_statement denotes We propose that glutamate contributes to BBB breakdown through the actions of peroxynitrite.
T1603 801033-801169 Epistemic_statement denotes The current study aims to determine whether glutamate induces peroxynitrite formation in a brain-derived endothelial cell line (b.End3).
T1604 802472-802568 Epistemic_statement denotes However, degeneration of Purkinje cells has also been described (Scherini and Bernocchi, 1994) .
T1605 802569-802765 Epistemic_statement 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.
T1606 803709-803819 Epistemic_statement denotes Potapenko Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
T1607 803820-803900 Epistemic_statement denotes The function of Na,K-ATPase in the brain is poorly studied and least understood.
T1608 804182-804364 Epistemic_statement 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.
T1609 804714-804983 Epistemic_statement 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.
T1610 804984-805078 Epistemic_statement denotes It should be noted that dysfunction of Na,K-ATPase leads to set of neurodegenerative diseases.
T1611 805137-805343 Epistemic_statement 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.
T1612 806531-806853 Epistemic_statement denotes Identification of signaling pathways associated with rat strain-dependent susceptibility to nerve injury by microarray-based expression profiling M. Swanberg, K. Duvefelt, J. Hillert, T. Olsson, F. Piehl and O. Lidman Karolinska Institute, Stockholm, Sweden Axonal damage is a common feature of many neurological diseases.
T1613 806854-807045 Epistemic_statement 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.
T1614 807046-807124 Epistemic_statement denotes It is not known to what extent the genetic background influences the response.
T1615 807627-807861 Epistemic_statement 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.
T1616 808014-808210 Epistemic_statement 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.
T1617 808437-808658 Epistemic_statement denotes 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.
T1618 808659-808818 Epistemic_statement denotes Recent evidence also indicates that aging is characterized by low-grade chronic inflammatory activity, with increased production of pro-inflammatory cytokines.
T1619 810258-810624 Epistemic_statement 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.
T1620 811796-811939 Epistemic_statement denotes These mechanisms could conditionate the overexpression of neurotoxic cytokines, also inducing an impairment of neuroprotection induced by VEGF.
T1621 812251-812398 Epistemic_statement 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.
T1622 812399-812624 Epistemic_statement 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.
T1623 812832-813032 Epistemic_statement 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.
T1624 813033-813221 Epistemic_statement 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.
T1625 813490-813760 Epistemic_statement 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).
T1626 815313-815507 Epistemic_statement 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.
T1627 815508-815710 Epistemic_statement 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.
T1628 815987-816118 Epistemic_statement denotes Consequently, microglial cells and oligodendrocytes can be considered as the predominant cell types involved in PLOSL pathogenesis.
T1629 816119-816259 Epistemic_statement denotes The myeloid origin of both microglial cells and osteoclasts provides a biological link between the CNS and bone pathology in PLOSL patients.
T1630 816627-816783 Epistemic_statement 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.
T1631 816974-817090 Epistemic_statement denotes In this study, we have focused whether these two chemokines systems are involved in stressinduced neurodegeneration.
T1632 817434-817516 Epistemic_statement denotes However, upregulated CXCR4 levels were found in the cerebellum and olfactory bulb.
T1633 817517-817666 Epistemic_statement denotes Interestingly, SDF was significantly increased in the hypothalamus and olfactory bulb whereas fractalkine was only upregulated in the olfactory bulb.
T1634 817667-817756 Epistemic_statement denotes Control groups showed a high negative correlation between SDF and hippocampal Bax levels.
T1635 817757-817890 Epistemic_statement denotes All together, these data suggest that hippocampal SDF 1 decreased levels might reduce neuroprotection under chronic restraint stress.
T1636 818411-818550 Epistemic_statement denotes The mechanisms of amyloid-beta (Abeta)-mediated neurotoxicity are unknown but it has been suggested that oxidative stress plays a key role.
T1637 818551-818698 Epistemic_statement 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.
T1638 818866-818999 Epistemic_statement denotes The reactive oxygen species (ROS) can cause great damage by lipid peroxidation and oxidation of proteins that may lead to cell death.
T1639 819000-819190 Epistemic_statement 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.
T1640 819409-819499 Epistemic_statement denotes Parkinson's disease (PD) is an age-related neurodegenerative disorder of unknown etiology.
T1641 820597-820830 Epistemic_statement 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.
T1642 822382-822510 Epistemic_statement denotes Extraintestinal organs, such as cerebellum, might be the unique target of this disease as occurs in gluten ataxia (GA) syndrome.
T1643 823374-823392 Epistemic_statement denotes RHS was suggested.
T1644 823521-823636 Epistemic_statement denotes RHS has been previously reported with coeliac disease, but never with GA, considered a mild and monophasic disease.
T1645 823637-823734 Epistemic_statement denotes We report an association between AGA and RHS, and between clinical severity of RHS and AGA titer.
T1646 824023-824243 Epistemic_statement denotes Armati a and K. Sheikh b a The University of Sydney, Sydney, Australia; b John Hopkins University, Baltimore, Maryland, USA Objective: To determine whether anti-GM1 and anti-GD1a antibodies directly mediate nerve injury.
T1647 824496-824675 Epistemic_statement 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.
T1648 824676-824809 Epistemic_statement denotes Until recently, attempts to develop animal models of anti-ganglioside antibody mediated nerve injury have given inconsistent results.
T1649 825080-825311 Epistemic_statement 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.
T1650 825558-825647 Epistemic_statement denotes Conclusion: These findings suggest that anti-GM1 and antiGD1a do cause nerve dysfunction.
T1651 825648-825735 Epistemic_statement denotes Whether this is via axonal degeneration or conduction failure remains to be determined.
T1652 826046-826127 Epistemic_statement denotes The mechanisms implicated and the participation of the immune system are unknown.
T1653 827103-827221 Epistemic_statement denotes We propose that mast cells, lymphocytes and immunoglobulins participate in the Buckthorn polyneuropathy demyelination.
T1654 827222-827314 Epistemic_statement denotes Our model can be useful for pathogenic mechanism studies in this and other polyneuropathies.
T1655 827340-827500 Epistemic_statement 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.
T1656 828129-828208 Epistemic_statement denotes The expressions in the sensory ganglions correlated partly with these findings.
T1657 828704-828826 Epistemic_statement denotes The noted strong expression of TGF-beta1 could be related to its property to increase axonal growth or to induce fibrosis.
T1658 828827-829227 Epistemic_statement denotes Effect of nordihydroguairetic acid on thermal hyperalgesia and cold allodynia in STZ-induced diabetic rats and mice M. Anjaneyulu and K. 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.
T1659 830317-830583 Epistemic_statement 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.
T1660 831175-831341 Epistemic_statement 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.
T1661 831457-831664 Epistemic_statement 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.
T1662 831665-831919 Epistemic_statement 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.
T1663 831920-832037 Epistemic_statement denotes In contrast, CD4+ TILs lacking CD25 expression are notable for their secretion of IFN-gamma and the absence of IL-10.
T1664 832038-832206 Epistemic_statement 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.
T1665 832207-832404 Epistemic_statement 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.
T1666 832405-832651 Epistemic_statement 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.
T1667 832652-832832 Epistemic_statement 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.
T1668 833481-833713 Epistemic_statement 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).
T1669 834617-834723 Epistemic_statement denotes No correlation or discernable pattern could be observed from proliferation and lymphocyte subset analyses.
T1670 834916-835009 Epistemic_statement denotes Detectable levels of IL-10 were observed displaying a weak association with shorter survival.
T1671 835010-835128 Epistemic_statement denotes Lymphocyte cytokine production correlated with lymphocyte infiltration but not DTH reactions at the immunization site.
T1672 838010-838148 Epistemic_statement 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.
T1673 838149-838335 Epistemic_statement 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.
T1674 839185-839329 Epistemic_statement denotes It is also possible, however, that the implantation of murine fibroblast-derived virusproducing cells may induce an immune response in patients.
T1675 840004-840202 Epistemic_statement 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.
T1676 840203-840442 Epistemic_statement denotes Delivery of interleukin 4 to experimental gliomas by viral vectors and neural stem-progenitor cells P. Tunici and G. Finocchiaro Laboratory of Experimental Neuro-Oncology and Gene Therapy, Istituto Nazionale Neurologico Besta, Milan, Italy
T1677 840443-840783 Epistemic_statement 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.
T1678 840784-841018 Epistemic_statement 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.
T1679 841019-841195 Epistemic_statement 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).
T1680 841680-841754 Epistemic_statement denotes This effect, however, decreased if more GBM cells (5Â10 4 ) were injected.
T1681 841854-842036 Epistemic_statement 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.
T1682 842037-842126 Epistemic_statement denotes Cancers can be partially attributed to defects in the regulation of apoptotic cell death.
T1683 843126-843290 Epistemic_statement denotes Interestingly, taurolidine suppressed the constitutive VEGF production of glioma cells displaying thus an antiangiogenic effect besides its antineoplastic activity.
T1684 843505-843716 Epistemic_statement 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.
T1685 843717-843832 Epistemic_statement denotes Multifunctional fusion cytokines for breaking cancer-induced immune anergy S. Paul Transgene SA, Strasbourg, France
T1686 843833-844046 Epistemic_statement 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.
T1687 844252-844461 Epistemic_statement 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.
T1688 844462-844603 Epistemic_statement denotes Previous work has shown that cytokine immune effectors can enhance host's immunity, and thus overcome a tumor-induced state of immune anergy.
T1689 844914-845128 Epistemic_statement 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.
T1690 845129-845262 Epistemic_statement denotes The antitumoral effect of IL-2/IL-18 murine fusokine is correlated with the activation of both CTLs, NK and antigen presenting cells.
T1691 845263-845447 Epistemic_statement denotes Microglia and gliomas may have a symbiotic relationship M. Graeber a and A. Flqgel b a Imperial College London, London, UK; b Max-Planck-Institute of Neurobiology, Martinsried, Germany
T1692 845448-845550 Epistemic_statement denotes The number of microglial glial cells/brain macrophages in malignant astrocytomas is surprisingly high.
T1693 845551-845692 Epistemic_statement denotes Based on in vitro findings, it has been speculated that brain macrophages derived from microglial cells may exert tumour cytotoxic functions.
T1694 845693-845816 Epistemic_statement denotes However, the biological bsuccessQ of malignant astrocytomas strongly suggests that this potential is not exploited in vivo.
T1695 846383-846704 Epistemic_statement 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.
T1696 846777-846912 Epistemic_statement denotes Symbiosis between microglia and a glial tumour seems a distinct possibility as gliomas are known to stimulate microglial proliferation.
T1697 847319-847424 Epistemic_statement denotes The aim of this work was to investigate the relationship between VEGF and IL-10 in brain tumour patients.
T1698 848193-848331 Epistemic_statement denotes There is a trend towards higher serum VEGF levels with advancing tumour grade, with the highest levels being seen in the metastatic group.
T1699 848429-848483 Epistemic_statement denotes There was no association between serum VEGF and IL-10.
T1700 849822-849937 Epistemic_statement denotes The significance of such increases in cytokine levels will require further analysis in a larger series of patients.
T1701 849938-850369 Epistemic_statement 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. Wintterle a , B. Schreiner a , M. Mitsdoerffer a , D. Schneider a , L. Chen b , R. Meyermann a , M. Weller a and H. 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.
T1702 851456-851648 Epistemic_statement 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.
T1703 851807-851966 Epistemic_statement denotes Recent studies suggest that microglia accumulation in glial tumors may reflect participation of these cells in supporting and promoting the invasive phenotype.
T1704 851967-852047 Epistemic_statement denotes Mutual interactions between microglia and glioma cells are not well established.
T1705 852584-852656 Epistemic_statement denotes However, a significant activation of Akt signaling pathway was observed.
T1706 852993-853150 Epistemic_statement denotes Our results suggest that glioma cells may activate microglial cells that further exert an activatory effect on glioma cells contributing to glioma pathology.
T1707 853517-853649 Epistemic_statement denotes In case of brain tumours, new therapies are desperately needed due to poor prognosis of patients and failure of classical therapies.
T1708 853650-853805 Epistemic_statement denotes Microglia represent a potential, though poorly exploited arm of defense which antitumour activity could be triggered by tumour-targeted gene immunotherapy.
T1709 853806-854094 Epistemic_statement 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.
T1710 854461-854643 Epistemic_statement 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.
T1711 854644-854871 Epistemic_statement 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.
T1712 855783-856021 Epistemic_statement 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.
T1713 856445-856625 Epistemic_statement 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.
T1714 856744-856940 Epistemic_statement 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.
T1715 856941-857170 Epistemic_statement 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.
T1716 857246-857431 Epistemic_statement 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.
T1717 857556-857698 Epistemic_statement denotes Ransohoff Cleveland Clinic Foundation, Cleveland, OH, USA It is unclear how immune cells traffic between the lymphoid compartment and the CNS.
T1718 858492-858767 Epistemic_statement 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.
T1719 858937-859088 Epistemic_statement 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.
T1720 859089-859168 Epistemic_statement denotes The nature of CCR7+ myeloid cells in the CNS parenchyma is under investigation.
T1721 859537-859678 Epistemic_statement denotes Viral infections often precede exacerbations, and hence infectious agents have been considered as triggers, although their nature is unknown.
T1722 859679-859822 Epistemic_statement denotes Molecular mimicry provides an elegant framework as to how similarities between foreign agents and autoantigens can trigger autoimmune diseases.
T1723 859823-860063 Epistemic_statement 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.
T1724 860272-860528 Epistemic_statement 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.
T1725 860693-860822 Epistemic_statement denotes Interestingly, two out of five TCC recognized multiple peptides from related organisms, mainly human herpes viruses and TT-virus.
T1726 860823-860923 Epistemic_statement denotes Our data strongly indicate that ubiquitous viral agents can activate CSF-infiltrating T cells in MS.
T1727 862315-862476 Epistemic_statement denotes Interactions between complement, immunoglobulins (IgG) and IgGreceptors (FcgammaR) could contribute to inflammation and demyelination in multiple sclerosis (MS).
T1728 862600-862677 Epistemic_statement denotes Expression of FcgammaR in active lesions has been described in another study.
T1729 863575-863743 Epistemic_statement 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.
T1730 863744-863910 Epistemic_statement denotes This suggests that the presence of complement in macrophages is associated with active demyelination, whereas expression of FcgammaRs is associated with inflammation.
T1731 864021-864384 Epistemic_statement denotes New antigenic candidates in multiple sclerosis: identification by serological proteome analysis D. Lefranc a , L. Almeras a , H. Drobecq b , J. de Seze c , S. Dubucquoi a , P. Vermersch c and L. 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
T1732 864385-864516 Epistemic_statement denotes Myelin antigen targets that are clearly associated with pathogenic events in multiple sclerosis (MS) patients remain to be defined.
T1733 864974-865077 Epistemic_statement denotes The aim of our study was to characterize the 26 discriminant antigenic bands detected on healthy brain.
T1734 865604-865807 Epistemic_statement 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.
T1735 865921-866058 Epistemic_statement denotes Disease mechanisms in MS at the molecular level remain poorly understood and no reliable proteinaceous disease markers are available yet.
T1736 866059-866177 Epistemic_statement denotes The goal of the present study is the construction of a protein database of cerebrospinal fluid (CSF) from MS patients.
T1737 866360-866484 Epistemic_statement denotes CSF is a secretion product of several CNS structures and its protein profile can be affected by several diseases of the CNS.
T1738 866485-866578 Epistemic_statement denotes Proteomic analysis of CSF could provide more insight into the pathogenesis of these diseases.
T1739 866974-867037 Epistemic_statement denotes However, some of these proteins have not been described so far.
T1740 867038-867150 Epistemic_statement denotes Further investigation will provide additional information on whether they are implicated in the MS pathogenesis.
T1741 867151-867250 Epistemic_statement denotes The constructed CSF database will be used in our future study on differentially expressed proteins.
T1742 867357-867878 Epistemic_statement denotes The role of the HLA-DR2 haplotype in multiple sclerosis K. Kawamura a , L. Fugger b and T. 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.
T1743 867879-868109 Epistemic_statement 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.
T1744 868110-868261 Epistemic_statement denotes Indeed, T cell responses to myelin antigens are readily detectable in MS patients, indicating that self-tolerance or regulatory mechanisms have failed.
T1745 868810-869024 Epistemic_statement 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.
T1746 869176-869351 Epistemic_statement 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.
T1747 869352-869455 Epistemic_statement denotes However, microarrays are subjected to many variables that complicate the interpretation of the results.
T1748 870554-870694 Epistemic_statement denotes Stuerzebecher b , F. Zipp a and C. Infante-Duarte a a Institute of Neuroimmunology, Charité, Berlin, Germany; b Schering AG, Berlin, Germany
T1749 870695-870886 Epistemic_statement 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.
T1750 870887-871225 Epistemic_statement 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.
T1751 871897-872171 Epistemic_statement 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.
T1752 872172-872487 Epistemic_statement denotes Human endogenous retrovirus-W envelope abundance and infectivity in multiple sclerosis J. Antony a , M. Izad b , K. Zhang a , K. Warren c , M. Vodjgani b and C. Power a a University of Calgary, Calgary, AB, Canada; b Tehran University of Medical Sciences, Tehran, Iran; c University of Alberta, Edmonton, AB, Canada
T1753 872488-872618 Epistemic_statement denotes Human endogenous retroviruses (HERVs) constitute 8% of the human genome yet their role (s) in health and disease remain uncertain.
T1754 872619-872831 Epistemic_statement 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.
T1755 873231-873467 Epistemic_statement 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.
T1756 873615-873853 Epistemic_statement 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.
T1757 873985-874238 Epistemic_statement denotes C. Serra a , G. Mameli a , G. Arru b , V. Astone a , S. Sotgiu b and A. 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
T1758 874239-874370 Epistemic_statement denotes Multiple sclerosis (MS) has unknown etiology and debated, immunemediated pathogenesis, including genetic and environmental factors.
T1759 874371-874567 Epistemic_statement 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.
T1760 875446-875628 Epistemic_statement 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.
T1761 875629-875738 Epistemic_statement denotes Multiple sclerosis associated retrovirus (MSRV) seems to be the important candidate for viral etiology of MS.
T1762 875739-875819 Epistemic_statement denotes The aim of the study was to analyze MSRV pol sequences in MS and control groups.
T1763 876341-876472 Epistemic_statement denotes The pattern of fiber-FISH signals suggests the presence of multiple copies of MSRV pol sequences, tandemly dispersed in the genome.
T1764 876473-876664 Epistemic_statement 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.
T1765 876665-877007 Epistemic_statement 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. Clonally expanded CD8 populations have been identified in brain specimens, peripheral blood and the CSF of patients with MS.
T1766 877008-877140 Epistemic_statement denotes Although their antigen-specificity is unknown to date, genuine CNS autoantigen(s) or viral antigens are the most obvious candidates.
T1767 877141-877251 Epistemic_statement denotes Notably, disease onset and exacerbations have been correlated to concomitant viral infections, especially EBV.
T1768 877942-878073 Epistemic_statement denotes Overall, MS patients showed a significant downregulation of CD28 in EBVreactive CD8-cells suggesting a chronic in vivo stimulation.
T1769 878501-879021 Epistemic_statement 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. Piccio a , L. Battistini c , B. Rossi a , S. Bach a , L. Ottoboni a , E. Scarpini b , G. Borsellino c and G. 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).
T1770 879679-879808 Epistemic_statement denotes Moreover, vascular cell adhesion molecule-1 (VCAM-1), but not PSGL-1, is critical for the adhesion of CD4 cells from MS patients.
T1771 879809-879940 Epistemic_statement denotes FACS analysis and functional data indicate that a large fraction of CD8 cells from MS patients display a memory-effector phenotype.
T1772 880422-880692 Epistemic_statement denotes Effects of IFN beta M. Giorelli, P. Livrea and M. Trojano Department of Neurological and Psychiatric Sciences, University of Bari, Bari, Italy Objective: To assess whether the dopamine network of lymphocytes is involved in the pathophysiology of Multiple Sclerosis (MS).
T1773 883360-883530 Epistemic_statement denotes et al., Neurology, 2004; 62: 60) , our results suggest that effects of VitD on reducing the proinflammatory activity of gamma-delta T cells may contribute to this effect.
T1774 884253-884376 Epistemic_statement denotes Class II HLA alleles carried by the patients are linked to the autoimmune disease that first arises in these patients, i.e.
T1775 884499-884698 Epistemic_statement 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.
T1776 884790-884996 Epistemic_statement 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.
T1777 886376-886517 Epistemic_statement denotes These channels can be a relevant target for immunosuppression and blockers of these channels can be putative drug candidates for treating MS.
T1778 886658-886756 Epistemic_statement denotes A role for both gamma/delta T lymphocytes and NK cells in disease pathogenesis has been suggested.
T1779 886942-887203 Epistemic_statement 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: Vdelta2TEMh cells, and Vdelta2TEMRA cells.
T1780 887433-887617 Epistemic_statement 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.
T1781 887618-887697 Epistemic_statement denotes Dendritic cells (DCs) are essential in orchestration of immunity and tolerance.
T1782 888596-888652 Epistemic_statement denotes In MS patients, no modulatory effects could be observed.
T1783 888947-889116 Epistemic_statement 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.
T1784 889117-889192 Epistemic_statement denotes Reactivation of immune response causes increased cerebral blood volume K.A.
T1785 889473-889818 Epistemic_statement 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.
T1786 890650-890814 Epistemic_statement 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.
T1787 890815-890968 Epistemic_statement denotes These findings may have implications for MS patients, and suggest that monitoring regional perfusion may be valuable in detecting early CNS inflammation.
T1788 891084-891466 Epistemic_statement 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. 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.
T1789 891664-891849 Epistemic_statement 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).
T1790 892091-892250 Epistemic_statement denotes Whether such decrease indicates that IFN-gamma producing cells are decreased or sequestered in peripheral tissues (such as the brain) requires further studies.
T1791 893604-893800 Epistemic_statement 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.
T1792 894333-894483 Epistemic_statement denotes Sequence analysis revealed multiple identical copies of TCR transcripts, strongly suggesting the presence of clonally expanded populations of T cells.
T1793 895241-895320 Epistemic_statement denotes However, demyelination of grey matter structures is prominent in some MS cases.
T1794 895485-895686 Epistemic_statement 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.
T1795 895983-896210 Epistemic_statement 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.
T1796 896276-896547 Epistemic_statement 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.
T1797 897898-898044 Epistemic_statement denotes Correlation of the T2 outcome of each lesion with the corresponding enhancing lesion, was high provided that the zenith Gd+ volume was considered.
T1798 898045-898161 Epistemic_statement denotes This correlation was usually high also in each patient, and patient specific correlation coefficients were observed.
T1799 898162-898235 Epistemic_statement denotes These data indicate that brain MS lesions follow common biological rules.
T1800 898236-898367 Epistemic_statement denotes In addition, these data indicate that the T2 outcome correlates with the corresponding Gd+ lesion, better than previously reported.
T1801 898495-898615 Epistemic_statement denotes Diagnosis continues to require two attacks separated in space and time but can utilize MRI to establish new MS activity.
T1802 898616-898752 Epistemic_statement denotes Cerebrospinal fluid (CSF) analysis and evoked potentials studies may still be employed to provide paraclinical evidence of the diseases.
T1803 899225-899309 Epistemic_statement denotes We did not find a correlation with age of patients and with duration of the disease.
T1804 899454-899728 Epistemic_statement denotes The role of immune mechanisms in multiple sclerosis (MS) patients with epilepsy D. Kountouris and K. Koutsobelis Neurological and Diagnostic Center, Athens, Greece Background: The aim of this study was to check any role of the immune mechanisms in MS patients with epilepsy.
T1805 900092-900144 Epistemic_statement denotes The Kurtzky EPSS were also taken into consideration.
T1806 900511-900563 Epistemic_statement denotes Therefore, treatment should be accordingly directed.
T1807 900862-901223 Epistemic_statement denotes Case history: We present seven cases of definite MS. 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.
T1808 901356-901466 Epistemic_statement denotes Conclusion: Intermediate uveitis may belong to a constellation of HLA-DR15 related disorders which include MS.
T1809 901467-901640 Epistemic_statement denotes Although MS and chronic inflammatory bowel disease (IBD) may share common predisposing factors, unsufficient information is available to speculate about possible mechanisms.
T1810 901847-902016 Epistemic_statement 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.
T1811 902017-902204 Epistemic_statement 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.
T1812 903574-903702 Epistemic_statement denotes In mixed cell cultures, these antibodies could activate the glutamate receptor and were shown to destroy neurons and astrocytes.
T1813 904500-904629 Epistemic_statement denotes We therefore suggest a specific attack by cytotoxic T lymphocytes as a possible mechanism responsible for astrocyte degeneration.
T1814 904630-904879 Epistemic_statement 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.
T1815 904880-905032 Epistemic_statement denotes Rasmussen's encephalitis (RE) is a severe epileptic disorder that may respond transiently to immunotherapies suggesting a possible autoimmune aetiology.
T1816 906177-906265 Epistemic_statement denotes These antibodies inhibit nAChR channel function and have the potential to be pathogenic.
T1817 906266-906408 Epistemic_statement denotes Ongoing studies are looking for these antibodies in patients with different forms of severe epilepsy, and testing their pathogenicity in vivo.
T1818 906409-906484 Epistemic_statement denotes HLA studies indicate immunogenetic susceptibility to adult Rasmussen's I.K.
T1819 906708-906752 Epistemic_statement denotes It can be present in childhood or adulthood.
T1820 906753-906847 Epistemic_statement denotes Autoimmunity is implicated in its pathogenesis, although the crucial mechanisms are not clear.
T1821 907372-907577 Epistemic_statement denotes Conclusions: 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.
T1822 907578-907809 Epistemic_statement 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.
T1823 909412-909560 Epistemic_statement denotes The observed morphological and functional effect on hippocampal neurons may suggest a pathogenetic role of GAD-Ab in the development of the disease.
T1824 910016-910328 Epistemic_statement 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.
T1825 910918-911058 Epistemic_statement denotes The PE specimens however contained significantly higher densities of T cells, B cells, plasma cells and macrophages compared to NPLE and RE.
T1826 911136-911292 Epistemic_statement denotes The higher inflammatory activity and broader spectrum of inflammatory cells in PE may be an indicator of inflammatory mechanisms beyond T cell cytotoxicity.
T1827 912945-912994 Epistemic_statement denotes If present, a thorough tumor search is warranted.
T1828 913093-913321 Epistemic_statement 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.
T1829 913322-913543 Epistemic_statement 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.
T1830 914265-914426 Epistemic_statement denotes The proteasome is important in nonlysosomal protein degradation and in antigen processing and presentation by major histocompatibility complex class I molecules.
T1831 914427-914554 Epistemic_statement denotes The proteasome antibodies in PCD may be of pathogenic importance by regulating the cellular metabolism and the immune response.
T1832 914555-914672 Epistemic_statement denotes Conformational epitopes can prevent the recognition of target antigens of autoantibodies in paraneoplastic syndromes.
T1833 914926-915156 Epistemic_statement 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.
T1834 915550-915700 Epistemic_statement denotes CRMP3 antibodies associated with limbic encephalitis and thymoma A. Knudsen a , G. Bredholt a , A. Storstein a , L. Oltedal b , S. Davanger b and C.A.
T1835 915904-916020 Epistemic_statement denotes Thymoma can be associated with various antibodies such as anti-AChR, anti-titin, anti-RyR, anti-VGKC and anti-CRMP5.
T1836 916161-916329 Epistemic_statement 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.
T1837 917079-917161 Epistemic_statement denotes Discussion: CRMP3 antibodies were associated with thymoma and limbic encephalitis.
T1838 917162-917262 Epistemic_statement denotes CRMP3 is present in the hippocampus and may be relevant for the pathogenesis of limbic encephalitis.
T1839 917263-917454 Epistemic_statement 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.
T1840 917546-917701 Epistemic_statement denotes Although inflammation in the brain following seizures has been well characterized, its role, which could be adaptive or detrimental, is still under debate.
T1841 917702-918077 Epistemic_statement 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.
T1842 918252-918486 Epistemic_statement 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.
T1843 918487-918766 Epistemic_statement 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.
T1844 918767-919078 Epistemic_statement denotes Antiepileptogenic and anticonvulsant activity of interleukin-1B in amygdala-kindled rats M. Sayyah a and S. 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.
T1845 919804-919968 Epistemic_statement 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.
T1846 920544-920641 Epistemic_statement denotes However, daily injection of LPS (2.5 Ag/rat) retarded acquisition of kindled behavioral seizures.
T1847 920642-920824 Epistemic_statement 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.
T1848 920825-921027 Epistemic_statement denotes Increased serum levels of interleukin-8 in patients with epilepsy L. Bastone, A. Bagalà, T. Ferraro, M. Casaletto, N. Romeo and L. Crescibene Institute of Neurological Sciences, CNR, Mangone (CS), Italy
T1849 921028-921158 Epistemic_statement denotes There are some evidences that inflammatory processes may be involved in clinical and neuropathological manifestations of epilepsy.
T1850 921350-921516 Epistemic_statement denotes Studies of patients with epilepsy and animals with experimental induced seizures indicate that cytokines may influence the electrophisiological properties of neurons.
T1851 921517-921648 Epistemic_statement denotes In adult rats, status epilepticus induces cytokine production by glia especially when seizures are associated with neuronal injury.
T1852 921649-921730 Epistemic_statement denotes This suggests that cytokines may play a role in seizures-induced neuronal damage.
T1853 922158-922225 Epistemic_statement denotes Our data support the hypothesis that cytokines groups is activated.
T1854 922226-922342 Epistemic_statement denotes Whether these elevated cytokines levels have some role in the pathogenesis of epilepsy must be investigated further.
T1855 922565-922692 Epistemic_statement denotes However, whether this increase is caused by seizures per se or some other underlying disease causing seizures is controversial.
T1856 923417-923509 Epistemic_statement denotes This finding provides further evidence about seizure induced production of cytokines in CNS.
T1857 923510-923637 Epistemic_statement denotes In addition, activation of cytokine cascade after ECS may have importance in the therapeutic effect of ECS in major depression.
T1858 924746-924875 Epistemic_statement denotes The strength of immunohistochemical staining was correlated with both the age of the patients and the duration of their seizures.
T1859 925214-925425 Epistemic_statement 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.
T1860 925426-925754 Epistemic_statement 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.
T1861 926622-926771 Epistemic_statement denotes Notably, these patients also had high titers of anti-gliadin IgG antibodies, although coeliac disease could not be demonstrated by intestinal biopsy.
T1862 926847-926968 Epistemic_statement denotes The strength of immunohistochemical staining was correlated with neither the severity nor the length of the PME syndrome.
T1863 926969-927238 Epistemic_statement 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.
T1864 927239-927397 Epistemic_statement 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.
T1865 927398-927510 Epistemic_statement denotes Introduction: CRMP5 is an onconeural antibody that is associated with small cell lung cancer (SCLC) and thymoma.
T1866 927511-927642 Epistemic_statement denotes The prevalence of CRMP5 antibodies in patients with such tumours, as well as the correlation with the prognosis is largely unknown.
T1867 928565-928738 Epistemic_statement denotes Background: Presence of anti-neuronal autoantibodies (Abs) has been well described in association with late onset cerebellar ataxia (LOCA) as a paraneoplastic manifestation.
T1868 928739-928850 Epistemic_statement denotes They are identified in the presence of certain cancers but may also rarely be seen in the absence of neoplasia.
T1869 928851-928942 Epistemic_statement denotes However, the frequency of these Abs and relevance in wider LOCA population remains unclear.
T1870 929500-929652 Epistemic_statement denotes Results: 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.
T1871 929900-930089 Epistemic_statement 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.
T1872 930572-930704 Epistemic_statement denotes High-dosage methylprednisolone treatment has been established as the standard therapy of acute inflammation of the optic nerve (ON).
T1873 931382-931472 Epistemic_statement denotes Thus, besides immunosuppressive strategies, neuroprotective approaches should be designed.
T1874 931473-931642 Epistemic_statement 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.
T1875 932121-932263 Epistemic_statement denotes The current objective is to determine whether Th1 and Th2 polarized T cells have different capacity for neurodegeneration in vitro and in EAE.
T1876 932876-932991 Epistemic_statement denotes Co-localization of inflammation and axonal loss showed a significant correlation in the spinal cord of EAE animals.
T1877 933168-933282 Epistemic_statement denotes We suggest that when T cells are appropriately activated, they can traffic into the CNS and induce neuronal death.
T1878 933283-933363 Epistemic_statement denotes The shift of T cells towards a Th2 phenotype decreases their potential toxicity.
T1879 933364-933730 Epistemic_statement denotes Direct impact of T cells on neurons as potential damage mechanism in neuroinflammatory disorders O. Aktas a , E. Pohl b , A. Smorodchenko a , C. Infante-Duarte a , R. Nitsch b and F. Zipp a a Institute of Neuroimmunology, Humboldt University Medical School Charité, Berlin, Germany; b Institute of Anatomy, Humboldt University Medical School Charité, Berlin, Germany
T1880 933731-933892 Epistemic_statement denotes The precise mechanisms of neuronal damage in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE) are poorly understood.
T1881 933893-934083 Epistemic_statement 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.
T1882 936267-936405 Epistemic_statement 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.
T1883 936406-936587 Epistemic_statement 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.
T1884 936854-936972 Epistemic_statement denotes TRAIL was demonstrated on autoreactive T cells and may be involved in immune mediated apoptosis of brain target cells.
T1885 936973-937152 Epistemic_statement 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.
T1886 938207-938351 Epistemic_statement denotes These results may implicate JNK pathway involvement in TRAIL-induced selective oligodendrocytes demise in inflammatory/demyelinating conditions.
T1887 939135-939456 Epistemic_statement 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.
T1888 939457-939707 Epistemic_statement 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.
T1889 941552-941707 Epistemic_statement denotes These studies indicate that PAR-2 exerts a neuroprotective effect against lentivirus-induced brain disease that is augmented by pro-inflammatory cytokines.
T1890 941708-941869 Epistemic_statement 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.
T1891 941870-941985 Epistemic_statement denotes We investigated whether ER stress signaling is involved in ts1mediated neuronal loss in the brain of infected mice.
T1892 942792-942921 Epistemic_statement denotes Finally, neuronal degeneration in spongiform lesions was associated with increase in calcium (Ca2+) accumulation in mitochondria.
T1893 942922-943128 Epistemic_statement 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.
T1894 944279-944520 Epistemic_statement 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.
T1895 945325-945482 Epistemic_statement denotes The effects of NO on differentiation were assessed by immunolabeling the cells for neuronal (Tuj), oligodendrocyte-(O4) and astrocyte-(GFAP) lineage markers.
T1896 946347-946578 Epistemic_statement denotes 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.
T1897 946579-946847 Epistemic_statement 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.
T1898 947063-947269 Epistemic_statement 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).
T1899 947614-947880 Epistemic_statement 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.
T1900 947881-947992 Epistemic_statement denotes This mechanism may contribute to neurodegeneration observed in CNS infections caused by Gram-positive bacteria.
T1901 948924-949126 Epistemic_statement 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.
T1902 949219-949349 Epistemic_statement denotes However, mice with deficiency in Fas and perf (perfÀ/Àgld) displayed a higher incidence of encephalitis and death after infection.
T1903 950549-950788 Epistemic_statement 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.
T1904 950789-950957 Epistemic_statement denotes Identification of astrocyte-derived genes that induce apoptosis of autoreactive T cells H. Hara and T. Tabira National Institute for Longevity Sciences, Obu City, Japan
T1905 950958-951034 Epistemic_statement denotes In EAE, apoptosis of T cells is mainly seen at the site of CNS inflammation.
T1906 951035-951143 Epistemic_statement denotes There are some reports that astrocytes may render T cells susceptible for induction of apoptotic cell death.
T1907 951780-951908 Epistemic_statement denotes First gene is unknown gene, named as astrocytederived immune suppressor factor (AdIF) and its length is 726 bp, 228 amino acids.
T1908 952217-952283 Epistemic_statement denotes This AdIF may be effective in the treatment of multiple sclerosis.
T1909 952433-952903 Epistemic_statement denotes Ljunggren c and K. 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.
T1910 953305-953522 Epistemic_statement 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.
T1911 953708-954016 Epistemic_statement 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. Exogenous agents as well as peripheral nerve lesions can alter the expression of NK cell stimulatory and inhibitory ligands in nervous tissue.
T1912 954098-954414 Epistemic_statement denotes Figueiredo, M. Faria Pais and S. 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.
T1913 954415-954589 Epistemic_statement denotes In addition, microglia when activated releases a metabolite of the tryptophan-kynurenine pathway, quinolinic acid (QA), which can be implicated in neurodegenerative diseases.
T1914 954590-954664 Epistemic_statement denotes QA can induce neurotoxicity through N-methyl-d-aspartate receptor (NMDAR).
T1915 954665-954841 Epistemic_statement 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.
T1916 954842-955036 Epistemic_statement 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.
T1917 955482-955618 Epistemic_statement denotes A specific NR1-NR2B complex blocker, ifenprodil, rescues cell death, suggesting that QA may bind to NR2B, a subunit absent in microglia.
T1918 955794-956205 Epistemic_statement denotes Beta amyloid 1-40 peptide selectively downregulates MMP-9 production in differentiated SH-SY5Y neuronal cell line M. Ruggieri a , F. Roselli a , C. Pica a , A. Lia a , C. Avolio b , M. Trojano a and P. Livrea a a University of Bari, Bari, Italy; b University of Foggia, Foggia, Italy Objective: Neuronal Matrix Metalloproteinases (MMPs) may be involved in memory consolidation processes and synaptic plasticity.
T1919 956206-956291 Epistemic_statement denotes MMP-9 expression has been detected in dentate gyrus neuron cell bodies and dendrites.
T1920 956292-956430 Epistemic_statement denotes Amyloid accumulation in strategic brain areas induce memory dysfunctions, but the effect of amyloid peptides on neuronal MMPs are unknown.
T1921 956431-956536 Epistemic_statement denotes We tested whether amyloid peptides could alter MMPs (or their inhibitors) production by neurons in vitro.
T1922 957260-957436 Epistemic_statement 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.
T1923 957437-957562 Epistemic_statement 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.
T1924 958028-958160 Epistemic_statement denotes The inflammatory reaction follows the dopaminergic neurons impairment, and is believed to contribute to neuronal death and survival.
T1925 958161-958373 Epistemic_statement 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.
T1926 958791-959018 Epistemic_statement 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.
T1927 960444-960605 Epistemic_statement 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.
T1928 960606-960797 Epistemic_statement 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.
T1929 961325-961464 Epistemic_statement denotes We examined whether human T-cells specific for myelin basic protein (MBP) and myelin oligodendrocyte protein (MOG) are able to secrete LIF.
T1930 961861-961992 Epistemic_statement denotes LIF secreting T-lymphocytes and macrophages could also be identified immunohistochemically in active and chronic active MS lesions.
T1931 962339-962564 Epistemic_statement denotes In conclusion, our in vitro studies indicate that LIF and CNTF are possible candidates for therapeutic interventions in MS. Factors that enhance the production of neurotrophins by T cells may provide new tools for MS therapy.
T1932 962783-962882 Epistemic_statement denotes Our hypothesis is that systemic autoimmunity affects central dopaminergic systems in diseased mice.
T1933 963013-963127 Epistemic_statement denotes Amphetamine was employed to further probe the relationship between mesolimbic damage and depressive-like behavior.
T1934 963820-963936 Epistemic_statement denotes In summary, results suggest that systemic autoimmunity damages dopaminergic systems and induces behavioral deficits.
T1935 964187-964205 Epistemic_statement denotes Sidor and B. Sakic
T1936 964206-964350 Epistemic_statement denotes Neuropsychiatric lupus (NP-SLE) is a complex manifestation of unknown etiology that can occur during the course of systemic lupus erythematosus.
T1937 964658-964809 Epistemic_statement denotes The presence of B-cells in the choroid plexus and toxicity of IgGrich CSF fractions suggest intrathecal synthesis of autoantibodies to neuronal tissue.
T1938 964810-964920 Epistemic_statement denotes The present study examines whether cytotoxic CSF from diseased MRL-lpr mice exhibits a unique protein profile.
T1939 965154-965340 Epistemic_statement 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.
T1940 965341-965547 Epistemic_statement 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.
T1941 966090-966174 Epistemic_statement denotes Glatiramer acetate (GA) may be effective to induce apoptosis of detrimental T cells.
T1942 966896-967064 Epistemic_statement 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.
T1943 967239-967446 Epistemic_statement 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.
T1944 967447-967648 Epistemic_statement denotes Modulation of soluble Fas levels in patients with Herpes simplex encephalitis (HSE) F. Sabri, A. Hjalmarsson, F. Granath, K. Lfvgren and B. Skfldenberg Karolinska University Hospital, Stockholm, Sweden
T1945 967649-967747 Epistemic_statement denotes Herpes simplex encephalitis (HSE) is the most common cause of sporadic, severe viral encephalitis.
T1946 967866-968125 Epistemic_statement 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.
T1947 968289-968469 Epistemic_statement 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.
T1948 968868-969085 Epistemic_statement 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.
T1949 969086-969186 Epistemic_statement denotes Oxidative stress and NF-kB activation are suggested to be linked to acute and chronic inflammations.
T1950 969388-969646 Epistemic_statement 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).
T1951 969647-969810 Epistemic_statement 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.
T1952 970123-970302 Epistemic_statement 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.
T1953 970303-970581 Epistemic_statement 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.
T1954 970647-970902 Epistemic_statement denotes Marinova b , D. Petrov c and L. 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
T1955 970903-971236 Epistemic_statement 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.
T1956 971778-971960 Epistemic_statement 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.
T1957 972234-972609 Epistemic_statement denotes Spinal neuroimmune activation induces behavioral sensitization in the animal models of chronic pain V. Raghavendra and J. 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.
T1958 974307-974377 Epistemic_statement denotes The mechanism of action of HSCT, however, has remained elusive so far.
T1959 975045-975247 Epistemic_statement 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.
T1960 975371-975495 Epistemic_statement denotes Mancardi, A. Uccelli and the Italian Gitmo-Neuro intergroup on ASCT for multiple sclerosis University of Genoa, Genoa, Italy
T1961 975496-975762 Epistemic_statement 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.
T1962 975763-975940 Epistemic_statement 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.
T1963 976560-976929 Epistemic_statement 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.
T1964 976930-977145 Epistemic_statement denotes Anti-ergotypic T cell responses in healthy controls and multiple sclerosis patients N. Hellings, C. Govarts, J. Raus and P. Stinissen Biomedisch Onderzoeksinstituut, Liburgs Universitair Centrum, Diepenbeek, Belgium
T1965 977146-977301 Epistemic_statement denotes Peripheral regulatory mechanisms may prevent the expansion of autoreactive T-cells that play a role in autoimmune diseases such as multiple sclerosis (MS).
T1966 977302-977430 Epistemic_statement denotes Anti-idiotypic and anti-ergotypic T-cells take part in these regulatory networks and can be boosted by T-cell vaccination (TCV).
T1967 977545-977649 Epistemic_statement denotes This study aims to further characterize anti-ergotypic T-cells in MS patients and healthy controls (HC).
T1968 978575-978704 Epistemic_statement denotes We are currently testing whether IL2R-specific TCL with similar properties can be isolated from MS patients before and after TCV.
T1969 978705-978773 Epistemic_statement denotes This will help unravel their actual role in T-cell immunoregulation.
T1970 980276-980477 Epistemic_statement 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.
T1971 980478-980645 Epistemic_statement 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.
T1972 980646-980824 Epistemic_statement denotes Atorvastatin regulates T cell anergy via the extracellular signal-related kinase pathway: a novel immunomodulatory function of 3-hydroxy-3methylglutaryl-CoA reductase inhibitors?
T1973 980825-980999 Epistemic_statement denotes S. Waiczies, C. Infante-Duarte, T. Prozorovski, S. Pikol and F. Zipp Institute of Neuroimmunology, Neuroscience Research Center, Charité, Humboldt University, Berlin, Germany
T1974 981000-981197 Epistemic_statement 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.
T1975 981198-981350 Epistemic_statement denotes We have previously reported that in vivo atorvastatin treatment could prevent and reverse disease progression in the animal model of multiple sclerosis.
T1976 981351-981435 Epistemic_statement denotes However, the mechanism of immunomodulation by statins has yet to be fully clarified.
T1977 981578-981733 Epistemic_statement denotes We could explain this by a failure of atorvastatin-treated cells to downregulate the negative cell cycle regulator p27Kip1 following a productive stimulus.
T1978 981954-982095 Epistemic_statement denotes Anergy induction was shown to be dependent on HMG-CoAR, since we could reverse this with mevalonate, an intermediary product of this pathway.
T1979 982096-982314 Epistemic_statement 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.
T1980 982315-982544 Epistemic_statement 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.
T1981 983659-983801 Epistemic_statement denotes The heightened CD8+ T-cell response corresponded with the longitudinal upregulation of ex vivo cytotoxic activity of GA-specific CD8+ T-cells.
T1982 983899-984114 Epistemic_statement 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.
T1983 984115-984245 Epistemic_statement denotes This also raises important questions about the immunologic effects of chronic GA therapy and the development of T-cell senescence.
T1984 984629-984838 Epistemic_statement 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.
T1985 984839-985084 Epistemic_statement denotes Objective: 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.
T1986 985440-985639 Epistemic_statement 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.
T1987 985800-985976 Epistemic_statement denotes Conclusion: 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.
T1988 986286-986406 Epistemic_statement denotes The aim of this study was to determine in vivo immune changes that are responsible for this profound therapeutic effect.
T1989 986808-986972 Epistemic_statement 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.
T1990 987136-987206 Epistemic_statement denotes These changes were highly correlated to and predictive of MRI outcome.
T1991 987207-987308 Epistemic_statement denotes We will describe the mechanism by which CD56bright NK cells may mediate peripheral tolerance in vivo.
T1992 987309-987384 Epistemic_statement denotes Our data reveal an intriguing pathway how to manipulate cytokine circuitry.
T1993 987534-988000 Epistemic_statement denotes Immunomodulatory effects of simvastatin in relapsing-remitting multiple sclerosis S. Markovic-Plese a,b , X. b , S. Giri c , D. Sujkowski a and I. 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: To study immunomodulatory therapeutic potential of simvastatin, CNS penetrating HMG-CoA reductase inhibitor, in relapsing-remitting multiple sclerosis (RR MS).
T1994 988871-989003 Epistemic_statement denotes Further analysis revealed consistently decreased expression of T-bet, transcription factor that regulates Th-1 cell differentiation.
T1995 989339-989490 Epistemic_statement denotes Conclusions: Due to multiple immunomodulatory mechanisms of action, statins represent a promising treatment for MS, a chronic inflammatory CNS disease.
T1996 989796-990015 Epistemic_statement 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.
T1997 990016-990101 Epistemic_statement denotes However, there is continued improvement in disability between 12-24 and 24-36 months.
T1998 990102-990289 Epistemic_statement 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.
T1999 990290-990495 Epistemic_statement 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.
T2000 990867-990993 Epistemic_statement denotes This finding suggests that Campath's immuno-modulation may, in part, be due to the apoptotic elimination of activated T cells.
T2001 990994-991152 Epistemic_statement denotes Increasing evidence indicates that the Epstein-Barr virus (EBV) has a role in the pathogenesis of many autoimmune diseases, including multiple sclerosis (MS).
T2002 991153-991533 Epistemic_statement 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.
T2003 991551-991904 Epistemic_statement 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. 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.
T2004 992930-993055 Epistemic_statement denotes It is less frequent than relapsing-remitting MS (RRMS) and some studies suggest it may represent a totally separated disease.
T2005 993210-993328 Epistemic_statement denotes Clinical diagnosis of PPMS was confirmed by nuclear magnetic resonance, evoked potential and lumbar puncture findings.
T2006 993824-993979 Epistemic_statement denotes Then, the patient was able to walk alone more than 100 m. However, the patient experienced two relapse in 2003 (optic neuritis, left arm neuropathic pain).
T2007 994116-994313 Epistemic_statement 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.
T2008 994314-994832 Epistemic_statement denotes Identification of novel lead compounds in modulation of pathogenic immune responses in multiple sclerosis M. Massa a , R. Campanelli a , A. Uccelli b , V. Meli c , P. Lanza c , R. Billetta c , A. Martini d and S. Albani e a IRCCS S. Matteo Hospital, Pavia, Italy; b University of Genoa, Genoa, Italy; c Androclus Therapeutics, San Diego, USA; d IRCCS G. 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.
T2009 994833-995079 Epistemic_statement 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).
T2010 995936-996125 Epistemic_statement 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.
T2011 996562-996722 Epistemic_statement 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.
T2012 996723-996939 Epistemic_statement 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.
T2013 997679-997811 Epistemic_statement denotes Co-stimulation is therefore a potential target for treating autoimmune diseases such as rheumatoid arthritis and multiple sclerosis.
T2014 997812-998056 Epistemic_statement 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).
T2015 998413-998591 Epistemic_statement 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.
T2016 998755-998808 Epistemic_statement denotes Nemtsova Kharkov Medical University, Kharkov, Ukraine
T2017 998809-999005 Epistemic_statement 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.
T2018 999006-999159 Epistemic_statement denotes The hormone estriol increases during pregnancy and has been shown to ameliorate experimental autoimmune encephalomyelitis and collagen-induced arthritis.
T2019 999553-999751 Epistemic_statement 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.
T2020 1000388-1000531 Epistemic_statement denotes In inflammatory/ demyelinating lesions, EC ZO-1 was diffuse, indicating that the alterations induced in vitro mimic those in active MS lesions.
T2021 1000532-1000714 Epistemic_statement 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.
T2022 1000715-1000866 Epistemic_statement denotes Type 1 interferons such as IFN-beta appear critical to trigger immunoregulatory mechanisms lying at the interface between innate and adaptive immunity.
T2023 1000867-1001057 Epistemic_statement 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.
T2024 1001058-1001208 Epistemic_statement 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.
T2025 1002174-1002355 Epistemic_statement denotes of Neurology, Innsbruck, Austria Background: Patients with multiple sclerosis receiving recombinant interferon-beta (IFN-beta) may develop binding antibodies (BAB) against IFN-beta.
T2026 1002454-1002563 Epistemic_statement denotes NAB are associated with greater BAB titers than NNAB, suggesting a quantitative influence on NAB development.
T2027 1002564-1002698 Epistemic_statement denotes The correlation between NAB and BAB is weak and there is evidence that IFN-beta neutralization also depends on qualitative components.
T2028 1003567-1003696 Epistemic_statement denotes Conclusions: After exclusion of confounding factors these results indicate that NAB have a higher affinity to IFN-beta than NNAB.
T2029 1005308-1005430 Epistemic_statement denotes IFN-beta has shown to be an effective treatment for multiple sclerosis (MS), however, some patients fail to respond fully.
T2030 1005548-1005634 Epistemic_statement denotes Deficiency of one or both of these subunits may lead to a loss of interferon activity.
T2031 1006942-1007038 Epistemic_statement denotes These T cells were believed to mediate processes of secondary degeneration of the neural tissue.
T2032 1007224-1007472 Epistemic_statement 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.
T2033 1007473-1007726 Epistemic_statement 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.
T2034 1007888-1008147 Epistemic_statement 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.
T2035 1008240-1008391 Epistemic_statement denotes High sensitivity of regulatory T cells to neurotransmitters might represent the bmissing linkQ between the immune and the nervous systems interactions.
T2036 1008392-1008538 Epistemic_statement denotes A bfine tuningQ on a level of regulatory T cells by neurotransmitters could be a promising therapy for autoimmune and neurodegenerative disorders.
T2037 1008691-1008988 Epistemic_statement 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.
T2038 1009168-1009403 Epistemic_statement 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.
T2039 1009404-1009577 Epistemic_statement 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.
T2040 1009578-1009848 Epistemic_statement 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.
T2041 1010134-1010442 Epistemic_statement denotes Much less is known about the few T cells found within the intact organ: 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.
T2042 1011484-1011781 Epistemic_statement denotes Anglen, C. Ploix and M. 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).
T2043 1012845-1013030 Epistemic_statement 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.
T2044 1013368-1013500 Epistemic_statement denotes Here we define whether immunoregulatory function of T cells in the induction of antoantigen-specific tolerance is mediated via APCs.
T2045 1014372-1014545 Epistemic_statement 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.
T2046 1014889-1014997 Epistemic_statement denotes Many of the cells (60-70%) cruise with unexpected speed (bmotile typeQ) and in seemingly undirected fashion.
T2047 1014998-1015101 Epistemic_statement denotes Other cells (30-40%), however, attach and begin to toss around some central object (bstationary typeQ).
T2048 1015102-1015315 Epistemic_statement 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.
T2049 1015507-1015658 Epistemic_statement denotes Second, the motility pattern correlates with the local reactivation level as well as with the pathogenic potential of the transferred effector T cells.
T2050 1015955-1016130 Epistemic_statement 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.
T2051 1016619-1016875 Epistemic_statement 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.
T2052 1017017-1017075 Epistemic_statement denotes The precise role of Treg in human autoimmunity is unclear.
T2053 1017815-1017954 Epistemic_statement denotes These results suggest that an impaired inhibitory effect of Treg on autoreactive T cell clones might be involved in the pathogenesis of MS.
T2054 1018275-1018428 Epistemic_statement 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.
T2055 1019423-1019532 Epistemic_statement denotes The role of this cell subset in the regulation of central nervous system autoimmunity is under investigation.
T2056 1019784-1019964 Epistemic_statement 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.
T2057 1019965-1020111 Epistemic_statement denotes We assessed the impact of Campath on these homeostatic mechanisms and their possible involvement in the subsequent development of Graves' disease.
T2058 1020112-1020254 Epistemic_statement denotes We demonstrate greater proliferation of unstimulated lymphocytes from untreated patients, suggesting increased homeostatic proliferation (HP).
T2059 1020255-1020323 Epistemic_statement denotes However, IL-7 serum levels were equivalent in patients and controls.
T2060 1020559-1020735 Epistemic_statement 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.
T2061 1020895-1021061 Epistemic_statement 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.
T2062 1021062-1021196 Epistemic_statement denotes Also, we have evidence that HP may be exaggerated in patients with MS perhaps suggesting a mechanism by which autoimmunity may arises.
T2063 1021410-1021508 Epistemic_statement denotes Probably equivalent expansion occurs in T cell subpopulations because ongoing antigen stimulation.
T2064 1021509-1021923 Epistemic_statement 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.
T2065 1021924-1022124 Epistemic_statement 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.
T2066 1022125-1022457 Epistemic_statement 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.
T2067 1022582-1022763 Epistemic_statement 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.
T2068 1022915-1023213 Epistemic_statement denotes Park a , M. Sospedra a , X. Wang a , J. Quandt a , C. Raine b , H.F. McFarland a and R. 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).
T2069 1023214-1023597 Epistemic_statement 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. 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).
T2070 1024452-1024618 Epistemic_statement 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.
T2071 1024619-1024957 Epistemic_statement denotes Putative mechanisms of statins in multiple sclerosis-preferential inhibition of activated T lymphocytes O. Neuhaus a , O. Stuve a , J.J. Archelos b and H.-P. Hartung a a Heinrich Heine University, Düsseldorf, Germany; b Karl Franzens University, Graz, Austria Objective: To investigate the effects of statins on human T and B lymphocytes.
T2072 1026087-1026292 Epistemic_statement denotes Conclusions: 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.
T2073 1026400-1026507 Epistemic_statement denotes The activation of autoreactive encephalitogenic T cells may be affected by statin treatment in MS patients.
T2074 1026864-1026969 Epistemic_statement denotes They control the reactivity of potentially harmful, self-reactive T cells and prevent autoimmune disease.
T2075 1026970-1027102 Epistemic_statement denotes Multiple sclerosis (MS) is an inflammatory autoimmune disease thought to be mediated by T cells recognizing myelin protein peptides.
T2076 1027798-1027969 Epistemic_statement 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.
T2077 1028103-1028554 Epistemic_statement denotes Quandt a , J. Huh a , D. Park a , C. Pinilla b , K. Ito c and R. 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.
T2078 1029773-1029860 Epistemic_statement denotes IL-12 suppresses CD4+CD25+ regulatory T cells: a possible mechanism of promoting EAE I.
T2079 1029875-1029920 Epistemic_statement denotes Segal University of Rochester, Rochester, USA
T2080 1029921-1030040 Epistemic_statement denotes The IL-12p40 family of monokines plays a critical role in the differentiation of T lymphocytes into Th1 effector cells.
T2081 1030041-1030290 Epistemic_statement 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.
T2082 1030834-1031059 Epistemic_statement 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.
T2083 1031060-1031193 Epistemic_statement denotes We conclude that one of the mechanisms by which IL-12 promotes EAE might be through inactivation of an endogenous population of Treg.
T2084 1031194-1031321 Epistemic_statement denotes Furthermore, Treg spontaneously infiltrate the CNS during EAE, suggesting that they might participate in triggering remissions.
T2085 1031959-1032052 Epistemic_statement denotes It is unknown whether the reported effects of cannabinoids on Th profile are relevant in EAE.
T2086 1032301-1032475 Epistemic_statement 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.
T2087 1032476-1032761 Epistemic_statement 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.
T2088 1032894-1032984 Epistemic_statement denotes These coordinated effects suggest a potential role of cannabinoids in autoimmune diseases.
T2089 1033435-1033601 Epistemic_statement denotes Although transcriptional regulation via CBF1 remains the bestcharacterised outcome of Notch signalling, alternative CBF1-independent pathways have also been proposed.
T2090 1034059-1034209 Epistemic_statement denotes These activities are associated with Delta1-modified differentiation of cells: inhibited Th1 development and acquisition of a shared Th2/Treg profile.
T2091 1034294-1034433 Epistemic_statement denotes Notch signalling may, therefore, provide a unique therapeutic approach to the treatment of autoimmune disorders such as multiple sclerosis.
T2092 1034791-1034940 Epistemic_statement 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.
T2093 1035103-1035286 Epistemic_statement 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.
T2094 1035919-1036104 Epistemic_statement 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.
T2095 1037616-1037806 Epistemic_statement denotes Conclusions: The usage of mathematical languages may increase our ability to predict, and thus pharmacologically manipulate, complex key phenomena in the pathogenesis of autoimmune diseases.
T2096 1037890-1038165 Epistemic_statement denotes Mathey a , A. Flugel b and C. 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
T2097 1038166-1038382 Epistemic_statement 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.
T2098 1038383-1038701 Epistemic_statement 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).
T2099 1038702-1038889 Epistemic_statement 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?
T2100 1038890-1039130 Epistemic_statement 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.
T2101 1039444-1039677 Epistemic_statement 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.
T2102 1040448-1040673 Epistemic_statement 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.
T2103 1041003-1041105 Epistemic_statement denotes However, VIP reduces their expression more than 80%, but different cytokines are affected selectively.
T2104 1041106-1041173 Epistemic_statement denotes IL-10 is the more expressed cytokine and IL-2Ra is little affected.