CORD-19-Sentences  

CORD-19:27a606f3c89e21ba2b287011593ed80b86a32113 JSONTXT 7 Projects

Annnotations TAB TSV DIC JSON TextAE-old TextAE

Id Subject Object Predicate Lexical cue
TextSentencer_T1 2-10 Sentence denotes Abstract
TextSentencer_T2 13-116 Sentence denotes John Newsom-Davis (JND) was a major international figure in the field of neurology and neuroimmunology.
TextSentencer_T3 117-251 Sentence denotes He combined clinical expertise with commitment to scientific understanding of disease mechanisms and their implications for treatment.
TextSentencer_T4 252-427 Sentence denotes He influenced a generation of neurologists and neuroscientists and his exceptional personal qualities of intelligence, tolerance, energy and modesty are greatly missed by all.
TextSentencer_T5 428-495 Sentence denotes JND brought clinical observations to the laboratory and vice versa.
TextSentencer_T6 496-702 Sentence denotes With experience of both muscle spindle electrophysiology and intensive care medicine, in 1973 he started collaborating with Ricardo Miledi at the University College London in work on myasthenia gravis (MG).
TextSentencer_T7 703-1004 Sentence denotes The discovery of antibodies to acetylcholine receptors in serum of these patients by Jon Lindstrom and colleagues, and the demonstration of passive transfer of disease to mice by injection of patients' IgG by Klaus Toyka and Dan Drachman, led JND to test the effects of plasma exchange as a treatment.
TextSentencer_T8 1005-1148 Sentence denotes The remarkable efficacy of this therapywhich lasted for several weeksshowed convincingly that myasthenia was indeed caused by humoral immunity.
TextSentencer_T9 1149-1277 Sentence denotes The discoveries that followed in JND's and others' laboratories owe much to the implications of this simple clinical experiment.
TextSentencer_T10 1278-1682 Sentence denotes Over the next 20 years, he and his team in London and then Oxford systematically investigated the role of the thymus and involvement of T cell immunity in MG, defined the existence of humoral immunity to voltage-gated calcium channels in the Lambert Eaton syndrome, and showed similarly that some cases of acquired neuromyotonia were associated with antibodies to voltage-gated potassium channels (VGKC).
TextSentencer_T11 1683-1961 Sentence denotes With retirement in 1998, JND stepped aside from the laboratory and, while continuing to see MG patients and "Editing" Brain, he began to establish a major international trial of thymectomy in MG with Gil Wolfe, Gary Cutter and many others; this was eventually funded by the NIH.
TextSentencer_T12 1962-2209 Sentence denotes Meanwhile his team has continued to identify new antibody-associated conditions, such as other forms of MG and central nervous system disorders, ensuring that his legacythe diagnosis and treatment of immunotherapyresponsive conditionswill persist.
TextSentencer_T13 2210-2319 Sentence denotes This talk will briefly review his achievements and how these have been taken forward over the last ten years.
TextSentencer_T14 2320-2483 Sentence denotes Josep Dalmau, MD, PhD Limbic encephalitis refers to an inflammatory process involving the hippocampi, amygdala and less frequently frontobasal and insular regions.
TextSentencer_T15 2484-2601 Sentence denotes This disorder used to be considered extremely rare, invariably associated with cancer, and unresponsive to treatment.
TextSentencer_T16 2602-2751 Sentence denotes However, recent studies indicate that limbic encephalitis is more frequent than previously thought, and a substantial number of patients may recover.
TextSentencer_T17 2752-2955 Sentence denotes This increased recognition of limbic encephalitis is due in part to the development of clinical diagnostic criteria and the identification of antibodies directed against two broad categories of antigens:
TextSentencer_T18 2956-3235 Sentence denotes 1) intracellular or classical paraneoplastic antigens, including Hu, Ma2, and CV2/CRMP5, among others, and 2) cell surface antigens including, voltage-gated potassium channels (VGKC), N-methyl-D-aspartate receptor (NMDAR), and others expressed in the neuropil of the hippocampus.
TextSentencer_T19 3236-3589 Sentence denotes While the disorders related to the first category of antibodies associate with cancer (lung, testis and other), prominent brain infiltrates of T-cells, and limited response to treatment, the disorders related to the second category of antibodies associate less frequently with tumors, appear to be antibody-mediated, and respond better to immunotherapy.
TextSentencer_T20 3590-3767 Sentence denotes While studying limbic encephalitis, we identified a large group of allied disorders in which the limbic system is often involved, but other areas of the brain are also affected.
TextSentencer_T21 3768-3908 Sentence denotes Of particular interest is the disorder that associates with antibodies to extracellular epitopes of NR1/NR2 heteromers of the NMDA receptor.
TextSentencer_T22 3909-4060 Sentence denotes Patients with this syndrome are often young women with ovarian teratoma, although the disorder can also affect men and children with or without tumors.
TextSentencer_T23 4061-4152 Sentence denotes Most patients present with severe psychiatric symptoms and are first seen by psychiatrists.
TextSentencer_T24 4153-4247 Sentence denotes Subsequently patients develop seizures, dyskinesias, autonomic instability or hypoventilation.
TextSentencer_T25 4248-4307 Sentence denotes There is a correlation between antibody titers and outcome.
TextSentencer_T26 4308-4484 Sentence denotes The antibodies are directed against the NR1 subunit of the NMDA receptor, differentiating this disease from a number of disorders attributed to antibodies against NR2 subunits.
TextSentencer_T27 4485-4583 Sentence denotes In vitro studies indicate that patients' NR1 antibodies can modulate the number of NMDA receptors.
TextSentencer_T28 4584-4733 Sentence denotes There are other autoimmune encephalitides for which the target antigens are on the cell surface of neurons and neuronal processes of the hippocampus.
TextSentencer_T29 4734-4938 Sentence denotes The phenotype of these patients is different from that of anti-NMDA receptor encephalitis and resembles more a classical limbic encephalitis with frequent relapsing-remitting seizures and memory deficits.
TextSentencer_T30 4939-5073 Sentence denotes Work in progress suggests that the autoantigens are ion channels or receptors critically involved in processes of learning and memory.
TextSentencer_T31 5074-5244 Sentence denotes In all, the study of these disorders provides a link between immunologic processes and neuronal events involved in memory, cognition, seizures, and neuronal degeneration.
TextSentencer_T32 5245-5434 Sentence denotes Interferons (IFNs)-inducible myxovirus resistance protein A (MxA) has recently been used as an indirect marker of neutralizing antibody against IFN in patients with multiple sclerosis (MS).
TextSentencer_T33 5435-5534 Sentence denotes MxA also inhibits viral replication by modifying cellular function including the apoptotic pathway.
TextSentencer_T34 5535-5673 Sentence denotes Moreover, a recent study has suggested that haplotypes of SNPs on the MxA promoter region affect the response to IFN-beta treatment in MS.
TextSentencer_T35 5674-5762 Sentence denotes Our goal is to investigate the genetic and pathological role of MxA in patients with MS.
TextSentencer_T36 5763-5849 Sentence denotes We examined SNPs of the MxA promoter region in 67 MS patients and 103 normal controls.
TextSentencer_T37 5850-5896 Sentence denotes All MS patients fulfilled McDonald's criteria.
TextSentencer_T38 5897-6073 Sentence denotes Moreover, to elucidate the functional roles of SNPs, we conducted Luciferase assay with pGL3-basic vector including patient-derived or artificially mutated MxA promoter region.
TextSentencer_T39 6074-6174 Sentence denotes We also examined MxA protein expression in peripheral blood monocytes (PBMC) by quantitative RT-PCR.
TextSentencer_T40 6175-6394 Sentence denotes We found a significantly higher frequency of the haplotype with −88T and −123A in MS patients which correlates with an overexpression of MxA and has been reported to be associated with a worse response to IFN-treatment.
TextSentencer_T41 6395-6564 Sentence denotes Moreover, we obtained novel findings showing that nt-88 played a leading part with type I IFNs while nt-123 played a similar role independently unrelated to type I IFNs.
TextSentencer_T42 6565-6661 Sentence denotes Quantitative RT-PCR demonstrated higher expression of MxA in MS patients than in normal control.
TextSentencer_T43 6662-6801 Sentence denotes SNPs on the MxA promoter region may play an important role in the pathophysiology of MS, and hyper expression of MxA is associated with MS.
TextSentencer_T44 6802-6873 Sentence denotes Further studies of MxA may lead to novel therapeutic strategies for MS.
TextSentencer_T45 6874-6899 Sentence denotes 3 -The plasmacytoid cell:
TextSentencer_T46 6900-6949 Sentence denotes A clue to the pathogenesis of multiple sclerosis?
TextSentencer_T47 6950-6967 Sentence denotes Crawford Colin L.
TextSentencer_T48 6968-7157 Sentence denotes 1 1 Imperial College of Medicine, Charing Cross Hospital, London, UK In secondary progressive multiple sclerosis (SPMS), lymphoid follicles containing B and plasma cells have been observed.
TextSentencer_T49 7158-7309 Sentence denotes However, these plasma cells stained with the specific marker CD138 were confined to the perivascular spaces and were not found in the brain parenchyma.
TextSentencer_T50 7310-7488 Sentence denotes In multiple sclerosis (MS) patients, cells in the brain parenchyma, considered to be plasma cells, contain subplasmalemmal linear densities (SPLDs) and are frequently binucleate.
TextSentencer_T51 7489-7541 Sentence denotes Both these features are not present in plasma cells.
TextSentencer_T52 7542-7695 Sentence denotes Instead, these cells could be plasmacytoid cells, which are the precursors of epithelioid cells in sarcoidosis and have also been found to contain SPLDs.
TextSentencer_T53 7696-7838 Sentence denotes In sarcoidosis, giant cells due to fusion are common, so that the binucleate cells in MS could also arise by cell fusion rather than division.
TextSentencer_T54 7839-7913 Sentence denotes The plasmacytoid cell has now been identified as a type of dendritic cell.
TextSentencer_T55 7914-8001 Sentence denotes These cells are increased tenfold in the cerebrospinal fluid of patients with early MS.
TextSentencer_T56 8002-8077 Sentence denotes Non-lepromatous leprosy is a granulomatous disorder similar to sarcoidosis.
TextSentencer_T57 8078-8284 Sentence denotes In order to produce an autoimmune animal model of nonlepromatous leprosy, Dutch Bantam rabbits were injected with a suspension of human sensory peripheral nerve (sural nerve and dorsal roots) plus adjuvant.
TextSentencer_T58 8285-8478 Sentence denotes Some of these rabbits developed a state of granulomatous hypersensitivity. ie an epithelioid cell granuloma was produced at skin test sites using dilute suspensions of peripheral nerve antigen.
TextSentencer_T59 8479-8633 Sentence denotes When various non-myelin fractions were used at these sites, cells whose cytoplasm contained abundant rough endoplasmic reticulum with SPLDs were observed.
TextSentencer_T60 8634-8744 Sentence denotes A cell was observed indistinguishable from a plasma cell containing a small thickening on the plasma membrane.
TextSentencer_T61 8745-8798 Sentence denotes Plasma-like cells were also found in the endoneurium.
TextSentencer_T62 8799-8994 Sentence denotes The most active fraction producing cells with SPLDs was a deoxycholate-extracted membrane fraction, in doses of 1 μg, produced from the low speed nuclear pellet after the myelin had been removed.
TextSentencer_T63 8995-9077 Sentence denotes This fraction also induced plasma-like cells and axonal damage in the endoneurium.
TextSentencer_T64 9078-9172 Sentence denotes Plasmacytoid dendritic cells could be identified in MS tissue using the specific marker CD123.
TextSentencer_T65 9173-9265 Sentence denotes If confirmed, a specific non-myelin autoantigen may be implicated in the pathogenesis of MS.
TextSentencer_T66 9266-9415 Sentence denotes Furthermore, as these plasmacytoid dendritic cells secrete large amounts of interferon alpha, this cytokine could cause axonal damage in MS patients.
TextSentencer_T67 9416-9548 Sentence denotes The implication of CD8 T cells in the pathogenesis of multiple sclerosis (MS) and its animal models is increasingly being appraised.
TextSentencer_T68 9549-9685 Sentence denotes CD8 T cells in the central nervous system (CNS) of MS patients have been shown to be highly activated with an effector memory phenotype.
TextSentencer_T69 9686-9790 Sentence denotes Contribution of CNS factors to the acquisition of such phenotype by CD8 T cells has not been elucidated.
TextSentencer_T70 9791-9918 Sentence denotes Interleukin-15 (IL-15) is a pro-inflammatory cytokine that is crucial for the generation and maintenance of memory CD8 T cells.
TextSentencer_T71 9919-10130 Sentence denotes IL-15 produced by cells in the tissue microenvironment of other inflammatory diseases has been revealed as a potent activator of infiltrating CD8 T cells leading to an enhanced cytotoxicity towards target cells.
TextSentencer_T72 10131-10377 Sentence denotes Our goals are i) to investigate whether IL-15 is present in the CNS in the context of MS ii) to determine whether IL-15 in situ can enhance deleterious CD8 T cell responses against CNS target cells thus contributing to the observed tissue damage.
TextSentencer_T73 10378-10557 Sentence denotes Primary cultures of human astrocytes significantly increased their IL-15 expression upon activation with pro-inflammatory stimuli (IFNgamma, TNF-alpha, IL-1beta) (flow cytometry).
TextSentencer_T74 10558-10693 Sentence denotes In order to determine if such cells could be a functional IL-15 source, they were cultured with myelin specific human CD8 T cell lines.
TextSentencer_T75 10694-10850 Sentence denotes Upon co-culture with activated astrocytes, CD8 T cells acquired an effector memory phenotype with increased perforin and granzyme B levels (flow cytometry).
TextSentencer_T76 10851-10971 Sentence denotes Moreover, these CD8 T cells were more cytotoxic towards primary cultures of human adult oligodendrocytes (51Cr release).
TextSentencer_T77 10972-11097 Sentence denotes These astrocyte-mediated functional enhancements of CD8 T cell function were all abrogated by anti-IL-15 blocking antibodies.
TextSentencer_T78 11098-11284 Sentence denotes Immunohistochemistry performed on active MS lesions showed an increased proportion of astrocytes expressing IL-15, demonstrating the physiological relevance of our in vitro observations.
TextSentencer_T79 11285-11460 Sentence denotes Our results underline the contribution of CNS resident cells, namely astrocytes, to a microenvironment favoring cytotoxic CD8 T cell responses via sufficient amounts of IL-15.
TextSentencer_T80 11461-11627 Sentence denotes In situ IL-15 has already been shown to promote autoimmune effector CD8 T cell responses in other autoimmune diseases such as rheumatoid arthritis and celiac disease.
TextSentencer_T81 11628-11766 Sentence denotes IL-15 bioavailability in the CNS may be implicated in the exacerbation of tissue damage targeting oligodendrocytes during MS pathogenesis.
TextSentencer_T82 11767-11936 Sentence denotes Diagnosing Multiple Sclerosis (MS) is not always easy because MS and other demyelinating diseases such as neuromyelitis optica (NMO) may be indistinguishable clinically.
TextSentencer_T83 11937-12095 Sentence denotes Although anti-Aquaporin (AQP) 4 antibody can differentiate NMO from MS clinically, the possible link between the two demyelinating diseases remains a mystery.
TextSentencer_T84 12096-12293 Sentence denotes Recent advances in the proteomic technology in search of biomarker or biomarker signature that accurately identifies the clinical syndrome would allow for improved diagnosis and disease monitoring.
TextSentencer_T85 12294-12669 Sentence denotes Magnetic bead-based purification followed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was employed to profile human cerebrospinal fluids (CSF) proteins and peptides in a total of 82 samples from patients with definite MS (remission and relapse), NMO (remission and relapse) and primary progressive multiple sclerosis (PPMS).
TextSentencer_T86 12670-12729 Sentence denotes All study participants gave their written informed consent.
TextSentencer_T87 12730-12879 Sentence denotes We used a reagent set of chemically coated magnetic beads, reversed phase (C8) (ClinProtTM) and a-cyano-4hydroxycinnamic acid as the matrix solution.
TextSentencer_T88 12880-13085 Sentence denotes The eluted samples were then dropped onto a MALDI sample plate (AnchorchipTM), and spectra were obtained by an Autoflex II and a subsequent tandem MS analysis was performed by Ultraflex (Bruker Daltonics).
TextSentencer_T89 13086-13205 Sentence denotes The criteria for peak detection were: signal-to-noise ratio N5, 2-Da peak-width filter, and maximum peak number of 200.
TextSentencer_T90 13206-13341 Sentence denotes The pretreated data were graphed as spectra and evaluated by statistical analysis using the ClinProToolsTM software (Bruker Daltonics).
TextSentencer_T91 13342-13464 Sentence denotes Reproducible profiles were obtained as clear signals and approximately fifty peaks were detected from each of CSF samples.
TextSentencer_T92 13465-13633 Sentence denotes A differential distribution of samples from MS and NMO both in remission was noticeable, while samples from PPMS were not separated effectively using the same platform.
TextSentencer_T93 13634-13811 Sentence denotes One of the key variables contributing to the separation with an m/z of 3511 was defined as c-terminal fragment (182-212) of neuroendocrine peptide 7B2 by the tandem MS analysis.
TextSentencer_T94 13812-14003 Sentence denotes The application of magnetic bead-based separation combined with MALDI-TOF-MS technique for CSF samples holds the potential to advance our understanding of the biochemical basis of MS and NMO.
TextSentencer_T95 14004-14125 Sentence denotes Further studies are required to validate the clinical effectiveness and disease specificity of the identified biomarkers.
TextSentencer_T96 14126-14565 Sentence denotes 6 -Role of granzyme B in T cells-induced neurotoxicity and neuroprotective strategies using the new serine-protease inhibitor Serpina3n 1 Osaka University, Osaka, Japan 2 Boehringer-ingelheim, Osaka, Japan 3 Toyonaka municipal hospital, Osaka, Japan Significant roles of Semaphorin in immune system were reported recently, while it has been investigated mainly as an axonal guidance molecule in the developing central nervous system (CNS).
TextSentencer_T97 14566-14645 Sentence denotes Class 4 semaphorin Sema4A is expressed in antigen presenting cells and T cells.
TextSentencer_T98 14646-14796 Sentence denotes It is suggested to activate T cells via T cell immunoglobulin domain and mucin domain (Tim)-2, and is a critical molecule for the Th1 differentiation.
TextSentencer_T99 14797-14921 Sentence denotes Therefore, we generated monoclonal anti-Sema4A antibodies by immunizing Sema4A-deficient mice, and established ELISA system.
TextSentencer_T100 14922-15088 Sentence denotes We have measured serum levels of Sema4A in 41 multiple sclerosis (MS) patients, 10 patients with spinocerebellar degeneration (SCD) and 15 patients with encephalitis.
TextSentencer_T101 15089-15142 Sentence denotes Statistical analysis was performed by Welch's t-test.
TextSentencer_T102 15143-15280 Sentence denotes Serum Sema4A level was significantly higher in MS patients than patients with SCD and encephalitis (p b 0.001 and p b 0.02 respectively).
TextSentencer_T103 15281-15485 Sentence denotes Especially one-third of patients with MS exhibited marked high level of expression, which suggest the involvement of Sema4A in the pathogenesis of MS and may also suggest heterogeneity of MS pathogenesis.
TextSentencer_T104 15486-15588 Sentence denotes We next investigated the expression of Sema4A in experimental autoimmune encephalomyelitis (EAE) mice.
TextSentencer_T105 15589-15725 Sentence denotes Immunohistochemical examination revealed that infiltrating cells into the spinal cord of EAE mice exhibited marked expression of Sema4A.
TextSentencer_T106 15726-15874 Sentence denotes Overall, these results suggest that Sema4A may be a potential biomarker for MS, and that it may be an important molecule for the pathogenesis of MS.
TextSentencer_T107 15875-16080 Sentence denotes Oligoclonal IgG bands in cerebrospinal fluid (CSF) are found in up to 95% of patients with multiple sclerosis (MS), a chronic inflammatory demyelinating disorder affecting the central nervous system (CNS).
TextSentencer_T108 16081-16430 Sentence denotes An important issue is whether these Igs recognize (1.) a disease-relevant structure [neural targets, e.g. GalCer]; or (2.) a cross-reactive infectious agent [e.g. Mycoplasma, E. coli], or whether they (3.) reflect intrathecal activation of B-lineage cells secreting Igs directed at undetermined specific antigens derived in the inflammatory process.
TextSentencer_T109 16431-16882 Sentence denotes We have postulated a lipid mimicry pathogenesis for the induction of MS autoimmunity, and examined CSF IgGs for cross-reactivity between myelin and microbial lipids focusing respectively upon: (a.) acetyl-cerebrosides designated as FMCs or 'fast migrating cerebrosides' of higher TLC Rf than GalCer and other myelin lipids, (b.) MfGL-II, a glyco-glycero-cholinolipid from M. fermentans, (c.) LPS of E. coli J5 (UK+) strain, and other bacterial lipids.
TextSentencer_T110 16883-17088 Sentence denotes The analysis of 38 patients included 29 CSF samples from MS patients who were further classified into relapsing-remitting (RRMS) (16), secondary progressive (SPMS) (10), and primary progressive (PPMS) (3).
TextSentencer_T111 17089-17226 Sentence denotes Comparison was to nine other neurological disease (OND) controls divided into inflammatory (I-OND) (5) and non-inflammatory (NI-OND) (4).
TextSentencer_T112 17227-17521 Sentence denotes The elevated anti-FMC-7 antibodies were significantly higher in the PPMS group compared to SPMS group (66.67% vs. 0%, p = 0.0385) and in the RRMS in remission group compared to SPMS group (63.64% vs. 0%, p = 0.0039) while lesser changes were found for anti-GalCer and anti-sulfatide antibodies.
TextSentencer_T113 17522-17831 Sentence denotes It is striking and of considerable interest that highly elevated anti-microbial (M. fermentans, E. coli) antibodies were found in meningitis (3 patients), one patient with subacute sclerosing panenecephalitis (SSPE) and one patient with meningoencephalitis (I-OND group) compared to NI-OND control (p b 0.05).
TextSentencer_T114 17832-17944 Sentence denotes It is noteworthy that the anti-lipid antigen elevations occurred in tandem for both microbial and self antigens.
TextSentencer_T115 17945-18218 Sentence denotes The findings are consistent with cross-reactivity of immunoglobulins in human MS CSF between microbial and myelin glycolipids in some MS patients, and suggest a role for microbial surface and myelin antigens, and particularly glycolipid antigens, in the pathogenesis of MS.
TextSentencer_T116 18219-18324 Sentence denotes Further examination of a larger number of MS and control Istituto Tecnologie Biomediche, CNR, Bari, Italy
TextSentencer_T117 18325-18487 Sentence denotes We studied six monozygotic (MZ) twin pairs (5 female and 1 male) discordant for multiple sclerosis (MS) and two disease concordant MZ pairs (1 female and 1 male).
TextSentencer_T118 18488-18606 Sentence denotes Unrelated couples of patient-healthy control subjects were age-and sex-matched to each twin pair and analyzed as well.
TextSentencer_T119 18607-18660 Sentence denotes All patients were free of immunomodulatory treatment.
TextSentencer_T120 18661-18871 Sentence denotes MZ twins and unrelated subjects were analysed independently to avoid that the expected high biological variation between these two groups might prevent the discovery of differentially expressed genes and exons.
TextSentencer_T121 18872-19117 Sentence denotes When array data from MZ twins were loaded and normalized by RMA in oneChannelGUI environment, the subsequent principal component (PCA) analysis confirmed the strong clustering of each twin pair (already observed with other platformsunpublished).
TextSentencer_T122 19118-19441 Sentence denotes To overcome this bias (the observed biological variability among couples of MZ twins was higher than the variability observed into each couple obscuring the identification of differently expressed genes), we imported array data into Partek GS software where an ad hoc ANOVA model could be implemented to handle this effect.
TextSentencer_T123 19442-19637 Sentence denotes After the batch removal a new ANOVA model was built in Partek GS in order to take into account the remaining sources of variation (patient status, gender, the age and all potential interactions).
TextSentencer_T124 19638-19769 Sentence denotes These ANOVA factors were then used to select lists of genes differently expressed and significant to a BH-corrected p-value b 0.05.
TextSentencer_T125 19770-19905 Sentence denotes We focused also on the detection of specific alternative splicing events by means of the identification of differently expressed exons.
TextSentencer_T126 19906-20058 Sentence denotes This analysis was performed in Partek GS environment using an ANOVA model in which the alternative splicing factor was set to the status of the patient.
TextSentencer_T127 20059-20316 Sentence denotes The above parameters identified 10 differentially expressed genes and 1 exon in disease discordant MZ twins, 3 genes and 1383 exons in unrelated patients and healthy controls, 0 genes and 422 exons in healthy co-twins compared to unrelated healthy controls.
TextSentencer_T128 20317-20441 Sentence denotes 121 of these 422 exons were also in the list of 1383 exons differentially expressed between unrelated patients and controls.
TextSentencer_T129 20442-20692 Sentence denotes The gradient in the number of differentially expressed exons among twins (1), among healthy twins and unrelated healthy subjects (422), and among unrelated patients and controls (1383) supports the hypothesis of an "MS trait" in the healthy co-twins.
TextSentencer_T130 20693-20797 Sentence denotes The relevance of the alternative splicing data is being verified by means of specific RT-PCR approaches.
TextSentencer_T131 20798-20868 Sentence denotes Darlington Peter⁎ 1 , Johnson Trina 1 , Bar-or Amit 1 , Antel Jack 1 1
TextSentencer_T132 20869-21027 Sentence denotes Neurons are susceptible to cytotoxic immune-mediated injury in neuro-inflammatory disorders including multiple sclerosis and acute and chronic encephalitides.
TextSentencer_T133 21028-21163 Sentence denotes The restricted expression of MHC molecules on neurons implicates injury mediated by MHC/antigen-independent immune effector mechanisms.
TextSentencer_T134 21164-21358 Sentence denotes Previously, we reported that innate immune cells (NK and gamma-delta-T cells) induced loss of human neurons in vitro consequent to initial destruction of supporting astrocytes (Darlington et al.
TextSentencer_T135 21359-21361 Sentence denotes J.
TextSentencer_T136 21362-21372 Sentence denotes Neuropath.
TextSentencer_T137 21373-21377 Sentence denotes Exp.
TextSentencer_T138 21378-21385 Sentence denotes Neurol.
TextSentencer_T139 21386-21402 Sentence denotes 2008, in press).
TextSentencer_T140 21403-21552 Sentence denotes Short-term anti-CD3-activated T cells did not kill neurons or astrocytes but caused caspase-dependent fragmentation of the cytoskeletal protein GFAP.
TextSentencer_T141 21553-21689 Sentence denotes Our goal was to further characterize the mechanism of such astrocyte injury and determine the overall consequence for neuronal survival.
TextSentencer_T142 21690-21846 Sentence denotes Short-term anti-CD3-activated T cells induced sub-lethal caspase-3 activity, leading to caspase-dependent fragmentation of GFAP in primary human astrocytes.
TextSentencer_T143 21847-21891 Sentence denotes This occurred in a contact dependent manner.
TextSentencer_T144 21892-22012 Sentence denotes Further cytotoxicity experiments indicate that these effects could be attributed to CD8 T cells rather than CD4 T cells.
TextSentencer_T145 22013-22244 Sentence denotes Incubation of anti-CD3 activated CD8 T cells with the exogenous lectin phytohemagglutinin (PHA), which promotes adhesion between cell surface glycosylated receptors, resulted in actual astrocyte cytotoxicity leading to neuron loss.
TextSentencer_T146 22245-22337 Sentence denotes This lectindependent effect was not observed with short term anti-CD3 activated CD4 T cells.
TextSentencer_T147 22338-22477 Sentence denotes However, both polyclonally expanded (short term anti-CD3) and MBP-reactive Th1 CD4 T cells induced lectin-dependent astrocyte cytotoxicity.
TextSentencer_T148 22478-22562 Sentence denotes Th2 polarized CD4 T cells were less cytotoxic than their Th1 polarized counterparts.
TextSentencer_T149 22563-22775 Sentence denotes This data indicates that the extent of T cell-mediated target cell injury is determined by both the intrinsic cytotoxic potential of these cells and the extent of cell-cell contact interaction with their targets.
TextSentencer_T150 22776-22985 Sentence denotes T cells with cytotoxic potential may induce sub-lethal injury of astrocytes when cell-cell interaction is limited; the long term consequence of such astrocyte injury on neuronal survival remains to be defined.
TextSentencer_T151 22986-23343 Sentence denotes Whether there is sufficient up-regulation of cell adhesion molecules in the inflamed CNS to support T cell mediated cytotoxicity and/or whether there are endogenous lectins capable of supporting immune-neural interactions in the CNS also remains to be established. from conventional multiple sclerosis (CMS) for their similarities in clinical manifestation.
TextSentencer_T152 23344-23621 Sentence denotes To investigate the feasibility of diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) assessment of microscopic fiber tract injury in the corpus callosum (CC) and other normal-appearing white matter (NAWM) in patients with NMO and multiple sclerosis (MS) .
TextSentencer_T153 23622-23864 Sentence denotes In this study, we proposed a novel approach, using apparent diffusion coefficient (ADC) and fractional anisotropy (FA) of the brain derived from DTI and MRS as classification feature, to discriminate patients with RNMO/OSMS from CMS in Japan.
TextSentencer_T154 23865-24083 Sentence denotes Twenty patients with RNMO/OSMS (median expanded disability status score [EDSS] 4.6) and 23 CMS patients (median EDSS, range 2.5) were studied with T2 weighted images, DTI, MRS (chemical shift imaging and single voxel).
TextSentencer_T155 24084-24245 Sentence denotes Brain MRS allows in vivo examination of axonal integrity by quantifying the neuronal marker N-acetylaspartate (NAA), often expressed as a ratio to creatine (Cr).
TextSentencer_T156 24246-24418 Sentence denotes We have tested directly the relationship between changes in these DTI parameters and NAA concentrations in the MS lesion, NAWM, and normal appearing corpus callosum (NACC).
TextSentencer_T157 24419-24851 Sentence denotes This study indicates that 1) FA in MS patients was significantly decreased in NACC and NAWM, possibly due to a reduction of smallcaliber axons; 2) the data showed significantly lower FA for posterior limb of internal capsule in RNMO/OSMS patients than in those in CMS patients and healthy volunteers after Bonferroni adjustment, 3) NAA/Cr in RNMO/ OSMS group was significantly decreased in the posterior lobe subdivisions of the WM.
TextSentencer_T158 24852-24979 Sentence denotes The decrease in FA in any of the CC and WM and the decrease of NAA in WM did not correlate with disease duration or EDSS score.
TextSentencer_T159 24980-25237 Sentence denotes In conclusion, the proposed method on the basis of combined features is more effective for classification than those merely using the features separately, and it may be helpful in differentiating RNMO/ OSMS from CMS patient. controls than in MS (p = 0.016).
TextSentencer_T160 25238-25326 Sentence denotes No differences between groups in concentrations of IL-17, IL-13 and IL-10 were observed.
TextSentencer_T161 25327-25527 Sentence denotes Our results indicate that no apparent deviation of immune regulatory T cell phenotypes can be seen at a systemic level with regard to transcriptional deviation and in vivo cytokine secretory patterns.
TextSentencer_T162 25528-25778 Sentence denotes Although both T-bet and RORC display higher relative expression in MS, representing a transcriptional deviation towards the Th17 and Th1 phenotypes, this has to be evaluated together with the finding that IFN-g was decreased in plasma of MS patients.
TextSentencer_T163 25779-25916 Sentence denotes Subsequent analysis of subgroups of MS, as well as cytokine levels and transcription factor expression in cerebrospinal fluid will ensue.
TextSentencer_T164 25917-26088 Sentence denotes 16 -The persistency of high levels of PSTAT3 expression in circulating CD4+ T cells from CIS patients favours the early conversion to clinically defined multiple sclerosis
TextSentencer_T165 26090-26217 Sentence denotes Not all patients with clinically isolated syndrome (CIS) suggestive of multiple sclerosis develop clinically defined MS (CDMS).
TextSentencer_T166 26218-26414 Sentence denotes In this study we evaluated the expression of T-bet, pSTAT1, pSTAT3 in CD4+ and CD8+ T cell and monocytes from peripheral blood of CIS patients during and 3-6 months after the first clinical event.
TextSentencer_T167 26415-26564 Sentence denotes Furthermore we correlated the expression of transcription factors with patient clinical outcome and with IFNg production, IL6, IL17 and IL10 by PBMC.
TextSentencer_T168 26565-26642 Sentence denotes In our study we included 18 CIS patients and 20 sex and age matched controls.
TextSentencer_T169 26643-26729 Sentence denotes Detection of pSTAT-1, pSTAT-3 and T-bet was performed by intracellular flow cytometry.
TextSentencer_T170 26730-26803 Sentence denotes The production of IFNg, IL17, IL6 and IL10 by PBMC was measured by ELISA.
TextSentencer_T171 26804-26937 Sentence denotes Higher levels of pSTAT1 and pSTAT3 were observed in CD4+T cells and in monocytes from CIS patients in acute phase than from controls.
TextSentencer_T172 26938-27167 Sentence denotes T-bet expression was higher only in monocytes from CIS patients in acute phase than in ones from controls. pSTAT1 and T-bet expression were higher in CD14+ cells from patients in acute phase than from patients in remission phase.
TextSentencer_T173 27168-27275 Sentence denotes IFNgamma, IL17 and IL10 levels were significantly higher in CIS patients in acute phase than from controls.
TextSentencer_T174 27276-27358 Sentence denotes IFNg levels decreased in remission phase while IL17 and IL10 levels remained high.
TextSentencer_T175 27359-27420 Sentence denotes During the follow-up period, 8/18 patients converted to CDMS.
TextSentencer_T176 27421-27725 Sentence denotes In acute phase both groups of patients who did or did not converted to CDMS showed higher expression of pSTAT1 and pSTAT3 in CD4+ T cells and higher expression of T-bet and pSTAT3 in CD14+ cells than controls while only non-converted patients showed higher pSTAT1 expression in CD14+ cells than controls.
TextSentencer_T177 27726-27806 Sentence denotes Both groups of patients showed higher production of IFNg and IL10 than controls.
TextSentencer_T178 27807-27927 Sentence denotes In remission CIS patients who converted to CDMS showed higher pSTAT1 and pSTAT3 expression in CD4+T cells than controls.
TextSentencer_T179 27928-28030 Sentence denotes In addition pSTAT3 expression was higher in CD4+ cells from converted than from nonconverted patients.
TextSentencer_T180 28031-28205 Sentence denotes Both groups of patients showed higher production of IFNg and IL10 than controls while only IL10 was higher in patients who did than in patients who did not converted to CDMS.
TextSentencer_T181 28206-28412 Sentence denotes IL17 seems to play a pathogenetic role in CIS and the persistency of high levels of pSTAT3 in circulating CD4+T cells from CIS patients after the first clinical event may favor the early conversion to CDMS.
TextSentencer_T182 28413-28522 Sentence denotes 17 -The relapsing dynamics of multiple sclerosis depends on control properties of peripheral immune tolerance
TextSentencer_T183 28524-28633 Sentence denotes Autoimmunity is characterized by the presence of a relapsingremitting dynamics such as in Multiple Sclerosis.
TextSentencer_T184 28634-28862 Sentence denotes The goal of our study was to demonstrate that this relapsing-remitting dynamic can be generated by a failure in the feed-back control of two competing populations regulating peripheral tolerance: effector and regulatory T cells.
TextSentencer_T185 28863-29031 Sentence denotes We developed a computational model of the human immune system, using the Systems Dynamics framework and stochastic differential equations based in biological knowledge.
TextSentencer_T186 29032-29229 Sentence denotes Our analysis shows that by fine-tuning the parameters regulating the negative feedback between effector and regulatory T-cells, the immune system is able to generate a relapsing-remitting dynamics.
TextSentencer_T187 29230-29361 Sentence denotes Such autoimmune dynamic was stable and obtained in a wide range of parameters close to the normal functioning of the immune system.
TextSentencer_T188 29362-29518 Sentence denotes In addition, we found that stochastic stimulation of the immune system strongly influences the timing at which relapses appear, preventing their prediction.
TextSentencer_T189 29519-29715 Sentence denotes We also found some unexpected predictions because the increase in the activity of effector T-cells in some circumstances generates a strong control response that prevents the presence of relapses.
TextSentencer_T190 29716-29866 Sentence denotes Finally, we introduced perturbations into the model mimicking immunotherapies aimed to increase the activity of either effector or regulatory T-cells.
TextSentencer_T191 29867-30239 Sentence denotes We demonstrate that the effect of such therapies was highly dependent on the timing and the underlying dynamic of the immune system, implying that immunotherapies must be developed in a personalized manner and focused in obtaining a healthier dynamic in the control module of the peripheral tolerance, more than in keeping the absolute number of T-cells in certain ranges.
TextSentencer_T192 30240-30369 Sentence denotes In summary, our study provides a view of autoimmunity as a dynamic process and provides new clues for developing immunotherapies.
TextSentencer_T193 30370-30485 Sentence denotes Helminth infections concurrent with MS significantly reduce disease severity, as previously shown by these authors.
TextSentencer_T194 30486-30745 Sentence denotes Growing evidence indicates that B cells play a key role in restraining unwanted self-reactive T cell responses in different autoimmune models in mice, and that helminth infections in MS patients give rise to a B cell population producing high levels of IL-10.
TextSentencer_T195 30746-30836 Sentence denotes Toll-like receptors (TLR) function as sentinels recognizing different microbial molecules.
TextSentencer_T196 30837-31011 Sentence denotes To elucidate the role of TLR in helminth infections, we examined the expression of TLR-2, TLR-4, TLR-5, and TL-9 on B cells in helminthinfected and in uninfected MS patients.
TextSentencer_T197 31012-31174 Sentence denotes Peripheral blood CD19+ B cells from 12 helminth-infected MS subjects, 12 uninfected MS patients and 12 healthy controls were purified using magnetic cell sorting.
TextSentencer_T198 31175-31328 Sentence denotes Surface expression of TLR-2 on B cells was significantly higher in helminth-infected MS patients compared to uninfected MS patients and healthy controls.
TextSentencer_T199 31329-31409 Sentence denotes No differences in TLR-4, TLR-5 or TLR-9 expression were observed between groups.
TextSentencer_T200 31410-31556 Sentence denotes Moreover, in helminth-infected MS patients TLR-2 engagement induced preferential expansion of IL-10 secreting B cells in a MyD88-dependent manner.
TextSentencer_T201 31557-31856 Sentence denotes To examine whether this differential activation of regulatory B cells had an impact on T cell immune responses, B cells previously stimulated with TLR-2 ligands were cocultured with allogenic CD4+ FoxP3-T cells, and examined by flow cytometry for FoxP3 expression and IL-17 and IFN-gamma production.
TextSentencer_T202 31857-32072 Sentence denotes TLR-2 stimulated B cells were highly efficient in inducing FoxP3 expression on alloreactive T cells, converting over 50% to FoxP3 positivity, whereas TLR-4, TLR-5 and TLR9 engagements did not alter FoxP3 expression.
TextSentencer_T203 32073-32178 Sentence denotes Likewise, following TLR-2 stimulation, B cells induced the generation of IL-10 producing FoxP3-Tr1 cells.
TextSentencer_T204 32179-32392 Sentence denotes Moreover, the percentage of CD4+ T cells expressing IFN-gamma and IL-17 was significantly lower in cultures containing B cells stimulated with TLR-2 agonists, compared to those activated via TLR-4, TLR-5 or TLR-9.
TextSentencer_T205 32393-32521 Sentence denotes In this experimental setting, suppression of both IFN-gamma and IL-17 was abrogated when MyD88 expression was silenced by siRNA.
TextSentencer_T206 32522-32709 Sentence denotes Our data indicate that IL-10 producing B cells link recognition of helminth products via TLR-2, providing a novel target for the parasites to suppress T cell-mediated autoimmune diseases.
TextSentencer_T207 32710-32953 Sentence denotes 19 -CD4+CD25+FOXP3+PD1− naïve regulatory T cells in acute and stable relapsing-remitting multiple sclerosis and their modulation by therapy Regulatory T cells (Treg) play a fundamental role in preventing immune reactions against self antigens.
TextSentencer_T208 32954-33179 Sentence denotes Recent data suggest that the intracellular expression of the programmed death receptor 1 (PD1) identifies a subset of naïve Treg with enhanced suppressive ability; antigen stimulation results in the surface expression of PD1.
TextSentencer_T209 33180-33442 Sentence denotes Because the role of Treg impairments in MS is still contradictory, we analyzed naïve (CD4+CD25++FoxP3+PD1−) and activated (CD4+CD25++FoxP3+ PD1+) Treg in peripheral blood of 50 relapsing-remitting Multiple Sclerosis (RR-MS) patients and of healthy controls (HC).
TextSentencer_T210 33443-33533 Sentence denotes CSF of 5 MS patients and 5 individuals with non-inflammatory conditions was also examined.
TextSentencer_T211 33534-33700 Sentence denotes Results showed that, whereas CSF naïve Treg were significantly augmented in MS patients, these cells were comparable in the peripheral blood of patients and controls.
TextSentencer_T212 33701-33993 Sentence denotes Clinical sub analyses nevertheless demonstrated that peripheral naïve Treg were significantly increased in patients with stable (SMS) compared to those with relapsing (AMS) disease, and in patients responding to Glatimer Acetate (Copaxone; COPA) compared to AMS and COPA-unresponsive patient.
TextSentencer_T213 33994-34086 Sentence denotes In contrast, activated Treg were similar in CSF and peripheral blood of all groups analyzed.
TextSentencer_T214 34087-34333 Sentence denotes Naïve Treg were not increased in the peripheral blood of interferon b (IFNb)-responsive patients, but the suppressive ability of Treg was significantly higher in SMS and in COPA-or IFNb-responsive compared to AMS and COPA-unresponsiveindividuals.
TextSentencer_T215 34334-34539 Sentence denotes The data herein suggest that naïve Treg play a pivotal role in the pathogenesis of MS and offer a biological explanation for disease relapse and for the mechanism associated with response to COPA and IFNb.
TextSentencer_T216 34540-34784 Sentence denotes Clinically isolated syndrome (CIS) represents first neurological symptoms suggestive of demyelinating lesion in the central nervous system (CNS) according to magnetic resonance imaging (MRI) with the risk of multiple sclerosis (MS) development.
TextSentencer_T217 34785-34928 Sentence denotes So far there are no sufficient immunological markers predicting even disease activity or efficiency of registered CIS treatmentinterferon beta.
TextSentencer_T218 34929-34946 Sentence denotes Aim of the study:
TextSentencer_T219 34947-35252 Sentence denotes To compare immunological status before and after 6 months of interferon beta 1-a, 30 μg intramuscularly once weekly (IFNb) treatment in two groups of CIS patients: responders (R) and non-responders (NR) to IFNb therapy according to clinical and MRI disease activity within the first year of the treatment.
TextSentencer_T220 35253-35274 Sentence denotes Patients and methods:
TextSentencer_T221 35275-35451 Sentence denotes Peripheral blood was taken before any treatment and after 6 months of IFNb therapy in 17 CIS patients (8 Raverage age 30 years, F/M = 5/3, 9 NRaverage age 32 years, F/M = 6/3).
TextSentencer_T222 35452-35609 Sentence denotes CIS was defined as a first demyelinating event with at least 2 lesions on T2W or FLAIR MRI images and positivity of oligoclonal bands in cerebrospinal fluid.
TextSentencer_T223 35610-35728 Sentence denotes NR was defined by occurrence of at least one relapse and one new T2W lesion on MRI during first year of the treatment.
TextSentencer_T224 35729-35909 Sentence denotes Flow cytometer FACSCalibur and monoclonal antibodies BD Bioscience were used for mononuclear cells immunophenotyping (CD3, CD4, CD8, CD19, CD3-CD16, 56+, and CD45RA subpopulation).
TextSentencer_T225 35910-36043 Sentence denotes Student t test and Pearson correlation were used for statistical analysis, intergroup paired comparisons were performed using MANOVA.
TextSentencer_T226 36044-36284 Sentence denotes The only statistically significant correlation was found between amount of CD19+ cells in the peripheral blood before any treatment and relapse frequency during the first year of IFNb treatment (p = 0.004, r = − 0.9759) in five NR patients.
TextSentencer_T227 36285-36447 Sentence denotes There was no other statistically significant correlation or intergroup difference between any of the tested immunological markers and IFNb treatment responsivity.
TextSentencer_T228 36448-36623 Sentence denotes Based on our preliminary results number of CD19+ cells in the peripheral blood may be one of the immunological markers in MS prognosis and determination of treatment efficacy.
TextSentencer_T229 36624-36878 Sentence denotes Multiple Sclerosis (MS) is an autoimmune central nervous system (CNS) disease characterized by inflammatory infiltrates in alongside demyelinated axons, axonal transections and degenerating neurons; the exact pathological process though is still unclear.
TextSentencer_T230 36879-37061 Sentence denotes We have been exploring the possibility that innate immune responses are involved in disease immunopathogenesis, in particular gammadelta T cells which are concentrated in MS lesions.
TextSentencer_T231 37062-37270 Sentence denotes We have previously reported on gammadelta T cell direct cytotoxicity and cytokine release, but here we examine the possibility that injury can also be mediated via antibody dependent cell cytotoxicity (ADCC).
TextSentencer_T232 37271-37332 Sentence denotes Autoantibodies to myelin components are found in MS patients.
TextSentencer_T233 37333-37505 Sentence denotes Activated gammadelta T cells up-regulate the expression of Fcg receptor (CD16) raising the possibility that they can bind antibody which facilitates ADCC-type interactions.
TextSentencer_T234 37506-37659 Sentence denotes An in vitro experimental system was established using a humanized anti-CD20 antibody rituximab as the bridging antibody and CD20+ B lymphomas as targets.
TextSentencer_T235 37660-37754 Sentence denotes Cytotoxicity was measured with in-house developed multiple parameter flow cytometry technique.
TextSentencer_T236 37755-38187 Sentence denotes Our results show that, with E:T ratio at 4:1, the ADCC cytotoxicity of gammadelta T cells against the target cell lines was significantly increased by the presence of rituximab (p b 0.02), and this effect could be abrogated by removal of Fc portion of the antibody (p b 0.05 vs. integral rituximab) or by using CD16-effector cells (p b 0.05 vs. CD16+ population), suggesting a CD16-specific antibody-mediated cytolytic contribution.
TextSentencer_T237 38188-38358 Sentence denotes Furthermore, by using intracytoplasmic flow cytometry, we found that antibodycoated target cells could induce the production of both Th cytokines from gammadelta T cells.
TextSentencer_T238 38359-38482 Sentence denotes Interestingly, the capability of producing Th2 subtype cytokines is exclusively resided in the CD16+ population (p b 0.05).
TextSentencer_T239 38483-38811 Sentence denotes Our findings tie together the innate and adaptive immune responses through an interaction that involves the stimulation of antibody production, possibly against CNS molecules such as myelin, via CD16 expressing gammadelta T cells that could use these antibodies to enact a guided attack on CNS targets via the mechanism of ADCC.
TextSentencer_T240 38812-38980 Sentence denotes This study offers further novel insights into the possible role of gammadelta T cells in MS that can involve both potentially pathogenic and immunoregulatory functions.
TextSentencer_T241 38981-39063 Sentence denotes Natural Killer (NK) cells are a major effector cell of the innate immune response.
TextSentencer_T242 39064-39134 Sentence denotes Their relevance to several autoimmune diseases is under investigation.
TextSentencer_T243 39135-39210 Sentence denotes Valleys in cytotoxicity been implicated in multiple sclerosis (MS) relapse.
TextSentencer_T244 39211-39305 Sentence denotes Cytotoxicity may be one way NK cells regulate the nature and scale of the autoimmune response.
TextSentencer_T245 39306-39561 Sentence denotes Our objective was to examine NK cytotoxicity in newly diagnosed treatment naive MS subjects, not in relapse, and compare it to age and sex matched healthy controls and controls from another static neurological condition: stable chronic spinal cord injury.
TextSentencer_T246 39562-39570 Sentence denotes Methods:
TextSentencer_T247 39571-39724 Sentence denotes A four-hour chromium 51 release assay using a K562 target cell line was used, with the laboratory technician blind to the clinical status of the subject.
TextSentencer_T248 39725-39828 Sentence denotes Three different effector:target (E:T) cell ratios were studied, these were analyzed with paired t test.
TextSentencer_T249 39829-39837 Sentence denotes Results:
TextSentencer_T250 39838-40039 Sentence denotes Eighteen MS subjects naïve to any immunotherapy, 23 spinal cord injured (SCI) subjects with static neurologic deficits, as well as their individually matched by age and sex healthy laboratory controls.
TextSentencer_T251 40040-40311 Sentence denotes There is a statistically significant reduction in NK percent kill in both the MS subjects as compared to their age and sex matched controls (at 25:1 mean 5.7 SEM 1.8 vs. 17.9 SEM 2.6; at 50:1 mean 14.7 SEM 2.7 vs 32.0 SEM 3.9; at 100:1 mean 25.0 SEM 3.9 vs 42.1 SEM 4.5).
TextSentencer_T252 40312-40493 Sentence denotes This difference was statistically significant at all three E:T cell ratios (t = 3.9, df = 17 p = 0.001; at 50:1 t = 4.50 df = 17, p = 0.003; at 100:1, t = 3.65, df = 17; p = 0.002).
TextSentencer_T253 40494-40718 Sentence denotes For the 23 SCI subjects there was a statistically significant reduction in NK percent kill as compared to their age and sex matched controls at only the 25:1 (mean 10.6 SEM 2.9 vs. 27.8 SEM 8.0; t = 2.34, df = 22, p = 0.03).
TextSentencer_T254 40719-40820 Sentence denotes Although there were trends for the other two E:T ratios, they did not reach statistical significance.
TextSentencer_T255 40821-41073 Sentence denotes The MS subjects naïve to treatment with minimal neurologic deficits have a significant reduction in NK cytotoxic ability, as compared to health controls and as compared to a group with severe but static neurologic impairment without autoimmune disease.
TextSentencer_T256 41074-41224 Sentence denotes This supports the concept of intrinsic NK cytotoxicity dysfunction early in the MS disease process, possibly contributing to autoimmune dysregulation.
TextSentencer_T257 41225-41409 Sentence denotes Since there is evidence that their cytotoxic ability may be one way NK cells orchestrate their neuroregulation, these data would implicate them as potential targets for future therapy.
TextSentencer_T258 41410-41474 Sentence denotes Vereyken Elly 1 , Dijkstra Christine 1 , Teunissen Charlotte 1 1
TextSentencer_T259 41476-41635 Sentence denotes It is widely recognized that macrophages play an important role in the pathogenesis of multiple sclerosis (MS), having both beneficial and detrimental effects.
TextSentencer_T260 41636-41761 Sentence denotes Depletion of infiltrating macrophages has a suppres-sive effect on clinical signs of experimental allergic encephalomyelitis.
TextSentencer_T261 41762-41874 Sentence denotes Conversely, elimination of macrophages leads to impaired remyelination after lysolecithin induced demyelination.
TextSentencer_T262 41875-41977 Sentence denotes Different subtypes of macrophages exist with different functions in immune response and tissue repair.
TextSentencer_T263 41978-42135 Sentence denotes Two extremes are classically activated (CA) macrophages, which can be cytotoxic, and alternatively activated (AA) macrophages, which can be growth promoting.
TextSentencer_T264 42136-42300 Sentence denotes Both types of macrophages have been found in MS lesions, with CA being located mostly at the active border and AA more in the center of the lesion and perivascular.
TextSentencer_T265 42301-42508 Sentence denotes Due to these differences in localization our question became whether differently activated macrophages migrated differently and could be attracted by different cell types in the central nervous system (CNS).
TextSentencer_T266 42509-42670 Sentence denotes We studied the migration of differently activated macrophages in organotypic CNS cultures and the effect of either demyelination or neuronal damage on migration.
TextSentencer_T267 42671-42810 Sentence denotes Finally, the intrinsic migratory capacity of macrophages was studied by directed migration over a filter under the influence of chemokines.
TextSentencer_T268 42811-42906 Sentence denotes A higher number of AA macrophages migrated into untreated spheroids compared to CA macrophages.
TextSentencer_T269 42907-43006 Sentence denotes This difference in migration was also seen after the induction of demyelination or neuronal damage.
TextSentencer_T270 43007-43117 Sentence denotes Comparing demyelination and neuronal damage no difference in the number of migrating macrophages was observed.
TextSentencer_T271 43118-43286 Sentence denotes Both CA and AA macrophages could migrate deep into the spheroids and reach neuronal cell bodies and axons, however this was observed more frequently for AA macrophages.
TextSentencer_T272 43287-43459 Sentence denotes To study whether the differences in migration were due to intrinsic migratory capacity of the macrophages, we studied the migration across a filter in a blind well chamber.
TextSentencer_T273 43460-43562 Sentence denotes A higher number of AA macrophages migrated in response to CXCL12 and MCP-1 compared to CA macrophages.
TextSentencer_T274 43563-43694 Sentence denotes Macrophages migrated very well towards neuronally conditioned medium, indicating the presence of a soluble chemokine in the medium.
TextSentencer_T275 43695-43813 Sentence denotes The intrinsic migratory capacity of AA macrophages is greater compared to CA macrophages, even in the CNS environment.
TextSentencer_T276 43814-43964 Sentence denotes In spheroids AA macrophages migrate deeper, possibly due to neuronal attraction, which might also play a role in the localization of AA in MS lesions.
TextSentencer_T277 43965-44091 Sentence denotes 24 -Interferon-beta signal transduction, multiple sclerosis and auto-antibodies antibodies to phenotype specific cell subsets.
TextSentencer_T278 44092-44140 Sentence denotes The cells were then analyzed by multicolor FACS.
TextSentencer_T279 44141-44227 Sentence denotes In a second step we simplified the method for antibody detection by using a cell line.
TextSentencer_T280 44228-44359 Sentence denotes We have been able to evaluate signaling of interferon-beta in autologous sera and serum free media of treated and non-treated RRMS.
TextSentencer_T281 44360-44466 Sentence denotes By using a cell line and sera of RRMS patients we could rapidly detect auto-antibodies to interferon beta.
TextSentencer_T282 44467-44694 Sentence denotes Multi colour flow cytometry in conjunction with phosphoantibodies is a powerful reproducible tool to detect immediate effects of agents and molecules such as auto-antibodies or inhibitors on signaling pathways in primary cells.
TextSentencer_T283 44695-44822 Sentence denotes Defects in immune regulation could result in a breakdown of immune tolerance leading to development of Multiple Sclerosis (MS).
TextSentencer_T284 44823-45031 Sentence denotes It was postulated that because of molecular mimicry with cross-reacting and yet undefined epitopes, autoreactive T cells are activated, peripheral tolerance is broken, and disease is initiated or reactivated.
TextSentencer_T285 45032-45081 Sentence denotes The immune impairment of MS is extremely complex.
TextSentencer_T286 45082-45280 Sentence denotes Because the PD-1/PD-L1 pathway was shown to be associated with the production of the immunoregulatory cytokine IL-10, an impairment in these molecules could be associated with the development of MS.
TextSentencer_T287 45281-45499 Sentence denotes The aims of this study were to analyse the possible role of PD-L1/PD1 costimulatory pathway in the onset and the progression of MS and to verify whether immunotherapy has an effect on the expression of these molecules.
TextSentencer_T288 45500-45609 Sentence denotes We enrolled in the study 50 relapsing-remitting Multiple Sclerosis (RR-MS) patients subdivided in two groups:
TextSentencer_T289 45610-45682 Sentence denotes 26 with acute, relapsing disease (AMS) and 24 with stable disease (SMS).
TextSentencer_T290 45683-45878 Sentence denotes The expression of the costimulatory molecules PD-L1 and PD-1 as well as IL-10 production by myelin basic protein (MBP)-stimulated peripheral blood mononuclear cells was analysed by flowcytometry.
TextSentencer_T291 45879-46000 Sentence denotes The effects of different immunotherapies (Glatimer Acetate, Copaxone; COPA and interferon beta IFNb) were also evaluated.
TextSentencer_T292 46001-46359 Sentence denotes Results showed that the percentage of CD14+ and CD19+ cells expressing PD-L1 was reduced in AMS compared to SMS individuals (p = 0.038); this was associated with an important decrease in IL-10 production by MBP-stimulated CD14+ and CD19+ cells in the same patients (p = 0.025) COPA and IFN-beta treatment did not influence PD-L1/PD-1 costimulatory molecules.
TextSentencer_T293 46360-46548 Sentence denotes In conclusion our data suggest that impairments of thePD-L1/PD-1pathway resulting in a reduction of IL-10 production could play an important role in the pathogenesis of Multiple Sclerosis.
TextSentencer_T294 46549-46682 Sentence denotes Monitorage of the expression of these proteins could be a novel diagnostic tool. remitting multiple sclerosis (MS) for over a decade.
TextSentencer_T295 46683-46914 Sentence denotes Its mechanism of action remains elusive, although recent studies have suggested that multiple cellular and/or soluble factors might be involved in mediating GA's effects in MS and in experimental autoimmune encephalomyelitis (EAE).
TextSentencer_T296 46915-46971 Sentence denotes NK cells are potentially regulatory cells in MS and EAE.
TextSentencer_T297 46972-47041 Sentence denotes The fractalkine receptor, CX3CR1, is expressed on glial cells in CNS.
TextSentencer_T298 47042-47151 Sentence denotes Soluble fractalkine and CX3CR1 dictate the migration of NK cells to the CNS under pathological circumstances.
TextSentencer_T299 47152-47244 Sentence denotes Consequently, NK cells homing to the CNS is significantly impaired in CX3CR1 deficient mice.
TextSentencer_T300 47245-47358 Sentence denotes To investigate whether the impaired homing of NK cells to CNS influence the therapeutic effects of GA during EAE.
TextSentencer_T301 47359-47446 Sentence denotes EAE was induced in CXCR1−/− mice by immunization of MOG35-55 peptide with adjuvant CFA.
TextSentencer_T302 47447-47537 Sentence denotes Groups of wild type mice and CXCR1−/− mice were treated with GA or PBS upon EAE induction.
TextSentencer_T303 47538-47603 Sentence denotes Clinical parameters were monitored and compared among the groups.
TextSentencer_T304 47604-47802 Sentence denotes GA conferred moderate protection against EAE in wild type mice (mean clinical score 2.43 ± 0.24 vs. 1.56 ± 0.19, p b 0.05; maximum clinical score 4.0 ± 0.50 vs. 3.12 ± 0.21, p b 0.05, respectively).
TextSentencer_T305 47803-48020 Sentence denotes In contrast, GA treatment did not alter clinical course of EA E in CXCR1−/− mice (mean clinical score 2.78 ± 0.28 vs. 2.84 ± 0.29, p b 0.05; maximum clinical score 4.13 ± 0.51 vs. 4.12 ± 0.62, p N 0.05, respectively).
TextSentencer_T306 48021-48122 Sentence denotes Here we demonstrated that the therapeutic effects of GA in EAE are completely lost in CX3CR1−/− mice.
TextSentencer_T307 48123-48289 Sentence denotes Our current works focus on dissecting how NK cells might contribute to the therapeutic effects of GA using the combination of cell transfer and monoclonal antibodies.
TextSentencer_T308 48290-48498 Sentence denotes 27 -Induction of IL-12/IL-23 by Substance P in human PBMC and expression of Substance P receptor in peripheral blood of MS patients Substance P (SP) is a neuropeptide stored in the termini of sensory neurons.
TextSentencer_T309 48499-48611 Sentence denotes SP induces pro-inflammatory cytokines and mediates its effects by binding to specific Neurokinin (NK) receptors.
TextSentencer_T310 48612-48805 Sentence denotes Previous studies have shown that NK-1 receptor antagonist reduces clinical and histological signs of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS).
TextSentencer_T311 48806-48946 Sentence denotes IL-23 is a member of the IL-12 cytokine family that drives a pathogenic T cell population involved in the initiation of EAE and possibly MS.
TextSentencer_T312 48947-49018 Sentence denotes The expression and function of SP and NK-1 receptor in MS is not clear.
TextSentencer_T313 49019-49212 Sentence denotes Objectives: (1) To determine the effects of Substance P on IL-12p35, IL-12p40 and IL-12p19 expression in normal PBMC. (2) To determine the expression of NK-1 receptor in peripheral blood in MS.
TextSentencer_T314 49213-49381 Sentence denotes Method: (1) Normal PBMC were treated with SP (10^-6 M), SP (10^-6 M) + SP NK-1 receptor antagonist, SP (10^-6 M) + NK-1 pseudoantagonist, 1 μg LPS and control for 24 h.
TextSentencer_T315 49382-49475 Sentence denotes Quantitative real time PCR (qPCR) was performed with IL-12p35, IL-12p40 and IL-23p19 primers.
TextSentencer_T316 49476-49664 Sentence denotes Values were normalized with beta2 microglobulin (B2MG). (2) RNA was extracted from 15 whole blood MS samples and 9 controls, qPCR was performed with NK-1 primers, data normalised via B2MG.
TextSentencer_T317 49665-49860 Sentence denotes Results: (1) Treatment with SP increased the relative quantity of IL-12p40, IL-12p35 and IL-23p19 in PBMC 2) The relative quantity of NK-1 receptor RNA in MS patients was significantly lower than
T85978 49861-49983 Sentence denotes Natalizumab therapy reduces the number of CD4+ T cells within the CSF ten-fold more than the number of CD8+ T lymphocytes.
T95419 49984-50080 Sentence denotes In addition, the effect on cell numbers persists at least 6 months after cessation of treatment.
T45400 50081-50363 Sentence denotes To extend our studies on the prolonged, and differential, effect of natalizumab on T lymphocyte numbers in the CSF, we investigated the number and phenotypes of leukocytes, and the expression of major histocompatibility complex (MHC) I and II in cerebral perivascular spaces (CPVS).
T97103 50364-50459 Sentence denotes We hypothesized that natalizumab reduces the number of antigen presenting cells (APCs) in CPVS.
T59369 50460-50676 Sentence denotes Inflammatory cell numbers in the CPVS of cerebral tissue were assessed by immunohistochemical staining from a patient with MS who developed progressive multifocal leukoencephalopathy (PML) during natalizumab therapy.
T65630 50677-50875 Sentence denotes Controls included location-matched cerebral autopsy material of patients without CNS disease, MS patients not treated with natalizumab, and patients with PML not associated with natalizumab therapy.
T73705 50876-51059 Sentence denotes The absolute number of CPVS in the patient with MS treated with natalizumab was significantly lower than in all control groups due to extensive destruction of the tissue architecture.
T72899 51060-51234 Sentence denotes The expression of MHC class II molecules, and the numbers of CD209+ dendritic cells (DC) were significantly decreased in CPVS in the patient with MS treated with natalizumab.
T29710 51235-51267 Sentence denotes No CD4+ T cells were detectable.
T14620 51268-51387 Sentence denotes Our observations may explain the differential and prolonged effects of natalizumab therapy on leukocyte numbers in CSF.
T94853 51388-51590 Sentence denotes Multiple sclerosis (MS) is an inflammatory disease of the central nervous system in which axonal damage and degeneration contribute significantly to the progressive irreversible neurological disability.
T33079 51591-51742 Sentence denotes Similar to pathogenic myelin autoimmunity, autoimmune responses to neuronal antigens may contribute to axonal damage and irreversible disability in MS.
T23795 51743-51938 Sentence denotes Autoantibodies to the axonal cytoskeletal protein neurofilament light (NF-L) are associated with cerebral atrophy in MS and we have recently reported that NF-L autoimmunity is pathogenic in mice.
T43087 51939-52012 Sentence denotes However the T-cell response to NF-L in MS patients has not been examined.
T12823 52013-52179 Sentence denotes Here we identify and characterize T-cell proliferative responses to NF-L as compared to myelin oligodendrocyte glycoprotein (MOG) in MS patients and healthy controls.
T74687 52180-52400 Sentence denotes Using a carboxyfluorescein succinimidyl ester (CFSE) dilution assay we show that while responses to MOG are dominated by CD3+CD4+ T cells, responses to NF-L were observed in both CD3+CD4+ and CD3+CD8+ T-cell populations.
T7729 52401-52485 Sentence denotes Both MOG and NF-Lreactive cells expressed CD45RO+, indicative of a memory phenotype.
T50689 52486-52738 Sentence denotes Moreover, in contrast to MOG-stimulation which predominantly induced interferon-gamma, both Th1 and Th2-type T-cell responses to NF-L were observed as indicated by the induction of interferon-gamma, tumor necrosis factor-alpha as well as interleukin-4.
T62002 52739-52963 Sentence denotes The finding of T-cell responses to NF-L in MS patients may reflect transient activation of pathogenic potential but their presence also in healthy controls indicates that these cells are part of the normal immune repertoire.
T87379 52964-53210 Sentence denotes School of Biochemistry and Immunology, Dublin, Ireland MS patients treated with IFN beta have been reported to have reduced levels of pro-inflammatory cytokines such as IFN gamma and increased levels of anti-inflammatory cytokines, such as IL-10.
T53551 53211-53275 Sentence denotes However, the precise mechanism of action of IFN beta is unclear.
T19431 53276-53475 Sentence denotes Antigen presenting cells, particularly dendritic cells (DC), play a crucial role in directing T cell responses via the production of regulatory cytokines including the IL-12 family members and IL-10.
T71819 53476-53628 Sentence denotes IL-12 promotes the induction of IFN gamma-secreting T helper (Th) 1 cells, whereas IL-10 promotes the development of IL-10-secreting regulatory T cells.
T79193 53629-53835 Sentence denotes Recently, the IL-12 family member IL-23, together with IL-6 and IL-1, has been shown to promote the development of Th17 cells, which have been demonstrated to play a pathogenic role in autoimmune disorders.
T99264 53836-54045 Sentence denotes A protective role for IL-27, another IL-12 family member, has been demonstrated in the experimental autoimmune encephalitis (EAE) model, where it antagonises the induction of Th17 cells by up-regulating IL-10.
T35036 54046-54155 Sentence denotes Therefore, in this study we investigated the effect of IFN beta treatment on production of IL-27 by human DC.
T37926 54156-54201 Sentence denotes DC were stimulated with recombinant IFN beta.
T21908 54202-54260 Sentence denotes After 24 h, cytokine concentrations were assayed by ELISA.
T601 54261-54334 Sentence denotes Cells were stained for expression of ILT3 and analysed by flow cytometry.
T69444 54335-54478 Sentence denotes Alternatively, DC were cultured in the presence of IFN beta, activated with TLR ligands for 24 h, and used to stimulate allogenic CD4+ T cells.
T50062 54479-54542 Sentence denotes After 5 days, supernatants were assayed by ELISA for cytokines.
T27608 54543-54618 Sentence denotes We demonstrated that IFN beta enhanced production of IL-27 and IL-10 by DC.
T65176 54619-54766 Sentence denotes Furthermore, stimulation of allogenic CD4+ T cells with DC grown in the presence of IFN beta increased T cell IL-10 and decreased IL-17 production.
T27208 54767-54902 Sentence denotes Treatment of DC with IFN beta also upregulated the expression of ILT3, a cell surface inhibitory molecule and marker of tolerogenic DC.
T29418 54903-55081 Sentence denotes These data suggest that IFN beta may exert some of its protective effects by modulating the cytokine profile of both DC and T cells and by expanding or activating tolerogenic DC.
T71673 55082-55164 Sentence denotes Naïve CD4 T cells have a central role in initiating the autoimmune response in MS.
T61147 55165-55267 Sentence denotes Naïve T cells occupy an ecological niche in the periphery that is regulated by homeostatic mechanisms.
T52374 55268-55412 Sentence denotes Some investigators claim a naïve T cell homeostatic abnormality occurs in MS but the basis of this abnormality could not be clearly established.
T88939 55413-55646 Sentence denotes Our objective was to test the hypothesis that RRMS patients have premature thymic involution leading to reduced generation of recent thymic emigrants (RTEs) and followed by compensatory homeostatic proliferation of naïve CD4 T cells.
T77491 55647-55829 Sentence denotes To test this hypothesis, we used a FACSAria cell sorter to isolate subsets of naïve CD4 T cells (10 patients and 10 age-matched healthy controls), based on expression levels of CD31.
T58918 55830-55915 Sentence denotes Specifically, we isolated subsets of RTEs (CD31hi and CD31lo) and non-RTEs (CD31neg).
T57119 55916-56076 Sentence denotes Using real-time PCR, we quantified signal joint T cell receptor excision circles (sjTRECs) and beta TRECs in DNA from these subsets as markers of thymic output.
T59991 56077-56194 Sentence denotes Additional homeostatic markers (Bcl-2, CD127 and Ki-67) were analyzed by flow cytometry within the different subsets.
T74096 56195-56203 Sentence denotes Results:
T28464 56204-56387 Sentence denotes In controls, true RTEs (CD31hi) showed a significant decline in TREC levels with increasing age, whereas in RRMS comparable cells had consistently low TREC levels irrespective of age.
T60668 56388-56539 Sentence denotes Second, in RRMS, RTEs and non-RTEs showed significantly increased expression of the IL-7 receptor (CD127), whereas non-RTEs had increased Bcl-2 levels.
T36263 56540-56720 Sentence denotes We report first definitive evidence of a thymic abnormality in RRMS that leads to reduced thymic output and compensatory homeostatic proliferation affecting both RTEs and non-RTEs.
T911 56721-56803 Sentence denotes These naïve CD4 T cell changes may increase autoreactivity and predispose to RRMS.
T1774 56804-56894 Sentence denotes Multiple Sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS).
T17408 56895-57113 Sentence denotes Cytokines and chemokines are soluble mediators of the immune system that are involved in the pathogenesis of MS by regulating transmigration of immune cells to CNS and mediating subsequent development of tissue damage.
T57913 57114-57208 Sentence denotes Altered cytokine and chemokines profiles in the cerebrospinal fluid and blood have been shown.
T39941 57209-57354 Sentence denotes The aim of this study was to examine whether these molecules could be used as markers of disease activity or markers of different subtypes of MS.
T10643 57355-57363 Sentence denotes Methods:
T67364 57364-57396 Sentence denotes The study included 113 subjects:
T34746 57397-57515 Sentence denotes 74 patients with different subtype of MS, 17 patients with clinically isolated syndrome (CIS) and 22 healthy controls.
T90516 57516-57580 Sentence denotes Among MS patients 22 patients were treated with interferon-beta.
T46568 57581-57791 Sentence denotes The sera levels of 14 cytokines, including TRAIL, Fas, FasL, MIF, IL-10, TNF-alpha, IL-6, IL-12p70, IFN-gamma, IL-2, CXCL10, CCL2, CCL3 and CCL4 were determined using ELISA and Bio-Plex suspension array system.
T17532 57792-58018 Sentence denotes The median levels of macrophage migration inhibitory factor (MIF) in sera were lower in untreated patients with MS than healthy controls (199.9 vs. 340.8 pg/ml; p = 0.008), especially in relapsing-remitting MS (RRMS) patients.
T91518 58019-58138 Sentence denotes There was also significant difference between RRMS and primary progressive MS patients (53.6 vs. 284.4 pg/m; p = 0.01).
T90056 58139-58257 Sentence denotes The levels of MIF were also lower in CIS patients when compared to healthy controls (186.2 vs 340.8 pg/ml, p = 0.004).
T94243 58258-58424 Sentence denotes Also the levels of TNF-alpha were upregulated in MS patients when compared to healthy controls, but there were no differences between MS subtypes (4.8 vs. 3.7 pg/ml).
T39605 58425-58553 Sentence denotes In IFN-treated patients the levels of CXCL10 were upregulated when compared untreated patients (122.9 vs. 76.4 pg/ml; p = 0.01).
T66189 58554-58706 Sentence denotes These results showed that MIF could be used as a potential MS subtype marker, but this observation needs to be validated in substantial patients groups.
T34201 58707-59029 Sentence denotes Kondo Takayuki⁎ 1 , Komori Mika 2 , Tomimoto Hidekazu 2 , Tanaka Masami 3 , Tanaka Keiko 4 , Takahashi Ryousuke 2 , Matsuo Hidenori 1 , Saida Takahiko 5 1 Nagasaki Medical Center of Neurology, Nagasaki, Japan Multiple sclerosis (MS) in Japan is classified into two groups, conventional MS (CMS) and opticospinal MS (OSMS).
T86650 59030-59154 Sentence denotes It has been reported that while the former is associated with HLA-DRB1⁎1501, DPB1⁎0501 confers susceptibility to the latter.
T41263 59155-59391 Sentence denotes Following the finding of the positive association of neuromyelitis optica (NMO) and Japanese OSMS with antiaquaporin-4 (AQP4) antibody, the relationship among CMS, seropositive and seronegative OSMS has become a main focus of interests.
T42115 59392-59726 Sentence denotes Because longitudinally extensive myelitis is the most prominent feature related to Anti-AQP4 antibody positivity, we grouped our patients into the groups of CMS, seropositive and seronegative long spinal (LS) MS with a contiguous spinal cord lesion 3 or more segments in length, and studied HLA class II association within each group.
T30049 59727-59834 Sentence denotes 41 patients with CMS, 53 with seropositive LSMS and 40 with seronegative LSMS were enrolled for this study.
T98479 59835-59951 Sentence denotes After PCR-amplification of HLA-DR genes, the DR alleles were determined by sequence-specific oligonucleotide probes.
T97145 59952-60033 Sentence denotes HLA-DP alleles were amplified by allele-specific primers to determine DP alleles.
T30352 60034-60071 Sentence denotes The data published by Nalajima et al.
T67850 60072-60146 Sentence denotes (http://jshi.umin.ac.jp/hla_data/data.html) was used for control subjects.
T59309 60147-60249 Sentence denotes Compared to control subjects, HLA-DRB1⁎1501 alleles tended to be increased in CMS patients (DRB1⁎1501:
T657 60250-60277 Sentence denotes 18.3% vs. 11.6%, P = 0.09).
T43274 60278-60334 Sentence denotes Determination of HLA-DRB1⁎04 alleles remained ambiguous.
T20053 60335-60475 Sentence denotes Allele frequencies of DR4 carried by CMS were higher than the controls (42.7% vs. 24.4%, P = 0.0024) and LSMS (42.7% vs. 16.7%, P = 0.0023).
T34287 60476-60594 Sentence denotes The frequencies of DR4 in seropositive and seronegative LSMS also differed significantly (11.3% vs. 23.8%, P = 0.024).
T66983 60595-60687 Sentence denotes The frequency of DRB1⁎1502 carried by CMS was lower than in LSMS (3.7% vs. 11.8%, P = 0.03).
T79278 60688-60874 Sentence denotes DRB1⁎0101 was increased in LSMS, compared with controls (seropositive LSMS 8.5%, seronegative LSMS 11.3%, total LSMS 9.7% vs. controls 3.9%, P = 0.003) and CMS (9.7% vs. 1.2%, P = 0.01).
T36981 60875-61016 Sentence denotes Allele frequencies of HLA-DPB1⁎0501 in CMS, seropositive and seronegative LSMS and controls were 51.2%, 43.8%, 50.0% and 40.7%, respectively.
T65487 61017-61056 Sentence denotes No significant difference was observed.
T63144 61057-61194 Sentence denotes If we consider the linkage disequilibrium of DRB1 with DPB1, we failed to find a difference in the number of subjects with HLA-DPB1⁎0501.
T39138 61195-61261 Sentence denotes Our study revealed that CMS and LSMS have different immunogenesis.
T30229 61262-61412 Sentence denotes However, we failed to show that particular DP alleles confer the susceptibility to any of the three groups, in contrast to previous reports by others.
T63854 61413-61633 Sentence denotes 34 -Soluble trail and BAFF levels in multiple sclerosis during interferon-β therapy 3 Hacettepe University, Oncology Institute, Departement of Basic Oncology Ankara, Turkey 4 Primer Medical Imaging Center, Ankara, Turkey
T69879 61634-62028 Sentence denotes Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor family with immunomodulatory capacity having a protective role against autoimmunity TRAIL inhibits T cell activation, cell cycle progression, and IFN-gamma and IL-4 production and may be important in modulating disease expression by downregulation of mechanisms in T-cell-driven responses.
T15020 62029-62134 Sentence denotes Being critical for B cell survival and maturation BAFF, affects both humoral and cell-mediated responses.
T73603 62135-62232 Sentence denotes Increased soluble BAFF (sBAFF) protein levels have been reported in several autoimmune disorders.
T23881 62233-62467 Sentence denotes This study focuses on the expression of TRAIL levels on lymphocytes of multiple sclerosis (MS) patients and healthy individuals, and further evaluates the effect of β-interferon therapy on soluble TRAIL and BAFF levels in MS patients.
T51542 62468-62577 Sentence denotes Age and gender matched 35 relapsing remitting MS patients and 18 healthy controls were included in the study.
T60306 62578-62703 Sentence denotes All patients were evaluated for prognosis, age of disease onset, disease duration and expanded disease severity score (EDSS).
T51105 62704-62906 Sentence denotes Also cranial magnetic resonance details as number of infra and supratentorial plaques, number of contrast enhancing plaques, corpus callosum atrophy and enhancement and brain atrophy have been analysed.
T36714 62907-63104 Sentence denotes Karni Arnon⁎ 1 , Urshansky Natali 2 , Mausner Karin 1 , Fahoum Firas 2 1 Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel 2 Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
T20316 63105-63185 Sentence denotes Neurotrophins have been implicated to play a neuroprotective role in MS lesions.
T84475 63186-63323 Sentence denotes We have reported that in patients with RR-MS PBMCs secreted low levels of BDNF and its up-regulation after CD40 stimulation is defective.
T26939 63324-63451 Sentence denotes Here we studied the production and regulation of neurotrophins mRNA (BDNF, NGF and NT3) in immune cells of patients with RR-MS.
T70258 63452-63898 Sentence denotes PBMCs from 30 patients with RR-MS (13 untreated patients and 17 patients treated with interferon-β) and 17 matched healthy controls (HC) were incubated for 1 h with anti-CD3 or anti-CD40 monoclonal antibodies (mAb) or their isotype controls (IC). mRNA quantity of BDNF, NGF and NT3 in PBMCs was studied by real-time qRT-PCR reactions on a LightCycler® 1.5 Instrument while GAPDH gene was run in parallel as internal control for each reaction set.
T92281 63899-63986 Sentence denotes Results are expressed by the production ratio of each neurotrophin mRNA vs. GAPDH mRNA.
T34341 63987-64281 Sentence denotes For the basal expression of neurotrophins mRNA: BDNF mRNA was similar in the patients (3.6 ± 1.0) and the HC (3.9 ± 0.9, p = N.S), NGF mRNA tend to be lower in the patients (1.4 ± 0.4) vs. HC (2.9 ± 0.8, p = 0.11) and NT3 mRNA was lower in the patients (2.2 ± 0.8) vs. HC (4.6 ± 1.2, p = 0.03).
T51286 64282-64421 Sentence denotes Stimulation of PBMCs with anti-CD40 mAb up-regulated mRNA expression of BDNF, NGF and NT3 as compared to the effect of IC in HC (BDNF mRNA:
T28013 64422-64479 Sentence denotes 9.5 ± 3.1 vs 3.0 ± 0.7, respectively, p = 0.04; NGF mRNA:
T88459 64480-64538 Sentence denotes 6.0 ± 0.8 vs. 2.8 ± 0.8, respectively, p b 0.05; NT3 mRNA:
T48613 64539-64589 Sentence denotes 10.2 ± 2.7 vs. 4.4 ± 1.2, respectively, p b 0.05).
T7691 64590-64768 Sentence denotes In the comparison of the up-regulatory capacity of CD40 stimulation using the ratio of mRNA production after CD40 stimulation vs. IC between HC and the patients: BDNF mRNA ratio:
T11927 64769-64834 Sentence denotes 2.7 ± 0.5 vs. 1.1 ± 0.1, respectively, p b 0.001, NGF mRNA ratio:
T26407 64835-64900 Sentence denotes 4.1 ± 1.3 vs. 1.4 ± 0.4, respectively, p = 0.008, NT3 mRNA ratio:
T87820 64901-64951 Sentence denotes 3.9 ± 0.9 vs. 1.1 ± 0.4, respectively, p = 0.006).
T13942 64952-65084 Sentence denotes No significant differences of neurotrophins mRNA expression were found between PBMCs of untreated and interferon-β treated patients.
T69267 65085-65323 Sentence denotes The patients were followed-up under interferon-β treatment and their initial, 3rd, 6th, 9th and 12th month blood for TRAIL expression on lymphocytes and soluble TRAIL and BAFF levels were analysed by flow cytometry and ELISA respectively.
T5260 65324-65450 Sentence denotes All patients were analysed for gender, age of disease onset, disease duration, initial symptoms, prognostic factors, and EDSS.
T54713 65451-65577 Sentence denotes MS patients' mean basal flow-TRAIL expression rates was 11.11 ± 15 while in control group it was detected as 2.16 ±1.64 (0-6).
T25780 65578-65712 Sentence denotes However, of MS patients, 17 (48.6%) had basal f-TRAIL levels as N3.8 (valuesN control mean basal trail+ 2SD) whereas others have b3.8.
T40301 65713-65829 Sentence denotes There was no significant difference in aspect of gender, age of disease onset, disease duration, prognosis and EDSS.
T4273 65830-65893 Sentence denotes Two groups were also similar for detailed cranial MRI features.
T68208 65894-66102 Sentence denotes In the patient group with high f-TRAIL levels, after treatment with interferon-β for 3 months, mean f-TRAIL level was found to be 3.14 ± 5.30 (p b 0.025) whereas after 6 months it was 2.00 ± 3.21 (p b 0.025).
T46623 66103-66270 Sentence denotes MS patients' mean soluble basal TRAIL levels were 634.75 ± 195.44 and it was 693.6 ± 379.36 (180-742) in the control group having no statistical difference (p N 0,05).
T43307 66271-66404 Sentence denotes Mean soluble TRAIL level was 634.75 ± 195.44 and this value significantly increased on the sixth month of therapy (1278.66 ± 868.42).
T73857 66405-66548 Sentence denotes Mean basal BAFF levels of controls were 1.98 ± 0.14 while in MS patients it was 2.11 ± 0.2 (1.8-2.6) with statistical significance (p b 0.0.5).
T35212 66549-66638 Sentence denotes No statistical significance of sBAFF levels has been found during treatment for 9 months.
T1025 66639-66741 Sentence denotes Our study evaluates the effect of β-interferon therapy on serial TRAIL and BAFF levels longitudinally.
T21134 66742-66873 Sentence denotes During the pre-treatment period we did not detect any significant difference in serum sTRAIL levels compared with healthy controls.
T44458 66874-66970 Sentence denotes Serum levels of sTRAIL were significantly higher on the 6th month than the pre-treatment values.
T10034 66971-67211 Sentence denotes MS patients' mean basal flow-TRAIL expression rates were higher than control group, however, we also observed that there are two subgroups of patients expressing different TRAIL rates as similar or higher levels when compared with controls.
T50261 67212-67308 Sentence denotes TRAIL expression levels were significantly lower on the 6th month than the pre-treatment values.
T15103 67309-67452 Sentence denotes Detected decrease of TRAIL levels after therapy may depend on the cleavage of membranous TRAIL by specific metalloproteases into soluble TRAIL.
T46327 67453-67666 Sentence denotes Supporting the literature of other autoimmune disease, in pretreatment period BAFF levels have been found significantly higher in MS group, however, interferon β treatment had no significant effect longitudinally.
T40408 67667-67842 Sentence denotes Our data suggests that β-interferon can lead the modulation of soluble TRAIL levels leading to a secondary compensatory mechanism that downregulates the inflammatory response.
T1863 67843-67903 Sentence denotes Haile Yohannes⁎ 1 , Pasichnyk Dion 1 , Giuliani Fabrizio 1 1
T75414 67904-68058 Sentence denotes Infiltration of T cells and macrophages characterizes the lesions of inflammatory diseases of the central nervous system, such as Multiple Sclerosis (MS).
T38736 68059-68206 Sentence denotes Activated cytotoxic T cells release Granzyme B (GrB), a serine protease, and induce neurotoxicity by degrading the myelin and/ or injuring neurons.
T94506 68207-68330 Sentence denotes However, the separate effect of the subsets of T cells in terms of GrB expression and neurotoxicity has not been described.
T77870 68331-68540 Sentence denotes The objective of this study is to explore and compare the level of GrB expression on lymphocytes and its subsets (CD4 and CD8) as well as to evaluate the separate effect of CD4 or CD8 on human neuronal injury.
T89709 68541-68685 Sentence denotes Human lymphocytes were activated for 3 days with anti CD3antibody before or after negative selection into CD4 and CD8 using magnetic separation.
T34568 68686-68764 Sentence denotes Expression of Granzyme B in the T cells subsets was measured by real-time PCR.
T29175 68765-68955 Sentence denotes Human cortical foetal neurons (HFNs) (15-20 wks age) were cultured alone or co-cultured with unactivated, activated whole T cells, CD4 or CD8 subsets on poly-ornithine coated culture plates.
T60073 68956-69105 Sentence denotes After 24 h, neuronal viability was assessed using immunocytochemistry for microtubule associated protein-2 (MAP-2) and neurons were counted manually.
T69117 69106-69206 Sentence denotes RT-PCR revealed that activated T cells express GrB above 40 fold in comparison to unactivated cells.
T99400 69207-69286 Sentence denotes Activated CD8 cells also expressed about 3 fold more GrB compared to CD4 cells.
T35211 69287-69419 Sentence denotes In contrast, when CD8 cells were activated in the absence of CD4 cells, the levels of GrB were comparable between CD4 and CD8 cells.
T56390 69420-69631 Sentence denotes The viability of HFNs was significantly low in the co-cultures with activated Tcells (39.1 ± 15%) and activated CD8 cells (38.2± 13.7%) whereas about 70% HFNs survived in the co-culture with activated CD4 cells.
T80061 69632-69740 Sentence denotes Our findings demonstrate that anti-CD3-activation on lymphocytes triggers high expression of GrB by T cells.
T10334 69741-69794 Sentence denotes GrB mRNA expression correlates with neuronal killing.
T46405 69795-69849 Sentence denotes CD8 cells are the major effectors of neuronal killing.
T36909 69850-69936 Sentence denotes However, activation of CD8 T cells is dependent on CD4 cells for their GrB expression.
T95090 69937-70037 Sentence denotes Further studies are going on to evaluate the cytotoxic effect of post-selection activated CD8 cells.
T80455 70038-70180 Sentence denotes Aranami Toshimasa⁎ 1 , Sato Wakiro 1 , Yamamura Takashi 1 1 Department of Immunology, National Institute of Neuroscience, NCNP, Kodaira, Japan
T88144 70181-70436 Sentence denotes Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, in which activation of autoreactive CD4+ T cells targeting myelin antigens and differentiation into Th1 or Th17 effector cells are presumed to play a pathogenic role.
T26499 70437-70650 Sentence denotes It was reported that CD4+ T cells lacking costimulatory molecule CD28 expression (CD28null T cells) are expanded in MS patients and T cell clones derived from these T cells exhibited high ability to produce IFN-g.
T26707 70651-70747 Sentence denotes However, the specific antigen and the pathogenic role for these T cells in MS have been unclear.
T69743 70748-71003 Sentence denotes Here we report that CD28null T cells in MS are abnormally differentiated Th1 cells and are enriched in those specific for alphaBcrystallin (CRYAB), which is highly expressed in oligodendrocytes and astrocytes in active MS lesions but not in normal brains.
T8252 71004-71134 Sentence denotes Age and sex-matched forty untreated MS patients in the remission state and nine healthy subjects (HS) were enrolled in this study.
T48528 71135-71306 Sentence denotes We examined cytokine production by these T cells upon polyclonal stimulation with PMA and ionomycin and found that they predominantly produce IFN-g but not IL-17 nor IL-4.
T11506 71307-71509 Sentence denotes We analyzed expression of T-bet, an essential transcription factor for Th1 cells, with intracellular Tbet staining and found that CD28null T cells are the only T-bet(high) population among CD4+ T cells.
T73431 71510-71746 Sentence denotes Albeit the higher expressions of T-bet in CD28null T cells than those in CD28+ T cells, CD28null T cells contain fewer cells expressing TIM-3, which has been reported to be induced on Th1 but not Th2 cells and regulate IFN-g production.
T80277 71747-72029 Sentence denotes When we analyzed the frequencies of T cells responding to ovalbumin (OVA), myelin basic protein (MBP) or CRYAB, we have found that the frequencies of T cells responding to CRYAB but not to OVA nor MBP in CD28null T cells from MS patients are significantly higher than those from HS.
T15003 72030-72106 Sentence denotes CD28+ T cells from both MS and HS specifically responded to neither antigen.
T44705 72107-72283 Sentence denotes These results suggest that CD28null T cells are enriched in abnormally differentiated Th1 cells autoreactive to CRYAB and might contribute to the autoimmune inflammation in MS.
T90541 72284-72432 Sentence denotes Multiple sclerosis (MS) pathology was studied in vivo through evaluation of kinetics of lesion volume variations over time using frequent MRI scans.
T80282 72433-72670 Sentence denotes For this purpose patients with Relapsing Remitting MS course (n = 13) were followed and 29 new lesions showing persistent Blood Brain Barrier (BBB) damage, visualized by contrast enhancement for at least three observations were selected.
T78147 72671-72731 Sentence denotes Each lesion was analyzed using six consecutive observations.
T71538 72732-72942 Sentence denotes Each lesion volume was calculated using a semi-automated contouring method in FLAIR (mainly sensitive to water changes) and T1w sequences after administration of two different contrast doses of Gadolinium (Gd).
T19812 72943-73109 Sentence denotes In the acute phase, lesions visualized by FLAIR sequences consistently resulted larger than T1 Gd enhancing volumes, but followed over time a similar kinetic profile.
T24416 73110-73291 Sentence denotes However once Gd enhancement disappeared, visualization by FLAIR sequences persisted, reaching a stable volume consistently smaller than the maximum volume of the Gd enhancing phase.
T82603 73292-73559 Sentence denotes Interpolation of the volume kinetic of each lesion with a multiparametric fitting suitable for describing diffusive expansion and contraction phenomena in biological environment, generated random walk type profiles describing in more detail the FLAIR volume kinetics.
T5749 73560-73940 Sentence denotes These profiles resulted from two different phenomena, each following two different kinetics: the first one, mainly associated to the earliest part of the curve, probably depending by the BBB disruption and by the inflammation; the second one, following the first but partly overlapping, probably reflecting the cellular infiltration cause of the irreversible tissue abnormalities.
T70347 73941-74141 Sentence denotes These results indicate that tissue damage involves only part of the MS lesion visualized during the acute phase and that, a unifying hypothesis on the underlying pathogenic mechanism can be generated.
T27346 74142-74504 Sentence denotes This hypothesis supports a model of acute MS lesions with a "target" morphology organized as follows:in the center mainly the inflammatory infiltrate and tissue damage;in the inner periphery the BBB damage, caused by soluble inflammatory factors diffused from the infiltrate;in the external periphery the edema, made by fluids diffused from the BBB damaged area.
T61422 74505-74772 Sentence denotes In addition, when the acute phase is over and each lesion shrinks usually leaving a stabilized hyperintensity, the model implies that this stable abnormality is made by the center of the acute lesion: tissue damage and cell infiltrates persisting behind a healed BBB.
T50694 74773-74999 Sentence denotes Renewed interest in the role of B cells as antigen presenting cells (APCs) has occurred, following recent results demonstrating the beneficial effects of B cell depletion therapy on relapsing remitting multiple sclerosis (MS).
T53882 75000-75131 Sentence denotes Since this effect is fairly immediate, it is likely that peripheral B cells have a central role in the pathogenesis of the disease.
T22595 75132-75279 Sentence denotes We have demonstrated that CD40L activated peripheral B cells are capable of efficiently presenting myelin antigen to autologous peripheral T cells.
T4271 75280-75483 Sentence denotes In contrast, CpG oligodeoxynucleotide activated peripheral B cells from both MS patients and healthy controls were unable to stimulate autologous T cells to proliferate in response to any antigen tested.
T62815 75484-75666 Sentence denotes A small population of B cells from MS patients but not healthy control B cells efficiently bound myelin basic protein by flow cytometry, but this did not correlate with APC function.
T37483 75667-75789 Sentence denotes In addition, we have begun to dissect the capacity of ex vivo peripheral naïve and memory B cells in antigen presentation.
T63421 75790-75959 Sentence denotes Thus far we have observed that both naïve and memory B cells are capable of presenting a recall antigen to autologous T cells from both healthy controls and MS patients.
T4535 75960-76108 Sentence denotes As predicted, memory B cells, but not naïve B cells from MS patients were able to present myelin oligodendrocyte glycoprotein to autologous T cells.
T61193 76109-76221 Sentence denotes These results suggest that memory/activated B cells may be an important population of APCs in the context of MS.
T63921 76223-76438 Sentence denotes Methyltioadenosine (MTA) have immunomodulatory activity by inhibiting the activation of NFkB and preventing methylation after Tcell activation, showing beneficial effects in animal models of Multiple Sclerosis (MS).
T73126 76439-76584 Sentence denotes The goal of our study was to compare MTA therapy against MS disease modifying drugs (DMD) and to assess tissue injury protection mediated by MTA.
T43143 76585-76740 Sentence denotes MTA therapy was evaluated in the C57B6 mice immunized with MOG35-55 peptide developing chronic-progressive experimental autoimmune encephalomyelitis (EAE).
T37748 76741-76875 Sentence denotes Murine interferon beta (IFNbeta) and Glatiramer acetate, as well as MTA were administered i.p. every day from the day of immunization.
T81836 76876-76931 Sentence denotes Clinical and histological scores were recorded blinded.
T62680 76932-76993 Sentence denotes Axonal protection was quantified through confocal microscopy.
T64425 76994-77152 Sentence denotes MTA therapy demonstrated a dose-response effect in ameliorating EAE in the C57 mice, with complete suppression of the disease at the higher dose (192 mcM/kg).
T13155 77153-77279 Sentence denotes At the intermediate dosage, MTA showed better efficacy than murine IFN-beta (5000 U/day) or GA (0.1 mg/day) in preventing EAE.
T63292 77280-77426 Sentence denotes Indeed, we found synergy between MTA and Glatiramer acetate, since suboptimal dosage combination of both drugs efficiently suppressed the disease.
T49979 77427-77552 Sentence denotes Tissue damage was prevented by decreasing the amount of axonal damage as quantified by confocal microscopy of labelled axons.
T96010 77553-77610 Sentence denotes Finally, we found no toxicity at any of the doses tested.
T86611 77611-77724 Sentence denotes MTA have a potent immunomodulatory effect and display synergy with DMD, preventing axonal damage in models of MS.
T42539 77726-78027 Sentence denotes The effects of Glatiramer Acetate (GA) in combination with Minocycline (MIN), a second-generation tetracycline, have been investigated on the course of EAE in mice, resulting in a significant reduction in disease severity and burden with attenuation of the inflammation, axonal loss and demyelination.
T16904 78028-78228 Sentence denotes Here we investigate the effects of combination therapy with GA and MIN on the induction, maturation and phenotyping of blood monocyte-derived dendritic cells (DCs) in Multiple Sclerosis (MS) patients.
T44015 78229-78399 Sentence denotes The expression of HLA-DR, CD11c, CD83 and CD1a was studied by flow cytometric analysis on immature (iDCs) and mature DCs (mDCs) from untreated and GA treated MS patients.
T27950 78400-78497 Sentence denotes Thirteen relapsingremitting MS patients and 13 healthy controls (HCs) were included in the study.
T81416 78498-78580 Sentence denotes Ten of the MS patient group were re-tested after a 2 month period of GA treatment.
T86911 78581-78786 Sentence denotes The marker expression on DC from untreated MS and HCs was studied in vitro in the absence or presence of GA and GA+MIN; and on DCs from GA treated MS patients without and with the in vitro addition of MIN.
T14432 78787-79041 Sentence denotes We found that in vitro GA alone (p b 0.05) or in combination with MIN (p b 0.05) downregulated DCs antigen presentation capability (HLA-DR), whereas only the combination treatment affected (p = 0.05) also myeloid DCs activation (CD83) in both MS and HCs.
T46655 79042-79296 Sentence denotes Prolonged GA treatment (in vivo for two months) affected (p = 0.05) antigen presentation capability by DCs, whereas when treated in vitro with MIN these cells also reduced (p b 0.05) activation marker expression and myeloid phenotype acquisition (CD11c).
T92615 79297-79425 Sentence denotes The present data demonstrate possible combination effects of GA and MIN on peripheral blood monocyte derived DCs in MS patients.
T21387 79426-79568 Sentence denotes Cytokine-neuroantigen (NAg) fusion proteins have promise as a new class of antigen-specific therapies for treatment of CNS autoimmune disease.
T74042 79569-79720 Sentence denotes The primary objective of this study was to assess therapeutic efficacy of selected cytokine-neuroantigen fusion proteins in the Lewis rat model of EAE.
T30123 79721-79893 Sentence denotes Expression systems for several cytokine-NAg fusion proteins were derived in which the cytokine domain was comprised of IL-1RA, IL-2, IL-4, IL-10, IL-13, IL-16, or IFN-beta.
T99593 79894-80059 Sentence denotes The antigenic domain of each fusion protein was comprised of the major encephalitogenic determinant of myelin basic protein (referred to as the neuroantigen or NAg).
T56994 80060-80369 Sentence denotes The prediction was that the cytokine domain would bind the respective cytokine receptors on antigen presenting cells (APC) and simultaneously promote anti-inflammatory or tolerogenic activity by those APC while targeting the NAg domain to the class II MHC antigen processing pathway for enhanced presentation.
T2886 80370-80515 Sentence denotes The targeted presentation of NAg by these cytokine-conditioned APC would predictably inhibit NAg-specific T cells that interacted with those APC.
T78513 80516-80636 Sentence denotes These fusion proteins were expressed, purified, and subcutaneously administered in saline to test for inhibition of EAE.
T40324 80637-80712 Sentence denotes Three different cytokine-NAg fusion proteins were potent inhibitors of EAE.
T88141 80713-80981 Sentence denotes These fusion proteins incorporated the IL-2 cytokine as the N-terminal domain (the IL2NAg fusion protein), the secreted IL-16 cytokine as the C-terminal domain (the NAgIL16 fusion protein), or the IFN-beta cytokine as the N-terminal domain (IFNbetaNAg fusion protein).
T79176 80982-81089 Sentence denotes These fusion proteins were administered to rats once per week for a total of three injections over 3 weeks.
T11922 81090-81171 Sentence denotes Then at least one week later, rats were challenged with NAg in CFA to induce EAE.
T54439 81172-81276 Sentence denotes Compared to NAg alone, these fusion proteins strongly attenuated the subsequent active induction of EAE.
T48634 81277-81389 Sentence denotes These fusion proteins also inhibited EAE when administered after encephalitogenic challenge during onset of EAE.
T50985 81390-81494 Sentence denotes In NAgIL16 pretreated rats, the mechanism of tolerance was active as shown by adoptive transfer studies.
T16730 81495-81671 Sentence denotes In conclusion, cytokine-NAg fusion proteins that incorporate IL-2, IL-16, or IFN-beta cytokine domains may comprise an effective tolerogenic therapy for CNS autoimmune disease.
T70433 81672-81818 Sentence denotes The objective of this study was to elucidate statins' therapeutic potential in suppressing chronic autoimmune response in multiple sclerosis (MS).
T45580 81819-81844 Sentence denotes Specifically, we studied:
T91124 81845-82095 Sentence denotes 1) statin-induced changes in dendritic cell (DCs) maturation and antigen presenting capacity; and 2) statin-induced changes in DCs' cytokine production, which may both modify Th17 cell differentiation and the development of autoimmune response in MS.
T81321 82096-82321 Sentence denotes In order to assess the statin-induced changes in DCs' maturation, we measured surface expression of HLA class I and class II, CD80, CD86, CD40, and CD83 on the surface of DCs matured in the absence or presence of simvastatin.
T29169 82322-82577 Sentence denotes Our results on 10 patients with relapsing remitting (RR) MS revealed that simvastatin significantly decreased the percentage of HLA Class I (p = 0.017), CD40 (p = 0.023) and CD80 (p = 0.040) expressing cells, consistent with inhibition of DCs' maturation.
T8061 82578-82763 Sentence denotes Functionally, the effect of simvastatin-induced inhibition of DCs' antigen presenting capacity was confirmed in experiments with myelin basic protein (MBP) 83-99-reactive T-cell clones.
T73846 82764-83008 Sentence denotes In RT-PCR studies that measured simvastatin-induced changes in DCs' cytokine production, we detected a significant up-regulation of IL-27 (p = 0.032) and IL-4 (p = 0.01), and inhibition of IL-6 (p = 0.042) and IL-23 (p = 0.043) gene expression.
T78747 83009-83262 Sentence denotes Measurement of secreted cytokines from the same DC cultures revealed up-regulated IL-27 (p = 0.01) and down-regulated IL-1b (p = 0.005), TGFb1 (p = 0.000008), and IL-23 (p = 0.01) protein level in statin-treated in comparison to the un-treated cultures.
T98860 83263-83418 Sentence denotes Finally, we evaluated to what extent statin-induced inhibition of DCs' maturation and changes in DCs' cytokine secretion inhibit Th17 cell differentiation.
T63997 83419-83572 Sentence denotes We identified that both simvastatin-treated DCs cell-to cell contact and supernatant of simvastatin-treated DCs inhibited the Th17 cells differentiation.
T31772 83573-83746 Sentence denotes Our results revealed that simvastatin suppresses DCs' antigen presenting capacity and changes DCs' cytokine production, which collectively inhibit Th17-cell differentiation.
T41055 83747-83762 Sentence denotes 5 -Case-report:
T11215 83763-84008 Sentence denotes Cladribine and alemtuzumab haematological treatment of chronic lymphatic leukemia and stabilizing effect on secondary-progressive multiple sclerosis Multiple sclerosis (MS) is a chronic demyelinating disorder of the central nervous system (CNS).
T32730 84009-84280 Sentence denotes Several MS forms are known: relapsing-remitting form (RRMS) at the beginning of MS with typical autoimmune inflammatory activity usually proceeds after 6-10 years into secondary-progressive form (SPMS) with prevailing neurodegeneration and variable residual inflammation.
T64341 84281-84454 Sentence denotes All current MS drugs are directed against inflammation with no significant neuroregenerative potential, therefore their effect is greatest at RRMS and is decreasing in SPMS.
T30903 84455-84668 Sentence denotes Several new drugs are now studied in MS including cytostatic agent cladribine and monoclonal antibody against CD52 cell surface marker of T and B cellsalemtuzumab, already used in haematooncological (HO) practice.
T83368 84669-84680 Sentence denotes Objectives:
T57955 84681-84761 Sentence denotes To report stabilizing effect of cladribine and alemtuzumab HO treatment on SPMS.
T14366 84762-84774 Sentence denotes Case-report:
T23593 84775-84918 Sentence denotes 51-year-old Caucasian man with MS history since 1974, first symptom optic neuritis of the left eye and secondary progressive course since 1985.
T25989 84919-85342 Sentence denotes Treatment history involved corticosteroids during MS relapses, combined immunosuppression with low-dose oral corticosteroid and azathioprine 50 mg daily (1996) (1997) (1998) , and later methotrexate 7.5 mg weekly (1999) (2000) (2001) (2002) (2003) (2004) (2005) Inflammation is a central process in the pathophysiology of Multiple Sclerosis (MS) and all available treatments for MS patients target the inflammatory process.
T77995 85343-85736 Sentence denotes Accordingly, in a gene expression study performed in the three main clinical forms of MS and in experimental autoimmune encephalomyelitis (EAE), an animal model for MS, we found an overall modulation of the expression of inflammatory genes and, in particular, we found an up regulation of CCR2, a chemokine receptor already described as associated with pathological inflammation in MS and EAE.
T10259 85737-85937 Sentence denotes We therefore tested CCR2 functional activity in vivo in 150 SJL mice affected by relapsing-remitting (RR)-EAE, modulating its activity using the engineered monomeric MCP-1 variant named [8A]-MCP-11-2.
T91273 85938-86003 Sentence denotes We administered [8A]-MCP-1 both preventively and therapeutically.
T43228 86004-86181 Sentence denotes We compared the efficacy of different doses of [8A]-MCP-1 with methylprednisolone (reference compound) and we compared subcutaneous (sc) and intraperitoneal (ip) administration.
T70065 86182-86317 Sentence denotes Preventive treatment significantly delayed disease onset in a dose dependent way, but displayed no effect on other clinical parameters.
T3856 86318-86413 Sentence denotes We did not observe significant clinical effects when treatment was started after disease onset.
T8202 86414-86522 Sentence denotes Neuropathological analysis, on the other hand, showed efficacy of the therapeutic treatment with [8A]-MCP-1.
T32557 86523-86755 Sentence denotes We found statistically significant and dose-dependent decrease of demyelination, axonal loss and number of infiltrating cells in the mice spinal cord (CD3+ T cells and macrophages) in [8A]-MCP-1-treated mice as compared to controls.
T15619 86756-86951 Sentence denotes Immunological analysis revealed, as expected, that [8A]-MCP-1 does not act on Ag-specific T cell proliferation and does not interfere with the differentiation of IFNγ-releasing effectors T cells.
T16493 86952-87028 Sentence denotes However, we observed an inhibition of IFNγ release upon antigen stimulation.
T37510 87029-87340 Sentence denotes Taken together, these results suggest that the therapeutic mechanism of [8A]-MCP-1 may rely on interference with immune cell recruitment: it includes a mild clinical efficacy in a preventive setting and a neural protection from tissue damage evaluated when administration starts after the first clinical attack.
T98542 87341-87516 Sentence denotes were comprised of an N-terminal cytokine domain (rat GM-CSF, M-CSF, or IL-6) and a C-terminal antigenic domain (NAg; the encephalitogenic determinant of myelin basic protein).
T81552 87517-87705 Sentence denotes The biological activities of the cytokine-NAg fusion proteins were examined through in vitro assays utilizing irradiated splenic APCs and myelin basic protein (MBP)-specific T cell clones.
T33122 87706-87929 Sentence denotes The GMCSF-NAg fusion protein was approximately 1000 fold more potent than NAg alone in stimulating antigenic proliferation of MBP-specific T cell clones, and the MCSF-NAg fusion protein was 10-100 fold more potent than NAg.
T77632 87930-87996 Sentence denotes The IL6-NAg fusion protein was only slightly more potent than NAg.
T39081 87997-88273 Sentence denotes The ability of the fusions proteins to potentiate antigenic proliferation was dependent on the covalent linkage between the cytokine and NAg domains, because the addition of GM-CSF or M-CSF plus NAg, as separate molecules, did not potentiate MBP-specific T cell proliferation.
T12847 88274-88409 Sentence denotes Additional data reinforced the concept that cytokine-NAg fusion proteins enhanced antigenic proliferation by targeting antigen to APCs.
T88975 88410-88585 Sentence denotes For instance, NAg targeting by GMCSF-NAg or MCSF-NAg was specifically inhibited by pre-treatment of the assays with the respective cytokine, GMCSF or MCSF, but not vice versa.
T55889 88586-88719 Sentence denotes In addition, cytokine-NAg fusion proteins specifically potentiated antigenic proliferation in the presence of particular APC subsets.
T2166 88720-88945 Sentence denotes GMCSF-NAg and MCSF-NAg were 100-1000 fold more potent than NAg alone in the presence of DC or macrophages, but these fusion proteins did not stimulate potentiated antigen recognition in the presence of B cells or T cell APCs.
T89491 88946-89074 Sentence denotes In conclusion, the GMCSF and MCSF cytokine domains targeted the NAg domain to DCs and macrophages, but not to other APC subsets.
T41739 89075-89280 Sentence denotes These data indicate that cytokine-antigen fusion proteins may provide an important tool to study APC subsets that promote inflammatory or tolerogenic responses in experimental autoimmune encephalomyelitis.
T6744 89282-89375 Sentence denotes Natalizumab is a recombinant humanized antibody directed against the integrin alpha-4-beta-1.
T47065 89376-89538 Sentence denotes This novel agent prevents the migration of immune cells into the brain and reduces the number of relapses by 68% in relapsing-remitting multiple sclerosis (RRMS).
T83323 89539-89813 Sentence denotes A significant increase of tumor necrosis factor (TNF) expression and production by peripheral blood mononuclear cells (PBMCs) as well as a trend towards worsened fatigue has previously been reported in 19 patients with RRMS treated with natalizumab for a period of 6 months.
T83244 89814-90173 Sentence denotes Here we report the relative expression of cytokines in both cerebrospinal fluid (CSF) and PBMCs in 22 patients with RRMS before and after 12 months of natalizumab treatment, and its long-term effect on the fatigue severity scale (FSS), expanded disability status scale (EDSS), multiple sclerosis impact scale (MSIS-29) and symbol digit modalities test (SDMT).
T91573 90174-90260 Sentence denotes The relative mRNA expression of cytokines was measured by realtime RT-PCR methodology.
T51847 90261-90391 Sentence denotes Administration of natalizumab (300 mg iv infusion every 4 weeks) dramatically reduced the CSF mononuclear cell count (p b 0.0001).
T56073 90392-90611 Sentence denotes Expression of TNF and interferon-gamma (IFN-g) mRNAs was significantly increased in PBMCs (p b 0.001; p b 0.001) but interleukin (IL)-4, IL-10, IL-13, IL-17, IL-23 and transforming growth factor-beta remained unchanged.
T49958 90612-90751 Sentence denotes In contrast, in the CSF cells, expression levels of IFN-g and IL-23 were decreased (p b 0.01; p b 0.02) and IL-10 was increased (p b 0.01).
T13439 90752-90980 Sentence denotes Although EDSS improved significantly (p b 0.01), the FSS, MSIS-29 and SDMT remained unchanged compared to baseline scores in the entire cohort, however, these scores improved in patients with severe disease (EDSS N 4.5; n = 13).
T98990 90981-91189 Sentence denotes Attenuation of immune cell trafficking to the brain and reduction of proinflammatory cytokines in the central nervous system compart-ment correlate to improvement in neurological functions measured with EDSS.
T45066 91190-91326 Sentence denotes Relative differences in other functional measures, such as fatigue, were only detected in the group with severe neurological disability.
T64685 91327-91492 Sentence denotes We speculate that increased production of proinflammatory cytokines in the periphery may impede the improvement of fatigue in natalizumab treated patients with RRMS.
T90939 91493-91685 Sentence denotes Azathioprine (Aza), 6-Mercaptopurine (6-MP) and 6-Thioguanine (6-TG) are thiopurine drugs widely used as immunosuppressants/ anti-inflammatory agents in organ transplantation and chemotherapy.
T72257 91686-91897 Sentence denotes As shown by several clinical trials, Aza is effective in modifying the course of MS and administered at lymphocyte-suppressing doses is well tolerated and effective in reducing MS new brain inflammatory lesions.
T55036 91898-91977 Sentence denotes In our study we investigated the action of 6-MP on human dendritic cells (DCs).
T74873 91978-92297 Sentence denotes We described for the first time that 6-MP impairs in vitro differentiation of DCs, has an inhibitory effect during DC activation processes, may inhibit fully activation process on DCs inducing a functionally less immunogenic phenotype and that 6-MP reduces DC CCR7 expression of the 50% and more, comparing to controls.
T23823 92298-92371 Sentence denotes All these findings add a novel action mechanism in Aza immune modulation.
T55565 92372-92482 Sentence denotes DCs differentiated from CD14+ were cultured in the presence and absence of two doses of 6-MP (10-6 and 10-5M).
T25099 92483-92539 Sentence denotes Immature DCs were activated for 24 h with 1 μ/ml of LPS.
T53534 92540-92652 Sentence denotes Maturation state was evaluated as surface marker expression HLA-DR, CD14, CD80, CD86 and CD83 by flow cytometry.
T26422 92653-92731 Sentence denotes Dendritic cell macropinocytosis capability was examined by Dextran-FITC assay.
T85529 92732-92833 Sentence denotes DC function was evaluated as allostimulatory ability, antigen specific stimulation and CK production.
T11238 92834-92881 Sentence denotes CCR7 expression was evaluated by real-time PCR.
T36820 92882-93006 Sentence denotes Our results show that 6-MP inhibits DC differentiation from CD14 precursors and reduce CD83 expression after LPS activation.
T33177 93007-93268 Sentence denotes We found that down regulation of CD83 results in less potent induction of allogeneic T cell proliferation and in reduced antigen specific proliferation, thus to treat with 6MP during DC LPS activation lead to a decreased stimulation of naïve and memory T cells.
T46720 93269-93541 Sentence denotes Moreover, our finding that DCs treated with 6MP retain endocytic activity after LPS stimulation indicates that reduced expression of CD83 not only determines a less efficient costimulation but goes together with a less mature, and therefore more tolerogenic, DC phenotype.
T7761 93542-93687 Sentence denotes When mature DCs were incubated with 6-MP the CCR7 expression was reduced, indicating that 6-MP down-modulate this molecule from the cell surface.
T81539 93688-93831 Sentence denotes Our data suggest that immunomodulatory effects of Aza involve both side of immune synapse: DCs and T cells, revealing a specific way of action.
T89431 93832-93964 Sentence denotes In the future it will be of interest to investigate ex vivo isolated DCs from treated patients together with the Treg subpopulation.
T93619 93965-94105 Sentence denotes Celecoxib is a cyclooxygenase-2 (COX-2)-specific non-steroidal anti-inflammatory drug (NSAID) indicated for treatment of arthritis and pain.
T55774 94106-94250 Sentence denotes Recent studies have shown benefits in treatment of colorectal cancer, though associated risk of cardiovascular events may impede implementation.
T1854 94251-94554 Sentence denotes We have recently shown that a trifluoromethyl analogue of celecoxib (abbreviated as TFM-celecoxib), that lacks COX-2-inhibitory activity, induces cellular retention of IL-12 through a post-translational mechanism involving perturbation of Ca2+ in the endoplasmic reticulum and chaperones of the ER (Mol.
T84978 94555-94565 Sentence denotes Pharmacol.
T29013 94566-94640 Sentence denotes 69: [1579] [1580] [1581] [1582] [1583] [1584] [1585] [1586] [1587] 2006) .
T60877 94641-94739 Sentence denotes We have also demonstrated that celecoxib inhibits EAE by a COX-2-independent mechanism (Brain 129:
T6213 94740-94865 Sentence denotes 1984 (Brain 129: -1992 (Brain 129: , 2006 ) that is mediated by downregulation of cytokines, adhesion factors and chemokines.
T22262 94866-95012 Sentence denotes In the present study, we have analysed the mode of action of TMF-celecoxib in more detail and have, as well, assessed its effect in the EAE model.
T18991 95013-95243 Sentence denotes Using recombinant cell lines established in our lab, we found that TMF-celecoxib blocks secretion of IL-12 (p40/p35 heterodimers), p80 (p40/p40 homodimers) and IL-23 (p40/p19 heterodimers) with same potency as wild-type celecoxib.
T83507 95244-95444 Sentence denotes A comprehensive analysis of 25 ERresident chaperones/foldases and associated co-factors showed that TMF-celecoxib induces significant transcriptional upregulation of GRP78, DNAJB9, ERO1LB and HERPUD1.
T96113 95445-95571 Sentence denotes HERPUD1 is part of a molecular mass protein complex involved in retrotranslocation of misfolded proteins prior to degradation.
T48948 95572-95786 Sentence denotes Further experiments using siRNA "knockdown" as well as immunoprecipitation of selected ER chaperones reveal a picture of multiple chaperone interactions involved in ER retention of these cytokines by TMF-celecoxib.
T8766 95787-95865 Sentence denotes We have also for the first time assessed the efficacy of TMF-celecoxib in EAE.
T37577 95866-95973 Sentence denotes TMF-celecoxib appeared to decrease the clinical score, and its effect was indistinguishable from celecoxib.
T89746 95974-96095 Sentence denotes Further analysis is being performed to assess its effect on IL-12, IL-23, IFN-gamma and IL-17 secretion in the EAE model.
T73155 96096-96283 Sentence denotes TMF-celecoxib may constitute the first drug for treatment of neuroinflammatory disorders, such as multiple sclerosis, that works through a mechanism disrupting cytokine folding in the ER.
T4468 96284-96516 Sentence denotes Its total lack of COX-2 inhibitory activity is beneficial, since inhibition of prostaglandin synthesis has been associated with deleterious alterations in endothelial cells, potentially contributing to development of cardiac events.
T82168 96517-96613 Sentence denotes Multiple sclerosis is the most common demyelinating disease of the central nervous system (CNS).
T41866 96614-96763 Sentence denotes Though the etiologic agent of MS is still unknown, epidemiologic data suggest that an environmental agent, such as a virus, may initiate the disease.
T5267 96764-96934 Sentence denotes Theiler's murine encephalomyelitis virus (TMEV) is a murine picornavirus that induces a demyelinating disease in susceptible strains of mice when injected intracranially.
T1452 96935-97028 Sentence denotes Theiler's virusinduced demyelination (TVID) lesions are similar to those seen in MS patients.
T16991 97029-97087 Sentence denotes Thus, TVID is a valuable animal model for the study of MS.
T62096 97088-97166 Sentence denotes Currently, interferon-beta (IFNB) is a major treatment option for MS patients.
T36039 97167-97278 Sentence denotes Unfortunately, IFNB treatment is not successful in all MS patients and often produces undesirable side effects.
T47719 97279-97381 Sentence denotes Thus, the search for alternative therapies is an area of intense investigation within the field of MS.
T78771 97382-97536 Sentence denotes Interferon tau (IFNT) is a Type I IFN produced in ruminants during pregnancy that is less cytotoxic than IFNB, but equally effective for immunomodulation.
T27154 97537-97650 Sentence denotes Cross-species reactivity of IFNT is key to its use as a treatment for human immune-mediated diseases, such as MS.
T23197 97651-97764 Sentence denotes The therapeutic potential of oral IFNT in the treatment of MS is now being assessed in Stage III clinical trials.
T11225 97765-97894 Sentence denotes The objectives of this study were to test the ability of IFNT to ameliorate TVID and to elucidate mechanisms of immunomodulation.
T32026 97895-97989 Sentence denotes TMEV-infected mice were injected ip with encapsulated IFNT once every 14 days for eight weeks.
T16559 97990-98033 Sentence denotes Treatment began at 11 weeks post-infection.
T58795 98034-98167 Sentence denotes We hypothesized that IFNT would stabilize the clinical score, decrease inflammation and demyelination, and decrease Type 1 cytokines.
TextSentencer_T318 98168-98278 Sentence denotes Initial results revealed that IFNTtreated mice had improved clinical scores starting at 2 weeks posttreatment.
TextSentencer_T319 98279-98421 Sentence denotes Likewise, a test of coordination revealed that mice treated with IFNT regained function while non-treated mice exhibited increased disability.
TextSentencer_T320 98422-98507 Sentence denotes Histopathology revealed a decrease in inflammation and demyelination in treated mice.
TextSentencer_T321 98508-98660 Sentence denotes Lastly, splenicderived T cells stimulated ex vivo with TMEV, increased expression of both Type 1 and Type 2 cytokines [IFNG, TNFA, IL2, IL12, and IL10].
TextSentencer_T322 98661-98741 Sentence denotes These results indicate the possibility of remyelination within IFNTtreated mice.
TextSentencer_T323 98742-98962 Sentence denotes Studies using electron microscopy are underway to test this hypothesis as are flow cytometric studies to elucidate phenotype of cells and expression of chemokine/cytokine receptors in IFNTtreated versus non-treated mice.
TextSentencer_T324 98963-98978 Sentence denotes POSTER SESSION:
TextSentencer_T325 98979-99458 Sentence denotes Blood-brain barrier and chemokines 1 -Blood-brain barrier breakdown and repair following gliotoxic drug injection in the brainstem of streptozotocin-diabetic rats Bondan Eduardo⁎ 1 , Lallo Maria Anete 1 1 University Paulista, University Cruzeiro do Sul, São Paulo, Brazil Ethidium bromide (EB) causes local oligodendroglial and astrocytic disappearance, with primary demyelination, glia limitans disruption, supposed blood-brain barrier (BBB) breakdown and Schwann cell invasion.
TextSentencer_T326 99459-99566 Sentence denotes Hyperglycemia observed in Diabetes mellitus is known to cause some changes in the behaviour of glial cells.
TextSentencer_T327 99567-99705 Sentence denotes The aim of this study was to investigate the BBB integrity after the injection of EB into the brainstem of diabetic and non-diabetic rats.
T60694 99706-99954 Sentence denotes Adult male Wistar rats were used and some received a single intravenous injection of streptozotocin (50 mg/kg), being submitted 10 days later to a single injection of 10 μL of 0.1% EB (group I) or 0.9% saline solution (II) into the cisterna pontis.
T84906 99955-100079 Sentence denotes Ten microlitres of 0.1% EB or 0.9% saline solution was also injected in non-diabetic rats (groups III and IV, respectively).
T90060 100080-100394 Sentence denotes The rats were anaesthetized, perfused through the heart from 24 h to 31 days after EB or saline injection and brainstem sections were collected and processed for light and transmission electron microscopy studies and immunohistochemical staining using glial fibrillary acidic protein (GFAP) as an astrocyte marker.
T38859 100395-100520 Sentence denotes From each group some animals received colloidal carbon ink by intravenous route, 20 min before being submitted to euthanasia.
T9351 100521-100651 Sentence denotes In rats from groups II and IV, there was no sign of astrocyte loss and no leakage of ink from blood vessels in the injection site.
T77516 100652-100782 Sentence denotes In groups I and III, astrocyte disappearance began at 48 h and some areas were still devoid of astrocytic processes 31 days after.
T65008 100783-100914 Sentence denotes Leakage of carbon particles was seen from 48 h to 15 days in group I and from 48 h to 7 days in group III in the EBinduced lesions.
T61338 100915-101052 Sentence denotes Tight junctions did not show any detectable ultrastructural change due to the lack of perivascular astrocytes in groups injected with EB.
T13018 101053-101181 Sentence denotes Diabetic rats from group I presented delayed macrophagic activity and lesser remyelination in comparison to rats from group III.
T38800 101182-101384 Sentence denotes Although oligodendrocytes were the major remyelinating cells in the brainstem, Schwann cells invaded EB-induced lesions, firstly appearing at 11 days in nondiabetic rats and by 15 days in diabetic rats.
T11438 101385-101588 Sentence denotes Results indicate that short-term streptozotocin-induced diabetes hindered BBB reconstruction and both oligodendrocyte and Schwann cell remyelination in comparison to non-diabetic rats after EB injection.
T53960 101589-101781 Sentence denotes Interleukin-15 (IL15) is a proinflammatory cytokine with elevated concentrations in autoimmune diseases involving the periphery (e.g., rheumatoid arthritis) and CNS (e.g., multiple sclerosis).
T56401 101782-101862 Sentence denotes How circulating IL15 affects neuroinflammation has not been fully characterized.
T62269 101863-101999 Sentence denotes In this report, we will show the regulatory changes of the IL15 system in the endothelial cells composing the blood-brain barrier (BBB).
T6541 102000-102112 Sentence denotes A mouse model of lipopolysaccharide (LPS) treatment will be used to illustrate the mechanisms of BBB regulation.
T19149 102113-102473 Sentence denotes There are four aspects of the study: pharmacokinetic assays of BBB permeability to blood-borne IL15; transcriptional regulation of IL15 receptor subunits at the BBB level; post-translational regulation of endothelial IL15 and its receptors which differed greatly from their respective mRNA transcripts; and evidence of CNS inflammation induced by IL15 and LPS.
T22670 102474-102626 Sentence denotes IL15 remained intact for at least 10 min after intravenous injection and reached CNS parenchyma with regional differences between brain and spinal cord.
T71829 102627-102731 Sentence denotes Both in-vivo and in-situ brain perfusion of IL15 showed that its permeation of the BBB was nonsaturable.
T71199 102732-102871 Sentence denotes LPS induced a significant increase of IL15 uptake by the brain and spinal cord, partly related to a higher general permeability of the BBB.
T37249 102872-103009 Sentence denotes There was a striking activation of the IL15 system in both cerebral endothelia and CNS parenchymal cells that mediated neuroinflammation.
T43647 103010-103148 Sentence denotes The results suggest that the BBB is an interface for blood-borne IL15 to interact with the CNS in the basal state and during inflammation.
T66553 103149-103311 Sentence denotes 3 -Blood-brain barrier characteristics in multiple sclerosis Kooij Gijs 1 , van Horssen Jack 1 , van der Pol Susanne 1 , Dijkstra Christine 1 , de Vries Elga⁎ 1 1
T39793 103312-103552 Sentence denotes The blood-brain barrier (BBB) is a selective barrier between the central nervous system (CNS) and the systemic circulation and is essential for maintenance and regulation of the neuroparenchymal environment and optimal neuronal functioning.
T32798 103553-103749 Sentence denotes It acts as a physical barrier due to the presence of well-developed tight junctions between brain endothelial cells that impede the entrance of circulating molecules and immune cells into the CNS.
T48798 103750-103969 Sentence denotes Specific transporter systems on the luminal and abluminal membranes regulate the transcellular traffic of small hydrophilic molecules and exclude potentially harmful compounds through multi-drug resistance efflux pumps.
T38118 103970-104125 Sentence denotes Previously, we demonstrated that loss of BBB integrity is apparent in multiple sclerosis (MS) and its animal model experimental allergic encephalomyelitis.
T73719 104126-104327 Sentence denotes Magnetic resonance imaging using the newly developed contrast agent, ultrasmall particles of iron oxide (USPIO) specifically imaged inflammatory events and BBB leakage in animal models and MS patients.
T42806 104328-104478 Sentence denotes Post-mortem analysis of well-characterized MS patient material also revealed alterations at the vascular level and the surrounding perivascular space.
T52594 104479-104625 Sentence denotes However, it remains unknown whether the molecular function of the BBB is affected in the course of MS and whether this contributes to the disease.
T24618 104626-104890 Sentence denotes Immunohistochemical analysis in active and inactive lesions of post-mortem MS patient material reveals that the expression of multiple multi-drug resistance (MDR) proteins are decreased predominantly in chronic active lesions at the level of the brain endothelium.
T72618 104891-104980 Sentence denotes In contrast, no alterations in the expression of nutrient transporters could be detected.
T11819 104981-105179 Sentence denotes In our in vitro model for the bloodbrain barrier we demonstrated that both gene and protein expression of the glucose transporter (GLUT-1) and the MDR proteins were decreased by inflammatory agents.
T67104 105180-105344 Sentence denotes Interestingly, the efflux capacity of brain endothelial cells to pump out ligands of these multi-drug resistance pumps was diminished under inflammatory conditions.
T19174 105345-105484 Sentence denotes Our data suggest that alteration of BBB function at both the physical and molecular level is a critical determinant in MS lesion formation.
T81775 105485-105614 Sentence denotes As such BBB dysfunction contributes to tissue damage due to accumulation of unwanted compounds and cells in the brain parenchyma.
T45869 105615-105917 Sentence denotes 4 -Interleukin-25 improves tumor necrosis factor-alpha-induced disruption of blood brain barrier properties in mouse brain capillary endothelial cells Sonobe Yoshifumi⁎ 1 , Takeuchi Hideyuki 1 , Kataoka Kunio 1 , Kawanokuchi Jun 1 , Mizuno Tetsuya 1 , Suzumura Akio 1 1 Nagoya University, Nagoya, Japan
T87303 105918-106004 Sentence denotes Interleukin (IL)-25 is a member of IL-17 family cytokines including IL-17A and IL-17F.
T42923 106005-106111 Sentence denotes IL-25 mRNA is reportedly expressed by the activated T cells, lung macrophages, and lung endothelial cells.
T82523 106112-106195 Sentence denotes IL-25 promotes T helper type 2 (Th2) immune responses via producing IL-4 and IL-13.
T51175 106196-106427 Sentence denotes In addition, it is reported that IL-25-deficient mice are highly susceptible to experimental autoimmune encephalomyelitis (EAE) compared with wild type mice, suggesting that IL-25 regulates Th17 function via inducing Th2 cytokines.
T45364 106428-106502 Sentence denotes Interestingly, IL-25 mRNA is also reportedly detected in the brain tissue.
T40292 106503-106587 Sentence denotes However, the cellular source of IL-25 and its function in the brain remains unclear.
T9958 106588-106667 Sentence denotes Thus, we tested which cells express IL-25 and how IL-25 functions in the brain.
T22400 106668-106705 Sentence denotes In this study, we used C57BL/6J mice.
T23765 106706-106968 Sentence denotes To assess the expression of IL-25 mRNA, we extracted total mRNA from the whole brain tissue, mixed glial cell culture, primary microglia, primary astrocytes, primary fibroblasts, primary neurons, and mouse primary endothelial cells (BCECs), and performed RT-PCR.
T26096 106969-107059 Sentence denotes To explore the protein expression, we performed immunohistochemistry and Western blotting.
T94594 107060-107276 Sentence denotes To evaluate the permeability of blood brain barrier (BBB), we used MBEC4, a BCEC line and an established BBB model, and performed permeability assays using Evan's blue albumin and counting transmigrated CD4+ T cells.
T50134 107277-107467 Sentence denotes RT-PCR and immunohistochemical analysis showed that brain capillary endothelial cells (BCECs) produced IL-25, while microglia, astrocytes, neurons, fibroblasts, and oligodendrocytes did not.
T97999 107468-107799 Sentence denotes Additionally, IL-25 increased TJ proteins, occludin and claudin-5 and recovered their expression levels downregulated by tumor necrosis factor (TNF)-alpha in BCECs Permeability assay and CD4+ T cell transmigration assay confirmed that IL-25 partially suppresses TNFalpha-increased permeability and T cell migration across the BCEC.
T86747 107800-108016 Sentence denotes Collectively, these results suggest that IL-25 produced by the brain endothelial cells protects against TNF-alpha-associated collapse of the BBB and controls inflammatory T cell migration across the BBB in MS or EAE.
T13836 108017-108181 Sentence denotes The destruction of blood-brain barrier (BBB) is an integral feature of neuroinflammatory process in pathogenesis of experimental autoimmune encephalomyelitis (EAE).
T29342 108182-108427 Sentence denotes In this study, we utilize Triptolide (TRD, a purified effective ingredient of Tripterygium wilfordii of Chinese herb) to EAE rats to investigate the kinetic changes of BBB, as well as the expression of intercellular adhesion molecule-1 (ICAM-1).
T62132 108428-108492 Sentence denotes EAE was induced in Wistar rats and treated with TRD (100 μg/kg).
T27071 108493-108622 Sentence denotes Clinical score was evaluated among EAE, TRD-treated, and complete Freund's adjuvant (FCA) groups according to five forked method.
T19002 108623-108765 Sentence denotes Albumin in serum (S) and cerebrospinal fluid (CSF) samples of all rats were examined on the days 6, 8, 10, 12, 14, 16 post-inoculation (p.i.).
T87218 108766-108850 Sentence denotes The permeability of BBB was evaluated by calculating CSF to S albumin quotient (QA).
T39688 108851-108944 Sentence denotes At the same time, the brains and spinal cords were removed for immunohistochemistry staining.
T40492 108945-109008 Sentence denotes The EAE model in our study presented one-way course of disease.
T38574 109009-109138 Sentence denotes The disease did not appear in FCA group, but the clinical symptoms occurred on day 12 p.i. in both EAE group and TRD-treat group.
T58720 109139-109281 Sentence denotes On day 14 p.i. the clinical symptoms reached the peak to display hindlimb paralysis, irritability, the rapid loss of body weight in EAE group.
T19808 109282-109400 Sentence denotes The mean clinical score in EAE group was higher than that in TRD-treated group (2.19 ± 1.68 vs 0.14 ± 0.08, p b 0.01).
T24070 109401-109529 Sentence denotes On day 8 p.i., QA reached the peak in EAE group, which was higher than that in FCA group (0.30 ± 0.05 vs 0.13 ± 0.05, p b 0.01).
T2205 109530-109558 Sentence denotes Then QA gradually decreased.
T96207 109559-109737 Sentence denotes In TRDtreated group, QA increased slightly in the initial stage, gradually increased and reached the maximum (0.19 ± 0.02) on day 14 p.i., which was later than that in EAE group.
T46816 109738-109903 Sentence denotes Our result suggests that the difference of QA was statistically significant between EAE group and TRD-treated group(0.17 ±0.09 vs 0.08 ± 0.07, F = 28.340, p b 0.01).
T65241 109904-110104 Sentence denotes Image analysis shows that the mean staining photodensity of ICAM-1 in TRDtreated group was lower than that in EAE group (2345.04 ± 1053.24 vs 3203.77 ± 1858.24, F = 17.11, p b 0.01) on days 12-16 p.i.
T73898 110105-110189 Sentence denotes In early stage of EAE, the injury of BBB is prior to appearance of clinical symptom.
T57558 110190-110276 Sentence denotes TRD was not only down-regulated ICAM-1, but also repaired the BBB and ameliorated EAE.
T41455 110277-110395 Sentence denotes Semaphorins are a family of soluble or membrane-associated proteins that are characterized by a conserved Sema domain.
T53599 110396-110556 Sentence denotes Although semaphorins were originally identified as axonal guidance molecules, it is emerging that several semaphorins play significant roles in immune response.
T494 110557-110689 Sentence denotes For example, Sema4D is expressed in T cells and functions as a ligand to enhance the humoral and cellular immune responses via CD72.
T22730 110690-110821 Sentence denotes Sema4D-deficient mice are resistant to experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS).
T9258 110822-110961 Sentence denotes Another semaphorin, Sema4A provides a costimulatory signals to T cells and has a non-redundant role in the regulation of Th1/Th2 responses.
T61328 110962-111039 Sentence denotes Treatment of mice with anti-Sema4A antibody inhibited the development of EAE.
T62856 111040-111152 Sentence denotes Thus semaphorins have significant roles in the peripheral immune systems in pathological conditions such as EAE.
T79442 111153-111326 Sentence denotes However, it is unclear whether semaphorins are related with immune responses in the other systems such as the blood-brain barrier (BBB) or the central nervous systems (CNS).
T99378 111327-111425 Sentence denotes Here we investigate the expression of a semaphorin in the CNS of EAE and its relevance to the BBB.
T44941 111426-111572 Sentence denotes EAE was induced in C57BL/6 mice by immunization with MOG35-55 peptide and spinal cords of the mice were subjected to immunohistochemical analysis.
T90277 111573-111673 Sentence denotes The semaphorin is expressed in the infiltrating cells around the meninges in the spinal cord of EAE.
T31210 111674-111774 Sentence denotes Some of the cells expressing semaphorin were lymphocytes and the others were presumably macrophages.
T74460 111775-111941 Sentence denotes The plexin, one of the candidate receptors for the semaphorin, was expressed in lectin-positive cells which were supposed to be microglia and endothelial cells (ECs).
T79971 111942-112077 Sentence denotes From this expression pattern, we considered the possibility that the semaphorin is associated with immune cell trafficking through BBB.
T68686 112078-112172 Sentence denotes In the analysis in vitro, the semaphorin enhanced the expression of adhesion molecules on ECs.
T11059 112173-112341 Sentence denotes These results indicate that semaphorin is expressed in infiltrating cells in the spinal cord of EAE and may be associated with trafficking of immune cells into the CNS.
T85620 112342-112572 Sentence denotes 7 -Interferon-beta regulates CD73 and adenosine expression at the blood-brain barrier Interferon (IFN)-beta treatment reduces the relapse rate in multiple sclerosis (MS) but its mechanism of action remains incompletely understood.
T51922 112573-112660 Sentence denotes Our aim was to clarify further the beneficial effect of IFNbeta in the treatment of MS.
T93214 112661-112761 Sentence denotes Ecto-5′-nucleotidase (CD73) is an ectoenzyme producing adenosine from adenosine monophosphate (AMP).
T18076 112762-112955 Sentence denotes AMP is abundantly present at sites of inflammation and, more importantly, adenosine, the product of ecto-5′-nucleotidase activity, possesses both anti-inflammatory and neuroprotective activity.
T14426 112956-113518 Sentence denotes In the current study we elected to assess the influence of IFN-beta treatment on i) CD73 expression on the surface of primary cultures of human blood-brain barrier endothelial cells (BBB-ECs) and human astrocytes using immunofluorescence staining and flow cytometry, ii) transmigration of CD4+ T lymphocytes using an in vitro model of BBB, iii) ecto-5′-nucleotidase activity in the serum of MS patients using a radiochemical assay and finally iv) CD73 expression in postmortem MS brain samples and skin biopsies of MS patients using immunohistochemical staining.
T13736 113519-113633 Sentence denotes Our results show that IFN-beta increases the expression of ecto-5′-nucleotidase both on BBB-ECs and on astrocytes.
T79103 113634-113723 Sentence denotes As a consequence, transmigration of lymphocytes through BBB-ECs is significantly reduced.
T97957 113724-114002 Sentence denotes CD73 is strongly expressed in microvasculature in samples of post-mortem MS brain and moreover, in the majority of MS patients there was a clear upregulation both in the soluble serum ecto-5′-nucleotidase activity and skin microvascular CD73 expression after IFN-beta treatment.
T63010 114003-114197 Sentence denotes Upregulation of ecto-5′-nucleotidase and a subsequent increase in adenosine production might contribute to the beneficial effects of IFNbeta on MS via enhancing the endothelial barrier function.
T58404 114198-114346 Sentence denotes ADAM-17 (a disintegrin and metalloprotease) is the principal convertase of tumour necrosis factor (TNF), which is a major immunomodulatory cytokine.
T3059 114347-114559 Sentence denotes In addition, ADAM-17 also cleaves a number of other membrane-bound proteins, including the chemokine and adhesion molecule, fractalkine (CX3CL1), which has been implicated in multiple sclerosis (MS) pathogenesis.
T55881 114560-114755 Sentence denotes ADAM-17 expression in endothelial cells in MS white matter and in the spinal cord of rats with experimental autoimmune encephalomyelitis (EAE) has been shown by our laboratory to be up-regulated.
T7177 114756-114964 Sentence denotes Here we studied the in vitro expression of ADAM-17, its inhibitor (TIMP-3), and fractalkine in a human brain endothelial cell line, hCMEC/D3, at the mRNA and protein level under pro-inflammatory conditions.
T79728 114965-115101 Sentence denotes ADAM-17, TIMP-3 and fractalkine were up-regulated at the mRNA level under TNF treatment, however, only fractalkine was significantly so.
T88163 115102-115219 Sentence denotes Immunocytochemical analysis revealed that this increase in fractalkine expression also occurred at the protein level.
T62854 115220-115301 Sentence denotes To determine the shedding activities of ADAM-17 we then performed an ELISA assay.
T66262 115302-115490 Sentence denotes Cells treated with TNF at 100 ng/ml released 775.7 ng fractalkine/mg protein, which is 10 times greater than the amount of fractalkine bound to the cell membrane under the same conditions.
T68282 115491-115577 Sentence denotes We then sought to determine the protein expression of ADAM-17 following TNF treatment.
T45268 115578-115726 Sentence denotes A significant increase in ADAM-17 protein expression could not be determined using either immunocytochemistry, or western blotting and densitometry.
T3837 115727-115890 Sentence denotes We thus hypothesize that the increased shedding of fractalkine is due to increased enzyme activity of ADAM-17 and not increased protein expression of the protease.
T8096 115891-116022 Sentence denotes Activity assays for ADAM-17 under pro-inflammatory conditions using an InnozymeTM activity kit are ongoing to test this hypothesis.
T30583 116023-116169 Sentence denotes We are also investigating the immunohistochemical co-localisation and expression levels of ADAM-17 and fractalkine in MS and control brain tissue.
T9361 116170-116296 Sentence denotes The extent of associated inflammatory, demyelinated and neurodegenerative processes within the tissue is assessed in parallel.
T32735 116297-116427 Sentence denotes This study highlights shedding of fractalkine in inflammatory conditions is a critical event which requires further investigation.
T20303 116428-116687 Sentence denotes Shed fractalkine from endothelial cells could mediate leukocyte recruitment and extravasation via modulating the expression of certain adhesion molecules or it could act to prevent fractalkine receptor mediated migration of leukocytes by masking the receptor.
T87863 116688-117182 Sentence denotes 9 -S100B as a novel and accessible determinant for the development and severity of monocyte-driven encephalitis in aids MacLean Andrew⁎ 1 , Redmann Rachel 1 , Ivey Nathan 1 , Didier Peter 1 , Lackner Andrew 1 1 Tulane National Primate Research Center, New Orleans, United States Despite a reduced incidence of HIV dementia in patients on highly active antiretroviral therapy (HAART), the improved survival has resulted in increased cumulative prevalence of nervous system complications of AIDS.
T11391 117183-117321 Sentence denotes Fundamental gaps remain in knowledge relating to mechanisms and pathways involved in the development of HIV-associated neurologic disease.
T5007 117322-117565 Sentence denotes Lesions associated with encephalitis include marked astrocytic and microglial activation with frequent multinucleated giant cells, high viral load and lesions consisting of multiple disseminated foci of inflammatory cells throughout the brain.
T59953 117566-117673 Sentence denotes The pathogenesis of the lesions is unknown, but it is thought to be associated with alterations in the BBB.
T24309 117674-117789 Sentence denotes Heretofore, it has not been possible to determine if an individual has encephalitis before post mortem examination.
T70121 117790-118104 Sentence denotes In order to determine if it is possible to predict encephalitis in macaques infected with SIV we have correlated the levels of S100β protein in serum/plasma not just with the presence of encephalitis, but with the degree of encephalitis of a particular animal as determined by blinded histopathological evaluation.
T24069 118105-118298 Sentence denotes These studies were then taken further to quantify tight junction proteins. zo-1 was found to be diminished most in those animals with the highest degree of encephalitis/levels of S100β protein.
T99362 118299-118397 Sentence denotes Although disruption of the BBB is present in terminal AIDS, it is not as yet known when it begins.
T30008 118398-118472 Sentence denotes BBB disruption has been demonstrated in vivo using S100β protein in serum.
T43818 118473-118661 Sentence denotes Using this technique, it would be possible to determine when a particular animal was developing encephalitis, and thus be in a position to schedule a necropsy during these earliest stages.
T30735 118662-118869 Sentence denotes By determining levels of the glial protein S100β in serum, we show that it is possible not only to determine correlates post mortem, but also to predict which individuals will have encephalitis before death.
T37555 118870-119154 Sentence denotes This could have profound impact on elucidating the pathogenesis of neuroAIDS using the rhesus macaque model allowing one to euthanize an animal during the earliest stages of neurological disease or to predict HIVE in patients infected with HIV and thus, tailor treatment administered.
T45188 119155-119416 Sentence denotes 10 -Sonic hedgehog is secreted by human astrocytes and promotes optimal blood-brain barrier functioning The blood-brain barrier (BBB), composed of tightly bound endothelial cells (ECs), regulates the entry of blood-borne molecules and immune cells into the CNS.
T21431 119417-119537 Sentence denotes Perivascular astrocytes regulate BBB permeability by secreting essential factors, the identity of which remains unclear.
T42742 119538-119705 Sentence denotes Recent studies indicate that the Hedgehog (Hh) signaling pathway in adult tissues plays an important role in vascular proliferation, differentiation and tissue repair.
T9188 119706-119939 Sentence denotes Our study shows that human astrocytes express and secrete Sonic Hh and conversely, that human BBB-ECs bear the Hh receptor Patched-1 (Ptch-1), the signal transducer Smoothened (Smo) as well as transcription factors of the Gli family.
T29918 119940-120291 Sentence denotes Furthermore, we show that activation of the Hh pathway in BBB-ECs restricts the passage of soluble tracers (FITC-BSA and C14-sucrose), decreases the surface expression of intercellular cell adhesion molecule 1 (ICAM-1), and decreases BBB-ECs secretion of pro-inflammatory chemokines interleukin-8 (IL-8) and monocyte chemoattractant protein 1 (MCP-1).
T29564 120292-120470 Sentence denotes In our modified Boyden chamber assay, the migration of CD4+ lymphocytes across human BBB-EC monolayers is also reduced after BBB-EC treatment of Sonic Hh and Hh pathway agonists.
T30595 120471-120723 Sentence denotes In vitro treatment of BBB-derived ECs with inflammatory cytokines, TNFalpha and IFN-gamma, down-regulates the mRNA expression of Ptch-1, Smo and Gli-1, deregulating the Hh signaling pathway and preventing the barrier stabilizing properties of Sonic Hh.
T6094 120724-120964 Sentence denotes Our data provide strong evidence for an anti-inflammatory and BBB-promoting effect of astrocyte-secreted Sonic Hh and suggest that a pro-inflammatory environment disrupts the BBB by impacting, at least in part, on Hh signaling in brain ECs.
T1869 120966-121053 Sentence denotes The blood-brain barrier (BBB) regulates entry of both cells and molecules to the brain.
T91709 121054-121229 Sentence denotes Entry of cells and macromolecules to the brain parenchyma (BBB breakdown) correlates with clinical symptoms in inflammatory pathological conditions such as multiple sclerosis.
T91635 121230-121374 Sentence denotes The Renin-Angiotensin system (RAS) is a complex hormone system with multiple functions primarily regulating blood vessel tonus and permeability.
T47855 121375-121446 Sentence denotes The active compound, angiotensin II acts on two receptors: AT1 and AT2.
T69419 121447-121517 Sentence denotes The objective of this study was to examine the role of RAS at the BBB.
T45859 121518-121570 Sentence denotes Two distinct models of brain inflammation were used.
T94038 121571-121878 Sentence denotes The entorhinal cortex lesion model allows the study of an inflammatory response to traumatic brain injury at the site of stab wound with direct bleeding into the parenchyma, simultaneous with a milder inflammatory response at the distal dentate gyrus, where synapses degenerate, leading to glial activation.
T47767 121879-122040 Sentence denotes In the second model, MBP/CCL2 transgenic mice overexpressing the chemokine CCL2 in the brain show perivascular accumulation of leukocytes without other symptoms.
T15167 122041-122148 Sentence denotes Treatment with pertussis toxin (PTx) results in cellular infiltration to the parenchyma (Toft-Hansen et al.
T80391 122149-122175 Sentence denotes 2006 J Immunol.;177:7242).
T29867 122176-122304 Sentence denotes The presence and location of RAS components were investigated by realtime RT-PCR and immunohistology in these two animal models.
T77699 122305-122441 Sentence denotes The AT1 receptor was upregulated on astrocytes in the dentate gyrus of the ipsilateral hippocampus 3 days post entorhinal cortex lesion.
T16153 122442-122524 Sentence denotes Horseradish peroxidase (HRP) leakage across the BBB was not observed at this site.
T2105 122525-122675 Sentence denotes In PTx-treated MBP/CCL2 mice BBB breakdown and loss of glia limitans integrity were shown by HRP leakage and loss of betadystroglycan (b-DG) staining.
T26729 122676-122773 Sentence denotes In this model AT1 staining was not observed whereas the other receptor subtype, AT2 was detected.
T88444 122774-122898 Sentence denotes AT2 staining was closely associated to GFAP and b-DG staining consistent with expression by astrocytes at the glia limitans.
T59642 122899-123002 Sentence denotes AT2 was also seen at the glia limitans at the site of stab wound in the entorhinal cortex lesion model.
T12043 123003-123146 Sentence denotes These findings suggest differential roles of the two receptors in brain inflammation and raise interesting new questions as to their functions.
T23533 123147-123515 Sentence denotes Basivireddy Jayasree⁎ 3 , Buttmann Mathias 2 , Rieckmann Peter 3 2 Dept of Neurology, University of Wuerzburg, Wuerzburg, Germany, Germany 3 Dept of Neurology, University of British Columbia, Vancouver, Canada, Dept of Neurology, University of Wuerzburg, Wuerzburg, Germany, Canada Junctional adhesion molecule-A (JAM-A) is a member of the immunoglobulin super family.
T55737 123516-123660 Sentence denotes It is a major constituent of endothelial tight junctions where it is thought to regulate tight junction assembly and immune cell transmigration.
T5319 123661-123772 Sentence denotes JAM-A expressed in epithelial tight junctions has been shown to regulate paracellular permeability for solutes.
T35553 123773-123891 Sentence denotes In thrombocytes, the monoclonal antibody M.Ab.F11, a potent JAM-A agonist, induced platelet secretion and aggregation.
T43956 123892-124124 Sentence denotes Here, we used this antibody to investigate JAM-A-mediated changes in cell morphology and paracellular permeability as well as underlying intracellular signaling mechanisms in an in vitro-model of the human blood-brain barrier (BBB).
T3362 124125-124264 Sentence denotes Immortalized as well as low-passage primary human cerebral endothelial cells were cultured in vitro and stimulated with M.Ab.F11R antibody.
T16283 124265-124349 Sentence denotes Cell morphology was determined by phase contrast microscopy and immunocytochemistry.
T36665 124350-124457 Sentence denotes Paracellular permeability for solutes was assessed using fluorescent-labeled dextran in a transwell system.
T7086 124458-124529 Sentence denotes The role of MAP kinases was elucidated by specific chemical inhibitors.
T93685 124530-124607 Sentence denotes The phosphorylation status of MAP kinases was determined by Western blotting.
T83185 124608-124812 Sentence denotes Activation of JAM-A induced changes in cell morphology from a typical confluent cobble-stone pattern to a widening of intracellular spaces and development of lammellipodial and filopodial cell extensions.
T34593 124813-124864 Sentence denotes Actin staining showed a reduction of stress fibres.
T42538 124865-124993 Sentence denotes Permeability assays revealed increased permeability to small molecular weight dextrans of 3000 and 10,000 but not of 70,000 kDa.
T98387 124994-125098 Sentence denotes JAM-A activation induced delayed and sustained ERK phosphorylation while it did not activate JNK or p38.
T87614 125099-125243 Sentence denotes These JAM-A effects were largely neutralized by parallel treatment with chemical inhibitors of ERK phosphorylation but not of other MAP kinases.
T99966 125244-125379 Sentence denotes JAM-A-induced alteration of cell morphology and increase of paracellular permeability for solutes could be abolished by ERK inhibitors.
T43395 125380-125553 Sentence denotes Therefore, ERK signalling but not disruption of interendothelial JAM-A interactions by antibody binding mediated the observed effects in our in vitro model of the human BBB.
T26163 125554-125788 Sentence denotes JAM-A or intracellular signalling pathways activated by JAM-A may be a novel therapeutic target in neurological diseases where a breakdown of the BBB and edema formation play a pathogenic role, such as in stroke or multiple sclerosis.
T28903 125789-125900 Sentence denotes Our study also shows the possibility of circulating antibodies that cause breakdown of blood barrier integrity.
T33984 125901-126223 Sentence denotes 13 -Ninjurin-1 is an adhesion molecule of the blood-brain barrier involved in monocyte recruitment to the CNS In Multiple Sclerosis (MS), inflammatory demyelinating lesions are associated with a compromised blood-brain barrier (BBB) and with perivascular infiltration of immune cells into the central nervous system (CNS).
T57028 126224-126396 Sentence denotes The movement of leukocytes from the blood to the CNS is orchestrated by many factors including cell adhesion molecules that enable immune cells to adhere and cross the BBB.
T18603 126397-126556 Sentence denotes Nerve injury-induced protein (Ninjurin)-1 was described as an adhesion molecule that promotes nerve regeneration, in a homotypic Ninjurin-1-Ninjurin-1 fashion.
T46512 126557-126689 Sentence denotes We recently identified Ninjurin-1 in a proteomic screen for BBB-associated proteins using human BBB-derived endothelial cells (ECs).
T62887 126690-126777 Sentence denotes Our goal is to study the role of Ninjurin-1 in the trans-BBB migration of immune cells.
T29241 126778-126945 Sentence denotes Expression, regulation and localization of Ninjurin-1 on human BBB-ECs was determined by Western blot (WB), flow cytometry and immunocyto-and immunohisto-fluorescence.
T26735 126946-127039 Sentence denotes The functional role of Ninjurin-1 has been assessed using an in vitro model of the human BBB.
T38898 127040-127264 Sentence denotes We confirmed expression of Ninjurin-1 in vitro on BBB-ECs by WB and flow cytometry, in situ by confocal microscopy and we show regulation of Ninjurin-1 upon treatment with pro-inflammatory cytokines TNF, IFN-gamma and IL-17.
T38999 127265-127467 Sentence denotes Furthermore, Ninjurin-1 immunoreactivity was detected in vitro on astrocytes and in situ in MS lesion and in CNS material obtained from its animal model, experimental autoimmune encephalomyelitis (EAE).
T65729 127468-127638 Sentence denotes We demonstrate that Ninjurin-1 is present on peripheral blood immune cells, with a preferential expression on CD14 monocytes, as compared to CD4, CD8 or CD19 lymphocytes.
T61250 127639-127928 Sentence denotes Finally, using a modified Boyden chamber assay, we show that migration of ex vivo CD14 monocytes across the human endothelium is significantly reduced following treatment of BBB-ECs with a competing Ninjurin-1 peptide (PARWGWRHGPIN) and that Ninjurin-1 blockade increases BBB permeability.
T43630 127929-128080 Sentence denotes Our findings suggest that Ninjurin-1 is a novel adhesion molecule of the CNS endothelium that acts as a regulator of monocyte migration into the brain.
T61408 128081-128155 Sentence denotes 14 -Doxycycline treatment decreases morbidity and mortality of murine NCC:
T77823 128156-128285 Sentence denotes Evidence for reduction of apoptosis, oxidative stress and MMP activity Alvarez Jorge⁎ 1 , Krishnamurthy Janani 1 , Teale Judy 1 1
T57765 128286-128439 Sentence denotes Murine neurocysticercosis (NCC) is characterized by differential disruption of the barriers protecting the central nervous system (CNS) microenvironment.
T92762 128440-128573 Sentence denotes Among the host factors involved in this response, Matrix Metalloproteinases (MMPs) have been recently described as important players.
T13396 128574-128712 Sentence denotes Doxycycline is a commonly prescribed antimicrobial drug that also acts as an anti-inflammatory agent with broad MMP inhibitory properties.
T97590 128713-128802 Sentence denotes In this study we examined the effect of doxycycline treatment in the murine model of NCC.
T10798 128803-128939 Sentence denotes Animals treated with doxycycline exhibit lower numbers of parasites and reduced morbidity and mortality through the course of infection.
T77615 128940-129204 Sentence denotes Although similar levels of leukocyte infiltration were observed in both treatments, doxycycline seems to provide the appropriate conditions for host survival as reduced levels of apoptosis and oxidative stress were detected among infiltrates as well as CNS tissue.
T68580 129205-129424 Sentence denotes As an established MMP blocker, doxycycline appears to reduce degradation of junctional complex proteins in parenchymal vessels and also lowered the levels of cytokines known to increase the permeability of CNS barriers.
T48651 129425-129589 Sentence denotes In addition, doxycycline treatment was associated with an overall reduction in the expression and activity of MMPs, particularly in areas of leukocyte infiltration.
T15037 129590-129896 Sentence denotes These results indicate that partial inhibition of a broad range of MMPs establishes an environment within the CNS conducive to restrain the infection and promote host survival, suggesting the potential of doxycycline as a therapeutic agent to control the exacerbated response often found in CNS infections.
T73425 129897-129976 Sentence denotes The pathogenesis of idiopathic intracranial hypertension (IIH) remains unclear.
T10489 129977-130172 Sentence denotes IIH is almost always associated with obesity, which is recognised as a proinflammatory state, with increased expression of a number of adipokines, cytokines and chemokines including CCL2 (MCP-1).
T22481 130173-130259 Sentence denotes Whether these mediators play a role in the pathogenesis of IIH remains uninvestigated.
T5240 130260-130443 Sentence denotes The aim of this study was to investigate any significant differences in the expression of CCL2, IL-1a and leptin in IIH patients when compared to an age and sex matched control group.
T1741 130444-130636 Sentence denotes These 3 mediators were selected from a preliminary screen of forty two different cytokines and chemokines on an immunoblot which showed an apparent difference between IIH and control patients.
T7807 130637-130852 Sentence denotes CCL2, IL-1a and leptin levels were measured using enzyme linked immunosorbent assay (ELISA) in the cerebrospinal fluid (CSF) and serum of thirty-seven patients with a diagnosis of IIH and forty-two control subjects.
T81695 130853-131129 Sentence denotes Controls were subdivided into three groups: patients with inflammatory neurological disease (n = 14), patients with noninflammatory neurological disease (n = 7) and patients presenting with headache or other neurological symptoms whose investigations were all normal (n = 20).
T60850 131130-131207 Sentence denotes Statistical analysis utilised Kruskal Wallis test and analysis of covariance.
T47397 131208-131345 Sentence denotes CSF and serum levels of CCL2, IL-1a and leptin levels were not significantly different between IIH patients and the three control groups.
T33957 131346-131443 Sentence denotes Serum leptin levels were significantly associated with body mass index in all groups (p = 0.002).
T940 131444-131682 Sentence denotes Our findings suggest that CSF and serum CCL2, IL-1a and leptin levels in IIH patients do not differ compared to those who do not have the condition, suggesting that these specific mediators do not a play a role in the pathogenesis of IIH.
T27359 131683-131785 Sentence denotes Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system.
T39696 131786-131861 Sentence denotes T cells in inflamed lesions express the chemokine receptors CXCR3 and CCR5.
T77639 131862-132098 Sentence denotes The role of chemokines binding to CXCR3 receptors like interferon gamma-inducible protein 10 (CXCL10) or interferon-inducible T-cell alpha-chemoattractant (CXCL11) as well as CCL5 binding to CCR5 in the pathogenesis of MS is unresolved.
T89849 132099-132356 Sentence denotes The aim of the study was to estimate the levels of CCL5, CXCL10 and CXCL11 in serum and cerebrospinal fluid(CSF) in relapsing-remitting MS (RRMS) patients during relapse and stable stage of the disease and to compare results with those in the control group.
T14628 132357-132499 Sentence denotes We also decided to evaluate the effect of methylprednisolone (MP) therapy on CCL5, CXCL10 and CXCL11 serum levels in MS patients with relapse.
T95230 132500-132629 Sentence denotes The studied groups consisted of 17 RRMS patients during relapse, 30 RRMS patients in stable stage of the disease and 25 controls.
T58941 132630-132801 Sentence denotes In the group of relapsing MS patients the blood samples were obtained both before steroid therapy and after five days treatment with MP in a dose of 1.0 g i.v. once daily.
T77685 132802-132866 Sentence denotes The levels of the chemokines have been measured by ELISA method.
T35520 132867-133105 Sentence denotes The levels of CXCL10 were significantly higher in the CSF of RRMS patients both during relapse (298.2 ± 143.8 pg/ml) and stable phase of the disease (323.7 ± 183 pg/ml) in comparison with the control group (152.4 ± 97.7 pg/ml, p b 0.001).
T23452 133106-133223 Sentence denotes The CSF levels of CCL5 were significantly higher in patients with relapses in comparison with stable RRMS, p b 0.005.
T77735 133224-133291 Sentence denotes The CXCL11 levels did not differ significantly from control values.
T66473 133292-133373 Sentence denotes There was no effect of MP therapy on the serum levels of CCL5, CXCL10 and CXCL11.
T63871 133374-133466 Sentence denotes The results suggest involvement of CCL5 and CXCL10 but not CXCL11 in the pathogenesis of MS.
T71690 133467-133851 Sentence denotes 17 -Cleavage of CCL2 by MMPs 2 and 9 reduces cell migration which may supplement the effects of immunomodulatory therapy in multiple sclerosis Chemokines direct the migration of peripheral blood mononuclear cells (PBMCs) across the blood brain barrier (BBB) into the central nervous system (CNS); a process thought to initiate the tissue damage that occurs in multiple sclerosis (MS).
T70926 133852-133961 Sentence denotes Expression of the chemokine CCL2 has been demonstrated within active lesions in MS, but not in control brain.
T3481 133962-134097 Sentence denotes A low percentage of T cells and the majority of peripheral blood and cerebrospinal fluid monocytes express CCR2, the receptor for CCL2.
T84892 134098-134186 Sentence denotes CCL2 is thus considered to play a key role in the recruitment of PBMCs at the BBB in MS.
T48845 134187-134365 Sentence denotes Matrix metalloproteinases (MMPs), particularly MMPs 2 and 9, are involved in MS pathogenesis, including BBB disruption, and are colocalised with CCL2 in CNS inflammatory lesions.
T2092 134366-134426 Sentence denotes MMPs can cleave chemokines, thereby altering their activity.
T7142 134427-134519 Sentence denotes We investigated processing of CCL2 by MMPs 2 and 9, and the effects on chemotactic activity.
T94776 134520-134760 Sentence denotes Effects of in vivo immunomodulatory treatment on PBMC migration in response to CCL2 are currently under investigation, and will demonstrate whether drug treatment has specific effects which could be further influenced by truncation of CCL2.
T73800 134761-134929 Sentence denotes In vitro processing of CCL2 by MMPs 2 and 9 was analysed using matrix-assisted laser desorption/ionisation quadrupole time-of-flight mass spectrometry (MALDI Q-TOF MS).
T43932 134930-135141 Sentence denotes Cell chemotaxis to cleaved and intact CCL2 was assessed using migration assays utilising calcein AM to fluorescently label cells, prior to addition to inserts with a fluorescentblocking membrane with 3 μm pores.
T44476 135142-135253 Sentence denotes Measurement of fluorescence from the underside of the membrane enabled acquisition of real time migration data.
T76788 135254-135500 Sentence denotes Assessment of the effects of in vivo drug treatments on PBMC migration to CCL2 pre-and post-treatment (3 and 6 months) in up to 50 patients on either interferon beta (beta interferon-1b, and -1a), glatiramer acetate or natalizumab, is in process.
T75059 135501-135695 Sentence denotes MMPs 2 and 9 each cleaved four amino acids from the N-terminus of CCL2 within 3 h, resulting in a two-fold reduction in migration of THP-1 cells (a monocytic cell line), compared to intact CCL2.
T27393 135696-135812 Sentence denotes Increases (3-5 fold) in migration of PBMC from untreated MS patients occurred within 90-120 min in response to CCL2.
T38850 135813-135880 Sentence denotes In vivo migration is likely to be reduced to MMP2/9-truncated CCL2.
T26245 135881-136105 Sentence denotes Moreover, expression of MMPs 2 or 9 in the CNS in MS is likely to result in truncation of CCL2, which may augment the effects of immunomodulatory therapy in reducing further migration of monocytes and T cells across the BBB.
T71973 136106-136345 Sentence denotes 18 -Skewed pro-inflammatory innate immunity in immune deficient mice impairs cognitive function through inhibition of synaptogenesis Recent evidence suggests that T cells can influence neuronal plasticity by supporting learning and memory.
T86310 136346-136546 Sentence denotes For example, severe combined immune-deficient (scid) mice were shown to have impaired cognitive performance, which was reversed following injection of exogenous Tcells from genetically matched donors.
T19316 136547-136644 Sentence denotes The mechanisms underlying the beneficial effects of T cells in the brain are not well understood.
T3117 136645-136828 Sentence denotes Here we show that scid mice possess fewer hippocampal synapses along with a reduced hippocampal expression of the synaptogenic protein, thrombospondin1 (TSP1), as compared to WT mice.
T28173 136829-136991 Sentence denotes Moreover, myeloid cells occupying subarachnoid and ventricular spaces exhibits a skewed pro-inflammatory phenotype in scid mice as compared to wild type controls.
T83873 136992-137142 Sentence denotes Pro-inflammatory cytokines produced by meningeal myeloid cells are proposed to diffuse into brain parenchyma and affect astroglial expression of TSP1.
T33606 137143-137439 Sentence denotes We show that while antiinflammatory cytokine, interleukin (IL)-4 increased TSP1 expression in astrocytes, pro-inflammatory cytokines suppress, such as IL-6 and TNF-a inhibit its expression, which is, supposedly, responsible for reduced synapses and for cognitive impairment observed in scid mice.
T3141 137440-137720 Sentence denotes Our results not only shed a light on the mechanism underlying cognitive dysfunctions associated with immune decline but might also lead to a development of new future therapies for cognitive and mental conditions that target immune cells for the benefit of central nervous system.
T518 137721-138065 Sentence denotes Using image-guided pathological analysis, we previously demonstrated that multiple sclerosis (MS) lesions which were abnormal on T2weighted, T1-weighted images (WI) and magnetization transfer ratio (T2/ T1/MTR lesions) showed axonal swelling and reduced axonal Na+-K+ ATPase, as contrasted with lesions abnormal only on T2-WI (T2-only lesions).
T26055 138066-138139 Sentence denotes Here, we compare leukocyte accumulation in T2/T1/MTR and T2-only lesions.
T57620 138140-138255 Sentence denotes To address inflammatory mechanisms, we characterized expression of the chemokine receptor/ligand pair CXCR4/CXCL12.
T58936 138256-138379 Sentence denotes The study comprised autopsy brain tissue from five secondary progressive MS (SPMS) and five non-neurological control cases.
T78829 138380-138461 Sentence denotes Based on imaging characteristics, thirty regions of interest (ROIs) were excised.
T37452 138462-138605 Sentence denotes Using immunohistochemistry, we evaluated myelin status, leukocyte accumulation and CXCR4/CXCL12 expression in the selected MS and control ROIs.
T97448 138606-138697 Sentence denotes Eight of ten T2/T1/MTR regions were chronic-active or chronicinactive demyelinated lesions.
T71774 138698-138817 Sentence denotes T2-only regions were histopathologically diverse, ranging from normal or partial myelination to complete demyelination.
T10312 138818-138886 Sentence denotes Demyelinated T2-only regions corresponded to chronic active lesions.
T67735 138887-139006 Sentence denotes Mononuclear phagocyte distribution in T2-only chronicactive lesions resembled that in T2/T1/MTR chronic-active lesions.
T48376 139007-139116 Sentence denotes Parenchymal T-cells were significantly increased in T2/T1/MTR ROIs as compared to T2-only lesions and MS NWM.
T95162 139117-139246 Sentence denotes CXCR4 and phospho-CXCR4 expression was associated with reactive microglia and macrophages in active or chronic active MS lesions.
T57215 139247-139321 Sentence denotes CXCL12 expression was increased in astrocytic cells and vascular elements.
T4204 139322-139469 Sentence denotes Inflammatory cell distribution and numbers correlated more with stages of demyelination than with T2/T1/MTR versus T2-only imaging characteristics.
T17892 139470-139592 Sentence denotes Therefore, imaging correlations to axonal pathology were not affected by differential inflammatory leukocyte distribution.
T60045 139593-139736 Sentence denotes Robust expression of CXCR4/CXCL12 on inflammatory elements in MS lesions highlights a role of this chemokine/receptor pair in CNS inflammation.
T78379 139737-139752 Sentence denotes POSTER SESSION:
T98097 139753-140068 Sentence denotes Neuroimmune pharmacology and crosstalk 1 -A pilot trial of low dose naltrexone in primary progressive multiple sclerosis Multiple Sclerosis Study Center, Hospital of Gallarate, Gallarate (Va), Italy Naltrexone is an orally semi synthetic opiate antagonist licensed for the treatment of heroin and alcohol addiction.
T52709 140069-140294 Sentence denotes However, its opiate antagonist activity is completely abrogated at lower doses (=5 mg) while triggering a prolonged up regulation of β-endorphins (BE), an endogenous opioid with neuroprotective and immunomodulatory functions.
T99970 140295-140476 Sentence denotes A symptomatic effect on spasticity, pain and fatigue of low dose naltrexone (LDN) in multiple sclerosis (MS) has been reported, but only anecdotic observations are available so far.
T66452 140477-140707 Sentence denotes A sixth-month, phase II, multicentre, open-label, therapeutic trial with LDN (4 mg/die) has been carried out in 40 patients (pts) with a diagnosis of primary progressive (PP) MS (21:19 female:male; mean age 53.4; median EDSS 6.0).
T76812 140708-140793 Sentence denotes Thirty-five (87.5%) patients completed the 6 months of therapy, 5 drop-outs occurred.
T35363 140794-140918 Sentence denotes Two major adverse events (5% of pts) of grade III (severe) and IV (life-threatening or disabling) occurred during the trial.
T66445 140919-141052 Sentence denotes The remaining adverse events were of grade I (not interfering with function) or II (not interfering with activities of daily living).
T55823 141053-141202 Sentence denotes Transitory haematological abnormalities (35% of pts), urinary tract infections (20% of pts), and mild irritability (12.5% of pts) were the commonest.
T88662 141203-141287 Sentence denotes Neurological disability progressed in only 1 (2.5%) patient at the end of the study.
T39618 141288-141438 Sentence denotes Regarding efficacy measures, a significant reduction of spasticity along with some evidence of a positive effect on fatigue and depression were found.
T2577 141439-141583 Sentence denotes As regards quality of life, there was a general trend of improvement between final and baseline evaluation albeit not statistically significant.
T36859 141584-141682 Sentence denotes Physical functioning, role physical, energy, and social functioning were the most benefited items.
T18496 141683-141851 Sentence denotes PBMC levels of BE (but not of MOR) started increasing 3 months after beginning of the therapy and were still increased 1 month after therapy discontinuation (p b 0.05).
T92980 141852-141952 Sentence denotes No association was found between allelic variants of the OPRM1 gene and responsiveness to treatment.
T67894 141953-142006 Sentence denotes LDN is safe and well tolerated in patients with PPMS.
T49960 142007-142095 Sentence denotes We were also able to show some positive influence on spasticity, fatigue and depression.
T85923 142096-142193 Sentence denotes A pure placebo-like effect is improbable because of the temporal profile of the observed changes.
T47284 142194-142361 Sentence denotes A longer time of drug administration and a longer follow-up could definitely address whether or not LDN can be considered a reliable therapeutic option in MS patients.
T8693 142363-142598 Sentence denotes Bipolar disorder (BPD) and schizophrenia (SCZ) are severe disorders representing an enormous social, familiar and individual burden, being SCZ the most disabling psychiatric disorder characterized by psychosis and cognitive impairment.
T10879 142599-142697 Sentence denotes It is well known that SCZ and BPD are associated with abnormalities in dopamine signaling pathway.
T71771 142698-142869 Sentence denotes Recent data in the literature have demonstrated altered expression levels of some proteins involved in the modulation of this pathway in both brain and peripheral tissues.
T92205 142870-143083 Sentence denotes It was shown that protein and mRNA levels of dopamine and cAMP regulated phosphoprotein (DARPP-32) was downregulated in dorsolateral prefrontal cortex (DLPFC) of patients with SCZ or BPD when compared to controls.
T13665 143084-143401 Sentence denotes Due to the difficulty to access brain tissue and the absence of objective laboratory tests for bio-markers, we measured DARPP-32 expression in blood cell sub-populations (CD4+ T lymphocytes, CD56+ NK cells, CD19+ B lymphocytes and CD14+ monocytes) taking advantage of the close relation of nervous and immune systems.
T48444 143402-143674 Sentence denotes Using flow cytometry as the analytical method, our results have shown that the DARPP-32 expression was diminished in CD4+T lymphocytes, CD19+ B lymphocytes and CD14+ monocytes of BPD patients and was also decreased in CD4+ T lymphocytes and CD56+ NK cells of SCZ patients.
T13931 143675-143820 Sentence denotes These results showed that DARPP-32 expression in immune cells agree with reports of reduced DARPP-32 protein in the DLPFC of BPD or SCZ patients.
T63489 143821-144013 Sentence denotes Our data suggest that DARPP-32 expression in lymphocytes and monocytes could be used as a source of bio-markers to help in the diagnosis and/or treatment response of neuropsychiatry disorders.
T771 144014-144052 Sentence denotes Mohan Shekher⁎ 1 , Fernando Samodha C.
T2672 144053-144130 Sentence denotes 2 The mu opioid receptor (hMOR) plays a significant role in opioid tolerance.
T53654 144131-144227 Sentence denotes Expression of hMOR has been shown to be differentially regulated following cytokine stimulation.
T6395 144228-144418 Sentence denotes We aim to determine the dose and time-dependent effects of IL-1beta and morphine on hMOR expression in SK-N-SH cells using quantitative real-time-PCR (qRT-PCR) and immunocytochemistry (ICC).
T67067 144419-144490 Sentence denotes A time-dependent IL-1beta-induced up-regulation of hMOR was identified.
T82424 144491-144621 Sentence denotes 10 and 100 ng/mL of IL-1beta for 6 h (p b 0.001) and 12 h (p b 0.05) induced hMOR up-regulation as measured using qRT-PCR (n = 5).
T27726 144622-144799 Sentence denotes 10 and 100-fold pretreatment with IL-1 receptor antagonist (IL-1ra) reduced IL-1beta (10 ng/mL) induced up-regulation of hMOR, concluding a plausible IL-1R1 dependent mechanism.
T8492 144800-144942 Sentence denotes The effect of morphine (1, 10 and 100 03BCM) on hMOR expression showed a timedependent (24 h) down-regulation of hMOR mRNA expression (n = 5).
T30629 144943-145097 Sentence denotes Using Confocal microscopy, ICC showed that IL-1beta and morphine induced changes in hMOR mRNA expression are reflected in hMOR protein expression changes.
T96376 145098-145266 Sentence denotes In conclusion, evidence for the interactions between IL-1beta, morphine and hMOR expression in vitro may elucidate the mechanism behind opioid-induced opioid tolerance.
T44639 145267-145357 Sentence denotes Next we aim to measure these changes in hMOR protein expression using immunoblot analysis.
T54650 145358-145527 Sentence denotes Future studies include elucidating the signal transduction pathways that result in changes in hMOR expression in neurons treated with IL-1beta and morphine concurrently.
T38895 145528-145727 Sentence denotes With the use of signaling inhibitors, we aim to determine if IL-1beta effect on hMOR expression in SK-N-SH cells is dependent on specific intracellular signaling proteins (p38MAPK-ERK-MEK-NF-kappaB).
T82960 145728-145944 Sentence denotes Understanding the neuroimmune interactions between IL-1beta and hMOR expression, may identify potential molecular targets for the prevention of opioid receptor expression down-regulation and perhaps opioid tolerance.
T18071 145945-146219 Sentence denotes EAE was induced in male, age-matched C57Bl/6 mice with myelin oligodendrocyte glycoprotein (MOG) peptide in adjuvant and monitored for disease severity using a 5-point scale (1, limp tail; 2, ataxia + limp tail; 3, weak hind limb; 4, complete hind limb paralysis; 5, death).
T12028 146220-146309 Sentence denotes Inhibitor was administered daily at 25 mg/kg p.o. beginning at 21 days post-immunization.
T89013 146310-146427 Sentence denotes Lymphocyte activation and cytokine production were measured in splenocytes following ten days of inhibitor treatment.
T87416 146428-146583 Sentence denotes We found that mice treated with MIF inhibitor had less severe EAE within seven days of treatment (cumulative disease index of 25.4 ± 15.9 vs. 48.9 ± 23.4).
T67984 146584-146808 Sentence denotes Inhibitor-treated mice also had a larger population of CD4 + 25 + FoxP3+ regulatory T cells (5.1% vs. 3.8%), but proliferation and production of the cytokines IL-10, IL-17, and IFNgamma in response to antigen were unchanged.
T33180 146809-146960 Sentence denotes Following conclusion of treatment, mice remained protected compared to vehicle-treated controls (cumulative disease index 46.3 ± 29.0 vs. 85.0 ± 40.4).
T80835 146961-147091 Sentence denotes These findings demonstrate that an inhibitor of MIF is protective in EAE, potentially through the expansion of regulatory T cells.
T35172 147092-147223 Sentence denotes However, inhibitor treatment does not dampen the peripheral immune response to antigen or the production of inflammatory cytokines.
T34013 147224-147327 Sentence denotes This suggests an alternate role for MIF, perhaps in the trafficking of inflammatory cells into the CNS.
T93032 147328-147566 Sentence denotes Because of their bioavailability and mechanism of protection, these inhibitors could be a novel therapeutic approach for the treatment of ongoing MS and other inflammatory diseases. (Supported by NIH grant AI 064320 and NMSS grant RG3272)
T83568 147567-147676 Sentence denotes Multiple sclerosis (MS) is an idiopathic inflammatory demyelinating and neurodegenerative disease of the CNS.
T57131 147677-147837 Sentence denotes It is currently believed that environmental and genetic factors contribute to both the onset and progression of the disease which occurs during early adulthood.
T24268 147838-148038 Sentence denotes Interestingly, both infectious agents and psychological stress have been suspected to play a role in the acquisition and progression of this disease since its early characterization in the late 1800s.
T72782 148039-148333 Sentence denotes Theiler's murine encephalomyelitis virus (TMEV) is a picornavirus which upon intracranial inoculation of susceptible mice (i.e. SJL) causes a persistent infection that is characterized by an acute polioencephalitis followed by chronic inflammatory demyelinating disease that resembles human MS.
T64759 148334-148436 Sentence denotes We have been interested in the effects of stress on the pathogenesis of this experimental model of MS.
T53647 148437-148637 Sentence denotes In the current study we were interested in both the effects of chronic stress on virus-specific adaptive immune responses to TMEV in SJL mice and the mechanisms by which these responses are modulated.
T44145 148638-148811 Sentence denotes Using known immunodominant viral peptides specific for either CD4+ or CD8+ T cells we found that stress decreased virus-specific T cell responses in both the spleen and CNS.
T42182 148812-149082 Sentence denotes Intriguingly, stress increased virus-specific circulating antibody responses in the serum of stressed mice when compared to non-stressed mice, but did not result in a shift from type 1 toward type 2 immunity as indicated by serum cytokines and T cell stimulation assays.
T62254 149083-149238 Sentence denotes Moreover, this suppression of T cell responses did not appear to be fully attributable to alterations in T cell percentages as indicated by flow cytometry.
T66227 149239-149477 Sentence denotes Finally, glucocorticoids were found to be partially responsible for the decreased responses on T cell function as the effects of stress were in part reversed by concurrent RU486 administration but mimicked by dexamethasone administration.
T31528 149478-149665 Sentence denotes As T cells are thought to mediate viral clearance in this model, our data indicate that stress induced immunosuppression may provide a means for enhanced viral persistence within the CNS.
T67955 149666-149921 Sentence denotes 6 -Active immunization with amyloid-beta 1-42 significantly impairs memory performance in healthy mice Active immunization with Amyloid-beta 1-42 (Abeta) was shown to prevent amyloid plaque deposition in different mouse models of Alzheimer's disease (AD).
T91100 149922-150028 Sentence denotes Whether the induction of an immune response to Abeta also improves memory function is still controversial.
T15615 150029-150171 Sentence denotes Here, we identify the cognitive and immunological phenotype of healthy C57BL/6 mice immunized with Abeta and complete Freund's adjuvant (CFA).
T92328 150172-150349 Sentence denotes Immunization significantly altered the behavioral phenotype of mice compared to control mice receiving Abeta or CFA only or Myelin oligodendrocyte glycoprotein induced EAE mice.
T10446 150350-150527 Sentence denotes Abeta and CFA immunized mice revealed decreased locomotor activity, reduced habituational learning and highly deficient spatial-learning abilities in an object recognition task.
T76697 150528-150720 Sentence denotes Quantitative rtPCR data demonstrated the upregulation of a number of macrophage and T cell related genes in the CNS of Abeta mice, in particular C3, CD3, CD14, Cxcl10, IL-1b, IFN-g and S100A8.
T383 150721-150883 Sentence denotes Furthermore, reactive gliosis was detected in Abeta mice in the chronic phase of disease as shown by GFAP immunohistochemistry and by quantitative rtPCR for GFAP.
T75163 150884-151027 Sentence denotes In peritoneal macrophages from immunized mice, CD14, CSF 3, IL-1b, IL-6, MMP9, Nos2, S100A8 and TNF-a gene transcripts were highly upregulated.
T23758 151028-151166 Sentence denotes In summary, immunization of healthy mice with Abeta and CFA induced an inflammatory cascade significantly impairing cognitive functioning.
T39981 151167-151345 Sentence denotes These results illustrate the potential danger of active immunization with neuronal antigens and demonstrate the complexity of immune responses to Abeta in the pathogenesis of AD.
T81307 151346-151474 Sentence denotes Abeta immunization in plaque pathology free animals even provides a suitable model for autoimmune mediated cognitive impairment.
T70746 151475-151607 Sentence denotes Lewitus Gil⁎ 1 , Wilf-Yarkoni Adi 1 , Ziv Yaniv 1 , Shabat-Simon Maytal 1 , Gersner Roman 1 , Zangen Abraham 1 , Schwartz Michal 1 1
T8480 151608-151729 Sentence denotes Depression in an animal model is often associated with reduced BDNF levels, and impaired neurogenesis in the hippocampus.
T48559 151730-151954 Sentence denotes Our previous observations that T cells recognizing CNS-specific antigens can regulate adult brain neurogenesis and expression of BDNF, created the basis of the present study of boosting T-cell levels to cope with depression.
T69988 151955-152103 Sentence denotes Here we show that vaccination with a weak agonist of a myelinderived peptide ameliorated depressive behavior induced by chronic mild stress in rats.
T58162 152104-152202 Sentence denotes The behavioral outcome was accompanied by restoration of hippocampal BDNF levels and neurogenesis.
T36042 152203-152351 Sentence denotes The results of the present study introduce a novel approach of vaccination with CNS-related antigens as a therapeutic means for fighting depression.
T6638 152352-152504 Sentence denotes Vaccination, as an antidepressant therapy, encompasses several molecular and cellular mechanisms that are known to be regulated by antidepressant drugs.
T67878 152505-152729 Sentence denotes Therefore, we suggest that immunebased therapies should be considered for treatment of depression. myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS.
T33051 152730-152972 Sentence denotes The striatum, which is particularly prone to degenerate in MS, was rather selectively involved in EAE, and striatal neurons exhibited a marked up-regulation of AMPA receptor-mediated transmission since the presymptomatic phase of the disease.
T10395 152973-153184 Sentence denotes Altered striatal glutamate transmission was secondary to abnormal expression and phosphorylation state of AMPA receptors triggered by microglia activation, TNF-a release, and modulation of Arc/Arg3.1 early gene.
T64201 153185-153348 Sentence denotes Accordingly, application of activated microglia or of TNF-a, but not of activated T lymphocytes, replicated in normal neurons the synaptic defects observed in EAE.
T81463 153349-153498 Sentence denotes These data reveal an important role of synaptic dysfunction and soluble factors released from activated microglia in the pathological process of EAE.
T94072 153499-153735 Sentence denotes Macroautophagy delivers cytoplasmic constituents for lysosomal degradation in skeletal muscle tissue and thereby could affect adaptive immune responses via delivery of intracellular antigens for MHC class II presentation on these cells.
T46555 153736-153961 Sentence denotes We investigated constitutive and immune-mediated macroautophagy regulation and MHC expression in primary human myoblasts and in a rhabdomyosarkoma cell line (CCL 136) by immunocytochemistry, immunoblotting and flow cytometry.
T89432 153962-154113 Sentence denotes We identified TNF-alpha from complex mixtures of inflammatory cytokines as the predominant regulatory factor for macroautophagy in the skeletal muscle.
T44188 154114-154290 Sentence denotes While loss of macroautophagy did not predispose muscle cells for TNFreceptor mediated apoptosis, TNF-alpha enhanced HLA-DR surface levels in interferon-gamma treated myoblasts.
T73330 154291-154515 Sentence denotes The synergistic effect of TNF-alpha and IFN-gamma did not result in higher intracellular HLA-DR expression, suggesting that TNF-alpha facilitates antigen processing via macroautophagy for more efficient MHC class II loading.
T11342 154516-154813 Sentence denotes Our findings establish a mechanism through which TNF-alpha regulates both macroautophagy and MHC class II expression in skeletal myocytes and suggest that TNF-alpha is a key mediator and a potential therapeutic target in T cell-mediated inflammatory myopathies in which macroautophagy is involved.
T41413 154814-154886 Sentence denotes Endogenous opioids as well as exogenous opiates affect immune responses.
T65002 154887-155093 Sentence denotes This is achieved by their indirect action via binding to opioid receptors expressed on cells of the neuroendocrine system and by their direct action via binding to opioid receptors expressed on immunocytes.
T14077 155094-155207 Sentence denotes The effect of direct action of opioids on immunocytes is modulation of their proliferation, activation and death.
T60796 155208-155321 Sentence denotes Expression of opioid receptors of the kappa class (KOR) on cells of monocyte-macrophage origin has been reported.
T62782 155322-155406 Sentence denotes However, precise role(s) of KOR and their regulation have not been fully understood.
T42334 155407-155508 Sentence denotes In this study we have examined the expression of KOR on cells of a murine macrophage cell line, J774.
T92753 155509-155625 Sentence denotes That was done at transcriptional and protein level by using semi-quantitative RT-PCR and Western blot, respectively.
T2071 155626-155739 Sentence denotes Mouse or rat brain cells, and mouse T-cell line R1.1, selectively expressing KOR, were used as positive controls.
T7817 155740-155812 Sentence denotes The data obtained have shown that J774 cells express KOR at both levels.
T59184 155813-155919 Sentence denotes Further, we examined the ability of pro-inflammatory cytokine interferon-gamma to regulate KOR expression.
T70183 155920-155994 Sentence denotes IFN-gamma increased KOR mRNA in a concentration-and time-dependent manner.
T66722 155995-156087 Sentence denotes This finding was confirmed by increased level of KOR protein in IFNgamma-treated J774 cells.
T64957 156088-156216 Sentence denotes Collectively, the data presented have shown that J774 cells basally express KOR and that KOR could be up-regulated by IFN-gamma.
T88088 156217-156534 Sentence denotes This observation is in line with our previous finding that KOR-selective ligand Dynorphin-A modulates NO secretion and proliferation of J774 cells ( Cerebral ischemia is accompanied by an acute inflammation, involving the activation of microglia and the infiltration of neutrophils (PMN) and monocytes into the brain.
T67870 156535-156618 Sentence denotes Whether and how microglia can protect neurons from ischemic death is still debated.
T45551 156619-156765 Sentence denotes Using a model of application of innate immune cells onto hippocampal slices (OHC), we investigated their effects on neuronal death after ischemia.
T86336 156766-156906 Sentence denotes We show that applied PMN exacerbated neuronal damage, whereas microglia protected neurons from oxygen glucose deprivation (OGD) in two ways.
T46507 156907-157109 Sentence denotes Applying an approach of transgenic OHC from mice (eYFP expression in neurons) and fluorescently labeled microglia, we observed that microglia is engaged in close physical contact with neurons after OGD.
T68310 157110-157211 Sentence denotes Blockage of microglia migration to the neurons after OGD abolished the microglia mediated protection.
T17335 157212-157334 Sentence denotes Moreover, the application of microglia and PMN simultaneously indicated that microglia counteracted the PMN neurotoxicity.
T96441 157335-157400 Sentence denotes Time-lapse imaging revealed the phagocytosis of PMN by microglia.
T88749 157401-157537 Sentence denotes Interference with the phagocytosis using RGDS and N-Acetyl-Glucosamine abrogated the microglial ability to reduce the PMN neurotoxicity.
T30545 157538-157750 Sentence denotes Taken both observations together: microglia might protect neurons after ischemia in two ways: (i) directly by physical interaction with neurons and (ii) indirectly by clearance the inflamed tissue from toxic PMN.
T64347 157751-157840 Sentence denotes Thus, non-selective anti-inflammatory treatment after ischemia would be counterintuitive.
T75157 157841-158020 Sentence denotes Cerebral ischemia is among other immunological events characterised by an early response of microglia cells within the endangered region and microglia from surrounding parenchyma.
T62536 158021-158143 Sentence denotes Migration of surrounding microglia to the site of injury is a key event in exerting the response in the respective region.
T98463 158144-158239 Sentence denotes Whether microglia cells then exhibit beneficial or detrimental effects is still highly debated.
T87397 158240-158445 Sentence denotes It has been shown that the serine protease thrombin is an inflammatory mediator that acts via protease-activated receptors (PAR1, PAR3 and PAR4) and modulates microglia function (e.g. cytokine production).
T30628 158446-158516 Sentence denotes We have been focusing on the role of PAR4 on microglia after ischemia.
T21723 158517-158693 Sentence denotes Using an in vitro co-culture of primary hippocampal neurons and the microglia cell line BV-2, we show that microglia migration activity is dramatically enhanced after ischemia.
T9927 158694-158852 Sentence denotes Similar migration enhancement of microglia in the co-culture has been seen after selective PAR4 activation by an activating peptide without ischemic exposure.
T77692 158853-158984 Sentence denotes Moreover, we investigated the PAR4 dependent regulation of ED-1 expression that shows the lysosomal activity of phagocytotic cells.
T7372 158985-159086 Sentence denotes We found a down regulation of ED-1 expression after selective activation of PAR-4 on microglia cells.
T63149 159087-159278 Sentence denotes To characterise the cytokine production and thereby the status of microglia-activation we analysed the level of pro-inflammatory TNF-alpha in PAR-4 stimulated primary microglia and BV2 cells.
T85144 159279-159393 Sentence denotes Our results implicate that microglia activation by PAR4 might regulate microglia function after cerebral ischemia.
T62111 159394-159607 Sentence denotes We recently demonstrated that cyclooxygenase 2 (COX-2) was expressed in dying oligodendrocytes at the onset of demyelination in the Theiler's Murine Encephalomyelitis Virus (TMEV) model of multiple sclerosis (MS).
T93462 159608-159863 Sentence denotes This finding is consistent with the hypothesis that COX-2 expression in oligodendrocytes might render these cells more susceptible to glutamate-mediated excitotoxicity in much the same manner that COX-2 expression in neurons increases neuronal cell death.
T58986 159864-159875 Sentence denotes Objectives:
T25338 159876-160052 Sentence denotes Our goal was to determine whether COX-2 inhibitors can decrease demyelination in TMEV induced demyelination (TMEV-IDD) and limit excitotoxic death of oligodendrocytes in vitro.
T13869 160053-160223 Sentence denotes Mice were infected intracerebrally with the DA strain of TMEV and either given a control diet or chow containing the COX-2 inhibitor CAY10452 (a derivative of celecoxib).
T79161 160224-160394 Sentence denotes Spinal cords of control and CAY10452-treated mice were harvested 35 days after infection and scored for inflammation and demyelination following Luxol fast blue staining.
T68096 160395-160548 Sentence denotes For the in vitro experiments, organotypic cultures were prepared from post natal day 8 spinal cords and grown on permeable filters at 37°C with 5% CO 2 .
T62805 160549-160688 Sentence denotes Cultures were then exposed to the excitotoxin kainic acid (KA) (300 μM) in the presence or absence of the COX-2 inhibitor CAY10452 (30 μM).
T6036 160689-160925 Sentence denotes Cell death in white matter and gray matter was assessed 24 h later by immunofluorescence confocal microscopy using the cell death indicator activated caspase 3 and the oligodendrocyte marker cyclic nucleotide phosphodiesterase (CNPase).
T36118 160926-161124 Sentence denotes In the TMEV-IDD model of MS, COX-2 inhibitors had no effect on the score for inflammation but significantly decreased the amount of demyelination (p b 0.05 by the Mann-Whitney nonparametric t-test).
T84642 161125-161264 Sentence denotes In vitro, COX-2 inhibitors decreased the amount of KA-induced cell death in white matter and gray matter (p b 0.01 by ANOVA, Tukey-Kramer).
T77169 161265-161341 Sentence denotes The COX-2 inhibitor CAY10452 can reduce demyelination in the TMEV-IDD model.
T80905 161342-161497 Sentence denotes In vitro, our results indicate that COX-2 inhibitors may have a therapeutic effect by limiting glutamate-mediated excitotoxicity and oligodendrocyte death.
T8285 161498-161845 Sentence denotes Voulgari-Kokota Anda⁎ 1 , Delorme Bruno 6 , Taoufik Era 7 , Tseveleki Vivian 8 , Charbord Pierre 9 , Probert Lesley 10 1 Anda Voulgari-Kokota, Athens, Greece Bone marrow mesenchymal stem cells (MSCs) are a nonhematopoetic, multipotent stem cell population which can differentiate into osteoblasts, adipocytes and chondrocytes in vivo and in vitro.
T76196 161846-162087 Sentence denotes In bone marrow, MSCs support hemopoiesis providing the proper environment for hematopoietic stem cell renewal, proliferation and differentiation while they substitute osteoblasts, osteocytes and non-hematopoietic cells in bone marrow stroma.
T77766 162088-162215 Sentence denotes According to their supportive role, MSCs secrete a plethora of different cytokines, trophic factors and anti-apoptotic factors.
T58299 162216-162431 Sentence denotes It has been shown that MSCs are recruited to the sites of neural injury and inflammation and that they prevent neuronal death secreting neurotrophic and antiapoptotic factors as well as promoting local neurogenesis.
T44635 162432-162543 Sentence denotes The aim of this study was to evaluate MSCs neuroprotective capacity and investigate pathways that are involved.
T12058 162544-162636 Sentence denotes Bone marrow mesenchymal stem cells were flushed from C57bl/6 mice and cultured to passage 3.
T52893 162637-162752 Sentence denotes FACS analysis confirmed the purity of MSCs cultures (N = 98% cells CD11b-negative, CD44-positive and Sca1positive).
T87743 162753-162828 Sentence denotes Mouse embryonic cortical neurons were isolated from 15days C57bl/6 embryos.
T93280 162829-162923 Sentence denotes On div.5 for neurons, the two cell populations were cultured together using coculture inserts.
T4516 162924-163038 Sentence denotes Cells were then exposed to NMDA excitotoxicity (30 μM) and neuronal death was assessed 24 h later using LDH assay.
T11085 163039-163180 Sentence denotes Alternatively, embryonic cortical neurons on day 5 were cultured in MSCs' conditioned medium for 24 h and then NMDA was added in the culture.
T22391 163181-163419 Sentence denotes Gene expression arrays which were performed using neuronal RNA samples showed that MSCs induce the expression of many neuroprotective and neurotrophic factors by neural cells, suppressing at the same time a variety of apoptotic molecules.
T99155 163420-163551 Sentence denotes Our results show that the presence of MSCs or MSCs-conditioned medium significantly protect neurons in the excitotoxic environment.
T47433 163552-163686 Sentence denotes 5 -Cytotoxic effects of myasthenia gravis sera on cardiomyocytes in vitro different antibody composition and varying disease severity.
T68660 163687-163880 Sentence denotes Cytotoxic effects were assessed by evaluating morphology, measurement of adenylate kinase (AK) release from the cells, and by using flow cytometry after propidium iodide and Annexin-V staining.
T37302 163881-164017 Sentence denotes Incubation with MG sera did not induce morphological changes in the cells compared to cells treated with sera from healthy human donors.
T14161 164018-164168 Sentence denotes Perinuclear vesicles and inclusion bodies were present in a minority of cells treated with human sera, regardless of whether patient or control serum.
T91101 164169-164310 Sentence denotes The mean normalized AK release value from cells treated with MG sera in concentration 1:10 was 80.3% of controls (standard deviation = 28.8).
T56529 164311-164419 Sentence denotes One-way ANOVA analysis revealed no significant difference between the patient and control groups (p = 0.24).
T18061 164420-164519 Sentence denotes When comparing patients within the MG group, no significant differences were detectable (p = 0.09).
T10504 164520-164692 Sentence denotes Girardi cells treated with MG-sera in concentration 1:10 for 24 h prior to flow cytometric examination showed a cell death rate of 9.3%, compared to 8.4% for control serum.
T27917 164693-164806 Sentence denotes The standard error of the mean for the two groups was 1.26 and 1.45, respectively (p = 0.69, One-way ANOVA test).
T29927 164807-164934 Sentence denotes Less than 1% Annexin-V positive cells (indicative of apoptosis) could be detected in both the MG patient and the control group.
T80795 164935-165112 Sentence denotes There was no systematic variation according to antibody profile or concentration, MG severity or other clinical parameters, and the observations were not dose or time dependant.
T53283 165113-165196 Sentence denotes We conclude that MG sera have no cytotoxic effect in our heart cell culture system.
T46150 165197-165327 Sentence denotes If there is a causal link between MG and heart disease, a direct affection of the cardiomyocytes is not the most likely mechanism.
T45781 165328-165645 Sentence denotes EBV latency phenotypes were characterised for the lines used here; these lines were then screened for the expression of neurotrophin ligands and their receptors: the selective high affinity Tropomyosin receptor kinases TrkA, TrkB and TrkC and the (common) low affinity, tumour necrosis factor receptor member, p75NTR.
T20388 165646-165723 Sentence denotes FDC-like cell lines were also analysed for neurotrophin component expression.
T97907 165724-165840 Sentence denotes This was to question FDCs as potential providers of paracrine neurotrophin signalling to Burkitt's lymphoma B cells.
T25923 165841-166003 Sentence denotes Neurotrophin and neurotrophin receptor expression was detected by flow cytometry, reverse transcription polymerase chain reaction (PCR) and real time PCR methods.
T11712 166004-166191 Sentence denotes Cell lines with the full complement of EBV latency genes expressed were positive for the neurotrophin, Brain Derived Neurotrophic Factor (BDNF) and all neurotrophin receptors in question.
T5471 166192-166317 Sentence denotes Burkitt's lymphoma cells expressing limited EBV latency genes revealed more restricted expression of neurotrophin components.
T37531 166318-166515 Sentence denotes FDC-like lines also express neurotrophin and neurotrophin receptors, thus paracrine signalling between Burkitt's lymphoma cells and FDCs may occur via this axis, perhaps to enhance B cell survival.
T93094 166516-166675 Sentence denotes Multiple sclerosis (MS) is a common cause of severe neurological disability resulting from the interruption of myelinated tracts in the central nervous system.
T55820 166676-166882 Sentence denotes Familial aggregation of cases and differences in disease risk among ethnic groups residing in the same geographical regions are well documented, supporting the role of genetic influences in MS pathogenesis.
T63009 166883-166995 Sentence denotes However, its modest heritability reflects complex genetic effects and multifaceted geneenvironment interactions.
T58208 166996-167128 Sentence denotes The human leukocyte antigen (HLA) gene cluster in chromosome 6p21.3 represents the strongest susceptibility locus for MS genomewide.
T53413 167129-167366 Sentence denotes The primary signal arises from the HLA-DRB1 gene in the class II genomic segment of the locus, but complex hierarchical cis and trans allelic effects were detected, including a protective signal in the class I region near the HLA-C gene.
T13945 167367-167565 Sentence denotes The past two years have seen substantial progress in the development of laboratory and analytical approaches to perform large-scale genome-wide association studies in MS and other complex disorders.
T65087 167566-167666 Sentence denotes A trio-based study using 500,000 SNPs arrays in 931 MS families was recently completed and reported.
T33868 167667-167771 Sentence denotes The classic HLA risk locus stood out with remarkably strong statistical significance (P b 1 × 10 − 81 ).
T64051 167772-167873 Sentence denotes The study also yielded several promising non-HLA leads, which were pursued in an independent dataset.
T47613 167874-168240 Sentence denotes A combined analysis of more than 12,000 samples identified a number of genes associated with disease susceptibility, including the interleukin 2 receptor alpha chain (IL2RA also known as CD25) on chromosome 10p15, which has been also implicated in the pathogenesis of type 1 diabetes and Graves' disease; CD58 on chromosome 1p13; and IL7R (CD127) on chromosome 5p13.
T28562 168241-168571 Sentence denotes Progress in high-throughput genotyping and sequencing technologies and a better understanding of the structural organization of the human genome, together with powerful brain imaging techniques that refine the phenotype suggest that the tools may finally exist to identify the full set of genes influencing the pathogenesis of MS.
T65026 168572-168891 Sentence denotes Baylor College of Medicine, Houston, Texas, USA Whereas Watson-Crick DNA base pair changes have long been recognized as a mechanism for mutations, rearrangements of the human genome including deletions, duplications, and inversions have been appreciated only more recently as a significant source for genetic variation.
T35960 168892-168980 Sentence denotes Diseases that result from DNA rearrangements have been referred to as genomic disorders.
T53567 168981-169070 Sentence denotes Rearrangements of our genome can be responsible for inherited as well as sporadic traits.
T86171 169071-169252 Sentence denotes Rearrangements associated with genomic disorders can be recurrent, with breakpoint clusters resulting in a common sized deletion/duplication, or nonrecurrent and of different sizes.
T15458 169253-169536 Sentence denotes The analyses of breakpoints in the proximal short arm of chromosome 17 (17p) reveal nonallelic homologous recombination (NAHR) as a major mechanism for recurrent rearrangements, whereas nonhomologous end-joining (NHEJ) can be responsible for many of the non-recurrent rearrangements.
T83960 169537-169673 Sentence denotes Genome architectural features consisting of low-copy repeats (LCRs), also called segmental duplications, can stimulate and mediate NAHR.
T48173 169674-169739 Sentence denotes There are positional hotspots for the crossovers within the LCRs.
T92378 169740-169883 Sentence denotes We recently elucidated a DNA replication mechanism for nonrecurrent rearrangements that we termed FoSTeS -Fork Stalling and Template Switching.
T50905 169884-170035 Sentence denotes Rearrangements introduce variation into our genome for selection to act upon and as such serve an evolutionary function analogous to base pair changes.
T13527 170036-170219 Sentence denotes Genomic rearrangements may cause Mendelian diseases, complex traits such as behavioral and psychiatric traits (e.g. autism, schizophrenia), or represent benign polymorphic variations.
T59948 170220-170296 Sentence denotes The latter copy number variations (CNVs) are ubiquitous in the human genome.
T483 170297-170456 Sentence denotes In fact, any two humans contain more base-pair differences due to structural variation of the genome than resulting from single nucleotide polymorphism (SNPs).
T86726 170457-170778 Sentence denotes The mechanisms by which rearrangements convey phenotypes are diverse and include gene dosage, position effects, unmasking of coding region mutations (cSNPs) or other functional SNPs, creating gain-of-function fusion genes or loss of function gene mutations at the breakpoints, and perhaps through effects of transvection.
T42302 170779-171079 Sentence denotes De novo genomic rearrangements have been shown to cause both chromosomal and Mendelian disease, as well as sporadic traits, but our understanding of the extent to which genomic rearrangements, gene CNV, and/or gene dosage alterations are responsible for common and complex traits remains rudimentary.
T34769 171080-171242 Sentence denotes During cellular differentiation, both permissive and repressive epigenetic modifications must be negotiated to create cell-type specific gene expression patterns.
T92692 171243-171492 Sentence denotes At cell fate decision checkpoints, dynamic developmental decisions are made to establish specific epigenetic patterns, but the mechanisms by which these heritable states are created, especially the loss of repressive methyl marks, have been elusive.
T94192 171493-171654 Sentence denotes The Tbox transcription factor family is critically important in several developmental systems ranging from embryogenesis to the differentiation of adult tissues.
T68722 171655-171824 Sentence denotes In the immune system, the T-box factors T-bet and Eomes are responsible for cellular differentiation events in several cell types, most notably Th1 cell differentiation.
T40758 171825-171999 Sentence denotes We have explored the mechanisms by which developmentally important transcription factors contribute to the establishment of epigenetic patterns by utilizing T-bet as a model.
T50949 172000-172210 Sentence denotes A comprehensive mutagenesis study surprisingly suggested that in addition to DNA binding, the highly conserved T-box domain is responsible for recruiting chromatin-modifying activities to target gene promoters.
T77728 172211-172558 Sentence denotes By examining point mutations known to be responsible for several different human genetic diseases found within the T-box factors Tbx3, Tbx5, Tbx20, Tbx22 and T-pit, we have found that two distinct surfaces of the T-box domain recruit chromatin-modifying activities to promoters and are required for the functional activation of T-bet target genes.
T72596 172559-172748 Sentence denotes Our data suggest that T-bet is required and sufficient to alleviate repressive H3K27 methylation marks and that this is mediated through a functional interaction with the demethylase JMJD3.
T72161 172749-172923 Sentence denotes After repressive modifications are removed, a permissive chromatin environment is created by the T-box dependent recruitment of an H3K4 methyltransferase to the target genes.
T31397 172924-173169 Sentence denotes Collectively, the data suggest that the ability of the T-box DNA binding domain to functionally establish the epigenetic state of its target genes is required for its ability to initiate cell-type specific developmental gene expression patterns.
T40119 173170-173291 Sentence denotes Characterization of encephalitogenic T cells is critical for identifying therapeutic targets for multiple sclerosis (MS).
T10650 173292-173492 Sentence denotes To this end, we have used small interfering RNA (siRNA) to suppress molecules expressed by encephalitogenic T cells to determine if the molecule is essential for immune-mediated demyelinating disease.
T76575 173493-173655 Sentence denotes Using a siRNA specific for T-bet, a transcription factor, we found T-bet to be critical for the differentiation and effector function of encephalitogenic T cells.
T79446 173656-173844 Sentence denotes Systemic administration of T-bet specific siRNA inhibites the onset of experimental autoimmune encephalomyelitis (EAE) and treatment of established EAE with this siRNA ameliorates disease.
T26427 173845-173945 Sentence denotes We found that the interferon-γ, STAT1, and IL-23 receptor genes are all directly regulated by T-bet.
T93960 173946-174073 Sentence denotes In addition, the pathogenic capacity of both myelin-specific Th1 and Th17 cells is greatly diminished when T-bet is suppressed.
T67564 174074-174211 Sentence denotes Interestingly, adoptive transfer of myelin-specific Th1 cells results in the generation of host-derived Th17 cells found only in the CNS.
T13873 174212-174307 Sentence denotes Thus, it appears that the CNS is a conducive environment for the differentiation of Th17 cells.
T46485 174308-174519 Sentence denotes However, systemic administration of T-bet siRNA following adoptive transfer of Th1 cells prevents the generation of Th17 cells in the CNS, indicating that T-bet plays a role in the differentiation of Th17 cells.
T17149 174520-174718 Sentence denotes In addition, myelin-specific T cells from mice with spontaneous EAE fail to transfer EAE if T-bet is suppressed, confirming a critical role for T-bet in spontaneous autoimmune demyelinating disease.
T17813 174719-174964 Sentence denotes In an effort to determine the role of myelin-specific Th17 cells in pathogenesis, we have found Th17 cells differentiated in vitro with IL-6+TGFβ do not transfer EAE and are a distinct population from the pathogenic Th17 cells generated in vivo.
T15878 174965-175084 Sentence denotes This data suggest that T-bet may be a viable therapeutic target for MS, capable of suppressing both Th1 and Th17 cells.
T22373 175085-175163 Sentence denotes The La Jolla Institute for Allergy and Immunology, La Jolla, CA, United States
T31658 175164-175296 Sentence denotes The intestinal mucosa forms the largest body surface exposed to exogenous antigens, both innocuous and pathogenic non-self antigens.
T58881 175297-175482 Sentence denotes Consistent with chronic antigen exposure, the gut mucosa also lodges a large collection of activated lymphocytes that under physiological conditions remain in an immune quiescent state.
T87137 175483-175636 Sentence denotes This so-called "gut physiological inflammation" is controlled by distinct regulatory mechanisms, including different types of regulatory DCs and T cells.
T90029 175637-175776 Sentence denotes An important molecule in this context is TGF-β, abundantly produced in the gut and crucial for both systemic and mucosal immune-regulation.
T97430 175777-175931 Sentence denotes Among multiple roles, TGF-β has the capacity to block Th1 and Th2 differentiation and to convert naïve CD4 cells into Foxp3-expressing induced Treg cells.
T65490 175932-176148 Sentence denotes Paradoxically, TGF-β also displays pro-inflammatory roles and in the presence of pro-inflammatory cytokines such as IL-6, IL-21, IL-1β and TNF, TGF-β promotes the conversion of naïve T cells into effector Th17 cells.
T74703 176149-176356 Sentence denotes This contrasting deviation puts TGF-β as a principal controller of immune responses and underscores a central role of this cytokine in orchestrating the pro-and anti-inflammatory nature of adaptive immunity.
T9803 176357-176776 Sentence denotes Nowhere else is a critical regulation of this balance between productive and suppressive immunity, of more significance that at the mucosal surface of the gut where efficient immune protection against pathogens has to coincide with maintenance of the mucosal barrier integrity and selftolerance as well as tolerance towards the vast load of harmless nonself antigens derived from food and beneficial commensal bacteria.
T56524 176777-177069 Sentence denotes We identified a metabolite of the nutrient vitamin A, retinoic acid, as a key regulator of TGF-β-dependent immune responses, capable of inhibiting the IL-6-driven induction of pro-inflammatory Th17 cells and promoting the peripheral differentiation of anti-inflammatory Foxp3 + induced Tregs.
T78504 177070-177216 Sentence denotes This intestinal induced regulatory mechanism allows for environmental factors to control aberrant endogenous immune responses from the outside in.
T67590 177217-177427 Sentence denotes The induced immune tolerance is not irreversible however and in the presence of innate danger signals retinoic acid effects condense or synergize with innate responses to promote or enhance protective immunity.
T47107 177428-177566 Sentence denotes Dendritic cells (DCs) are antigen presenting cells that influence the activities of all types of lymphocytes, including B, NK and T cells.
T58872 177567-177618 Sentence denotes Two main pathways of DC development are recognized:
T35940 177619-177669 Sentence denotes 1) the myeloid DCs (mDCs) with two unique subsets:
T43774 177670-177816 Sentence denotes Langerhans cells and interstitial DCs; and 2) the plasmacytoid DCs (pDCs), a main source of the antiviral and immunomodulatory type 1 interferons.
T26796 177817-177952 Sentence denotes Subsets of DCs display unique combinations of surface markers, such as lectins, that endow them with distinct phenotypes and functions.
T37583 177953-178044 Sentence denotes DCs also are an unavoidable target in the prevention, treatment and development of disease.
T69986 178045-178241 Sentence denotes In the settings of infection and cancer, microbes and tumors can exploit DCs to evade immunity, but DCs also can generate resistance, a capacity that is readily enhanced with DC-targeted vaccines.
T25131 178242-178343 Sentence denotes In the context of patient care, DCs are providing new approaches to disease pathogenesis and therapy.
T95242 178344-178430 Sentence denotes In particular it is clear that DCs play a critical role in the process of vaccination.
T98201 178431-178502 Sentence denotes To address this, we are exploring new vaccine designs that harness DCs.
T80950 178503-178635 Sentence denotes In cancer, DCs are generated ex vivo by culturing either blood monocytes or bone marrow progenitor cells with cytokine combinations.
T82053 178636-178737 Sentence denotes These DCs are then loaded with tumor antigens in different forms and injected back into the patients.
T46900 178738-178843 Sentence denotes This has resulted in the induction of clear tumorspecific immune responses as well as clinical responses.
T94089 178844-178944 Sentence denotes We are expanding this strategy to other cancer types as well as to infectious diseases, such as HIV.
T91071 178945-179028 Sentence denotes Novel strategies have been proposed to directly target the antigens to DCs in vivo.
T7719 179029-179230 Sentence denotes Multiple DC surface molecules have been considered as targets, as they need to allow internalization of the antigen cargo and its processing for presentation on both MHC class I and class II molecules.
T26455 179231-179317 Sentence denotes We are characterizing DC subsets that may be effective targets for anti-DC antibodies.
T39096 179318-179472 Sentence denotes These antibodies can be fused to antigens and carry them directly to the desired DCs for maximum immune response against a variety of infectious diseases.
T94820 179473-179504 Sentence denotes Neuroimmunology Division, Inst.
T9080 179505-179597 Sentence denotes Experimental Immunology, Department of Pathology, University Hospital of Zurich, Switzerland
T21806 179598-179736 Sentence denotes During the formation of an immune synapse between APCs and Tcells, cytokines have the capacity to orchestrate the ensuing immune response.
T94772 179737-179884 Sentence denotes In the context of MS and its animal model EAE, the precise function and phenotype of the encephalitogenic disease-mediating T cell remains elusive.
T35976 179885-180145 Sentence denotes For more than 10 years, the cytokine secretion profile of effector TH cells divided them into TH1 and TH2 cells and "immune deviation" from pathogenic TH1 to regulatory TH2 cells was widely held to be an attractive therapeutic strategy for the treatment of MS.
T73949 180146-180315 Sentence denotes This paradigm was dismantled when it was discovered that IL-23 rather than its TH1 inducing sister cytokine IL-12 is essential for the development of autoimmune disease.
T98036 180316-180419 Sentence denotes IL-23 was demonstrated to drive the expression of IL-17 in TH cells and the term TH17 cells was coined.
T60099 180420-180598 Sentence denotes The clear association of this newly described T H 17 phenotype with autoimmune pathogenicity now implicates T H 17 cytokines as critical mediators of chronic autoimmune diseases.
T99640 180599-180760 Sentence denotes However, this notion relies almost exclusively on correlations and associations and a causative link between TH17 cytokines and pathogenicity has yet to be made.
T49185 180761-181026 Sentence denotes In order to study the actual function of TH17 cytokines in the context of autoimmunity in vivo, we generated a number of transgenic and gene-targeted mice and discovered that the current notion of the pathogenic TH17 cells is again far too simplistic and erroneous.
T55261 181027-181279 Sentence denotes I will discuss that TH17 cytokines, while clearly associated with pathogenicity, do not or only marginally contribute to the development of autoimmune CNS-disease and that the master cytokine IL-23 drives pathogenicity independent of TH17 polarization.
T56532 181280-181453 Sentence denotes B cell contribution to MS pathophysiology has generally been considered based on their potential to react to particular CNS antigens and produce CNS-directed autoantibodies.
T13926 181454-181775 Sentence denotes The presence of abnormal CSF immunoglobulin (Ig) with typical oligoclonal band (OCB) pattern, pathologic features of demyelinating lesions and molecular analyses of B cell lineagetogether have implicated contribution of CNSspecific antibodies in MS (e.g. complement-mediated injury, antibody-directed cytotoxicity (ADCC).
T32108 181776-182061 Sentence denotes While elegant approaches have confirmed that at least a portion of the CNS Ig bind myelin targets, it remains unclear whether all CNS antibodies directly contribute to pathogenesis, are generated as a consequence of tissue injury, or represent epiphenomenon of active CNS inflammation.
T1064 182062-182321 Sentence denotes Certain CNSdirected antibodies may actually be beneficial such as through the support of remyelination, or by helping to remove debris including growth inhibitory molecules such as Nogo, thereby providing a more permissive environment for axonal regeneration.
T64235 182322-182430 Sentence denotes B cell contribution to MS has also been considered beyond their capacity to become antibody-producing cells.
T27592 182431-182719 Sentence denotes Distinct B cell subsets have been identified that function as effective APC to T cells and normal human B cells are now recognized to actively contribute to the regulation of immune responses in part through secretion of distinct effector cytokine profiles in a context-dependent fashion.
T81962 182720-182977 Sentence denotes In some patients with MS, chronically activated B cells have been described in structures reminiscent of germinal centers that may affect the CNS independent of T cells as well as promote ongoing T cell activation and propagation of the MS disease activity.
T75531 182978-183156 Sentence denotes A deficiency in the ability of MS patient B cells to produce the downregulatory cytokine IL-10 has been reported, implicating them directly in the dysregulated MS immune process.
T37897 183157-183515 Sentence denotes Promising results from early phase MS studies of B cell depletion with rituximab (anti-CD20 antibody) further support a role for B cells in disease pathogenesis, and the rapid onset of action of this strategy (without obvious effects on IgG levels) suggests that antibody-independent functions of B cells likely contribute to the observed therapeutic effect.
T12247 183516-183730 Sentence denotes Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Rome, Italy Epstein-Barr virus (EBV) infection has been implicated in several major autoimmune diseases, including multiple sclerosis (MS).
T57600 183731-183856 Sentence denotes In MS, evidence supporting a pathogenic role for EBV comes from epidemiological, immunological and histopathological studies.
T10873 183857-184492 Sentence denotes The presence of abnormal deposits of EBV-infected B cells/plasma cells in post-mortem brain tissue from cases with acute, relapsing-remitting and progressive MS courses is compatible with abnormalities in humoral immunity, such as persistence of B-cell clones that expand and produce immunonoglobulins intrathecally and formation of intrameningeal B-cell follicles (as latent EBV infection promotes B-cell activation and growth), and with increased immune reactivity to EBV in the patients' blood and cerebrospinal fluid (as both the latent and lytic EBV proteins are potent immunogens and elicit strong B-and T-cell immune responses).
T28928 184493-184778 Sentence denotes EBV could promote chronic brain inflammation through mechanisms that involve autoimmunity (e.g., molecular mimicry or rescue of self-reactive B cells) and/or virus-induced immunopathology resulting from the inability of the immune system to control viral infection in the CNS properly.
T14794 184779-185076 Sentence denotes In this talk, I shall present findings that expand previous evidence of dysregulated EBV infection in the MS brain and discuss a scenario in which cytotoxic immune responses targeting intracerebral EBV deposits may play a major role in maintaining a chronic inflammatory condition in the MS brain.
T77382 185077-185198 Sentence denotes Accumulating data indicate that B lymphocytes and antibodies are involved in the pathogenesis of multiple sclerosis (MS).
T8276 185199-185284 Sentence denotes Rituximab is a monoclonal antibody that depletes circulating CD20+ B cells in humans.
T32261 185285-185382 Sentence denotes We report the results from an investigator-initiated trial of rituximab in relapsing MS patients.
T74399 185383-185576 Sentence denotes 30 relapsing-remitting MS (RRMS) patients with continued clinical and magnetic resonance imaging (MRI) activity despite treatment with an FDA-approved immunomodulatory drug (IMD) were enrolled.
T53681 185577-185667 Sentence denotes Subjects received 4 doses of 375 mg/m 2 rituximab over 4 weeks, and continued to take IMD.
T50023 185668-185774 Sentence denotes Twenty-three subjects underwent two spinal taps, at one week pre-treatment and at week 24 after treatment.
T21474 185775-185915 Sentence denotes Immunoglobulin (Ig)G concentration, IgG index, IgG synthesis rate and electrophoresis for oligoclonal bands were performed by a central lab.
T32003 185916-186021 Sentence denotes The concentrations of B and T lymphocytes in cerebrospinal fluid (CSF) were determined by flow cytometry.
T89521 186022-186104 Sentence denotes ELISAs were used to quantitate chemokine levels in CSF before and after rituximab.
T46122 186105-186226 Sentence denotes Post-treatment, CSF B cells and T cells were decreased significantly compared to pre-treatment, as reported (Cross et al.
T78614 186227-186229 Sentence denotes J.
T83379 186230-186243 Sentence denotes Neuroimmunol.
T2067 186244-186251 Sentence denotes 2006 ).
T30385 186252-186426 Sentence denotes To address why T cells decreased following treatment with a monoclonal antibody targeting only B cells, an array of chemokines was compared in CSF before and after treatment.
T74072 186427-186501 Sentence denotes In 19 of 23 subjects, CSF CXCL13 levels decreased by N20% after treatment.
T27402 186502-186558 Sentence denotes In 4 subjects, CXCL13 remained unchanged post-treatment.
T18758 186559-186630 Sentence denotes CXCL13 did not increase in CSF in any subject post-rituximab treatment.
T71387 186631-186736 Sentence denotes The proportional decline in CSF CXCL13 correlated with the proportional decline in T cell numbers in CSF.
T19229 186737-186844 Sentence denotes No significant reductions in CSF IgG index, IgG concentration or number of oligoclonal bands were observed.
T51011 186845-186914 Sentence denotes A trend toward decreased IgG synthesis rate post-treatment was noted.
T66177 186915-186999 Sentence denotes B cells and T cells were significantly reduced in CSF at six months after rituximab.
T9825 187000-187137 Sentence denotes The decline in T cell numbers correlated with alterations in the CSF chemokine pattern, specifically with a decline in CSF CXCL13 levels.
T65353 187138-187261 Sentence denotes National MS Society USA (RG3292), National Institutes of Health (K24RR017100; MO1RR00036), Genentech, Inc. and Biogen Idec.
T51733 187262-187306 Sentence denotes LP is a Fellow of the NMSS USA (FG1665-A-1).
T16703 187307-187480 Sentence denotes Although the presence of leukocytes within MS lesions is indisputable, the route and adhesion molecules by which these cells access the brain are still not fully understood.
T71954 187481-187706 Sentence denotes Using a lipid raft-based proteomic approach we identified melanoma cell adhesion molecule or MCAM/CD146 as an immunoglobulin superfamily member potentially involved in leukocyte migration across the blood-brain barrier (BBB).
T86615 187707-187910 Sentence denotes Using an in vitro model of the human BBB and the animal model of MS, experimental autoimmune encephalomyelitis (EAE), we characterized the role and function of MCAM in immune cell migration to the brain.
T76038 187911-188078 Sentence denotes We demonstrate that MCAM is expressed on BBB endothelial cells, in vitro and in situ, and that MCAM expression can be upregulated with inflammatory cytokines in vitro.
T75967 188079-188216 Sentence denotes Since MCAM's ligand is MCAM itself, we analysed MCAM expression on peripheral blood leukocytes from human healthy donors and MS patients.
T68148 188217-188385 Sentence denotes MCAM is detected on a subset of activated memory CD4+ and CD8+ lymphocytes and the proportion of MCAM+ T cells appears to be higher in MS patients compared to controls.
T75536 188386-188493 Sentence denotes Furthermore, in vitro microscopy studies suggest that MCAM plays a role lymphocyte adhesion and diapedesis.
T89372 188494-188662 Sentence denotes Our preliminary data provides evidence that MCAM is expressed by both the BBB and the immune cells and suggest that MCAM is potentially involved in MS lesion formation.
T57746 188663-188845 Sentence denotes The aim of this project was to identify novel targets of an autoimmune response in multiple sclerosis (MS) patients and to test the potential pathogenic relevance in an animal model.
T99065 188846-188970 Sentence denotes To this end myelin glycoproteins were purified from human postmortem brain and separated by two-dimensional electrophoresis.
T74041 188971-189028 Sentence denotes Binding of IgG from MS sera was screened by Western Blot.
T62928 189029-189160 Sentence denotes Mass spectrometry of immunoreactive spots identified contactin-2 as a novel target of the disease associated autoantibody response.
T746 189161-189395 Sentence denotes Contactin-2 and its rat homolog TAG-1 (transiently-expressed axonal glycoprotein 1) are sequestered in the juxtaparanodal domain of myelinated axons, but are also expressed by adult cortical neurons as we show by immunohistochemistry.
T44691 189396-189616 Sentence denotes Contactin-2/TAG-1-specific autoantibodies were detected in both the sera and cerebrospinal fluid (CSF) of some MS patients and were shown to recognize native antigen on the surface of transfected cells by flow cytometry.
T97686 189617-189782 Sentence denotes This autoantibody response was accompanied by contactin-2-specific Th1/Th17 T-cell responses in peripheral blood as demonstrated by ELISPOT and proliferation assays.
T79784 189783-189948 Sentence denotes The pathogenic significance of these autoimmune responses was then explored in adoptive T cell mediated experimental autoimmune encephalitis (EAE) models in the rat.
T46250 189949-190123 Sentence denotes Adoptive transfer of TAG-1 specific T-cells induced an encephalitis characterized by extensive inflammation of white and gray matter tracts of the spinal cord and the cortex.
T63194 190124-190320 Sentence denotes Co-transfer of TAG-1 specific T cells with a myelin oligodendrocyte glycoprotein (MOG)specific mAb generated focal perivascular demyelinating lesions in the cortex similar to those reported in MS.
T27773 190321-190532 Sentence denotes This study identifies contactin-2 as a novel autoantigen targeted by T cells and autoantibodies in MS and suggests that these responses may contribute to the development of gray matter pathology in this disease.
T72710 190533-190654 Sentence denotes Recently, there has been increasing evidence that CD8 T cells can participate in Multiple Sclerosis (MS) pathophysiology.
T67507 190655-190860 Sentence denotes In vitro and in vivo studies suggest that CD8 T cells may be involved in both the loss of myelin and axonal damage, the latter being regarded as a cause of permanent neurological impairment observed in MS.
T12045 190861-191018 Sentence denotes However, a directly damaging interaction between antigen-specific CD8 T cells and the central nervous system (CNS) has not yet been unambiguously documented.
T45455 191019-191141 Sentence denotes We have therefore established an organotypic CNS slice culture system derived from transgenic mice expressing GFP+ myelin.
T43209 191142-191303 Sentence denotes This "ex vivo" approach allowed us to directly monitor the interaction between OT1 derived CD8 T cells and myelinated axons by confocal microscopic live imaging.
T24452 191304-191501 Sentence denotes Strikingly, we observed direct myelin damage mediated by CD8 T cells only when (1) slices had been pulsed with SIINFEKL peptide, the cognate antigen for OT1 T cells, and (2) T cells were activated.
T19515 191502-191598 Sentence denotes Furthermore, we detected a decrease of neurofilament at sites of repeated T cell-myelin contact.
T51249 191599-191678 Sentence denotes In some instances, we could even document the transsection of myelinated axons.
T74643 191679-191798 Sentence denotes We have thus shown for the first time that myelin loss can be the result of a direct immunologic attack by CD8 T cells.
T93134 191799-192002 Sentence denotes Importantly, this damage was confined to an antigen-specific interaction and could not be observed in an unspecific set-up, e.g. with wildtype CD8 T cells or after pulsing the slice with control peptide.
T67357 192003-192304 Sentence denotes Accordingly, we suggest that the observed transsection of myelinated axons is composed of at least a two-step mechanism: first, an antigen specific process causing myelin damage by CD8 T cells, presumably by release of perforin/granzyme, and second, axonal injury as the result of "collateral damage".
T30701 192305-192487 Sentence denotes The high prevalence of autoimmune diseases in industrialized countries may, in part, be due to reduced early life exposure to common microbial agents and a more hygienic environment.
T65703 192488-192782 Sentence denotes To investigate this concept, we modeled the effects of neonatal exposure to a common pathogen-associated molecular pattern, lipopolysaccharide (LPS) in experimental autoimmune encephalomyelitis (EAE) by assessing LPS-mediated effects on neuroimmune parameters and ensuing neurological outcomes.
T94553 192783-192945 Sentence denotes A single intraperitoneal exposure to LPS as neonates delayed the onset and reduced severity of MOG-induced EAE compared to littermate PBS-exposed mice (p b 0.05).
T5769 192946-193214 Sentence denotes T lymphocyte proliferation in response to MOG-exposed antigen presenting cells (APCs) was suppressed among T cells derived from LPS-exposed animals although there was a selective expansion of CD4 + FoxP3+ T cells mediated by APCs from the LPS-exposed group (p b 0.05).
T61835 193215-193392 Sentence denotes Splenic CD11c+ dendritic cells from LPS-exposed animals exhibited reduced expression of MHC Class II together with induction of CD80 and CD86 prior to and during EAE (p b 0.05).
T56698 193393-193618 Sentence denotes Spinal cord transcript levels from animals with EAE revealed both CD3-epsilon and F4/80 were lower in LPS-compared to PBS-exposed animals, which were associated with increased IL-10 levels in the LPS-exposed group (p b 0.05).
T19854 193619-193819 Sentence denotes Neuropathological studies disclosed reduced axonal and myelin loss in spinal cords from the LPScompared to the PBS-exposed animals with EAE, which was associated with increased FoxP3 immunoreactivity.
T51638 193820-193960 Sentence denotes Indeed, there was a robust inverse correlation between EAE severity and the number of FoxP3+ T cells detected in the spinal cord (p b 0.05).
T74717 193961-194182 Sentence denotes These findings support the concept of early-life pathogen exposure biasing the immune system towards a more tolerant state with improved disease outcomes and might provide new insights for neuroprotective immunotherapies.
T76743 194183-194687 Sentence denotes Kawachi Izumi⁎ 1 , Arakawa Musashi 1 , Yanagawa Kaori 1 , Nishizawa Masatoyo 1 1 Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan IL-17 plays a critical role in autoimmune and allergic conditions: disease progression of experimental allergic encephalitis is severely attenuated in IL-17-deficient mice and IL-17-secreting lymphocytes have been detected in the cerebrospinal fluids of multiple sclerosis (MS) patients, but their identity and properties remain elusive.
T83757 194688-194778 Sentence denotes Our objective is to characterize and evaluate the function of IL-17-producing cells in MS.
T58414 194779-194921 Sentence denotes Peripheral blood was obtained from patients with relapsingremitting MS, other neuro-inflammatory diseases (ONID), and healthy volunteers (HS).
T50421 194922-195101 Sentence denotes We analyzed the expression of several chemokine receptors on the cell surface of peripheral mononuclear cells (PBMC), and detected intracellular IL-17 and IFN-g by flow cytometry.
T13002 195102-195305 Sentence denotes Within the CD4 T cell population (CD3+CD4+CD8−), the frequency of IFN-gproducing cells (TH1), IL-17-producing cells (TH17), and Foxp3expressing Treg cells in PBMC did not differ between MS, ONID, and HS.
T16587 195306-195463 Sentence denotes However, within the double negative T (DN T) cell population (CD3 +CD4−CD8−), IFN-g-producing cells decreased in frequency in PBMC from MS as compared to HS.
T863 195464-195571 Sentence denotes More strikingly, IL-17-producing cells were more frequent in DN T cells from MS as compared to ONID and HS.
T50619 195572-195749 Sentence denotes Furthermore, we found that the sorted DN T cell population in MS had higher expression of transcripts encoding RORgt (RORC) than that in HS by the real-time quantitative RT-PCR.
T44465 195750-195872 Sentence denotes These results suggest that the distinct pool of IL-17-producing DN T cells in MS might be larger than that in ONID and HS.
T81119 195873-195979 Sentence denotes Innate T cells, including gd T cells, Va24i and Va7.2iT cells constitute a large percentage of DN T cells.
T29381 195980-196142 Sentence denotes In mice, it has been shown that innate T cells such as NK1.1negVa14iT and gd T cells have the ability to produce IL-17 in airway neutrophilia and other disorders.
T5375 196143-196260 Sentence denotes But in this setting, it was impossible that we detected gd T cells and Va24iT cells expressing IL-17 in PBMC from MS.
T55694 196261-196496 Sentence denotes Therefore we suspect that the production of IL-17 derived from not only TH17 per se, but also distinct lineage of innate T cells, except gd T and Va24iT cells, might be critical elements contributing to autoimmune disorders such as MS.
T32667 196497-196572 Sentence denotes We identified the distinct population of DN T cells expressing IL-17 in MS.
T7713 196573-196738 Sentence denotes Future study should be performed to investigate the identification of innate T cell lineage with production of IL-17, and pathogenesis of the IL-17/IL-23 axis in MS.
T84898 196739-196822 Sentence denotes Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the CNS.
T64627 196823-196925 Sentence denotes Studies on experimental autoimmune encephalomyelitis have shown a pathological function of Th17 cells.
T17699 196926-197097 Sentence denotes Th17 cells have been recently identified as a further T effector cell type, producing the proinflammatory cytokine IL-17 and expressing the transcription factor RORgammat.
T36360 197098-197149 Sentence denotes However, their role in MS remains to be elucidated.
T34342 197150-197345 Sentence denotes We examined the frequency of IL-17A-producing CD4+ T cells in the blood and the cerebrospinal fluid (CSF) of MS patients at different stages of the disease, and during remission and exacerbation.
T20529 197346-197544 Sentence denotes Our data demonstrate that while the frequency of Th17 cells in peripheral blood remains constant during the disease course the number of Th17 cells dramatically increases in the CSF during relapses.
T19867 197545-197645 Sentence denotes At the same time, we observed a significant decrease of Th1 cells in the CSF of patients in relapse.
T84303 197646-197733 Sentence denotes Th17 and Th1 T cell clones were generated from peripheral blood and CSF of MS patients.
T91033 197734-197873 Sentence denotes Such clones have been phenotypically analyzed by flow cytometry, and gene expression profiles obtained from microarray analysis and RT-PCR.
T89006 197874-198014 Sentence denotes Altogether, our data suggest that Th17 cells have a high pathogenic potential and thus they are likely to contribute to the pathology of MS.
T21310 198015-198179 Sentence denotes We developed T cell receptor (TCR)-transgenic mice (RR mice) carrying a TCR specific for myelin oligodendrocyte glycoprotein (MOG) peptide 92-106 presented by I-As.
T23813 198180-198343 Sentence denotes RR mice on the SJL/J background spontaneously develop relapsing-remitting and, in fewer cases, chronic progressive experimental autoimmune encephalomyelitis (EAE).
T84668 198344-198477 Sentence denotes Development of spontaneous EAE involves recruitment of MOG autoreactive B cells from the endogenous repertoire by transgenic T cells.
T19301 198478-198619 Sentence denotes Autoantibody formation is dependent on the presence of the MOG autoantigen and occurs only in TCR transgenic substrains prone to develop EAE.
T22322 198620-198758 Sentence denotes MOG reactive autoantibodies are secreted from B cells within the CNS and bone marrow and are directed against conformational MOG epitopes.
T86607 198759-198922 Sentence denotes We hypothesize that MOG is released from subclinical lesions and that autoantibodies are formed subsequently either in the local lymph node or directly in the CNS.
T68392 198923-199118 Sentence denotes Lesions in the CNS are characterized by massive demyelination and deposition of immunoglobulins; in vitro anti MOG antibodies activate complement leading to lysis of MOG expressing transfectants.
T29110 199119-199246 Sentence denotes Therefore, we consider the formation of MOG autoantibodies as a pro-pathogenic step which enhances severity of spontaneous EAE.
T76054 199247-199464 Sentence denotes RR mice represent the first spontaneous animal model for the most common form of Multiple Sclerosis (MS), relapsing remitting-MS and are especially appropriate to study the spontaneous autoimmune T-B cell cooperation.
T84110 199465-199621 Sentence denotes MuSK antibody positive myasthenia gravis (MuSK-MG) has more prominent bulbar and facial involvement than AChR antibody positive myasthenia gravis (AChR-MG).
T96805 199622-199758 Sentence denotes MuSK antibodies appear to be predominantly IgG4 (non-complement fixing) although IgG1 and IgG2 antibodies are also seen at lower levels.
T59645 199759-199832 Sentence denotes However it remains unclear how these antibodies impair neurotransmission.
T25964 199833-199947 Sentence denotes We immunised C57BL/6 mice with 30 μg recombinant human MuSK or phosphate buffer solution (with Freund's adjuvant).
T19711 199948-199983 Sentence denotes Two further boosts were then given.
T13092 199984-200040 Sentence denotes Some mice also received pertussis toxin at days 0 and 2.
T43132 200041-200148 Sentence denotes The mice immunised with recombinant MuSK had antibody titres equivalent to those seen in the human disease.
T99382 200149-200315 Sentence denotes These MuSK antibodies were predominantly IgG1 (non complement fixing) and IgG2c (complement fixing) determined using an immunoflourescence cell based assay and ELISA.
T2663 200316-200392 Sentence denotes Moreover these antibodies appear to be able to activate complement in vitro.
T19437 200393-200553 Sentence denotes The MuSK immunised mice showed minimal limb muscle weakness on an inverted screen/horizontal bar although there was a trend towards impaired swallowing ability.
T77680 200554-200782 Sentence denotes Ex vivo we found a modest but consistently significant reduction in both miniature endplate potential (MEPP) and endplate potential (EPP) amplitudes with preservation of quantal content (QC), confirming postsynaptic dysfunction.
T90202 200783-200922 Sentence denotes The mean MEPP was 0.96 mv (±0.03) in MuSK immunised group compared with 1.27 mv (±0.05) in the control group (p b 0.0001; unpaired t-test).
T97595 200923-201112 Sentence denotes Furthermore we identified a modest but significant reduction in both endplate area and length of the neuromuscular junctions in diaphragm muscle using fluorescently labelled a bungarotoxin.
T81955 201113-201292 Sentence denotes The mean area was 222.7 square micrometres (±4.98) in the MuSK immunised group compared with 290.2 square micrometres (±4.90) in the control group (p b 0.0001; Mann Whitney test).
T42464 201293-201484 Sentence denotes These studies demonstrate that MuSK antibodies are able to activate complement in vitro, and to impair neurotransmission and cause morphological changes at the neuromuscular junction in vivo.
T645 201485-201565 Sentence denotes This provides further evidence to their potential pathogenic role in causing MG.
T90893 201566-201663 Sentence denotes 3 -Anti-CD20 B cell depletion in immune intervention of central nervous system autoimmune disease
T82431 201665-201812 Sentence denotes To investigate the immunological mechanisms associated with anti-CD20 mediated B cell depletion in experimental autoimmune encephalomyelitis (EAE).
T43564 201813-201824 Sentence denotes Background:
T37470 201825-201923 Sentence denotes B cells and myelin-specific antibodies (ab) both play a pathogenic role in CNS autoimmune disease.
T7419 201924-202003 Sentence denotes Recent studies indicate that naïve B cells may also have a regulatory function.
T12906 202004-202165 Sentence denotes Anti-CD20 mediated B cell depletion, approved for treatment of B cell lymphoma and rheumatoid arthritis, may also reduce inflammation in multiple sclerosis (MS).
T51123 202166-202497 Sentence denotes To understand its immunomodulatory properties, B cell depletion was tested in EAE induced either by recombinant mouse MOG 1-117 (rMOG), which activates B cells and directs secretion of ab against conformational MOG or by its encephalitogenic T cell determinant MOG p35-55, a model that does not require B cells in its pathogenesis.
T9426 202498-202599 Sentence denotes EAE was induced in human CD20-transgenic C57BL/6 mice in which anti-hCD20-ab (m2h7) depletes B cells.
T99641 202600-202717 Sentence denotes For EAE prevention, mice received weekly injections of m2 h7 or IgG2a-isotype starting 21 days prior to immunization.
T64893 202718-202799 Sentence denotes In reversal-experiments, mice were randomized to treatment at onset of paralysis.
T78603 202800-202961 Sentence denotes Anti-CD20 treatment reversed paralysis induced by rMOG, which was associated with reduction in CNS inflammation, frequency of CNS B cells and myelin-specific ab.
T97116 202962-203071 Sentence denotes Frequencies of myelin-specific Th1 and Th17 cells, as well as FoxP3+ regulatory T cells (Treg), were reduced.
T28843 203072-203211 Sentence denotes Remaining antigen-presenting cells (APC) from B cell-depleted mice did not promote Th1 and Th17 differentiation of myelin-specific T cells.
T95062 203212-203278 Sentence denotes In contrast, B cell depletion exacerbated MOG peptide-induced EAE.
T58569 203279-203350 Sentence denotes While Treg were also reduced, Th1 or Th17 polarization was not altered.
T2134 203351-203490 Sentence denotes When used as APC, B cells from rMOG-, but not from MOG peptide-immunized mice stimulated naive MOG-specific T cells to proliferate to rMOG.
T83766 203491-203586 Sentence denotes Anti-CD20 B-cell depletion has differential effects on MOG peptide-and MOG-protein induced EAE.
T84903 203587-203707 Sentence denotes In peptide-induced EAE, depletion of exclusively naïve B cells appears to be solely associated with a reduction of Treg.
T40300 203708-203877 Sentence denotes In protein-induced EAE however, depletion of myelin-specific B cells results in reduced frequencies of Th1 and Th17 due to the lack of T cell activation by residual APC.
T60870 203878-204096 Sentence denotes An important contribution of B cells and autoantibodies has been demonstrated in the pathogenesis of multiple sclerosis (MS) leading to interest in the use of such autoantibodies as diagnostic or prognostic biomarkers.
T30752 204097-204333 Sentence denotes Using a cDNA phage display library derived from MS brain plaques, we applied 'Serological Antigen Selection' to identify antigenic targets specifically interacting with antibodies present in the cerebrospinal fluid (CSF) of MS patients.
T23708 204334-204569 Sentence denotes A panel of 8 antigenic targets was identified which, after a detailed serological analysis on a large panel of individual MS patient and control CSF showed 86% specificity and 45% sensitivity in discriminating MS patients and controls.
T63686 204570-204698 Sentence denotes The objective of this study was to further characterize these novel antigenic targets and associated antibody biomarkers for MS.
T53994 204699-204878 Sentence denotes Analysis of the immunoreactive profiles revealed that autoantibody reactivity was demonstrated in different MS subtypes and was found at an early stage in a subset of MS patients.
T85689 204879-204986 Sentence denotes Moreover, an increasing reactivity towards the antigenic targets with clinical disability was demonstrated.
T11690 204987-205113 Sentence denotes Detailed bio-informatic analyses was performed on the 8 CSF-reactive epitopes which ranged in size from 11 to 121 amino acids.
T88931 205114-205151 Sentence denotes This revealed a novel antigen SPAG16.
T79920 205152-205247 Sentence denotes The remaining antigens constitute novel epitopes encoded by transcript variants of known genes.
T8584 205248-205379 Sentence denotes Several clones represented epitopes from cerebral proteins, or epitopes from novel cDNA sequences originating from brain libraries.
T25652 205380-205473 Sentence denotes Of note, 3 of 8 antigenic targets represented epitopes similar to viral proteins such as EBV.
T16763 205474-205630 Sentence denotes At present, we have successfully expressed recombinant proteins for 4 of the antigenic targets and obtained synthetic peptides for the remaining candidates.
T53267 205631-205722 Sentence denotes Immunoreactivity for each purified recombinant protein and synthetic peptide was confirmed.
T35397 205723-205814 Sentence denotes We are currently extending our screening on these purified proteins and synthetic peptides.
T18965 205815-206055 Sentence denotes In addition, we have used the synthetic peptides and expressed proteins for monoclonal antibody production and are performing immunohistochemical staining on experimental autoimmune encephalomyelitis tissue with these monoclonal antibodies.
T35789 206056-206283 Sentence denotes In conclusion, autoantibody profiles against epitopes derived from MS brain tissue could serve as diagnostic markers or form the basis for the identification of a subgroup of MS patients who may benefit from specific therapies.
T17243 206284-206470 Sentence denotes Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS) in which the autoimmune response is directed to yet unidentified white matter antigens.
T21972 206471-206637 Sentence denotes A distinctive feature of MS is the presence of a local immune response within the CNS which give raise to IgG oligoclonal bands (OB) in the cerebrospinal fluid (CSF).
T65034 206638-206753 Sentence denotes One of the still obscure pathogenic aspects of MS concerns the identification of the antigen(s) targeted by IgG OB.
T41026 206754-206903 Sentence denotes In order to identify the MS autoantigen(s) recognized by OB IgG present in the CSF, we have applied a proteomic approach coupled with immunoblotting.
T88181 206904-207311 Sentence denotes Human white matter proteins have been separated by bi-dimensional electrophoresis and transferred to nitrocellulose membranes, which have been probed with CSF IgG from 12 MS patients all showing CSF OB; for each case, we have separated IgG OB from non-OB IgG on agarose gels after isoelectrofocusing; the reactivity of each IgG fraction has been analyzed in parallel with whole CSF IgG by 2D immunoblotting.
T75051 207312-207469 Sentence denotes The presence of IgG OB-specific autoantigens has been then assessed by the comparative analysis of immune-reactive spots obtained with the two IgG fractions.
T8526 207470-207688 Sentence denotes Preliminary results showed that CSF OB IgG in all cases recognized a restricted number of neural protein isoforms; among these, a specific isoform of transketolase (TK) was recognized by CSF OB IgG of most MS patients.
T49627 207689-207779 Sentence denotes A more detailed analysis will provide a complete picture of the fine reactivity of OB IgG.
T69440 207780-208031 Sentence denotes The results obtained indicate that TK is a major autoantigen in MS, since a specific TK isoform is the target of the autoimmune response in the CSF of about 50% of MS patients and here we showed that such molecule is specifically recognized by OB IgG.
T97489 208032-208223 Sentence denotes The identification of additional autoantigens in those cases not targeting TK will be instrumental to define the complete scenario of the molecular targets of the autoimmune response in MS. .
T82843 208224-208315 Sentence denotes We now tested whether local BAFF production is linked to local Ig production in MS lesions.
T20281 208316-208434 Sentence denotes Local Ig production and expression of 18 TNF family members were quantified by qPCR in active and inactive MS lesions.
T8402 208435-208571 Sentence denotes We observed elevated transcripts of BAFF and its relative APRIL (a proliferationinducing ligand) in both active and inactive MS lesions.
T22190 208572-208695 Sentence denotes Local IgG production within MS lesions correlated strongly with local BAFF and to a lesser extent with APRIL transcription.
T44406 208696-208857 Sentence denotes These results underscore the relevance of the BAFF/APRIL system for maintenance of B lineage cells in the chronic inflammatory process in the CNS of MS patients.
T88965 208858-208912 Sentence denotes Thus BAFF and APRIL are promising therapeutic targets.
T26227 208913-209013 Sentence denotes Gray matter disease in multiple sclerosis is poorly understood in part due to a lack of mouse model.
T71788 209014-209220 Sentence denotes We examined the role of CXCR6 in entry of T cells into the white and gray matter of the CNS during experimental autoimmune encephalomyelitis (EAE) with and without a secondary injury to the cerebral cortex.
T72335 209221-209385 Sentence denotes We used intravital two-photon laser scanning microscopy in intravital mice to image the role of CXCR6 in gray and white matter disease in the spinal cord and brain.
T97452 209386-209492 Sentence denotes CXCR6-deficient mice were susceptible to EAE induced by MOG (35-55) peptide in Complete Freund's Adjuvant.
T36851 209493-209656 Sentence denotes At the peak of EAE, GFP+ T cells were predominantly CD4+, exclusively present in the spinal cord, and absent in the brain in both CXCR6gfp/gfp and CXCR6gfp/+ mice.
T87627 209657-209810 Sentence denotes In the spinal cord, GFP+ T cells were mostly restricted to the white matter with preferential locomotion along the rostral-caudal axis in both genotypes.
T39816 209811-210022 Sentence denotes During remission (Nday 20 EAE), IL-17 and interferon-γ producing T cells were N65% GFP+, whereas Foxp3+ cells were 20% GFP+ with no difference in the ratio of Foxp3+ to IL-17 producing T cells in both genotypes.
T59942 210023-210186 Sentence denotes Recruitment of GFP+ T cells to the gray matter was further evaluated by inducing a small laser injury in layer 1 barrel cortex during day 16-20 post EAE induction.
T99756 210187-210299 Sentence denotes Laser injury recruited GFP+ T cells into the cortical gray matter of the CXCR6gfp/+, but not, CXCR6gfp/gfp mice.
T52518 210300-210439 Sentence denotes CXCL16, the ligand for CXCR6, was induced in the spinal cord as well as the brain of the active (day 16) and recovering (Nday 20) EAE mice.
T3038 210440-210507 Sentence denotes CXCR6 is necessary for entry of T cells in gray matter of EAE mice.
T50453 210508-210666 Sentence denotes We propose a two hit model for T cell infiltration in the cerebral cortex requiring both neuro-inflammation induced CXCL16 expression and local tissue injury.
T20596 210668-210884 Sentence denotes The therapeutic potential of adult neural stem cells (aNSCs) has been suggested in several models of central nervous system (CNS) insult. aNSCs injected intravenously can migrate and home to damaged areas of the CNS.
T7907 210885-211130 Sentence denotes Previously, we analyzed the expression of integrin and chemokine receptors before and after in vitro differentiation of aNSCs, in an effort to elucidate their potential contributions to adhesion, migration and homing to damaged areas of the CNS.
T10303 211131-211307 Sentence denotes Here, we show elevated expression of CXCL12 [Stromal cell derived factor 1a (SDF-1a)] in inflamed areas of the CNS in mice with experimental autoimmune encephalomyelitis (EAE).
T42474 211308-211403 Sentence denotes We also show upregulated expression of CXCR4, the receptor for CXCL12, in differentiated aNSCs.
T50398 211404-211566 Sentence denotes Studies are now focused on searching the source of CXCL12 in insulted CNS, and on the involvement of other molecules potentially involved in migration and homing.
T27665 211567-211762 Sentence denotes Immunostaining analysis has shown that reactive astrocytes found in large number in the inflamed regions of EAE mice are the major source of elevated levels of CXCL12 in the inflamed spinal cord.
T95036 211763-211892 Sentence denotes We also found oligodendrocyte progenitor cells immunoreactive for NG2 and CXCL12 as another potential source of increased CXCL12.
T71495 211893-212059 Sentence denotes Interestingly, the transcript of the non-classical cytokine, receptor activator of NF-kB ligand (RANKL) was found in the inflamed CNS compared to CNS of healthy mice.
T27355 212060-212219 Sentence denotes Further analysis revealed that the expression of Osteoprotegerin (OPG), the RANKL decoy receptor, was significantly induced following differentiation of aNSCs.
T46520 212220-212311 Sentence denotes The activating receptor RANK was not expressed by undifferentiated or differentiated aNSCs.
T23613 212312-212562 Sentence denotes Studies on the effect of pro or anti-inflammatory cytokines on the differential expression of OPG and the involvement of CXCR4/CXCL12, CXCR5/CXCL13 and OPG/RANKL in the migration of aNSCs towards insulted areas of the CNS are now under investigation.
T65516 212563-212678 Sentence denotes 3 -Aberrant CXCR3 signaling due to CXCL10 deficiency impairs the anti-viral response to herpes simplex virus type 1
T39231 212679-212935 Sentence denotes Carr Dan⁎ 1 , Wuest Todd 1 1 The University of Oklahoma Health Sciences Center, Oklahoma City, United States CXCL9 and CXCL10, chemokines that are chemotactic for NK cells, activated T cells, and dendritic cells are highly expressed during viral infection.
T60720 212936-213033 Sentence denotes We hypothesized that the absence of these chemokines would increase the sensitivity to infection.
T14059 213034-213245 Sentence denotes To test this hypothesis, a neurotropic pathogen, herpes simplex virus type 1 (HSV-1) was evaluated in mice deficient in CXCL9, CXCL10, the receptor for these ligands, CXCR3, or a combination of CXCL10 and CXCR3.
T20560 213246-213428 Sentence denotes In the present study, following ocular herpes simplex virus-1 (HSV-1) infection, viral titers were elevated in the central nervous system (CNS) of CXCL10 deficient (CXCL10 −/−) mice.
T81601 213429-213543 Sentence denotes Moreover, CXCL10 deficiency resulted in a more severe phenotype in comparison to mice deficient in CXCR3 or CXCL9.
T5145 213544-213670 Sentence denotes Deletion of CXCL10 resulted in impaired recruitment of NK, dendritic, and antigen-specific CD8+ T cells to the nervous system.
T52033 213671-213882 Sentence denotes Although NK and dendritic cell mobilization were similar between CXCL10 −/− and CXCR3 deficient (CXCR3 −/−) mice, CXCR3 −/− mice did not exhibit any modification in mobilization of antigen-specific CD8+ T cells.
T83324 213883-214061 Sentence denotes The defect in trafficking of HSV-1specific CD8+ T cells to the CNS of CXCL10 −/− mice is not due to the absence of CXCL10 signaling through a chemokine receptor other than CXCR3.
T27940 214062-214303 Sentence denotes CXCL10 and CXCR3 double deficient mice exhibit no significant change in recruitment of HSV-1 specific CD8+ T cells compared to wild type control mice indicating the defect observed in CXCL10 −/− mice is a result of defective CXCR3 signaling.
T45102 214304-214515 Sentence denotes There is a selective loss in resistance to HSV-1 infection in CXCL10 −/− mice directly related to the aberrant recruitment of HSV-specific CD8+ T cells to the nervous system and is dependent on CXCR3 expression.
T96042 214516-214574 Sentence denotes Toft-Hansen Henrik⁎ 1 , Løbner Morten 1 , Owens Trevor 1 1
T96088 214575-214783 Sentence denotes Leukocytes accumulate spontaneously in the perivascular space of transgenic mice that express the chemokine CCL2 (CCL2 Tg) in the central nervous system (CNS) under control of a myelin basic protein promoter.
T35901 214784-214831 Sentence denotes This is not associated with clinical pathology.
T65764 214832-215121 Sentence denotes We have previously shown that systemic injection of pertussis toxin (PTx) to these mice induces parenchymal infiltration across the glia limitans, and that this correlates to the development of encephalopathy with stupor-like symptoms and weight loss (Toft-Hansen et al., 2006, J Immunol).
T88034 215122-215323 Sentence denotes This experimental model allows us to dissociate events involved in leukocyte migration across the endothelial barrier and across the glia limitans, as two separate components of the neurovascular unit.
T42704 215324-215509 Sentence denotes We have used laser microdissection followed by real-time RT-PCR on amplified RNA to determine gene expression by cells in the perivascular area in CCL2 transgenic mice treated with PTx.
T39917 215510-215749 Sentence denotes Since PTx causes recruitment of both monocytes/macrophages as well as T cells to the CNS of CCL2 Tg mice, we investigated if expression of CD11c and class II transactivator (CIITA), molecules related to antigen presentation, was regulated.
T90772 215750-215901 Sentence denotes We found lower levels (normalized to GAPDH) of both CD11c and CIITA expressed in PTx treated CCL2 Tg mice compared to PBS treated CCL2 Tg control mice.
T34097 215902-216177 Sentence denotes The expression by perivascular cells of cytokines IL-6, TNF-alpha and IFN-gamma was not altered by PTx, whereas IL-17 went from being detected at a relatively low level in only 1 of 6 control CCL2 Tg mice to being detected at higher levels in 5 of 6 PTx treated CCL2 Tg mice.
T24985 216178-216316 Sentence denotes These results may reflect a differential participation of IFN-gamma and IL-17 expressing cells in migration across the neurovascular unit.
T19565 216317-216533 Sentence denotes To further analyze involvement of antigen presentation and T cell receptor specificity, we have crossed CCL2 Tg mice with 2D2 TCR Tg mice whose T cells are specific only for myelin oligodendrocyte glycoprotein (MOG).
T86055 216534-216751 Sentence denotes The double-transgenic offspring shows no signs of spontaneous clinical disease, suggesting that trans-endothelial migration of MOG-specific T cells to the perivascular space is not sufficient to induce encephalopathy.
T28665 216752-216942 Sentence denotes Prior studies indicate that CNS expression of the chemokine CXCL12 normally occurs along basolateral surfaces of the microvasculature, thereby controlling leukocyte access to the parenchyma.
T87997 216943-217183 Sentence denotes In patients with multiple sclerosis (MS) and in mice with experimental autoimmune encephalomyelitis (EAE), however, CXCL12 is relocated to lumenal surfaces of CNS venules, allowing egress of autoreactive leukocytes from perivascular spaces.
T39264 217184-217396 Sentence denotes As the relocation of CXCL12 highly correlates with the extent of perivascular infiltrates, we hypothesized that leukocyte-derived inflammatory mediators relocate CXCL12 via altered expression of CXCL12 receptors.
T35756 217397-217584 Sentence denotes We examined CXCL12 relocation after intravenous administration of cytokines to naïve mice and in cytokine receptor-deficient mice immunized with myelin oligodendrocyte glycoprotein (MOG).
T71717 217585-217789 Sentence denotes We also identified perivascular leukocyte subsets during induction of EAE and determined whether leukocyte-derived cytokines affect the endothelial cell expression of the CXCL12 receptors CXCR4 and CXCR7.
T25384 217790-218090 Sentence denotes Examination of CNS specimens from MOG-immunized mice at preclinical time-points revealed that venular CXCL12 relocation occurs prior to the onset of clinical disease and that 100% of these venules contain perivascular CD3+, but not CD11b+, cells, which expressed IL-1β and were CD4+, CD8+ and γδTCR+.
T8315 218091-218266 Sentence denotes Administration of IL-1β, but not TNF-a, induced CXCL12 relocation in 90.1% of vessels and mice with targeted deletion of IL-1R did not relocate CXCL12 at the microvasculature.
T47499 218267-218457 Sentence denotes In contrast, MOGimmunized, TNFR1 −/− mice exhibited both relocation of CXCL12 and a predominance of perivascular γδT cells, suggesting a role for these cells in relocating CXCL12 at the BBB.
T30869 218458-218567 Sentence denotes In addition, bone marrow chimeric experiments revealed that loss of CNS IL-1R determines the severity of EAE.
T6910 218568-218671 Sentence denotes Finally, in vitro treatment of brain endothelial cells with IL-1β induced the expression of CXCR7 mRNA.
T31850 218672-218852 Sentence denotes These results suggest that the CNS trafficking of γδT cells during autoimmunity leads to altered expression of CXCL12 at the BBB via increased endothelial cell expression of CXCR7.
T84190 218853-218993 Sentence denotes We studied five patients with acute axonal motor neuropathy (AMAN) and 2 patients with acute inflammatory demyelinating polyneuritis (AIDP).
T74902 218994-219116 Sentence denotes All patients had an antecedent Campylobacter jejuni infection and 6 patients had serum antibodies against GM1 and/or GD1a.
T20584 219117-219182 Sentence denotes We isolated monocytes from 4 healthy subjects and 7 GBS patients.
T78740 219183-219370 Sentence denotes Immature dendritic cells expressing CD1 molecules, cultured with autologous T cells, were stimulated with LPS obtained from two CJ strains isolated from GBS patients and with GM1 or GD1a.
T4341 219371-219495 Sentence denotes The T cell response to LPS and to gangliosides was determined by the release of the proinflammatory cytokines IFNg and TNFa.
T10532 219496-219644 Sentence denotes In all patients a tight correlation existed between T cell reactivity to the gangliosides and individual antibody responses to the same ganglioside.
T60000 219645-219840 Sentence denotes In conclusion, our findings provide the evidence of molecular mimicry also at the level of T cell responses, and suggest an important contribution of cellular immunity in the pathogenesis of GBS.
T50194 219842-219976 Sentence denotes Guillain-Barré syndrome (GBS) is an immune-mediated polyneuropathy which typically develops after infection with Campylobacter jejuni.
T5364 219977-220138 Sentence denotes The antibodies that are produced to clear the infection cross-react with gangliosides present in peripheral nerves causing nerve damage and neurological disease.
T59275 220139-220289 Sentence denotes The polyreactive character of these antibodies as well as the lack of a memory response suggests a T-cell independent mechanism for B-cell activation.
T94449 220290-220580 Sentence denotes Since dendritic cells (DC) play an important role in the presentation of bacterial antigens and can regulate B-cell activity, we investigated whether lipooligosaccharide (LOS) antigens isolated from Campylobacter jejuni strains can activate DCs and subsequently induce B-cell proliferation.
T38209 220581-220770 Sentence denotes Monocyte-derived DCs from healthy donors were stimulated with control Escherichia coli lipopolysaccharide (LPS) and with LOS from six different C. jejuni strains isolated from GBS patients.
T78733 220771-220948 Sentence denotes We observed that C. jejuni LOS was more effective than control E. coli LPS in upregulating the costimulatory molecules CD80, CD86, CD40 and HLA-DR indicating full DC activation.
T76179 220949-221069 Sentence denotes In addition C. jejuni LOS induced a dose-dependent secretion of the cytokines IL-6, IL-8, IL-10, IL-12p40 and TNF-alpha.
T19674 221070-221286 Sentence denotes LOS from C. jejuni did not enhance anti-IgM induced proliferation of mucosal B-cells, however when culture supernatant of DCs stimulated with C. jejuni LOS was added, B-cell proliferation was significantly increased.
T92814 221287-221507 Sentence denotes The effect of C. jejuni LOS was partly dependent on the presence of sialic acid since LOS from cst-II mutant strains as well as sialidase-treated LOS was less effective in inducing DC activation and B-cell proliferation.
T58566 221508-221658 Sentence denotes Our results indicate that LOS from GBS-associated C. jejuni can activate DCs to produce soluble factors that subsequently enhance Bcell proliferation.
T14994 221659-221720 Sentence denotes This effect is partially dependent on the sialydation of LOS.
T19482 221721-221928 Sentence denotes Further unraveling of the cellular mechanism behind the antibody response causing GBS is necessary to develop novel strategies to limit disease progression and improve clinical outcome. antecedent infection.
T13504 221929-222003 Sentence denotes Intravenous immunoglobulin and plasma exchange are efficacious treatments.
T57111 222004-222131 Sentence denotes Recently, nerve growth factor (NGF) as a new drug is commonly used in many peripheral nerve disorders, including GBS, in China.
T17689 222132-222256 Sentence denotes We aimed to determine whether NGF was safe in Guillain-Barré syndrome, and to make preliminary observations of its efficacy.
T57323 222257-222362 Sentence denotes We reported this study at two university hospitals, located in the west and north of China, respectively.
T33575 222363-222434 Sentence denotes The study was designed as a parallel group randomized controlled trial.
T84362 222435-222845 Sentence denotes GBS demyelination group 58 patients were divided into treatment group A (20 patients, 14/6) and controlled group B (38 patients, 18/20); GBS mixed group 53 patients were divided into treatment group C (32 patients, 16/16) and controlled group D (21 patients, 10/11); GBS axonal degeneration group 44 patients were divided into treatment group E (21 patients, 10/11) and controlled group F (23 patients, 13/10).
T11339 222846-223021 Sentence denotes Group A, C, E were treated with intravenous immunoglobulin and intramuscular NGF 9000AU (purityN = 98%, specific activityN = 5.0 × 10^5 AU/mg protein) daily for up to 8 weeks.
T45715 223022-223086 Sentence denotes Group B, D, F were only treated with intravenous immunoglobulin.
T89565 223087-223203 Sentence denotes Patients' neurological function and electrophysiology test were evaluated at the beginning and end of the treatment.
T19307 223204-223339 Sentence denotes The rate and extent of recovery and motor nerve conduction velocity (NCV) in group A were more better than those in group B (P b 0.05).
T40815 223340-223476 Sentence denotes Recovery rate, full recovery rate, motor NCV and motor nerve wave range in group C were greatly better than those in group D (P b 0.05).
T67036 223477-223688 Sentence denotes Clinical recovery rates and full recovery rates showed no obvious difference between group E and F (P N 0.05), but motor nerve wave range in group E demonstrated obviously higher than that in group F (P N 0.05).
T30951 223689-223739 Sentence denotes In addition, no serious adverse events were found.
T71083 223740-223884 Sentence denotes Nerve growth factor, as a kind of safe treatment, possesses significant effects on the recovery of demyelination and axonal degeneration in GBS.
T54906 223885-223979 Sentence denotes Circulating nucleic acids (CNAs) have been shown to have diagnostic utility in human diseases.
T96654 223980-224147 Sentence denotes The aim of this study was to sequence and organize an extensive catalog of CNAs and compare the normal range to CNAs from patients with Acute Multiple Sclerosis (AMS).
T17509 224148-224299 Sentence denotes Serum DNA from 34 otherwise healthy humans and 13 AMS patients was extracted, amplified, sequenced using pyrosequencing (454/Roche) and categorized by:
T19093 224300-224449 Sentence denotes 1) origin (human versus xenogeneic), 2) functionality (repeats, coding or non-coding genes), and 3) chromosomal localization and genomic frequencies.
T21912 224450-224600 Sentence denotes 3.1e5/8.9e4 (normals/AMS) sequences were derived from a total of 5.1e7/1.6e7 nucleotides, of which 84%/79% was attributed to known database sequences.
T53009 224601-224699 Sentence denotes Approximately 99% of the known sequences were genomic and 1% were xenogeneic (bacterial or viral).
T87221 224700-224819 Sentence denotes Of the genomic sequences, 34% originated from repeats and 40% from annotated genes, which is within the expected range.
T9333 224820-224922 Sentence denotes Interestingly, coding sequences were significantly underrepresented (0.25% ± .07% vs 1.25%; p b .001).
T98274 224923-225071 Sentence denotes AMS patients comprised an overrepresentation of sequences from HS17 and ALU sequences (p b 0.001), reaching an odds ratio of 90 (p b 0.001; c-index:
T36511 225072-225078 Sentence denotes 0.94).
T45996 225079-225147 Sentence denotes Unexpectedly, one normal was found to have HBV genotype F sequences.
T54274 225148-225307 Sentence denotes Whereas the distribution of CNA was mostly comparable to the genome, the under-representation of CDS argues strongly against a solely apoptotic origin of CNAs.
T33363 225308-225492 Sentence denotes The results for HS19 and ALU, already found to be associated with MS, could open a diagnostic horizon using this technology, as well as the capability for uncovering occult infections.
T45264 225493-225648 Sentence denotes Vosslamber Saskia⁎ 1 , van der Voort Laura 1 , van Baarsen Lisa 1 , Heijmans Roel 1 , Crusius Bart 1 , Killestein Joep 1 , Polman Chris 1 , Verweij Cor 1 1
T26250 225649-225770 Sentence denotes Multiple sclerosis (MS) is a heterogeneous disease, reflected by a differential response to therapy, in particular IFN-b.
T48347 225771-225872 Sentence denotes Previously, a heterogeneous pharmacological response to IFN-b therapy in RRMS patients was described.
T62695 225873-226021 Sentence denotes Evidence was provided that the baseline status of the IFN type I activity negatively correlates with the pharmacological effects of IFN-b treatment.
T17108 226022-226240 Sentence denotes It is hypothesized that the inter-individual differences in the IFN type I response program at baseline, and concomitant variation in IFNb responsiveness may be the result of inter-individual variation in IFNb biology.
T74933 226241-226396 Sentence denotes In this study we investigated the role of genetic variation in IFN signaling components in relation to the heterogeneous pharmacological response to IFN-b.
T56384 226397-226516 Sentence denotes To determine biological response, peripheral blood was collected from 30 RRMS patients before and during IFN-b therapy.
T43620 226517-226694 Sentence denotes From 20 untreated RRMS patients peripheral blood was collected at two time points over a three to twelve month time period to analyze the stability of baseline values over time.
T81977 226695-226872 Sentence denotes Baseline stability and biological response rate, were analyzed by Taqman Low Density Arrays (TLDA) using the mean gene expression level of a set of 10 IFN type I response genes.
T14633 226873-227017 Sentence denotes Genetic variation was determined in several components of the IFN signaling cascade using Taqman Genotyping Assays and conventional genomic PCR.
T13116 227018-227179 Sentence denotes The ratios of gene expression levels before and during therapy were compared with the occurrence of genetic variation in components of the IFN signaling pathway.
T31256 227180-227331 Sentence denotes The extent of the biological response correlated negatively with the baseline expression of the type I IFN response gene set (R = −0.3891; P = 0.0336).
T53334 227332-227438 Sentence denotes The baseline stability over time was reflected by a correlation efficient of r = 0.54; P = 0.029 (n = 20).
T87275 227439-227625 Sentence denotes Next we determined the association of genetic variation in IFN signalling components with IFN type I response gene activity at baseline and after pharmacological intervention with IFN-b.
T27253 227626-227803 Sentence denotes This analysis revealed a significant association between genetic variation in one of the IFN signalling components and baseline IFN type I response gene expression (P = 0.0198).
T213 227804-227932 Sentence denotes Accordingly, a significant reduced biological response was observed for patients who contained the genetic variant (P = 0.0057).
T39750 227933-228068 Sentence denotes Variation in the IFN signaling may determine (part) of the heterogeneity in the pharmacological and clinical response to IFN-b in RRMS.
T97519 228069-228202 Sentence denotes Multiple sclerosis (MS), and its mouse model EAE, are autoimmune (AI) diseases that depend on both genetic and environmental factors.
T80417 228203-228301 Sentence denotes Shared immunopathology genes, e.g., tyrosine kinase-2 (Tyk2), may also be shared AI disease genes.
T97717 228302-228489 Sentence denotes B10.DI-tyk2 mice have a single 2538 G to A missense mutation in tyk2 making them AI arthritis resistant and T. gondii susceptible, unlike the wild-type B10.Q/Ai (B10.Q/Ai-Tyk2) substrain.
T16712 228490-228608 Sentence denotes We induced EAE in B10.DI-tyk2 and B10.Q/Ai-Tyk2 mice with MOG79-96-CFA using a double injection protocol (2× MOG-CFA).
T97467 228609-228613 Sentence denotes B10.
T8717 228614-228751 Sentence denotes Q/Ai-Tyk2 mice were resistant (0/46) to EAE while B10.Q/Ai-Tyk2 (31/ 36) and reciprocal F1 hybrids (42/51) were susceptible (p b 0.0001).
T96690 228752-228866 Sentence denotes Antigen specific production of RANTES, IL-6 and IFN-gamma was specifically increased in B10.Q/Ai-Tyk2 and F1 mice.
T77465 228867-228983 Sentence denotes Thus, tyk2 is a shared AI susceptibility gene, and EAE can be complemented genetically by one wild-type Tyk2 allele.
T18359 228984-229141 Sentence denotes Next, we tested whether EAE in B10.DI-tyk2 mice could be complemented by environmental factors using MOG79-96-CFA + pertussis toxin (PTX) (1× MOG-CFA + PTX).
T22527 229142-229294 Sentence denotes B10.DI-tyk2 mice immunized with 1× MOG-CFA + PTX were significantly more susceptible to EAE than 2× MOG-CFA immunized mice (33/37 vs. 0/46; p b 0.0001).
T51405 229295-229408 Sentence denotes A large number of Th1 and Th17 cytokines and chemokines increased when PTX was included as an ancillary adjuvant.
T14795 229409-229517 Sentence denotes In contrast only IFN-gamma, IL-6 and RANTES changed significantly with both genetic and PTX complementation.
T38731 229518-229667 Sentence denotes In summary, tyk2 is both a shared immunopathology and AI disease susceptibility allele that can be complemented both genetically and environmentally.
T14095 229668-229792 Sentence denotes Such SNPs are of considerable significance given the potential role of gene-by-environment interaction in MS susceptibility.
T7790 229793-229974 Sentence denotes The Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder of the peripheral nervous system which is characterised by proximal muscle weakness and autonomic dysfunction.
T60135 229975-230156 Sentence denotes Approximately 60% of patients have an associated small cell lung carcinoma (SCLC), whilst approximately 90% of patients have autoantibodies to voltage-gated calcium channels (VGCC).
T18037 230157-230283 Sentence denotes These transmembrane proteins are located at the presynaptic nerve terminal, in the cerebellum and on the surface of the SCLCs.
T55785 230284-230530 Sentence denotes It has been postulated that antibodies raised against determinants on the tumour may cross react with the VGCC at the nerve terminal resulting in the neurological dysfunction, and such antibodies may convey a survival advantage to these patients.
T22885 230531-230753 Sentence denotes One hundred consecutive, unselected patients with biopsy-proven SCLC were recruited at time of tumour diagnosis from hospitals within the Trent region of the UK and assayed for autoantibodies to VGCC and onconeuroantigens.
T50175 230754-230915 Sentence denotes The survival rates of patients with paraneoplastic neurological syndromes or positive onconeural antibodies and SCLC, and patients with SCLC alone were compared.
T39604 230916-230972 Sentence denotes Overall, 10 patients (10%) had positive VGCC antibodies.
T82140 230973-231167 Sentence denotes Eight patients had P-/Q-type VGCC antibodies (range 70-1101 pM), one had low levels of N-type VGCC (97 pM), whilst one had both P-/Q-type and N-type VGCC antibodies (795 and 69 pM respectively).
T92066 231168-231264 Sentence denotes Of these ten patients, only four had typical clinical and electrophysiological features of LEMS.
T61272 231265-231397 Sentence denotes A further 6 patients had onconeural antibodies (Hu antibodies in 2 patients and Hu and Ri, Ri, amphiphysin, and Ma2 in four others).
T17822 231398-231634 Sentence denotes The median survival of the four antibody positive LEMS patients (19.6 months, p = 0.038, unpaired two-way t-test) was considerably greater than that for the antibody negative (8.9 months) or all antibody positive patients (10.5 months).
T72119 231635-231815 Sentence denotes Although preliminary, these results indicate that the presence of functionally active autoantibodies confers an increased survival advantage compared to antibody negative patients.
T39621 231816-231958 Sentence denotes Additionally, the VGCC antibody-positive LEMS survive longer than patients with similar VGCC autoantibodies but without neurological symptoms.
T79654 231959-232076 Sentence denotes In 50% of the patients with Lambert-Eaton myasthenic syndrome (LEMS) a small cell lung carcinoma (SCLC) can be found.
T88278 232077-232199 Sentence denotes We reported Sox-1 antibodies to be specific and rather sensitive (64%) for paraneoplastic LEMS by phage display screening.
T9986 232200-232271 Sentence denotes This study reports preliminary results of a more amenable assay system.
T81214 232272-232369 Sentence denotes We cloned the Sox-1 gene and used recombinant Sox-1 protein in an ELISA to titrate serum samples.
T62297 232370-232496 Sentence denotes We tested 12 healthy controls, 11 patients with SCLC, 46 patients with LEMS without a SCLC and 45 patients with SCLC and LEMS.
T54130 232497-232626 Sentence denotes A sample was considered positive if the OD value was at least 0.1 and more than three SD over the average OD of healthy controls.
T71087 232627-232677 Sentence denotes In SCLC-LEMS patients 35/45 (76%) tested positive.
T14236 232678-232802 Sentence denotes Of the twentynine samples tested in both assays, twenty-three tested positive in ELISA and seventeen (58%) by phage display.
T52772 232803-232891 Sentence denotes In our ELISA, positive values were found in 17% of the LEMS without SCLC and 9% in SCLC.
T96427 232892-233030 Sentence denotes Median and average OD values were 0.62 and 1.46 for SCLC-LEMS, 0.08 and 0.09 for LEMS without SCLC and 0.05 and 0.05 for HC, respectively.
T52570 233031-233108 Sentence denotes High titers above an OD of 0.4 were found only in the SCLC-LEMS group (26/45:
T26818 233109-233188 Sentence denotes 58%), while none tested strongly positive in the other two groups (p b 0.0001).
T66563 233189-233270 Sentence denotes To rule out false positives an immunoblot can be useful to confirm low OD titers.
T79519 233271-233447 Sentence denotes In five patients Sox-1 and VGCC-titers were available before and after treatment; in all titers were strongly positive before treatment and all were diminished after treatment.
T94554 233448-233476 Sentence denotes VGCC became negative in two.
T31173 233477-233553 Sentence denotes High titer Sox-1 antibodies are highly specific for LEMS patients with SCLC.
T62767 233554-233658 Sentence denotes An ELISA using recombinant protein is as sensitive and specific as a more elaborate phage display assay.
T81211 233659-233793 Sentence denotes Biollaz Gregoire 1 , Bernasconi Luca 1 , Cretton Christine 1 , Püntener Ursula 1 , Frei Karl 1 , Fontana Adriano 1 , Suter Tobias⁎ 1 1
T54861 233794-233833 Sentence denotes Glioma are among the most fatal tumors.
T18736 233834-233919 Sentence denotes This has been attributed to immunosuppressive features of both the tumor and the CNS.
T30520 233920-234022 Sentence denotes However, the relative contribution of either the glioma or its localization has not been investigated.
T78438 234023-234233 Sentence denotes We report here that the syngeneic GL261 glioma triggers a protective immune response only when growing subcutaneously, despite the fact that also intracerebrally grown gliomas are infiltrated by DC and T cells.
T43382 234234-234678 Sentence denotes This failure to control intracerebral gliomas correlates with increased immunosuppressive conditions in intracerebral tumors: tumor infiltrating dendritic cells from intracerebral gliomas are not able to stimulate T cell proliferation in vitro; brainlocalized GL261 gliomas are characterized by significantly higher numbers of Foxp3+ regulatory T cells and higher expression of TGF-b1 and TGF-b2 mRNA when compared to GL261 gliomas in the skin.
T60897 234679-234812 Sentence denotes Moreover, we show that DCs from intracranial tumors induce in vitro higher numbers of regulatory T cells than subcutaneous tumor DCs.
T33250 234813-234921 Sentence denotes Our data show that not the tumor but its location dictates the efficiency of the anti-tumor immune response.
T13084 234922-235090 Sentence denotes Mesenchymal stem cells (MSC) are a promising therapeutic tool for autoimmune diseases because couple immune-suppressive properties with multi-differentiation potential.
T40941 235091-235263 Sentence denotes Multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), are autoimmune diseases characterized by widespread demyelination and axonal loss.
T53495 235264-235405 Sentence denotes The aim of this study was the assessment of the clinical efficacy and the molecular mechanisms of adipose-derived MSC (A-MSC) in chronic EAE.
T29548 235406-235514 Sentence denotes We administered A-MSC to treat MOG35-55 induced EAE in C57BL/6J mice by two distinct experimental protocols.
T73827 235515-235701 Sentence denotes The intravenous administration of A-MSC before disease onset (preventive protocol) significantly ameliorated the clinical course and decreased spinal cord inflammation and demyelination.
T40370 235702-235907 Sentence denotes The effect was mostly due to peripheral impairment of T cell function, as GFP+ A-MSC migrated and persisted into lymphoid organs inhibited T cell proliferation and production of pro-inflammatory mediators.
T57355 235908-236052 Sentence denotes In addition, a significant number of A-MSC was also found within inflamed spinal cord, where a small proportion underwent glial differentiation.
T78485 236053-236318 Sentence denotes In addition to the preventive effect, A-MSC significantly reduced EAE clinical and pathological scores when administered after disease stabilization (25-28 days post-immunization; therapeutic protocol), with a significant reduction of demyelination and axonal loss.
T73021 236319-236452 Sentence denotes In this experimental condition, migration of A-MSC to lymph nodes as well as ex vivo inhibition of T cells was significantly reduced.
T28166 236453-236677 Sentence denotes The A-MSC administered by the therapeutic protocol efficiently migrated into the inflamed CNS; within demyelinated areas, A-MSC infiltration was accompanied by increased number of oligodendrocyte progenitors of donor origin.
T53559 236678-236839 Sentence denotes A significant subset of A-MSC expressed alpha4 integrins and anti-alpha4 antibody inhibited their penetration into inflamed CNS of mice with established disease.
T27042 236840-236986 Sentence denotes Taken together our data suggest that A-MSC produce a beneficial effect in chronic EAE by a bimodal mechanism, similarly to neural precursor cells.
T89328 236987-237209 Sentence denotes Depending on the inflammatory background, these cells may inhibit the autoimmune response in lymphoid organs in early disease stages and/or promote local neuroregeneration when administered during chronic phase of disease.
T86253 237210-237362 Sentence denotes We previously demonstrated that systemic infusion of mesenchymal stem cells (MSC) induces peripheral tolerance against encephalitogenic myelin antigens.
T97810 237363-237590 Sentence denotes However it is still unknown whether systemic delivery of MSC could affect the immune response inside the central nervous system (CNS) and if local delivery (intra-cysternal, i.c.) may result in a significant clinical advantage.
T90463 237591-237783 Sentence denotes Thus, we compared the effect of MSC injected systemically or i.c. in myelin oligodendrocyte glycoprotein (MOG) immunized experimental autoimmune encephalomyelitis (EAE) affected C57Bl/6J mice.
T55401 237784-237890 Sentence denotes We observed that both route of administration led to similar improvement of clinical and histology scores.
T27285 237891-237967 Sentence denotes No significant evidence of transdifferentiation was observed in both groups.
T40778 237968-238145 Sentence denotes Systemic infusion of MSC induced an increase of CD4+ FoxP3+, T regulatory cells and a decrease of Th17 effector cells isolated from the CNS of treated mice compared to controls.
T65440 238146-238395 Sentence denotes Thus, the immunomodulatory activity of systemically infused MSC occurs not only through the induction of peripheral tolerance but also through the inhibition of migration of effector cells and the expansion of T regulatory cells in the target organ.
T98751 238396-238741 Sentence denotes We evaluated the MSC-mediated effects in MOG-induced experimental autoimmune encephalomyelitis by histology and molecular analysis of central nervous system specimen showing that they decreased axonal sufferance through the inhibition of astrogliosis and microglia activation and the upregulation of genes involved in the BMP and Notch pathways.
T78056 238742-238961 Sentence denotes Finally, we demonstrated that MSC express arginase, an enzyme that plays important roles in several biological processes including nitric oxide (NO) production by limiting the pool of arginine available for NO synthase.
T92663 238962-239055 Sentence denotes As consequence, N9 microglial cells, cultured in the presence of MSC, decrease NO production.
T67473 239056-239160 Sentence denotes These findings suggest that MSC therapeutic effect may be the result of an impaired arginine metabolism.
T60064 239161-239272 Sentence denotes Thus, irrespective of the lack of neural differentiation, MSC exert a remarkable neuroprotective effect in EAE.
T53618 239273-239467 Sentence denotes The University of Texas Health Science Center at Houston, Houston, Texas, USA Magnetic resonance imaging (MRI) was first used to image living subjects with multiple sclerosis (MS) ∼25 years ago.
T37369 239468-239742 Sentence denotes Despite limitations of early relatively low field scanners and crude imaging sequences it was immediately evident that MRI provided an important portal to the pathology of this disease; pathology that previously could only be adequately sampled once in a patient's lifetime.
T30190 239743-239981 Sentence denotes Early studies based completely on the constraints placed on the relaxation properties of water molecules imposed by the structural characteristics of their microenvironment provided an early look at well established MS lesions or plaques.
T34406 239982-240166 Sentence denotes The introduction of paramagnetic contrast agents and their use in longitudinal serial scanning of patients unveiled the very dynamic nature of lesion formation and evolution over time.
T34300 240167-240371 Sentence denotes MRI has secured an important place in the diagnosis of the disease, in monitoring the evolution of the disease process and in the investigation of the potential benefit of new treatments for the disorder.
T98939 240372-240706 Sentence denotes MRI also provides important information for the categorization of disease activity that may be crucial for understanding the results of investigations into the aberrant immune responses of MS patients; phenomena that appear to be fundamental to our current understanding and approaches to manage this potentially devastating disorder.
T63319 240707-240877 Sentence denotes At least in the early clinical phases of MS, MRI not only aids in securing the diagnosis of the disease, but also enables short-term prognosis as to the disease's course.
T90104 240878-241255 Sentence denotes While the specificity of MRI findings for the pathologic changes that are present in affected tissues places some limitations on the correlation between quantitative MRI findings and clinical disability that currently constrains the use of MRI is a true surrogate, they have not undermined the ability of serial MRI to measure the biological efficacy of new therapeutic agents.
T15217 241256-241844 Sentence denotes Central issues that are actively being addressed include whether composite measures of conventional MRI parameters can provide better concomitant and predictive correlations with clinical disease status in the short or long term, if better pulse acquisitions or higher field imaging can better delineate cortical pathology and its evolution, and do the more global changes in brain pathology as seen with advanced MRI approaches reflect distributed change in neuronal pathways that are the consequences of classic focal lesions or do they bespeak an independent neurodegenerative process.
T9473 241845-241994 Sentence denotes Subtle changes in T cell effector function are clinically critical, e.g. in autoimmune disease, allergy, and insufficient immune responses to cancer.
T45605 241995-242287 Sentence denotes As the foundation for the design of molecular therapeutics it is thus important to understand, how modest changes in receptor engagement on the T cell surface are processed under varying physiological circumstances in the complex T cell signaling network to regulate T cell effector function.
T88285 242288-242429 Sentence denotes The ability of signaling intermediates to interact with each other in such networks is encoded by extensively studied biochemical properties.
T91360 242430-242560 Sentence denotes In addition and much less well understood, the concentrations of signaling intermediates inside live cells vary in time and space.
T50266 242561-242619 Sentence denotes We refer to these variations as 'spatiotemporal patterns'.
T96490 242620-242810 Sentence denotes They are critical for how the efficiency of signaling is regulated in live cells, as enrichment of two proteins in the same location at the same time increases their interaction probability.
T27500 242811-242879 Sentence denotes Spatiotemporal patterning needs to be studied in a systems approach.
T9254 242880-243064 Sentence denotes The spatiotemporal patterning of an individual signaling intermediate only becomes of interest when it can be compared to the patterns of multiple other components of the same network.
T24663 243065-243230 Sentence denotes First, we have therefore determined the spatiotemporal patterns of 26 elements of T cell activation in the activation of primary T cells by antigen presenting cells.
T36965 243231-243331 Sentence denotes The most striking finding was that every signaling intermediate had a unique spatiotemporal pattern.
T72674 243332-243404 Sentence denotes Such diversity of spatiotemporal patterning is of critical significance.
T61479 243405-243708 Sentence denotes Since spatiotemporal patterning differed dramatically between signaling intermediates, the likelihood of signaling intermediates to interact with each other varies substantially in time and space during T cell activation; spatiotemporal patterning has to be a significant regulator of T cell activation.
T55003 243709-243769 Sentence denotes Second, we have provided causal support for this hypothesis.
T16948 243770-243974 Sentence denotes Addressing a particular signaling intermediate, the central regulator of cell polarity Cdc42, we have shown that subcellular localization not overall cellular activity is most critical for Cdc42 function.
T18779 243975-244151 Sentence denotes Together, these data establish that the regulation of spatiotemporal pattering in T cell activation is a critical element in the control of the efficiency of T cell activation.
T6675 244152-244333 Sentence denotes Molecular therapeutics targeting such regulation may be of great utility in modulating T cell activation in autoimmune disease, allergy, and insufficient immune responses to cancer.
T97522 244334-244424 Sentence denotes How MR-based technology is changing our views on the pathophysiology of multiple sclerosis
T82183 244425-244663 Sentence denotes Neuroimaging Research Unit, Department of Neurology, Scientific Institute and University Ospedale San Raffaele, Milan, Italy A dramatic paradigm shift is taking place in our understanding of the pathophysiology of multiple sclerosis (MS).
T39630 244664-245006 Sentence denotes An important contribution to such a shift has been made possible by advances in magnetic resonance imaging (MRI) technology, which allows accurate and quantitative estimates of structural central nervous system (CNS) damage to be obtained from patients with MS and to follow its evolution over the course of the disease with high sensitivity.
T49138 245007-245302 Sentence denotes In the past few years, the use of modern quantitative MR techniques has indeed reshaped the picture of MS leading to the formulation of the so called "axonal hypothesis" (i.e., changes in metabolism, morphology, or density of the axons are important determinants of functional impairment in MS).
T72024 245303-245627 Sentence denotes In this context, metrics derived from magnetization transfer and diffusion-weighted MRI enable us to quantify the extent of structural changes occurring within T2-visible lesions and normal-appearing tissues (including gray matter) with increased pathological specificity to irreversible tissue damage over conventional MRI.
T95353 245628-245729 Sentence denotes Proton MR spectroscopy adds valuable pieces of information on the biochemical nature of such changes.
T87666 245730-245902 Sentence denotes Finally, functional MRI is providing new insights into the role of cortical adaptive changes in limiting the clinical consequences of MS-related irreversible tissue damage.
T60496 245903-246252 Sentence denotes As a consequence of the extensive application of these MR techniques our current understanding of the pathophysiology of MS is that it is not only a disease of the white matter, characterized by focal inflammatory-demyelinating lesions, but is also associated to more subtle and diffuse damage throughout the white and gray matter of the entire CNS.
T19857 246253-246438 Sentence denotes The inflammatory and neurodegenerative components of the disease process are present from the earliest clinical phases of the disease, but appear to be, at least partially, dissociated.
T73498 246439-246684 Sentence denotes In addition, recovery and repair play an important role in the genesis of the clinical manifestations of the disease, involving both structural changes (e.g., clearance of inflammation and remyelination) and plastic reorganization of the cortex.
T89611 246685-246987 Sentence denotes This new picture of MS has important implications in the context of treatment options, since it suggests that agents that protect against neurodegeneration or promote tissue repair may have an important role to play alongside agents acting on the "more classical" inflammatory component of the disease.
T66542 246988-247117 Sentence denotes Anti-GQ1b ganglioside antibodies are found in the acute phase sera of more than 90% of the Miller Fisher Syndrome (MFS) patients.
T32391 247118-247212 Sentence denotes These antibodies are believed to be the pathogenic factors leading to neuromuscular paralysis.
T34465 247213-247494 Sentence denotes We have previously shown in an in vitro mouse model using diaphragm muscle-nerve preparations that anti-GQ1b antibody binds presynaptically at the neuromuscular junction and activates the complement system, culminating in the formation of the membrane attack complex (MAC; C5b-C9).
T5185 247495-247738 Sentence denotes Functional and electrophysiological analyses showed block of synaptic transmission at the neuromuscular junction, after an initial period of a dramatically high and asynchronous release of acetylcholine, and associated paralysis of the muscle.
T62 247739-247832 Sentence denotes Morphology showed MAC deposition at the neuromuscular junction and neurofilament degradation.
T38678 247833-247992 Sentence denotes Since complement involvement with the formation of MAC is an important factor in membrane injury in general, it forms an attractive pharmacotherapeutic target.
T45557 247993-248177 Sentence denotes We have tested two experimental drugs that are able to inhibit the complement cascade at the level of C5, without affecting the immunoprotective role of upstream complement components.
T85954 248178-248485 Sentence denotes Eculizumab (Alexion Pharmaceuticals) is a humanized mouse monoclonal IgG that specifically binds human C5 and blocks its cleavage into C5a and C5b, the latter being the first component of MAC. rEV576 is a recombinant form of a soft tick saliva protein, which also effectively inhibits C5 cleavage in humans.
T77501 248486-248591 Sentence denotes We used our mouse model for MFS to assess the efficacy of these drugs in an antibody-mediated neuropathy.
T35711 248592-248788 Sentence denotes The results demonstrate that both drugs are effective blockers of MAC formation in the in vitro mouse model and thus completely prevent the development of neuronal damage and associated paralysis.
T84922 248789-248971 Sentence denotes Eculizumab was also tested in an in vivo mouse MFS model, generated through intraperitoneal injection of anti-GQ1b antibody, followed by normal human serum as a source of complement.
T21538 248972-249283 Sentence denotes While untreated mice developed respiratory paralysis due to transmission block at the diaphragm neuromuscular junctions and showed functional and morphological hallmarks of terminal motor neuropathy, intravenous injection of eculizumab was found to protect mice against complement-mediated damage in murine MFS.
T83124 249285-249412 Sentence denotes Narcolepsy is a lifelong, debilitating disease caused by a deficiency in the orexin/hypocretin signalling pathway in the brain.
T25268 249413-249541 Sentence denotes The orexinexpressing neurons are located in the lateral hypothalamus and play an important role in sleep regulation and feeding.
T80682 249542-249703 Sentence denotes Orexin is absent from the CSF of N90% of patients with narcolepsy/cataplexy and postmortem studies have demonstrated that the neurons are absent in narcoleptics.
T97580 249704-249832 Sentence denotes The disease is very highly associated with the MHC class II allele, DQB1⁎0602, suggesting that the condition is immune-mediated.
T54216 249833-250027 Sentence denotes Our hypothesis is that the destruction of the orexin neurons is caused by autoimmunity and more specifically by T-cells that cross the blood brain-barrier and target the orexin expressing cells.
T26301 250028-250195 Sentence denotes Our aim was to generate an animal model of narcolepsy by immunizing mice that express human MHC class II molecules with a peptide derived from preproorexin (Orx 1-14).
T19266 250196-250256 Sentence denotes This peptide had previously been shown to bind to DQB1⁎0602.
T36107 250257-250387 Sentence denotes Mice (females 10-12 weeks old) were immunised subcutaneously with 100 μg of the peptide or PBS in Complete Freunds Adjuvant (CFA).
T80038 250388-250502 Sentence denotes 500 ng of Pertussis toxin (PTX) was injected intraperitoneally at day 0 and 48 h post-immunisation in all animals.
T62491 250503-250593 Sentence denotes 9 days after immunisation, lymph node derived T-cells were tested in proliferation assays.
T60515 250594-250715 Sentence denotes Orx 1-14 peptide was very potent in activating the cells in vitro and the Orx 1-14 sensitive T cells were DQ6 restricted.
T91105 250716-250845 Sentence denotes Groups of immunised and control animals were tested for sleepiness and motivational status for up to 12 weeks after immunisation.
T99463 250846-250931 Sentence denotes No significant differences were observed between the experimental and control groups.
T12245 250932-251150 Sentence denotes Finally, brains from various stages after immunisation (day 9, day 21, and week 8) were analysed for numbers of orexin neurons in the hypothalamus, T-cell infiltration and for markers of immune and neuronal activation.
T87291 251151-251240 Sentence denotes No neuronal loss or activation was observed and practically no T-cells entered the brain.
T16131 251241-251308 Sentence denotes We observed strong peripheral T-cell activation, restricted to DQ6.
T86703 251309-251420 Sentence denotes However, this immune activation had no effect on the behaviour of the animals or generated any brain pathology.
T86316 251421-251588 Sentence denotes This lack of symptoms may be explained by the fact that the T-cells in the periphery did not cross the blood-brain barrier (BBB) despite the use of PTX as an adjuvant.
T41403 251589-251636 Sentence denotes Further immunisation protocols are in progress.
T72561 251637-251800 Sentence denotes The pathogenesis of inflammatory autoimmune diseases of the peripheral nervous system leading to demyelination and/or axonal damage is still incompletely resolved.
T17746 251801-252026 Sentence denotes In particular, it is controversial to which extent (i) the autoimmune-mediated destruction of peripheral nerves results in secondary damage of the central nervous system and (ii) CD4 and CD8 T cells contribute to the disease.
T35767 252027-252142 Sentence denotes To address these questions we applied the murine model of P0106-125 induced experimental autoimmune neuritis (EAN).
T59856 252143-252243 Sentence denotes Immunization of C57BL/6 mice with P0106-125 resulted in severe axonal damage and mild demyelination.
T58152 252244-252448 Sentence denotes Importantly, mice developed a dying back axonopathy with apoptosis of a large fraction of neurons in the anterior horn of the lumbar and thoracic spinal cord and a progressive neurogenic muscular atrophy.
T5696 252449-252543 Sentence denotes T cell depletion experiments identified CD4, but not CD8 T cells as decisive mediators of EAN.
T52411 252544-252872 Sentence denotes CD4 T cells were the major cellular source of antigen-specific Interferon-γ and Interleukin-17 production, regulated the number of tumor necrosis factor+ and inducible nitric oxide synthase+ macrophages in the diseased sciatic nerve, mediated axonal damage, and, subsequently, neuronal apoptosis and neurogenic muscular atrophy.
T96189 252873-252979 Sentence denotes In contrast, demyelination of peripheral nerves was only slightly ameliorated in CD4 T cell-depleted mice.
T52856 252980-253118 Sentence denotes In conclusion, P0106-125-induced EAN is a CD4 T cell-mediated autoimmune disease affecting both the peripheral and central nervous system.
T97494 253119-253533 Sentence denotes These observations have implications for the pathogenesis of autoimmune T cell-mediated diseases of peripheral nerves, and clinically relevance for the development of specific therapeutic strategies aiming to inhibit the autoimmune attack against peripheral nerves and to prevent a dying back axonopathy, in particular, by conferring axonal protection, which is of upmost importance for the final clinical outcome.
T42012 253534-253627 Sentence denotes Kiyozuka Tetsuhito⁎ 1 , Fujioka Toshiki 1 , Kudeken Tsukasa 1 1 Toho University, Tokyo, Japan
T53903 253628-253754 Sentence denotes To investigate the effect of statin on experimental autoimmune neuritis (EAN) atorvastatin was given orally to EAN rats daily.
T35594 253755-253860 Sentence denotes EAN was induced in female Lewis rats by injecting synthetic peptide of bovine myelin P2 protein with CFA.
T94829 253861-253913 Sentence denotes EAN rats fed with vehicle only were used as control.
T74774 253914-253976 Sentence denotes Clinical signs were assessed daily using 8 grade-score system.
T73287 253977-254191 Sentence denotes Cauda equina (CE) were removed at 4, 10, 12, 14, 18, 21, and 24 days post-immunization (DPI). mRNA expression of IFN-gamma, IL-10, IL-12 p35, IL-17 and IL-23 p19 in the CE was studied using semiquantitative RT-PCR.
T60792 254192-254319 Sentence denotes Both groups developed EAN at 12 DPI simultaneously although atorvastatin-treated rats showed milder signs and earlier recovery.
T76821 254320-254436 Sentence denotes Mononuclear cell infiltration seen in the CE of atorvastatin-treated rats was also milder than that of control rats.
T9530 254437-254626 Sentence denotes RT-PCR revealed that IFN-gamma and IL-12 p35 mRNA expression at 10 DPI and IL-10 and IL-17 mRNA expression at 12 DPI in atorvastatintreated rats were decreased compared to the control rats.
T57308 254627-254766 Sentence denotes Conversely IL-23 p19 mRNA expression through 14 DPI and thereafter in atorvastatin-treated rats was increased compared to the control rats.
T71264 254767-254904 Sentence denotes In EAN atorvastatin suppressed the neurological deficit and Th1 cytokines although reciprocal up-regulation of Th2 cytokine was not seen.
T68419 254905-255009 Sentence denotes Moreover suppression of IL-17 was observed in atorvastatintreated rats with up-regulated IL-23 p19 mRNA.
T66762 255010-255153 Sentence denotes Out data suggest that, in EAN, atorvastatin suppressed Th1 and Th17 activity irrelevant to Th2 cytokine up-regulation or IL-23 p19 suppression.
T54533 255154-255305 Sentence denotes Previous studies have shown that anti-ganglioside GD1a antibody causes neuromuscular presynaptic blocking on mouse phrenic nervediaphragm preparations.
T42465 255306-255445 Sentence denotes The aim of this study was to determine whether anti-GM1-or anti-GD1a-positive sera affect neuromuscular transmission in human limb muscles.
T41523 255446-255713 Sentence denotes Axonal-stimulating single fiber electromyography was performed in the extensor digitorum communis muscle of four patients with acute motor axonal neuropathy (AMAN) with anti-GM1 and GD1a antibodies and four with acute inflammatory demyelinating polyneuropathy (AIDP).
T92662 255714-255765 Sentence denotes Anti-ganglioside antibodies were measured by ELISA.
T51817 255766-255863 Sentence denotes Anti-GM1 or GD1a antibodies were positive in all four AMAN patients and in none of AIDP patients.
T93126 255864-255983 Sentence denotes All AMAN patients showed normal jitter and no blockings in the acute phase of the disease (within 2 weeks after onset).
T82071 255984-256073 Sentence denotes In AIDP patients, jitter was normal in three and slightly increased in the remaining one.
T58201 256074-256282 Sentence denotes Neuromuscular transmission does not appear to be impaired in AMAN patients with anti-GM1/GD1a antibodies, and this suggests that these antibodies do not affect neuromuscular transmission in human limb muscle.
T31238 256283-256377 Sentence denotes Our results failed to support the findings in experimental studies in the mouse phrenic nerve.
T83741 256378-256537 Sentence denotes Anti-ganglioside antibodies would involve the nodes of Ranvier of distal motor axons near the motor nerve terminals, but not the neuromuscular junction itself.
T34351 256538-256681 Sentence denotes Early studies evidenced the presence of inflammatory infiltrates in the muscles of some facioscapulohumeral muscular dystrophy (FSHD) patients.
T19630 256682-256957 Sentence denotes In order to evaluate the contribution of inflammation to FSHD pathogenesis and progression in this study we evaluated in peripheral blood mononuclear cells (PBMC) from FSHD patients and controls the percentages of pSTAT1, T-bet and pSTAT3-positive CD4+, CD8+ and CD14+ cells.
T93496 256958-257191 Sentence denotes Moreover we correlate the percentage of T-bet, pSTAT1 and pSTAT3 expressing cells with PBMC production of IFNg, IL6, IL10, TNFa, IL12, TGFb and disease severity, evaluated by Magnetic Resonance Imaging (MRI) and clinical examination.
T74225 257192-257270 Sentence denotes In our study we included 25 FSHD patients and 15 sex and age matched controls.
T83247 257271-257357 Sentence denotes Detection of pSTAT-1, pSTAT-3 and T-bet was performed by intracellular flow cytometry.
T1384 257358-257440 Sentence denotes The production of IFNg, IL6, IL10, TNFa, IL12, TGFb by PBMC was measured by ELISA.
T25043 257441-257769 Sentence denotes No difference was found in the percentage of circulating CD4+pSTAT1+, CD8+pSTAT1+T cells and CD14+pSTAT1+ cells, CD4+pSTAT3+, CD8+pSTAT3+T cells and CD14+pSTAT3+ cells, CD4+T-bet+, CD8+T-bet+T cells between FSHD patients and controls while a higher percentage of CD14+T-bet+ cells was observed in FSHD patients than in controls.
T90426 257770-257906 Sentence denotes We found higher IFNg, IL6, TNFa, IL10 and IL12 levels in FSHD patients than in controls while no difference was observed in TGFa levels.
T54302 257907-258247 Sentence denotes When we divided FSHD patients in two different groups according to MRI parameters, a higher percentage of CD8+pSTAT1+ and CD8+T-bet+T cells and CD14+pSTAT1+ cells, CD14+pSTAT3+ cells and CD14+T-bet+ cells was found in peripheral blood of FSHD patients with inflammatory pattern than in patients without inflammatory pattern and in controls.
T75857 258248-258337 Sentence denotes In addition the number of CD8+pSTAT1+ and CD8+T-bet+T cells correlated with MRI-T2 score.
T57964 258338-258509 Sentence denotes FSHD patients with MRI inflammatory pattern showed significant higher IFNg, TNFa and IL12 levels than both FSHD patients without inflammatory pattern and healthy subjects.
T51876 258510-258715 Sentence denotes IL6 and IL10 production was higher in FSHD patients with inflammatory pattern then in FSHD patients without inflammatory pattern and both groups of patients showed higher IL6 and IL10 levels than controls.
T4733 258716-258891 Sentence denotes Our data suggest that inflammation, mainly mediated by CD8+T cells, may play an important role in FSHD promoting the muscle pathology and favouring the disability progression.
T72647 258892-259010 Sentence denotes The thymus has been implicated as a possible site of origin that triggers autoimmunity such as myasthenia gravis (MG).
T32998 259011-259106 Sentence denotes Several groups have previously reported the analysis of regulatory T cells (Treg) in MG thymus.
T56808 259107-259187 Sentence denotes However, certain pattern in the changes of T cell subsets has not been revealed.
T30851 259188-259378 Sentence denotes To examine the pathogenesis of MG, we analyze what patterns of Treg and IL-17 producing T cells (Th17) are observed in the thymus between the specimens from MG (MG+) and non-MG (MG-) humans.
T88542 259379-259685 Sentence denotes Thymic tissue consisted of MG-group (child thymus with no immunological diseases, n = 6; adult thymus with no immunological diseases, n = 5; and adult thymus with thymoma, n = 5) and MG+ group (adult thymus with no neoplasmas, n = 9; adult thymus with hyperplasia, n = 6; adult thymus with thymoma, n = 6).
T46781 259686-259772 Sentence denotes Child and adult thymi without immunological diseases were obtained at cardiac surgery.
T4953 259773-259863 Sentence denotes In the samples of thymoma, nonneoplastic thymic tissues adjacent to thymoma were analyzed.
T61920 259864-259925 Sentence denotes We performed immunohistochemical analysis of thymic sections.
T89513 259926-260059 Sentence denotes To visualize Treg and IL-17 producing cells, antibodies specific for Foxp3 and IL-17 were used in combination with anti-CD4 antibody.
T70349 260060-260114 Sentence denotes All data were obtained with Leica confocal microscopy.
T43007 260115-260210 Sentence denotes Quantification of Foxp3 positive cells and IL-17 signals was measured by using ImageJ software.
T49074 260211-260286 Sentence denotes This study was approved by the Ethics Committee of University of Tokushima.
T82816 260287-260412 Sentence denotes 1) The number of Foxp3 positive cells and the pixels of IL-17 signals in thymic medulla were higher than those in the cortex.
T53518 260413-260502 Sentence denotes 2) The number of Foxp3 positive cells in child thymi was higher than that in adult thymi.
T48628 260503-260624 Sentence denotes However, there was no significant difference in the number of Foxp3 positive cells among adult thymi with and without MG.
T18090 260625-260706 Sentence denotes 3) IL-17 signals in MG+ thymi seemed to be more prominent than those in MG-thymi.
T53165 260707-260790 Sentence denotes IL-17 producing cells rather than Treg may be altered in the thymus of MG patients.
T20365 260791-260861 Sentence denotes To investigate the occurrence of AQP4-Ab in Japanese patients with MG.
T31457 260862-260960 Sentence denotes To detect AQP4-Ab, we employed immunofluorescence using HEK 293 cells transfected with human AQP4.
T97254 260961-261083 Sentence denotes Sera from 41 patients with MG being followed up in our department were collected after obtaining written informed consent.
T1682 261084-261145 Sentence denotes Two patients with MG had symptoms related to CNS disturbance.
T85318 261146-261392 Sentence denotes MRI investigation of the brain and spinal cord revealed a long spinal cord lesion in one patient with recurrent optic neuritis and paraplegia consistent with NMO, and demyelination in the midbrain tegmentum and cerebral white matter in the other.
T43345 261393-261439 Sentence denotes Only these patients were positive for AQP4-Ab.
T53072 261440-261546 Sentence denotes Development of MG and sub-sequent thymectomy preceded the development of multiple sclerosis in both cases.
T9506 261547-261591 Sentence denotes Patients with MG frequently exhibit AQP4-Ab.
T82862 261592-261710 Sentence denotes The occurrence of this antibody is strongly related to the development of CNS demyelinating disorder in such patients.
T48846 261711-261797 Sentence denotes Myasthenia Gravis (MG) is an autoimmune disorder affecting the neuromuscular junction.
T37835 261798-261967 Sentence denotes Muscle specific kinase (MuSK) antibodies are found in a variable proportion of patients with generalised disease who are acetylcholine receptor (AChR) antibody negative.
T87582 261968-262121 Sentence denotes Typically these patients have more prominent ocular, facial, bulbar, neck and respiratory weakness and often require long term immunosuppressive therapy.
T65154 262122-262229 Sentence denotes We document the clinical course of two such patients who have been under long term follow up at our centre.
T11968 262230-262332 Sentence denotes We correlated this with their MuSK antibody titres using the standard radio-immunoprecipitation assay.
T1464 262333-262506 Sentence denotes We examined the IgG subclasses and ability to activate complement (C3/Membrane Attack Complex) in vitro at several time points during their disease using a cell based assay.
T74497 262507-262603 Sentence denotes Finally we analysed the functional effects of the IgG antibodies on cultured C2C12 muscle cells.
T5376 262604-262751 Sentence denotes The MuSK antibodies in both patients were mainly of the IgG4 subclass although IgG2 and IgG1 antibodies were also seen later in the disease course.
T17913 262752-262892 Sentence denotes We found that the MuSK antibodies have the ability to activate complement in vitro, although the role of complement in vivo remains unclear.
T80768 262893-263073 Sentence denotes We also demonstrate that MuSK antibodies from these patients have variable ability to cause dispersal of acetylcholine receptor clusters in fully differentiated C2C12 muscle cells.
T98284 263074-263225 Sentence denotes These studies show that MuSK antibodies cause instability of preformed AChR clusters which has potential to disrupt neuromuscular transmission in vivo.
T38984 263226-263378 Sentence denotes Furthermore, IgG subclass switching and increased ability to activate complement in vitro may be responsible for fluctuations during the disease course.
T82075 263379-263553 Sentence denotes Long-term corticosteroid (CS) therapy is effective in treating myasthenia gravis (MG), but the problem of the cumulative side effects and toxicity still needs to be resolved.
T98242 263554-263708 Sentence denotes Some studies showed that the therapeutic efficacy of cyclosporine (CyA), a potent immunosuppressive agent, in MG, and CyA is expected to reduce CS dosage.
T92440 263709-263796 Sentence denotes However, CyA has side effects including dose-dependent nephrotoxicity and hypertension.
T1963 263797-263948 Sentence denotes In 2000, a new oral microemulsion form CyA (meCyA) was developed. meCyA is equally biologically active with much lower dosage than the old formulation.
T74220 263949-264060 Sentence denotes The present study was to evaluate the CS-dosage reduction effect and safety of meCyA therapy in generalized MG.
T75116 264061-264191 Sentence denotes Twenty three patients with generalized MG [14 women and 9 men; age median (60 y.o.) range 30-74 y.o.] were enrolled in this study.
T93973 264192-264427 Sentence denotes The diagnosis of MG was based on typical clinical features, positive response to edrophonium or neostigmine, decremental response at low-frequency repetitive nerve stimulation, and a positive anti-acetylcholine receptor antibody assay.
T40760 264428-264517 Sentence denotes All the patients underwent thymectomy and were receiving CS daily prior to meCyA therapy.
T66319 264518-264853 Sentence denotes The initial meCyA dosage of 3-5 mg/kg was divided into two doses per day and then gradually reduced during treatment to a minimal efficacious dosage by monitoring meCyA blood levels(adjusted to maintain a trough level less than 200 ng/mL), renal function (serum creatinine and BUN) and on the basis of clinical response (MG-ADL score).
T79773 264854-265068 Sentence denotes After meCyA therapy, the daily CS dosage was significantly reduced from 18.5 ± 14.2 mg to 5.8 ± 4.9 mg, while the MG-ADL scores significantly improved from 7.4 ± 4.4 points to 3.8 ± 2.8 points at the 6-month point.
T8901 265069-265149 Sentence denotes There was also a significant decrease in the HbA1c levels following the therapy.
T30945 265150-265369 Sentence denotes The side effects of meCyA encountered (an increase of serum creatinine, trichosis and hypertension) were all mild and tolerable. meCyA therapy is effective and safe in reducing CS dosage in patients with generalized MG.
T94577 265370-265636 Sentence denotes Patients with early-onset Myasthenia Gravis (EOMG; onset b age 40) have autoantibodies to the acetylcholine receptor (AChR); also lymph node-like infiltrates in the thymic medulla, including T cell areas and germinal centers, which are implicated in MG pathogenesis.
T27713 265637-265875 Sentence denotes Most of those with muscle-specific kinase (MuSK) antibodies have normal thymi, whereas N60% of the remaining patients have low affinity antibodies to AChR and thymi similar to those in EOMG (though some from either subgroup are atrophic).
T2038 265876-266091 Sentence denotes To investigate the potential for lymphocyte trafficking, we compared the thymic lymphatic vessels (LV) and high endothelial venules (HEV) in MG patients with those in infant and aged-matched non-myasthenic controls.
T38559 266092-266276 Sentence denotes We stained paraffin sections of thymi from 73 MG patients and 22 controls for lymphatic vessels (anti-LYVE-1 mAb), HEV (MECA-79 mAb) and blood vessels (anti-Von Willebrand factor pAb).
T12315 266277-266416 Sentence denotes Frequency, disposition and cellular content of both HEV and LV were analyzed over entire sections using a semi-quantitative scoring system.
T83898 266417-266513 Sentence denotes We also double-stained by immuno-fluorescence for CD20, CD1a, CD3, Ki67 or FOXP3 on lymphocytes.
T79693 266514-266578 Sentence denotes We found LV at similar overall frequencies in all adult samples.
T23899 266579-266670 Sentence denotes Most were in the fat/septa around the residual thymic tissue, and appeared empty/collapsed.
T43408 266671-266908 Sentence denotes However, in control infants, and even in most adult MG samples with infiltrates (90% in EOMG and 55% in those with low affinity AChR abs), we also found some LV within the thymic tissue at cortico-medullary junctions or near infiltrates.
T81190 266909-267090 Sentence denotes Notably, these 'internal LV' were usually dilated/packed with CD1alymphocytes, a few of which were CD20+; of the many CD3+ cells, a few were FOXP3+, consistent with emigrant status.
T18923 267091-267203 Sentence denotes Neither lymphatic endothelial cells nor lymphocytes showed signs of cell division (they were negative for Ki67).
T92765 267204-267287 Sentence denotes As expected, HEV were restricted to the infiltrates in MG thymi and appeared empty.
T5891 267288-267492 Sentence denotes Finally, a small proportion of atrophic MG samples showed more LV (containing lymphocytes) and HEV in the remaining parenchymal areas than in adult controls; they may be relics of 'burnt-out' infiltrates.
T22469 267493-267657 Sentence denotes Overall, the results suggest increased accessibility of MG thymi to incoming lymphocytes (via HEV) and increased export via lymphatics into the general circulation.
T64376 267658-267800 Sentence denotes That agrees with the involvement of the thymus in pathogenesis of EOMG and, notably, also in MG patients with low affinity antibodies to AChR.
T4372 267801-267970 Sentence denotes T-bet, a tissue-specific transcription factor, controls Th1 differentiation and IFN-gamma production, affects IgG class switching and pathogenic autoantibody production.
T35655 267971-268033 Sentence denotes New evidence suggests that Tbet also regulates the Th17 cells.
T16286 268034-268225 Sentence denotes In this study we examined the influence of T-bet deficiency (T-bet−/−) on the development of experimental autoimmune myasthenia gravis (EAMG), an animal model of human myasthenia gravis (MG).
T32887 268226-268321 Sentence denotes MG and EAMG are T celldriven, antibody-mediated autoimmune disorder of neuromuscular junctions.
T79633 268322-268441 Sentence denotes EAMG was induced in T-bet−/− and C57BL/6 mice by immunization of acetylocholine receptor (AChR) combined with adjuvant.
T85140 268442-268540 Sentence denotes Onset, incidence and severity of EAMG were compared between T-bet deficient mice and control mice.
T51072 268541-268679 Sentence denotes The responses of T helper cells (Th1/ Th2/Th17) and B cells as well as the phenotypes and functions of regulatory cells were investigated.
T56826 268680-268829 Sentence denotes We show that T-bet −/− mice are less susceptible to EAMG, which was associated with a defect of Th1 T cell, B cell and dendritic cell (DC) responses.
T23072 268830-268959 Sentence denotes This was correlated with an expansion of CD4+CD25+ regulatory (Treg) cells as well as an enhanced response of Th2 and Th17 cells.
T67797 268960-269060 Sentence denotes These results suggest that T-bet might provide a potential therapeutic target for myasthenia gravis.
T54136 269062-269322 Sentence denotes The severity of symptoms shows an intraindividual correlation with titers of IgG autoantibodies in myasthenia gravis (MG) with antibodies to the acetylcholinereceptor (AChR) or to muscle specific kinase (MuSK), and the Lambert Eaton myasthenic syndrome (LEMS).
T96717 269323-269400 Sentence denotes However, the interindividual correlation between titers and symptoms is weak.
T39958 269401-269560 Sentence denotes Evidence exists that the inflammatory properties of IgG depend on the type of glycosylation of the Fc moiety affecting the interaction with Fc-gamma receptors.
T95448 269561-269681 Sentence denotes A high degree of galactosylation of IgG antibodies has been associated with clinical remissions in rheumatoid arthritis.
T9448 269682-269773 Sentence denotes Differences in glycosylation might also play a role in the autoimmune myasthenic syndromes.
T98940 269774-269855 Sentence denotes Autoantibodies are mainly IgG1 and IgG3 in AChR MG and LEMS, but IgG4 in MuSK MG.
T77696 269856-269997 Sentence denotes Both AChR MG and LEMS occur as a paraneoplastic syndrome or as an idiopathic autoimmune disease in association with the HLA B8-DR3 haplotype.
T13363 269998-270098 Sentence denotes In contrast, MuSK MG is not known as a paraneoplastic disorder, and has a different HLA association.
T50774 270099-270229 Sentence denotes To explore the immunopathogenesis in more detail, we studied the glycosylation profile of IgG in these three myasthenic syndromes.
T6587 270230-270295 Sentence denotes Fc-part tryptic glycopeptides were analyzed by mass spectrometry.
T15173 270296-270521 Sentence denotes Statistical analysis was performed by PLSDA (partial least square for discriminant analysis), which sharpens the separation between groups of observations to obtain maximum separation between the classes control and patients.
T15480 270522-270789 Sentence denotes IgG1 of LEMS was characterized by a low degree of galactosylation compared to age-matched controls: next to the biantennary, corefucosylated agalacto N-glycan structure (IgG-G0), also its bisected counterpart (carrying an additional N-acetylglucosamine) was elevated.
T68553 270790-270897 Sentence denotes Likewise, AChR MG patients, but not MuSK MG patients showed a reduced galactosylation of the IgG Fc moiety.
T6574 270898-270989 Sentence denotes Several IgG glycoforms of LEMS patients showed a correlation with the occurrence of a SCLC.
T18707 270990-271148 Sentence denotes The bisected IgG1-G0 and IgG2-G1 glycoform decorated with a sialic acid residue were elevated, whereas the non core-fucosylated IgG4-G1 glycoform was reduced.
T37133 271149-271258 Sentence denotes A reduced degree of galactosylation was found in patients with LEMS and AChR MG, but not in MuSK MG patients.
T23024 271259-271340 Sentence denotes IgG glycosylation was also different between LEMS patients with and without SCLC.
T34570 271341-271488 Sentence denotes Current studies aim at corroborating these findings in larger patient cohorts, and at associating IgG glycosylation with clinical disease severity.
T35531 271489-271690 Sentence denotes 14 -B cell regulating activity in patients with myasthenia gravis Myasthenia gravis (MG) is characterized by the presence of auto antibodies (Ab) to acetylcholine receptor (AChR) in 85-90% of patients.
T61871 271691-271863 Sentence denotes Only among anti-AChR negative patients, a subgroup has also been defined with antibodies against muscle-specific kinase (MuSK) and with overlap of these antibody responses.
T27540 271864-272015 Sentence denotes The regulation of the differential Ab production, B cell activity and related inducing T cell activity in disease subgroups is evaluated in this study.
T82776 272016-272222 Sentence denotes Peripheral blood mononuclear cells are stained for B cell (CD38, CD138, B cell activating factor of the TNF family (BAFF) receptor (BAFF-R) and Th2 cell (CD4 and CCR4) markers and analyzed by flowcytometry.
T76444 272223-272310 Sentence denotes BAFF levels are measured in the sera of MG patients and healthy controls (HC) by ELISA.
T45181 272311-272512 Sentence denotes MG group consisted of 22 generalized patients without thymoma and with 2 anti-MuSK Ab (+) patients, 10 anti-AChR Ab (+) patients and 10 patients with none of these Ab and compared to age-matched 13 HC.
T62675 272513-272623 Sentence denotes In the peripheral blood of patients, B cells (CD19+) with or without CD38 or CD138 did not differ from the HC.
T46299 272624-272688 Sentence denotes B cells were strongly positive for BAFFR in both groups as well.
T73037 272689-272780 Sentence denotes The BAFF levels were lower in the MG group (0.74 vs. 1.39 pg/ml, p = 0.001) compared to HC.
T5570 272781-272923 Sentence denotes However Th2 subtype, defined by CD4 and CCR4 co-expression, was significantly increased in MG group compared to HC (11.3 vs. 7.9%, p = 0.005).
T35254 272924-273052 Sentence denotes The reported increase of BAFF levels in some antibody mediated autoimmune diseases is not supported for MG in the present study.
T34708 273053-273184 Sentence denotes However, the increase of B cell regulating T cell subset in MG implicates differential effects in MG subgroups on production of Ab.
T17104 273185-273260 Sentence denotes The present work was supported by the Research Fund of Istanbul University.
T53914 273262-273446 Sentence denotes Myasthenia gravis (MG) is an autoimmune disease defined by muscle weakness due to autoantibody mediated depletion of acetylcholine receptors (AChR) at the neuromuscular junction (NMJ).
T41102 273447-273572 Sentence denotes Recently we have shown that C57BL6 mice immunized with LPS and AChR develop MG-like disease which is CD4+ T cell-independent.
T5677 273573-273741 Sentence denotes In LPS-AChR induced EAMG, CD4−/− mice are able to produce significant quantities of high affinity isotype switched anti-AChR IgG, particularly complement binding.IgG2b.
T51714 273742-273847 Sentence denotes Recent studies of patients with MG indicate innate immune signals such as TLR4 and BAFF are up-regulated.
T20765 273848-273980 Sentence denotes To evaluate the role of TLR4 signaling in the development of EAMG, we utilized the LPS-AChR EAMG model because LPS is a TLR4 ligand.
T6095 273981-274158 Sentence denotes TLR4−/− and WT C57BL10 mice were immunized with LPS and AChR and evaluated for generalized muscle weakness, sera anti-AChR antibodies, and pathologic IgG and C3 deposits at NMJ.
T79720 274159-274303 Sentence denotes Both WT and TLR4−/− mice developed MG-like muscle weakness, sera anti-AChR IgG2b and IgG2c antibodies, and IgG, C3, and MAC deposits at the NMJ.
T1842 274304-274484 Sentence denotes However, TLR4−/− mice developed less severe disease with reduced incidence compared to WT mice which was associated with significantly reduced titers and avidity of IgG2b for AChR.
T10828 274485-274666 Sentence denotes TLR4−/− mice also had reduced muscle C3 deposits M = 58.33 + −19.22 vs M = 91.25 + −6.44 in WT mice and reduced muscle MAC deposits M = 59.86 + − 3.2 vs M = 69.5 + − 9.6 in WT mice.
T57237 274667-274839 Sentence denotes Following boost immunization with AChR and LPS, lymph node cells were stimulated in vitro with AChR or AChR plus LPS and analyzed for proliferation and cytokine production.
T55250 274840-274938 Sentence denotes TLR4−/− cells proliferated in response to AChR stimulation but failed to proliferate to LPS alone.
T41481 274939-275073 Sentence denotes Stimulation of cells with AChR and LPS synergizes to produce significantly higher amounts of IFN-g in WT mice but not in TLR4−/− mice.
T62615 275074-275165 Sentence denotes Both WT and TLR4−/− cells stimulated with AChR alone induced IL-10 but not IL-6 production.
T55452 275166-275296 Sentence denotes However, addition of LPS with or without AChR induced significant production of IL-6 by WT lymph node cells but not TLR4−/− cells.
T20209 275297-275433 Sentence denotes These data indicate that TLR4 promotes EAMG by increasing anti-AChR IgG2b avidity and enhancing lymph node production of IL-6 and IFN-g.
T64496 275434-275726 Sentence denotes To elucidate the prognostic and pathogenic significance of IL-6 in NMO, another inflammatory disorder with transverse myelitis, CSF IL-6 levels of 6 NMO, 22 relapsing remitting multiple sclerosis (RRMS), 15 optic neuritis patients and 15 neurologically normal controls were measured by ELISA.
T69848 275727-275847 Sentence denotes Indirect immunofluorescence studies showed a vascular staining pattern typical of NMO-IgG in the sera of 3 NMO patients.
T84640 275848-276120 Sentence denotes NMO patients had significantly (p b 0.01) elevated CSF IL-6 levels (33-553 pg/ml; 219.41 pg/ml ± 89.44) as compared to RRMS patients (13-100 pg/ml; 27.85 pg/ml ± 3.85), optic neuritis patients (12-85 pg/ml; 23.29 pg/ml ± 4.89) and controls (2-8 pg/ml; 4.45 pg/ ml ± 1.61).
T20656 276121-276300 Sentence denotes Particularly, NMO IgG positive patients displayed higher CSF IL-6 levels (265-553 pg/ml; 401.09 pg/ml ± 83.6) than NMO IgG negative NMO patients (33-40 pg/ml; 37.73 pg/ml ± 2.25).
T56812 276301-276386 Sentence denotes Our results suggest that IL-6 is involved in NMO pathogenesis and NMO IgG production.
T23039 276387-276577 Sentence denotes By 2D-PAGE and immunoblotting we found that CSF IgG from HE patients specifically recognized 3 spots, which were identified as dimethylargininase-I (DDAHI) and aldehyde reductase-I (AKRIAI).
T89899 276578-276760 Sentence denotes DDAHI was present in two isoforms recognized respectively by five and four HE patients; immunohistochemistry with anti-DDAHI antiserum depicted endothelial cells in normal human CNS.
T42827 276761-276888 Sentence denotes AKRIAI was recognized by three HE CSF and this enzyme was widely distributed on neurons and endothelia by immunohistochemistry.
T65682 276889-276968 Sentence denotes IgG from HE CSF immunostained both neuronal and endothelial cells in mouse CNS.
T47196 276969-277264 Sentence denotes The presence of these autoantibodies selectively in the CSF of HE patients may have important diagnostic and pathogenetic implications, since the autoimmune response to DDAHI and AKRIAI enzymes may lead to vascular and/or neuronal damage, two major mechanisms involved in the pathogenesis of HE.
T49118 277266-277495 Sentence denotes A broad spectrum of neuropsychiatric symptoms including chorea, hyperactivity, tics, emotional lability, and obsessive-compulsive symptoms, are described in association with group A beta hemolytic streptococcal (GABHS) infection.
T69510 277496-277581 Sentence denotes Patients suffering from such symptoms are diagnosed with Sydenham's chorea or PANDAS.
T91897 277582-277834 Sentence denotes It has been suggested that antibodies produced against GABHS, may cross the blood brain barrier and react with neural cells in a process involving molecular mimicry, which might lead to the emergence of neuropsychiatric symptoms in these two disorders.
T23016 277835-277911 Sentence denotes To date there is no animal model for either Sydenham's chorea or for PANDAS.
T81811 277912-278054 Sentence denotes We have recently found that Lewis rats immunized with a mutanolysin GABHS extract showed increased compulsivity as well as motor disturbances.
T51021 278055-278195 Sentence denotes Sera taken from immunized rats demonstrated strong immunoreactivity to GABHS antigens and to neural tissue compared to sera of control rats.
T58832 278196-278443 Sentence denotes In addition sera from rats demonstrating movement and behavior disturbances induced high levels of a calcium/calmodulin-dependent protein (CaM) kinase activity in human neuroblastoma cells as shown previously in acute Sydenham's chorea and PANDAS.
T29931 278444-278593 Sentence denotes Autoantibodies in immunized rats targeted striatum and thalamus, two brain regions implicated in the pathophysiology of Sydenham's chorea and PANDAS.
T91723 278594-278679 Sentence denotes We are currently working to identify the brain epitopes involved in antibody binding.
T52952 278680-278946 Sentence denotes These preliminary results support the hypothesis that an immune response to GABHS may in part underlie the behavioral and movement abnormalities reported in PANDAS and Sydenham's chorea, and provide an important step toward identification of the specific mechanisms.
T21084 278947-279220 Sentence denotes 4 -Autoantibodies against GLuR epsilon 2 in adult patients with non-paraneoplastic acute limbic encephalitis Takahashi Yukitoshi⁎ 1 , Kubota Yuko 1 , Yamasaki Etsuko 1 , Nishimura Shigeko 1 , Tsunogae Hisano 1 , Fujiwara Tateki 1 1 National Epilepsy Center, Shizuoka, Japan
T37633 279221-279373 Sentence denotes The incidence of acute encephalitis is 19.0/1 million/year in Japanese adults and only 22.4% of the patients have the evidence of viral invasion in CNS.
T5826 279374-279708 Sentence denotes We developed the methods of detection of autoantibodies to NMDA-type glutamate receptor (GluR) epsilon 2 and GluR delta 2 using their whole molecules synthesized by PEX system, and found the autoantibodies to GluR epsilon 2 in 13 patients with Rasmussen syndrome and two patients with acute encephalitis (Y Takahashi, Neurology 2003).
T31277 279709-279936 Sentence denotes Thereafter, we found the IgMautoantibodies to GluR epsilon 2 in 6 of 26 CSF samples in acute stage of localized encephalitis, but not in 10 samples in acute stage of widespread encephalitis (Y Takahashi, Future Neurology 2006).
T3992 279937-280059 Sentence denotes Recently, paraneoplastic anti-NMDAR encephalitis associated with ovarian teratoma was reported (Dalmau, Ann Neurol, 2007).
T70573 280060-280185 Sentence denotes We examined the autoantibodies to GluR epsilon 2 in adult patients with non-paraneoplastic acute limbic encephalitis (NPALE).
T69379 280186-280520 Sentence denotes We examined autoantibodies to GluR epsilon 2 in sera and CSF from 91 adult patients with NPALE, using full-length GluR epsilon 2 molecules by immunoblot, and n-terminal epitope of the autoantibodies by immunoblot using bacterial fusion proteins containing n-terminal peptides of the GluR epsilon 2 (amino acid residues 1 to 48) (NT1).
T73879 280521-280618 Sentence denotes Autoantibodies against GluR epsilon 2 were found mainly in NPALE patients around 15-34 years old.
T89913 280619-280873 Sentence denotes Autoantibodies to GluR epsilon 2 in sera were detected in approximately 55% of NPALE patients from acute to chronic stages, and the autoantibodies in CSF were detected in 51.8% (acute stage), 41.4% (recovery stage), and 28.6% (chronic stage) of patients.
T48520 280874-280984 Sentence denotes 13 of 19 CSF with IgM-autoantibodies to GluR epsilon 2 were detected within five days from the onset of NPALE.
T57232 280985-281091 Sentence denotes All four CSF with autoantibodies to GluR epsilon 2 included epitope to n-terminal of GluR epsilon 2 (NT1).
T3549 281092-281284 Sentence denotes These data suggest that autoantibodies against GluR epsilon 2 produced in sera after infection infiltrate into CNS through damaged BBB in acute stages, and affect n-terminal of GluR epsilon 2.
T80674 281285-281375 Sentence denotes In chronic stage, recovery of function of BBB reduces levels of the autoantibodies in CSF.
T70862 281376-281544 Sentence denotes Because BBB in hippocampi and amygdala are vulnerable, autoantibodies against GluR epsilon 2 including epitope to n-terminal may bring the limbic symptoms around onset.
T27620 281545-281695 Sentence denotes Most patients with myasthenia gravis (MG) have IgG1 antibodies against the nicotinic acetylcholine receptors (AChRs) or muscle specific kinase (MuSK).
T40194 281696-281933 Sentence denotes The remaining patients, termed seronegative myasthenia (SNMG) have been shown recently to have antibodies that bind to AChRs when they are densely clustered on the surface of transfected cells (as they are at the neuromuscular junction).
T28022 281934-282003 Sentence denotes MuSK antibodies are thought to be predominantly of the IgG4 subclass.
T49980 282004-282273 Sentence denotes Antibodies against aquaporin-4, a membrane water channel expressed in astrocytes and choroid plexus epithelial cells, are found in a high proportion of patients with neuromyelitis optica (NMO), clinically characterised by optic neuritis and myelitis, and are also IgG1.
T41955 282274-282422 Sentence denotes The pathogenic mechanisms are not always clear and we have established techniques for measuring the IgG subclass and complement activation in vitro.
T87870 282423-282524 Sentence denotes HEK cells were transfected either with AChRs clustered using rapsyn or with MuSK or with aquaporin-4.
T590 282525-282715 Sentence denotes After incubating with patients' sera, IgG subclasses or activated complement components (C3b and membrane attack complex, MAC) were visualised using fluorescent labeled secondary antibodies.
T20832 282716-282774 Sentence denotes Flow cytometry was used to quantify some of these results.
T35433 282775-282886 Sentence denotes Antibodies against clustered AChRs in SNMG were predominantly of the IgG1 sub-type, similar to seropositive MG.
T5012 282887-283011 Sentence denotes Deposition of activated complement components, C3b and MAC, was demonstrated in-vitro in a proportion of patients with SNMG.
T69020 283012-283152 Sentence denotes Antibodies against MuSK were predominantly IgG4, but also had significant amounts of IgG1 antibodies and could activate complement in-vitro.
T71511 283153-283240 Sentence denotes NMO sera had mainly IgG1 antibodies that activated the complement system very strongly.
T73161 283241-283365 Sentence denotes The degree of complement activation correlated significantly with the presence of IgG1 antibodies in all groups of patients.
T50005 283366-283539 Sentence denotes We show that immunocytofluorescence techniques can be useful not only for identifying the presence of antibodies but also to demonstrate some of their functional properties.
T58962 283540-283780 Sentence denotes This study provides further in-vitro evidence of complement activation in these autoimmune neurological disorders, giving insight into their pathogeneses and making them potentially suitable for targeted therapy using complement inhibitors.
T19476 283781-283956 Sentence denotes Recent studies reported contrasting results with respect to the presence of anti-myelin protein antibodies in Multiple Sclerosis (MS) and their relation with disease activity.
T79767 283957-284109 Sentence denotes This may be due to the heterogeneous specificity of autoantibodies in MS and the inability of most methods to detect pathogenically relevant antibodies.
T75167 284110-284220 Sentence denotes Here, myelin particles were used to detect anti-myelin antibodies in cerebrospinal fluid (CSF) of MS patients.
T25128 284221-284284 Sentence denotes Subsequently, their relation with MRI parameters was evaluated.
T70727 284285-284465 Sentence denotes Anti-myelin IgG antibody reactivity was determined in CSF of MS patients (n = 82) and clinically isolated syndrome (CIS) patients (n = 37) using a novel flow cytometry-based assay.
T19725 284466-284637 Sentence denotes In addition, CSF of patients with other neurological diseases (OND, n = 17), inflammatory neurological diseases (IND, n = 21) and healthy controls (HC, n = 22) was tested.
T73362 284638-284935 Sentence denotes Compared to HC, increased anti-myelin IgG antibody reactivity was most frequently found in CSF of CIS patients (46%, p = 0.002), relapsingremitting (RR) MS patients (69%, p b 0.001) and secondary progressive (SP) MS patients (66%, p b 0.001), together constituting 85% of all positive CSF samples.
T62483 284936-285170 Sentence denotes In contrast, elevated anti-myelin IgG antibody responses were present in a minority (12%) of the primary progressive (PP) MS patients and IND patients (30%), marginally present in healthy controls (5%) and absent in OND patients (0%).
T71637 285171-285334 Sentence denotes Most strikingly, anti-myelin IgG antibody reactivity was related to the number of T2 lesions on brain MRI in CIS and relapse-onset MS patients (r =0.37, p =0.007).
T18102 285335-285470 Sentence denotes CSF anti-myelin IgG antibodies are promising, specific biomarkers in CIS and relapse-onset MS and correlated to MR measures of disease.
T45459 285471-285889 Sentence denotes The spectrum of neurological disorders associated with serum voltage-gated potassium channel (VGKC) antibodies includes neuromyotonia (NMT), affecting the peripheral nervous system; limbic encephalitis (LE), affecting the central nervous system; and Morvan's syndrome (MoS), which combines features of NMT and LE and often additional autonomic dysfunction (e.g. hyperhidrosis and bladder difficulties) and weight loss.
T91371 285890-286012 Sentence denotes These diseases are considered to have an autoimmune basis because they often respond well to steroids and plasma exchange.
T74723 286013-286167 Sentence denotes The wide phenotypic spectrum of VGKC antibodyassociated disorders, however, suggests that there may be different antibody specificities in each condition.
T32383 286168-286288 Sentence denotes We hypothesized that antibodies specific for VGKC subtype or for associated proteins might distinguish these conditions.
T2163 286289-286431 Sentence denotes We used a variety of biochemical and immunological approaches to investigate the specificity of the antibodies in sera from patients with MoS.
T20831 286432-286600 Sentence denotes MoS sera immunoprecipitated a subpopulation of VGKCs solubilised from rabbit brain, radioactively-labeled with 125I-alpha-dendrotoxin which binds to Kv1.1, 1.2 and 1.6.
T28738 286601-286744 Sentence denotes Surprisingly, however, MoS sera did not bind directly to HEK-293 cell lines transfected with cDNA encoding any of the Kv1.1, 1.2, 1.6 subunits.
T74425 286745-286859 Sentence denotes Moreover, addition of SDS detergent to the VGKC extract, to try to disengage associated proteins, reduced binding.
T46233 286860-287014 Sentence denotes We therefore tested known associated proteins and found that MoS IgG bound to HEK293 cells expressing a protein known to interact with potassium channels.
T50925 287015-287098 Sentence denotes This was confirmed by direct immunoprecipitation of EGFP-tagged associated protein.
T96432 287099-287144 Sentence denotes MoS is a rare treatable neurological disease.
T61789 287145-287226 Sentence denotes The clinical spectrum is very broad and the condition can easily be misdiagnosed.
T52781 287227-287451 Sentence denotes The observation that the MoS antibodies bind to a Kv1-associated protein, rather than directly to the Kv1s themselves, should help to explain the varied clinical spectrum of MoS and provide a more definitive diagnostic test.
T75152 287452-287561 Sentence denotes In previous studies we detected complex antibody profiles against retinal antigens in patients with glaucoma.
T11362 287562-287657 Sentence denotes Heat shock proteins play an important role in cell survival under normal and stress conditions.
T90379 287658-287774 Sentence denotes Antibodies against heat shock protein 27 (HSP27) have been identified in these studies in sera of glaucoma patients.
T28759 287775-287931 Sentence denotes The aim of this study was to analyze if immunization with HSP27 can cause retinal ganglion cell loss in rats similar to the loss found in glaucoma patients.
T92466 287932-288163 Sentence denotes Lewis rats were immunized with 100 mg HSP27 (plus Freund's adjuvant and pertussis toxin) and divided into three groups: group 1 was euthanized after 4 weeks (n = 6), group 2 after 5 weeks (n = 6), and group 3 after 6 weeks (n = 9).
T42024 288164-288258 Sentence denotes Control animals that received no immunization were euthanized after 6 weeks (n = 10, group 4).
T70840 288259-288371 Sentence denotes Intraocular pressure was measured during the course of the study and blood was collected at several time points.
T69058 288372-288485 Sentence denotes Serum was used to detect IgG antibody patterns against retina via Western blotting and Protein G bead techniques.
T38135 288486-288561 Sentence denotes The antibody patterns were analyzed by multivariate statistical techniques.
T31496 288562-288727 Sentence denotes Eyes were harvested the day the animals were euthanized and were fixed and flatmounts were stained with Brn-3a, which detects the retinal ganglion cell (RGC) nuclei.
T43186 288728-288784 Sentence denotes We used a computer assisted quantitation of RGC density.
T94831 288785-288877 Sentence denotes No significant changes in intraocular pressure were observed during the course of the study.
T81647 288878-288978 Sentence denotes The animals immunized with HSP27 showed a lower number of RGCs in comparison to controls (P b 0.05).
T59168 288979-289052 Sentence denotes All animals showed complex antibody profiles with both detection methods.
T87682 289053-289166 Sentence denotes Through multivariate statistical methods we could show a significant difference between group 1 and 4 (P b 0.05).
T30293 289167-289272 Sentence denotes Group 3 showed a significant difference to the control group 2 and 4 weeks after immunization (P b 0.05).
T46080 289273-289372 Sentence denotes After immunization with HSP27 animals developed complex antibody profiles against retinal antigens.
T99911 289373-289481 Sentence denotes Previous studies could demonstrate specific antibody profiles against retinal antigens in glaucoma patients.
T20356 289482-289700 Sentence denotes Thus, this animal model might be a beneficial approach to study the development and actions of anti-retinal antibodies and their possible involvement in neurodegenerative processes of the optic nerve e. g. in glaucoma.
T88477 289701-289746 Sentence denotes Supported by Boehringer Ingelheim Foundation.
T49684 289747-289829 Sentence denotes Ganglioside complexes (GSCs) are target antigens in Guillain-Barré syndrome (GBS).
T56246 289830-290017 Sentence denotes GM1 and GalNAc-GD1a are thought to locate on axolemma of motor nerves and to be antigens associated with pure motor GBS, and they may exist in the vicinity and colocalize on the axolemma.
T24998 290018-290118 Sentence denotes Patients with pure motor GBS may have antibodies to GSC antigens associated with GM1 or GalNAc-GD1a.
T79727 290119-290334 Sentence denotes The purpose of this study is to investigate GBS sera on antibodies to a mixture of GM1 and GalNAc-GD1a and to analyze clinical and electrophysiological findings of patients with antibodies to a GSC, GM1/GalNAc-GD1a.
T14051 290335-290515 Sentence denotes Sera from 224 patients with GBS were surveyed for antibodies to GSCs consisting of two of nine gangliosides (GM1, GM2, GM3, GD1a, GD3, GT1a, GT1b, GQ1b and GalNAc-GD1a) with ELISA.
T83815 290516-290622 Sentence denotes We analyzed clinical and electrophysiological features of patients with IgG antibodies to GM1/GalNAc-GD1a.
T25344 290623-290678 Sentence denotes Ten GBS patients had IgG antibodies to GM1/GalNAc-GD1a.
T87290 290679-290817 Sentence denotes Six of the anti-GM1/GalNAc-GD1a-positive patients had other anti-ganglioside antibodies such as anti-GD1a, GD1b, GD1a, or GT1b antibodies.
T20556 290818-291017 Sentence denotes Clinical findings of the anti-GM1/ GalNAc-GD1a-positive patients were featured by preserved sensory system and infrequent cranial nerve deficits, in accordance with characteristics of pure motor GBS.
T79600 291018-291267 Sentence denotes According to criteria by Hadden et al. (Ann Neurol 1998;44:780-788), electrodiagnostic findings were classified into demyelinating pattern in four patients and acute motor axonal neuropathy in two, and few abnormalities were found in sensory nerves.
T44433 291268-291417 Sentence denotes Early motor conduction block at intermediate nerve segments of motor nerves without lowering of motor conduction velocity was found in five patients.
T94997 291418-291634 Sentence denotes GM1 and GalNAc-GD1a may form a complex in axolemma at nodes of Ranvier or paranodes of motor nerves, which may be a target antigen in pure motor GBS, especially in the form of acute motor conduction block neuropathy.
T69120 291635-291801 Sentence denotes Neuromyelitis optica (NMO), or Devic's disease, is a rare welldescribed demyelinating neurological syndrome with distinct clinical features and management approaches.
T41508 291802-291976 Sentence denotes The differentiation of NMO from more common causes of transverse myelitis, in particular secondary to systemic infection, is important for prognostic and therapeutic reasons.
T462 291977-292046 Sentence denotes The presence of serum NMO-IgG antibodies supports a diagnosis of NMO.
T16936 292047-292227 Sentence denotes The detection of NMO-IgG by indirect immunofluorescence (IIF), on rodent brain and renal tissues1 is the only method currently available for routine use in diagnostic laboratories.
T68897 292228-292383 Sentence denotes Our group has recently observed the presence of atypical NMO-IgG-like IIF staining in a patient with transverse myelitis secondary to systemic melioidosis.
T73131 292384-292537 Sentence denotes As this atypical staining could be mistaken for NMO-IgG, we evaluated the presence of atypical NMO-IgG-like IIF staining patterns in systemic infections.
T57733 292538-292800 Sentence denotes Sera from patients with serological evidence of acute infection caused by common bacterial and viral pathogens (INF, n = 57) and other controls (CTRL, n = 27) were tested using fresh frozen sections of rodent brain and renal papilla and anti-human IgG conjugate.
T81327 292801-292880 Sentence denotes None of these patients fulfilled clinical or radiological criteria [2] for NMO.
T46465 292881-292964 Sentence denotes IIF staining was interpreted according to the original description of NMO-IgG [1] .
T20146 292965-293083 Sentence denotes A variety of different NMO-IgG-like IIF patterns were detected in 5/ 57 INF sera (10%), and in 1/27 (4%) of CTRL sera.
T57224 293084-293339 Sentence denotes Although different combinations of staining of the central nervous system (CNS) microvessels, pia, subpia, Virchow-Robin space and tubules of renal papilla were detected, the overall patterns were atypical compared with that defined by Lennon et al. [1] .
T58265 293340-293436 Sentence denotes This study demonstrates the importance of experience in the interpretation of the NMO-IgG assay.
T28898 293437-293657 Sentence denotes Strict adherence to original description of NMO-IgG is essential for the correct interpretation of NMO-IgG IIF patterns, 1 particularly in patients with systemic infections that may be complicated by transverse myelitis.
T34338 293658-293904 Sentence denotes Given the clinical implications of a diagnosis of NMO, there is an urgent need to standardise the reporting of NMO-IgG IIF patterns and develop a robust confirmatory assay to reduce the risk of reporting atypical NMO-IgG-like patterns as NMO-IgG.
T9639 293905-294094 Sentence denotes Antibodies against aquaporin-4 (AQP4), a water channel particularly expressed on perivascular astrocytic podocytes, are proposed as a marker for the diagnosis of neuromyelitis optica (NMO).
T66253 294095-294188 Sentence denotes However, a consensus on seroprevalence and optimal detection method has not yet been reached.
T41711 294189-294221 Sentence denotes We set-up five different assays.
T96282 294222-294333 Sentence denotes Two of them were capable to detect perivascular IgG reactivity on brain tissue by immunofluorescence (NMO-IgG).
T63745 294334-294517 Sentence denotes The other three assays have been set to specifically detect anti-AQP4 antibodies: immunofluorescence and flow cytometry on AQP4-expressing cells, and a radioimmunoprecipitation assay.
T88859 294518-294824 Sentence denotes We assessed sensitivity and specificity of the different assays by interrogating sera of 33 NMO patients, 13 patients at high risk to develop NMO (hrNMO), 6 patients affected by acute partial transverse myelitis (APTM), 20 patients with multiple sclerosis (MS), and 67 age and sex matched healthy controls.
T17549 294825-294971 Sentence denotes As expected, we found that the presence of serum NMO-IgG and anti-AQP4 reactivity is almost exclusively restricted to patients with NMO and hrNMO.
T25540 294972-295049 Sentence denotes Seroprevalence and sensitivity ranged from 30 to 47%, depending on the assay.
T96223 295050-295085 Sentence denotes Specificity ranged from 95 to 100%.
T5961 295086-295179 Sentence denotes Comparing results obtained in the five assays we noticed lack of concordance in some samples.
T33313 295180-295262 Sentence denotes However, sensitivity increased to over 60% if all assays were used in combination.
T82224 295263-295462 Sentence denotes Detection of NMO-IgG or anti-AQP4 antibodies may represent, in the very near future, a valuable tool to assist neurologists in the differential diagnosis between patients with NMO, hrNMO, APTM or MS.
T38716 295463-295601 Sentence denotes The current lack of a gold standard to detect anti-AQP4 antibodies implies the necessity to standardize the detection of these antibodies.
T50408 295602-295765 Sentence denotes The MS patient used for SAS analysis had oligoclonal antibody bands (OCB) in both CSF and serum with unique OCB in CSF, indicating intrathecal antibody production.
T78395 295766-295912 Sentence denotes Both body fluids were used in parallel to affinity select a MS cDNA phage display library to enrich for antigens recognized by MS immunoglobulins.
T42632 295913-296010 Sentence denotes After 4 selection rounds phage were screened for enrichment by colony PCR and DNA fingerprinting.
T2344 296011-296088 Sentence denotes Phage ELISA testing was used to confirm specific enrichment in CSF and serum.
T87042 296089-296248 Sentence denotes We identified 14 enriched clones; 6 of these were exclusively enriched by serum selections and 2 were solely identified in selection rounds performed with CSF.
T24827 296249-296347 Sentence denotes Moreover, we identified 6 common cDNA clones, enriched by both serum and CSF selection procedures.
T49461 296348-296458 Sentence denotes Phage ELISA was performed to confirm immunoreactivity against the selected phage clones in both CSF and serum.
TextSentencer_T328 296459-296575 Sentence denotes Six clones showed immunoreactivity in both compartments while 3 other clones showed exclusive reactivity in the CSF.
TextSentencer_T329 296576-296703 Sentence denotes Immunoreactivity in CSF was remarkably higher compared to serum reactivity, consistent with an intrathecal antibody production.
TextSentencer_T330 296704-296940 Sentence denotes One of the cDNA clones that was extensively enriched and displayed immunoreactivity in both CSF and serum was identified as a member of the Mitogen Activated Protein Kinase (MAPK)-family and has not yet been described in relation to MS.
TextSentencer_T331 296941-297106 Sentence denotes Expression of this cDNA clone was demonstrated in spinal cord of healthy and experimental autoimmune encephalomyelitis mice by Western blot and immunohistochemistry.
TextSentencer_T332 297107-297274 Sentence denotes The use of SAS to study autoantibody profiles in MS CSF and serum in parallel provides clues regarding intrathecal and systemic autoantibody production in the disease.
TextSentencer_T333 297275-297483 Sentence denotes Antibodies were produced by the immortalization of B cells from CSF and peripheral blood of 4 MS patients and 11 control patients with non-inflammatory or other inflammatory neurological disease (NIND/ OIND).
TextSentencer_T334 297484-297729 Sentence denotes Peripheral blood mononuclear cells (PBMC) or CSF cells were cultured in the presence of Epstein-Barr virus (EBV) and polyclonal growth factor CpG2006, combined with T cell inhibitory and B cell stimulating factors and irradiated allogeneic PBMC.
TextSentencer_T335 297730-297866 Sentence denotes After 2 weeks the culture supernatant was screened for the presence of immunoglobulin G (IgG) and positive cultures were further cloned.
TextSentencer_T336 297867-298009 Sentence denotes The resulting monoclonal antibodies are representative for the enriched B cell populations in vivo and will be compared between CSF and blood.
TextSentencer_T337 298010-298066 Sentence denotes The B cell immortalization procedure has been optimized.
TextSentencer_T338 298067-298219 Sentence denotes At present, we obtained 18 IgG-positive B cell lines from 2 MS patients, 7 originating from the CSF of 1 patient and 11 from PBMC of another MS patient.
TextSentencer_T339 298220-298401 Sentence denotes From 4 NIND patients, 7 immortalized B cell lines have been isolated, 2 derived from CSF cells of one patient, 3 from PBMC of a second patient and 2 from PBMC of two other patients.
TextSentencer_T340 298402-298505 Sentence denotes To investigate monoclonality, B cell spectratyping analysis was performed on the obtained B cell lines.
TextSentencer_T341 298506-298570 Sentence denotes Most of the IgG-positive B cell lines appeared to be monoclonal.
T72661 298571-298753 Sentence denotes B cell immortalization has proved to be a useful method for the production of monoclonal antibodies but further optimization is necessary to increase the efficiency of the procedure.
T82129 298754-298848 Sentence denotes In conclusion, we obtained a panel of IgG-positive B cell lines from MS patients and controls.
T11124 298849-299160 Sentence denotes In future experiments, culture supernatant of the monoclonal B cells will be used to screen for antibody binding to a human oligodendroglial cell line (HOG), healthy and experimental autoimmune encephalomyelitis (EAE) brain tissue from rat and rhesus monkey and to viruses such as cytomegalovirus (CMV) and EBV.
T22563 299161-299194 Sentence denotes 14 -Devic's neuromyelitis optica:
T94875 299195-299387 Sentence denotes Prognostic implications of NMO IgG status in Turkish patients Devic's neuromyelitis optica (NMO) is an inflammatory/demyelinating disorder predominantly affecting optic nerves and spinal cord.
T24415 299388-299689 Sentence denotes There has been some debate on the classification, and naming of the disorder; recent findings showed an underlying humoral abnormality in NMO, characterized by the presence of a highly specific serum antibody against aquaporin-4, the most abundant water channel in the CNS (called NMO-IgG or Aqp4-Ab).
T24141 299690-299830 Sentence denotes In this study, we aimed at evaluating the NMO-IgG/Aqp4-Ab status among Turkish patients with NMO, and to find out any clinical significance.
T90304 299831-300066 Sentence denotes Serum samples from 21 patients with NMO, diagnosed according to the 2006 criteria, who were being followed-up in our Multiple Sclerosis and Myelin Disorders unit were evaluated for NMO-IgG/ Aqp4-Ab using an indirect immunofluorescence.
T72194 300067-300159 Sentence denotes Confirmation was carried out by immunoprecipitation employing recombinant human aquaporin-4.
T35811 300160-300247 Sentence denotes Mean age at onset was 29.1 + 11.2 years, and mean disease duration was 9.9 + 7.0 years.
T88442 300248-300279 Sentence denotes Sex ratio (F:M) was 16:5 (3.2).
T23672 300280-300361 Sentence denotes Disease followed monophasic course in five patients and multiphasic course in 16.
T59081 300362-300462 Sentence denotes First clinical episode was optic neuritis in 14, transverse myelitis in two, and both in five cases.
T69573 300463-300538 Sentence denotes 17 of the sera were taken at an acute attack, four were taken at remission.
T57428 300539-300592 Sentence denotes NMO-IgG/Aqp4-Ab was positive in 12/21 (57%) patients.
T2659 300593-300882 Sentence denotes Among the NMO-IgG seropositive cases, nine had an EDSS of six or more, whereas only two patients in the seronegative group had such severe disability (p b 0.05), and the NMO-IgG positive cases had a mean EDSS score of 5.5 + 1.6 compared with 3.8 + 1.9 in NMO-IgG negative cases (p b 0.05).
T39115 300883-300975 Sentence denotes All seropositive cases were female whereas 5 of the seronegative cases were male (p b 0.05).
T90073 300976-301087 Sentence denotes Disease duration, age at onset and being monophasic or multiphasic did not differ significantly between groups.
T13698 301088-301202 Sentence denotes Three of the seropositive cases and one seronegative case were sampled at remission (difference, not significant).
T28074 301203-301336 Sentence denotes One seronegative case and eight of seropositive cases were under some immunosuppressant treatment at the time of sampling (p b 0.05).
T33030 301337-301400 Sentence denotes NMO is relatively uncommon among other demyelinating disorders.
T95480 301401-301542 Sentence denotes Our findings in this relatively large single-center cohort suggest that the presence of NMO-IgG/Aqp4-Ab might have a prognostic significance.
T7664 301543-301592 Sentence denotes This should be further assessed in larger series.
T62424 301593-301747 Sentence denotes There are an increasing number of diseases in which specific antibodies to membrane proteins have been identified and new antibodies are being discovered.
T79109 301748-301812 Sentence denotes The associated diseases usually respond well to immunotherapies.
T7367 301813-302002 Sentence denotes There is a need to establish simple quantitative non-radioactive immunoassays for these antibodies and to test for novel antibodies in other patients with unexplained neurological diseases.
T2007 302003-302355 Sentence denotes We used a new fluorescent immunoprecipitation (FIPA) method for antibodies to membrane proteins using expression of fluorescent protein (FP)-or luciferase-tagged proteins in human embryonic kidney cells, extraction in detergent solution, incubation in patient or control sera, and immunoprecipitation with either Protein A beads or with anti-human IgG.
T54965 302356-302500 Sentence denotes The precipitate is then measured for fluorescence on a plate reader or, after addition of the substrate luciferin, for light with a luminometer.
T50515 302501-302686 Sentence denotes Acetylcholine receptor (AChR) antibodies can be measured by immunoprecipitation of enhanced green FP-acetylcholine receptor and MuSK antibodies by immunoprecipitation of mCherryFP-MuSK.
T29470 302687-302784 Sentence denotes The results correlate well with those obtained with the standard radioimmunoprecipitation assays.
T29432 302785-302948 Sentence denotes More than 70% of patients with neuromyelitis optica had serum AQP-4 antibodies using either enhanced green FP-AQP4 (Waters et al 2008 in press) or luciferase-AQP4.
T1095 302949-303128 Sentence denotes Finally, we tested the possibility that a patient with a severe form of encephalopathy with rigidity, myoclonus and excessive startle had a novel antibody to the glycine receptor.
T76911 303129-303329 Sentence denotes Using EGFP-glycine receptor, we found high levels of specific antibody at onset and levels fell substantially following treatment, corresponding to clinical remission (Hutchinson et al 2008 in press).
T83201 303330-303505 Sentence denotes The results show the potential of either fluorescent protein or luciferase constructs to provide novel clinical assays for a range of antibodies to existing and novel targets.
T98976 303506-303592 Sentence denotes This approach is proving useful for identifying new antibodies (see S Irani abstract).
T41892 303593-303786 Sentence denotes Several myelin proteins of the central nervous system (CNS) have been investigated as potential targets for humoral immune response involved in the formation of multiple sclerosis (MS) lesions.
T91698 303787-303999 Sentence denotes In most studies, investigators employed recombinant antigens and/or relevant peptides from pre-selected targets but in spite of these efforts, the precise identity of MS antigens has not been clearly defined yet.
T95519 304000-304228 Sentence denotes In the present study we overcome the traditional approach using a large panel of native protein antigens derived from white matter homogenates of human healthy CNS, resolved by bi-dimensional electrophoresis (2D-PAGE) technique.
T64975 304229-304482 Sentence denotes We compared the IgG repertoires in sera and cerebrospinal fluid (CSF) from 19 control subjects and 18 MS patients (4 primary progressive, 4 secondary progressive, 10 relapsing remitting) by immunoblot after 2D-PAGE resolution of white matter homogenate.
T25270 304483-304588 Sentence denotes Nine spots have been specifically recognized by CSF of MS patients with statistical relevance (p b 0.05).
T65194 304589-304785 Sentence denotes They corresponded to isoforms of cytoskeletal proteins (CNPase I, Radixin, Collapsin response mediator protein 2, Tubulin beta-4, NAD-dependent deacetylase sirtuin-2, actin interacting protein 1).
T14120 304786-304887 Sentence denotes Of particular interest is one isoform of Transketolase (TK) specifically recognized by 50% of MS CSF.
T56722 304888-305079 Sentence denotes Interestingly, TK was mostly localized by double immunohistochemistry on mature oligodendrocytes (OL) and less prominently on NG-2 positive OL precursors and neurons in the healthy human CNS.
T84627 305080-305304 Sentence denotes In MS sections, TK immunoreactivity markedly decreased in the core of demyelinated lesions but was still present in a subpopulation of NG-2 positive OL precursors at the lesion border, in reactive astrocytes and macrophages.
T21390 305305-305453 Sentence denotes In addition to TK autoreactivity, CSF IgG from secondary progressive MS patients showed a significant reactivity to the above cytoskeletal proteins.
T96573 305454-305524 Sentence denotes Eight spots have been specifically recognized by seric IgG (p b 0.05).
T71030 305525-305768 Sentence denotes They corresponded to specific isoforms of proteins involved in the regulation of cytoskeleton (Alpha-centractin, Collapsin response mediator protein 5/1, Syntaxin binding protein 1, CNPase I) and in the energy production (TK, Pyruvate kinase).
T48217 305769-305866 Sentence denotes Among these proteins, the most frequently recognized by serum MS IgG was one isoform of CNPase I.
T20602 305867-306094 Sentence denotes Our immunomic approach sheds new light on the autoimmune repertoire present in MS patients revealing novel oligodendroglial and/or neuronal molecules, with potential important pathogenic, diagnostic and prognostic implications.
T67537 306095-306260 Sentence denotes Neuromyelitis optica (NMO) is an idiopathic, chronic demyelinating and inflammatory disease characterised by predominant involvement of Optic nerves and Spinal cord.
T8442 306261-306394 Sentence denotes Recently, an antibody response against the water channel protein aquaporin-4 (AQP-4) was established as diagnostic biomarker for NMO.
T67671 306395-306512 Sentence denotes Current assay methodologies consist of indirect immunofluorescence and radioimmunoprecipitation assays, respectively.
T78493 306513-306711 Sentence denotes Here we introduce a cell based flow cytometry assay to measure antibodies to AQP-4; the human glioblastoma cell line LN18 was stably transfected using a lentiviral vector to overexpress human AQP-4.
T32498 306712-306804 Sentence denotes Expression was further confirmed by immnocytochemistry and Western blotting of cell lysates.
T42467 306805-306946 Sentence denotes We tested antibody reactivity in 160 serum samples (25 healthy controls (HC), 50MS, 50 OND, and 70 NMO) by flow cytometry at 1/100 dilutions.
T52414 306947-307102 Sentence denotes Results were expressed as median fluorescence intensities (MFI) corrected for background binding to the control cell line transfected with an empty vector.
T34417 307103-307173 Sentence denotes Samples are deemed positive if the MFI above cut-off (MFI (HC) +10SD).
T21925 307174-307358 Sentence denotes 70 NMO samples were positive (median MFI 835, range 66-4800), but no MS, HC samples, respectively (p b 0,005; ANOVA for Multiple MFI comparison); median endpoint titres were N1/10,000.
T33107 307359-307471 Sentence denotes The antibodies were confined to the IgG1 isotope and highly dependent on the native conformation of the protein.
T28457 307472-307573 Sentence denotes We established a novel assay that allows fast and reliable quantification of autoantibodies to AQP-4.
T76412 307574-307700 Sentence denotes This assay improves AQP-4 autoantibody testing and may provide new insights into the pathogenic role of the antibodies in NMO.
T33228 307701-307734 Sentence denotes Mascaro-Blanco A.⁎ 1 , Alvarez K.
T67125 307735-307853 Sentence denotes 1 Sydenham chorea is a neurological disorder resulting from group A streptococcal infection and acute rheumatic fever.
T52104 307854-307993 Sentence denotes This disorder is characterized by rapid and involuntary movements of the body extremities and face and other neuropsychiatric disturbances.
T26267 307994-308241 Sentence denotes Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) classification is applied to a subgroup of children whom tic disorders or obsessive-compulsive disorders develop following a streptococcal infection.
T78592 308242-308383 Sentence denotes It is believed that streptococcal infection induces a crossreactive humoral response directed against neuronal determinants in basal ganglia.
T91126 308384-308542 Sentence denotes Our goal was to study and compare autoantibody reactivity in acute and convalescent sera of Sydenham chorea, PANDAS and Tics patients against lysoganglioside.
T88004 308543-308733 Sentence denotes Human monoclonal antibodies (mAbs) against lysoganglioside derived from Sydenham chorea were shown to be high avidity and result in neuronal cell signaling and elevated levels of CaM kinase.
T78418 308734-308892 Sentence denotes Using the ELISA we studied patients sera collected longitudinally and patterned dose response curves of concentration of antibody versus optical density (OD).
T13981 308893-309105 Sentence denotes The results show that anti-lysoganglioside autoantibodies are elevated in sera taken in the acute phase or during flares of disease and correlate with activation of CaM kinase in neuronal cells by serum antibody.
T36607 309106-309233 Sentence denotes Elevation of autoantibodies against lysoganglioside correlated with disease or exacerbations of behavior and movement symptoms.
T73481 309234-309403 Sentence denotes Our data suggest that assay for levels of anti-lysoganglioside antibodies may be used along with the clinical findings for diagnosis of Sydenham chorea, Tics and PANDAS.
T36661 309404-309606 Sentence denotes Our data also suggest that the anti-lysoganglioside antibodies associated with disease activity and antibody-mediated neuronal cell signaling are high avidity and may contribute to disease pathogenesis.
T56639 309607-309763 Sentence denotes Acute disseminated encephalomyelitis (ADEM) is a rare monophasic CNS demyelinating disease that affects both grey and white matter of brain and spinal cord.
T56031 309764-309907 Sentence denotes Even though ADEM and multiple sclerosis (MS) share pathological characteristics, the clinical course of ADEM is very different from that of MS.
T15202 309908-309986 Sentence denotes Therefore differentiation of ADEM and MS is important for effective treatment.
T58279 309987-310169 Sentence denotes The role of autoantibodies in CNS demyelinating disease is unknown however the detection of Myelin-Oligodendrocyte Glycoprotein (MOG) reactive antibodies was reported in MS and ADEM.
T45402 310170-310254 Sentence denotes The role of these antibodies for diagnosis and prognosis has remained controversial.
T90799 310255-310437 Sentence denotes Here we introduce a cell based flow cytometry assay based on surface expression of MOG on human glioblastoma cell line transfected with lentiviral vector containing the MOG sequence.
T54805 310438-310563 Sentence denotes Expression of native MOG on transfected cell line was confirmed by flow cytometry, immunohistochemistry and western blotting.
T73184 310564-310729 Sentence denotes We tested native MOG reactivity in healthy donors, patients with relapsing remitting (RR-MS), secondary progressive (SP-MS), primary progressive MS (PP-MS) and ADEM.
T49141 310730-310874 Sentence denotes Results were expressed as median fluorescence intensity (MFI) corrected for background binding to a cell line transfected with the empty vector.
T94828 310875-310959 Sentence denotes Samples were deemed positive if the MFI above cut-off MFI (HC) +10 SD were observed.
T1271 310960-311112 Sentence denotes While antibodies to native MOG are significantly elevated in MS patients compared to controls, very high titers are primarily observed in ADEM patients.
T10554 311113-311232 Sentence denotes The findings confirm previous reports from other and our group with respect to antibodies to native MOG in MS and ADEM.
T3254 311233-311357 Sentence denotes Further studies are warranted to determine whether anti-MOG antibodies are useful to discriminate between ADEM and early MS.
T3996 311358-311523 Sentence denotes We studied AChR, VGKC and AQP4 antibodies serially in samples from a woman with a 30 year history of ocular MG which was treated only with cholinesterase inhibitors.
T38064 311524-311611 Sentence denotes In 2003, she developed rapidly progressive LE with very high levels of VGKC antibodies.
T22926 311612-311691 Sentence denotes She was treated with intravenous immunoglobulins, steroids and plasma exchange.
T44228 311692-311754 Sentence denotes The VGKC antibodies fell rapidly and she made a good recovery.
T17646 311755-311936 Sentence denotes In 2005 she had a short period of transverse myelitis which responded to treatment, but six months later relapsed with quadraparesis and longitudinallyextensive spinal cord lesions.
T75173 311937-312066 Sentence denotes We measured her antibodies to AChR, VGKC and AQP4 in all available samples and correlated the results with her clinical findings.
T50507 312067-312198 Sentence denotes VGKC antibodies were very high at onset of VGKC-LE (N5000 pM) and fell substantially following treatment, normalising after 1 year.
T94428 312199-312330 Sentence denotes AChR antibodies were present (N60 nM) throughout the period of study but fell appreciably when the patient was treated for VGKC-LE.
T99246 312331-312467 Sentence denotes AQP4 antibodies were present before the onset of myelitis, rose markedly at the time of her major relapse and have fallen after therapy.
T37628 312468-312553 Sentence denotes The clinical features at each time point reflected well the relative antibody titres.
T58366 312554-312727 Sentence denotes This case illustrates well three different antibody-associated diseases in a single patient, and the correlation between antibodies and disease status during serial studies.
T99657 312728-312801 Sentence denotes However, AQP4 antibodies can be present in the absence of overt myelitis.
T78022 312802-313039 Sentence denotes Sydenham's chorea (SC) is a central nervous system (CNS) disorder and sequela of group A streptococcus-induced acute rheumatic fever (ARF) where deposition of antibodies in brain may result in movement and neuropsychiatric abnormalities.
T56985 313040-313304 Sentence denotes Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) represent a subgroup of obsessive compulsive disorder (OCD) and tic disorders which may share a common set of symptoms as well as a similar proposed etiology with SC.
T83075 313305-313419 Sentence denotes The goal of the study was to characterize SC and PANDAS antibody responses to streptococcal and neuronal antigens.
T77312 313420-313631 Sentence denotes Our study investigated streptococcal and neuronal antigen specificity as well as cytotoxic capabilities of SC and PANDAS antibodies using enzyme linked immunosorbant assay (ELISA) and chromium-51 release assays.
T71297 313632-313814 Sentence denotes Streptococcal M type 5 protein and Nacetyl-beta-D-glucosamine (GlcNAc), the immunodominant epitope of the group A carbohydrate, have been suggested as cross-reactive antigens in ARF.
T89051 313815-313979 Sentence denotes Acute SC sera and cerebrospinal fluid (CSF) showed significantly greater IgG reactivity to M5 protein and GlcNAc than did matched convalescent sera and control CSF.
T76059 313980-314222 Sentence denotes Although matched PANDAS sera did not show a similar pattern of IgG reactivity to intact streptococcal antigens, PANDAS acute sera showed significantly elevated IgG levels to M5 protein N-terminal peptides in comparison to non-PANDAS controls.
T71079 314223-314415 Sentence denotes For SC acute sera and CSF, IgG subclass distribution analysis showed elevated levels of IgG1 and IgG3 to the M5 protein in contrast to PANDAS acute sera which only demonstrated increased IgG1.
T31452 314416-314496 Sentence denotes Both acute SC and PANDAS sera showed elevated IgG2 concentrations to GlcNAc-BSA.
T31978 314497-314568 Sentence denotes Of interest was the increased IgG1 response to GlcNAc by SC acute sera.
T93164 314569-314710 Sentence denotes SC CSF IgG recognized lysoganglioside, a CNS ganglioside associated with signal transduction in the brain, more strongly than did PANDAS CSF.
T74926 314711-314816 Sentence denotes SC and PANDAS sera and CSF were tested for complement-mediated cytotoxicity by chromium-51 release assay.
T75850 314817-314908 Sentence denotes Sera and CSF samples did not induce cytotoxicity against SK-N-SH human neuroblastoma cells.
T34933 314909-315074 Sentence denotes Analysis of IgG subclass distribution of cell surface-bound antibody demonstrated that IgG2 from SC CSF was the predominant subclass to label SK-N-SH neuronal cells.
T39171 315075-315263 Sentence denotes The new data supports the hypothesis that anti-group A carbohydrate antibody of the non-complement activating IgG2 subclass may play an important role in the pathogenesis of SC and PANDAS.
T74228 315264-315369 Sentence denotes We report a patient suffered from a chronic sensory ataxic neuropathy associated with oculomotor paresis.
T12080 315370-315599 Sentence denotes Immunological studies revealed IgM lambda paraprotein, cold agglutinin and IgM autoantibodies reacting with GD1b, GQ1b, GD3 and GT1b but not GM1, GD1a or GM2 suggesting the presence of antibodies reacting with disialosyl epitope.
T459 315600-315673 Sentence denotes Sural nerve biopsy revealed demyelinating neuropathy without IgM deposit.
T33163 315674-315707 Sentence denotes All features suggested a CANOMAD.
T89032 315708-315802 Sentence denotes A partial response to intravenous immunoglobulin and plasmapheresis is reported in some cases.
T54598 315803-315888 Sentence denotes Rituximab have gained widespread acceptance in the management of B-cell malignancies.
T59628 315889-316031 Sentence denotes More recently, they have been used to treat a number of autoantibody-mediated diseases, including some neuropathies, with encouraging results.
T41968 316032-316157 Sentence denotes We evaluated the effect of Rituximab using the protocol recommended for rheumatoid arthritis, i.e. 1000 mg at J1, J15 and M6.
T16964 316158-316247 Sentence denotes We observed a disappearance of disialosyl antibodies at M3 followed by an increase at M6.
T83199 316248-316314 Sentence denotes CD19 numbering in blood was 4.9% at M0, 0.2% at M3 and 0.3% at M6.
T65899 316315-316490 Sentence denotes We observed at M3 a reduction of the ataxy and the handicap scoring ONLS (7 at J0 and 4 at M3) and an escalation at M6 correlating with evolution of the autoantibodies levels.
T3448 316491-316544 Sentence denotes The results of this case report are very encouraging.
T99217 316545-316657 Sentence denotes Further studies of Rituximab therapy for neuropathy associated with disialosyl IgM autoantibodies are warranted.
T30797 316658-316814 Sentence denotes Sydenham chorea is a central nervous system (CNS) disorder characterized by involuntary movements affecting limbs and face, leading to loss of coordination.
T74623 316815-316927 Sentence denotes Chorea patients may exhibit psychiatric and psychological abnormalities including obsessive-compulsive disorder.
T97843 316928-317123 Sentence denotes Mechanisms of pathogenesis in Sydenham chorea are associated with antecedent Group A streptococcal infection which induces a crossreactive humoral response directed against neuronal determinants.
T30220 317124-317256 Sentence denotes Antibodies (Abs) to Group A streptococcal carbohydrate N-acetyl-beta-D-glucosamine (GlcNAc) are elevated in sera of chorea patients.
T1063 317257-317503 Sentence denotes Chorea-derived human anti-streptococcal monoclonal antibody (mAb) 24.3.1 crossreacted with GlcNAc, tubulin, and lysoganglioside and induced increased Ca++/calmodulin dependent protein kinase (CaM kinase) II activity in a human neuronal cell line.
T97500 317504-317631 Sentence denotes Our objective was to create transgenic (Tg) mice expressing mAb 24.3.1 heavy and light chain variable region (VH and VL) genes.
T87241 317632-317793 Sentence denotes V gene-expressing Tg mice were studied for antibody deposition in the brain to gain insight into the mechanisms of CNS disorders involving anti-brain antibodies.
T13058 317794-317900 Sentence denotes Tg mice were created by pronuclear microinjection of mAb 24.3.1 VH and VL constructs into C57Bl/6 embryos.
T4304 317901-317961 Sentence denotes Double (VH + VL) and single (VH-only) Tg mice were produced.
T1592 317962-318038 Sentence denotes Gene-integration was verified by tail DNA PCR using V-gene-specific primers.
T41394 318039-318178 Sentence denotes ELISA determined expression of chimeric (human V gene/mouse constant region) IgG1a antibody and its antigen specificities in Tg mouse sera.
T69679 318179-318353 Sentence denotes Experiments were performed to see if the chimeric Ab would deposit in brains of Tg mice if the blood-brain barrier was breeched by administration of lipopolysaccharide (LPS).
T97601 318354-318420 Sentence denotes Brains and organs of sacrificed Tg and non-Tg mice were collected.
T90849 318421-318530 Sentence denotes FACS analysis characterized splenic, lymph node and bone marrow B cells and confirmed chimeric Ab expression.
T72609 318531-318580 Sentence denotes RT-PCR of splenic RNA verified V gene expression.
T99322 318581-318678 Sentence denotes Ab deposition in brains was determined by immunohistochemistry with allotype-specific antibodies.
T37105 318679-318874 Sentence denotes Tg mice developed crossreactive Ab specificities for GlcNAc, lysoganglioside and tubulin in serum and chimeric chorea Ab expressed in Tg mice penetrated and bound to antigen in the brain in vivo.
T42091 318875-318970 Sentence denotes Deposition of IgG1a was observed in the brain of double Tg but not single VH Tg or non-Tg mice.
T2564 318971-319113 Sentence denotes Anti-brain autoantibodies against lysoganglioside and tubulin may contribute to CNS disturbances in Sydenham chorea and other brain disorders.
T25660 319114-319410 Sentence denotes To clarify a pathological implication of AQP1 in Alzheimer disease (AD), we investigated the possible relationship between amyloid-beta (Abeta) deposition and astrocytic AQP1 expression in the motor cortex and the hippocampus of 11 AD patients and 16 age-matched other neurological disease cases.
T83403 319411-319511 Sentence denotes In all cases, AQP1 was expressed exclusively in a subpopulation of multipolar fibrillary astrocytes.
T48504 319512-319728 Sentence denotes The great majority of AQP1-expressing astrocytes were located on the top of Abeta plaques in AD brains but not in non-AD cases, whereas those independent of Abeta deposition were found predominantly in non-AD brains.
T35437 319729-319940 Sentence denotes By Western blot, cultured human astrocytes constitutively expressed AQP1, and the levels of AQP1 protein expression were not affected by exposure to Abeta1-42 peptide, but elevated by hypertonic sodium chloride.
T85211 319941-320131 Sentence denotes By immunoprecipitation, the C-terminal fragmentbeta (CTFbeta) of amyloid precursor protein (APP) interacted with the N-terminal half of AQP1 spanning the transmembrane helices H1, H2 and H3.
T93194 320132-320368 Sentence denotes A unique subset of AQP1-expressing astrocytes have a direct contact with Abeta in AD brains, suggesting the possibility that Abeta deposition causes abnormal brain water homeostasis by interfering with astrocytic water channel function.
T76168 320369-320433 Sentence denotes Alzheimer's disease (AD) is a major cause of dementia in humans.
T1382 320434-320624 Sentence denotes The main hallmarks of this disorder are the over production and aggregation of beta-amyloid (Abeta) peptides and the formation of neurofibrillary tangles of hyperphosphorylated tau proteins.
T27913 320625-320756 Sentence denotes The appearance of cognitive decline is linked to the overproduction of the short peptide Abeta in both soluble and aggregate forms.
T38534 320757-320915 Sentence denotes In the brain parenchyma, microglia are known to surround Abeta deposits and to internalize this peptide, and in some circumstances, target it for degradation.
T64351 320916-321013 Sentence denotes Thus, stimulating microgliosis should be beneficial in preventing the development of the disease.
T88733 321014-321251 Sentence denotes Here, we show that injecting macrophage colony-stimulating factor (M-CSF) to APPSwe/PS1 transgenic mice, a well documented model for AD, on a weekly basis prior to the appearance of learning and memory deficits, prevented cognitive loss.
T49084 321252-321376 Sentence denotes The M-CSF-injected group, tested in the T-water maze task, showed no difference when compared to the wild-type (WT) animals.
T37348 321377-321500 Sentence denotes However, the number of trials needed to achieve the task nearly doubled for the saline-injected APPSwe/PS1 transgenic mice.
T39333 321501-321680 Sentence denotes M-CSF also increased the number of microglia in the parenchyma (2.4 fold and 2.7 fold increase in cortex and hippocampus, respectively) and decreased the number of Abeta deposits.
T2405 321681-321821 Sentence denotes Senile plaques were smaller and less dense in the brain of M-CSF-treated mice compared to littermate controls treated with vehicle solution.
T34947 321822-322051 Sentence denotes Interestingly, a higher ratio of microglia internalized Abeta in the brain of M-CSF-treated animals and the phagocytosed peptides were located in the late endosomes and lysosomes as shown by colocalization with the LAMP-2 marker.
T32849 322052-322220 Sentence denotes Less Abeta40 and Abeta42 monomers were also detected in the extracellular protein enriched fractions of M-CSF-treated transgenic mice when compared to vehicle controls.
T48413 322221-322485 Sentence denotes Together these results provide compelling evidence that systemic M-CSF administration is a powerful treatment to stimulate microglia proliferation into the brain, degrade Abeta, and prevent the cognitive decline associated with Abeta burden in a mouse model of AD.
T83888 322487-322696 Sentence denotes Microglia are the immune cells of the brain, they are activated in the brain of Alzheimer's disease (AD) patients and mouse models of AD and they express the innate immune receptor toll-like receptor 2 (TLR2).
T1955 322697-322792 Sentence denotes The present study investigated role of this receptor in the progression of AD-like pathologies.
T50799 322793-322891 Sentence denotes Here we show that amyloid beta (Aβ) stimulates TLR2 expression in a small proportion of microglia.
T69669 322892-323081 Sentence denotes We then generated triple transgenic mice that are deficient in TLR2 from mice that harbor a mutant human presenelin 1 (PS1) and a chimeric mouse/human amyloid precursor protein (APP) genes.
T26452 323082-323253 Sentence denotes TLR2 deficiency accelerated spatial and contextual memory impairments, which correlated with increased levels of Aβ1-42 and transforming growth factor beta 1 in the brain.
T61685 323254-323350 Sentence denotes NMDA-R1 and NMDA-R2A expression levels were also lower in the dentate gyrus of APP-TLR2−/− mice.
T78902 323351-323489 Sentence denotes Gene therapy in cells of the bone marrow using lentivirus constructs expressing TLR2 rescued the cognitive impairment of APP-TLR2−/− mice.
T2623 323490-323632 Sentence denotes Indeed, lentiGFP/TLR2 treatment had beneficial effects by restoring the memory consolidation process disrupted by TLR2-deficiency in APP mice.
T66697 323633-323759 Sentence denotes These data suggest that TLR2 acts as an endogenous receptor for the clearance of toxic Aβ by bone marrow-derived immune cells.
T36242 323760-323838 Sentence denotes The cognitive decline is markedly accelerated in a context of TLR2 deficiency.
T93499 323839-323960 Sentence denotes Up-regulating this innate immune receptor may then be considered as a potential new powerful therapeutic approach for AD.
T25884 323961-324034 Sentence denotes Ron-Harel Noga⁎ 1 , Segev Yifat 1 , Cardon Michal 1 , Schwartz Michal 1 1
T39970 324035-324174 Sentence denotes The hippocampus is one of the brain regions that are prominently affected by functional decline, even in what is considered "normal aging".
T64474 324175-324268 Sentence denotes Age-related decrease is found in hippocampus-dependent spatial and episodic memory abilities.
T65829 324269-324526 Sentence denotes Our previous studies have shown that immune cells are involved in maintaining various aspects of hippocampal plasticity at adulthood: neurogenesis, BDNF production and performance in the learning/memory task in the MWM are impaired in immune-deficient mice.
T90556 324527-324731 Sentence denotes In the current study we were able to dissect out spatial learning ability from long-term memory performance and show that peripheral immune cells specifically support hippocampus-dependent spatial memory.
T59911 324732-324921 Sentence denotes Moreover, a sudden imposition of immune compromise in young healthy mice caused spatial memory impairment, whereas immune reconstitution reversed memory impairment in immune deficient mice.
T22041 324922-325286 Sentence denotes Hippocampal mRNA analysis suggested that immune-dependent spatial memory maintenance was, at least partially, mediated by regulation of presynaptic proteins involved in fast neurotransmitter release: reduced expression levels of genes encoding presynaptic proteins were found in immune-deficient mice, and returned to normal levels following immune reconstitution.
T21917 325287-325446 Sentence denotes Finally, the relevancy of our findings to aging was demonstrated: increasing peripheral immune activity in aged mice improved their spatial memory performance.
T41365 325447-325611 Sentence denotes Our results suggest that age-related memory loss may be reversible, at least to some extent, by a remote controlvia the rejuvenation of the senescent immune system.
T26296 325612-325798 Sentence denotes Cognitive impairments, including spatial working memory deficits, occur even in the early stage of Parkinson's disease (PD) when the motor symptoms are barely observed (pre-motor phase).
T31105 325799-325941 Sentence denotes Most of cognitive deficits concern however developed PD when motor functions are disturbed and the central dopamine content deeply diminished.
T1307 325942-326036 Sentence denotes It is then possible that dopamine level depletion may influence also cognitive function in PD.
T22411 326037-326208 Sentence denotes In the present study 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration and influence of content dopamine depletion on memory impairment have been studied.
T3969 326209-326301 Sentence denotes One year old C57/BL male mice, received MPTP 40 mg/kg, and control group received 0.9% NaCl.
T997 326302-326396 Sentence denotes To evaluate learning and memory abilities, the Morris water maze behavioral test was provided.
T48960 326397-326675 Sentence denotes We didn't notice statistical significant differences in the latency to reach the hidden platform, swim distance to reach the hidden platform, swim speed, percentage time spent in the correct quadrant, annulus crossing during the probe trial between MPTP and the control animals.
T23226 326676-326836 Sentence denotes The results of swimming speed, latency and swim distance during visible platform test were similar for all groups and did not differ significantly between them.
T63430 326837-326918 Sentence denotes MPTP intoxication does not alter the locomotors activity during the memory tests.
T2854 326919-327136 Sentence denotes After completion of the behavioral experiments the brain concentration of monoamine: dopamine (DA), noradrenaline (NA), 5-hydroxytryptamine (5-HT) were estimated by using high-performance liquid chromatography (HPLC).
T43172 327137-327292 Sentence denotes Correlation between the results of the behavioral testing in the probe trial in the water maze and the level of monoamines in the striatum were calculated.
T34181 327293-327393 Sentence denotes The accuracy of spatial memory was not reliably correlated with any monoamine level in the striatum.
T84495 327394-327471 Sentence denotes Dopamine content in the striatum decrease to 27% of the control (p b 0.0000).
T14632 327472-327577 Sentence denotes Our results suggest that place navigation learning does not critically depend on the dopaminergic system.
T39680 327578-327721 Sentence denotes Probably other distant brain structures degeneration besides nigrostriatal pathway might to be involved in spatial learning and memory process.
T94735 327722-327964 Sentence denotes More investigation and long-term observation are necessary to check if neurodegenerative changes in distant structures of the brain induced by nigrostriatal degeneration might cause memory deficits in animals with injured dopaminergic system.
T2385 327965-328200 Sentence denotes AAV2-SYN or AAV2-GFP was injected into the SN of male C57BL/6 mice and 2, 4 and 12 weeks post-treatment, microglial activation was examined using immunohistochemical staining for CD68 and quantitative PCR for proinflammatory cytokines.
T50690 328201-328451 Sentence denotes In addition, the participation of components of the adaptive immune response, including Blymphocytes, T-lymphocytes and mouse immunoglobulin (IgG) was studied immunohistochemically using the markers CD45R, CD3 and a goat anti-mouse IgG, respectively.
T96072 328452-328607 Sentence denotes The difference in B and Tlymphocyte infiltration into the SN between the two groups was quantified by counting the cells present using unbiased stereology.
T61864 328608-328736 Sentence denotes The difference in IgG and CD68 immunoreactivity between the groups was evaluated by an observer blinded to the treatment groups.
T51615 328737-328871 Sentence denotes Enhanced immunoreactivity for mouse IgG was detected early in the AAV2-SYN animals, at 2 weeks, and persisted at 4 weeks and 12 weeks.
T6341 328872-328943 Sentence denotes This IgG staining was associated with microglia, neurons, and neuropil.
T52253 328944-329081 Sentence denotes At 4 weeks, increased CD68 stained microglia were present in the AAV2-SYN animals, and there was a marked increase in both B and T cells.
T79574 329082-329159 Sentence denotes At 12 weeks, CD68 staining declined, but B and T cell infiltration persisted.
T8514 329160-329278 Sentence denotes Pro-inflammatory cytokine levels were elevated at both 2 and 4 weeks in AAV2-SYN group compared to the AAV2-GFP group.
T29163 329279-329413 Sentence denotes These observations suggest that over-abundance of human aSYN can result in both an adaptive immune response and microglial activation.
T60765 329414-329554 Sentence denotes The temporal course, with early appearance of IgG staining, suggests that the humoral immune and microglial responses may be closely linked.
T63890 329555-329624 Sentence denotes This inflammatory process may contribute to dopamine neuronal injury.
T23666 329625-329716 Sentence denotes Modulation of this response may be a useful target for slowing the progression of human PD.
T1893 329718-329821 Sentence denotes Vascular endothelial growth factor (VEGF) is well known as one of the major regulators of angiogenesis.
T94888 329822-329926 Sentence denotes Recently, there have been reports implicating VEGF as an important trophic factor in the nervous system.
T721 329927-330034 Sentence denotes For example low levels of VEGF in mice result in an adultonset amyotrophic lateral sclerosis like syndrome.
T31764 330035-330211 Sentence denotes We wanted to examine the role of VEGF in the context of cerebellar degeneration-in particular, the autosomal dominant degenerative disease spinocerebellar ataxia type 1 (SCA1).
T52640 330212-330383 Sentence denotes SCA1 belongs to the family of polyglutamine neurodegenerative disorders that are caused by the increased number of CAG repeats in the coding region of respective proteins.
T97070 330384-330522 Sentence denotes Ataxin-1, the protein mutated in SCA1, is ubiquitously expressed and recent data suggest that it plays role in transcriptional regulation.
T29136 330523-330683 Sentence denotes In a well-studied mouse model of this disease (SCA1 knock-in mouse), we have discovered that VEGF protein levels are perturbed relatively early in pathogenesis.
T28091 330684-330914 Sentence denotes To begin to understand the mechanism by which this reduction occurs, we performed Laser Capture Microdissection of Purkinje cells, the cell type predominantly affected in SCA1, followed by RNA purification and quantitative RT-PCR.
T36957 330915-331014 Sentence denotes We have found a significant reduction in VEGF mRNA levels in Purkinje cells derived from SCA1 mice.
T90845 331015-331146 Sentence denotes Employing VEGF promoter luciferase reporter, we were able to show that mutant ataxin-1 inhibits transcription at the VEGF promoter.
T85385 331147-331346 Sentence denotes Furthermore, we could also demonstrate by chromatin immunoprecipitation that ataxin-1 occupies the VEGF promoter, suggesting that ataxin-1 induces repression via a direct effect on the VEGF promoter.
T37067 331347-331568 Sentence denotes These studies raise the exciting possibility that decreased VEGF levels could starve Purkinje neurons of key trophic factor or angiogenic support; conversely increasing VEGF might be able to ameliorate the SCA1 phenotype.
T75617 331569-331727 Sentence denotes To test these ideas, we have taken a genetic approach where we have mated mice that transgenically overexpress VEGF (in neurons) with the SCA1 knock-in model.
T88624 331728-331809 Sentence denotes We have found that overexpressing VEGF indeed improves the SCA1 ataxic phenotype.
T3375 331810-331997 Sentence denotes Our findings implicate ataxin-1 as a novel regulator of VEGF transcription and suggest a therapeutic role for VEGF in SCA1, expanding its role as an important player in neurodegeneration.
T44125 331998-332077 Sentence denotes Synaptic injury is associated with the memory loss of Alzheimer's disease (AD).
T37881 332078-332171 Sentence denotes Shank proteins are abundant in the postsynaptic density (PSD) of central excitatory synapses.
T20651 332172-332353 Sentence denotes Increasing evidence suggests that Shank promotes the maturation and enlargement of dendritic spines, suggesting an important role for Shank proteins in normal cognitive development.
T67554 332354-332494 Sentence denotes GEPT combination of herbal extracts, also called GETO, consists of four active components: panaxoside, flavonoids, tenuifolin and curcumine.
T32462 332495-332603 Sentence denotes Previous studies show that GEPT extracts work to improve memory decline and to postpone MCI in old patients.
T38580 332604-332785 Sentence denotes This study was to investigate the effect of GEPT extracts on shank1 expression in CA1 subfield within the hippocampus of the APPV717I transgenic mice in the early stage of dementia.
T61353 332786-333068 Sentence denotes APPV717I transgenic mice were randomly divided into GEPT group by intragastric administration of 0.3 g/kg/d, and a donepezil group by intragastric administration of 0.92 mg/kg/d, a APPV717I transgenic model group and a normal group by intragastric administration of distilled water.
T11577 333069-333164 Sentence denotes A four-month treatment regimen with GEPT extracts was administered to APPV717I transgenic mice.
T1053 333165-333222 Sentence denotes Spatial memory ability was measured in Morris water maze.
T8347 333223-333400 Sentence denotes The total area covered by shank1 and integral optical density in CA1 subfield within the hippocampus was determined using immunohistochemical stains and Image-Pro plus analysis.
T54160 333401-333679 Sentence denotes After GEPT treatment regimen, the mean escape latency period was significantly shortened (35.3 ± 15.3 vs 59.9 ± 15.5, P b 0.05), and the target quadrant search time was significantly increased (44.5 ± 9.9 vs 29.1 ± 10.4, P b 0.05) compared to the APPV717I transgenic model mice.
T14110 333680-333888 Sentence denotes There was a significant higher level in the expression of shank1 detected in the hippocampal CA1 area of APPV717I transgenic mice treated with GEPT than the levels in the APPV717I transgenic model mice alone.
T59235 333889-334224 Sentence denotes The total area of positive cells covered by shank1 and their integral optical density in the hippocampal CA1 area of the APPV717I transgenic mice treated with GEPT were significantly increased more than those of the APPV717I transgenic model mice (11744.4 ± 2246.5 vs 8119.4 ± 1770.8, P b 0.05; 245.9 ± 55.0 vs 134.0 ± 44.7, P b 0.05).
T80265 334225-334433 Sentence denotes GEPT extracts can obviously improve the spatial memory ability of APPV717I transgenic mice in the early stage of dementia, and its probable mechanism may be associated with enhancing the expression of Shank1.
T37972 334434-334576 Sentence denotes Multiple sclerosis (MS) is a common inflammatory demyelinating disorder of central nervous system with lesions disseminated in time and space.
T55943 334577-334656 Sentence denotes The diagnosis of MS is supported by evidence of intrathecal antibody synthesis.
T96479 334657-334744 Sentence denotes However, other autoimmune neurological disorders may show a similar laboratory pattern.
T45931 334745-334829 Sentence denotes We present a case with paraneoplastic disorder with immune profile distinct from MS.
T99694 334830-334941 Sentence denotes We report a 58-year old right handed woman with an episode of post-traumatic acute loss of left central vision.
T68366 334942-335089 Sentence denotes Magnetic resonance imaging (MRI) of the brain showed several small non-enhancing T2 hyperintensity in subcortical and periventricular white matter.
T93940 335090-335141 Sentence denotes Five years later, she developed vertigo and ataxia.
T83308 335142-335167 Sentence denotes Repeat MRI was unchanged.
T54996 335168-335298 Sentence denotes Cerebrospinal fluid analysis showed numerous oligoclonal bands, elevated IgG index and synthesis rate and lymphocytic pleocytosis.
T44748 335299-335457 Sentence denotes Based on the clinical presentation and CSF findings, a diagnosis of MS was made and treatment was commenced with interferon β1-a and later glatiramer acetate.
T56608 335458-335522 Sentence denotes She continued to worsen and developed spastic-ataxic dysarthria.
T70159 335523-335575 Sentence denotes Axial and appendicular ataxia rendered her bedbound.
T40090 335576-335755 Sentence denotes Further workup included a comprehensive paraneoplastic antibody evaluation which was negative except for a low positive P/Q-type calcium channel antibody (80 pmol/L, normal b 20).
T5140 335756-335852 Sentence denotes Additional CSF studies again showed oligoclonal bands and evidence of intrathecal IgG synthesis.
T28612 335853-335992 Sentence denotes By flow cytometry, the CSF lymphocytes were predominantly B cells (52% CD19+) and the T cells were predominantly CD8+ (CD4/CD8 ratio, 0.4).
T38403 335993-336122 Sentence denotes Biopsy of an enlarged inguinal lymph node showed high grade neuroendocrine carcinoma consistent with a primary small cell cancer.
T78048 336123-336195 Sentence denotes MS is a complex disorder in which helper T-cells play an important role.
T96820 336196-336304 Sentence denotes At least some forms of central paraneoplastic disorders are mediated by the action of cytotoxic CD8 T cells.
T91219 336305-336387 Sentence denotes Both disorders are associated with the inappropriate production of autoantibodies.
T87665 336388-336440 Sentence denotes In MS, the majority of cells in the CSF are T cells.
T82159 336441-336617 Sentence denotes The predominance of B cells and CD8 cells in the CSF seen in this patient may be a unique and diagnostically-useful characteristic of the paraneoplastic neurological syndromes.
T50726 336618-336804 Sentence denotes Paraneoplastic anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe, but treatment responsive encephalitis that predominantly affects young women with an ovarian teratoma.
T53146 336805-337025 Sentence denotes Patients usually develop prodromal fever or headache followed by prominent psychiatric symptoms, short-term memory loss, seizures, progressive catatonia-like stage, dyskinesias, autonomic instability and hypoventilation.
T20345 337026-337219 Sentence denotes We report the immunopathological analysis of the brain and ovarian teratoma specimens of two patients who died of anti-NMDARassociated encephalitis and of the tumor of 9 patients who recovered.
T81285 337220-337379 Sentence denotes Prominent microgliosis and deposits of IgG with rare T and B lymphocyte infiltrates were observed in the hippocampus, forebrain, basal ganglia and spinal cord.
T66512 337380-337501 Sentence denotes Detection of cells expressing markers of cytotoxicity (TIA, granzyme B, perforin, Fas/Fas ligand) was extremely uncommon.
T83369 337502-337611 Sentence denotes Moderate amounts of plasma cells (CD79) detected on brain sections suggested intrathecal antibody production.
T72577 337612-337651 Sentence denotes No complement deposits were identified.
T64673 337652-337799 Sentence denotes All tumor samples showed NMDARexpressing neurons and extensive infiltrates of T lymphocytes, macrophages/monocytes, B lymphocytes and plasma cells.
T99393 337800-337996 Sentence denotes The ovarian teratoma samples from patients without NMDAR associated encephalitis showed similar infiltrates of T cells and macrophages/ monocytes, but few or absent B lymphocytes and plasma cells.
T43223 337997-338080 Sentence denotes In all patients the predominant anti-NMDAR IgG subclasses were IgG1, IgG3 and IgG4.
T7977 338081-338217 Sentence denotes The antibody immune-response is more relevant than cytotoxic Tcell mechanisms in the pathogenesis of anti-NMDAR-associated encephalitis.
T12263 338218-338305 Sentence denotes 11 -Uptake and cytotoxic specificity of anti-Yo antibody for cerebellar Purkinje cells:
T37701 338306-338503 Sentence denotes Purkinje cells in organotypic culture are killed by anti-Yo IgG but not by IgG from neurologically normal ovarian cancer having other anticerebellar antibodies Greenlee John E.⁎ 3 , Hill Kenneth E.
T24541 338504-338737 Sentence denotes 2 Purkinje cell destruction in paraneoplastic cerebellar degeneration (PCD) in patients gynecological cancer is accompanied by high serum and CSF titers of "anti-Yo", an antibody which reacts with internal antigens of Purkinje cells.
T85036 338738-338811 Sentence denotes The role of anti-Yo antibody in causing Purkinje cell death is not known.
T17021 338812-338989 Sentence denotes We have recently found that Purkinje cells in organotypic culture can incorporate IgG and that uptake of anti-Yo IgG, but not IgG from normal individuals, results in cell death.
T52521 338990-339151 Sentence denotes We and others have also found that occasional neurologically normal ovarian cancer patients exhibit anticerebellar antibodies which do not recognize Yo antigens.
T5356 339152-339407 Sentence denotes An important question in PCD is thus whether the cytotoxic effect for Purkinje cells by anti-Yo antibody is specific or whether it is shared with other anticerebellar antibodies, such as those from ovarian cancer patients who remain neurologically normal.
T47114 339408-339684 Sentence denotes We studied sera from three neurologically normal patients with ovarian cancer (2 adenocarcinoma and one sarcoma) who had high titers of anticerebellar antibodies reactive with Purkinje cells but who remained neurologically normal over many months until cancerassociated death.
T15876 339685-339746 Sentence denotes None of their sera reacted with Yo antigens in Western blots.
T76583 339747-339898 Sentence denotes Rat cerebellar organotypic cultures were incubated with sera from these 3 patients or with sera from PCD patients exhibiting anti-Yo antibody response.
T74 339899-339982 Sentence denotes Concentrations of antibody were adjusted to approximate those found in patient CSF.
T50986 339983-340139 Sentence denotes Cultures were harvested at intervals through 144 hours and stained for antibody uptake using Cy-5 conjugated anti-human IgG followed by confocal microscopy.
T37677 340140-340214 Sentence denotes Purkinje cell death was determined using the dead cell stain, SYTOX green.
T90561 340215-340303 Sentence denotes Cultures incubated with anti-Yo antibody showed widespread IgG uptake by Purkinje cells.
T76669 340304-340390 Sentence denotes Death of Purkinje cells containing IgG began by 72 h and was extensive after 96-120 h.
T11781 340391-340558 Sentence denotes Although Purkinje cell uptake of IgG was also seen in cultures incubated with sera from our three neurologically normal patients, Purkinje cell death was not observed.
T65059 340559-340750 Sentence denotes The cytotoxic effect of anti-Yo antibody on cerebellar Purkinje cells is specific and is not shared by anticerebellar antibodies from ovarian cancer patients who remain neurologically normal.
T12963 340751-340799 Sentence denotes to further characterize the pathogenesis of PNS.
T61528 340800-340870 Sentence denotes Here we report a new antibody that is co-expressed with Yo antibodies.
T18094 340871-341048 Sentence denotes Serum samples from three different patients with known paraneoplastic cerebellar degeneration and Yo antibodies were pooled and used for screening a rat cerebellum cDNA library.
T11136 341049-341178 Sentence denotes One of the antibodies found reacted with an uncharacterised protein known as coiled-coil domain-containing protein 104 (ccdc104).
T60321 341179-341246 Sentence denotes This protein has also been found in other species and is conserved.
T87154 341247-341412 Sentence denotes Immunoblotting with protein extracts showed that the ccdc104 protein is widely expressed in the central nervous system, except in the frontal cortex and spinal cord.
T8624 341413-341494 Sentence denotes The protein is also present in other organs, especially in the spleen and testes.
T36871 341495-341747 Sentence denotes Sera from 103 patients with various cancers and onconeural antibodies against Hu, Yo, Ri, CRMP5, amphiphysin or Ma2, as well as sera from 100 healthy blood donors without onconeural antibodies were screened by a sensitive immunoprecipitation technique.
T95498 341748-341943 Sentence denotes Four patients with Yo antibodies (2 with ovarian cancer, one with lymphoma and one with prostate cancer) also had ccdc104 antibodies, whereas these antibodies were not detected in the other sera.
T31155 341944-342030 Sentence denotes Anti-ccdc104 is a potentially new onconeural antibody that is associated with anti-Yo.
T29536 342031-342074 Sentence denotes The function of ccdc104 is largely unknown.
T50975 342076-342161 Sentence denotes Myasthenia gravis (MG) is the prototypical autoimmune disorder of the nervous system.
T14969 342162-342231 Sentence denotes Some patients have paraneoplastic MG associated with thymic neoplasm.
T83274 342232-342348 Sentence denotes Thymoma and MG may be associated with other autoimmune neurological disorders including paraneoplastic encephalitis.
T32510 342349-342579 Sentence denotes This report describes a second case of multifocal cortical encephalitis associated with thymoma and establishes an association of this thymoma-related paraneoplastic syndrome with voltage-gated potassium channel (VGKC) antibodies.
T7396 342580-342739 Sentence denotes A 43-year old right handed woman had a history of seropositive MG and invasive thymoma which was treated successfully with surgery, radiation and chemotherapy.
T91460 342740-342795 Sentence denotes MG was in pharmacological remission with mycophenolate.
T58737 342796-342912 Sentence denotes Four years after thymectomy, she presented with acute onset of confusion and seizure progressing to complete mutism.
T21028 342913-342971 Sentence denotes On examination, she was awake, alert but globally aphasic.
T77136 342972-343033 Sentence denotes She was able to imitate and had normal strength and reflexes.
T38524 343034-343228 Sentence denotes Magnetic resonance imaging of the brain showed innumerable nonenhancing cortically-based signal abnormalities as well as extensive left mesial temporal lobe abnormality with minimal enhancement.
T66750 343229-343321 Sentence denotes Cerebrospinal fluid analysis showed lymphocytic pleocytosis (70 cells) and elevated protein.
T36475 343322-343409 Sentence denotes Electroencephalogram showed left temporal periodic lateralized epileptiform discharges.
T67393 343410-343543 Sentence denotes On chest computed tomography, there was abnormal pleural thickening of the left lung which proved to be recurrent metastatic thymoma.
T78328 343544-343648 Sentence denotes Serological evaluation was positive for AChR, striational and voltagegated potassium channel antibodies.
T68538 343649-343773 Sentence denotes She had a partial improvement response to immunotherapy and one cycle of chemotherapy, but ultimately died two months later.
T48022 343774-343868 Sentence denotes Most examples of paraneoplastic encephalitis involve the limbic system and related structures.
T40283 343869-343974 Sentence denotes This is the second case with a unique pattern of multifocal cortical involvement associated with thymoma.
T71794 343975-344095 Sentence denotes Potassium channel antibodies were found in this case while CRMP-5 antibodies were found in the previously reported case.
T42362 344096-344250 Sentence denotes Paraneoplastic encephalitis associated with thymoma should be considered in the differential diagnosis of MG patients who develops new cognitive symptoms.
T43838 344251-344506 Sentence denotes 14 -Induction of TLR expression in the peripheral nerve upon the neurodegeneration Van Avondt K., Goethals S., Jacobs A., Timmerman V., Janssens S.⁎ Peripheral Neuropathy Group, Molecular Genetics Department, VIB, University of Antwerp, Antwerpen, Belgium
T5791 344507-344681 Sentence denotes In recent years, the field of innate immunity changed dramatically due to the discovery of the families of so-called Toll-like receptors (TLRs) and Nod-like receptors (NLRs).
T83788 344682-344824 Sentence denotes Both induce different signaling cascades, culminating on activation of NF-κB, MAPKs, interferon responsive factor (IRF) or production of IL-1.
T57072 344825-345154 Sentence denotes Interestingly, while originally these receptors were thought to be involved exclusively in the detection of pathogens, more and more data accumulate that they are also important in the recognition of endogenous ligands, like hsp proteins or degraded extracellular matrix breakdown products, all indicative of some kind of stress.
T56758 345155-345282 Sentence denotes Therefore these receptors are now categorized as "danger" receptors and known to be pivotal to elicit a proper stress response.
T26782 345283-345393 Sentence denotes Also the peripheral nervous system contains a defense mechanism to alert the immune system in cases of danger.
T59781 345394-345452 Sentence denotes In this defense response, Schwann cells play a major role.
T89091 345453-345615 Sentence denotes Upon neurodegeneration, they adopt a macrophage like phenotype and start secreting factors that are important in the recruitment of other inflammatory cell types.
T73011 345616-345689 Sentence denotes How Schwann cells become activated by neurodegeneration is not clear yet.
T81007 345690-345849 Sentence denotes We would like to test the hypothesis that certain released components of dying axons can trigger Toll like receptors expressed on the surface of Schwann cells.
T8890 345850-346066 Sentence denotes Though recent data report the expression of various TLRs on glial cells in the central nervous system, the situation in the peripheral nervous system is less studied and remains limited to the study of selected TLRs.
T13435 346067-346157 Sentence denotes Therefore, we first analysed basal expression levels of all TLRs in primary Schwann cells.
T91527 346158-346281 Sentence denotes Schwann cells appear to express mainly TLR3, TLR4 and TLR5 while TLR6 and TLR9 are hardly detectable in unstimulated cells.
T51685 346282-346421 Sentence denotes Through the use of NF-κB signaling as readout, we could show that most TLRs are functional, with especially TLR2 showing a strong response.
T88933 346422-346559 Sentence denotes Next, we focused on a comprehensive qPCR analysis of innate immune receptor components in unstimulated versus activated peripheral nerve.
T93800 346560-346634 Sentence denotes We induced neurodegeneration through axotomy of the sciatic nerve in mice.
T98438 346635-346764 Sentence denotes Control and axotomised nerves were isolated at several time points upon injury and processed for RNA isolation and qPCR analysis.
T52179 346765-346903 Sentence denotes In the unstimulated nerve, TLR3, TLR4, TLR5 and TLR7 were mostly expressed, which is comparable to the situation in primary Schwann cells.
T18749 346904-347065 Sentence denotes We detected a major induction of TLR1, TLR2, TLR6 and TLR9 upon nerve injury, pointing to a possible role of these receptors in the context of neurodegeneration.
T77603 347066-347189 Sentence denotes While TLR1, TLR6 and TLR9 reached peak expression levels 32 h upon injury, TLR2 was already induced at earlier time points.
TextSentencer_T342 347190-347399 Sentence denotes In conclusion, our data show a major shift in TLR expression pattern upon neurodegeneration, most likely illustrating specialized functions of TLRs in basal versus activated conditions of the peripheral nerve.
TextSentencer_T343 347400-347623 Sentence denotes Through the use of wild type versus knockout mice, we would like to find out which receptor is of main importance in the triggering of the innate immune response in Schwann cells versus sciatic nerve upon neurodegeneration.
TextSentencer_T344 347624-347717 Sentence denotes Genetic factors are believed to be of importance for outcome of traumatic brain injury (TBI).
TextSentencer_T345 347718-347810 Sentence denotes However, so far mainly allelic variation in apolipoprotein E4 has been studied in human TBI.
TextSentencer_T346 347811-347970 Sentence denotes A strategy for the identification of genes regulating complex traits is to perform linkage analysis in large intercrosses of susceptible and resistant strains.
TextSentencer_T347 347971-348164 Sentence denotes Previously we have identified several gene regions that regulate different aspects of inflammation and neurodegeneration induced by spinal ventral root avulsion (VRA) in inbred DA and PVG rats.
TextSentencer_T348 348165-348321 Sentence denotes These quantitative traits (QTL) include Vra1, which regulate axotomyinduced nerve cell loss, and Vra4 that regulate expression of MHC class II on microglia.
TextSentencer_T349 348322-348452 Sentence denotes It is, however, not known if these QTLs regulate general aspects of neuroinflammation and cell death after traumatic CNS injuries.
T93233 348453-348620 Sentence denotes In order to study the role of genetic factors in experimental TBI, we examined parental DA and PVG strains, as well as Vra1 and Vra4 congenic strains on DA background.
T30692 348621-348821 Sentence denotes A standardized weight drop injury was used, inflicting a parietal cortical contusion by letting a weight fall onto a rod with a flat end diameter of 1.8 mm from a height of 6.0 cm on the exposed dura.
T1556 348822-348883 Sentence denotes The rod was allowed to compress the tissue a maximum of 3 mm.
T53377 348884-348942 Sentence denotes Some rats received only craniotomy and served as controls.
T21082 348943-349096 Sentence denotes The pericontusional area was dissected 6 days after TBI and real time PCR was used to evaluate differences in apoptotic and inflammatory mRNA expression.
T86780 349097-349341 Sentence denotes There was a significant upregulation of inflammatory molecules, such as complement factors C1q and C3, the class II invariant chain CD74, and apoptotic factors such as the transformation related protein trp53, after TBI as compared to controls.
T9104 349342-349415 Sentence denotes Levels of several of these transcripts were higher in DA compared to PVG.
T78797 349416-349596 Sentence denotes The increase in CD74 was attenuated in Vra4 congenic rats, consistent with a prominent regulatory effect of allelic differences in the Mhc2ta gene located in the congenic fragment.
T67610 349597-349718 Sentence denotes Vra1 congenics displayed a significant difference in trp53 levels, indicating differences in the regulation of apoptosis.
T54412 349719-349920 Sentence denotes These results provide further evidence for a genetic component in TBI and also support the notion that QTLs regulating VRA are also implicated in the regulation of inflammation and apoptosis after TBI.
T82636 349921-350014 Sentence denotes These strains now constitute an important tool for the study of genetic influences after TBI.
T41196 350015-350125 Sentence denotes 48 children with autistic regression fulfilling the diagnostic criteria according to the DSM-IV were included.
T48001 350126-350299 Sentence denotes A questionnaire for assessment of cognitive/behavioral regression, detailed neurological and psychiatric evaluations and Childhood Autism Rating Scale (CARS) were performed.
T99491 350300-350371 Sentence denotes In our study, DNA isolation was accomplished by using standard methods.
T35920 350372-350497 Sentence denotes IL-10, IL-6, TNF-alpha, TGF-beta1b, and IFNgamma were genotyped by using PCR with sequence-specific primers (PCR-SSP) method.
T67337 350498-350583 Sentence denotes The sera of 48 patients diagnosed as autism and 75 healthy individuals were included.
T48220 350584-350638 Sentence denotes The allele frequencies between groups were determined.
T61613 350639-350703 Sentence denotes HLA typing for A, B, DR alleles was performed by PCR-SSO method.
T67211 350704-350884 Sentence denotes When the patient group and control group were compared as regards the frequency of the HLA antigens, significant difference was found only in HLA A2 as higher in the patient group.
T3386 350885-351106 Sentence denotes Though not significant statistically, the ones with odds ratio over 2 included A11, B38, B39, B48, B52, B53, B55, B58, DRB1⁎14, DR14 was more frequent in the patients; A29, B27, B40, B41 was more frequent in the controls.
T21319 351107-351203 Sentence denotes The controls had A69; B37; B54; B57, DRB1⁎09; DR9 while they did not exist in the patient group.
T54291 351204-351263 Sentence denotes One of the patients had B58 while none of the controls had.
T63104 351264-351479 Sentence denotes In the TGF-beta gene region, TGF-beta1 (C/T codon 10, C/G codon 25) polymorphism was examined and the TT-GG genotype frequency was found high in controls while TC-GG genotype frequency was high in the patient group.
T94333 351480-351666 Sentence denotes This study showed various immunological abnormalities in autistic children, which might be markers of a special condition, that is, autistic regression seen in autism spectrum disorders.
T93511 351667-351772 Sentence denotes Chemokines and chemokine receptors (CCR) have been detected in normal human central nervous system (CNS).
T34857 351773-351973 Sentence denotes Recent evidence suggests that chemokines and CCR are involved in the pathogenesis of immune-mediated inflammation of chronic neurodegenerative disorders as Alzheimer's (AD) and Parkinson disease (PD).
T22657 351974-352187 Sentence denotes For instance, increased expressions of CCR5 and CCR2 have been reported in the CNS of patients with AD and PD, which has been associated with pathological changes that characterize both neurodegenerative diseases.
T17527 352188-352590 Sentence denotes In order to establish the importance of this polymorphism in neurodegenerative disorders, 100 Venezuelan patients diagnosed with sporadic AD according to NINCDS-ADRDA criteria (mean age 71-10 years), 50 patients with PD according to the PD Society Brain Bank criteria, and 100 healthy individuals (mean age 71-10 years) without any kind dementia based on the Mini-Mental State Examination were studied.
T878 352591-352648 Sentence denotes The CCR5 59029 A/G polymorphism was analyzed by PCR-RFLP.
T85563 352649-352705 Sentence denotes Genotype frequencies were determined by direct counting.
T10120 352706-352842 Sentence denotes Statistical significance of genotype frequency was estimated by Fisher's exact test and p values were corrected according to Bonferroni.
T39721 352843-352944 Sentence denotes Odds Ratio (OR) with 95% confidence intervals was calculated to measure the strength of associations.
T93926 352945-353059 Sentence denotes Statistically significant differences were found when the AD and PD patients were compared with the control group.
T70513 353060-353196 Sentence denotes The frequency of the A/A genotype was observed decreased in both group of patients compared with healthy individuals (OR b 1; p b 0.05).
T2597 353197-353356 Sentence denotes In contrast, the frequency of the A/G genotype was observed increased in both neurodegenerative disorders compared with healthy individuals (OR N 1; p b 0.05).
T49526 353357-353488 Sentence denotes The results suggest a possible involvement of CCR5 gene in the development of late-onset Alzheimer's disease and Parkinson disease.
T72080 353489-353615 Sentence denotes In 2007, various reports identified and confirmed for the first time non-HLA susceptibility genes for multiple sclerosis (MS).
T73349 353616-353761 Sentence denotes SNPs in the IL2RA and IL7RA receptor genes were found to constitute heritable risk factors for multiple sclerosis with odds ratios of around 1.2.
T67371 353762-353993 Sentence denotes Though numerous earlier studies have reported associations or lack thereof between cytokine (receptor) genes and multiple sclerosis, a systematic screen covering genetic diversity at multiple cytokine loci has never been performed.
T72571 353994-354421 Sentence denotes Using a haplotype-tagging approach based on selection of SNPs from the CEU-HapMap, we have analysed association between MS and around 380 SNPs in the major different functional classes of cytokines, their receptors and associated cytokine signal transduction factors (gamma-c-dependent cytokines; interleukin-17 group; gp130-dependent IL-6-like cytokines; IL-12-like cytokines; members of the IL-1 family; SOCS family members).
T75593 354422-354535 Sentence denotes In total, 49 genes or chromosomal gene clusters were included for 60 discrete cytokine or cytokine-related genes.
T22908 354536-354617 Sentence denotes The majority of included genes have never been analysed before in relation to MS.
T93731 354618-354719 Sentence denotes Wherever possible, haptag-SNPs were selected to coincide or be complemented with non-synonymous SNPs.
T74273 354720-354821 Sentence denotes In addition, our screen included 8 glutamate receptor genes from the GRIA, GRIK and EAAT subfamilies.
T25287 354822-354954 Sentence denotes The latter selection was motivated by a growing body of evidence for a significant role of glutamate signalling in glial cell death.
T34607 354955-355110 Sentence denotes Genotyping was performed using Golden Gate technology (Illumina) in around 1000 MS patients and controls using a 2-stage design (Basurto Hospital, Bilbao).
T70786 355111-355226 Sentence denotes Exhaustive single-and multiplemarker data analysis was performed with HaploView, PLINK, HelixTree and MDR software.
T22493 355227-355505 Sentence denotes Following the first stage, we have identified 2 associated SNPs, one in suppressor of cytokine signaling-1 (SOCS1) and one in oncostatin M receptor (OSMR) with significant values withstanding permutation correction, and found modest evidence for cytokine gene interaction in MS.
T74322 355506-355626 Sentence denotes A suggestive trend for association with non-synonymous polymorphisms in glutamate receptor GRIA1 and GRIA2 was observed.
T97668 355627-355676 Sentence denotes The second stage of the study is being completed.
T40426 355677-355768 Sentence denotes We will present the results from the combined two stages on the occasion of the conference.
T52904 355769-355983 Sentence denotes While our data contribute to furthering our understanding of cytokine genetics in MS, it is clear that confirmatory studies in additional cohorts will be needed to substantiate any findings arising from our screen.
T70531 355984-356057 Sentence denotes Neurodegeneration is an important feature of many neurological disorders.
T11208 356058-356150 Sentence denotes So far the degree of genetic regulation on axotomy-induced nerve cell loss has been unknown.
T28127 356151-356327 Sentence denotes In previous studies we have described substantial differences in the degree of loss of motoneurons after spinal ventral root avulsion (VRA) across different inbred rat strains.
T14182 356328-356431 Sentence denotes We now use an unbiased experimental approach using genetic dissection to elucidate relevant mechanisms.
T25779 356432-356617 Sentence denotes In a first step a whole genome scan in a F2 DA x PVG intercross showed evidence of linkage of nerve cell loss VRA to quantitative trait loci (QTLs) on chromosomes 8 (Vra1) and 5 (Vra2).
T22272 356618-356722 Sentence denotes An advanced intercross line (AIL) was created by reciprocal breeding of DA and PVG-RT1av1 (PVGav1) rats.
T80495 356723-356837 Sentence denotes Subsequent crossings of offspring from 50 breeding pairs were carried out for eight (G8) or ten (G10) generations.
T3826 356838-356973 Sentence denotes We here studied 126 and 186 male rats subjected to VRA with 14 days post-operative survival in the G8 and G10 population, respectively.
T29816 356974-357107 Sentence denotes Linkages to both Vra1 and Vra2 are reproduced and reduce the confidence intervals of linkage peaks to 13.1 and 29.3 Mb, respectively.
T45156 357108-357210 Sentence denotes A pure additive effect of the two loci is seen, and both significantly contribute to the additive LOD.
T46770 357211-357439 Sentence denotes Individual rats in the AIL homozygote for DA or PVG alleles at both Vra1 and Vra2 display neuronal survival similar to the corresponding parental strain, suggesting that strain differences are mainly regulated by these two QTLs.
T1477 357440-357603 Sentence denotes Overlapping congenic strains with PVGav1 alleles on DA background demonstrate that a 9 Mb Vra1 fragment significantly attenuated the loss of motoneurons after VRA.
T77941 357604-357799 Sentence denotes These congenic strains are now used to dissect mechanism and preliminary evidence suggest that increased microglia activation early after injury correlate with increased nerve cell loss later on.
T59324 357800-358055 Sentence denotes These results demonstrate that naturally occurring allelic variability affects susceptibility to axotomy-induced nerve cell death, where Vra1 and Vra2 represent the first QTLs to be characterized and fine mapped using AIL and overlapping congenic strains.
T28519 358056-358242 Sentence denotes Exact positioning of the gene(s) in the QTLs will be of importance to understand how genetic susceptibility to neurodegeneration is regulated in diseases such as progressive forms of MS.
T18065 358243-358449 Sentence denotes Many human autoimmune diseases, including multiple sclerosis (MS), are regulated by the MHC complex and the susceptibility to experimental autoimmune encephalomyelitis (EAE) maps to the MHC class II region.
T95722 358450-358594 Sentence denotes This supports the notion that qualitative differences in class II mediated antigen presentation to be of pivotal importance in these conditions.
T34258 358595-358783 Sentence denotes Previously we have described large differences in MHC II expression on microglia after a standardized mechanical nerve injury (ventral root avulsion; VRA) in a panel of inbred rat strains.
T98478 358784-358971 Sentence denotes Using a DAxPVG F2 intercross and an advanced intercross line (AIL) differences in MHC II expression was positioned to a genetic variation in Mhc2ta (encoding the class II transactivator).
T1840 358972-359228 Sentence denotes Recently we demonstrated that congenic strains carrying allelic variations of Mhc2ta display variable susceptibility to EAE, suggesting that quantitative aspects of MHC II expression may also be of importance for regulation of autoimmune neuroinflammation.
T28035 359229-359352 Sentence denotes The BN rat displays higher constitutive MHC II expression compared to DA and LEW.1N although BN has the same Mhc2ta allele.
T58348 359353-359535 Sentence denotes In this study we performed a genome-wide linkage analysis in a F2(LEW.1NxBN) intercross (n = 151) in order to map additional genetic influences on the expression of MHC II after VRA.
T4515 359536-359679 Sentence denotes The mRNA levels of CD74 (invariant chain), co-stimulatory molecule B7-2 and beta2microglobulin (b2m) were determined using quantitative RT-PCR.
T92063 359680-359725 Sentence denotes In addition, Ox6 immunostaining was recorded.
T58685 359726-359793 Sentence denotes Identified QTLs were subsequently studied in a DAxPVG.1AV1 G12 AIL.
T76667 359794-359906 Sentence denotes Several regions were found to regulate MHC II, with the two strongest QTLs being located on chromosomes 1 and 7.
T79545 359907-359951 Sentence denotes The chr 1 QTL was reproduced in the G12 AIL.
T63685 359952-360017 Sentence denotes In addition, there were evidence of epistatic and gender effects.
T90500 360018-360163 Sentence denotes Two regions were found to regulate several phenotypes; Ox6, C1q, Il-1beta and C3 receptor on chr 10, and B7-2, b2m, C3 and C3 receptor on chr 11.
T92536 360164-360289 Sentence denotes These results demonstrate a high degree of genetic heterogeneity in the expression of MHC II on microglia after nerve injury.
T57241 360290-360447 Sentence denotes Differences in MHC II across strains are regulated mainly by one dominant QTL containing Mhc2ta, but with additional effects from several other gene regions.
T27060 360448-360613 Sentence denotes Identification of the genes underlying these additional QTLs will be of importance for the understanding of the genetic background to autoimmune diseases such as MS.
T4975 360614-360747 Sentence denotes We present two separate studies focus on the role of IRF5 gene and chromosome 19q13 in the susceptibility to multiple sclerosis (MS).
T47005 360748-360865 Sentence denotes IRF5 is a transcription factor involved both in the type I interferon and the toll-like receptor signalling pathways.
T90343 360866-361003 Sentence denotes Previously, IRF5 has been found to be associated with systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel diseases.
T78027 361004-361143 Sentence denotes Here we investigated whether polymorphisms in the IRF5 gene would be associated with yet another disease with features of autoimmunity, MS.
T72223 361144-361266 Sentence denotes Previous studies have suggested a role of allelic variation on chromosome 19q13 in multiple sclerosis (MS) susceptibility.
T96196 361267-361329 Sentence denotes Three subregions of 19q13 were tested for association with MS.
T29665 361330-361636 Sentence denotes In the first study we genotyped nine single nucleotide polymorphisms (SNPs)and one insertion-deletion polymorphism in the IRF5 gene in a collection of 2337 patients with MS and 2813 controls from three populations: two case-control cohorts from Spain and Sweden, and a set of MS trio families from Finland.
T17224 361637-361864 Sentence denotes Two SNPs (rs4728142, rs3807306) and a 5 bp insertion-deletion polymorphism located in the promoter and first intron of the IRF5 gene, showed association signals with pvalues b 0.001 when the data from all cohorts were combined.
T57192 361865-361951 Sentence denotes The predisposing alleles were present on the same common haplotype in all populations.
T48748 361952-362234 Sentence denotes Using electrophoretic mobility shift assays we observed allele-specific differences in protein binding for the SNP rs4728142 and the 5 bp indel, and by a proximity ligation assay we demonstrated increased binding of the transcription factor SP1 to the risk allele of the 5 bp indel.
T69710 362235-362372 Sentence denotes In the second study we tested 14 markers, both SNPs and microsatellites across three subregions of 19q13 in 440 Finnish MS trio families.
T26173 362373-362464 Sentence denotes The marker D19S876 on 19q13.1 showed nominally significant association with MS (p = 0.007).
T67418 362465-362541 Sentence denotes Another association was found with an APOE haplotype (p = 0.007) on 19q13.2.
T8440 362542-362627 Sentence denotes Both associations were not replicated in another independent dataset of 317 families.
T23576 362628-362747 Sentence denotes Previous suggestions on ILT6 deficiency or association with D19S585 on 19q13.3-q13.4 were not replicated in this study.
T71284 362748-362858 Sentence denotes These findings add IRF5 to the short list of genes shown to be associated with MS in more than one population.
T48605 362859-363077 Sentence denotes Our study adds to the evidence that there might be genes or pathways that are common in multiple autoimmune diseases, and that the type I interferon system is likely to be involved in the development of these diseases.
T66503 363078-363243 Sentence denotes The formation of antibodies to Interferon beta (IFNβ), a proteinbased disease-modifying agent for multiple sclerosis (MS), is a crucial problem in clinical practice.
T51945 363244-363367 Sentence denotes These antibodies may neutralize the biological effects of the protein drug, potentially decreasing its therapeutic effects.
T18843 363368-363511 Sentence denotes The goal was to find HLA alleles which are associated with the development of antibodies against interferon-beta therapy in multiple sclerosis.
T49762 363512-363832 Sentence denotes HLA genotyping for HLA-A, -B, -C, DRB1 and DQB1 was performed by hybridization of sequence-specific oligonucleotide probes immobilized on microspheres with amplified genomic DNA samples followed by flow fluorescence intensity analysis according to the instructions of the manufacturer (One Lambda, Canoga Park, CA, USA).
T78712 363833-363973 Sentence denotes By high resolution HLA classes I and II typing we identified two HLA class II alleles associated with the development of antibodies to IFNβ.
T10938 363974-364086 Sentence denotes In two independent continuous and binary trait association studies, HLA-DRB1⁎0401 and HLA-DRB1⁎0408 (odds ratio:
T21737 364087-364210 Sentence denotes 5.15)but not other HLA alleleswere strongly associated with the development of binding and neutralizing antibodies to IFNβ.
T75867 364211-364409 Sentence denotes The associated HLA-DRB1⁎04 alleles differ from not associated HLA-DRB1⁎04 alleles by a glycine to valine substitution in position 115 of the epitope-binding alpha-helix of the HLA class II molecule.
T93860 364410-364612 Sentence denotes The peptide binding motif of HLA-DRB1⁎0401/⁎0408 might promote binding and presentation of an immunogenic peptide which may eventually break T cell tolerance and facilitate antibody development to IFNβ.
T35712 364613-364742 Sentence denotes This is the first study that identified genetic factors determining the immunogenicity of a protein-based diseasemodifying agent.
T87760 364743-364819 Sentence denotes Toll-like receptors (TLRs) play an essential role in host defense responses.
T51729 364820-364987 Sentence denotes Following recognition of pathogen-associated molecules and self molecules TLR generally trigger pro-inflammatory factors and enhance antigen-presenting cell functions.
T7434 364988-365117 Sentence denotes In our previous studies, we demonstrated the presence of various TLRs in and on human astrocytes, microglia and oligodendrocytes.
T81825 365118-365190 Sentence denotes Marked differences, however, separate TLRs on either type of glial cell.
T9546 365191-365319 Sentence denotes In microglia, a rather diverse set of TLRs are expressed and at least TLR3 and TLR4 can be found only inside endosomal vesicles.
T96961 365320-365438 Sentence denotes Astrocytes and oligodendrocytes on the other hand, express a more limited set of TLRs, and only on their cell surface.
T19181 365439-365523 Sentence denotes Upon activation of astrocytes a selective and strong induction of TLR3 was observed.
T99521 365524-365630 Sentence denotes Gene profiling and functional data indicated that TLR3 activation on astrocytes acts as a repair mediator.
T18175 365631-365976 Sentence denotes The aim of this study was to investigate the expression, regulation and the function of TLRs in adult human microglia and rat oligodendrocyte progenitor cells (OPCs) using real time PCR, antibody array and in the case of oligodendrocytes morphological evaluation, viability assays as well immunofluorescence staining for differentiation markers.
T90016 365977-366084 Sentence denotes Adult human microglia in culture express all TLRs with TLR1, 2, 3, 4 and 10 at relatively high mRNA levels.
T14219 366085-366184 Sentence denotes TLR expression is also controlled by TLR ligation itself and by treatment with different cytokines.
T7811 366185-366257 Sentence denotes Remarkably, TLR3 was the strongest induced TLR, especially by poly I: C.
T36408 366258-366454 Sentence denotes In addition, in vivo expression of TLRs was examined using mRNA extracted from both control and multiple sclerosis brains, revealing enhanced expression of TLR3 and in some cases of TLR1 and TLR2.
T71515 366455-366570 Sentence denotes OPCs on the other hand express a limited set of TLRs with high levels of TLR2 and to a lesser extent TLR3 and TLR4.
T61786 366571-366725 Sentence denotes Profiling of 42 cytokines/ chemokines responses indicated that TLR agonists elicit broad and similar cytokine/chemokine response in human adult microglia.
T57806 366726-366847 Sentence denotes In highly purified oligodendrocyte precursors, poly I:C was a potent inducer of oligodendrocytes death and demyelination.
T62496 366848-366923 Sentence denotes LPS and zymosan, in contrast, promoted survival and myelin sheet formation.
T87015 366924-367141 Sentence denotes Together, these data indicate that TLRs in the CNS play important roles in the regulation of innate immune responses and in oligodendrocyte development and that especially TLR3 acts as a dominant regulator in the CNS.
T67912 367142-367396 Sentence denotes Alzheimer's disease (AD) is a neurodegenerative disease, which is characterised by deposition of amyloid-beta (A-beta) containing plaques and also by neuroinflammatory changes, typified by an increase in pro-inflammatory cytokine expression in the brain.
T21784 367397-367628 Sentence denotes Activated microglia are considered to be the major source of proinflammatory cytokines in AD, and recent studies have highlighted the importance of adaptive immune responses, in particular T cells, in the pathology of this disease.
T32676 367629-367847 Sentence denotes Clinical trials involving active immunisation with A-beta in adjuvants resulted in development of meningoencephalitis in a subset of patients, which was associated with increased infiltration of T cells into the brain.
T66358 367848-367918 Sentence denotes Moreover, A-beta-specific T cells have been identified in AD patients.
T17911 367919-368012 Sentence denotes However the interaction of these A-beta-specific T cells with microglia is poorly understood.
T33062 368013-368166 Sentence denotes In this study, we have examined the role of Th1, Th2, IL-17producing T cells (Th17) and regulatory T cells (Treg) on A-betainduced microglial activation.
T55285 368167-368243 Sentence denotes We developed methods for generating A-beta-specific T cell subtypes ex vivo.
T71010 368244-368360 Sentence denotes We then assessed the effects of the different T cell subtypes and their secreted cytokines on microglial activation.
T29515 368361-368597 Sentence denotes Microglial activation was determined by measuring the production of the pro-inflammatory cytokines IL-1beta, IL-6, and TNFalpha by ELISA and by quantifying cell-surface expression of MHC class II, CD80, CD86, and CD40 by flow cytometry.
T72734 368598-368720 Sentence denotes The data show that Th1 and Th17 cells enhanced A-beta-induced production of IL-1beta, TNF-alpha and IL-6 from glial cells.
T34036 368721-368805 Sentence denotes They also increased surface expression of MHC class II, CD80, and CD86 on microglia.
T17177 368806-368979 Sentence denotes Th2 and Treg cells induced significantly smaller increases in TNF-alpha and IL-6 production and microglial expression of CD80 and CD86 when compared with Th1 and Th17 cells.
T41521 368980-369229 Sentence denotes Recombinant IFN-gamma and IL-17 stimulated activation of microglia in a manner similar to that of Th1 and Th17 cells respectively, albeit to a lesser extent, while IL-10 suppressed A-beta-induced production of IL-6 and TNF-alpha and CD86 expression.
T63623 369230-369463 Sentence denotes Our findings demonstrate that both Th1 and Th17 cells can promote microglial activation through production of IFN-gamma and IL-17 respectively and that these inflammatory responses can be suppressed by the regulatory cytokine, IL-10.
T35575 369464-369586 Sentence denotes Schwann cell disturbance followed by segmental demyelination in the peripheral nervous system occurs in diabetic patients.
T95389 369587-369722 Sentence denotes In the ethidium bromide (EB) demyelinating model, Schwann cells are known to invade and contribute to myelin repair in the spinal cord.
T74118 369723-369978 Sentence denotes As Schwann cell remyelination in the central nervous system is a well known event in this gliotoxic model, the aim of our investigation was to observe the behaviour of such cells after local EB injection in the spinal cord of streptozotocin diabetic rats.
T8407 369979-370248 Sentence denotes Forty-nine adult Wistar rats were used, from which 28 received a single intravenous injection of streptozotocin (50 mg/kg), being submitted 10 days after to a local injection of 1 μl of 0.1% EB (group I, n = 21) or 0.9% saline solution (II, n = 7) into the spinal cord.
T53306 370249-370434 Sentence denotes A laminectomy was performed on the first lumbar vertebra to allow 1 μl of 0.1% EB solution or 0.9% saline solution to be injected into the dorsal columns by means of a Hamilton syringe.
T50994 370435-370509 Sentence denotes One microlitre of EB was also injected in non-diabetic rats (III, n = 21).
T94929 370510-370752 Sentence denotes Rats from all groups were anaesthetized, perfused through the heart at 7, 9, 11, 15, 17, 21 and 31 days after EB or saline injection and spinal cord sections were collected and processed for light and transmission electron microscopy studies.
T40747 370753-370988 Sentence denotes Comparison between the final balance of myelin repair in groups I and III at 31 days was assessed using a semi-quantitative method for documenting the extent and nature of remyelination in semithin sections from the EB-induced lesions.
T51897 370989-371212 Sentence denotes Diabetic rats presented delayed macrophagic activity, with greater amounts of myelin-derived membranes in the center of the EBinduced lesions, and lesser remyelination at peripheral areas in comparison to non-diabetic rats.
T34426 371213-371428 Sentence denotes Although oligodendrocytes contributed to myelin reconstruction, invading Schwann cells were the major sources of remyelination and they firstly appeared at 9 days in nondiabetic rats and by 15 days in diabetic rats.
T26543 371429-371489 Sentence denotes Astrocyte behaviour did not seem to be affected by diabetes.
T17618 371490-371575 Sentence denotes Evidence of glial loss and primary demyelination was not noted in rats from group II.
T74483 371576-371851 Sentence denotes Results indicate that short-term streptozotocin-induced diabetes hindered both Schwann cell and oligodendrocyte remyelination (mean remyelination scores of 2.02 for Schwann cells and 0.71 for oligodendrocytes) in comparison to non-diabetic rats (3.89 and 1.57, respectively).
T16130 371852-371924 Sentence denotes Microglia are resident immune cells of the central nervous system (CNS).
T20793 371925-372002 Sentence denotes Microglia are usually isolated from primary cultures to study their function.
T80730 372003-372077 Sentence denotes This procedure is time consumable and inefficient due to low cell numbers.
T61622 372078-372247 Sentence denotes The microglia-derived oncogenically transformed cell line BV2 was successfully applied in certain experiments, but BV2 cells are limited in several microglial functions.
T16070 372248-372390 Sentence denotes Therefore, we established several microglial cell lines from mouse embryonic stem (mES) cells, which are suitable to study microglia function.
T6745 372391-372505 Sentence denotes Two mES cell lines (ES-C57BL/6 and MPI-II; derived from 129Sv mice) were differentiated into microglia cell lines.
T95290 372506-372602 Sentence denotes In total, 7 independent cell lines were generated which exhibited a stable microglial phenotype.
T60094 372603-372727 Sentence denotes ES cell derived microglia (ESdM) cell lines were characterized by flow cytometry, immunocytochemistry and functional assays.
T76745 372728-372825 Sentence denotes ESdM were immunoreactive for IBa1, CD11b, CD45, F4/80, CD49d, CD29, CXCR4, MHC class II and B7.2.
T54339 372826-373064 Sentence denotes Furthermore, stimulation with IFN gamma and LPS showed upregulation of proinflammatory cytokines (i.e. iNos, IL1beta and TNFalpha) and downregulation of anti-inflammatory cytokines (i.e. TGFbeta) at comparable levels to primary microglia.
T21779 373065-373154 Sentence denotes ESdM expressed CX3CR1 and showed a concentration dependent migration towards fractalkine.
T12253 373155-373292 Sentence denotes The capacity to migrate and phagocytose Abeta or microsphere beads of ESdM was comparable to primary microglia and superior to BV2 cells.
T72972 373293-373441 Sentence denotes For in vivo characterization, ESdM were lentivirally transduced with green fluorescent protein (GFP) and transplanted into the CNS of neonatal mice.
T87595 373442-373592 Sentence denotes Analysis of engrafted cells after 4 weeks showed a typical ramified microglial-like structure of ESdM and colocalization with the marker protein IBa1.
T76427 373593-373710 Sentence denotes Functionality of ESdM in vivo was shown after transplantation into the entorhinal cortex of aged transgenic APP mice.
T42468 373711-373851 Sentence denotes Sites of transplantation showed decreased plaque size and less amyloidbeta peptide load compared to the non-transplanted contralateral site.
T27109 373852-373994 Sentence denotes In summary, ESdM have many characteristics of primary microglia making them a suitable tool to study microglial function in vitro and in vivo.
T11857 373995-374104 Sentence denotes Insult to the central nervous system (CNS) leads to initiation of a glial response that is innate to the CNS.
T68795 374105-374241 Sentence denotes This glial response includes the induction of inflammatory cytokines and chemokines, which promote recruitment of leukocytes to the CNS.
T18443 374242-374531 Sentence denotes The transcription factors, signal transducer and activator of transcription (STAT), nuclear factor-KB (NF-KB) and interferon regulatory factors (IRF), are associated with cytokine responses, and signal for cellular growth, proliferation, differentiation, apoptosis and antiviral functions.
T48691 374532-374679 Sentence denotes We have studied the involvement of these transcription factors in glial responses in the hippocampus following transection of entorhinal afferents.
T58356 374680-374773 Sentence denotes Axonal lesioning induced upregulation of STAT1/2 and IRF7 gene expression in the hippocampus.
T54333 374774-374874 Sentence denotes STAT1/2 upregulation was localized precisely to zones of synaptic degeneration in the dentate gyrus.
T79554 374875-375038 Sentence denotes Whereas STAT1/nuclear STAT1 colocalized with both microglia and astrocytes, STAT2/phosphoSTAT2 staining was restricted to astrocytes within denervated hippocampus.
T91020 375039-375210 Sentence denotes Notably, the induction of IRF7 in lesion-reactive hippocampus was dependent on STAT1 and Type I interferon receptor, and astroglial STAT2 upregulation was NF-KB-dependent.
T90681 375211-375391 Sentence denotes In addition, lesion-induced CCL2 mRNA expression and leukocyte infiltration into the hippocampus were significantly reduced in mice with inactivated NF-KB signalling in astrocytes.
T88263 375392-375500 Sentence denotes Our findings indicate the involvement of transcription factors in lesion-induced glial responses in the CNS.
T54839 375501-375634 Sentence denotes Neuroinflammatory changes are now acknowledged to be a characteristic feature of neurodegenerative diseases like Alzheimer's disease.
T95801 375635-375910 Sentence denotes These changes are typified by activation of microglia and increased production of proinflammatory cytokines, like Interleukin-1beta (IL-1beta), which are released from activated microglia; in experimental models, these changes are coupled with deficits in cognitive function.
T47501 375911-376040 Sentence denotes It is now recognized that interaction of microglia with other cells contributes to maintenance of microglia in a quiescent state.
T31645 376041-376245 Sentence denotes We have shown that the interaction between the glycoprotein CD200 which is expressed on neurons, and its receptor, CD200R which is expressed on microglia, is important in modulating microglial activation.
T52834 376246-376450 Sentence denotes The evidence indicates that the anti-inflammatory cytokine, IL-4 increases neuronal expression of CD200 but CD200 expression is decreased in neurons prepared from IL-4 knockout mice (Lyons et al., 2007) .
T92953 376451-376799 Sentence denotes Here we report that, while addition of neurons prepared from wild-type mice attenuated the LPS-induced release of pro-inflammatory cytokines from glia, neurons prepared from IL-4 knockout (KO) mice failed to do so; we propose that this is due to the decreased expression of CD200 and consequently the decreased interaction between neurons and glia.
T11101 376800-377053 Sentence denotes However addition of CD200Fc attenuated the LPS-induced increase in IL-1beta to a similar extent in mixed glia prepared from wild-type and IL-4 KO mice; this is consistent with the finding that CD200R expression was similar in wild-type and IL-4 KO mice.
T15842 377054-377307 Sentence denotes Treatment of young and aged, WT and IL-4 KO mice with LPS, resulted in an exaggerated increase in expression of CD40, IL-1beta and IL-6 in hippocampal tissue prepared from aged, compared with young, mice and this was further exacerbated in IL-4 KO mice.
T41849 377308-377372 Sentence denotes These changes were coupled with a reduction in CD200 expression.
T6466 377373-377643 Sentence denotes These data suggest that IL-4 plays a central role in modulating neuronal expression of CD200 and we propose that the decrease in CD200 expression in tissue prepared from IL-4 KO mice contributes to the accentuated LPS-induced neuroinflammation observed in these animals.
T8619 377644-377960 Sentence denotes To mimic axonal transection in early lesions in MS, T-cells reactive to myelin basic protein (MBP) were transferred to female SJL/N mice, that subsequently were subjected to perforant pathway (PP) lesion in the entorhinal cortex resulting in a dense anterograde axonal and terminal degeneration in the dentate gyrus.
T78876 377961-377983 Sentence denotes Brains from mice with:
T72228 377984-378254 Sentence denotes 1) T-cell transfer and PP-lesion with 7 days survival post lesion, 2) T-cell transfer alone, 3) PP-lesion alone, or 4) unmanipulated control mice, were processed immunohistochemically for T-cells, microglia-macrophages and for MBP to evaluate clearance of myelin debris.
T37192 378255-378498 Sentence denotes Axonal lesion resulted in a massive infiltration of CD3+, CD4+ and to a smaller extent CD8+ cells in the deafferented dentate gyrus of the PP-lesioned T-cell recipient mice compared to PP-lesioned mice, T-cell recipient mice, and control mice.
T11835 378499-378631 Sentence denotes PP-lesioned T-cell recipient mice also showed enhanced activation of CD11b+ microglia, and signs of enhanced macrophage recruitment.
T40063 378632-378873 Sentence denotes Observation of reduced amounts of MBP+ particles in PP-lesioned T-cell recipient mice compared to PPlesioned mice indicated that the presence of T-cells in deafferented dentate gyrus enhanced microglial-macrophage clearance of myelin debris.
T60631 378874-379077 Sentence denotes This was confirmed by increased numbers of CD11b+ microglia-macrophages containing intracellular MBP+ material as a sign of phagocytosis in PP-lesioned T-cell recipient mice compared to PP-lesioned mice.
T62890 379078-379252 Sentence denotes Axonal and terminal degeneration distal to sites of axonal transection may precipitate the development of new inflammatory lesions along the anterogradely degenerating axons.
T665 379253-379407 Sentence denotes Enhancement of microglial-macrophage phagocytotic capacity by T cell infiltration could prove beneficial to regenerative processes following an MS attack.
T39476 379408-379519 Sentence denotes A possible role for inflammation in the onset and progression of neurodegenerative diseases has been suggested.
T61855 379520-379669 Sentence denotes Using the mouse ME7 prion model, we previously showed that systemic inflammation causes "primed" microglia to switch to a pro-inflammatory phenotype.
T62383 379670-379764 Sentence denotes This study aimed to investigate the molecular mechanism associated with this phenotype switch.
T51479 379765-379940 Sentence denotes Mice infected with the ME7 prion agent were systemically challenged with lipopolysaccharide or saline in the late stage of the disease (18 weeks) and compared to control mice.
T51798 379941-380080 Sentence denotes Hippocampal tissue was collected and subjected to microarray analysis, quantitative-RT-PCR and immunohistochemistry for selected receptors.
T29310 380081-380221 Sentence denotes In ME7-infected mice a large number of molecules that have a role in the immune response and signalling pathway showed increased expression.
T28376 380222-380340 Sentence denotes These included all four Fc receptors (FcR), which signal through either activating (ITAM) or inhibitory (ITIM) motifs.
T29244 380341-380495 Sentence denotes Systemic inflammation induced a further increase in the activating FcRIII and FcRIV, while FcRI did not change and the inhibitory FcRII was downregulated.
T65327 380496-380715 Sentence denotes The changes in FcR expression were accompanied by entry of IgG into the parenchyma and we have preliminary data showing the presence of (auto)-antibodies in sera of ME-7 infected mice and their capacity to bind neurons.
T66626 380716-380901 Sentence denotes Systemic inflammation during chronic neurodegeneration changed the ratio of activating and inhibitory FcR expression on microglia, lowering the signalling threshold for cell activation.
T53312 380902-381105 Sentence denotes We hypothesize that cross-linking of activating FcR results in excessive microglia activation and production of cytotoxic molecules that are detrimental to degenerating neurons within the demented brain.
T79398 381106-381233 Sentence denotes The situation may be compounded by entry of circulating IgG (auto) antibodies into the parenchyma and their binding to neurons.
T26772 381234-381277 Sentence denotes This study was supported by Wellcome Trust.
T6000 381278-381378 Sentence denotes Microglia are resident cells of the central nervous system (CNS) that belong to the myeloid lineage.
T24572 381379-381568 Sentence denotes In experimental models of neuroinflammation, microglia have demonstrated limited capacity to function as professional antigen presenting cells (APCs) when compared to dendritic cells (DCs).
T1136 381569-381856 Sentence denotes Human peripheral blood monocytes can differentiate into immature DCs when exposed to granulocytemacrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 and then into mature DCs if subsequently stimulated with lipopolysaccharide (LPS), thereby becoming highly efficient APCs.
T67417 381857-381964 Sentence denotes We addressed the potential of human adult microglia to acquire phenotypic and functional properties of DCs.
T27292 381965-382191 Sentence denotes Primary cultures of human adult microglia treated with GM-CSF + IL-4 with or without subsequent LPS activation were compared to human monocytes treated under similar conditions for DC phenotypic and functional characteristics.
T34467 382192-382388 Sentence denotes Analogous to monocytes, human microglia modified their surface phenotype upon GM-CSF + L-4 treatment by downregulating CD14, a monocyte marker, and by acquiring CD209, an adhesion receptor of DCs.
T72216 382389-382556 Sentence denotes Unlike monocytes however, treated microglia decreased major histocompatibility complex (MHC) class II expression and did not acquire CD1a, a lipid presenting molecule.
T23673 382557-382674 Sentence denotes Upon LPS stimulation, microglia lacked CD83, a mature DC marker, and only slightly increased costimulatory molecules.
T16543 382675-382945 Sentence denotes LPS-activated monocyte-derived DCs efficiently promoted CD4 T cell proliferation in an allogeneic mixed leukocyte reaction whereas similarly treated adult microglia had a decreased ability to stimulate CD4 T cell proliferation compared with their untreated counterparts.
T47314 382946-383124 Sentence denotes Monocyte-derived DCs produced high levels of tumor necrosis factor (TNF), IL-12 and IL-10 whereas microglia produced IL-10, relatively low amounts of TNF and no detectable IL-12.
T58132 383125-383317 Sentence denotes Monocytes differentiated into DC downregulated MafB mRNA, a transcription factor associated with macrophage differentiation, whereas similarly treated microglia maintained high levels of MafB.
T35238 383318-383468 Sentence denotes However, such microglia remained CD14-and had a low phagocytic activity, suggesting that they did not acquire a complete macrophage or a DC phenotype.
T66748 383469-383722 Sentence denotes Our data show that conditions inducing efficient professional APC from monocytes generate microglia with more modest APC functions and lesser inflammatory properties, suggesting a potential microglial role in dampening local inflammation within the CNS.
T13788 383723-383794 Sentence denotes an autoimmune response can be directed against Schwann cell components.
T10281 383795-383899 Sentence denotes Whether Schwann cells promote this response by presenting autoantigens to T-cells remains controversial.
T1224 383900-384097 Sentence denotes Here, we show by immunohistochemistry that human Schwann cells express the intracellular machinery required for processing and presenting antigens to autoreactive T cells both in vitro and in vivo.
T13936 384098-384238 Sentence denotes Addition of interferon-gamma results in increased expression of antigen processing and presenting molecules in cultured human Schwann cells.
T95441 384239-384450 Sentence denotes Furthermore, Schwann cells in sural nerve biopsies from GBS patients show increased expression of antigen associated transport proteins and antigen presenting MHC classes I and II complexes compared to controls.
T70553 384451-384641 Sentence denotes In coculture experiments rodent Schwann cells expressing ovalbumin as model antigen activate proliferation of ovalbumin specific CD4+ T cells when pre-treated with proinflammatory cytokines.
T59941 384642-384792 Sentence denotes These data suggest that glia cells of the peripheral nervous system have the ability to process and present antigen and activate autoreactive T cells.
T18747 384793-384885 Sentence denotes Schwann cells may therefore promote local autoimmune responses in inflammatory neuropathies.
T63117 384886-385009 Sentence denotes Specifically targeting this pathological function of Schwann cells may in the future extend our therapeutic options in GBS.
T60546 385010-385106 Sentence denotes Astrocyte and microglial responsiveness to TLR ligands have been addressed in vivo and in vitro.
T1732 385107-385238 Sentence denotes Astrocytes were purified by flow cytometric cell-sorting from transgenic mice expressing EGFP under the control of a GFAP promotor.
T31742 385239-385279 Sentence denotes Microglia were sorted as CD45-dim cells.
T74464 385280-385492 Sentence denotes Quantitative real-time PCR was used to measure gene expression by astrocytes and microglia isolated from naive mice and from mice that received ligands for TLR3 (Poly-I:C) and TLR4 (LPS) by intrathecal injection.
T27173 385493-385687 Sentence denotes As expected naive microglia expressed a wide range of TLR receptors and co-receptors (e.g. TLR's 1, 2, 3, 4, 6, and CD14), and naive astrocytes predominantly expressed message for TLR3 and TLR6.
T25220 385688-385814 Sentence denotes At 18 h following injection of LPS or Poly-I:C, both astrocytes and microglia showed significant upregulation of TLR2 message.
T81894 385815-385914 Sentence denotes Consistent with published reports astrocytes expressed relatively low levels of TLR4 and CD14 mRNA.
T73894 385915-386023 Sentence denotes However, at the dosage used, LPS was as effective as Poly-I:C in induction of TLR2 expression by astrocytes.
T36842 386024-386200 Sentence denotes To examine the role of microglia in the astrocyte response, we measured LPS responsiveness of astrocytes in primary cultures containing variable proportions of both cell types.
T49619 386201-386444 Sentence denotes Astrocytes in cultures containing N30% microglia responded to LPS by upregulating TLR2 3-fold, whereas in cultures with b5% microglia, TLR2 was not induced on astrocytes, although in both cases expression was strongly upregulated on microglia.
T84689 386445-386622 Sentence denotes Astrocytes were shown to respond to Poly I:C stimulation by a 2-fold induction of TLR2 in cultures containing b5% microglia and 6-fold induction in cultures with N30% microglia.
T7554 386623-386757 Sentence denotes This suggests that astrocytes upregulate TLR2 in response to direct stimulation and to factor(s) released from TLR-signaled microglia.
T56380 386758-386854 Sentence denotes Absence of TLR signals in the sterile injury model could explain the lack of TLR2 on astrocytes.
T69252 386855-386933 Sentence denotes We are currently investigating the factor(s) and signalling pathways involved.
T26475 386934-387072 Sentence denotes Microglia, the resident immune cells of the central nervous system, are normally quiescent but become activated after infection or injury.
T27910 387073-387152 Sentence denotes Their properties then change and they promote both repair and damage processes.
T25179 387153-387251 Sentence denotes The extent of microglial activation is regulated, in part by activation-induced cell death (AICD).
T10289 387252-387426 Sentence denotes Although many apoptotic aspects of the microglial AICD mechanism have been elucidated, little is known about the connection between the activation step and the death process.
T44844 387427-387555 Sentence denotes Employing a DNA microarray approach we identified the ectoenzyme CD38 as a potential mediator of microglial activation and AICD.
T19323 387556-387816 Sentence denotes Using mouse primary microglial cultures, we show that the CD38, via its calcium-mobilizing metabolite cyclic-ADP-ribose (cADPR), helps promote microglial activation and AICD induced by LPS plus IFNgamma (LPS/IFNg), suggesting that CD38 links the two processes.
T15839 387817-387979 Sentence denotes Accordingly, CD38 expression and activity, as well as intracellular calcium concentration ([Ca2+]i) in the primary microglia were increased by LPS/IFNg treatment.
T68617 387980-388121 Sentence denotes Moreover, CD38 deficiency or treatment with cADPR antagonists conferred partial resistance to LPS/IFNg-induced AICD and also reduced [Ca2+]i.
T91862 388122-388377 Sentence denotes Microglial activation, indicated by induced expression of nitric-oxide-synthase-2 mRNA and production of NO, secretion and mRNA expression of TNFα and IL-12 p40, and expression of IL-6 mRNA, was attenuated by CD38 deficiency or cADPR-antagonist treatment.
T93500 388378-388549 Sentence denotes The observed effects of CD38 on microglial activation is probably mediated via a cADPRdependent increase in [Ca2+]i, and the effect on AICD by regulation of NO production.
T83469 388550-388742 Sentence denotes Our results thus suggest that CD38 significantly affects regulation of the amount and function of activated microglia, with important consequences for injury and repair processes in the brain.
T81010 388743-388892 Sentence denotes In the adult mammalian brain, multipotent and self-renewing neural progenitor cells (NPCs) may generate new neurons, astrocytes and oligodendrocytes.
T37769 388893-388979 Sentence denotes NPCs may thus serve as a regenerative tool by which brain damage could be compensated.
T47080 388980-389195 Sentence denotes However, repair processes in response to inflammatory (and other) forms of brain injury are characterized by the failure of neuronal regeneration and the predominant occurrence of astrocytes (known as astrogliosis).
T49036 389196-389334 Sentence denotes Moreover, inflammation, which generates an oxidative milieu, has recently been reported to directly inhibit neurogenesis within the brain.
T69545 389335-389528 Sentence denotes We therefore intended to clarify possible molecular pathways underlying inflammation-mediated inhibition of neurogenesis and enhancement of astrogenesis in chronic autoimmune neuroinflammation.
T35497 389529-389737 Sentence denotes We systematically investigated the effects of redox modulation in neural stem cells in vitro and in vivo, as well as in the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE).
T61442 389738-389928 Sentence denotes We found that subtle (non-toxic) oxidation suppressed proliferation of NPCs and directed their differentiation towards the astroglial lineage at the expense of the neuronal (and vice versa).
T77311 389929-390118 Sentence denotes Our findings indicate that oxidation plays an instructive role in directing uncommitted NPCs to differentiate towards the astroglial lineage by altering their "default" development program.
T93052 390119-390482 Sentence denotes According to our data, Sirt1, a class III NAD+-dependent histone deacetylase involved in various cellular processes that comprise energy metabolism, transcriptional silencing, and DNA repair, mediates the observed redox effects, as mild oxidation in NPCs leads to increased Sirt1 deacetylase activity at the promoter of the proneuronal transcription factor Mash1.
T65892 390483-390572 Sentence denotes Furthermore, ongoing analysis of Sirt1 regulation in the course of EAE will be presented.
T57159 390573-390732 Sentence denotes Our results provide evidence for an as yet unknown metabolic master switch which has an impact on the fate of neural progenitors under inflammatory conditions.
T17670 390733-390902 Sentence denotes 14 -Role of CD38 in IL-1beta-induced astrocyte glutamate clearance impairment Astrocytes are numerically the most abundant cell-type in the central nervous system (CNS).
T95882 390903-391065 Sentence denotes One of the most essential functions of astrocytes is to regulate the level of extracellular glutamate, the major excitatory neurotransmitter in the mammalian CNS.
T50040 391066-391236 Sentence denotes Astrocytes express glutamate transporters, most prominently excitatory amino acid transporter 2 (EAAT2), which performs the vast majority of synaptic glutamate clearance.
T48964 391237-391340 Sentence denotes This prevents excitotoxicity, the overactivation of glutamate receptors on the cell surface of neurons.
T26102 391341-391451 Sentence denotes However, during neuroinflammatory conditions, cytokines have been shown to inhibit astrocyte glutamate uptake.
T94759 391452-391644 Sentence denotes CD38 is a 45 kD ectoenzyme involved in the synthesis of potent calcium mobilizing agents, cyclic adenosine diphospho-ribose (cADPR), and nicotinic acid adenine dinucleotide phosphate (NAADP+).
T9574 391645-391854 Sentence denotes Our previous studies demonstrated that astrocyte CD38 expression was upregulated upon immune or viral stimulation and, it played an important role in astrocyte inflammatory responses upon cytokine stimulation.
T81540 391855-392038 Sentence denotes We performed this study focusing on the effects of IL-1beta, a proinflammatory cytokine on the expression of EAAT2 in astrocytes and its results on astrocyte glutamate uptake ability.
T60519 392039-392097 Sentence denotes The potential role of CD38 in this effect was also tested.
T2614 392098-392163 Sentence denotes Primary human astrocytes were cultured and treated with IL-1beta.
T9747 392164-392288 Sentence denotes The glutamate uptake ability of astrocytes was determined by performing an Amplex Red Glutamic Acid/Glutamate Oxidase Assay.
T57214 392289-392358 Sentence denotes The astrocyte IL-6, IL-8, and MCP-1 production was examined by ELISA.
T56266 392359-392450 Sentence denotes EAAT2 expression in astrocytes was tested by real-time PCR and immunocytochemical analyses.
T99758 392451-392617 Sentence denotes Our results showed that IL-1beta induced astrocyte activation as indicated by significant increases in production of cytokine/chemokines such as IL-6, IL-8 and MCP-1.
T23661 392618-392813 Sentence denotes Furthermore, we detected that IL-1beta time-dependently reduced glutamate uptake ability of astrocytes, which was completely reversed by co-incubation with 8-Br-cADPR, a specific cADPRantagonist.
T96161 392814-392942 Sentence denotes We also found a decrease in astrocyte EAAT2 expression induced by IL-1beta, which was reversed by co-incubation with 8-Br-cADPR.
T68430 392943-393138 Sentence denotes These results indicate that the glutamate clearance capability of astrocytes is impaired by cytokine activation and the decreased expression of EAAT2 in astrocytes contributes to this impairment.
T21555 393139-393309 Sentence denotes In addition, we provide new evidence that CD38 upregulation in immune-activated astrocyte contributes to its functional dysregulation during neuroinflammatory conditions.
T50022 393310-393439 Sentence denotes In HIV-1-infected patients in the post-HAART era, a new syndrome, Immune Reconstitution Inflammatory Syndrome (IRIS) has emerged.
T36110 393440-393598 Sentence denotes In some patients it may rapidly progress toward the development of severe encephalitis, and ultimately death, even in the absence of opportunistic infections.
T72990 393599-393771 Sentence denotes CNS-IRIS is largely mediated via activated-T cells, which differentiates it from HIV-1 encephalitis that is accompanied by macrophage infiltration and a paucity of T cells.
T30850 393772-393985 Sentence denotes This paradoxical infiltration of the brain with T cells in patients who are immune suppressed, with low peripheral CD4 cell counts due to HIV-1 infection, represents a diagnostic challenge and a treatment dilemma.
T64774 393986-394365 Sentence denotes To determine the mechanism of T cell activation in IRIS, lymphocytes from normal donors were seeded into a 96-well plate at 2 × 105 cells/well, and treated with 200 nM HIV-1-encoded Tat (transactivator of transcription) in the presence or absence of 10 μM TPCK (NFkB blocker), 100 nM RO-32-0432 (pan-PKC inhibitor), 10 μM chloroquine, 10 μM pyramethamine, or CD3/CD28 antibodies.
T49696 394366-394534 Sentence denotes To map the epitope of Tat that activates T cells, lymphocytes were exposed to 15-mer Tat peptides derived from HIV-1 clade B (BRU strain) overlapping by 10 amino acids.
T98087 394535-394638 Sentence denotes As an indicator of T cell activation, granzyme B levels were measured in culture supernatants by ELISA.
T75136 394639-394728 Sentence denotes The mean + SEM was determined from 5 donors and analyzed by ANOVA with Dunnet correction.
T21983 394729-394802 Sentence denotes The data indicate that Tat activated T cells in a dose-responsive manner.
T94043 394803-394897 Sentence denotes This activation required the NF-kB pathway (p = 0.032), but was independent of PKC activation.
T29782 394898-395052 Sentence denotes The endocytotic pathway was important in Tat-mediated activation of T cells, as treatment with chloroquine decreased T cell activation by Tat (p = 0.021).
T78869 395053-395091 Sentence denotes No effect was seen with pyramethamine.
T79757 395092-395215 Sentence denotes The cysteine rich region of Tat was critical in activation of CD4+ and CD8+ T cells (p = 0.0039; p = 0.0134, respectively).
T60180 395216-395312 Sentence denotes HIV-1 Tat activates T cells to secrete effector molecules, as exemplified by granzyme B release.
T25883 395313-395469 Sentence denotes The mechanism of Tat-induced activation is dependent on endocytosis of Tat and NF-kB signaling, which may represent novel therapeutic targets to treat IRIS.
T66407 395470-395542 Sentence denotes The cysteine rich region of Tat is critical for mediating these effects.
T61755 395543-395654 Sentence denotes The neurologic symptoms associated with dengue fever are many and have been recognized for more than a century.
T55373 395655-395798 Sentence denotes Symptoms range from drowsiness, irritability, short term memory, and depression, through mononeural palsies, to encephalitis seizure and death.
T30092 395799-395998 Sentence denotes Optic spinal syndrome following Monophasic neuromyelitis optica (NMO) has been observed in Dengue virus infection, suggesting an influence of the genetic background in the susceptibility to post-NMO.
T82289 395999-396116 Sentence denotes Despite the high prevalence of tropical/subtropical countries there is no vaccine/medicine available for the disease.
T13842 396117-396242 Sentence denotes Heat Shock Proteins (Hsps) are highly conserved molecules and expressed in all cell types under various stressful conditions.
T73612 396243-396414 Sentence denotes The objective of the present study was to determine the effect of Dengue virus infection on relative expression of Hsps and their role in the progression of the infection.
T25682 396415-396629 Sentence denotes As macrophages are the primary host for Dengue, human promonocytic myeloblastoma U937, monocytic THP1 cells and blood derived macrophages were infected with Dengue virus type 2 for the evaluation of Hsp expression.
T66515 396630-396795 Sentence denotes A significant expression of Hsp60 was observed in virally infected U937 cells where as Hsp70 was predominantly expressed in blood derived macrophages and THP1 cells.
T29667 396796-396973 Sentence denotes In order to determine the correlation between Hsp60/70 expressions and viral multiplication in infected cells, expression of Hsp60 and 70 was down regulated by RNA interference.
T57179 396974-397159 Sentence denotes Accumulation of activated macrophages and microglia is a hallmark of viral encephalitis, however mechanisms of recruitment and function during infection of the brain are poorly defined.
T6552 397160-397339 Sentence denotes While leukocyte infiltration is critical for virus eradication, these cells can cause irreparable damage to neurons, contributing to increased morbidity and mortality of the host.
T26942 397340-397457 Sentence denotes West Nile Virus (WNV) encephalitis has a significant immunopathological component, however this is poorly understood.
T69188 397458-397534 Sentence denotes This study investigates the role of inflammatory monocytes in WNV infection.
T87892 397535-397756 Sentence denotes Intranasal inoculation of WNV resulted in a 3-fold increase in CD11b+/ CD45lo-int/CD11c-microglia and a 5-fold increase in CD11b+/CD45hi/ CD11c-/Ly6G-macrophages in the brain at d7 post infection (p.i.) by flow cytometry.
T10785 397757-397845 Sentence denotes Bromodeoxyuridine pulsing showed that few microglia had undergone proliferation in situ.
T14680 397846-398034 Sentence denotes Depletion of GR1+/CD11b+/CCR2+ peripheral inflammatory monocytes during infection abrogated increases in both microglia and macrophages, suggesting that they share a circulating precursor.
T5521 398035-398045 Sentence denotes At d7 p.i.
T41591 398046-398325 Sentence denotes C57BL/6 chimeras recon-stituted with c-fms/EGFP bone marrow showed large numbers of GFP+ peripherally-derived CD45lo-int microglia and CD45hi macrophages, expressing a GR1+ (Ly6C+) phenotype in the brain, suggesting that these cells have a common inflammatory monocyte precursor.
T9853 398326-398496 Sentence denotes Furthermore, adoptively transferred inflammatory monocytes migrated to the brain and expressed microglial and macrophage phenotypes during WNV infection, confirming this.
T77835 398497-398619 Sentence denotes Inflammatory monocyte-derived macrophages and microglia utilised different adhesion molecules to enter the infected brain.
T93298 398620-398758 Sentence denotes Blockade of Very Late Antigen-4 (VLA-4) reduced macrophage immigration by 66% and resulted in 10% long term survival in this lethal model.
T58184 398759-398885 Sentence denotes Lymphocyte Function-associated Antigen-1 (LFA-1) blockade reduced macrophage immigration by 33%, but did not improve survival.
T88100 398886-398971 Sentence denotes Importantly, VLA-4 or LFA-1 blockade had no impact on numbers of immigrant microglia.
T6279 398972-399061 Sentence denotes The majority (75%) of macrophages infiltrating into the brain produced nitric oxide (NO).
T89394 399062-399225 Sentence denotes Treatment with aminoguanidine on d6 p.i. resulted in a 6-fold reduction in numbers of NO-producing macrophages, with an increase in mouse survival of up to 4 days.
T14063 399226-399342 Sentence denotes Together these data indicate a role for NO-mediated immunopathology by infiltrating macrophages in WNV encephalitis.
T20515 399343-399520 Sentence denotes Herpes simplex encephalitis (HSE) is the most commonly identified cause of acute, sporadic non-epidemic encephalitis and is characterised by severe swelling of the brain tissue.
T60963 399521-399651 Sentence denotes The purpose of inflammation is to restore homeostasis by eliminating invading pathogens and promoting recovery from tissue damage.
T46210 399652-399883 Sentence denotes Cytokines and other immune mediators play an essential role in CNS inflammation through the activation of chemokines and adhesion molecules, recruitment of immune cells into the parenchyma and stimulation of endogenous glial cells.
T27187 399884-400078 Sentence denotes If this inflammatory response however, is not regulated adequately it can lead to chronic tissue damage caused by the infiltration of peripheral lymphocytes into the CNS and collagen deposition.
T26283 400079-400356 Sentence denotes The aim of this study was to provide a controlled in vitro system for measuring the cytokine response upon HSV infection by means of a cytometry-based assay allowing for multiplexed analysis, and to finally investigate the effect of anti-inflammatory agents on cytokine levels.
T30599 400357-400623 Sentence denotes A cell model comprising pure murine microglia, astrocytes, neurons and a co-culture of these cell lines was established to explore the cytokine response upon infection with the moderately neurovirulent HSV-1 strain VR3 and the highly neurovirulent strain HSV-1 SC16.
T99768 400624-400817 Sentence denotes The cell culture supernatants taken at indicated time points were subsequently probed for a total of 23 cytokines utilising a commercially available Bio-Plex assay and compared with each other.
T43124 400818-400983 Sentence denotes Cells infected with SC16 generated a more vigorous cytokine response compared to cells infected with VR3 with microglia producing by far the highest cytokine levels.
T46516 400984-401174 Sentence denotes Contrary to previous studies the experiment clearly indicated neurons and astrocytes to sense infection however, synthesis was restricted to certain types of cytokines at low concentrations.
T60742 401175-401377 Sentence denotes In addition, compared to pure microglia the co-culture revealed a shift in cytokine expression, with a marked decrease in KC (functional IL-8) levels suggesting cross-talk between individual cell types.
T62442 401378-401820 Sentence denotes As the cytokine cascade represents a vast inter-dependent network the study of multiple cytokines provides an improved insight into their role in the pathophysiology of HSV CNS infection and the Human immunodeficiency virus type 1 (HIV-1) invades the central nervous system (CNS) during the early stages of infection where it triggers a profound humoral immune response distinguished by plasmablast infiltration and intrathecal IgG synthesis.
T56375 401821-401930 Sentence denotes The aim of our study was to characterize the memory B cell receptor usage in HIV-1 cerebrospinal fluid (CSF).
T47432 401931-402089 Sentence denotes Single-cell RT-PCR was used to sample CSF CD27+CD19+ memory B cell repertoires, including CD27^high plasmablasts, from a treated and an untreated HIV patient.
T5816 402090-402286 Sentence denotes Sequencing of amplified variable region heavy-(VH) and light-chain (VL) products identified the rearranged variable region and J segment and determined the degree of homology to germline sequence.
T56160 402287-402365 Sentence denotes Expanded memory B cell clones were detected in the CSF of both HIV-1 subjects.
T91969 402366-402552 Sentence denotes Both HIV-1 repertoires demonstrated a similar distribution of VH and VL family germline usage: VH3 family heavy chains and VK1 family light chains dominated their respective repertoires.
T4395 402553-402772 Sentence denotes Treated and untreated HIV-1 repertoires, however, showed significant differences in the amount of B cell clonal expansion (21.2% vs. 32.3%, p = 0.02) and the degree of VH germline homology (95.7% vs. 92.3%, p = 0.0002).
T30600 402773-402981 Sentence denotes The increased memory B cell clonal expansion and somatic hypermutation observed in the untreated subject were associated with the presence of intrathecal HIV-1 virus and increased numbers of CSF plasmablasts.
T76946 402982-403045 Sentence denotes HIV-1 infection elicits a prominent CNS memory B cell response.
T7136 403046-403198 Sentence denotes Clonal expansion and somatic hypermutation are enhanced in the presence of intrathecal virus consistent with a targeted antibody response against HIV-1.
T26138 403199-403533 Sentence denotes Rearranged VH and VL sequences in clonally expanded HIV-1 B cells may be used to generate recombinant antibodies that recreate the epitopic specificity of the humoral immune response in treated and untreated disease. with the neurotropic JHM strain of mouse hepatitis virus (JHMV) results in extensive OPC migration and remyelination.
T15161 403534-403682 Sentence denotes As OPC are transplanted into an environment in which a persistent virus is present, it is possible that these cells may be susceptible to infection.
T70684 403683-403842 Sentence denotes Therefore, the experimental goals of this study were to determine if OPC were able to support JHMV replication and if cytokine treatment affected viral growth.
T97364 403843-403984 Sentence denotes The present study demonstrates that JHMV is able to infect and replicate within primary cultures of OPC derived from neural progenitor cells.
T19481 403985-404110 Sentence denotes In addition, treatment of infected OPC with recombinant mouse IFN-gamma inhibits viral replication in a dosedependent manner.
T19452 404111-404299 Sentence denotes Although IFN-β production (mRNA and protein) is muted in JHMV-infected OPC, IFN-β is produced by IFN-gammatreatment of JHMV-infected cells and recombinant IFN-β inhibits viral replication.
T80136 404300-404408 Sentence denotes Finally, IFN-gamma is unable to control JHMV replication in OPC derived from type I receptor knock-out mice.
T50149 404409-404586 Sentence denotes These data indicate that JHMV is capable of infecting OPC generated from neural progenitor cells and IFN-γ-mediated control of viral replication is dependent on IFN-β secretion.
T98268 404588-404645 Sentence denotes identified as a cellular receptor for some strains of MV.
T31813 404646-404790 Sentence denotes Inhibition of cell proliferation through engagement of MV with CD46 has been proposed as an important mechanism of MV-induced immunosuppression.
T37344 404791-404921 Sentence denotes Additional cells exhibiting immuno-suppressive activity may be involved in the mechanisms responsible for MV-induced SSPE as well.
T55649 404922-405082 Sentence denotes In this study, MV-induced immuno-suppression has been evaluated by the characterization of peripheral blood cells (PBC) from SSPE patients compared to controls.
T31922 405083-405143 Sentence denotes PBC of totally 70 SSPE patients (31 girls/39 boys, mean age:
T75895 405144-405200 Sentence denotes 8.3 years) and 55 children (20 girls/ 35 boys, mean age:
T33806 405201-405428 Sentence denotes 10.4 years) with non-inflammatory or inflammatory diseases were stained and phenotypical cell subsets have been These results implicate that CD46 may also be used as a cell entry receptor by some strains of MV which cause SSPE.
T69271 405429-405561 Sentence denotes The lower presence of the inhibitory NK receptors on CD8+ cells in SSPE may be caused by altered regulation of CD8+ T cells as well.
T31021 405562-405648 Sentence denotes The present work was supported by the Research Fund of Istanbul University (Project #:
T11573 405649-405654 Sentence denotes 192).
T73767 405655-405753 Sentence denotes Maingat Ferdinand 1 , Viappiani Serena 1 , Zhu Yu 1 , Afkhami-Goli Amir 1 , Power Christopher⁎ 1 1
T19085 405754-405976 Sentence denotes Infection by the human immunodeficiency virus (HIV) results in neurodegeneration caused by aberrant activation of glial cells although the impact of concurrent systemic infections on neurological disease remains uncertain.
T54265 405977-406160 Sentence denotes We studied the role of recurrent immune activation on neurological function and viral replication in the brain using an HIV/ AIDS model, feline immunodeficiency virus (FIV) infection.
T47970 406161-406320 Sentence denotes We administered lipopolysaccharide (LPS), a component of the membrane of gram-negative bacteria, to cats infected with FIV at 7, 9 and 11 weeks post-infection.
T22087 406321-406520 Sentence denotes Following serial neurobehavioral assessments, protein and mRNA were extracted from cerebral cortex and basal ganglion for immunoblotting of neuronal markers and RT-PCR analyses of inflammatory genes.
T67381 406521-406738 Sentence denotes FIV-infected and uninfected animals differed significantly on multiple neurobehavioral tasks of gait and memory over time, which was associated with reduced weight gain and immunosuppression in the FIV-infected group.
T59104 406739-406902 Sentence denotes FIVinfected cars treated with LPS developed less severe neurobehavioral deficits (mean deficit score 1.4 +/− 0.2 in FIV-LPS group versus 3.6 +/ − 0.2 in FIV group.
T60527 406903-407006 Sentence denotes CD4+ T cell levels in blood were suppressed in both FIV infected groups compared to uninfected animals.
T87023 407007-407223 Sentence denotes However, CD8+ T cell levels in blood were also lower in blood which was accompanied by reduced CD3e transcript abundance in brain among the LPS-treated FIV-infected animals relative to untreated FIV-infected animals.
T41969 407224-407524 Sentence denotes The presynaptic protein, synaptophysin, and the vesicular acetylcholine transporter were reduced in FIV-infected animals together with upregulation of mRNA for chemokine, IP10, in neurons of both basal ganglia and cortex of FIV-infected animals but these effects were also reversed by LPS treatments.
T40459 407525-407741 Sentence denotes Repeated LPS exposure improved neurological function and rescued synaptic architecture in FIV-infected animals through a mechanism involving reduced viral replication and concomitant T cell infiltration of the brain.
T22573 407742-407856 Sentence denotes Our findings underscore the beneficial aspects of selective activation of innate immunity in neurological disease.
T80705 407858-408084 Sentence denotes Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States Microglia and astrocytes are important effector cells of the CNS innate immune response to parenchymal infections.
T32284 408085-408303 Sentence denotes The Toll-like receptor (TLR) family of pattern recognition receptors (PRR) facilitates the recognition of conserved antigenic motifs of various pathogens, leading to the downstream production of inflammatory mediators.
T12136 408304-408429 Sentence denotes TLR2 is pivotal for glial recognition of S. aureus, a prevalent CNS pathogen, and eliciting proinflammatory mediator release.
T66693 408430-408706 Sentence denotes Recent studies from our laboratory have revealed a correlation between the loss of TLR2 signaling and aberrant Th17 infiltrates in the S. aureus brain abscess model, which may provide insights as to how TLR2 interfaces with adaptive immunity during CNS parenchymal infections.
T21179 408707-408958 Sentence denotes Since IL-17 exerts many proinflammatory activities, we propose that the exaggerated release of IL-17 in TLR2-deficient mice is a compensatory mechanism to mount an effective anti-bacterial immune response in the face of the loss of this important PRR.
T30032 408959-409114 Sentence denotes In other studies, signaling via the TLR/IL-1R adaptor MyD88 was essential for the induction of CNS innate immunity in the experimental brain abscess model.
T7151 409115-409362 Sentence denotes Specifically, the absence of MyD88 signaling significantly impaired the production of a wide range of proinflammatory molecules, attenuated neutrophil and macrophage influx into the CNS, and resulted in the exaggerated necrosis of infected tissue.
T65290 409363-409562 Sentence denotes Collectively, these studies reveal important roles for the TLR/IL-1R family of molecules in regulating both innate and adaptive immune responses during gram-positive infections in the CNS parenchyma.
T71456 409563-409760 Sentence denotes Sydenham chorea is the major neurologic sequelae of group A streptococcal-induced acute rheumatic fever (ARF) and is most likely due to autoimmunity and molecular mimicry between host and pathogen.
T85821 409761-410259 Sentence denotes Our first clue to the pathogenesis of the disease was the identification of human monoclonal antibodies(mAb) derived from Sydenham chorea that demonstrated crossreactivity and specificity for group A streptococcal antigen and reacted with striatal tissue and brain antigens lysoganglioside and tubulin. mAb and acute Sydenham chorea sera and CSF targeted the surface of human neuronal cells and caused induction of calcium-calmodulin dependent protein (CaM) kinase II activity and dopamine release.
T17078 410260-410463 Sentence denotes Sera from other streptococcal diseases or sequelae and convalescent Sydenham chorea sera did not demonstrate such increased antibody reactivity with brain or antibody mediated signaling of CaM kinase II.
T81274 410464-410606 Sentence denotes Primary neuronal cells from striatal tissue demonstrated increased CaM kinase II activity when reacted with acute Sydenham chorea sera or CSF.
T63516 410607-410729 Sentence denotes New preliminary data suggest that dopamine D1 and D2 receptors are targeted by the crossreactive anti-brain mAbs and sera.
T19478 410730-411108 Sentence denotes Serum antibodies from related disorders such as Pediatric Autoimmune Neurologic Disorder Associated with Streptococci with obsessive compulsive behaviors, vocal tics or tic-like movements demonstrated that the level of the CaM kinase II activity was increased at an intermediate level and the reactivity with lysoganglioside was not as evident although present in some patients.
T83333 411109-411292 Sentence denotes However, comparison of matched acute and convalescent PANDAS sera taken before and during the exacerbation demonstrated an elevation in CaM kinase II activity associated with disease.
T17272 411293-411586 Sentence denotes Study of an animal model of Sydenham chorea revealed that immunization with group A streptococcal antigen led to behavioral changes which correlated with antibody deposition in the striatum as well as reactivity of serum IgG with dopamine receptors and the induction of CaM kinase II activity.
T12480 411587-411804 Sentence denotes These data are consistent with the current hypothesis that disinhibition of basal ganglia-thalamo-cortical pathways may be involved in Sydenham chorea and with its treatment with haloperidol, a D2 receptor antagonist.
T39099 411805-412014 Sentence denotes Department of Neurology, Johns Hopkins University, Baltimore, MD, United States Some patients with HIV infection when aggressively treated with antiretroviral drugs develop a paradoxical subacute encephalitis.
T58643 412015-412127 Sentence denotes The development of this syndrome coincides with a drop in viral load and recovery of T cell counts in the blood.
T24152 412128-412183 Sentence denotes Left untreated it may result in death over a few weeks.
T3655 412184-412298 Sentence denotes Neuropathological evaluation shows massive infiltration of T cells with a predominance of cytotoxic and CD8 cells.
T49751 412299-412396 Sentence denotes This is associated with glial cell activation and neuronal injury but relative sparing of myelin.
T74111 412397-412571 Sentence denotes To study the pathophysiology of this syndrome, we first determined the mechanism of activation of T cells by an HIV protein, Tat that is not impacted by antiretroviral drugs.
T39405 412572-412669 Sentence denotes Tat-mediated activation of T cells occurs independent of T cell receptors but is NF-kB dependent.
T19714 412670-412772 Sentence denotes Using human neuronal cultures, we found that supernatants from these activated T cells are neurotoxic.
T57832 412773-412850 Sentence denotes Granzyme B is a major neurotoxic substance released by the activated T cells.
T52210 412851-413170 Sentence denotes Granzyme B causes neuronal injury independent of perforin and the mechanism of neuronal injury by granzyme B sequentially involves the activation of a Gi-protein coupled receptor, notch-signaling pathways and over expression of potassium channel, Kv1.3 followed by neurite trimming and neuronal cell death by apoptosis.
T99673 413171-413280 Sentence denotes Pharmacological or molecular blockade of Kv1.3 results in protection against T cell mediated neuronal injury.
T94734 413281-413355 Sentence denotes Previous studies have suggested a role for Kv1.3 in activation of T cells.
T39065 413356-413424 Sentence denotes Thus, Kv1.3 represents a novel therapeutic target for this syndrome.
T24355 413425-413479 Sentence denotes Bone marrow stern cell in the rescue of brain diseases
T45878 413480-413541 Sentence denotes Microglia are the immune cells of the central nervous system.
T60557 413542-413673 Sentence denotes They patrol the brain environment with their ramifications and they respond quickly in the presence of pathogens and brain damages.
T46736 413674-413835 Sentence denotes Bone marrow derived cells (BMDCs) have the ability to populate the CNS and differentiate into functional parenchymal microglia as well as perivascular microglia.
T74336 413836-414034 Sentence denotes Even though BMDCs can enter the brain parenchyma throughout the CNS in normal mice, it seems that they are preferentially attracted to regions afflicted by neurodegeneration or neurological insults.
T12019 414035-414301 Sentence denotes Of great interest is the fact that blood-derived microglial cells are associated with amyloid plaques and these cells are able to prevent the formation or eliminate the presence of amyloid deposits in mice that develop the major hallmark of Alzheimer's Disease (AD).
T98800 414302-414405 Sentence denotes These cells are also recruited in the brain of other mouse models of brain diseases and acute injuries.
T79451 414406-414487 Sentence denotes The exact mechanisms involved in these events have yet to be fully characterized.
T834 414488-414644 Sentence denotes It is likely that stressed or damaged neurons send signal to resident microglia or produce specific chemokines to cause recruitment of BM-derived microglia.
T31540 414645-414820 Sentence denotes A number of proteins can act as endogenous ligands for tolllike receptors (TLRs) expressed on the surface of microglia and then trigger NF-kB signaling and gene transcription.
T26566 414821-414951 Sentence denotes This would necessarily lead to a subtle inflammatory response and consequently proliferation and chemoattraction of myeloid cells.
T36075 414952-415047 Sentence denotes Of interest is the fact that there is no need of a massive neurodegeneration and BBB breakdown.
T87220 415048-415291 Sentence denotes We can therefore propose that neurons, especially those in danger, have the ability to interact with microglia and stimulate their proliferation and recruitment, although the physiological relevance of this phenomenon is still largely unknown.
T12206 415292-415425 Sentence denotes We can speculate that this natural process takes place to provide survival signals and help to stressed, injured or infected neurons.
T99363 415426-415639 Sentence denotes A timely controlled innate immune response may also limit CNS toxicity by eliminating foreign materials and debris, thus contributing to create an environment that is more permissive for regeneration and recovery.
T15478 415640-415839 Sentence denotes Since toxic and secreted proteins are frequently the cause of many brain diseases, such a cellular therapy may prove to be quite effective to prevent and remove the main trigger of neurodegeneration.
T79124 415840-416000 Sentence denotes Hematopoietic stem cells represent therefore a fantastic new vehicle for delivering key molecules to improve recovery, repair and elimination of toxic proteins.
T51348 416001-416074 Sentence denotes The Canadian Institutes in Health Research (CIHR) supports this research.
T51854 416075-416206 Sentence denotes Transforming growth factor-beta TGF-beta) has pleiotropic effects, both beneficial and harmful in the central nervous system (CNS).
T68026 416207-416357 Sentence denotes Transgenic mice overproducing this cytokine from astrocytes have higher numbers of T cell in their brains without showing overt signs of inflammation.
T11127 416358-416494 Sentence denotes However, when immunized against an endogenous or ectopically expressed CNS antigen, T cell infiltration and inflammation are aggravated.
T41534 416495-416700 Sentence denotes Consistent with these observations, TGF-beta1 synthesis in glial cells and TGF-beta signaling in the CNS were activated several days before the onset of paralysis in mice with autoimmune encephalomyelitis.
T88588 416701-416830 Sentence denotes Sequentially, after glial cells were modulated, TGF-β1 signals then were induced in infiltrating T cells in inflammatory lesions.
T41251 416831-416994 Sentence denotes Pharmacological inhibition of TGF-β signaling ameliorated the paralytic disease, reducing the accumulation of pathogenic T cells and expression of IL-6 in the CNS.
T53676 416995-417158 Sentence denotes Priming of peripheral T cells was not altered, nor was the TH17 pathway, indicating that this effect was directed within the brain, yet affected the immune system.
T7224 417159-417294 Sentence denotes The early production of TGF-β1 in the CNS creates a permissive and dangerous environment for the initiation of autoimmune inflammation.
T61056 417295-417410 Sentence denotes Inhibition of TGF-β signaling may have benefits in the treatment of the acute phase of autoimmune CNS inflammation.
T11796 417411-417446 Sentence denotes Late pregnancy is beneficial in MS.
T80535 417447-417537 Sentence denotes The third trimester has been associated with an approximate 80% reduction in relapse rate.
T56774 417538-417627 Sentence denotes Estriol, the estrogen unique to pregnancy, reaches highest levels in the third trimester.
T8395 417628-417814 Sentence denotes Estriol treatment was previously shown to ameliorate experimental autoimmune encephalomyelitis (EAE) when used at a dose equivalent to what occurs naturally during late murine pregnancy.
T28720 417815-417892 Sentence denotes Numerous mechanisms are involved in estriol mediated protection from disease.
T81306 417893-417968 Sentence denotes These include both anti-inflammatory as well as neuroprotective mechanisms.
T329 417969-418106 Sentence denotes Anti-inflammatory mechanisms have previously included the induction of favorable changes in cytokines, chemokines and T regulatory cells.
T73576 418107-418222 Sentence denotes Here we will present our recent observations of effects of estriol treatment on matrix metalloproteinase-9 (MMP-9).
T32490 418223-418352 Sentence denotes Neuroprotective effects include a sparing of axon densities and myelin white matter, as well as neuronal staining in gray matter.
T3824 418353-418469 Sentence denotes Estrogen receptor (ER)-alpha and ER-beta differentially mediate these anti-inflammatory and neuroprotective effects.
T31356 418470-418643 Sentence denotes Together these observations in EAE provide a rationale for a clinical trial of treatment with estriol, at a pregnancy dose, in relapsing remitting multiple sclerosis (RRMS).
T10500 418644-418734 Sentence denotes This trial will include both antiinflammatory as well as neuroprotective outcome measures.
T75171 418735-418852 Sentence denotes A distinct female predominance exists for a variety of human autoimmune disorders, including multiple sclerosis (MS).
T95160 418853-419032 Sentence denotes This differential gender susceptibility has also been observed in many experimental animal models of autoimmune disease, including experimental autoimmune encephalomyelitis (EAE).
T65444 419033-419147 Sentence denotes The increased levels of sex hormones produced during pregnancy are reported to reduce the clinical symptoms of MS.
T25538 419148-419257 Sentence denotes Interestingly, the clinical symptoms of MS worsen post-partum, which is marked by reduced sex hormone levels.
T4145 419258-419508 Sentence denotes The work from our laboratory illustrates the large number of complex processes affected by estrogen that might contribute to the striking ability of 17-beta estradiol (E2) and its derivatives to inhibit clinical and histological signs of EAE in mice.
T19638 419509-419777 Sentence denotes These effects require sustained exposure to relatively low doses of exogenous hormone and offer better protection when initiated prior to induction of EAE, although oral ethinyl estradiol (EE) could partially reverse clinical EAE when given after the onset of disease.
T93764 419778-420244 Sentence denotes The main areas to be discussed include E2-mediated inhibition of encephalitogenic T cells, the role in E2 regulation of the newly described GPR30 membrane receptor (mER) and the E2 agonist G1, inhibition of inflammatory cell migration into central nervous system tissue, neuroprotective effects that promote axon and myelin survival, and finally new data showing synergistic treatment effects of E2 in combination with T cell receptor peptide therapy in MS patients.
T11275 420245-420480 Sentence denotes E2 effects on EAE were mediated through Esr1 (alpha receptor for E2) and GPR30, but not Esr2 (beta receptor for E2) and resulted in the dramatic down-regulation of IL-17 recently demonstrated to be the major pathogenic cytokine in EAE.
T71066 420481-420676 Sentence denotes Chimera studies demonstrated that E2 does not directly inhibit pathogenic T cells, but rather mediates its suppressive effects through other cell types, including macrophages and dendritic cells.
T4675 420677-420873 Sentence denotes Of mechanistic importance, immunosuppression that can prevent EAE also involves E2-dependent up-regulation of Foxp3 and PD-1 that contribute to the activity of CD4+CD25+ regulatory T cells (Treg).
T65409 420874-421093 Sentence denotes New findings indicate that G1, an E2 agonist that binds selectively to mER (GPR30), can mediate full protection against EAE by upregulating the PD-1 pathway in Treg cells as well as the antiinflammatory cytokine, IL-10.
T98757 421094-421192 Sentence denotes The protective effects of E2 and E2 agonists in EAE suggest their potential use as therapy for MS.
T52629 421193-421417 Sentence denotes Fred Hutchinson Cancer Research Center, and the University of Washington, Seattle, WA USA Microchimerism (Mc) refers to harboring a small number of cells (or DNA) that originated from another genetically distinct individual.
T10838 421418-421551 Sentence denotes Some cells traffic between the mother and fetus during pregnancy and have been found to persist many years later in respective hosts.
T82777 421552-421793 Sentence denotes Hematopoietic cell transplantation (iatrogenic chimerism) is often complicated by chronic graft-vs.-host disease which is a condition that resembles some autoimmune diseases and is strongly determined by the donor-recipient HLA-relationship.
T21425 421794-421981 Sentence denotes Considering these observations together led to the hypothesis that naturally acquired Mc from pregnancy and the childmother HLA relationship impacts risk of subsequent autoimmune disease.
T43179 421982-422144 Sentence denotes Mc can also be acquired from a twin or from a blood transfusion, and possibly from an older sibling transferred via the maternal circulation to a later pregnancy.
T41917 422145-422170 Sentence denotes Antibodies and the brain:
T51929 422171-422206 Sentence denotes Lessons from lupus Betty Diamond B.
T10228 422207-422218 Sentence denotes Diamond, P.
T51238 422219-422229 Sentence denotes Huerta, C.
T21447 422230-422239 Sentence denotes Kowal, J.
T55376 422240-422450 Sentence denotes Lee and B Volpe A subset of anti-DNA antibodies present in lupus patients crossreacts with NMDA receptors (NMDARs) and modulates NMDAR function, mediating excitotoxic death of neurons both in vitro and in vivo.
T16340 422451-422584 Sentence denotes These antibodies are preset in serum of 30-50% of lupus patients and can also be found in their cerebrospinal fluid and brain tissue.
T85700 422585-422755 Sentence denotes We have demonstrated that these antibodies, when present in the circulation cause no brain injury until there is a compromise to the integrity of the blood-brain barrier.
T36487 422756-422891 Sentence denotes They then may cause a memory deficit or behavior disturbance depending on whether they penetrate hippocampus or amygdala, respectively.
T74182 422892-422961 Sentence denotes Histopathologic analysis displays a non-inflammatory loss of neurons.
T31869 422962-423209 Sentence denotes These antibodies, via transplacental transmission, can cause abnormal fetal brain development, leading to a thin cortical plate, delayed acquisition of normal reflexes and impairments in adulthood in isolated tasks that depend on an intact cortex.
T6963 423210-423398 Sentence denotes Overall, these studies demonstrate the capacity of antibodies to cause acquired changes in cognition and behavior and to cause congenital nongenetic alterations in fetal brain development.
T43388 423399-423541 Sentence denotes We speculate that brainreactive antibodies may often be present and, therefore, be a frequent threat to optimal brain function or development.
T7203 423543-423687 Sentence denotes In myasthenia gravis (MG), a T-cell dependent antibody response is directed against acetylcholine receptor (AChR) at the neuromuscular junction.
T49175 423688-423947 Sentence denotes To study immune tolerance to this autoantigen, we generated a transgenic mouse in which the AChR alpha chain was expressed in the normal physiological pattern (muscle N brain ≫ thymus) and used this model to assess the mechanisms regulating tolerance to AChR.
T74341 423948-424136 Sentence denotes Since AChR is expressed in the thymus, we expected that central tolerance would dominate, but several lines of evidence suggest that peripheral mechanisms may play a more significant role.
T24644 424137-424334 Sentence denotes First, T cell tolerance is maintained with age in spite of thymic involution; responses to the self determinant, but not to foreign antigens, were still seen in very old mice (28-30 months of age).
T8447 424335-424427 Sentence denotes Second, T cell tolerance remains functional in Aire knockout animals carrying the transgene.
T23868 424428-424536 Sentence denotes Third, when crossed to mice carrying a transgenic TCR specific for this ligand, tolerance was easily broken.
T43028 424537-424735 Sentence denotes Fourth, adoptive transfer of TCR transgenic T cells labeled with CFSE revealed a slight decrease in the number of cell divisions seen in an AChRα transgenic host as opposed to a non-transgenic host.
T71867 424736-424900 Sentence denotes Fifth, using thymus transplant approaches, we demonstrated that T-cell tolerance to AChRα is dependent on transgene expression in the muscle, but not in the thymus.
T73896 424901-425094 Sentence denotes Lastly, the tolerant state could be overcome by treating the mice with anti-CD25; this is consistent with a mechanism of tolerance that is regulated peripherally by regulatory T (T reg ) cells.
T49467 425095-425273 Sentence denotes To explore this further, a second transgenic founder line was generated in which the AChRα transgene is expressed at a slightly higher level (2-3 fold) in both muscle and thymus.
T17771 425274-425417 Sentence denotes Preliminary thymus transplant and adoptive transfer experiments with this new founder line suggest that central tolerance may also be involved.
T55937 425418-425658 Sentence denotes Ongoing studies with the second transgenic line are designed to assess whether Aire and/or T reg cells play a role and if so, whether the level of expression and/or the distribution of the ligand among thymic epithelial subsets is critical.
T46166 425659-425855 Sentence denotes This work was supported in part by an APC Subcontract, pilot grants from the San Antonio Area Foundation and the Myasthenia Gravis Foundation of America, a UTHSCSA ERC grant, and NIH R36 AG029667.
T32015 425856-425941 Sentence denotes Classical complement pathway and IL-6 in autoimmune myasthenia gravis pathogenesis P.
T3324 425942-426153 Sentence denotes Christadoss Mice deficient for complement factors C3, C4 or C5 are resistant to CD4 cell-dependent antibody mediated autoimmune myasthenia gravis (EAMG) induced by CFA-acetylcholine receptor (AChR) immunization.
T52047 426154-426283 Sentence denotes AChR immune C3 deficient mice lymph node cells (LNC) produced less IL-6 and EAMG resistant IL-6 deficient mice had less serum C3.
T50681 426284-426408 Sentence denotes Moreover, increased serum C1q-circulating immune complex (CIC) levels correlated with EAMG disease severity in RIIIS/J mice.
T94635 426409-426524 Sentence denotes The CIC promotes EAMG severity by stimulating the production of IL-6, C1q and C3 via Fc gamma receptor interaction.
T95264 426525-426696 Sentence denotes However, MBL and C5a receptor deficient mice were equally susceptible to EAMG as wild-type mice, implicating that MBL pathway and C5a are not involved in EAMG development.
T16314 426697-426864 Sentence denotes Both complement accumulation and IL-6 up-regulation were also observed in the recently discovered CD4-independent EAMG in C57BL6 mice induced by LPS-AChR immunization.
T31261 426865-427053 Sentence denotes Anti-C1q antibody administration before and following AChR immunization suppressed EAMG by reducing LNC IL-6 production and neuromuscular junction deposits of IgG, C3 and C5b-C9 complexes.
T67230 427054-427215 Sentence denotes Treatment with anti-C1q antibody twice a week for four weeks in mice with ongoing clinical EAMG reduced the clinical severity of disease and LNC IL-6 production.
T45414 427216-427325 Sentence denotes Anti-IL6 antibody administration suppressed EAMG by reducing anti-AChR Ig2b antibodies which bind complement.
T51392 427326-427442 Sentence denotes Therefore, agents which block the CCP factors C1q, C2 or C4 and/or IL-6 could be used in the targeted therapy of MG.
T90941 427443-427704 Sentence denotes Research Team for Molecular Biomarkers, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan MuSK antibodies were found in seronegative MG patients, but the experimentally autoimmune MG model was required to show the pathogenicity of MuSK antibodies in MG.
T73742 427705-427818 Sentence denotes We have provided the evidence that active immunization with MuSK protein reproduces myasthenia gravis in rabbits.
T85938 427819-427865 Sentence denotes Next we focus on how MuSK antibodies cause MG.
T23460 427866-428071 Sentence denotes The pathogenic roles of MuSK antibodies in MG have been questioned as the number of AChRs is not reduced and complement is not deposited at the NMJ of biceps brachii muscles MuSK-positive patients with MG.
T63551 428072-428224 Sentence denotes The mechanisms of MG caused by AChR antibodies are well delineated, but the revealed mechanisms are not able to simply apply to MG with MuSK antibodies.
T55326 428225-428329 Sentence denotes MuSK antibodies have been identified as predominantly IgG4 subclass, which does not activate complement.
T65360 428330-428530 Sentence denotes We found that agrin-induced clustering of AChR was strongly blocked in the presence of MuSK antibodies, whereas absorption of the antibodies with purified MuSK products prevented this blocking effect.
T80484 428531-428645 Sentence denotes These results showed that the MuSK antibodies effectively inhibited the formation of agrininduced AChR clustering.
T67611 428646-428883 Sentence denotes Intriguingly, the monovalent Fab fragments of MuSK antibodies from rabbits with EAMG also inhibited AChR clustering by agrin on C2C12 cells, indicating that complement-mediated mechanisms are not necessarily required for such inhibition.
T87826 428884-429014 Sentence denotes We then examined the reduced expression of AChR at NMJ in soleus muscles of paretic and normal rabbits by fluorescence microscopy.
T87462 429015-429158 Sentence denotes In addition, the structure of NMJ in our paretic rabbits, as well as the size and branching of the motor terminals, were significantly reduced.
T44031 429159-429441 Sentence denotes Electron microscopic observations of NMJ in rabbits with EAMG induced by injection of MuSK protein demonstrated a significant loss of complexity of convoluted synaptic folds but no destruction, and EAMG model cited here resembles the phenotype of humans with MG and MuSK antibodies.
T77554 429442-429593 Sentence denotes Our results showed that MuSK antibodies inhibit both anterograde and retrograde signals required for maintaining the synaptic structures in mature NMJ.
T62275 429594-429793 Sentence denotes The EAMG model with MuSK antibodies will facilitate the understanding of the pathogenic mechanisms of MG with MuSK antibodies and functional roles of MuSK molecules in mature neuromuscular junctions.
T72040 429794-430014 Sentence denotes T cells constitutively expressing the immuno-tolerogenic human histocompatibility leukocyte antigen G (HLA-G) have recently been described as a new type of human natural thymus-derived regulatory T cells (HLA-Gpos Treg).
T43601 430015-430134 Sentence denotes Treg suppress immune responses against foreign and self-antigens and play a key role in the mechanisms of autoimmunity.
T92675 430135-430241 Sentence denotes We here challenge the role of HLA-Gpos Treg with respect to their function and role in multiple sclerosis.
T33735 430242-430363 Sentence denotes HLA-G positive (HLA-Gpos) T cells can be found in the cerebrospinal fluid (CSF) and in tissue specimens from MS patients.
T72357 430364-430489 Sentence denotes In contrast to other noninflammatory neurological diseases (OND), CD4+ HLA-Gpos T cells are enriched in CSF from MS patients.
T28158 430490-430682 Sentence denotes A substantial population of CD3+ T cells co-expresses HLA-G and localize to inflammatory lesions from MS patients, suggesting that HLA-Gpos T cells accumulate at the sites of CNS inflammation.
T75550 430683-430914 Sentence denotes CSF-derived HLA-Gpos T cells revealed a clear predominance of central memory T cell (CD45RA-CD27+) phenotype, showed markers of activation (ICOS), and had significantly higher expression of the inflammatory chemokine receptor CCR5.
T87989 430915-431158 Sentence denotes Using an in vitro model of human blood brain barrier we show that HLA-Gpos T cells have a propensity to migrate and are vigorously driven by inflammatory chemokines such as MIP1a and RANTES (ligands of CCR5), but not to MIP3b (ligand of CCR7).
T52382 431159-431319 Sentence denotes In contrast to CD4+CD25+FoxP3+CD127dim Treg, purified peripheral blood CD4 HLA-Gpos Treg cells don't differ in their suppressive capacity from healthy controls.
T22808 431320-431468 Sentence denotes Most importantly, CD4+ HLA-Gpos T cells directly isolated from the CSF of MS patients potently suppress proliferation of autologous responder cells.
T66578 431469-431592 Sentence denotes This work characterizes the pathophysiological role of HLA-Gpos Treg, a novel population of human Treg, with respect to MS.
T18137 431593-431775 Sentence denotes Our data show that HLA-Gpos natural Treg have a chemokine-dependent propensity to transmigrate the blood-brain barrier, and accumulate in the CSF and in CNS lesions from MS patients.
T86373 431776-431912 Sentence denotes Importantly, patientderived HLA-Gpos Treg are functionally active and suppress autologous T cell activation at the site of inflammation.
T19223 431913-432071 Sentence denotes It is therefore assumed that these natural regulatory cells are specifically recruited to the CNS in order to counterbalance autoimmune inflammatory activity.
T33326 432072-432303 Sentence denotes Our work contributes to the understanding of HLA-Gpos natural Treg and provides an important pathophysiological example of beneficial T cell inflammation in MS, implicating both from pathophysiological/therapeutical points of view.
T2859 432304-432461 Sentence denotes The blood-brain barrier (BBB) plays a crucial role in protecting the central nervous system (CNS) by restricting entry of cells and molecules into the brain.
T23951 432462-432660 Sentence denotes In the CNS disorder multiple sclerosis (MS), breakdown of the BBB allows activated leukocytes to infiltrate the brain parenchyma, leading to the formation of the characteristic demyelinated lesions.
T11606 432661-432801 Sentence denotes Interleukin (IL)-17-secreting lymphocytes (TH17) appear to be essential in the pathogenesis of numerous inflammatory diseases, including MS.
T42406 432802-433016 Sentence denotes In spite of the intensified focus on TH17 lymphocytes, their contribution to the disruption of the BBB and leukocyte infiltration into the CNS, both important early events in the development of MS, remains unclear.
T629 433017-433175 Sentence denotes We developed and optimized a method to successfully generate human TH17 lines in vitro from peripheral blood CD4+CD45RO+ memory lymphocytes of healthy donors.
T42143 433176-433382 Sentence denotes We demonstrate that in response to IL-23, human TH17 memory CD4+CD45RO+ lymphocytes, but not naive CD4+CD45RA+ lymphocytes, produce IL-17 and IL-22, with a subset of cells co-expressing IL-17 and IFN-gamma.
T88843 433383-433557 Sentence denotes We show that IL-17 and IL-22 disrupt BBB tight junctions in vitro and in vivo and that receptors for these cytokines are upregulated on human endothelium during inflammation.
T55242 433558-433785 Sentence denotes Moreover, human TH17 cells transmigrate efficiently across brain endothelial cells via adhesion molecules ALCAM and ICAM-1 and promote CD4+ lymphocyte recruitment across the BBB, through the concerted action of IL-17 and IL-22.
T39432 433786-434090 Sentence denotes Interestingly, we also note an increase in the percentage of IL-17+ and IL-22+ lymphocytes, as well as in the subpopulation of cells co-producing IL-17 and IFN-gamma in TH17 cell lines expanded from the peripheral blood of women with active MS than in those generated from healthy men and women controls.
T933 434091-434291 Sentence denotes Our study further refines the phenotype of human TH17 lymphocytes and emphasizes the importance of TH17 lymphocyte infiltration into the CNS and their consequent involvement in lesion formation in MS.
T47260 434292-434380 Sentence denotes In this study, we examined the role of MOG-specific Th17 cells in microglial activation.
T2775 434381-434542 Sentence denotes We also assessed the ability of neurons to modulate Th17-induced microglial activation and investigated the possible role for CD200 ligand-receptor interactions.
T65343 434543-434746 Sentence denotes Microglial activation was assessed by measuring cell surface expression of MHC class II, CD40, CD80 and CD86 by flow cytometry and the production of proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6).
T58984 434747-434993 Sentence denotes The results demonstrate that Th17 cells were potent activators of microglial cells, upregulating cell surface expression of MHC class II, CD40, CD80 and CD86 and inducing the production of TNF-alpha (⁎⁎p b 0.01), IL-1beta and IL-6 (⁎⁎⁎p b 0.001).
T10325 434994-435175 Sentence denotes Neurons attenuated the Th17 cell-induced production of TNF-alpha, IL-1beta and IL-6 (⁎⁎p b 0.01) from microglia but had no effect on of MHC class II, CD40, CD80 and CD86 expression.
T91286 435176-435361 Sentence denotes The inhibitory effect of neurons on Th17 cell-induced proinflammatory cytokine production from microglia was reversed by co-incubation with an anti CD200 receptor antibody (⁎⁎p b 0.01).
T83356 435362-435543 Sentence denotes These findings show that Th17 cells are potent activators of microglia and that this activation can be attenuated by CD200 ligandreceptor interactions between neurons and microglia.
T80150 435544-435643 Sentence denotes Experimental autoimmune encephalomyelitis (EAE) is a well known animal model of multiple sclerosis.
T67739 435644-435745 Sentence denotes Upon activation, myelin reactive T cells invade the central nervous system (CNS) to initiate disease.
T61129 435746-435854 Sentence denotes It remains unknown whether myelin reactive T cells may also infiltrate into the CNS during disease recovery.
T10908 435855-436026 Sentence denotes We investigate whether the CNS is still susceptible for the infiltration, activation and proliferation of resting myelin reactive T cells during the recovery phase of EAE.
T54031 436027-436176 Sentence denotes Resting myelin reactive T cells were obtained by isolating the draining lymph nodes of immunized animals followed by in vitro restimulation with MBP.
T3126 436177-436286 Sentence denotes Subsequently, cells were incubated with IL-2 during 24 h and then rested on IL-2 deprived medium during 72 h.
T35591 436287-436363 Sentence denotes Flow cytometric analyses were performed to characterize the resting T cells.
T27660 436364-436480 Sentence denotes At time of transfer, cells were labeled with SPIO or CFSE and intravenously injected at different stages during EAE.
T94213 436481-436631 Sentence denotes At 24 h and 72 h post transfer, either MRI was performed or the CNS and immune organs were isolated and analyzed for the expression of CFSE and 7-AAD.
T97252 436632-436786 Sentence denotes Flow cytometric analysis showed that resting myelin reactive T-cells generated in vitro and used for transfer were CD25low, CD45RC negative and CD62L low.
T39108 436787-436953 Sentence denotes When transferred at recovery, cells could be detected in the CNS as soon as 24 h after transfer using in vivo MRI and remained present in the CNS for at least 3 days.
T15680 436954-437074 Sentence denotes Flow cytometric analysis showed that more than 90% of the transferred cells proliferated in the CNS 72 h after transfer.
T78548 437075-437139 Sentence denotes Proliferation of these cells was less abundant in the periphery.
T34200 437140-437210 Sentence denotes A low number (19%) of the cells in the CNS were apoptotic or necrotic.
T97412 437211-437289 Sentence denotes The amount of cell death was much higher in the periphery compared to the CNS.
T46919 437290-437408 Sentence denotes Finally, transfer of resting myelin reactive T cells during the recovery phase also led to a clinical disease relapse.
T45529 437409-437486 Sentence denotes This is in contrast to the normal monophasic disease course in these animals.
T5370 437487-437652 Sentence denotes These results show that during clinical recovery, the CNS in EAE is still susceptible to the infiltration and the inflammatory activities of myelin reactive T cells.
T45974 437653-437792 Sentence denotes This could indicate that immunoregulation of myelin reactive T cells during recovery is primarily mediated in the peripheral immune organs.
T56862 437793-437945 Sentence denotes Intravenously injected T cells can possibly escape this control by a direct extravasation from the blood and exert their pathogenic function in the CNS.
T73820 437947-438142 Sentence denotes Flow cytometric analysis of infiltrating immune cells during inflammation or after injury of the Central Nervous System (CNS) offers valuable insights into mechanisms of disease and regeneration.
T44090 438143-438352 Sentence denotes Due to the limited number of these cells isolated from individual animals during disease models, it has been necessary to limit the characterization to a small number of markers and/or to pool several samples.
T84156 438353-438541 Sentence denotes We have now established a 7-color flow cytometric approach, which allows us to identify infiltrating immune cell types and their differentiation/maturation-status with only four stainings.
T37544 438542-438765 Sentence denotes The combination of markers for CD4+ and CD8+ T cells, NK and NK T cells, B cells, macrophages, microglia and dendritic cells in one staining gives us the opportunity to dissect subsets of immune cells in a very precise way.
T91840 438766-438885 Sentence denotes Additionally, fluorescent labelled beads can be used to quantify absolute numbers of these cell populations in the CNS.
T82762 438886-439124 Sentence denotes During Experimental Autoimmune Encephalomyelitis (EAE), we could show that even before onset of disease, certain cell types already infiltrate in considerable amounts, amplify after onset of symptoms and peak at the maximum disease score.
T69483 439125-439278 Sentence denotes After relapse, the immune response is constricted, and the composition of immune cell types is altered substantially compared to before onset of disease.
T28875 439279-439518 Sentence denotes By using markers for specific cell subsets (naive/effector/ memory cells, regulatory cells) in combination with intracellular cytokine staining, we can follow the transition stages of CD4+ T cell differentiation in the inflammatory lesion.
T43053 439519-439699 Sentence denotes Finally, the presence of antigen-presenting cells (APC), like macrophage or dendritic cell subsets, and changes in their maturation can be monitored over the course of the disease.
T45201 439700-439818 Sentence denotes This protocol has also successfully been applied to the study of brain-infiltrating cells in a mouse model for stroke.
T77843 439819-440007 Sentence denotes Combining this flow cytometry data with histological analysis in the context of disease course allow for a very well defined representation of the mechanisms involved in disease pathology.
T29655 440008-440255 Sentence denotes We report here the paradoxical development of spontaneous experimental autoimmune encephalomyelitis (EAE) in a myelin oligodendrocyte glycoprotein (MOG)-specific T cell receptor (TCR) transgenic mice (2D2) in the absence of the target autoantigen.
T51116 440256-440381 Sentence denotes We show that in these animals T cells cross-react against an alternative, self-mimicking autoantigen, neurofilament-M (NF-M).
T57673 440382-440511 Sentence denotes In the transgenic 2D2 strain, more than 90% of all CD4+ T cells express transgenic TCR recognizing MOG p35-55 in context of I-Ab.
T72859 440512-440609 Sentence denotes Between 10-20% of these mice spontaneously develop EAE that involves optic nerve and spinal cord.
T51663 440610-440745 Sentence denotes We now report the same proportion of 2D2 mice come down with spontaneous EAE in the absence of the cognate target autoantigen i.e. MOG.
T99809 440746-440930 Sentence denotes EAE in MOGsufficient (MOG+/+) and MOG-deficient (MOG−/−) 2D2 mice was indistinguishable in its clinical expression, in number and location of lesions and in their cellular composition.
T90783 440931-441096 Sentence denotes We isolated proteins from MOG−/− CNS material and found that a fraction containing predominantly NF-M protein induced strong proliferative activation of 2D2 T cells.
T43748 441097-441180 Sentence denotes The salient epitope sequence shared with MOG p35-55 essential TCR contact residues.
T14739 441181-441371 Sentence denotes The response of 2D2 T cells to recombinant NF-M protein and synthetic peptides was heteroclitic with regard to MOG p35-55, resulting in higher proliferation activity and cytokine production.
T90467 441372-441584 Sentence denotes It appears that cross-reaction between MOG and NF-M is not a private response pattern limited to the 2D2 TCR, but was also noted in oligoclonal MOG reactive CD4+ T cells freshly isolated from primed C57BL/6 mice.
T77779 441585-441705 Sentence denotes This is the first report on immunological self-mimicry involving two distinct autoantigens within the same target organ.
T73084 441706-441844 Sentence denotes Neurodegeneration is an important feature of multiple sclerosis (MS) while the underlying mechanisms of axonal loss are poorly understood.
T39716 441845-442050 Sentence denotes We investigated whether two-pore-domain potassium channel TASK1 contributes to neurodegeneration in experimental autoimmune encephalomyelitis (EAE) using TASK1 knockout mice and pharmacological approaches.
T21617 442051-442193 Sentence denotes We used ELISA, proliferation assays, FACS analysis and electrophysiological measurements to characterize T lymphocytes of TASK1 knockout mice.
T54590 442194-442262 Sentence denotes EAE was induced with MOG peptide in wildtype mice and knockout mice.
T29127 442263-442405 Sentence denotes Neurodegeneration was measured by immunohistochemical staining of spinal cord sections and by magnetic resonance imaging (MRI) of mouse brain.
T32384 442406-442479 Sentence denotes TASK1 knockout mice showed a dramatic amelioration in EAE disease course.
T73394 442480-442731 Sentence denotes As shown by immunohistochemical staining for SMI-31/-32 and subsequent counting of axons in predefined areas of the spinal cord TASK1 knockout mice also were less susceptible to neurodegeneration compared with wildtype mice (29%-43% less axonal loss).
T46442 442732-442799 Sentence denotes The immune system of TASK1 knockout mice showed a normal phenotype.
T23888 442800-442974 Sentence denotes The endogenous cannabinoide anandamide which is known to block TASK1 failed to reduce INFgamma production and proliferation rate in isolated T lymphocytes from knockout mice.
T52500 442975-443125 Sentence denotes Anandamide also showed no effect on the potassium outward current in TASK1−/− CD4+ T lymphocytes as demonstrated by electrophysiological measurements.
T19817 443126-443305 Sentence denotes Daily application of anandamide in wildtype mice undergoing EAE reduced disease severity and brain atrophy as assessed by repeated MRI scans of individual mice (34% less atrophy).
T59544 443306-443537 Sentence denotes TASK1 channels are members of the two-pore domain potassium channel (K2P) family that are widely expressed within the brain and contribute to maintaining and regulating the resting membrane potential of various neuronal cell types.
T43037 443538-443686 Sentence denotes Efflux of K+ ions plays a major role in apoptotic cell death in neurons suggesting a role of TASK1 channels in neurodegeneration as it occurs in MS.
T35970 443687-443860 Sentence denotes Modulation of TASK1 channels may provide neuroprotective potential, therefore further studies on leak potassium channels in neuroinflammatory disorders are urgently awaited.
T63206 443861-444055 Sentence denotes In multiple sclerosis (MS) disease susceptibility has been tied to the major histocompatibility complex (MHC) HLA-DR2 haplotype containing both the DRB5⁎0101 (DR2a) and DRB1⁎1501 (DR2b) alleles.
T64724 444056-444211 Sentence denotes Exhibiting almost complete linkage disequilibrium, recent studies have suggested differential roles for the gene pair in driving or modifying autoimmunity.
T83899 444212-444487 Sentence denotes To characterize the specific contribution of DR2a to disease pathogenesis, humanized transgenic (Tg) mice carrying the DR2a allele were created and subsequently crossed to Tg mice carrying an MS patient-derived myelin basic protein (MBP) 83-99 specific T cell receptor (TCR).
T22169 444488-444610 Sentence denotes Two lines expressing different levels of DR2a showed differential skewing in the generation of CD4 versus CD8 populations.
T28894 444611-444811 Sentence denotes In Rag+/+ as well as Rag−/− animals, MBP-autoreactive T cells can escape deletion and drive spontaneous autoimmunity at low rates (1 to 5% in Rag+/+ animals) depending on the level of DR2a expression.
T20653 444812-445101 Sentence denotes Inflammatory infiltrates, demyelination and associated neuronal damage were present throughout the spinal cord consistent with a classical MBP EAE disease, in addition to minor involvement of the brainstem and peripheral nerve roots in both spontaneous as well as actively induced disease.
T85091 445102-445321 Sentence denotes Positional scanning combinatorial libraries (PSCL) demonstrated the degeneracy of this TCR with recognition of epitopes within several bacterial, viral, and human proteins that can serve as molecular mimics of MBP83-99.
T3899 445322-445522 Sentence denotes In vivo studies are ongoing both in TCR/HLA DR2a and HLA DR2a transgenic mice to determine the pathological relevance of these cross-reactivities and their relationship to antigenic spreading in vivo.
T69454 445523-445754 Sentence denotes These studies emphasize the pathologic contribution of the HLA-DRB5⁎0101 allele to the development of autoreactive T cells when expressed as the sole MHC class II molecule, defining a pathological role for DR2a in CNS autoimmunity.
T842 445755-445894 Sentence denotes Multiple sclerosis (MS) is a complex disease and one of the most common chronic inflammatory disorders of the central nervous system (CNS).
T15442 445895-446177 Sentence denotes A model commonly used for dissection of genes in neuroinflammation is myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (MOG-EAE) that mimics the human disease to a large extent both in the chronicity and the pattern of histopathological lesions.
T97518 446178-446489 Sentence denotes A genome-wide linkage analysis previously performed in an F2 cross between the EAE-susceptible LEW.AV1 and the MHC identical but EAE-resistant PVG.AV1 rat strains identified a quantitative trait locus (QTL) on rat chromosome 1 regulating LPS-induced production of proinflammatory cytokines, namely TNF and IL-6.
T66733 446490-446663 Sentence denotes Using a congenic line between these two rat strains, we confirmed a role of this locus not only in regulation of proinflammatory cytokines but also in regulation of MOG-EAE.
T35726 446664-446751 Sentence denotes Further fine-mapping of this region was performed in an advanced intercross line (AIL).
T13975 446752-446918 Sentence denotes Influence on EAE was dissected in G10 generation of AIL and influence on LPSinduced IL-6 and TNF production and pristane-induced arthritis (PIA) was dissected in G12.
T63536 446919-446966 Sentence denotes The initial EAE QTL was resolved into two loci.
T188 446967-447088 Sentence denotes The first locus regulates clinical phenotypes in EAE and overlaps two QTLs regulating anti-MOG IgG2b and IL-6 production.
T40068 447089-447208 Sentence denotes This locus of 5 Mb harbors approximately 10 genes, including RGMa, a gene playing a role in spinal cord injury in mice.
T8648 447209-447312 Sentence denotes The second locus regulates EAE and overlaps a QTL that regulates PIA, anti-MOG IgG1 and TNF production.
T77792 447313-447514 Sentence denotes Among the interesting genes in this QTL are IL-4R, IL-21R, IL-27, NFAT and LAT are of particular interest due to their involvement in immune regulation, autoimmune diseases or in activation of T-cells.
T83586 447515-447636 Sentence denotes Functional studies showed differential expression of IL-4R, IL-4 and IL-21R in spleens of congenic and parental PVG rats.
T52620 447637-447831 Sentence denotes We were thus able to define two important QTLs in the rat that affect the outcome of both experimental encephalomyelitis and arthritis, which associate with a regulation of cytokines production.
T37950 447832-448058 Sentence denotes Association studies are being performed in a large material of MS patients and controls in addition to more functional studies in the congenic rats with the aim of defining the gene and the pathogenic mechanisms of EAE and MS.
T4165 448059-448218 Sentence denotes Multiple sclerosis (MS) is a sexually dimorphic, chronic, demyelinating autoimmune disease of the central nervous system resulting in disability and paralysis.
T42493 448219-448412 Sentence denotes In the murine model of MS, experimental allergic encephalomyelitis (EAE), young male SJL/J mice have been reported to be resistant to EAE while older males and all aged females are susceptible.
T50128 448413-448564 Sentence denotes By comparing a wide age range of mice immunized with PLP 139-151 and CFA on D0 and D7, we found that female disease severity remains constant with age.
T77456 448565-448789 Sentence denotes In contrast, EAE disease severity increases with increasing age of immunization in males with young males having significantly less severe EAE and older males having significantly more disease than equivalently aged females.
T86100 448790-448931 Sentence denotes Cumulative disease score, peak severity, days affected and severity index all increased with age of immunization in males but not in females.
T17966 448932-449005 Sentence denotes Incidence was not affected by age or sex but there was a seasonal effect.
T96423 449006-449208 Sentence denotes Since castration of young SJL/J mice restores relapsing remitting EAE susceptibility, we compared testes gene expression and hormone levels in young susceptible (B10.PL) and resistant (SJL/J) male mice.
T32465 449209-449318 Sentence denotes Serum progesterone levels remained constant in SJL/J males while levels in B10.PL males fluctuated over time.
T96138 449319-449446 Sentence denotes Specifically, serum progesterone was significantly lower in SJL/J mice from 4-8 wks and converged with B10.PL levels at 10 wks.
T80319 449447-449577 Sentence denotes This time frame correlates with previously published changes in susceptibility to EAE and delayed-type hypersensitivity responses.
T70341 449578-449878 Sentence denotes Microarray analysis of 4 wks old testes found 3-beta-hydroxysteroid dehydrogenase, the enzyme that converts pregnelone to progesterone, was significantly lower in SJL/J mice compared to B10.PL suggesting that lower serum levels of progesterone are due to reduced progesterone synthesis in the testes.
T4510 449879-450007 Sentence denotes To verify that progesterone levels are related to EAE susceptibility, we planned to implant progesterone pellets and induce EAE.
T24501 450008-450107 Sentence denotes When placebo pellets were implanted and EAE induced, the previous sexual dimorphism was eliminated.
T7625 450108-450318 Sentence denotes Implantation of the sham pellet increased EAE severity to equal female EAE severity while non-implanted males had significantly less severe EAE suggesting stress of implantation abrogates the sexual dimorphism.
T29473 450319-450523 Sentence denotes These studies show that age, season and stress can alter the EAE sexual dimorphism in SJL/J mice illustrating the importance of gene-by-environment interactions in EAE disease severity and susceptibility.
T31140 450524-450636 Sentence denotes 36 male Wistar rats were randomly divided into 2 groups: the normal group (18 rats), and the EAE group (18rats).
T93852 450637-450855 Sentence denotes First, we detected the functional and morphological changes by brain stem auditory evoked potential (BAEP), somatosensory evoked potentials (SEP), routine neuropathological methods and immunohistochemical examinations.
T68855 450856-450931 Sentence denotes Second, we analyzed on miRNA expression using miRNA expression microarrays.
T47810 450932-451063 Sentence denotes Third, oligonucleotide microarray was carried out, and the data were correlated with published data on protein and gene expression.
T47382 451064-451185 Sentence denotes The results showed that clinical onsets in the EAE group were sudden, and the time of onset was average 10.6 ± 0.58 days.
T86582 451186-451214 Sentence denotes The incidence rate was 100%.
T49571 451215-451247 Sentence denotes Clinical scores were 3.2 ± 1.12.
T61539 451248-451438 Sentence denotes The pathological manifestations included significant inflammatory cell infiltration of cerebrospinal tissues, formation of vessel gloves but no apparent amyelination zone on myelin staining.
T4208 451439-451554 Sentence denotes Immunohistochemical examination found that there were a large number of activated T cells in brain and spinal cord.
T32812 451555-451680 Sentence denotes Compared with the normal group, 60 pieces of miRNAs up-regulation more than twice, 86 pieces down-regulation more than twice.
T66270 451681-451935 Sentence denotes In addition, the results correlated with relevant DNA microarray data, some of the miRNAs that control the expression of 3 genes (aquaporins-4, interleukin-10 and matrix metalloproteinase-9) known to be important in the progression of MS were identified.
T17030 451936-452024 Sentence denotes The miRNAs participate in posttranscriptional gene regulation in pathophysiology on EAE.
T56116 452025-452118 Sentence denotes Some miRNAs might be molecular features that become biomarkers in MS and related pathologies.
T22191 452120-452409 Sentence denotes We have previously shown that T cell autoreactivity directed against epitopes in the second extracellular loop of myelin proteolipid protein (PLP) correlates strongly with the development of brainstem and cerebellar lesions in multiple sclerosis (MS) patients and in an animal model of MS.
T13766 452410-452588 Sentence denotes PLP is present throughout compact myelin and on the external face of the myelin membrane, and the second extracellular loop would therefore potentially be accessible to antibody.
T30015 452589-452772 Sentence denotes In the current study, we investigate the putative functional properties of auto-antibodies directed against the same region of PLP, and the role that they play in lesion localization.
T7676 452773-453019 Sentence denotes By ELISA, patients with MS (n = 100) were found to have increased serum levels of antibodies specific for myelin proteolipid protein (PLP) compared to healthy controls (n = 40) and patients with other disorders of the CNS (CND patients) (n = 30).
T29373 453020-453186 Sentence denotes Whole human PLP (h-PLP) and multiple PLP peptides were tested: the most consistent reactivity was directed against peptides from the second extracellular loop of PLP.
T7915 453187-453356 Sentence denotes Anti-PLP antibodies from MS patients were usually a mixture of IgM and IgG1 isotypes, with occasional IgG2, whereas the majority of control sera were of the IgM isotype.
T2086 453357-453467 Sentence denotes PLP-specific antibodies were also tested for their ability to opsonize myelin for phagocytosis by macrophages.
T82772 453468-453645 Sentence denotes Sera that contained high titres of PLP peptide-specific antibodies were pre-adsorbed with the PLP peptides or with control peptides before being used in the opsonization assays.
T92776 453646-453752 Sentence denotes PLP peptides could specifically absorb out the opsonizing activity, to some degree, in all samples tested.
T72361 453753-453871 Sentence denotes There was a positive correlation between the ability of sera to opsonize myelin and the EDSS score of the MS patients.
T85536 453872-454011 Sentence denotes Anti-PLP antibodies were then tested for their ability to affect where lesions develop and the degree of demyelination in the animal model.
T12052 454012-454140 Sentence denotes When PLP-specific T cells alone were injected into C3H/ HeJ mice, lesions developed in the brainstem, but not in the cerebellum.
T45967 454141-454269 Sentence denotes Anti-PLP190-209-specific antibodies injected together with the T cells resulted in lesions in both the brainstem and cerebellum.
T99705 454270-454387 Sentence denotes The results strongly suggest that PLP-specific antibodies could be of functional relevance in the pathogenesis of MS.
T15138 454388-454502 Sentence denotes To determine frequencies and functions of natural killer (NK) cells in untreated patients with multiple sclerosis.
T74607 454503-454708 Sentence denotes Background: NK cells are multicompetent lymphocytes of the innate immune system, whose central role in host defense, immune regulation and autoimmunity has been increasingly recognized over the last years.
T26127 454709-454839 Sentence denotes Notably, expansion of CD16-CD56bright NK cells correlates with treatment response in daclizumab (anti-IL-2Ra)-treated MS patients.
T63108 454840-455217 Sentence denotes Frequency, phenotype and expansion of blood-derived NK cell and T cell subsets were investigated by flow cytometry ex vivo, following activation with the classical NK cell mitogen interleukin (IL)-2 and limiting concentrations of the monokine IL-12 in 20 untreated patients with clinically isolated syndrome (CIS) and relapsing remitting MS compared to 25 healthy blood donors.
T21035 455218-455482 Sentence denotes In addition, we determined the cytolytic activity of resting and cytokine-activated NK cells and cytolytic T cells towards a CD4+ T cell line (CEM) and allogeneic mitogen-stimulated CD3+ T cell blasts by a flow cytometry-based cytotoxocity and degranulation assay.
T65483 455483-455565 Sentence denotes Ex vivo frequencies of NK cells and T cells were similar in patients and controls.
T24100 455566-455735 Sentence denotes In contrast, MS patients showed an impaired expansion of both CD16+CD56+ and CD16-CD56 bright NK cells but not CD4+ or CD8+ T cells following IL-2 and IL-12 stimulation.
T85760 455736-455917 Sentence denotes Expression levels of activation markers (CD25, HLA-DR, NKp44) were consistently higher on both NK cell subsets, but similar in T cells from MS patients compared to healthy controls.
T77541 455918-456111 Sentence denotes Resting NK cells from MS patients showed an increased cytolytic activity towards both CEM T cells and primary allogeneic T cell blasts, which was not further increased upon cytokine activation.
T15995 456112-456180 Sentence denotes Phenotype and function of CD16+ and CD16-NK cells are altered in MS.
T37299 456181-456352 Sentence denotes The increased activation and cytolytic potential towards T cells but impaired expansion suggest that NK cells are involved in regulating antigen-driven autoimmunity in MS.
T63002 456353-456527 Sentence denotes Natalizumab is a humanized recombinant monoclonal antibody against very late activation antigen-4 (VLA-4) approved for the treatment of patients with multiple sclerosis (MS).
T95635 456528-456765 Sentence denotes A phase II study failed to demonstrate a difference between natalizumab treatment groups and the placebo group with regard to gadolinium enhancing lesions on magnetic resonance imaging (MRI) three months after discontinuation of therapy.
T98643 456766-457004 Sentence denotes The objective of this study was to assess clinical MS disease activity, surrogate disease markers on MRI, immunological parameters in peripheral blood and CSF, as well as safety in MS patients after discontinuation of natalizumab therapy.
T23521 457005-457201 Sentence denotes This study is a longitudinal and serial cross-sectional assessment, in which 23 patients who were treated with natalizumab in the context of two phase III clinical trials were originally enrolled.
T55929 457202-457253 Sentence denotes A subgroup of patients was followed over 14 months.
T82749 457254-457536 Sentence denotes The annual relapse rate, neurological disease progression assessed by the Expanded Disability Status Scale, disease surrogate markers on magnetic resonance imaging (MRI), cellular and humoral immune markers in peripheral blood and CSF, and adverse events of the drug were monitored.
T14019 457537-457666 Sentence denotes With regard to clinical disease activity, neuroimaging, and immune responses, the majority of patients in our cohort were stable.
T61235 457667-457785 Sentence denotes Decreased lymphocyte cell numbers and altered cell ratios returned to normal 14 months after cessation of natalizumab.
T99726 457786-457828 Sentence denotes No infectious complications were observed.
T87508 457829-457908 Sentence denotes This is the first long-term follow-up of patients who discontinued natalizumab.
T44381 457909-458035 Sentence denotes We did not observe a clinical, radiographic, or immunological rebound phenomenon after discontinuation of natalizumab therapy.
T15773 458036-458177 Sentence denotes Stoop Marcel 1 , Verbraak Evert⁎ 1 , Jafari Naghmeh 1 , van Meurs Marjan 1 , Wierenga Annet 1 , Luider T 1 , Laman Jon 1 , Hintzen Rogier 1 1
T11755 458178-458283 Sentence denotes Multiple sclerosis (MS) is a complex disease of which the underlying mechanisms remain poorly understood.
T23558 458284-458493 Sentence denotes Systematic comparison of differentially occurring peptides in the cerebrospinal fluid (CSF) in MS patients versus reference groups allows identification of disease related secreted molecules and tissue debris.
T76518 458494-458669 Sentence denotes We therefore performed state of the art MALDI-TOF Mass Spectrometry on large series of CSF samples, as CSF is the closest source of brain secretory products and tissue debris.
T93257 458670-458790 Sentence denotes This allowed the identification of differentially occurring peptides between MS patients and the selected control group.
T53493 458791-458877 Sentence denotes One of the peptide sequences differentially detected was clusterin (apolipoprotein J).
T17545 458878-459048 Sentence denotes The normal adult brain is one of the major clusterin expressing sites while during chronic inflammation and injury of the brain clusterin expression is further increased.
T58991 459049-459197 Sentence denotes Several functions have been ascribed to clusterin i.e. phagocyte recruitment signaling, cell aggregation, complement inhibition and lipid transport.
T68520 459198-459349 Sentence denotes This study aimed at further unraveling whether clusterin sequences found in the CSF are expressed at the mRNA and protein level within MS brain tissue.
T6261 459350-459500 Sentence denotes Quantitative PCR was used for the analysis of Clusterin mRNA expression within MS brain, normal appearing white matter and non-demented control brain.
T71368 459501-459624 Sentence denotes Clusterin mRNA expression was significantly increased in MS brain tissue compared to brain tissue of non-demented controls.
T77874 459625-459769 Sentence denotes Moreover, in situ analysis showed elevated clusterin protein expression in active and in preactive lesions as compared to non-demented controls.
T36226 459770-459851 Sentence denotes Preliminary data suggest that the main cells expressing clusterin are astrocytes.
T93316 459852-459942 Sentence denotes In addition cells within the perivascular infiltrates also occasionally express clusterin.
T21761 459943-460054 Sentence denotes Collectively the data show that clusterin is actively expressed on both the mRNA and protein level in MS brain.
T35140 460055-460154 Sentence denotes These results support the hypothesis that clusterin is actively involved during inflammation in MS.
T31577 460155-460212 Sentence denotes Myelin T cells reactive may play a pathogenic role in MS.
T27027 460213-460411 Sentence denotes We and others have shown that regulatory CD4+CD25+FOXP3+CD127low T cells (Tregs) are functionally disturbed in relapsing-remitting (RR) MS patients but not in secondary progressive (SP) MS patients.
T22066 460412-460585 Sentence denotes The goal of our current study was to clarify this difference in Treg activity between early and chronic disease stages in MS by studying Treg function and homeostasis in MS.
T51019 460586-460711 Sentence denotes We analyzed the functional capacity and homeostatic parameters of (precursor) naive Tregs (nTregs) and memory Tregs (mTregs).
T40020 460712-461021 Sentence denotes We also measured MBP and MOG proliferative responses of CD4total T cells (including Tregs), naive (CD45RAhigh) and memory (CD45RA-) CD4+CD25-CD127high T cells (no Tregs included) of RR-and SP-MS patients and HC by means of a CFSE dilution assay and measured cytokine production of the myelin reactive T cells.
T46949 461022-461184 Sentence denotes The suppressive capacity of FACS-sorted nTregs was impaired in both early and chronic MS patients, whereas only the latter group showed a restored mTreg function.
T75663 461185-461323 Sentence denotes Chronic MS patients had increased numbers of mTregs as compared to age-matched early MS patients whereas nTreg frequencies did not differ.
T9193 461324-461459 Sentence denotes T cell receptor excision circle (TREC) numbers were reduced in nTregs of early MS patients indicating a diminished nTreg thymic output.
T86950 461460-461666 Sentence denotes MBP and MOG proliferative responses of CD4total T cells but not of Treg-depleted naive and memory CD4+CD25-CD127high T cells were significantly higher in RR-MS patients as compared to HC and SP-MS patients.
T79266 461667-461785 Sentence denotes A significantly higher proportion of myelin reactive memory T cells from MS patients as compared to HC produced IL-17.
T7033 461786-461894 Sentence denotes These data provide evidence for a disturbed thymic nTreg development and function in early MS disease stage.
T97352 461895-462005 Sentence denotes This may play a role in the peripheral activation of myelin antigen reactive T cells leading to CNS pathology.
T56818 462006-462161 Sentence denotes Future therapeutic immune interventions for MS may focus on an early restoration of Treg function and suppression of pathogenic myelin reactive Th17 cells.
T60123 462162-462382 Sentence denotes 6 -Inflamed blood-brain barrier promotes recruitment of effector memory CD8+ T lymphocytes However the phenotype of migrating CD8+ T lymphocytes and the mechanism by which such cells cross the BBB remain largely unknown.
T1680 462383-462486 Sentence denotes Our objective is to evaluate the phenotype of and mechanism by which CD8+ T lymphocytes access the CNS.
T73093 462487-462708 Sentence denotes Using CSF obtained from MS patients and spinal cord material from MOG (35-55)-induced EAE, we demonstrate that CD8+ T lymphocytes are mostly of the effector memory (EM) phenotype (CD8+, CD62L-, CCR7-, CD28-, GranzymeBhi).
T40697 462709-462956 Sentence denotes We further show that purified human CD8+ TEM lymphocytes transmigrate more readily across human BBB endothelial cells than ex vivo un-fractionated CD8 lymphocytes and that BBB endothelium promotes the selective recruitment of CD8+ TEM lymphocytes.
T27565 462957-463133 Sentence denotes Furthermore, we provide evidence for an active and selective recruitment of IFN-g-and IL-17-secreting CD8+ lymphocytes by human and mouse BBB endothelium, in vitro and in vivo.
T30411 463134-463283 Sentence denotes Finally we show that the migration of CD8+ T lymphocytes across BBB-ECs is dependent on VLA-4, but independent of ICAM-1/LFA-1, ALCAM and P-selectin.
T11037 463284-463428 Sentence denotes Our study thus provides evidence for an active role of the BBB in the recruitment of potentially auto-aggressive CD8 TEM lymphocytes to the CNS.
T42486 463429-463598 Sentence denotes The small 27 kD heat shock protein (HSP27) is induced in a variety of cells following stress and inflammation, where it promotes cell survival and inhibits inflammation.
T955 463599-463749 Sentence denotes Little is known on the localization of HSP27 and its phosphorylated form in the central nervous system tissues after autoimmune or irradiation injury.
T99268 463750-463954 Sentence denotes In this study, we examined the expression of both HSP27 and phosphorylated form of HSP27 (phospho-HSP27) in the spinal cords with experimental autoimmune encephalomyelitis (EAE) and gamma ray irradiation.
T4503 463955-464126 Sentence denotes Western blot analysis showed that both HSP27 and phospho-HSP27 was weakly expressed in normal spinal cords, significantly increased in the spinal cord with EAE (P b 0.01).
T15642 464127-464410 Sentence denotes Immunohistochemistry showed that both HSP27 and phospho-HSP27 were constitutively expressed in neurons and some fibrous astrocytes in the spinal cords of normal rats; its immunoreactivity was increased primarily in fibrous astrocytes of the white matter in EAE-affected spinal cords.
T12851 464411-464486 Sentence denotes A similar finding was also recognized in the spinal cords with irradiation.
T53154 464487-464579 Sentence denotes However, few inflammatory cells in EAE were immunopositive for both HSP27 and phospho-HSP27.
T88347 464580-465019 Sentence denotes Collectively, we postulated that increased phosphorylation of HSP27, which is constitutively present in the neurons and glial cells, rescues host cells including neurons and glial cells against autoimmune attack or radiation induced injury in the central nervous system. ⁎This work was supported by a program of the Basic Atomic Energy Research Institute (BAERI), which is a part of the Nuclear R&D Programs funded by KOSEF in South Korea.
T71596 465020-465167 Sentence denotes An important neuropathological feature of Multiple Sclerosis (MS), but also other lesions within the brain, is the formation of an astroglial scar.
T66902 465168-465279 Sentence denotes Firm interaction of the astrocytes with extracellular matrix proteins is likely to be involved in astrogliosis.
T93007 465280-465474 Sentence denotes Indeed, an increased appearance of various extracellular matrix proteins, such as fibronectin, at the lesion sites in MS has been described (Sobel and Mitchell, 1989; van Horssen et al., 2005) .
T87172 465475-465581 Sentence denotes This astrogliosis represents a major mechanical impediment to remyelination and axonal regeneration in MS.
T44055 465582-465690 Sentence denotes Tissue transglutaminase (TG2) is a multifunctional enzyme, well known for its protein crosslinking activity.
T96307 465691-465907 Sentence denotes At the cellular level, TG2 has been implicated in adhesion and migration of fibroblasts and monocytic cells onto extracellular matrix proteins, including fibronectin (Akimov and Belkin, 2001; Balklava et al., 2002) .
T31284 465908-465977 Sentence denotes These data suggest a pivotal role of TG2 in cell-matrix interactions.
T1115 465978-466135 Sentence denotes As we observed that TG2 is present in astrocytes in active MS lesions, we questioned whether TG2 plays a role in astrocyte-fibronectin interactions in vitro.
T18019 466136-466241 Sentence denotes To this end, intracellular and surface expression of TG2 in primary cultured rat astrocytes was detected.
T13987 466242-466369 Sentence denotes In addition, we observed that inflammatory mediators, present in the CNS of MS patients, regulate TG2 production in astrocytes.
T9300 466370-466519 Sentence denotes Indeed, combinations of IFNγ, TNFα and IL-1β, enhance TG2 production (mRNA and protein) in primary cultured rat glial cells, particularly astrocytes.
T24259 466520-466595 Sentence denotes In contrast, TG2 surface expression is downregulated, particularly by TNFa.
T64950 466596-466764 Sentence denotes Furthermore, adhesion of astrocytes onto fibronectin is, at least, partly mediated by TG2 as determined by siRNA studies and pharmacological inhibition of TG2 activity.
T8079 466765-466958 Sentence denotes We conclude that TG2 present in and on astrocytes is differentially regulated by inflammatory mediators, suggesting that cellular pools of TG2 molecules exists with probable separate functions.
T93809 466959-467066 Sentence denotes TG2 is clearly involved in the interaction of astrocytes with the extracellular matrix protein fibronectin.
T22764 467067-467256 Sentence denotes Thus, TG2 contributes to astrogliosis and thereby possibly impairs regeneration of the Astrocytes play a number of important physiological roles in Central Nervous System (CNS) homeostasis.
T2477 467257-467405 Sentence denotes Inflammation stimulates astrocytes to secrete cytokines and chemokines that guide macrophages/microglia and T-cells to sites of injury/inflammation.
T20690 467406-467601 Sentence denotes Herein, we describe how these processes are controlled by the Suppressor Of Cytokine Signaling (SOCS) proteins, a family of proteins that negatively regulate adaptive and innate immune responses.
T26598 467602-467749 Sentence denotes The objective of this study was to determine how SOCS expression is regulated in primary astrocytes, and the functional implications of expression.
T59574 467750-467906 Sentence denotes In this study, we describe that the immunomodulatory cytokine IFN-β induces SOCS-1 and SOCS-3 expression in primary astrocytes at the transcriptional level.
T92875 467907-468014 Sentence denotes SOCS-1 and SOCS-3 transcriptional activity is induced by IFN-β through GAS elements within their promoters.
T56625 468015-468229 Sentence denotes Studies in STAT-1a deficient astrocytes indicate that STAT-1a is required for IFN-βinduced SOCS-1 expression, while STAT-3 siRNA studies demonstrate that IFN-β-induced SOCS-3 expression relies on STAT-3 activation.
T40854 468230-468554 Sentence denotes Specific siRNA inhibition of IFN-β-inducible SOCS-1 and SOCS-3 in astrocytes enhances their pro-inflammatory responses to IFN-β stimulation, such as heightened expression of the chemokines CCL2 (MCP-1), CCL3 (MIP-1a), CCL4 (MIP-1β), CCL5 (RANTES) and CXCL10 (IP-10), and promoting chemotaxis of macrophages and CD4+ T-cells.
T71572 468555-468709 Sentence denotes These results indicate that IFN-β induces SOCS-1 and SOCS-3 in primary astrocytes in order to attenuate its own chemokine-related inflammation in the CNS.
T53310 468710-468826 Sentence denotes As such, SOCS proteins may serve as therapeutic targets to attenuate unwanted inflammatory responses within the CNS.
T19089 468827-469001 Sentence denotes Microglia and infiltrating macrophages are considered major producers of tumor necrosis factor (TNF), which plays a key role in ischemic tissue injury and brain inflammation.
T91777 469002-469115 Sentence denotes We report that TNF produced by microglia, but not macrophages, is neuroprotective in experimental stroke in mice.
T5648 469116-469228 Sentence denotes We found that cortical infarction was significantly exacerbated in TNF-knock out mice compared to wildtype mice.
T89645 469229-469502 Sentence denotes Bone marrow-chimeric TNF-knock out mice grafted with wildtype bone marrow cells developed larger infarcts than bone marrow chimeric wildtype mice grafted with TNF-knock out bone marrow cells, identifying a neuroprotective role for microglial-but not macrophage-derived TNF.
T3002 469503-469699 Sentence denotes Increased infarction in TNF-p55 receptor (R)-knock out mice compared to TNF-p75R-knock out and wildtype mice suggested that microglial-derived TNF exerted neuroprotective effects through TNF-p55R.
T91268 469700-469918 Sentence denotes The absence of TNF was associated with reduced microglial population size and expression of Toll-like receptor 2 in unmanipulated brain, and enhanced proinflammatory gene expression in unmanipulated and ischemic brain.
T78525 469919-470150 Sentence denotes Our findings identify a neuroprotective role for microglial-derived TNF in the acute phase after focal cerebral ischemia and suggest that microglia determine to what extent endangered cortical neurons survive after ischemic stroke.
T28642 470151-470407 Sentence denotes The pathogenesis of neurogenerative disorders, including Human Immunodeficiency Virus (HIV)-1 associated dementia (HAD), is exacerbated by an imbalance between metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs).
T265 470408-470617 Sentence denotes As the TIMPs have exhibited diverse non-classical effects including anti-apoptotic effects, the induction of TIMP-1 in neuroinflammation likely serves multiple functions in addition to modulating MMP activity.
T964 470618-470775 Sentence denotes Our published studies demonstrated differential TIMP-1 expression in acute versus chronic activation of astrocytes and HAD brain tissues, specific to TIMP-1.
T49504 470776-470888 Sentence denotes Laboratory systems were used to study the mechanisms of astrocyte-TIMP-1 regulation and neuroprotective effects.
T2937 470889-471044 Sentence denotes Primary human neural cells, neurotoxins, virus/viral proteins and molecular manipulations such as TIMP-1 promoter-luciferase reporter constructs were used.
T92091 471045-471242 Sentence denotes Our results indicated that while acute interleukin (IL)-1beta activation upregulates TIMP-1 through multiple mechanisms, chronic downregulation of TIMP-1 is primarily under transcriptional control.
T660 471243-471350 Sentence denotes We show a novel CCAAT displacement protein (CDP) repressor element involved in astrocyte TIMP-1 regulation.
T96746 471351-471474 Sentence denotes Further, we used staurosporine, macrophage-tropic HIV-1 virus and glutamate to induce cell death in cultured human neurons.
T58701 471475-471608 Sentence denotes In these assays, TIMP-1 had equivalent neuroprotective effects as brain-derived neurotrophic factor (BDNF), a classical neurotrophin.
T73890 471609-471757 Sentence denotes Neuroprotective effects were also seen with TIMP-1-T2G, a mutant with no MMP binding, indicating that TIMP-1 neuroprotection is independent of MMPs.
T85763 471758-471858 Sentence denotes Neurotrophic signaling through Bcl-2/Bcl-xL has emerged as a possible pathway in our recent studies.
T19521 471859-471993 Sentence denotes Adenoviral injections in the SCID mouse HIVE model led to astrocyte expression of TIMP-1, suggesting a potential therapeutic approach.
T26421 471994-472157 Sentence denotes Taken together, our results demonstrate that astrocyte-TIMP-1 regulation in HAD is complex and may play a critical role in neuroprotective functions of astrocytes.
T43504 472158-472370 Sentence denotes These data are important for unraveling the mechanisms underlying astrocyte responses during chronic neuroinflammation and have broader implications in other inflammatory diseases that involve MMP/TIMP imbalance.
T78597 472372-472537 Sentence denotes Over the past decade many studies have focused on neuroinflammation as a harmful feature of AD, with the implication that antiinflammatory therapy may be beneficial.
T55102 472538-472640 Sentence denotes More recently, immunization with amyloid beta-peptide (Abeta) has been proposed as a treatment for AD.
T16878 472641-472830 Sentence denotes Experimental models have shown that Abeta accumulation in the brain, a key feature of the disease, can be reversed by immunotherapy mediated, at least in part, by phagocytosis by microglia.
T30070 472831-473037 Sentence denotes We are coordinating a collaborative clinical and neuropathological follow-up of the patients who were in the first trial of active Abeta immunization with full length Abeta42 peptide (Elan Pharmaceuticals).
T68489 473038-473165 Sentence denotes To date we have neuropathology on 9 immunized AD patients (iAD) who died between 4 and 64 months after first immunization dose.
T91614 473166-473309 Sentence denotes In these cases we are exploring the expression of microglial proteins in relation to plaque removal, and compared with unimmunized AD controls.
T43750 473310-473446 Sentence denotes CD68 immunostaining was observed in cerebral cortex of both the iAD cases and AD controls indicating phagocytic activity in both groups.
T75735 473447-473745 Sentence denotes However, the iAD cases showed Abeta within the lysosomes of activated microglia, indicating that Abeta had been phagocytosed; whereas the phagocytic activity in the AD controls was not associated with Abeta within microglia, suggesting that microglia are qualitatively different after immunization.
T84319 473746-473976 Sentence denotes These observations highlight the point that, rather than simply demonstrating that microglia have been activated, it is the specific way in which microglia are activated that is important in determining their role in AD pathology.
T60666 473977-474108 Sentence denotes To what extent the changes in the activation of microglia are reflected in changes in cognitive function, remains to be determined.
T79441 474109-474247 Sentence denotes However, our clinical data so far suggest that despite clearance of plaques, active Abeta immunization did not benefit cognitive function.
T79719 474248-474342 Sentence denotes Stressful life events are known to increase the risk of multiple sclerosis (MS) exacerbations.
T48544 474343-474459 Sentence denotes This phenomenon is thought to be caused by inadequate levels of the anti-inflammatory hormone cortisol after stress.
T49257 474460-474650 Sentence denotes Cortisol is the end product of the hypothalamus-pituitary-adrenal (HPA)-axis, also known as the stress-axis, and is routinely used in its synthetic form, prednisone, to treat relapses of MS.
T1617 474651-474748 Sentence denotes Post-mortem and in vivo studies clearly show that the stress-axis is chronically activated in MS.
T43431 474749-474948 Sentence denotes However, in a postmortem study of 16 MS brain donors, we recently found a highly significant inverse relationship between the responsivity of the stress-axis and severity of MS (Huitinga et al., Ann.
T72540 474949-474956 Sentence denotes Neurol.
T97743 474957-474964 Sentence denotes 2004 ).
T40409 474965-475126 Sentence denotes Therefore, we performed a follow-up study of 31 female MS brain donors to more specifically determine the consequences of stressaxis activity for severity of MS.
T12915 475127-475286 Sentence denotes Clinical, endocrine and neuropathological data of all included MS brain donors were analyzed using statistical software and clearly confirmed our earlier data.
T18140 475287-475456 Sentence denotes Moreover, levels of tau and glutamate in the cerebrospinal fluid (CSF) correlated with the amount of corticotropin releasing hormone (CRH), which drives the stress-axis.
T31185 475457-475636 Sentence denotes Furthermore, our analysis of the neuropathological reports revealed that increased demyelination and decreased remyelination was present in donors with low cortisol and severe MS.
T75187 475637-475824 Sentence denotes Our results emphasize the importance of high cortisol levels in overcoming MS inflammation, a phenomenon observed in pioneer animal studies in the early nineties (Tonelli et al., Immunol.
T24598 475825-475829 Sentence denotes Rev.
T55748 475830-475836 Sentence denotes 2001).
T14849 475837-475999 Sentence denotes The observed correlation of both tau and glutamate CSF levels with CRH suggests that neurodegeneration contributes to chronic activation of the stress-axis in MS.
T87946 476000-476146 Sentence denotes Based on these data, we postulate that low stress-axis responsivity, possibly as a consequence of genetic predisposition, leads to more severe MS.
T78307 476147-476441 Sentence denotes Currently, we are performing studies in MS lesions obtained from the Netherlands Brain Bank, to identify glucocorticoid driven mechanisms affecting the pathogenesis of MS lesions, using immunohistochemistry and laser dissection microscopy in combination with Q-PCR analysis (Koning et al., Ann.
T72623 476442-476449 Sentence denotes Neurol.
T89298 476450-476456 Sentence denotes 2007).
T80288 476457-476546 Sentence denotes A number of immunological functions are dependent on circadian rhythms and regular sleep.
T41679 476547-476667 Sentence denotes This has impact on the type and magnitude of immune responses following antigenic challenge, for example in vaccination.
T27076 476668-476716 Sentence denotes Little is known about the underlying mechanisms.
T57407 476717-476855 Sentence denotes One possibility could be the circadian and sleep-dependent modulation of immune responses by CD4+CD25+ natural regulatory T cells (nTreg).
T40000 476856-476957 Sentence denotes These cells have been shown in a variety of studies to negatively regulate adaptive immune responses.
T95254 476958-477115 Sentence denotes We could show that during normal sleep, the suppressive activity of nTreg was highest at night and almost no suppressive activity was present in the morning.
T85061 477116-477159 Sentence denotes Deprivation of sleep abrogated this rhythm.
T53974 477160-477315 Sentence denotes We now studied whether nTreg suppress T helper 1, 2 and 17 cytokines to the same extent and how this suppression is modified by sleep and circadian rhythm.
T16812 477316-477474 Sentence denotes In a within-subject cross-over design, six healthy young men were examined under defined conditions on two occasions, i.e. during sleep and sleep deprivation.
T36920 477475-477560 Sentence denotes Venous blood was drawn periodically every, 5 h, nTreg function was explored in vitro.
T25830 477561-477714 Sentence denotes nTreg suppress T helper 1 cytokine production and there is almost no suppression of T helper 2 or 17 cytokine production in the sleep and wake condition.
T55019 477715-477814 Sentence denotes In the wake condition suppression of T helper 1 cytokine production was decreased in the afternoon.
T18524 477815-477907 Sentence denotes Responsible for this nTreg functional rhythm might be the sleep dependent hormone prolactin.
T21778 477908-478010 Sentence denotes In preliminary in vitro experiments we could show that prolactin increased nTreg suppressive function.
T44148 478011-478145 Sentence denotes In this study we show that nTreg suppress T helper 1 cytokine production, and that this suppression is disturbed by sleep deprivation.
T90617 478146-478222 Sentence denotes Hence, nTreg contribute to a sleep-dependent modulation of immune responses.
T17607 478223-478447 Sentence denotes Although classically regarded as a disorder of the white matter, alterations of the neuronal compartment of the central nervous system (CNS) are precocious and largely independent of demyelination in multiple sclerosis (MS).
T52536 478448-478564 Sentence denotes Glutamate excitotoxicity has been proposed as a major determinant of neurodegeneration in MS and in experimental MS.
T23379 478565-478702 Sentence denotes However, a physiological study addressing synaptic transmission during immuno-mediated aggression of the central myelin is still lacking.
T51205 478703-478953 Sentence denotes By means of neurophysiological recordings from single neurons in slices, we investigated neuronal and synaptic functioning in major oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS.
T23641 478954-479248 Sentence denotes Striatal neurons, which are particularly prone to degenerate in MS, exhibited complex and dynamic alterations of glutamate-and GABA-mediated transmission, starting in the presymptomatic phase of the disease and evolving independently of inflammatory infiltrates, demyelination or axonal injury.
T91983 479249-479511 Sentence denotes Changes in the activity of NMDA and non-NMDA glutamate receptors, of Na+/Ca++ exchanger and of voltage-dependent Na+ channels, all contributed to up-regulate excitatory inputs to striatal neurons, while GABA-mediated transmission was persistently down-regulated.
T47536 479512-479708 Sentence denotes These data reveal an important role of synaptic dysfunction in the pathological process of EAE, and provide a rationale for the use of neuroprotective strategies since the very early stages of MS.
T18885 479709-479843 Sentence denotes Here we found that during Experimental Autoimmune Encephalomyelitis (EAE), MG cells specifically accumulated at the dorsal SVZ niches.
T25553 479844-480008 Sentence denotes Starting at pre-clinical stages, blood derived MG/macrophages and resident MG cells infiltrated the dorsal SVZs and initiated to secrete both IFNgamma and TNFalpha.
T82674 480009-480155 Sentence denotes Moreover, over-expression of either IFNgamma or TNFalpha by ependymal cells was sufficient to direct the mobilization of MG cells toward the SVZs.
T66397 480156-480250 Sentence denotes This finding prompted us to define the crosstalk between inflammatory cues and resident aNPCs.
T17222 480251-480409 Sentence denotes Thus, by using laser capture microdissection (LCM), we found the over-expression of a subset of chemokines (Ccl2, Cxcl9, Ccl19 and Cxcl10) within the EAE SVZ.
T672 480410-480530 Sentence denotes Moreover, IFNgamma or TNFalpha in vitro stimulation induced aNPCs to over-express some of the abovementioned chemokines.
T14263 480531-480631 Sentence denotes Thus, suggesting that aNPCs are capable of chemo-attracting blood derived cells during inflammation.
T48707 480632-480895 Sentence denotes The constitutive chemokine expression by aNPCs makes neurogenic niches a preferential site for inflammatory cells extravasation, thus impairing the physiological function and might explain the preferential affection of peri-ventricular areas by neuroinflammation.
T33963 480896-481008 Sentence denotes The crucial roles of cytokines in shaping T cell responses have been documented in numerous autoimmune diseases.
T30162 481009-481114 Sentence denotes IL-27, a recently described cytokine, has been shown to exhibit both pro-and antiinflammatory properties.
T94145 481115-481225 Sentence denotes IL-27 favors naïve CD4 T cells differentiation into Th1 cells to the detriment of Th17 or Th2 differentiation.
T55368 481226-481414 Sentence denotes In the absence of IL-27 receptor, mice had enhanced susceptibility to experimental autoimmune encephalomyelitis (EAE), due to the absence of IL-27 inhibitory signaling on Th17 development.
T13020 481415-481543 Sentence denotes Conversely, IL-27 has been demonstrated to promote CTL functions of mouse CD8 T cells, but no information on human cells exists.
T2422 481544-481594 Sentence denotes Moreover, no human CNS source has been identified.
T53706 481595-481732 Sentence denotes Our goals are to investigate the impact of IL-27 on human CD8 T cell functions and to determine the potential human CNS sources of IL-27.
T10321 481733-481850 Sentence denotes CD8 T cells from healthy donors were shortly stimulated in vitro and then analyzed using flow cytometry-based assays.
T89370 481851-482005 Sentence denotes Addition of IL-27 to anti-CD3 activated CD8 T cells led to a significant dosedependent increase of proliferation, and IFN-gamma and Granzyme B production.
T91366 482006-482095 Sentence denotes IL-27 had less impact on human CD4 T cells but significantly boosted their proliferation.
T78852 482096-482173 Sentence denotes Expression of both IL-27 subunits p28 and EBI3 was assessed by real-time PCR.
T78665 482174-482270 Sentence denotes Resting human adult microglia expressed very low/undetectable p28 and basal levels of EBI3 mRNA.
T63831 482271-482490 Sentence denotes Stimulation with TLR3 or TLR4 ligands significantly induced p28 and moderately boosted EBI3 mRNA levels suggesting that these local antigen presenting cells could produce IL-27 within the CNS upon environmental stimuli.
T95144 482491-482658 Sentence denotes These results underscore the pro-inflammatory impact of IL-27 on human CD8 T cells and show that this cytokine could be locally provided in the CNS by human microglia.
T95512 482659-482800 Sentence denotes We are currently investigating how CD8 T cells from MS patients react to stimulation with IL-27. burden that affects 1% people in world-wide.
T2430 482801-482881 Sentence denotes Several evidences indicate abnormalities in dopamine system in both SCZ and BPD.
T3822 482882-483152 Sentence denotes The neuronal calcium sensor NCS-1 is a protein that has many functions such as dopamine D2 receptor desensitization inhibition and involvement with many aspects of neurotransmission as regulation of ionic channels and neurotransmitters release enhancement and exocytose.
T58216 483153-483275 Sentence denotes Also, the NCS-1 protein and mRNA expression levels was found increased in prefrontal cortex (PFC) of SCZ and BPD patients.
T2714 483276-483437 Sentence denotes It is well documented the NCS-1 expression in neural and neuroendocrine cells; recently, it was shown that NCS-1 is also expressed in mast cells and neutrophils.
T40269 483438-483581 Sentence denotes NCS-1 has important functions in mast cells as it stimulates Fc epsilon RI-triggered exocytose and the release of arachidonic acid metabolites.
T7783 483582-483804 Sentence denotes Then, we sought to investigate whether NCS-1 could be expressed in peripheral blood mononuclear cells (PBMC) and if there is a correspondence of the expression on those cells with the levels in PFC of SCZ and BPD subjects.
T20016 483805-484041 Sentence denotes Using flow cytometry, our results have shown that NCS-1 expression was diminished in CD4+T lymphocytes, CD19+ B lymphocytes and CD14+ monocytes of BPD patients and also decreased in CD4+ T lymphocytes and CD56+ NK cells of SCZ patients.
T97083 484042-484154 Sentence denotes These results showed that there is no correlation with NCS-1 expression in PFC and PBMC of SCZ and BPD patients.
T67505 484155-484257 Sentence denotes However, these results showed that NCS-1 might be a putative biomarker for both psychiatric disorders.
T85342 484258-484345 Sentence denotes More work is necessary to investigate the NCS-1 functions in lymphocytes and monocytes.
T62474 484346-484379 Sentence denotes Financial Support: CNPq, FAPEMIG.
T63807 484380-484475 Sentence denotes Thymectomy was first reported as a treatment in non-thymomatous myasthenia gravis (MG) in 1941.
T90562 484476-484585 Sentence denotes However, indications for the use of thymectomy in this population based on randomized trial data are lacking.
T87136 484586-484735 Sentence denotes Over the last 30 years, corticosteroids and other pharmacological immunotherapies have been used increasingly in MG, either alone or with thymectomy.
T98598 484736-484802 Sentence denotes Over this time period, outcomes for MG have improved dramatically.
T2679 484803-485021 Sentence denotes Whether thymectomy has contributed to this positive development remains a point of contention, and recent data will be reviewed.The MGTX study group received funding by NINDS for a 5-year single-blinded, two-arm trial.
T31619 485022-485135 Sentence denotes Approximately 70 centers are participating worldwide with the intention of enrolling 200 generalized MG subjects.
T78168 485136-485618 Sentence denotes The primary study aims to answer three questions: does extended transsternal thymectomy (ETTX) combined with a strictly defined prednisone protocol, when compared with the prednisone protocol alone (1) result in a greater improvement in myasthenic weakness, (2) result in a lower total dose of prednisone, thus decreasing the likelihood of concurrent and long-term toxic effects, (3) enhance the quality of life by reducing adverse events and symptoms associated with the therapies?
T67176 485619-485798 Sentence denotes Inclusion criteria are MG Foundation of America Classes 2 to 4, acetylcholine receptor antibody positivity, age at least 18.0 years and b65.0 years, and disease duration b5 years.
T74032 485799-485839 Sentence denotes Patients can be prednisone naïve or not.
T47116 485840-485889 Sentence denotes Recruitment for the study commenced in late 2006.
T74886 485890-485986 Sentence denotes Diverse regulatory obstacles have been encountered due to the international nature of the trial.
T34812 485987-486081 Sentence denotes The average time for sites to satisfy local and U.S. federal regulations has been 14.5 months.
T41558 486082-486183 Sentence denotes As of July 2008, 61 centers were ready for enrollment and were screening all MG patients encountered.
T71390 486184-486261 Sentence denotes A total of 4575 MG patients have been screened, the vast majority ineligible.
T90154 486262-486300 Sentence denotes Fifty-one patients have been enrolled.
T98113 486301-486347 Sentence denotes The pace of recruitment has increased in 2008.
T36961 486348-486416 Sentence denotes An additional 17 sites are in various stages of regulatory approval.
T74269 486417-486570 Sentence denotes Entry criteria have been modified slightly to favor inclusionincreasing the upper age limit from 60 to b65 years and disease duration from 3 to b5 years.
T29874 486571-486798 Sentence denotes A result favoring thymectomy would establish its benefits unequivocally; failure to show a difference would suggest that thymectomy is an unnecessary procedure in this non-thymomatous population and should lead to cost savings.
T98014 486799-486849 Sentence denotes Thus the results will impact on clinical practice.
T81796 486850-487042 Sentence denotes Transcription of arginase-1 correlated with the presence and number of alternatively aaMph. iNOS transcription and protein expression was pronounced in WT mice but was absent in IL-13T/+ mice.
T56782 487043-487249 Sentence denotes These data provide first evidence of the development of aaMph in a CNS infectious disease model and highlight the essential role of IL-4 or IL-13 in immunopathology during C. neoformans meningoencephalitis.
T72761 487250-487438 Sentence denotes Agrawal Smriti⁎ 1 , Yong Wee 1 1 University of Calgary, Calgary, Canada MMP members have been implicated in detrimental roles in neuroinflammatory diseases such as multiple sclerosis (MS).
T81394 487439-487614 Sentence denotes However, the fact that MMP family members interact with, compensate for, and may even be inhibited by each other has made the biology of MMPs in MS a difficult one to examine.
T47913 487615-487798 Sentence denotes Several MMP members are simultaneously elevated in MS and in EAE, an animal model of MS, and this is thought to be the result of the activation of many cell types in these conditions.
T26906 487799-487899 Sentence denotes Another possibility is that a general inducer of several MMPs is engaged during the disease process.
T77055 487900-487995 Sentence denotes If so, a novel approach to affect MMPs in MS could be to alter the activity of such an inducer.
T31486 487996-488156 Sentence denotes The extracellular matrix metalloproteinase inducer (EMMPRIN, also known as basigin or CD147) is found on the surface of various cell types in an inactive state.
T47804 488157-488238 Sentence denotes EMMPRIN induces fibroblasts and tumor cells to produce and activate various MMPs.
T61872 488239-488308 Sentence denotes Whether EMMPRIN plays a similar role in the immune system is unclear.
T73586 488309-488439 Sentence denotes Our specific objective is to determine a role for extracellular matrix metalloproteinase (EMMPRIN) in MMP regulation in mouse EAE.
T3466 488440-488591 Sentence denotes We utilize a mouse model of EAE, wherein animals develop a clinically disease with infiltration of leukocytes into the CNS, resulting in demyelination.
T70406 488592-488745 Sentence denotes Various tissues from these mice are dissected out and utilized in flow cytometry (FACS), histological staining, Western blotting, and gelatin zymography.
T19905 488746-488882 Sentence denotes We report that the activation of (MOG35-55) specific T-cells in culture leads to their secretion of high levels of glycosylated EMMPRIN.
T74956 488883-489066 Sentence denotes In vivo, we find increased numbers of EMMPRIN positive cells in the CNS of mice from the onset of EAE signs, compared to controls, and these continue to rise with disease progression.
T36150 489067-489170 Sentence denotes EMMPRIN immunoreactivity is detected in the CNS in both infiltrating and resident cellular populations.
T65219 489171-489321 Sentence denotes Finally, EMMPRIN null mice, although susceptible to EAE, showed a slightly delayed onset and reduced severity in EAE disease versus wildtype controls.
T50073 489322-489514 Sentence denotes Taken together, our results indicate that the early rise of EMMPRIN is consistent with subsequent evolving pathology in EAE, and may be attributed to its role as an MMP inducer in the disease.
T77645 489515-489616 Sentence denotes If so, targeting EMMPRIN could help influence the marked elevation of MMPs and disease process of MS.
T72333 489617-489748 Sentence denotes Cytotoxic T lymphocytes (CTL) are considered as important effector cells contributing to CNS damage in neuroinflammatory disorders.
T95567 489749-489955 Sentence denotes We here challenge the mechanisms how CD8 T cells injure neurons and how major histocompatibility complex (MHC) class I restricted, cellcontact-dependent interaction of CTL with neuronal cells is determined.
T99701 489956-490067 Sentence denotes Specific emphasis is placed on the interdependency for perforin and granzyme B in immune-neuronal interactions.
T80161 490068-490244 Sentence denotes We used hippocampal neuronal cells in combination with T-cell receptor (TCR) transgenic CD8 T cells (OT-I) as a paradigm for MHC class I restricted immune-neuronal interaction.
T95008 490245-490431 Sentence denotes Cocultures were analyzed by time-lapse videomicroscopy and two-photon microscopy in conjunction with immunohistochemistry, electrophysiological recordings and molecularbiological assays.
T81512 490432-490554 Sentence denotes Time-lapse video-microscopy showed that CTL kill neurons fast and depending on cell-cell contact as well as antigen (appr.
T12265 490555-490569 Sentence denotes 30% over 4 h).
T54720 490570-490759 Sentence denotes Real-time electrophysiological recordings of basal neuronal parameters upon direct contact with effector CD8 T cells revealed immediate changes in membrane capacitance and resistance (appr.
T19650 490760-490784 Sentence denotes 60% decrease; b=10 min).
T11689 490785-490888 Sentence denotes With a similar kinetic and MHC restriction, neurons showed a rapid influx of Ca2+ upon CTL interaction.
T16713 490889-491103 Sentence denotes Assuming that observed effects most likely reflect the consequences of a TCRdependent poreformation via the granzyme/perforin pathway, we next studied the effects of OT-I cells deficient for granzyme B or perforin.
T76115 491104-491322 Sentence denotes Interestingly, quantification of neuronal killing revealed that CTL deficient for granzyme B or perforin maintain the same neurotoxicity, albeit migratory velocity was significantly slowed in the absence of granzyme B.
T2832 491323-491547 Sentence denotes Single-cell recordings however showed, that perforin deficient T cells had lost their capability to induce neuronal membrane changes or Ca2+ influx, while these immediate effects were maintained in the absence of granzyme B.
T60669 491548-491665 Sentence denotes CTL-mediated injury of MHC class I induced neuronal cells is a fast, antigen and cell-cell contact dependent process.
T3550 491666-491780 Sentence denotes CD8+ effector cells immediately affect basal cellular parameters and induce Ca2+ influx in a MHC I restricted way.
T48432 491781-491941 Sentence denotes While acute electrophysiological consequences of immune-neuronal interaction require perforin, perforin or granzyme B are redundant for long-term neurotoxicity.
T20717 491942-492034 Sentence denotes Fleisher-Berkovich Sigal⁎ 1 , Ben-Shmuel Sarit 1 1 Ben-Gurion University, Beer-Sheva, Israel
T2956 492035-492154 Sentence denotes Increasing evidence suggests that inflammation plays a crucial role in the deterioration of neurodegenerative diseases.
T85012 492155-492371 Sentence denotes The inflammatory response is sustained by chronic microglial activation that includes the over-production of toxic factors by microglial cells, such as proinflammatory cytokines, prostaglandins and nitric oxide (NO).
T31163 492372-492517 Sentence denotes Although NO has many physiological roles, it can turn harmful when produced at high levels (under inflammatory conditions) and lead to apoptosis.
T3093 492518-492733 Sentence denotes Brain inflammation can be regulated by neuropeptides, such as bradykinin (BK) and other members of the kinin family, a group of short-lived peptides formed in response to pathophysiological events like inflammation.
T70569 492734-492831 Sentence denotes BK exerts its effects via two kinin receptors: B1 and B2 receptors (G-protein coupled receptors).
T92857 492832-492969 Sentence denotes While B2 receptor is constitutively expressed in various cells, B1 receptor is induced after cell activation by pro-inflammatory factors.
T64000 492970-493094 Sentence denotes Although BK's pro-inflammatory functions in the periphery have been broadly studied, its role in the brain is not yet clear.
T9587 493095-493266 Sentence denotes Recently, a novel neuroprotective role for BK was suggested via inhibition of lipopolysaccharide (LPS)-induced release of pro-inflammatory cytokines from microglial cells.
T77681 493267-493416 Sentence denotes The goal of the present study was to examine the long term effect of BK receptors agonists on basal and LPS-induced NO release from microglial cells.
T97469 493417-493508 Sentence denotes Nitrite (a stable end-product of NO oxidation) levels were measured using the Griess assay.
T12235 493509-493613 Sentence denotes 24-48 h exposure of BV2 to BK (1, 10 nM) reduced basal NO release by about 75%, and 100 nM respectively.
T9713 493614-493673 Sentence denotes BK decreased NO production by over 90% from control levels.
T83991 493674-493841 Sentence denotes B1 receptor agonist, [Lys-des-Arg9]-BK (10, 100 nM), lead to 70% reduction in NO synthesis while B2 receptor agonist, (1, 10, 100 nM), reduced basal NO release by 40%.
T3906 493842-494029 Sentence denotes Also, BK (1, 10 and 100 nM) attenuated LPS-induced NO production, in a dosedependent manner, with a maximum decrease of 50% at a concentration of 100 nM compared with LPS treatment alone.
T97690 494030-494166 Sentence denotes Similarly, B1 and B2 receptors agonists dose-dependently attenuated LPS-induces NO production by a maximum of 40% and 45%, respectively.
T50469 494167-494326 Sentence denotes These results imply on a possible neuroprotective role of BK via attenuation of NO released from microglial cells under both basal and inflammatory conditions.
T58194 494327-494426 Sentence denotes Lindblom Rickard⁎ 1 , Piehl Fredrik 1 , Diez Margarita 1 1 Karolinska Institutet, Stockholm, Sweden
T22682 494427-494738 Sentence denotes The complement system has been implicated in several neurodegenerative disorders with inflammatory components, e.g. Multiple Sclerosis (MS), Alzheimer, Huntington and Amyotrophic Lateral Sclerosis (ALS), and in experimental systems neurons have proven to be extremely sensitive to lysis by activated complement.
T91558 494739-494842 Sentence denotes So far the degree of genetic heterogeneity in the regulation of the complement system has been unknown.
T12467 494843-494961 Sentence denotes We have here characterized expression of complement components in different rat strains after mechanical nerve injury.
T99419 494962-495117 Sentence denotes As injury model we used lumbar ventral root avulsion (VRA), which is a well characterized model of nerve injury-induced inflammation and neurodegeneration.
T32346 495118-495232 Sentence denotes A kinetic study was performed in inbred DA and PVG rats using several post-operative survival times up to 14 days.
T41021 495233-495333 Sentence denotes A linkage study was performed in a F2 BN × LEW intercross with 151 animals studied 5 days after VRA.
T4438 495334-495492 Sentence denotes Quantitative RT-PCR and immunohistochemistry was used to determine level of expression of C1q and C3, as well as the complement inhibitors clusterin and CD59.
T86315 495493-495636 Sentence denotes The kinetic study demonstrated increased expression of both C1q and C3 early after VRA, with significantly higher levels in DA compared to PVG.
T4202 495637-495778 Sentence denotes Clusterin mRNA was also increased after injury, but induction was slower with the highest expression at 14 days after injury in both strains.
T51397 495779-495833 Sentence denotes In contrast, expression of CD59 was reduced after VRA.
T42325 495834-495943 Sentence denotes Whereas levels had normalized in PVG by 14 days, levels in DA rats remained lower at all studied time points.
T49298 495944-496080 Sentence denotes A whole genome scan for expression of C1q and C3 was performed in the F2 (BN × LEW) intercross, showing linkage to several gene regions.
T91041 496081-496138 Sentence denotes One quantitative trait locus (QTL) regulating C1q on chr.
T96847 496139-496193 Sentence denotes 10 reached the threshold for genome-wide significance.
T48344 496194-496460 Sentence denotes The DA strain, which is more susceptible to nerve cell loss than PVG, displays higher levels of C1q and C3 and lower levels of CD59, supporting the notion that a dysregulated local inflammatory response involving complement activation contributes to nerve cell loss.
T27450 496461-496553 Sentence denotes Gene mapping in an F2 cross demonstrate a polygenic influence, with several suggestive QTLs.
T35474 496554-496630 Sentence denotes A large F2 (DA × PVG) intercross is currently under study in our laboratory.
T50396 496631-496804 Sentence denotes Exact positioning of the responsible genes will contribute to our knowledge about the role of the complement system in conditions of neuroinflammation and neurodegeneration.
T54368 496805-496900 Sentence denotes Microglial-driven inflammation is a feature of the aged brain and neurodegenerative conditions.
T92182 496901-497099 Sentence denotes The inflammatory changes are typified by cytokine release such as interleukin-1beta (IL-1b) and tumour necrosis factor alpha (TNFalpha), and an upregulation of the corresponding signalling pathways.
T28060 497100-497344 Sentence denotes Previous evidence from this laboratory has shown that rosiglitazone, a peroxisome proliferator activated receptor gamma (PPARg) agonist, has the ability to attenuate pro-inflammatory cytokine release and restore the age related deficits in LTP.
T74653 497345-497588 Sentence denotes The present findings suggest that pre-treatment of rosiglitazone did not affect PPARg activation since CD36 mRNA expression, a downstream indicator of activation, was unchanged; rosiglitazone also exerted no effect on PPARg protein expression.
T12502 497589-497720 Sentence denotes These findings concur with previous evidence suggesting that the anti-inflammatory action of rosiglitazone is independent of PPARg.
T30977 497721-497876 Sentence denotes Previous evidence from this laboratory has shown that the anti-inflammatory action of rosiglitazone is mediated by its ability to increase IL-4 expression.
T17720 497877-497994 Sentence denotes In this study the effect of rosiglitazone on mixed glia, astrocytes and microglia was mimicked by IL-4 pre-treatment.
T7007 497995-498125 Sentence denotes This study also showed that rosiglitazone treatment induced an increase in IL-4 from astrocytes (p b 0.05) but not from microglia.
T59356 498126-498244 Sentence denotes The evidence suggests that rosiglitazone attenuates the LPSinduced increase in IL-1b via IL-4 release from astrocytes.
T74987 498245-498320 Sentence denotes Many neurodegenerative disorders are characterized by microglia activation.
T19806 498321-498470 Sentence denotes Such a response must be tightly regulated because unrestrained activation can generate a chronic inflammatory milieu that might lead to autoimmunity.
T30712 498471-498601 Sentence denotes Extracellular adenosine can modulate cellular activation through G-protein coupled, adenosine receptor (ADORA)-mediated signaling.
T24201 498602-498824 Sentence denotes The cellular response to extracellular adenosine is orchestrated by the expression pattern of four different ADORA subtypes: A1, A2a, A2b and A3, which are characterized by their capacity to enhance or inhibit cAMP levels.
T6897 498825-499010 Sentence denotes To study the effects of adenosine during neuroinflammation, we characterized the ADORA expression profile on resting and on Toll-like receptor (TLR)8-activated primary rhesus microglia.
T27975 499011-499064 Sentence denotes Resting microglia expressed mRNA for A2a, A2b and A3.
T11628 499065-499164 Sentence denotes Upon activation, microglia strongly upregulated A2a and A2b and downregulated A3 expression levels.
T23323 499165-499406 Sentence denotes Since A2a and A2b-mediated signaling results in opposite effects than A3-mediated signaling, the predicted relative contribution of A2a and A2b over A3 to adenosine-mediated signaling would be enhanced by N50 fold in TLR-activated microglia.
T3861 499407-499562 Sentence denotes As a consequence, adenosinemediated inhibition of TLR-induced TNFa and IL-12p40p70 was much more potently inhibited in activated than in resting microglia.
T76964 499563-499725 Sentence denotes We could demonstrate that both the sensitivity to adenosine-mediated inhibition, as well as the overall inhibitory potential were enhanced in activated microglia.
T43698 499726-499877 Sentence denotes Microglia acquired this enhanced inhibitory phenotype b8 h upon TLR-mediated activation, and the enhanced inhibitory potential was sustained for N72 h.
T1002 499878-500084 Sentence denotes By using specific antagonists, we determined that the simultaneous increase in A2a, but not that of A2b, mediated signaling, and decrease in A3-mediated signaling were responsible for the described effects.
T65337 500085-500241 Sentence denotes In addition, we demonstrated that the induced ADORA profile on activated microglia was able to crossinhibit cytokine production induced by a variety of TLR.
T67839 500242-500491 Sentence denotes Our data reveal important novel mechanistic aspects of an endogenous brake on inflammation and would suggest exploration of partial A2a agonists and A3 antagonists as therapeutic possibilities to dampen microglial activation in ongoing inflammation.
T67745 500492-500644 Sentence denotes MicroRNAs form a family of several hundred short non-coding RNA molecules predicted to regulate the expression of about 30% of all protein-coding genes.
T32016 500645-500745 Sentence denotes MiRNA-mediated gene regulation is therefore expected to influence the pathogenesis of many diseases.
T45265 500746-500856 Sentence denotes In order to study this form of gene regulation in multiple sclerosis lesions, we followed a two-step strategy.
T889 500857-501004 Sentence denotes In a first step, we isolated MS lesions of different types, along with control white matter, by macrodissection of fixed and frozen brain sections.
T6048 501005-501074 Sentence denotes Total RNA extracted from these samples was amplified by realtime PCR.
T39782 501075-501180 Sentence denotes Among the examined 367 microRNAs, 269 could be detected which formed lesion specific expression profiles.
T81942 501181-501409 Sentence denotes In a second step, we combined Laser capture microdissection of individual cells with analysis of purified cultures of immune cell subsets and astrocytes, to assign the microRNAs regulated in MS lesions to specific cell lineages.
T80566 501410-501586 Sentence denotes Our data indicates that some of the microRNAs which had been upregulated in MS lesions were inducible in vitro during activation of T cells monocytes/macrophages or astrocytes.
T92586 501587-501688 Sentence denotes This work provides a first insight into miRNA mediated gene regulation in multiple sclerosis lesions.
T51169 501689-501718 Sentence denotes The study had two main parts.
T49505 501719-502096 Sentence denotes First, the numbers of Treg cells identified as CD3+CD4+CD25highFoxp3+ cells were determined using 4-color flow cytometry examinations of CSF and blood samples obtained from patients with acute viral meningitis or encephalitis (n = 7), or those experiencing acute relapse of MS (n = 5), as well as patients with non-inflammatory neurological diseases, used as controls (n = 11).
T75664 502097-502407 Sentence denotes Those Treg cells were significantly increased in the blood of MS patients as compared to those of CNS infection and the controls, while those in the CSF were also significantly increased in patients with CNS infection as compared to the controls, with an increasing trend seen in the CSF of active MS patients.
T88554 502408-502710 Sentence denotes Next, both the numbers of Treg cells identified as CD4+CD25highCD127dim cells and those of recently activated helper T cells with a surface CD4+ CD25lowCD127dim phenotype were determined in CSF and blood samples obtained from another series of MS patients in acute relapse as well as from the controls.
T80719 502711-502820 Sentence denotes Recently activated helper T cells were shown to be significantly increased in the blood of those MS patients.
T17386 502821-503052 Sentence denotes In addition, a follow-up study of a patient with tuberculous meningitis showed that Treg cells in the blood increased with improvement of infection, while those in the CSF were increased during early and peak stages of the disease.
T27797 503053-503226 Sentence denotes Treg cells in the CNS and systemic circulation in patients with CNS infection seem to have a regulatory role, thus their measurement is useful for monitoring disease status.
T71726 503227-503309 Sentence denotes In contrast, their numbers may not be relevant for monitoring MS disease activity.
T31458 503310-503429 Sentence denotes It is well established that neurodegenerative disorders are associated with evidence of microglial-driven inflammation.
T92280 503430-503543 Sentence denotes These inflammatory changes include enhanced activation of microglial cells and pro-inflammatory cytokine release.
T34312 503544-503791 Sentence denotes Recent data show that activation of the orphan receptor single Ig IL-1R-related molecule (SIGIRR) inhibits proinflammatory cytokine signalling but the ligand for SIGIRR and downstream signalling events triggered by receptor activation are unknown.
T39893 503792-503990 Sentence denotes In this study, we set out to investigate the effects of lipopolysaccharide (LPS) on microglial activation and cytokine secretion in hippocampal tissue prepared from SIGIRR knockout mice (SIGIRR−/−).
T55302 503991-504179 Sentence denotes We also assessed whether interleukin-1F5 (IL-1F5), a recentlycharacterised member of the IL-1 ligand superfamily which has anti-inflammatory properties, might modulate LPS-induced changes.
T43137 504180-504417 Sentence denotes Microglial activation was assessed by measuring cell surface expression of CD40, and intracellular adhesion molecule (ICAM) by polymerase chain reaction (PCR) and proinflammatory cytokines (IL-1beta, IL-6 and TNF-alpha) by PCR and ELISA.
T4370 504418-504509 Sentence denotes The interaction of IL-1F5 and SIGIRR was assessed by immunofluorescent confocal microscopy.
T70427 504510-504742 Sentence denotes The results demonstrate that the LPS-induced increase in expression of CD40 (p b 0.05), ICAM (p b 0.001), IL-1beta (p b 0.05), IL-6 (p b 0.05) and TNF-alpha (p b 0.05) mRNA was enhanced in SIGIRR−/− mice compared with wildtype mice.
T11469 504743-504893 Sentence denotes IL-1F5 attenuated the LPS-induced increase in IL-1beta (p b 0.01) in wildtype mice and these antagonistic effects were not observed in SIGIRR−/− mice.
T86475 504894-505036 Sentence denotes These findings show that SIGIRR has anti-inflammatory actions in the CNS since SIGIRR−/− mice showed enhanced responsiveness to LPS treatment.
T81637 505037-505238 Sentence denotes Furthermore, that IL-1F5 is a possible ligand for SIGIRR, since the antagonistic effects of IL-1F5 on LPS-induced signalling were not observed in SIGIRR−/− mice and IL-1F5 was co-localised with SIGIRR.
T18412 505239-505366 Sentence denotes Taken together, the data suggest that the interaction of SIGIRR and IL-1F5 is a significant immunomodulatory system in the CNS.
T44552 505367-505511 Sentence denotes Despite the advances in antibiotic management acute bacterial meningitis remains a life threatening neurological disease if not managed rapidly.
T511 505512-505641 Sentence denotes The estimated incidence is 2-5 per 100 000 people per year in developed countries and up to ten times this in developing regions.
T54608 505642-505838 Sentence denotes The cellular immune response in the CNS plays a major role in controlling the infection but the study of cytokines and any protective or harmful role they may play in the CNS is poorly understood.
T80131 505839-505999 Sentence denotes Glial cells, the main immune cells in the CNS are known to release cytokines and other immune mediators forming a network of stimulatory and inhibitory effects.
T6272 506000-506168 Sentence denotes The time and dose dependant release of 23 cytokines by microglia, astrocytes, neurons and mixed cultures were tested in each cell type following pneumococcal infection.
T29359 506169-506318 Sentence denotes Cell cultures were infected with 2 clinical isolates of Streptococcus pneumoniae; the first was isolated from CSF and the second from the oropharynx.
T90741 506319-506444 Sentence denotes Cytokine release into culture supernatants was measured at various time points using a commercially available Bio-Plex assay.
T8868 506445-506546 Sentence denotes Mixed cultures showed more controlled release of cytokines in comparison to pure microglial cultures.
T30510 506547-506696 Sentence denotes In contrast to findings from previous studies, infected pure microglial, astrocyte and neuron cultures were found to actively produce some cytokines.
T20835 506697-506799 Sentence denotes The infected cultures showed significant increase in cytokine release compared to uninfected cultures.
T76404 506800-506933 Sentence denotes The neurological isolate induced a backward dose effect with lower cytokine levels produced at higher concentrations of the organism.
T64657 506934-507056 Sentence denotes This effect was not seen with the orophanyngeal isolate and could be reversed by heat inactivating the infecting inoculum.
T56958 507057-507282 Sentence denotes The findings demonstrate a time and dose dependant profile of cytokine production in the CNS in response to pneumococcal infection and may be important in understanding the neurological pathogenesis of pneumococcal infection.
T52276 507283-507628 Sentence denotes 12 -Differentiation of primary adult microglia alters their response to TLR8-mediated activation but not their capacity as APC We show that although cell morphology and expression levels of activation markers were markedly different, differentiation with either factor yielded microglia that phenotypically and functionally resemble macrophages.
T23879 507629-507788 Sentence denotes Both M-CSF and GM-CSF-differentiated microglia were responsive to TLR1/2, 2, 3, 4, 5, 6/2, and 8-mediated activation, but not to TLR7 or 9-mediated activation.
T42745 507789-508037 Sentence denotes Intriguingly, M-CSF-differentiated microglia expressed higher levels of TLR8-encoding mRNA and protein and produced larger amounts of pro-inflammatory cytokines in response to TLR8-mediated activation as compared to GM-CSF-differentiated microglia.
T92907 508038-508288 Sentence denotes While differentiation of adult microglia by growth factors that can be produced endogenously in the central nervous system is thus unlikely to change their APC function, it can alter their innate responses to infectious stimuli such as ssRNA viruses.
T32580 508289-508386 Sentence denotes Resident primate microglia may thereby help shape rather than initiate adaptive immune responses.
T78465 508387-508667 Sentence denotes 13 -Immunoregulatory role for perforin in an animal model of CD8+ T cell-mediated demyelinating disease Accumulating evidence indicate that CD8+ T cells may contribute significantly to disease pathogenesis in multiple sclerosis and other autoimmune diseases of the nervous tissue.
T51138 508668-509041 Sentence denotes To gain insights into the potential mechanisms by which this T cell subset may induce nervous tissue injury, we study an animal model (herein referred to as L31 mice) that spontaneously develops a CD8+ T cell-mediated demyelinating disease associated with axonal damage primarily due to the transgenic expression of the B7.2 (CD86) T cell costimulatory ligand on microglia.
T73115 509042-509265 Sentence denotes We previously reported that the CD8+ T cells that accumulate in the central nervous system (CNS) of L31 mice are potent IFN-gamma producers and that responsiveness to this cytokine is a prerequisite for disease development.
T10993 509266-509693 Sentence denotes Since IFN-gamma is a powerful inducer of MHC-I expression and a common mechanism by which CD8+ T cells mediate destruction of MHC I-expressing cells is through the perforin pathway, we hypothesized that IFN-gamma production by CNS CD8+ T cells promotes upregulation of MHC-I expression on neurons and/or oligodendrocytes, which could become targets of a MHC-I-restricted perforin-dependent CD8+ T cellmediated cytotoxic attack.
T96879 509694-509876 Sentence denotes MHC-I expression was detected on oligodendrocytes but not on neurons in pre-clinical L31 animals and CD8+ T cells were observed in close contact to MHC I-expressing oligodendrocytes.
T41730 509877-510190 Sentence denotes L31 mice deficient in perforin expression (Perf−/−) exhibited the same clinical and pathological features as perforin competent animals but with an accelerated onset and hastened expansion/accumulation of CD8+ T cells in the CNS that couldn't be attributed to disparities in the peripheral CD8+ T cell population.
T28798 510191-510430 Sentence denotes Our results indicate that oligodendrocytes have the potential to interact with CNS CD8+ T cells in a MHC-I-dependent fashion before clinical manifestations of disease but demyelination does not occur through a perforin-dependent mechanism.
T91262 510431-510512 Sentence denotes Perforin appears rather to regulate the expansion of CD8+ T cells within the CNS.
T69983 510513-510717 Sentence denotes 14 -Diabetic ketoacidosis in mice elicits a unique cytokine response between serum and brain Diabetic keotacidosis (DKA) is a complication of type 1 diabetes requiring immediate recognition and treatment.
T34243 510718-510866 Sentence denotes Despite careful treatment, children are at high risk for intracranial complications during DKA therapy, such as brain swelling, stroke and bleeding.
T79447 510867-510913 Sentence denotes The causes of these complications are unknown.
T81844 510914-511003 Sentence denotes However, DKA elicits a systemic inflammatory response associated with elevated cytokines.
T94039 511004-511138 Sentence denotes Therefore, systemic or local production of cytokines in the CNS might contribute to neuroinflammation through a variety of mechanisms.
T3847 511139-511219 Sentence denotes We sought to determine levels of cytokines in serum and brain tissue during DKA.
T17579 511220-511327 Sentence denotes We used our juvenile mouse model of DKA that develops DKA 72 h after injection of streptozocin and alloxan.
T25573 511328-511651 Sentence denotes Serum and cortex samples obtained from both control and DKA mice were quantitatively analysed for the cytokines interleukin (IL)-1a, IL-1b, IL-2, IL-6, IL-9, IL-10, IL-18, keratinocyte-derived chemokine (KC; mouse ortholog of human IL-8), Interferon (IFN)-g and tumor necrosis factor (TNF)-a using multiplexed immunoassays.
T83704 511652-511718 Sentence denotes Transforming growth factor (TGF)-b1 levels were analysed by ELISA.
T4225 511719-511878 Sentence denotes Mice were confirmed to be in DKA by having significantly higher serum glucose, beta-OH-butyrate levels and weight loss compared to controls (p b 0.01, n = 10).
T25607 511879-512116 Sentence denotes Analysis of serum revealed DKA mice had significantly elevated levels of proinflammatory cytokines IL-6 and KC (p b 0.05, n = 9-10) and antiinflammatory cytokines IL-10 (p b 0.01, n = 7-9) and TGF-b1 (p b 0.05, n = 9-10) versus controls.
T43217 512117-512290 Sentence denotes In contrast, only anti-inflammatory cytokines were significantly altered in brain, IL-10 decreased (p b 0.05, n = 9-10) in DKA mice, and TGF-β1 increased (p b 0.01, n = 10).
T45405 512291-512452 Sentence denotes There was no significant difference in the levels of proinflammatory cytokines, IL-6 (p = 0.198, n = 10) and KC (p = 0.791, n = 10), in DKA mice versus controls.
T85627 512453-512659 Sentence denotes We also found that IL-6 (r^2 = −0.661) and KC (r^2 = −0.727) levels in serum correlate with weight lost in DKA mice (p b 0.05, n = 10) and blood glucose levels (r^2 = 0.923; r^2 = 0.914, p b 0.001, n = 10).
T41727 512660-512778 Sentence denotes These results are novel since the inflammatory response that occurs in the brain is unique from the systemic response.
T18054 512779-512918 Sentence denotes These differential changes in inflammation between serum and brain might be a contributing factor to intracranial complications during DKA.
T5213 512919-513035 Sentence denotes This also indicates that there maybe a relationship between levels of proinflammatory cytokines and severity of DKA.
T59694 513036-513336 Sentence denotes Panatecs, Tuebingen, Germany Autoimmune central nervous system (CNS) inflammation such as found in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) requires activation of myelin reactive T cell in the periphery and inside the target organ by antigen presenting cells (APC).
T46230 513337-513483 Sentence denotes Microglia are CNS resident APC and have been shown to present a cryptic epitope from myelin basic protein (MBP) inside CNS lesions in MS patients.
T99598 513484-513661 Sentence denotes In order to better understand the events leading to generation and display of this epitope, we investigated the antigen processing machinery and MBP processing during acute EAE.
T69138 513662-513804 Sentence denotes Different APC populations were isolated from susceptible DA and resistant ACI rats immunized with MBP85-99 at the onset of disease in DA rats.
T96513 513805-513876 Sentence denotes Cathepsin activities were determined using active site directed probes.
T48920 513877-514019 Sentence denotes In addition, human recombinant MBP was digested with lysosomal contents from microglia, splenic B cells and splenic DC and fragments analysed.
T11683 514020-514249 Sentence denotes We found that MBP processing in microglia from both rat strains was dominated by cathepsin D which destroyed the main immunogenic epitope MBP85-99 and that processing in both strains was similar both in the periphery and the CNS.
T22893 514250-514460 Sentence denotes MBP was efficiently destroyed in all cell types investigated, with no obvious differences between the two strains, suggesting that differences in processing cannot account for the differences in susceptibility.
T99659 514461-514749 Sentence denotes While in mouse microglia cultures, CatG is the protease dominating MBP processing, in rat primary microglia, CatD limits presentation of the MBP85-99 epitope during acute EAE, highlighting the need for caution in translating knowledge about antigen processing from one species to another.
T12064 514750-514818 Sentence denotes Oriane Cedile⁎ 1 , Natalia Popa 1 , Lucile Gioda 1 , Jose Boucraut 1
T69752 514819-514961 Sentence denotes We studied, in the model of olfactory axotomy, the recruitment of NK cells and the expression of MHC-Ia, b and NKG2D ligands, including Rae-1.
T34494 514962-515044 Sentence denotes The main olfactory bulb (MOB) is the first relay on the olfactory sensory pathway.
T24275 515045-515254 Sentence denotes The MOB receives the afferences from the olfactory mucosa and is the target of the neural progenitor cells generated in the subventricular zone (SVZ) and which migrate along the rostral migratory stream (RMS).
T57085 515255-515481 Sentence denotes Sensory deafferentation of the MOB by axotomy of the olfactory receptor neurons induces retrograde neuronal cell death in the mucosa, an increase of apoptotic cell death in the SVZ and along the rostrocaudal extent of the RMS.
T66752 515482-515630 Sentence denotes In parallel, an increase in cell proliferation in the SVZ and in the extension of the RMS located in the MOB preceding full neuronal repair appears.
T16040 515631-515737 Sentence denotes Using qPCR, we observed the expression in the olfactory bulbs of NKG2D and the NK specific receptor NKp46.
T48553 515738-515816 Sentence denotes The level of expression was similar than those observed in the hepatic tissue.
T60756 515817-515978 Sentence denotes The recruitment of immune cells after axotomy was confirmed with other techniques such as flow cytometry and immuno-labeling with anti-NKp46 polyclonal antisera.
T24600 515979-516060 Sentence denotes In the same experiment, we did not detect recruitment of immune cells in the SVZ.
T88961 516061-516210 Sentence denotes A weak expression of Rae-1 was detected by qPCR solely in some part of normal brain and its expression was strongly induced in the MOB after axotomy.
T58466 516211-516325 Sentence denotes We showed for the first time the recruitment of immune cells including NK cells in the model of olfactory axotomy.
T7591 516326-516552 Sentence denotes Deciphering the roles in vivo of NK cells and Rae-1 in neuronal death and neuronal repair is now our main objective. mice have shown that PD-L1 or PD-L2 blockade leads to an earlier onset and increased severity of the disease.
T23956 516553-516762 Sentence denotes Although, PD-1 and its ligands were observed on infiltrating immune and CNS cells during EAE, which cell types express these molecules have not been completely resolved, and no data are available on human CNS.
T77473 516763-516923 Sentence denotes Our goal is to assess the expression of PD-Ls by human CNS cells and to establish whether these molecules could locally contribute to modulate immune responses.
T47917 516924-517088 Sentence denotes Human primary CNS cultures were either kept in basal conditions or stimulated with pro-inflammatory cytokines respectively mimicking healthy vs. MS CNS environment.
T6260 517089-517166 Sentence denotes PD-L1 and PD-L2 expression were analyzed by real-time PCR and flow cytometry.
T12072 517167-517334 Sentence denotes Human primary cultures of astrocytes, oligodendrocytes, and brain endothelial cells expressed barely detectable PD-L1 and PD-L2 levels, at the mRNA and protein levels.
T64550 517335-517609 Sentence denotes Following pro-inflammatory cytokine (IFN-gamma, TNF-alpha, IL-1beta) treatments, we observed an increased expression of both PD-L1 and PD-L2 on these cells, especially PD-L1 on astrocytes and oligodendrocytes, while brain endothelial cells up-regulated preferentially PD-L2.
T56394 517610-517742 Sentence denotes Combinations of cytokines were more potent to enhance PD-L1 and PD-L2 expression on all cell type tested than either cytokine alone.
T82399 517743-517878 Sentence denotes Our results underline the enhancing effects of a pro-inflammatory environment on PD-L1 and PD-L2 basal expression by human brain cells.
T62135 517879-517980 Sentence denotes We are currently evaluating whether PD-Ls expressed by human CNS cells immuno-modulate human T cells.
T61291 517981-518050 Sentence denotes Research funded by a grant from Multiple Sclerosis Society of Canada.
T71656 518051-518186 Sentence denotes Neurocysticercosis (NCC) is the most common parasitic disease of the central nervous system (CNS) caused by the helminth Taenia solium.
T25085 518187-518295 Sentence denotes The disease is associated with a hyper inflammatory response which is thought to be detrimental to the host.
T70928 518296-518407 Sentence denotes Our primary goal is to understand the mechanisms involved in the induction of the inflammatory response in NCC.
T14511 518408-518496 Sentence denotes Toll-like receptors play important role in the induction of host inflammatory responses.
T26331 518497-518574 Sentence denotes We propose to study the role of TLRs in CNS immunopathogenesis in murine NCC.
T29161 518575-518689 Sentence denotes During murine NCC expression of Toll like receptors 1 through 13 was analyzed by real time PCR, and IF microscopy.
T12003 518690-518791 Sentence denotes All the TLRs, except TLR5, were expressed and up regulated differentially among different cell types.
T77008 518792-519036 Sentence denotes Among them, TLR2 was the first to be upregulated after parasite infection and was most abundantly expressed, particularly in astrocytes and their foot processes that terminate on blood vessels present in the periventricular and meningeal areas.
T94221 519037-519081 Sentence denotes Next, the role of TLR2 was analyzed in vivo.
T39885 519082-519174 Sentence denotes The tlr2−/− mice were highly susceptible to NCC as compared to their wild type counterparts.
T67717 519175-519373 Sentence denotes Histopathological analysis revealed severe pathology characterized by lack of perivascular lymphocytic cuffing, increased microgliosis, and more tissue damage when compared to the wild type animals.
T16633 519374-519526 Sentence denotes The tlr2−/− mice were observed to elicit a weaker immune response as determined by the reduced reactivity of the sera to the soluble parasitic antigens.
T29678 519527-519762 Sentence denotes Both the total number of infiltrating immune cells and individual cell types such as CD11b+ myeloid cells, alphabetaT cells, gammadeltaT cells, and B cells were significantly reduced both early (1 wk) and late (3 wk) during infections.
T10110 519763-519972 Sentence denotes Accordingly the levels of several of the pro-inflammatory cytokines and chemokines such as IL6, TNF-alpha, IFN-gamma, MCP1, RANTES, MIP1alpha and MIP1beta were reduced in CNS of TLR2-deficient mice during NCC.
T68356 519973-520176 Sentence denotes In TLR2-deficient mice the expression of inflammatory cytokines was reduced in astrocytes present in leptomeningeal and periventricular areas which are thought to be important early during CNS infection.
T90338 520177-520241 Sentence denotes TLR2−/− mice exhibit reduced immune responses during murine NCC.
T75989 520242-520427 Sentence denotes The death of TLR2-deficient mice during experimental NCC along with increased pathology, and parasite burden suggests an important role for TLR2 in the immunopathogenesis in murine NCC.
T75986 520428-520538 Sentence denotes Here, we report on the isolation of subpopulations of murine CNS-DC on the basis of different surface markers.
T63416 520539-520620 Sentence denotes The CD11c+ DC subsets differ in their capacity to stimulate T cell proliferation.
T94397 520621-520687 Sentence denotes In fact, one DC population inhibited the proliferation of T cells.
T17598 520688-520850 Sentence denotes The DC types also differ in their population dynamics during the course of EAE, which may indicate that they play different roles in the evolution of the disease.
T46997 520851-521020 Sentence denotes In order to investigate how EAE-CNS derived DC exert their different effector mechanisms, we compared regulatory and stimulatory DC by performing gene expression arrays.
T63940 521021-521150 Sentence denotes Pathway analysis showed that cellular growth and movement were the main biological processes distinguishing the three DC subsets.
T45970 521151-521339 Sentence denotes Genes involved in growth and cellular proliferation were investigated, particularly the expression of genes involved in the recognition, capture and presentation of antigens was validated.
T71692 521340-521516 Sentence denotes Several genes involved in chemotaxis and homing were differentially expressed in the DC subsets, suggesting that the DC subsets may attract different types of cells to the CNS.
T59241 521517-521619 Sentence denotes The differences observed between the three DC subsets may indicate distinct roles in EAE pathogenesis.
T90732 521620-521819 Sentence denotes The identification of specific markers as well as the phenotypical characterization of the DC subsets may help to specifically manipulate DC subsets in order to attenuate CNS autoimmune inflammation.
T85135 521820-522226 Sentence denotes 20 -MYD88-deficiency is associated with reduced disease severity and decreased TH1 inflammatory response in the brain during murine neurocysticercosis The symptomatic phase of neurocysticercosis (NCC) is associated with a TH1 type inflammatory cytokine response in the central nervous system (CNS), which is thought to be responsible for the severe neuropathology and mortality associated with the disease.
T25676 522227-522384 Sentence denotes Brain infection with Mesocestoides corti, a murine model for neurocysticercosis, induces a massive influx of immune cell types and a TH1 cytokine expression.
T21770 522385-522523 Sentence denotes To understand the mechanism involved in the development of the inflammatory response, the role of toll like receptors (TLRs) was analyzed.
T55007 522524-522683 Sentence denotes In murine NCC, all the TLRs (TLRs 1-13) , except TLR5 were upregulated and differentially expressed among various nervous tissue and infiltrating immune cells.
T71997 522684-522909 Sentence denotes Mice lacking MyD88 (MyD88−/−), the central regulator of TLR induced response, displayed enhanced ability to survive the infection as compared to the wild-type mice, although the numbers of parasites in brain remained similar.
T41578 522910-523048 Sentence denotes The CNS of MyD88−/− mice was more quiescent with an absence of perivascular lymphocytic cuffing, decreased microgliosis and tissue damage.
T3890 523049-523148 Sentence denotes The numbers of CD11b+ve myeloid cells, aβT cells, gdT cells, and B cells were present in the brain.
T5073 523149-523332 Sentence denotes Real time PCR and ELISA analysis showed a decreased level of several of the inflammatory cytokines and chemokines such as IL-6, TNF-a, IFN-g, and MCP-1 during the course of infection.
T80189 523333-523553 Sentence denotes IF microscopy analysis revealed that in MyD88−/− mice the expression of inflammatory cytokines was reduced in leptomeningeal and periventricular areas of brain which are known to influence leukocytes infiltration in NCC.
T31408 523554-523737 Sentence denotes MyD88 signaling also appeared to influence the humoral immunity as infection in the MyD88-deficient mice was associated with a lower parasite soluble antigen-specific IgG2a Ab titers.
T16216 523738-523931 Sentence denotes In patients infected with Taenia solium, the destruction of larvae by therapeutic treatment or during parasite life cycle associates with strong inflammatory response and disease manifestation.
T10497 523932-524157 Sentence denotes The better containment of the disease along with the absence of inflammatory response and lack of neuropathology in MyD88-deficient mice may help in formulating therapeutic immune intervention strategy for neurocysticercosis.
T99942 524158-524272 Sentence denotes Matsumoto Yoh⁎ 1 , Kohyama Kuniko 1 , Hiraki Keiko 1 1 Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan
T42558 524273-524469 Sentence denotes Accumulating evidence strongly suggests that T cells and autoantibodies reactive with myelin oligodendrocyte glycoprotein (MOG) play a critical role in the pathogenesis of multiple sclerosis (MS).
T37085 524470-524736 Sentence denotes In the present study, we have tried to elucidate the pathomechanisms of lesion formation and progression of MS by analyzing the role of T and B cells in MOG-induced experimental autoimmune encephalomyelitis (EAE) that exhibits various clinical subtypes mimicking MS.
T59512 524737-524871 Sentence denotes Special attention was paid to examine the presence or absence of autoantibodies against conformational epitope(s) of the MOG molecule.
T63389 524872-525071 Sentence denotes Relapsing remitting (RR) or secondary progressive (SP) EAE was induced in LEW.1AV1 rats by immunization with recombinant rat MOG or synthetic peptides covering the entire extracellular domain of MOG.
T96651 525072-525187 Sentence denotes The responses of T cells from immunized rats to MOG and MOG peptides were determined by T cell proliferation assay.
T92603 525188-525350 Sentence denotes Autoantibodies against linear and conformational epitopes were assayed with conventional ELISA and flow cytometry using native MOG-expressing cells, respectively.
T22757 525351-525520 Sentence denotes Immunization with synthetic peptides revealed that encephalitogenic epitopes resided in Peptide 7 (P7, residue 91-108) and P8 (residue 103-125) and induced RR or SP EAE.
T84476 525521-525612 Sentence denotes However, the disease severity of MOG peptide-EAE was generally milder than that of MOG-EAE.
T30539 525613-525790 Sentence denotes T cells taken from MOG-immunized and MOGP7-immunized rats responded to MOG and MOGP7 and sera from MOG-immunized rats reacted to MOG and MOGP1 throughout the observation period.
T93129 525791-525921 Sentence denotes Interestingly, sera from MOGP7-immunized rats with RR-EAE did not react to MOG protein and peptides during the observation period.
T31661 525922-525988 Sentence denotes There was no epitope spreading at both T cell and antibody levels.
T96411 525989-526140 Sentence denotes Analysis of conformational epitopes (cme) in sera from MOG-immunized rats revealed that the titers of anticme antibodies paralleled the disease status.
T45837 526141-526350 Sentence denotes These findings demonstrate that the development and relapse of MOG peptide-EAE occurs without autoantibody involvement but that autoantibodies play a role in the progression of the disease as found in MOG-EAE.
T77931 526351-526541 Sentence denotes Collectively, the disease processes of EAE, and probably of MS, are regulated by several different mechanisms and immunotherapy should be performed properly on the basis of such information.
T16432 526542-526657 Sentence denotes Tissue transglutaminase (TG2) is a multifunctional enzyme, involved in post-translational modification of proteins.
T95620 526658-526788 Sentence denotes During various inflammation-related processes, including cell adhesion and migration, TG2 has been suggested to play a major role.
T30370 526789-526887 Sentence denotes Therefore, we propose that TG2 can contribute to some of the pathological processes underlying MS.
T3799 526888-527061 Sentence denotes Since we observed that TG2 immunoreactivity is elevated in MS lesions, we questioned whether TG2 is present in the CNS of rats suffering from chronic relapsing EAE (cr-EAE).
T64537 527062-527359 Sentence denotes To study the expression of TG2 during cr-EAE, animals were sacrificed at different phases of clinical disease and we found an increased level of TG2 mRNA and protein in various cell types including infiltrating cells, mainly in the upper parts of the spinal cord during clinical disease of cr-EAE.
T50768 527360-527443 Sentence denotes Subsequently, we studied whether TG2 contributes to clinical disease during cr-EAE.
T16722 527444-527569 Sentence denotes KCC009, a specific irreversible inhibitor of TG2 was injected i.p. daily in cr-EAE animals from first clinical signs onwards.
T97934 527570-527664 Sentence denotes All animals were sacrificed when the PBS-treated controls reached the relapse phase of cr-EAE.
T92839 527665-527827 Sentence denotes Our data showed that inhibition of TG2 activity reduced clinical symptoms during cr-EAE dramatically and has an effect on the neuropathological outcome of cr-EAE.
T13316 527828-528041 Sentence denotes There was no significant effect on the mRNA levels of different genes which are normally higher expressed during cr-EAE such as CD68, inflammatory mediators, and genes involved in adhesion and migration processes.
T14575 528042-528322 Sentence denotes Immunohistochemical analysis with OX6, a MHC class II marker detecting monocytes, activated macrophages and microglia showed that KCC009 treatment attenuated monocyte infiltration in the spinal cord of cr-EAE animals whereas microglia remained activated in KCC009 treated animals.
T35395 528323-528528 Sentence denotes These data suggest that KCC009 mainly has a peripheral effect reducing TG2 activity in infiltrating cells and thereby attenuate cell adhesion and migration, an important pathological process underlying MS.
T75894 528529-528584 Sentence denotes Therefore, TG2 can be a novel therapeutic target in MS.
T47816 528585-528766 Sentence denotes This protocol induced an EAE-like disease characterized by massive infiltration of CD8+ T-cells to the brain and spinal cord as analysed by flow cytometry and histological analysis.
T87558 528767-528879 Sentence denotes Preliminary FACS analysis showed that 80% of the CNS infiltrating T-cells were CD8-positive in symptomatic mice.
T92185 528880-529007 Sentence denotes Non-symptomatic mice also showed T cell infiltration to the spinal cord, and 50% of the infiltrating T-cells were CD8-positive.
T9035 529008-529235 Sentence denotes These CD8 proportions were substantially greater than in our previous studies of conventionally-immunized MOG-or MOG peptide-induced EAE where proportions of CD8+ T-cells in the CNS of symptomatic mice were in the 10-30% range.
T7685 529236-529359 Sentence denotes Those studies indicated that CD8+ T-cells play a regulatory role despite displaying an activated memory-effecter phenotype.
T7083 529360-529606 Sentence denotes Results of this study suggest that the route of antigen presentation may determine whether activated CD8+ T-cells play a pathogenic role and that presentation through viral recognition pathways results in an encephalitogenic CD8+ T-cell response.
T32387 529607-529657 Sentence denotes This has implications for our understanding of MS.
T11546 529658-529786 Sentence denotes In an attempt to observe the effect of blocking angiogenesis in neuroinflammation, we synthesize 10 new prodrugs of thalidomide.
T80441 529787-529986 Sentence denotes A series of molecular or macromolecular amphiphilic derivatives of thalidomide were prepared starting from 3-N-(3-aminopropyl)aminothalidomide and exhibiting a modular hydrophilic-lipophilic balance.
T6684 529987-530123 Sentence denotes Their biological activities were examined using myelin oligodendrocyte glycoprotein 35-55 peptide-induced acute EAE in the C57BL6 mouse.
T65696 530124-530427 Sentence denotes When mice were treated on the second day when clinical signs were observed for a total of 7 days, two of these thalidomide derivatives (having molecular weights 7986 (AP05/09) and 14,244 (AP06/06) showed clear efficacy in reversing the clinical signs of EAE at 100 mg/ kg equivalent dose of thalidomide.
T37515 530428-530623 Sentence denotes These studies provide additional evidence that VEGF and angiogenesis are components of an acute lesion and this could provide an interesting target for limiting the extent of the acute MS attack.
T56768 530624-530777 Sentence denotes Experimental autoimmune encephalomyelitis (EAE) is a central nervous system (CNS) specific disease and a primary animal model of multiple sclerosis (MS).
T47186 530778-530876 Sentence denotes The common marmoset (Callitrix jacchus), which is used in this study, is a small New World monkey.
T25467 530877-531014 Sentence denotes The marmoset provides a highly useful model to study the pathogenesis of MS, due the outbred nature and immunological proximity to human.
T42296 531015-531246 Sentence denotes Immunization of this non-human primate with a synthetic peptide representing amino acids 34 to 56 of the human myelin/oligodendrocyte (MOG) protein in mineral oil (incomplete Freund's adjuvant; IFA) induces full-blown clinical EAE.
T67906 531247-531335 Sentence denotes Animals sensitized at 4 weeks interval all developed clinical EAE with body weight loss.
T45799 531336-531485 Sentence denotes Magnetic resonance brain images of presymptomatic monkeys were recorded on a 4.7 T spectrometer showing large hyperintense areas in the white matter.
T50140 531486-531659 Sentence denotes Immunohistology showed that the MRI-detectable abnormalities were large demyelinated lesions in the brain, and that lesions were also present in spinal cord and optic nerve.
T55210 531660-531912 Sentence denotes Positive proliferating T-cell responses to the MOG peptide 34 to 56 (MOG34-56) were observed and T-cell lines generated from the spleen and lymph nodes against MOG34-56 expressed phenotypes of NK-CTL like cells; CD3+, CD4+ and/or CD8+, CD56+ and CD16−.
T4802 531913-532075 Sentence denotes Specific cytotoxicity of the specific T-cells lines was confirmed using peptidepulsed EBV-transformed autologous and allogenous B-cells by chromium release assay.
T5244 532076-532173 Sentence denotes Target cell exchange studies show that cytolysis is peptide specific but target cell independent.
T99061 532174-532260 Sentence denotes This pleads for peptide presentation by an invariant MHC class I allele, being Caja-E.
T60050 532261-532380 Sentence denotes We conclude that the minimal requirement for induction of EAE in marmosets is prime-boost with MOG34-56 peptide in IFA.
T70707 532381-532553 Sentence denotes EAE is caused by the autoreactive cytotoxic T-cells which display specific cytolytic activity towards cells presenting peptide via non-classical MHC class I Caja-E alleles.
T1724 532554-532724 Sentence denotes IL-15 (KO) mice were recently available from Taconic where they were backcrossed 5 times onto C57BL/6NTac mice and intracrossed to make them homozygous for the IL15 (KO).
T11651 532725-532896 Sentence denotes We immunized the IL-15 (KO) (n =10) and C57BL/6NTac mice (background, n= 10) with myelin oligodendrocyte glycoprotein 35-55 peptide (200 μg) in complete Freund's adjuvent.
T76835 532897-533000 Sentence denotes Bordetella pertussis toxin (200 ng) was also administered i.p. on day 0 and 2 post immunization (p.i.).
T19943 533001-533139 Sentence denotes IL-15 (KO) mice had the same clinical signs as control mice until day 15-21 p.i. when they displayed more severe clinical signs (pb 0.05).
T51592 533140-533282 Sentence denotes Pathological changes were also significantly worse in spinal cord sections stained for inflammation (p = 0.024) and demyelination (p = 0.014).
T32210 533283-533388 Sentence denotes Unexpectedly, extensive demyelination (N20% of the sections) was observed in 4/10 of the IL-15 (KO) mice.
T55202 533389-533437 Sentence denotes Mice lacking IL-15 showed more severe acute EAE.
T91234 533438-533540 Sentence denotes We propose that there is a compensation by other inflammatory mediators which exacerbates the disease.
T86363 533541-533914 Sentence denotes 27 -Discrepant oxyradical production by phagocytes from marmosets and rhesus monkeys with differential encephalitis pathology Experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis (MS), can be induced in the non-human primate species rhesus macaques and common marmosets with recombinant human myelin oligodendrocyte glycoprotein (rhMOG).
T47277 533915-534167 Sentence denotes While EAE induction in rhesus macaques leads to acute ADEM-like neurological disease with highly destructive lesions, rhMOG immunization of marmosets induces MS-like progressive neurological disease with primary demyelination and conservation of axons.
T49075 534168-534411 Sentence denotes Since axonal damage may be caused by reactive oxygen species (ROS) that are produced by macrophages and microglia during phagocytosis of myelin debris, we have investigated the profile of ROS produced by activated phagocytes from both species.
T52446 534412-534578 Sentence denotes The production of superoxide anion (O 2 −) and hydrogen peroxide (H 2 O 2 ) was analyzed in PMA stimulated peripheral blood mononuclear cells (PBMC) and granulocytes.
T99871 534579-534681 Sentence denotes Superoxide dismutase inhibitable superoxide anion production was determined by lucigenin luminescence.
T3456 534682-534808 Sentence denotes The production of superoxide anion is much higher in rhesus monkey cells (1000-5000 cpm) than in marmoset cells (200-300 cpm).
T30591 534809-534962 Sentence denotes Production of hydrogen peroxide was measured by the horseradish peroxidase-catalyzed oxidation of amplex red to resorufin that can be measured at 570 nm.
T51925 534963-535105 Sentence denotes Hydrogen peroxide production by marmoset cells is hardly detectable (OD b 0.1), in contrast to the production by rhesus monkey cells (OD 0.6).
T7974 535106-535191 Sentence denotes In conclusion, we have found differences in the oxidative burst between both species.
T32993 535192-535307 Sentence denotes Sialic acid residues on gangliosides expressed in the axonal membranes and myelin are prominent scavengers of H2O2.
T94453 535308-535534 Sentence denotes We hypothesize that reaction of sialic acids with H 2 O 2 will affect the specific binding of neurons to myelin-associated glycoprotein (MAG) contributing to disruption of compact myelin and enhanced binding of autoantibodies.
T20096 535535-535748 Sentence denotes Since rhesus monkey cells produce more hydrogen peroxide than marmoset cells this may lead to more and faster disruption of compact myelin explaining the acute disease and destructive lesions in rhesus monkey EAE.
T9771 535749-535851 Sentence denotes We will discuss the expression of sialic acids and MAG in the brains of rhesus and marmosets with EAE.
T38068 535852-535933 Sentence denotes Moreover, data on the damage to DNA and proteins caused by ROS will be discussed.
T40985 535934-536051 Sentence denotes CD40 is a co-stimulatory molecule functioning at the interface of antigen presenting cell (APC) in the immune system.
T19710 536052-536342 Sentence denotes In the central nervous system (CNS), it is also expressed in reactive microglia and plays a role in neuroinflammatory disorders such as Alzheimer's disease, Parkinson's disease and multiple sclerosis by inducing various inflammatory molecules such as inducible nitric oxide synthase (iNOS).
T8541 536343-536448 Sentence denotes Therefore, we investigated a role of Class4 Semaphorin Sema4D/CD100, which could modulate CD40 signaling.
T54346 536449-536693 Sentence denotes Since the receptors of Sema4D are identified to be Plexin-B1 in the CNS while CD72 plays a major role in the immune system, we prepared primary microglia from wild-type, CD72-deficient and Plexin-B1-deficient newborn mice (C57 BL/6 background).
T61047 536694-536790 Sentence denotes When microglia are incubated with recombinant Sema4D, CD40-induced iNOS expression was enhanced.
T90239 536791-537018 Sentence denotes In addition, immunohistochemical studies revealed that Sema4D was expressed in the infiltrating cells in the spinal cord of experimental autoimmune encephalomyelitis (EAE) and Plexin-B1 was up-regulated in microglia/macrophage.
T33490 537019-537216 Sentence denotes When EAE was induced by adoptive transfer of wild-type MOG-reactive T cells to wild-type or Plexin-B1-deficient mice, Plexin-B1-deficient recipient mice exhibited a milder phenotype than wild-type.
T18444 537217-537372 Sentence denotes Collectively, these results suggest that Sema4D participates in the neuroinflammatory process by enhancing CD40-related inflammatory process via Plexin-B1.
T64985 537373-537496 Sentence denotes Interaction between an antigen-presenting cell (APC) and a T-cell leads to the rapid formation of an immunological synapse.
T70491 537497-537680 Sentence denotes Upon recognition of the appropriate antigen, a swift rise of intracellular calcium is triggered within the T-cell which can be used to monitor the activation status of the lymphocyte.
T38369 537681-537885 Sentence denotes While this approach is successful in cell culture, in vivo calcium imaging in T-cells still remains a major challenge as synthetic calcium indicators do not persist intracellularly for a sustained period.
T97760 537886-538052 Sentence denotes To overcome this problem we wanted to create transgenic T-cells stably expressing a fluorescent calcium sensor for long-term tracking and calcium measurement studies.
T92030 538053-538210 Sentence denotes By retroviral transduction we generated T-cells transgenically expressing the novel fluorescence resonance energy transfer (FRET)-based calcium sensor TNXXL.
T20542 538211-538368 Sentence denotes This sensor features spectrally optimized derivatives of the fluorescent proteins CFP and YFP as FRET pair linked by the calcium-sensitive domain Troponin C.
T3252 538369-538537 Sentence denotes Originally designed for calcium imaging in neurons, this sensor is also capable of responding to the more modest alterations in lymphocyte intracellular calcium levels.
T43959 538538-538655 Sentence denotes These transgenic T-cells will be used for in vivo imaging studies in experimental autoimmune encephalomyelitis (EAE).
T81926 538656-538825 Sentence denotes We plan to track the migration and activation of T-cells upon the encounter of APCs, e.g. during or after passing the blood-brain barrier and while infiltrating the CNS.
T13160 538826-539022 Sentence denotes For this purpose various inducible as well as spontaneous models of EAE are available in our lab thus providing the opportunity to investigate T-cell activation under different disease conditions.
T99116 539023-539102 Sentence denotes Interleukin-23 (IL-23) is a crucial mediator of tissue inflammation during EAE.
T41520 539103-539299 Sentence denotes As heterodimeric cytokine consisting of the IL12-B (p40) and the IL23-A (p19) subunits, it is produced by antigen-presenting cells as macrophages and dendritic cells and acts primarily on T cells.
T93530 539300-539389 Sentence denotes In the MOG35-55 model of EAE, IL-23 was shown to be vital for the development of disease.
T43957 539390-539553 Sentence denotes It is clear, that EAE induction upon peptide immunization will trigger a CD4 mediated response and that IL-23 has some influence on the polarization of TH17 cells.
T60910 539554-539682 Sentence denotes Nevertheless, we found, that IL-17 production is not only restricted to CD4+ T cells, but even a greater number of CD8+ T cells.
T23507 539683-539816 Sentence denotes Due to the CD4 bias of peptide induced EAE, CD8+ T cells have long been neglected in experimental models of CNS inflammatory disease.
T68578 539817-539899 Sentence denotes CD8+ T cells have been implicated in mediating axonal damage in both mice and men.
T96366 539900-540010 Sentence denotes Nevertheless, the interplay between IL-23 and CD8+ T cells in autoimmune CNS inflammation remains ill defined.
T30405 540011-540152 Sentence denotes Our mouse model relies on the expression of OVA under the control of a modified oligodendrocyte-specific myelin basic protein (MBP) promoter.
T65045 540153-540284 Sentence denotes Upon active immunization with the MHC class I OVA peptide or adoptive transfer of OT-1 T cells the mouse shows severe EAE symptoms.
T84506 540285-540428 Sentence denotes To address the impact of IL-23 on CD8+ T cells, we crossed these ODC-OVA mice onto the p40−/− and p19−/− background, the two subunits of IL-23.
T21329 540429-540609 Sentence denotes Preliminary data indicate that loss of IL-23 leads to a change in the disease pattern and that the IL-23/IL-17 axis applies not only to TH cells, but also to encephalitogenic CTLs.
T41686 540610-540730 Sentence denotes The primary impact of IL-23 appears to be on the cytotoxic capacity of CTLs rather than the local (CNS) tissue response.
T35884 540731-540877 Sentence denotes Further experiments will reveal the interaction of IL-23 with encephalitogenic CD8 T cells and the role of IL-17-secreting CD8 T cells during EAE.
T90733 540878-541056 Sentence denotes Bacterial cell wall peptidoglycan (PG) is a strong pro-inflammatory agent promoting development of Th17 cells and potentially stimulating multiple sclerosis (MS) lesion activity.
T52011 541057-541295 Sentence denotes PG is present in innate immune cells infiltrating MS brain tissue, and Staphylococcus aureus PG stimulates EAE (experimental autoimmune encephalomyelitis) in wildtype mice when admixed with autoantigen in incomplete Freund adjuvant (IFA).
T92243 541296-541439 Sentence denotes PG stimulates cells via innate immune receptors like membrane-associated Toll-like receptor 2 (TLR2) and cytosolic Nod1/ CARD4 and Nod2/CARD15.
T93088 541440-541545 Sentence denotes We hypothesized that the stimulatory effect of S. aureus PG on EAE is independent of TLR2 action in vivo.
T47439 541546-541705 Sentence denotes Hence we asked whether S. aureus PG as the single bacterial component admixed with autoantigen in IFA can induce EAE in animals genetically deficient for TLR2.
T92973 541706-541853 Sentence denotes Indeed, TLR2 knockout mice still developed EAE after induction with this well-characterized highly purified soluble PG from S. aureus and MOG35-55.
T32448 541854-541938 Sentence denotes TLR2 knockouts had similar disease incidence and severity compared to wildtype mice.
T18918 541939-542082 Sentence denotes TLR2-dependent and -independent activity of this S. aureus PG preparation in vitro was assessed using bone-marrow derived dendritic cells (DC).
T71437 542083-542273 Sentence denotes When stimulated with PG, wildtype DC upregulated the expression of CD40, and secreted the proinflammatory cytokines TNF-a, IL-6 and IL-12p70, as well as the anti-inflammatory cytokine IL-10.
T18879 542274-542347 Sentence denotes As expected, these parameters were reduced in DC from TLR2 knockout mice.
T24662 542348-542497 Sentence denotes However, the expression of TNF-a, IL-12p70 and IL-10 was not fully ablated in DC lacking TLR2, suggesting only a partial TLR2-dependent effect of PG.
T8662 542498-542507 Sentence denotes [Ongoing:
T77808 542508-542653 Sentence denotes Importantly, S. aureus PG induced production of IL-23, which is essential for sustaining Th17 polarization, by (human) antigen presenting cells].
T96677 542654-542798 Sentence denotes Our data provide proof of principle that this highly purified soluble S. aureus PG can effectively induce EAE in the absence of TLR2 engagement.
T97811 542799-542899 Sentence denotes This suggests that the Nod2-mediated action of S. aureus PG is reasonable sufficient to promote EAE.
T62166 542900-543100 Sentence denotes 32 -Loss of non-canonical NFkB signalling in antigen-presenting cells aborts adaptive immunity Hofmann Janin⁎ 1 , Greter Melanie 1 , Becher Burkhard 1 1 Neuroimmunology, University Zürich, Switzerland
T34495 543101-543216 Sentence denotes The inflammatory canonical NFkB pathway is critically involved in virtually all aspects of inflammation in general.
T7909 543217-543346 Sentence denotes On the other hand, the role of the alternative, non-canonical NFkB pathway in inflammation and adaptive immunity remains elusive.
T95750 543347-543512 Sentence denotes The alternative pathway is primarily mediated through the NFkappa-B inducing kinase (NIK) which in turn leads to the phosphorylation and the cleavage of p100 to p52.
T68633 543513-543639 Sentence denotes Among the receptors engaging NIK is the LTbR, which is also required to form the anlage for secondary lymphoid tissues (SLTs).
T22656 543640-543752 Sentence denotes Due to a point mutation within NIK, alymphoplasia (aly) mice do not develop SLTs and are highly immunodeficient.
T1276 543753-543953 Sentence denotes However, while the immunodeficiency of aly mice is widely held to stem from their developmental malformation, it has been overlooked, that the mutation of NIK itself could potentially lesion immunity.
T61508 543954-544124 Sentence denotes To verify this notion, we generated a series of bone marrow chimeric mice (BMC) in which the absence of SLTs was disconnected from the hematopoietic loss of NIK function.
T26688 544125-544311 Sentence denotes We generated mice, which lack all SLTs, but are equipped with a normal systemic immune system (wt→aly), and conversely, mice with normal SLTs, but lacking NIK in all leukocytes (aly→wt).
T5837 544312-544416 Sentence denotes Surprisingly, we discovered that NIK is vital for the development of autoimmune disease, while SLTs (ie.
T72259 544417-544482 Sentence denotes LNs, spleen etc.) are essentially dispensable for T cell priming.
T92003 544483-544629 Sentence denotes We discovered that NIK is required for the polarization of effector T cells and that TH17 and TH1 cells cannot be generated in the absence of NIK.
T20080 544630-544760 Sentence denotes However, the NIK lesion does not cause an intrinsic T cell defect but leads to the inability of APCs to drive T cell polarization.
T30702 544761-544886 Sentence denotes Diphtheria toxin-mediated cell depletion suggested a crucial role of NIK in dendritic cells (DCs) for the development of EAE.
T78638 544887-545027 Sentence denotes This data is strongly supported by the finding that aly DCs show functional deficits in maturation and pro-inflammatory cytokine production.
T30526 545028-545133 Sentence denotes Taken together, loss of non-canonical NFkB signalling in DCs ultimately leads to abortive T cell priming.
T86596 545134-545201 Sentence denotes Phosphodiesterases (PDEs) are enzymes degrading cyclic nucleotides.
T25266 545202-545476 Sentence denotes Inhibitors of some PDEs have been reported as therapeutic agents for experimental autoimmune encephalomyelitis (EAE), which is an animal model of multiple sclerosis (MS), by inhibiting antigenmediated T cell proliferation and down-regulating the production of Th1 cytokines.
T42199 545477-545631 Sentence denotes Cilostazol is known as a specific inhibitor of PDE3, which is used for treatment of ischemic disease by acting on antiplatelet and vasodilator properties.
T3636 545632-545705 Sentence denotes Besides, cilostazol suppresses the expression of such adhesion molecules.
T17851 545706-545787 Sentence denotes In this study, we investigated possible therapeutic effect of cilostazol for EAE.
T28134 545788-545862 Sentence denotes EAE was induced in B6 mice by inoculation with MOG35-55 as usual protocol.
T24149 545863-545954 Sentence denotes Mice were fed with blended solid diet with cilostazol (n = 28) or vehicle control (n = 28).
T33480 545955-546081 Sentence denotes Cilostazol suppressed the maximum EAE score and the average EAE scores on days 15, 16 and 17, compared with the control group.
T3204 546082-546270 Sentence denotes In the recall responses with MOG35-55, the proliferation and IFN-g production of lymphocytes from cilostazol-fed mice were significantly reduced in comparison with those from control mice.
T24156 546271-546397 Sentence denotes In contrast, no significant differences were detected in the level of TNF-a, IL-17 and IL-10 productions between these groups.
T18193 546398-546489 Sentence denotes Serum level of sICAM-1 was significantly lower in cilostazol-fed mice than in control mice.
T93665 546490-546650 Sentence denotes Cilostazol may have repressive effects on EAE by reducing the antigen specific T cell response and decreasing the expression level of adhesion molecule, ICAM-1.
T73047 546651-546813 Sentence denotes Although further investigation is needed to clarify the detailed mechanisms of therapeutic effects in EAE, cilostazol is a hopeful choice for the treatment of MS.
T92305 546814-546903 Sentence denotes IL-17 has recently emerged as a critical cytokine in T cell-mediated autoimmune diseases.
T19962 546904-547042 Sentence denotes IL-17 is produced by a T cell subset distinct from Th1 and Th2 cells, and induces IL-1, TNF-alpha and IL-6 expression in inflamed tissues.
T16038 547043-547255 Sentence denotes IL-6 and TGF-beta can induce naïve T cells to differentiate into IL-17-secreting CD4+ T cells in vitro and we have shown that IL-1 and IL-23 promote IL-17 production from T cells in the absence of TCR engagement.
T9018 547256-547413 Sentence denotes In this study we examined the infiltration of IL-17-producing T cells into the CNS during the development of experimental autoimmune encephalomyelitis (EAE).
T15620 547414-547583 Sentence denotes Mononuclear cells were isolated from peripheral immune and CNS tissue 7, 10, 14, 21 and 35 days post immunization and analyzed for cytokine expression by flow cytometry.
T47572 547584-547701 Sentence denotes The kinetics of changes in mRNA expression of a number of associated cytokines was also examined by quantitative PCR.
T78583 547702-547856 Sentence denotes We found significant infiltration of CD4+ and CD8+ T cells into the brain and spinal cord of mice immediately prior to the onset of clinical signs of EAE.
T36295 547857-547964 Sentence denotes Approximately, 6% of total CD3+ T cells in the CNS of mice produced IL-17 on day 14 after induction of EAE.
T99245 547965-548060 Sentence denotes CD4+ T cells constitute up to 40% of this CD3+ population, and 10-20% of these expressed IL-17.
T7539 548061-548119 Sentence denotes Furthermore, gamma delta T cells were detected in the CNS.
T91940 548120-548248 Sentence denotes Whilst these constitute only around 2% of the total CD3+ population, we show that 70% of these produced IL-17, but not IFNgamma.
T85740 548249-548443 Sentence denotes These findings correlated with increased expression of IL-1beta, IL-23, IL-6, TGF-beta, IFN-gamma, IL-17A and TNF-alpha mRNA in the cerebral cortex, cerebellum and spinal cord of mice on day 14.
T49276 548444-548629 Sentence denotes In contrast, IL-17 mRNA expression, as well as that of IL-1beta, IL-6 and IL-23, was significantly increased in the spleens of mice on day 7 of EAE, but subsided at the peak of disease.
T39384 548630-548724 Sentence denotes In addition, IL-17 producing CD3+ T cells were significantly increased in the spleen on day 7.
T33085 548725-548823 Sentence denotes NK cells and CD8+ T cells in the CNS did not express significant IL-17 over the course of disease.
T59778 548824-549045 Sentence denotes We hypothesise that IL-17-producing T cells are activated in the periphery early after immunisation and subsequently migrate to the CNS, where they stimulate local production of proinflammatory cytokines from glial cells.
T55828 549046-549298 Sentence denotes We found that gamma delta T cells infiltrated the CNS during the development of EAE and, at the onset of clinical symptoms, a very high percentage of these cells express IL-17 and may have the potential to induce local inflammatory response during EAE.
T19088 549299-549547 Sentence denotes Proteolipid Protein (PLP)-inoculation in SJL/J mice generates a form of Experimental Autoimmune Encephalomyelitis (EAE) that exhibits a relapsing-remitting course and is used to investigate mechanisms of disease relating to Multiple Sclerosis (MS).
T73277 549548-549635 Sentence denotes Hitherto, most studies have concentrated solely on the central aspects of MS pathology.
T60743 549636-549737 Sentence denotes However, it is becoming increasingly evident that systemic events also contribute to MS pathogenesis.
T61208 549738-549854 Sentence denotes We have observed histological changes in the livers of individuals with MS including the recruitment of neutrophils.
T72294 549855-550000 Sentence denotes We were interested to discover whether our model of EAE also exhibits cellular and molecular changes that might contribute to systemic pathology.
T77888 550001-550194 Sentence denotes We have previously shown that neutrophil recruitment to the liver after brain injury is associated with hepatic chemokine production and the expression of classical Acute Phase Proteins (APPs).
T99648 550195-550336 Sentence denotes We examined the liver from animals with EAE to discover whether this was also true for immune-mediated Central Nervous System (CNS) diseases.
T67014 550337-550559 Sentence denotes To induce EAE, female 8-12 week old SJL/J mice were injected subcutaneously with 25 μg of PLP emulsified in 50 μl Complete Freund's Adjuvant (CFA) or with Phosphate Buffered Saline (PBS) in 50 μl CFA for our control group.
T28038 550560-550703 Sentence denotes On the day of the immunization and 48 h later, both treatment groups received an intravenous injection of 200 ng pertussis toxin in 0.2 ml PBS.
T26741 550704-550880 Sentence denotes Using RT-PCR, we were able to establish the presence of an extended expression of APPs and chemokines in the liver of EAE mice prior to the development of overt clinical signs.
T82495 550881-551123 Sentence denotes We show an elevated expression of Serum Amyloid A1 (SAA1), Serum Amyloid A2 (SAA2), Serum Amyloid P (SAP), CCL 2 and CXCL 10 just before the onset of clinical symptoms at day 8 which in some cases persisted into the clinical phase of disease.
T17562 551124-551208 Sentence denotes Most of the APPs returned to naïve levels by day 18, during the period of remission.
T13509 551209-551329 Sentence denotes Furthermore, the production of these APPs and chemokines was associated with the recruitment of leukocytes to the liver.
T93693 551330-551458 Sentence denotes Thus systemic pathology accompanies EAE and MS and is likely to impinge on clinical signs and contribute to disease progression.
T95173 551459-551683 Sentence denotes The identification of the liver in particular as a preclinical component of MS defines an important time window between chemokine formation, lesion formation and an MS relapse which may be exploited for therapeutic purposes.
T18329 551684-551795 Sentence denotes An individual's risk to multiple sclerosis (MS) is determined by the triad of genes, environment and infection.
T78870 551796-551992 Sentence denotes Studies showing that the concordance of MS is higher in non-identical twins than in siblings from independent births suggest an influence of the simultaneous in utero exposure to maternal factors.
T43268 551993-552156 Sentence denotes We have tested in marmoset monkeys whether corticosteroid hormones leaking through the placenta influence the severity and course of MS-like disease in later life.
T40836 552157-552426 Sentence denotes In the context of a large multinational experiment funded by the European Commission (Grant QLRI-CT-2002-02758, EUPEAH) led by the German Primate Center pregnant female marmosets were treated with dexamethasone (DEX) in the form of a daily 5 mg/kg oral dose for 7 days.
T16444 552427-552603 Sentence denotes The offspring developed moderate metabolic changes reminiscent to those observed in children from mothers who received dexamethasone to limit complications of preterm delivery.
T44190 552604-552863 Sentence denotes We received five female monkeys that were siblings from mothers treated daily with DEX in the first trimester of pregnancy (day 42-48) and four females from mothers receiving DEX late in the second trimester (day 90-96) of the total 144 days gestation period.
T61952 552864-552941 Sentence denotes Four normal age and sex-matched control monkeys were added to the experiment.
T49816 552942-553082 Sentence denotes EAE was induced in all 14 monkeys by repeated immunization at 28 days interval with a mix of two MOG peptides (34-56 and 74-96) in adjuvant.
T59908 553083-553127 Sentence denotes All 14 monkeys developed overt clinical EAE.
T20034 553128-553273 Sentence denotes However, EAE in the monkeys that were prenatally exposed to DEX developed more rapidly and with a higher lesion load than in the control monkeys.
T74281 553274-553611 Sentence denotes The most remarkable immunological effect was that T-cells from the control monkeys proliferated against the two immunizing peptides, but not against recombinant human MOG protein (rhMOG), while T-cells from both DEX exposed groups proliferated also against rhMOG suggestive of epitope diversification beyond MOG peptides 34-56 and 74-96.
T21352 553612-553727 Sentence denotes These data suggest an influence of antenatal exposure to dexamethasone on the severity of EAE induced at adult age.
T60767 553728-554037 Sentence denotes To observe the change of phosphoprotein 53 (P53), tumor necrosis factor-a (TNF-a) and transforming growth factor-b (TGF-b) expression, as well as to study the immunosuppressive effects of Simvastatin in a dosage of 1 mg/kg intraperitoneally in Wistar rats with experimental autoimmune encephalomyelitis (EAE).
T45486 554038-554203 Sentence denotes Guinea pig spinal cord homogenate, in Complete Freund's adjuvant, mycobacterium bovis bacillus calmette-guerin and pertussis toxin were used to immunize Wistar rats.
T84292 554204-554288 Sentence denotes They were divided into two groups for the immunosuppressive effects of the medicine.
T82793 554289-554383 Sentence denotes Simvastatin group was intraperitoneally injected with Simvastatin once a day from 0 to 10 p.i.
T62846 554384-554447 Sentence denotes The clinical scores, body weight were recorded every other day.
T75645 554448-554603 Sentence denotes The brains and spinal cords were removed on days from 11 to 18 p.i. for HE staining and immunohistochemistry staining in different parts of nervous system.
T49860 554604-554765 Sentence denotes When compared with that of EAE group (2.33 ± 1.75), the clinical symptom of Simvastatin group (0.83 ± 1.28) was statistically significantly decreased (p b 0.05).
T87813 554766-554986 Sentence denotes The loss of body weight and the incidence in Simvastatin group was statistically significantly decreased when compared with those of EAE group (12.27 ± 4.95 vs 18.13 ± 5.00, p b 0.05; 40% vs 80%, p b 0.05, respectively).
T83800 554987-555119 Sentence denotes So was the differences of morbidity and number of infectious foci and onset date between Simvastatin group and EAE group (p b 0.05).
T94843 555120-555336 Sentence denotes On days 11 to 18 p.i., the expression of P53 and TGF-b in Simvastatin group was statistically significantly increased when compared with those of EAE group Simvastatin is a potential agent to inhibit EAE effectively.
T54428 555337-555521 Sentence denotes The inhibiting mechanism of Simvastatin is related to up-regulation of P53 and TGF-b and down-regulation of TNF-a, which may promote the transdifferentiation of Th1 cells to Th2 cells.
T65308 555522-555670 Sentence denotes P53 may exert protective function by suppressing expression of TNF-a and promoting expression of TGF-b in rats with EAE reported here in this paper.
T90149 555671-555811 Sentence denotes Multiple sclerosis is associated with some cognitive deficits, from the disturbances of memory, language fluency to full developed dementia.
T74016 555812-555940 Sentence denotes These deficits start, in some cases, very early during first years of the disease and develop independently from motor deficits.
T47486 555941-556109 Sentence denotes Animal studies showed that cognitive deficits in autoimmune encephalomyelitis (EAE), model of MS, also exist and may depend on degeneration of the cholinergic pathways.
T64043 556110-556237 Sentence denotes In this study we showed that such memory deficits existed in EAE may be also depended on pyramidal neurons loss in hippocampus.
T20114 556238-556330 Sentence denotes Lewis rats 3 months old were injected with 4 millions of anti-MBP CD4+ T cells to evoke EAE.
T51143 556331-556425 Sentence denotes Animals suffered from tail and hind limb paresis and recovered completely after about 10 days.
T4088 556426-556587 Sentence denotes T cells infiltrated all the white matter in the brain and also hippocampus CA1 and CA4 areas 5 days after EAE induction, than disappeared during recovery period.
T64986 556588-556693 Sentence denotes The number of pyramidal CA1 and CA4 neurons was decreased by 10-15% on day 21 and 60 after EAE induction.
T70177 556694-556769 Sentence denotes No cortical (frontal cortex) degeneration was visible on these time points.
T5401 556770-556910 Sentence denotes Microglial and astrocytes activation increased from day 5 to 21 in CA1 ad CA4 regions, and NG2+ cells reaction was also increased on day 30.
T53895 556911-557115 Sentence denotes In conclusion, anti-MBP CD4+ T cells are capable not only to evoke inflammatory reaction in spinal cord and brain leading to motor deficit, but also they may directly injure hippocampal pyramidal neurons.
T29283 557116-557330 Sentence denotes Tischner Denise⁎ 1 , van den Brandt Jens 1 , Herold Marco 2 , Reichardt Holger 1 1 Institute for Cellular and Molecular Immunology, Goettingen, Germany 2 Institute for Viroloty and Immunobiology, Wuerzburg, Germany
T85043 557331-557449 Sentence denotes Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system of presumed autoimmune origin.
T3756 557450-557619 Sentence denotes Acute relapses are most commonly treated with high doses of glucocorticoids (GCs), necessitating a better understanding of the mechanisms that underlie GC actions in MS.
T52228 557620-557750 Sentence denotes By using different cell-specific glucocorticoid receptor (GR) knockout mouse strains we could show that GCs mainly act on T cells.
T98699 557751-557849 Sentence denotes Nevertheless, the differential effects of GCs on effector versus bystander T cells remain elusive.
T52671 557850-558081 Sentence denotes Therefore we inactivated GR expression by retrovirally expressed miRNAs in fully differentiated encephalitogenic T cells (Tenc) and generated two cells lines with a constitutive knockdown of the GR as well as one control cell line.
T54018 558082-558241 Sentence denotes In various apoptosis assays the GRdeficient Tenc cells displayed a significantly increased survival rate after GC treatment, indicating a successful knockdown.
T66659 558242-558427 Sentence denotes In addition, repression of the effector cytokines IFN-gamma and IL-17 by GCs was impaired in those cells, suggesting that also the transrepressive activity of the receptor was affected.
T70690 558428-558744 Sentence denotes Collectively, we envisage that inactivation of the GR in differentiated Tenc cells by RNAi will allow for investigating the influence of GCs on pathogenic effector T cells during Experimental Autoimmune Encephalomyelitis (EAE) in vivo and thereby help to further elucidate the mechanisms underlying GC therapy of MS.
T66382 558745-558882 Sentence denotes Variations in severity and duration of experimental autoimmune encephalomyelitis (EAE) depend on the species and the method of induction.
T38217 558883-559065 Sentence denotes Previous studies have shown that astrocytic connexin43 (Cx43) expression is decreased in demyelinating lesions and increased in remyelinating lesions in the guinea pig chronic model.
T86297 559066-559316 Sentence denotes The purpose of this study was to determine whether Cx43 was also involved in chronic and recovering mouse EAE models and used RNA microarray studies to investigate the modulation of other gap junction activity and other potential therapeutic targets.
T68024 559317-559498 Sentence denotes In this study, we compared two methods of immunization with myelin oligodendrocyte glycoprotein (MOG 35-55) peptide or human recombinant MOG protein (rMOG), in female C57BL/6J mice.
T51319 559499-559630 Sentence denotes Animals used in this study include: MOG peptide chronic mice, n= 15, chronic controls, n =8, rMOG, n = 11, and acute controls, n=4.
T37912 559631-560100 Sentence denotes MOG peptide caused a chronic mouse model with continued demyelination and immune cell infiltration for at least 55 days post-immunization. rMOG immunization produced a less severe disease course with many animals recovering clinically with spinal cord remyelination Cx43 RNA levels were increased in the rMOG EAE model, as well as the oligodendrocyte connexin, Cx47, which shows that intercellular communication via connexin proteins in astrocytes and oligodendrocytes.
T20902 560101-560181 Sentence denotes The other connexin proteins expressed in the CNS were not altered significantly.
T82909 560182-560342 Sentence denotes Other, non-connexin RNA transcripts, and potential therapeutic targets, altered by at least 3-fold, were related to lymphocyte activation and immune regulation.
T40152 560343-560592 Sentence denotes Other molecules of interest with a 6-fold increase compared to healthy controls were: proteoglycan 4; neutrophilic granule protein; Hox10 (involved in CNS development), Clec7a (a calcium binding protein) and CD84 (found on activated T helper cells).
T91081 560593-560704 Sentence denotes These are the first studies to compare spontaneously recovering and non-recovering chronic mouse models of EAE.
T17933 560705-560908 Sentence denotes Each model has useful characteristics: the rMOG recovering model, using microarrays, in order to identify possible therapeutic targets, and the MOG peptide chronic model, to use for intervention testing.
T57982 560909-561160 Sentence denotes Cell communication via connexin gap junctions is potentially a significant factor required for recovery, since increased expression of Cx43, and potentially Cx47, has been observed in recovering mice, compared to chronic EAE mice and healthy controls.
T25708 561161-561291 Sentence denotes Recent studies have suggested that Th17 cells may play an important role in the development of autoimmune diseases, including EAE.
T77737 561292-561365 Sentence denotes However, the encephalitogenicity of Th17 cells has not been well studied.
T49277 561366-561582 Sentence denotes Using adoptive transfer, we demonstrated that MBP Ac1-11 specific Th17 cells differentiated in vitro with IL-6+TGFβ+/−IL-23 from naïve T cell receptor transgenic T cells do not transfer disease, whereas Th1 cells do.
T70438 561583-561807 Sentence denotes After secondary stimulation of these MBP-specific Th17 cells with MBP Ac1-11, three populations of Th cells are observed which include IL-17 producing cells, IFN-g producing cells and cells that produce both IL-17 and IFN-g.
T66349 561808-561886 Sentence denotes This mixed population of T cells transfer disease as efficiently as Th1 cells.
T14168 561887-562086 Sentence denotes Since IL-1β has also been implicated in Th17 differentiation, we have also investigated the possibility that an alternative differentiation pathway may result in Th17 cells that are encephalitogenic.
T77857 562087-562197 Sentence denotes We found that induction of T-bet was necessary for encephalitogenicity, regardless of differentiation pathway.
T80690 562198-562338 Sentence denotes Together, our findings suggest that Th1 cells are encephalitogenic and that IL-6+TGFβ induces Th17 cells that cannot transfer disease alone.
T26793 562339-562462 Sentence denotes The actual biological function of IL-23 in the context of inflammation of the central nervous system (CNS) remains elusive.
T2303 562463-562646 Sentence denotes Initial reports point towards a major impact of IL-23 on TH17 cell polarization and survival (the population of auto-aggressive cells thought to mediate autoimmune effector function).
T24951 562647-562900 Sentence denotes Loss of IL-23 results in the complete resistance to tissue-directed autoimmunity but surprisingly in the absence of IL-17A producing cells experimental autoimmune encephalitis (EAE) is only slightly ameliorated contradicting to the previous observation.
T15693 562901-563051 Sentence denotes However, it becomes increasingly evident that IL-23 has a profound impact on accessory cells and may not just be required for Th17 generation in vivo.
T80579 563052-563266 Sentence denotes Our goal is to decipher the precise mechanism by which IL-23 drives autoimmune inflammation and to systematically assess the effect it has on the biology of T cells as well as macrophages and dendritic cells (DCs).
T7282 563267-563495 Sentence denotes We have shown that in the absence of functional T and B cells, in vitro differentiated bone-marrow derived macrophages after IL-23 stimulation produce high amounts of pro-inflammatory cytokines such as MIP-1 alpha and TNF-alpha.
T40479 563496-563678 Sentence denotes Peritoneal injection of IL-23 into RAG animals upregulates the expression of its receptor and induces the production of IL-23, IL-6, IL-17F among others in a T cell free environment.
T11350 563679-563853 Sentence denotes To restrict the functional impact of IL-23 to accessory but not T cells, we generated mixed BM chimeras using the bone-marrow of RAG deficient and IL-12Rb1 knock-out animals.
T42954 563854-564138 Sentence denotes After the recovery period, EAE was induced and for our surprise these animals showed strong signs of EAE and we could observe the same number and pattern of infiltrating cells to the CNS as in wild-type animals indicating the crucial impact of IL-23 on antigen presenting cells(APCs).
T35098 564139-564291 Sentence denotes To further elucidate the function of IL-23R on a variety of cell types, we have generated a conditionally targeted allele of the IL-23R in C57Bl/6 mice.
T77838 564292-564365 Sentence denotes The gene-targeting strategy and its impact on immunity will be discussed.
T52881 564366-564550 Sentence denotes T helper 17 (Th17) cells have been identified to play a pivotal role in the development of experimental autoimmune encephalomyelitis (EAE) through the production of inflammatory IL-17.
T12689 564551-564775 Sentence denotes Although alltrans retinoic acid (ATRA) has been reported to suppress the development of Th17 cells, the application of ATRA for therapeutic treatment is limited due to its instability, poor bioavailability, and side effects.
T26434 564776-564965 Sentence denotes In this study, we examined whether Am80, a synthetic RARagonist with superior pharmacological properties, could control EAE by attenuating the inflammatory properties of pathogenic T cells.
T87493 564966-565198 Sentence denotes Splenic T cells stimulated under Th17-priming conditions (TGFb + IL-6) in the presence of ATRA, Am80, or LE540 (RAR-antagonist) were assessed for their expression of inflammatory cytokines and lineage-specific transcription factors.
T84554 565199-565299 Sentence denotes Suppressive effects of those retinoids were assessed for in vitro differentiated Th17 cells as well.
T57071 565300-565409 Sentence denotes B6 mice immunized with MOG35-55 peptide to induce EAE were treated orally with Am80 or LE540 every other day.
T752 565410-565492 Sentence denotes CNSinfiltrating T cells were analyzed for cytokine production and gene expression.
T6998 565493-565685 Sentence denotes Draining lymph node cells from MOG immunized B6 mice with or without oral retinoid treatment were analyzed for their proliferation and cytokine production after restimulation with MOG peptide.
T56075 565686-565835 Sentence denotes Am80 exerted more potent suppression of Th17 differentiation and reciprocal induction of regulatory T cells than ATRA did in a dose dependent manner.
T59289 565836-565948 Sentence denotes Both compounds suppressed the IL-17 secretion and RORgt expression of already differentiated Th17 cells as well.
T23874 565949-566044 Sentence denotes Oral administration of Am80 ameliorated severity of EAE, whereas LE540 exacerbated the disease.
T56927 566045-566251 Sentence denotes Am80 treatment showed 90% reduction of IL-17 or IFN-g production and 60% reduction of TNF-a production by CNS-infiltrating T cells upon stimulation, without affecting their accumulative properties into CNS.
T62189 566252-566424 Sentence denotes Intriguingly, infiltrated T cells in brain or spinal cord were characterized by their diverse production of inflammatory cytokines and unique response after Am80 treatment.
T46529 566425-566659 Sentence denotes Oral administration of Am80 to B6 mice immunized with MOG peptide led to a significant suppression of IL-17 production by draining lymph node T cells upon restimulation with MOG peptide, without affecting their proliferative response.
T59394 566660-566830 Sentence denotes Synthetic retinoid Am80 successfully inhibits inflammatory cytokine production by pathogenic T cells and could provide a novel therapeutic approach on multiple sclerosis.
T12625 566831-567136 Sentence denotes The goal of this study is to test the hypothesis that inhibiting glycogen synthase kinase-3 (GSK3) provides protection from multiple sclerosis (MS) and other inflammatory autoimmune diseases affecting the central nervous system (CNS), using the mouse model experimental autoimmune encephalomyelitis (EAE).
T30497 567137-567354 Sentence denotes Growing evidence indicate that the serine/threonine protein kinase GSK3 is a major regulator of the inflammatory response in the periphery, but the extent to which GSK3 regulates inflammation in the CNS is unresolved.
T47655 567355-567442 Sentence denotes We therefore investigated if lithium, an inhibitor of GSK3, can ameliorate EAE in mice.
T47292 567443-567793 Sentence denotes The GSK3 inhibitor lithium was therapeutic in EAE using three different treatment protocols: (1) treatment before induction of disease prevented EAE, (2) treatment initiated at the onset of clinical symptoms suppressed exacerbation of disease, and (3) treatment initiated at the peak of disease reduced clinical symptoms and induced partial recovery.
T2244 567794-567929 Sentence denotes The amelioration of EAE was associated with reduced demyelination, microglia activation, and leukocyte infiltration in the spinal cord.
T85270 567930-568007 Sentence denotes Conversely EAE was more severe in mice expressing constitutively active GSK3.
T83627 568008-568320 Sentence denotes Spleen and lymph node cells obtained from lithium-treated MOG35-55-immunized mice proliferated poorly to in vitro restimulation with antigen and also secreted much lower amounts of interferongamma, interleukin-6 and interleukin-17 as compared to mononuclear cells obtained from untreated MOG35-55-immunized mice.
T86362 568321-568497 Sentence denotes However, the ability of T-cells from lithium-treated mice to respond to anti-CD3 stimulation was normal indicating that lithium does not intrinsically affect T-cell activation.
T54886 568498-568686 Sentence denotes These results suggest that lithium therapy suppresses the generation, differentiation and/or expansion of MOG35-55-reactive effector T cells by acting on cells of the innate immune system.
T91658 568687-568842 Sentence denotes A major form of clinical MS is a relapsing/remitting disease, which is modeled in female SJL mice immunized with proteolipid protein peptide (PLP139-151) .
T59375 568843-569036 Sentence denotes The initiation of lithium treatment in PLPimmunized SJL mice after the first clinical episode of EAE suppressed relapses for over 70 days; however the disease relapsed after lithium withdrawal.
T36144 569037-569104 Sentence denotes Remarkably, restoration of lithium therapy led to partial recovery.
T54988 569105-569326 Sentence denotes Our results demonstrate that lithium suppresses EAE and identify GSK3 as a new target for inhibition that may be useful for therapeutic intervention of MS and other autoimmune and inflammatory diseases afflicting the CNS.
T95286 569327-569602 Sentence denotes Here we show that stimulatory or tolerogenic functional states of intracerebral DCs regulate the systemic activation of neuroantigenspecific T cells, the recruitment of these cells into the CNS and the onset and progression of experimental autoimmune encephalomyelitis (EAE).
T57872 569603-569822 Sentence denotes Intracerebral microinjection of stimulatory DCs exacerbated the onset and clinical course of EAE accompanied with an early T cell infiltration and a decreased proportion of regulatory FoxP3expressing cells in the brain.
T13808 569823-570000 Sentence denotes In contrast, the intracerebral microinjection of DCs modified by tumor necrosis factor (TNF-alpha) induced their tolerogenic functional state and delayed or prevented EAE onset.
T67020 570001-570161 Sentence denotes This triggered the generation of interleukin 10 (IL-10)-producing neuroantigen-specific lymphocytes in the periphery and restricted IL 17 production in the CNS.
T39376 570162-570304 Sentence denotes Our findings suggest DCs as a rate limiting factor for neuroinflammation and imply DC as a target for therapeutic strategies for CNS diseases.
T43244 570305-570514 Sentence denotes The clear association of the TH17 phenotype with autoimmune pathogenicity implicates TH17 cytokines as critical mediators of chronic autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE).
T71034 570515-570688 Sentence denotes To study the actual impact of IL-17 on CNS inflammation, we generated transgenic mice in which the expression of high levels of IL-17A can be initiated by cre-recombination.
T71974 570689-570878 Sentence denotes While the general overexpression of IL-17A leads to skin inflammation and granulocytosis, T cell driven IL-17A expression does not impact visibly on the development and health of the mouse.
T1602 570879-571064 Sentence denotes In the context of EAE, here we demonstrate that neither the T cell-driven overexpression of IL-17A nor its complete loss has a significant impact on the development of clinical disease.
T81180 571065-571250 Sentence denotes Since TH17 cells also produce IL-17F, which evidently acts through the same receptor complex as IL-17A, it is feasible that it could compensate for the loss of IL17A in IL-17Anull mice.
T13791 571251-571367 Sentence denotes To determine the actual function of IL-17F in autoimmune inflammation of the CNS, we next generated IL-17Fnull mice.
T28289 571368-571438 Sentence denotes They not only lack IL-17F, but also produce significantly less IL-17A.
T23577 571439-571585 Sentence denotes Nevertheless, they too are fully EAE susceptible and display unaltered emergence, expansion, and polarization of auto-reactive T cells during EAE.
T97343 571586-571761 Sentence denotes We conclude that IL-17A and IL-17F, while prominently expressed by encephalitogenic T cells, do not or only marginally contribute to the development of autoimmune CNS-disease.
T8908 571762-572007 Sentence denotes Experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS), is an ideal disease paradigm for dissecting the multiple functions of transcription factor NF-kB during autoimmune demyelination and neurodegeneration.
T14080 572008-572271 Sentence denotes In this study we applied conditional gene targeting in mice to delete the inhibitor of NF-kB kinase b (IKKb), a catalytic molecule in canonical NF-kB activation, in selected CNS cell lineages and to study its cell-specific functions during the development of EAE.
T44042 572272-572556 Sentence denotes Cell-specific IKKb deletion was achieved by mating mice carrying a loxP-flanked (F) IKKb gene (exon 3) (IKKbF/F) with transgenic mice expressing Cre recombinase under promoters specific for endothelial cells (Tie2-Cre mice), macrophages/microglia (CD11b-Cre) and neurons (CamkII-Cre).
T48968 572557-572775 Sentence denotes IKK-b deletion in endothelial cells (endIKKb-KO mice) did not alter the clinical course of EAE while deletion in CD11b-positive macrophages/microglia (mIKKb-KO mice) delayed the onset and ameliorated clinical symptoms.
T61655 572776-572867 Sentence denotes The deletion of IKK-b in CamkII-expressing neurons showed dual and opposite effects in EAE.
T47495 572868-573043 Sentence denotes Mice lacking neuronal IKK-b (nIKKb-KO) showed significant delay in disease initiation but subsequently developed a more severe, non-resolving disease compared to control mice.
T48877 573044-573313 Sentence denotes The increased pathology in nIKKb-KO spinal cord was associated with reduced expression of neuroprotective molecules and enhanced expression of immune mediators, including Th1-and TH17-related cytokines and chemokines that are known to be important for EAE pathogenesis.
T97867 573314-573582 Sentence denotes Our results show that neuronal IKK-b is important for the correct regulation of neuroprotective mechanisms and CNS immune responses during CNS autoimmune disease and further emphasize the importance of neuroprotective strategies in the treatment of multiple sclerosis.
T74462 573583-573739 Sentence denotes The growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF) is a well known cytokine affecting the differentiation of dendritic cells (DCs).
T52224 573740-573952 Sentence denotes DCs play a crucial role in regulating beneficial immune responses and in the development of autoimmune diseases such as multiple sclerosis (MS) or its animal model experimental autoimmune encephalomyelitis (EAE).
T19652 573953-574035 Sentence denotes GM-CSF preferentially induces the expansion of CD11b+ myeloid DCs (CD45hi CD11c+).
T77036 574036-574132 Sentence denotes This DC subset can be further differentiated into a F4/80-negative and a F4/80positive fraction.
T35491 574133-574310 Sentence denotes We previously found that, in contrast to F4/80-DCs, the F4/80+ DCs isolated from the EAE-diseased central nervous system (CNS) inhibited T cell proliferation and EAE occurrence.
T40824 574311-574409 Sentence denotes Thus we aimed at defining the differential role of GM-CSF in the development and remission of EAE.
T82662 574410-574541 Sentence denotes GM-CSF producing cells were injected intracerebrally into mice which were immunized with myelin oligodendrocyte glycoprotein (MOG).
T88868 574542-574647 Sentence denotes Depending on the time point of GM-CSF treatment, mice developed more severe EAE early after immunization.
T32862 574648-574753 Sentence denotes In order to analyze the origin of GM-CSF-induced DCs, we generated congenic bone marrow-chimeric animals.
T479 574754-574844 Sentence denotes The treatment with GM-CSF resulted in a preferential induction of F4/80-blood-derived DCs.
T21974 574845-574916 Sentence denotes In contrast, CNSderived DCs were predominantly of the F4/80+ phenotype.
T52992 574917-575053 Sentence denotes Furthermore, the GM-CSF-recruited F4/80-DCs stimulated T cell proliferation whereas the F4/80+ DC subset inhibited T cell proliferation.
T5815 575054-575257 Sentence denotes Finally, GM-CSF receptor (Csf2r)-deficient mice did not develop EAE and did not contain any infiltrates within the CNS during disease development despite unaltered priming compared to wild type controls.
T1269 575258-575391 Sentence denotes In summary, the data demonstrate that both the DC recruitment and the disease severity of EAE are enhanced in the presence of GM-CSF.
T86117 575392-575567 Sentence denotes The chimera experiment further suggests that the effect of GM-CSF on stimulatory F4/80-blood-derived DCs dominates over the GM-CSF-mediated induction of inhibitory F4/80+ DCs.
T17380 575568-575694 Sentence denotes In addition, the results with the Csf2r-deficient mice indicate that GM-CSF plays a crucial role in the effector phase of EAE.
T37641 575695-575899 Sentence denotes Experimental Autoimmune Encephalomyelitis (EAE) in Lewis rats was induced by transfer of myelin basic protein-reactive T cells genetically engineered to express green fluorescent protein (TMBP-GFP cells).
T80567 575900-576017 Sentence denotes After a disease free period of 3 days the autoreactive T cells induced CNS inflammation and severe paralytic disease.
T83675 576018-576145 Sentence denotes Using 2photon microscopy we visualized the infiltration process of TMBP-GFP cells into their target organ during incipient EAE.
T89750 576146-576306 Sentence denotes Intravital imaging of spinal cord in situ combined with imaging of spinal cord explants enabled us to track TMBP-GFP cells throughout the entire CNS parenchyma.
T89997 576307-576469 Sentence denotes Imaging was complemented by gene expression profiling of the autoaggressive TMBP-GFP cells isolated from different CNS locations by cytofluorometric cell sorting.
T56589 576470-576555 Sentence denotes The first TMBP-GFP cells arrived at the CNS within 24 h after T cell transfer (p.t.).
T73013 576556-576632 Sentence denotes These T cells were located in close contact to leptomeningeal blood vessels.
T17900 576633-576717 Sentence denotes The number of these vessel-associated TMBP-GFP cells increased during the next 24 h.
T32302 576718-576788 Sentence denotes The vast majority of T cells moved continuously at the vessel surface.
T58035 576789-576892 Sentence denotes A small proportion of the T cells (5%), however, were arrested in contact with perivascular phagocytes.
T84217 576893-577073 Sentence denotes On day 2.5 p.t. the TMBP-GFP cells started to distribute throughout the entire meningeal areas and to immigrate into the CNS parenchyma along the perivascular Virchow-Robin spaces.
T51822 577074-577190 Sentence denotes An increasing part of the T cells (25%) were now forming long lasting contacts to perivascular/meningeal phagocytes.
T7414 577191-577372 Sentence denotes From day 3 p.t. on, the T cells invaded the parenchyma adjacent to the meninges and CNS vessels and within the next 24 h they diffusely distributed throughout the entire CNS tissue.
T53041 577373-577469 Sentence denotes Within the CNS parenchyma 65% of the T cells were constantly moving whereas 35% were stationary.
T1652 577470-577601 Sentence denotes 2-Photon microscopy was complemented by studies of the gene expression profiles of TMBP-GFP cells on their way into the CNS tissue.
T40524 577602-577781 Sentence denotes TMBP-GFP cells residing in the spleen and circulating in blood displayed a "migratory" phenotype with low activation markers and upregulation of genes relevant for cell migration.
T66971 577782-577918 Sentence denotes Importantly, upon entry into the meningeal, TMBP-GFP cells were strongly activated producing high amounts of pro-inflammatory cytokines.
T92095 577919-577983 Sentence denotes Further activation occurred following entry into the parenchyma.
T50390 577984-578181 Sentence denotes We present data indicating that autoaggressive T cells enter their target organ via the meninges where they recognize endogenous autoantigen presented by resident meningeal/perivascular phagocytes.
T33286 578183-578287 Sentence denotes Multiple Sclerosis (MS) is an immune mediated demyelinating disease of the central nervous system (CNS).
T47896 578288-578404 Sentence denotes We aim to find mechanisms by which toll like receptors (TLRs) exacerbate or suppress CNS inflammatory demyelination.
T7946 578405-578601 Sentence denotes Both effects have been observed in experimental autoimmune encephalomyelitis (EAE) an animal model of MS-TLRs 2 and 9 in exacerbating disease, TLR4 in delaying onset and TLR3 in reducing severity.
T71939 578602-578733 Sentence denotes Naturally occurring CD4+CD25+ regulatory T cells (Tregs) can suppress autoimmune reactions and were recently found to express TLRs.
T71696 578734-578918 Sentence denotes We are in the process of studying the effect of TLR3 on Treg suppression in the mouse by co-culturing CD4+CD25-responder cells with different ratios of Tregs with or without poly(I:C).
T23866 578919-579140 Sentence denotes Preliminary studies indicate that TLR3 ligand poly(I:C) increases the suppressive ability of Tregs in C57BL/6 mice and this is a potential mechanism by which EAE disease severity is reduced after poly(I:C) administration.
T52811 579141-579240 Sentence denotes We also determined which cytokines and chemokines are induced by TLR stimuli in murine splenocytes.
T49171 579241-579411 Sentence denotes The inflammatory chemokine MCP-1 was unregulated by TLR stimuli-Pam3CSK (TLR1/2), HKLM (TLR2), LPS (TLR4), Flagellin (TLR5), follistatin-like 1 (TLR6) and ssRNA40 (TLR7).
T30033 579412-579537 Sentence denotes The anti-inflammatory cytokine IL-10 was unregulated by the same stimuli and also by poly(I:C) (TLR3) and CpG ODN1826 (TLR9).
T29527 579538-579588 Sentence denotes TLR9 also induced increased production of IL12p70.
T83213 579589-579649 Sentence denotes All TLR stimuli also induced increased T cell proliferation.
T34688 579650-579806 Sentence denotes The response of human monocyte derived dendritic cells (MDDCs) to TLR stimuli in terms of maturation and cytokine and chemokine production was also studied.
T58945 579807-579862 Sentence denotes MCP-1 was unregulated by TLR stimuli poly(I:C) and LPS.
T1832 579863-579973 Sentence denotes The inflammatory cytokines IL-6 and TNF-a were unregulated by these two stimuli and also by Pam3CSK4 and HKLM.
T79291 579974-580041 Sentence denotes The effects of TLR stimuli on MDDCs in MS patients are in progress.
T147 580042-580169 Sentence denotes We are also in the process of determining the effect of a range of TLR stimuli on the clinical and pathological outcome of EAE.
T1341 580170-580290 Sentence denotes TLR stimuli alter the regulatory ability of Tregs and this may contribute to disease exacerbation or suppression in EAE.
T39645 580291-580487 Sentence denotes TLR stimuli lead to the production of cytokines and chemokines that may regulate autoimmune diseases and there is potential to aid immunotherapy by targeting these TLRs and the cytokines produced.
T21508 580488-580828 Sentence denotes Rigolio Roberta⁎ 1 , Biffi Alessandro 1 , Oggioni Norberto 1 , Cavaletti Guido 1 1 Università degli Studi Milano-Bicocca, Monza, Italy Actively induced Experimental Autoimmune Encephalomyelitis (EAE) is a well reproducible model for portraying the acute phase of multiple sclerosis as well as good model to develop new promising treatments.
T39010 580829-580950 Sentence denotes Both lymph node and spinal cord (s.c.) have been widely described by means of molecular biology and immunohistochemistry.
T55328 580951-581128 Sentence denotes The aim of this study was to characterize both spleen and s.c. lymphocyte populations and to highlight possible useful markers to be monitored during new therapeutic treatments.
T90593 581129-581391 Sentence denotes Thus at the onset (day 10 after EAE induction) and at the peak of the disease (day 14 after EAE induction) we investigated CD4, CD8 and encephalitogenic TCRVb8.2+ T cells prevalence as well as the expression of adhesion molecules CD49d (VLA-4) and CD11a (LFA-1).
T36929 581392-581501 Sentence denotes EAE was actively induced by subcutaneously inoculation of 50 μg guinea pig Myelin Basic Protein (gifted by P.
T54804 581502-581584 Sentence denotes Riccio) in complete Freund's adjuvant with inactivated Mycobacterium tuberculosis.
T99972 581585-581793 Sentence denotes The spleen and s.c. were dissected from both healthy (controls) and EAE-induced animals, cells were collected, stained with different combinations of conjugated antibodies and acquired using a flow cytometer.
T81082 581794-581991 Sentence denotes In the spleen of EAE animal we reported a significant decrease in the mean absolute cell number on day 14, together with the presence of a CD45+ population other than lymphocytes as soon as day 10.
T62453 581992-582140 Sentence denotes Furthermore we observed an increase in CD4 and decrease in CD8 T cells compared to the controls on day 14, while no changes were reported on day 10.
T81132 582141-582303 Sentence denotes Moreover no alteration in the TCRVb8.2+ lymphocytes percentage as well as in CD49d (VLA-4) and CD11a (LFA-1) expression on CD4 and CD8 T cells was never observed.
T57288 582304-582378 Sentence denotes In the spinal cord no infiltrating lymphocytes were detected until day 14.
T92214 582379-582465 Sentence denotes Therefore the results on s.c. were compared to those obtained in the spleen on day 14.
T53470 582466-582565 Sentence denotes Thus CD4 lymphocytes percentage was higher in the s.c., while CD8 lymphocytes prevalence decreased.
T61447 582566-582759 Sentence denotes We also observed an increase in CD4 TCRVb8.2+ T cells percentage together with a significant increase in the expression of CD49d (VLA-4) which was more accentuated for CD4 than for CD8 T cells.
T62238 582760-582945 Sentence denotes Our results confirm that EAE in Lewis rats is a CD4 T cell mediated disease in which the expression of TCR Vb8.2 and adhesion molecules is probably regulated mainly in the target organ.
T26774 582946-583074 Sentence denotes We show that multiparametric flow cytometry can be an informative method to describe immune system cells during the EAE ongoing.
T40881 583076-583399 Sentence denotes While the elevation of several members of the matrix metalloproteinase (MMP) family is thought to promote the pathophysiology of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), the rise of particular MMP members may have contrary beneficial functions during disease processes.
T74955 583400-583574 Sentence denotes MMP-12 mRNA levels rise significantly in the spinal cord in EAE-afflicted mice (Weaver et al., FASEB J 19:1668-1670, 2005) and may have a beneficial role in EAE pathogenesis.
T96592 583575-583654 Sentence denotes We examined the role of MMP-12 in EAE and its potential mechanism(s) of action.
T10469 583655-583742 Sentence denotes 129/SvEv MMP-12 −/− mice were induced with myelin oligodendrocyte glycoprotein for EAE.
T39585 583743-583808 Sentence denotes Mice were followed for 60 days to determine EAE disease profiles.
T11764 583809-583928 Sentence denotes The spinal cords were isolated and analyzed using flow cytometry, protein array, western blot and histology during EAE.
T49140 583929-584086 Sentence denotes While MMP-12 −/− mice had similar day of onset of clinical signs as wildtype controls, their subsequent relapses in relapsing-remitting EAE were more severe.
T31731 584087-584185 Sentence denotes Residual disability of MMP-12 −/− mice at remission was also higher compared to wildtype controls.
T48886 584186-584431 Sentence denotes The worsened relapses and remissions in MMP-12 −/− mice occurred despite a deficiency of the antigen recall capacity of lymph nodederived cells, and a reduction in the proportion of macrophages in the spinal cord during the chronic phase of EAE.
T52110 584432-584627 Sentence denotes Significantly, large increases of levels of chemokines, pro-inflammatory and antiinflammatory cytokines, but low G-CSF levels, were found in the spinal cord of MMP-12 −/− mice during chronic EAE.
T18975 584628-584894 Sentence denotes We discovered as well that MMP-12 processes the multi-functional protein, osteopontin, into smaller fragments in vitro and in EAE; significantly, the higher severity of EAE in MMP-12 −/− mice returned to wildtype EAE scores in osteopontin and MMP-12 double −/− mice.
T9095 584895-585047 Sentence denotes These results highlight MMP-12 as a beneficial MMP in EAE through cytokine and chemokine regulation, as well as through an interaction with osteopontin.
T191 585048-585152 Sentence denotes Therapeutic interventions in MS that are aimed at reducing MMP activity should avoid MMP-12 as a target.
T93513 585153-585232 Sentence denotes The cytostatic drug Edelfosine is a synthetic analog of Lysophosphatidylcholin.
T75435 585233-585302 Sentence denotes It was originally regarded as an antitumor agent in cancer treatment.
T84952 585303-585401 Sentence denotes Edelfosine is incorporated by cells and it selectively activates the cell death receptor Fas/CD95.
T96763 585402-585482 Sentence denotes In contrast to other cytostatic drugs, Edelfosine does not intercalate into DNA.
T87456 585483-585675 Sentence denotes In vitro treatment of cells with Edelfosine showed that it is incorporated to effective intracellular concentrations by highly proliferating cells, like activated immune cells and tumor cells.
T46710 585676-585804 Sentence denotes Our aim was to study the effect of Edelfosine on the immune system in the context of experimental autoimmune encephalitis (EAE).
T26066 585805-586088 Sentence denotes In order to analyze the anti-inflammatory properties of Edelfosine we have used two models, C57BL/6 mice immunized with the peptide 35-55 of the myelin oligodendrocyte glycoprotein (MOG 35-55) and SJL mice immunized with the peptide 139-151 of the proteolipid protein (PLP 139-151) .
T96823 586089-586205 Sentence denotes The effect of Edelfosine on EAE disease course was evaluated by clinical, histological and flow cytometric analysis.
T63410 586206-586432 Sentence denotes We found that daily treatment of C57BL/6 mice with 10 mg/kg Edelfosine by gavage from the day of immunization led to a reduction of the maximum mean EAE score of 2.8 in control animals (gavage of PBS) to 0.7 in a 0 to 5 scale.
T21318 586433-586638 Sentence denotes In the control group all animals developed full blown EAE whereas only one mouse in the Edelfosine treatment cohort showed severe disease, while the others demonstrated weak signs of EAE or stayed healthy.
T42332 586639-586696 Sentence denotes No side effects due to drug administration were observed.
T66372 586697-586904 Sentence denotes Flow cytometry studies at day 29 after immunization in the C57BL/6 model revealed a reduction of the activated CD4+ lymphocyte fraction in secondary lymphoid organs of treated mice when compared to controls.
T70701 586905-587079 Sentence denotes These results point to a beneficial effect of Edelfosine on EAE disease severity and suggest that it interferes with immune cell infiltration into the central nervous system.
T38936 587080-587264 Sentence denotes Further analysis of the therapeutic value of Edelfosine is currently underway in order to examine further the potential of this drug Edelfosine for the treatment of multiple sclerosis.
T32661 587265-587545 Sentence denotes To identify the most critical factors of inflammation during animal model of multiple sclerosis (MS)-experimental autoimmune encephalomyelitis (EAE), we have used microarrays for the molecular analysis of the transcriptional profile of the central nervous system (CNS) infiltrate.
T44757 587546-587684 Sentence denotes Heat shock proteins (hsp), especially hsp70 were among the most prominent protein groups that genes expression was upregulated during EAE.
T85198 587685-587844 Sentence denotes Hsp, major inflammatory-induced proteins, were demonstrated to play both protective (e.g. anti-apoptotic), and proinflammatory (e.g. activation of TLRs) roles.
T76527 587845-587965 Sentence denotes In the recent study we aim to analyze the in vivo role of hsp expression in the development of autoimmune demyelination.
T82937 587966-588130 Sentence denotes To obtain a definite proof for the role in vivo of hsp70 in myelin antigen recognition we used mouse deficient for the major gene encoding inducible hsp70, hsp70.1.
T53273 588131-588324 Sentence denotes Immunization of hsp70.1−/− mice with myelin/ oligodendrocyte glycoprotein (MOG) peptide 35-55 showed their almost complete resistance to induction of experimental autoimmune encephalitis (EAE).
T13735 588325-588574 Sentence denotes The EAE resistance correlated with lost of MOG35-55 proliferative T cell responses as well as significantly downregulated secretion of proinflammatory cytokines like interferon gamma (IFNg) or interleukin 17 (IL17) by CD4+ T cell in hsp70.1−/− mice.
T69312 588575-588817 Sentence denotes Interestingly hsp70 deficiency resulted in CD4 T cell activation dysfunction demonstrated by antigen presentation assays which showed that MOG35-55 reactivity was abolished when T cells from hsp70.1−/− mice were cocultured with wild type APC.
T4821 588818-588902 Sentence denotes Hsp70 deficient CD4+ T cell also failed to transfer disease in passive model of EAE.
T47993 588903-589045 Sentence denotes The mechanism of CD4+ T cell failure in hsp70.1−/− mice in responding to MOG35-55 was TCR dependent and involved activation-induced apoptosis.
T67282 589046-589284 Sentence denotes These results provide a direct proof for the in vivo role of hsp, especially hsp70 in recognition of self myelin antigen MOG and strengthen the hypothesis that stress conditions leading to hsp70 induction may enhance autoimmune reactions.
T12777 589285-589401 Sentence denotes The present study was aimed to characterize the individual functions of myelin specific Th1 and Th17 T cells in EAE.
T67240 589402-589531 Sentence denotes We established polarized Th1 and Th17 populations, derived from MOG specific TCR transgenic mice with C57BL/6 genetic background.
T49643 589532-589672 Sentence denotes These cells were adoptively transferred, individually or as combination, to Rag2 deficient animals to test their encephalitogenic potential.
T3099 589673-589750 Sentence denotes We found that both Th1 and Th17 CD4+ subsets alone are capable to induce EAE.
T14356 589751-589846 Sentence denotes Notably, however, co-transfer of Th1 and Th17 cells induced more severe EAE with earlier onset.
T84988 589847-589885 Sentence denotes EAE differed in clinical presentation:
T64255 589886-590030 Sentence denotes Th1 alone and Th1+Th17 co-transfer induced more than 90% classical EAE, while around 50% of Th17 transferred mice developed an ataxic phenotype.
T83487 590031-590147 Sentence denotes Histological analyses indicated that lesion intensity largely correlated with astrogliosis and microglia activation.
T62828 590148-590258 Sentence denotes In Th1+Th17 transferred mice this was evident both in spinal cord and brain parenchyma, especially cerebellum.
T22865 590259-590491 Sentence denotes On the other hand, Th1 transferred mice showed more infiltration of spinal cord and perivascular spaces in brain, while Th17 transferred mice with classical EAE presented T cell infiltration both in spinal cord and brain parenchyma.
T57245 590492-590669 Sentence denotes We preformed cytotoxicity assays of Th1 and Th17 cells on astrocytes in order to elucidate in detail the pathogenic mechanisms of these two T cell subsets in CNS resident cells.
T97731 590670-590894 Sentence denotes Preliminary data show that, in contrast to Th17, Th1 cells are cytotoxic to astrocytes and that this cytotoxicity may be independent on the presence IFNg, as blocking MAbs added during co-culture did not affect cytotoxicity.
T6606 590895-591058 Sentence denotes However, we found a correlation between extent of cytotoxicity and the percentage of IFNg+ cells in the total CD4 Th1 population applied to the astrocytes culture.
T4034 591059-591239 Sentence denotes We conclude that both T helper cell subsets alone have the potential to induce EAE, probably by different mechanism, and that their interaction potentiates the autoimmune response.
T86701 591240-591422 Sentence denotes Both myelin-specific Th1 and Th17 cells have been implicated as the pathogenic T cells in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS).
T40614 591423-591657 Sentence denotes Recent studies have shown that IL-23-deficiency and systemic administration of anti-IL-23 monoclonal antibodies significantly reduces the incidence and severity of EAE, suggesting a critical role for IL-23 in the pathogenicity of EAE.
T40819 591658-591887 Sentence denotes IL-23 has been implicated as a critical factor in the differentiation, expansion, and survival of Th17 cells, thus speculating that IL-23 is critical for the production autoreactive Th17 cells and the subsequent induction of EAE.
T44521 591888-591965 Sentence denotes However, IL-23 receptor was originally described as a memory Th1 cell marker.
T59276 591966-592208 Sentence denotes We have confirmed that myelin-specific T cells differentiated into Th1 and Th17 cells express similar levels of IL-23 receptor, suggesting that in addition to Th17 differentiation, IL-23 may play a role in the effector functions of Th1 cells.
T17631 592209-592494 Sentence denotes To determine if IL-23 is playing a critical role in the differentiation or effector function of myelin-specific Th1 cells, we differentiated naive T cells specific for MBP Ac1-11 in vitro with IL-12 or IL-12 + anti-IL-23 antibody, and transferred these cells into naive recipient mice.
T92712 592495-592763 Sentence denotes Although both populations made equivalent amounts of IFN-gamma, the incidence of EAE in the mice that received Th1 cells differentiated in the presence of anti-IL-23 was significantly reduced compared to the mice that received Th1 cells differentiated with IL-12 only.
T3924 592764-592892 Sentence denotes This data suggest that IL-23 contributes to the encephalitogenic capacity of Th1 cells in immune-mediated demyelinating disease.
T59108 592893-593003 Sentence denotes 57 -Both blood-derived and CNS-derived APC contribute to antigen presentation during the effector phase of EAE
T78952 593005-593210 Sentence denotes During experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, MHCII expression is upregulated on a variety of different types of antigen presenting cells (APC) in the CNS.
T345 593211-593315 Sentence denotes Defining the respective roles of antigen presentation by these APC during EAE remains a major challenge.
T47189 593316-593617 Sentence denotes To address this question we have generated mice exhibiting altered patterns of MHCII expression by exploiting the fact that the class II transactivator (CIITA) gene, which encodes the master regulatory factor of MHCII genes, is controlled by three cell-type specific promoters called pI, pIII and pIV.
T83906 593618-593692 Sentence denotes We recently generated a strain of mice lacking pI driven CIITA expression.
T60218 593693-593868 Sentence denotes The analysis of MHCII expression in pI−/− mice demonstrated that pI is essential for driving CIITA and MHCII expression in interferongamma activated macrophages and microglia.
T19212 593869-593949 Sentence denotes It is also required to a variable degree in various dendritic cell (DC) subsets.
T31649 593950-594217 Sentence denotes In contrast, MHCII expression is affected only marginally in thymic epithelial cells and B cells. pI is thus critical for driving CIITA and MHCII expression in the APC (microglia, macrophages and DC) that are most likely to be implicated in the effector phase of EAE.
T70412 594218-594453 Sentence denotes We therefore studied the susceptibility of pI−/− mice to EAE induced by active immunization with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55, as well as by the adoptive transfer of MOGreactive encephalitogenic CD4+ T cells.
T21664 594454-594514 Sentence denotes In both models, pI−/− mice were almost completely protected.
T99748 594515-594640 Sentence denotes In the active immunization model, MOG-specific T cell priming was essentially normal despite the fact that EAE did not ensue.
T46480 594641-594809 Sentence denotes Taken together these results demonstrate that the block in EAE development in pI−/− mice lies at the level of antigen presentation during the effector phase in the CNS.
T34503 594810-595047 Sentence denotes To determine whether the absence of MHCII expression by CNS resident microglia or blood-derived APC is responsible for the resistance of pI−/− mice to EAE, we generated reciprocal bone marrow-chimeras between wild type and pI−/− animals.
T35060 595048-595210 Sentence denotes Interestingly, both types of chimeric mice (pI−/− into wt and wt into pI−/−) developed EAE, whereas pI−/− into pI−/− control chimeras remained strongly protected.
T33245 595211-595437 Sentence denotes These results show that MHCII-restricted antigen presentation by both blood-derived and CNS-derived APC is involved during the effector phase of EAE, and that these two APC compartments can compensate for each other's absence.
T31759 595438-595614 Sentence denotes Experimental autoimmune encephalomyelitis (EAE), an animal model for the human disease multiple sclerosis, is mediated by autoreactive CD4+ T cells targeted against CNS myelin.
T27204 595615-595754 Sentence denotes Phosphoinositide 3-kinases (PI3Ks) are intracellular signaling molecules that have been implicated in susceptibility to autoimmune disease.
T27772 595755-595860 Sentence denotes Existing evidence suggests that PI3K-gamma is important for migration of antigen presenting cells (APCs).
T3941 595861-596099 Sentence denotes We found that PI3K-gamma−/− (ko) mice, when immunized with myelin proteins, show a profound suppression of EAE clinical signs and a marked reduction in demyelination and inflammatory cytokine production relative to wildtype (wt) controls.
T65506 596100-596314 Sentence denotes We hypothesize that the primary mechanism of protection observed in ko mice is due to impaired myeloid cell migration to sites of inflammation, and not an inherent defect in the ability of APCs to activate T cells.
T10968 596315-596471 Sentence denotes Co-culture of ko APCs with competent T cells induced T cell proliferation, suggesting that PI3K-gamma is not critical for processing and presenting antigen.
T37904 596472-596634 Sentence denotes We developed ko and wt chimeras to test this hypothesis and found that wt animals reconstituted with ko bone marrow had less severe EAE than wt chimeric controls.
T47963 596635-596752 Sentence denotes This suggests that the protective phenotype observed in ko mice is mediated by immune cells located in the periphery.
T13141 596753-597056 Sentence denotes Taken together, these results demonstrate a key role for PI3Kgamma in the activation of peripheral immune compartments, and suggest that PI3K-gamma could be an important target for the treatment of autoimmune diseases. (Supported by NIH grants GM 068412, AI 064320 and National MS Society grant RG3272).
T76193 597057-597275 Sentence denotes 59 -The dominancy of encephalitogenic peptide correlates to its ability to induce potent regulatory T cells Lin Youwei⁎ 1 , Miyake Sachiko 1 , Yamamura Takashi 1 1 National Institute of Neuroscience, NCNP, Tokyo, Japan
T47394 597276-597367 Sentence denotes Like human counterpart MS, animal MS models can show a great diversity in clinical courses.
T38023 597368-597468 Sentence denotes The most famous model is EAE and its susceptibility is believed to be determined by genetic factors.
T29559 597469-597568 Sentence denotes SL/J mice are well known to develop relapsing-remitting EAE (RR-EAE) by immunization of PLP139-151.
T30943 597569-597754 Sentence denotes However, we found that priming with PLP136-150, overlapping peptide, induces monophasic EAE (M-EAE) resistant to relapse and also to reinduction of EAE with any peptides, unlike RR-EAE.
T85650 597755-597991 Sentence denotes We have already discovered that such resistance originated from a continuously high and selective induction of Foxp3+CD4+CD25+ regulatory T cells (Foxp3+Treg) co-expressing CD103 and CD69 in the LN cells during remission phase of M-EAE.
T31806 597992-598042 Sentence denotes We furthermore clarified the underlying mechanism.
T51829 598043-598156 Sentence denotes First, we compared T cell response or EAE primed with several peptides concerning with PLP136-150 and PLP139-151.
T90232 598157-598339 Sentence denotes Contrary to conventional understanding, truncation of N-terminal residues in PLP136-150 or elongation of C-terminal residue in PLP139-151 exacerbated relapse and re-induction of EAE.
T50592 598340-598480 Sentence denotes As such, dangerous self-peptide can differ from a less dangerous one only at flanking residues through prohibiting induction of potent Treg.
T89192 598481-598585 Sentence denotes We next checked the dominancy of PLP peptides in SJL/J mice by immunization with spinal cord homogenate.
T17929 598586-598773 Sentence denotes Surprisingly, PLP136-150 was more dominant than PLP139-151 among immuno-dominant epitope in SJL/J mice, and PLP136-150-primed LN cells could react effectively than PLP139-151-primed ones.
T32720 598774-599048 Sentence denotes By the experiments of priming with low-dose PLP peptides, we disclosed that the more dominant the encephalitogenic peptide is, the more resistant to reinduction EAE the peptide induced showed, indicating that TCRpeptide affinity determined the ability to induce potent Treg.
T60262 599049-599258 Sentence denotes Finally, we immunized the mice with peptide emulsified in IFA (not CFA) to check whether EAE induction is necessary or not and found that such phenomenon depends on peptide itself independent of EAE induction.
T25184 599259-599494 Sentence denotes These findings suggest that the variety of clinical prognosis in MS might depend on the different kinetics and potency of Treg induced by the different 'regulatogenicity' in the individuals, controlled by the dominancy of self-peptide.
T28630 599495-599550 Sentence denotes This would confirm the idea 'immunological homunculus'.
T63505 599551-599671 Sentence denotes Through exploring this, a new therapy into full recovery and resistance to relapse for a long period would be available.
T66820 599672-599796 Sentence denotes Pregnancy affects the clinical course of autoimmune disease such as multiple sclerosis (MS), rheumatoid arthritis and lupus.
T28086 599797-599970 Sentence denotes In this study, we determined the immunoregulatory role of pregnancy on the effector phase of murine experimental autoimmune encephalomyelitis (EAE), a model for studying MS.
T97376 599971-600119 Sentence denotes We used an adoptive transfer system with myelin basic protein (MBP) peptide NAc1-11 activated MBP T cell receptor (TCR) transgenic (Tg) donor cells.
T23960 600120-600210 Sentence denotes Donor cells are Th1 (Tg cells+Ag+/-IL-12) and Th17 (Tg cells+Ag+IL-6+TGFbeta+IL-23) cells.
T93084 600211-600310 Sentence denotes Transfer of Ag-specific activated Th1 cells into non-pregnant or virgin recipients resulted in EAE.
T43156 600311-600435 Sentence denotes However, transfer of Ag-specific activated Th17 cells to non-pregnant recipients resulted in severe EAE with 100% mortality.
T98817 600436-600755 Sentence denotes Our results show 1) transfer of activated Ag-specific Th1 cells to recipients during pregnancy resulted in EAE with a delayed onset and reduced clinical severity; 2) transfer of activated Ag-specific Th17 cells to recipients during pregnancy resulted in EAE with reduced cumulative scores but no reduction in mortality.
T46460 600756-600840 Sentence denotes We did observe the termination of pregnancy in some recipients of Th1 or Th17 cells.
T88064 600841-600948 Sentence denotes We investigated the mechanisms of pregnancy suppression of adoptively transferred EAE induced by Th1 cells.
T49190 600949-600980 Sentence denotes We explored three alternatives:
T80465 600981-601155 Sentence denotes 1) deletion of Ag-specific pathogenic T cells, 2) anergy of Ag-specific pathogenic T cells and 3) deviation from Ag-specific pathogenic T cells to Th2 and regulatory T cells.
T95177 601156-601252 Sentence denotes Our results show that pregnancy suppresses Agspecific proliferation and Th1 cytokine production.
T87984 601253-601374 Sentence denotes However, the number of donor Tg CD4+ cells increased in the pregnant environment compared with non-pregnant control mice.
T13393 601375-601541 Sentence denotes These results suggest that pregnancy provides an immunoregulatory environment including anergy and deviation that suppresses the activity of encephalitogenic T cells.
T37743 601542-601721 Sentence denotes Although several studies clearly demonstrate the ability of Foxp3+ T cells to prevent EAE in mice, not many address their phenotypic characteristics and their mechanism of action.
T81930 601722-601973 Sentence denotes We have performed a kinetic and cytokine analysis of the cellular composition of secondary lymphoid organs and of the central nervous system (CNS) at different time points after relapsing-remitting EAE induction in SJL by immunization with PLP139-151.
T21241 601974-602112 Sentence denotes We describe the kinetic and possible migration features of different subpopulation of CD4+Foxp3+ T cells during the course of the disease.
T99960 602113-602261 Sentence denotes We also, surprisingly, found that, approximately 10-12% of Foxp3+ T cells were positive for IL-2, IL-17, or IFNγ by intracellular cytokine staining.
T23550 602262-602356 Sentence denotes Cytokine positive CD4+Foxp3+ T cells were enriched in the CD25+, CD25-, CD103+ subpopulations.
T25353 602357-602574 Sentence denotes Our results, showing a small but consistent percentage of Tcells double positive for Foxp3 and effector cytokines, question the concept of Foxp3 as a marker tout court associated to suppressive functions also in mice.
T69876 602575-602933 Sentence denotes 62 -Liver X receptor agonist T0901317 ameliorates experimental autoimmune encephalomyelitis through suppressing IL-17 production Xu Jihong⁎ 1 , Drew Paul 1 1 University of Arkansas for Medical Sciences, Little rock, United States Liver X receptors (LXRs) are part of the nuclear receptor family and are believed to regulate cholesterol and lipid homeostasis.
T58783 602934-603237 Sentence denotes We have recently shown that liver X receptor agonist T0901317 has antiinflammatory effects on activated microglia and astrocytes, and it also has been demonstrated that T0901317 decreased the clinic severity of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS).
T68237 603238-603440 Sentence denotes MS is a T-cell initiated autoimmune disease, and recent data have established that IL-17-producing T cells, driven by IL-23 and referred to as Th17 cells, play a pivotal role in the pathogenesis of EAE.
T54443 603441-603545 Sentence denotes The aim of this work was to determine the effects of T0901317 on IL-17 production and IL-23R expression.
T29230 603546-603736 Sentence denotes Our studies demonstrated that LXR agonist T0901317 inhibited the production of IL-17 and IFN-gamma by activated T-cells from both MOG primed C57BL/6 mice and Va2.3/Vβ8.2 TCR-transgenic mice.
T62868 603737-603790 Sentence denotes T0901317 also inhibited IL-23R expression in T-cells.
T12719 603791-603994 Sentence denotes In addition, we assessed the effects of T0901317 on mRNA and protein expression of IL-17, IL-17R and IL-23R from spinal cord of EAE mice, and found that T0901317 significantly suppressed these molecules.
T98297 603995-604096 Sentence denotes These data suggest that LXR agonists may mediate autoimmune diseases by suppressing IL-17 production.
T19552 604097-604209 Sentence denotes Proliferation studies showed that naïve lymphocytes responded better in the presence of Non-PDC compared to PDC.
T94637 604210-604306 Sentence denotes Increasing the ratio PDC/T cells did not alter the T cell proliferation in contrast to non-PDCs.
T79676 604307-604418 Sentence denotes Since IL-17 is known to amplify effector immune responses the interplay of IL-17 with PDC is of great interest.
T59322 604419-604517 Sentence denotes Yet, the differentiation/ maturation of PDC from BM cells from IL-17ko and wt mice was comparable.
T89067 604518-604639 Sentence denotes Furthermore, the proliferation responses of naïve lymphocytes using PDC from IL-17ko versus wt mice showed no difference.
T82682 604640-604743 Sentence denotes Of specific note, adding anti-ICOS to the culture revealed inhibition only with wt-PDC not IL-17ko-PDC.
T61009 604744-604888 Sentence denotes When maturation of PDC was studied in mice lacking CD28 this resulted in less PDCA-1+ PDC among the BM cell population compared with wt animals.
T81478 604889-605021 Sentence denotes Nevertheless, no differences in stimulating autoantigen (MOG)specific lymphocytes using PDC from wt or CD28ko animals were observed.
T66428 605022-605197 Sentence denotes Interestingly, when using PDC from CD28ko mice MOGspecific secretion of IL-10 (anti-inflammatory) was decreased whereas the secretion of TNFa (pro-inflammatory) was increased.
T63237 605198-605309 Sentence denotes Our data help to better understand the maturation conditions of murine PDC, and their role in immunoregulation.
T8666 605310-605339 Sentence denotes Supported by BMBF 01 GZ 0708.
T57367 605340-605440 Sentence denotes This recombinant protein, produced in house in CHO cells, showed over a 90% homology to human OPN-A.
T64265 605441-605666 Sentence denotes Surprisingly, therapeutic daily administration of the OPN-like protein at 0.3 mg/ kg s.c. resulted in a significant decrease of the clinical score as well as in a reduction of duration of the paralysis during the acute phase.
T64703 605667-605856 Sentence denotes Histological analyses performed either after the peak of the primary attack or at the end of the treatment showed a reduction of leukocyte infiltration and number of macrophages in the CNS.
T28957 605857-606033 Sentence denotes In addition, detection of endogenous OPN plasma levels in EAE rats showed an increased quantity compared to that observed in healthy rats mimicking what is already known in MS.
T40634 606034-606167 Sentence denotes Administration of the OPN-like protein provided stable circulating levels during the course of the disease reaching around 100 ng/ml.
T35321 606168-606231 Sentence denotes This level did not induce changes in the endogenous OPN levels.
T3917 606232-606403 Sentence denotes However, it corresponds to over a 10-fold lower level than the one used in the previously published study where an exacerbating activity of rOPN was observed in mouse EAE.
T91141 606404-606681 Sentence denotes These findings suggest that OPN-like protein under certain treatment regimen may play an anti-inflammatory activity by modulating the infiltration of leukocytes within the CNS thus suggesting a possible action through its binding to CD44 and/or alpha-v-beta integrin receptors.
T59139 606682-606833 Sentence denotes To determine the role of TGF-B signaling cells in EAE pathogenesis, we used a transgenic TGF-B signaling reporter and ablative mouse model (SBE-lucRT).
T35043 606834-607043 Sentence denotes In the SBE-lucRT mouse, upon ligation of TGF-B1 with its receptors, Smad2/3 are phosphorylated, dimerized and then translocated into the nucleus subsequently activating the Smad binding element (SBE) promoter.
T42232 607044-607190 Sentence denotes Activation of the SBE promoter then drives the simultaneous expression of luciferase (luc), RFP (R) and herpes simplex virus-thymidine kinase (T).
T53189 607191-607331 Sentence denotes We show that upon initial EAE progression, microglia and astrocytes activation and TGF-B1 production precedes the onset of clinical disease.
T50535 607332-607483 Sentence denotes While, astrocytes and microglia are the main producers of TGF-B1, neurons and infiltrated T cells were identified as the primary TGF-B signaling cells.
T99091 607484-607652 Sentence denotes Blockade of TGF-B signaling by the systemic administration of a pharmacological drug reduced EAE disease, the accumulation of T cells and expression of IL-6 in the CNS.
T50178 607653-607826 Sentence denotes Concurrently, treatment of EAE in SBE-lucRT mice with Ganciclovir (GCV) led to the ablation of TGF-B signaling and dividing cells, as well as the alleviation of EAE disease.
T27686 607827-608018 Sentence denotes Upon further cellular analysis of systemic GCV treatment, there was little effect on the peripheral immune cell populations while the composition of CNS-infiltrating CD4 T cells were altered.
T98801 608019-608172 Sentence denotes Together, these results suggest a pathogenic role of TGF-B signaling cells, which broadens the view of potential pathogenic cells during EAE progression.
T61102 608173-608196 Sentence denotes Zuiderwijk-Sick Ella A.
T13357 608197-608198 Sentence denotes 1
T18368 608200-608337 Sentence denotes Activated microglia are prominent in Multiple Sclerosis lesions, but it is still unclear whether their role is beneficial or detrimental.
T99778 608338-608576 Sentence denotes In contrast to other organs, where terminally differentiated populations of resident antigen presenting cells (APC) outnumber colonizing precursors, the majority of microglia within the brain remain in an undifferentiated, immature state.
T36553 608577-608774 Sentence denotes Whereas the effects of differentiation on the activation process of monocyte-and bone marrow-derived APC have been extensively studied, much less is known about the effects on microglia activation.
T88032 608775-608863 Sentence denotes Recently we have demonstrated that differentiation can also affect microglia activation.
T33174 608864-609062 Sentence denotes Differentiation of primary microglia from adult rhesus monkeys on M-CSF or GM-CSF did not alter their APC capacities, but did change their responses to Toll-like receptor (TLR)8-mediated activation.
T23375 609063-609271 Sentence denotes New data from our lab show that exposure of microglia to the prototypic DC differentiation regime of GM-CSF + IL-4 indeed induces a cell surface molecule expression profile reminiscent of a DC-like phenotype.
T18848 609272-609485 Sentence denotes However, by marked contrast with conventional DC generated from the same donors, these cells no longer produce proinflammatory cytokines in response to TLR-mediated activation, irrespective of the TLR ligand used.
T73488 609486-609599 Sentence denotes We will here present data on the mechanism behind this block in TLR-induced pro-inflammatory cytokine production.
T85204 609600-609855 Sentence denotes The apparent paradox between cellular phenotype and the absence of a pro-inflammatory response to activating stimuli was unique to microglia, and is likely to impact on the strength and the type of immune response generated by microglia-T cell encounters.
T60817 609856-609998 Sentence denotes We will therefore also present data on the functional consequences of interactions between GM-CSF + IL-4-differentiated microglia and T cells.
T27476 609999-610186 Sentence denotes The anti-inflammatory or tolerogenic potential of these microglia might lead to new therapeutic avenues to halt ongoing immune responses and possibly even re-educate infiltrating T cells.
T75713 610187-610313 Sentence denotes The aim of the present study was to identify basic mechanisms how infections may induce a neuron-specific autoimmune response.
T55437 610314-610440 Sentence denotes We generated mice expressing OVA as neuronal autoantigen under control of the neuron-specific enolase promoter (NSE-OVA mice).
T64326 610441-610689 Sentence denotes Intracerebral, but not systemic infection with attenuated Listeria monocytogenes secreting OVA (ΔactA LMova) induced an atacticparetic neurological syndrome in NSE-OVA mice after bacterial clearance from the brain, whereas WT mice remained healthy.
T16951 610690-610858 Sentence denotes Immunization with ΔactA LMova prior to intracerebral infection strongly increased the number of intracerebral OVA-specific CD8 T cells aggravating neurological disease.
T64545 610859-610981 Sentence denotes T cell depletion and adoptive transfer experiments identified CD8 T cells as decisive mediators of the autoimmune disease.
T35014 610982-611136 Sentence denotes Importantly, NSE-OVA mice having received OVA-specific TCR transgenic CD8 T cells developed an accelerated, more severe and extended neurological disease.
T23775 611137-611359 Sentence denotes Adoptively transferred pathogenic CD8 T cells specifically homed to OVA-expressing MHC class I+ neurons and, corresponding to the clinical symptoms, ∼30% of neurons in the anterior horn of the spinal cord became apoptotic.
T57081 611360-611847 Sentence denotes From these studies it is concluded that molecular mimicry between a pathogen and neurons can induce a CD8 T cell-mediated neurological disease with its severity being influenced by the frequency of specific CD8 T cells and its induction, but not its symptomatic phase requiring the intracerebral presence of the pathogen. expression in lymphocytes Torres Karen⁎ 1 , Souza Bruno 1 , Sampaio Andre 1 , Barros Alexandre 1 , Gollob Kenneth 1 , Dutra Walderez 1 , Romano-Silva Marco Aurélio 1
T72526 611848-611898 Sentence denotes NCS-1 is a protein involved in the Ca2+ signaling.
T67206 611899-612106 Sentence denotes Its expression was found in neural and neuroendocrine cells and it is involved in several functions as exocytosis and neurotransmitter release enhancement and dopamine D2 receptor desensitization inhibition.
T21069 612107-612287 Sentence denotes Currently, it has been demonstrated that NCS-1 is important in mast cell functions as stimulates Fc epsilon RI-triggered exocytosis and the release of arachidonic acid metabolites.
T1212 612288-612477 Sentence denotes Then we sought to investigate whether NCS-1 could be expressed in lymphocytes and monocytes and if so evaluate which intracellular signaling pathways were compromised with NCS-1 expression.
T45838 612478-612708 Sentence denotes With PKB and MEK (PD0956 and UO126) inhibitors we have investigated the participation of MEK/ERK, PI3K/PKB intracellular signaling pathways in the NCS-1 expression from CD4+ T lymphocytes stimulated in vitro, using flow cytometry.
T91367 612709-612717 Sentence denotes Results:
T88417 612718-612874 Sentence denotes Data showed a downregulation of NCS-1 expression, dosedependent, in lymphocytes, in the presence of both MEK and PKB inhibitors, when cells were stimulated.
T23842 612875-612944 Sentence denotes The activation of cells was accompanied by CD69 increased expression.
T26067 612945-613087 Sentence denotes NCS-1 expression in CD4+ T lymphocytes depends on the PI3K/PKB and MEK/ERK commitment and these cells could be a good model for NCS-1 studies.
T11467 613088-613121 Sentence denotes Financial support: CNPq, FAPEMIG.
T49083 613122-613368 Sentence denotes To assess the relevance of the neuroinflammatory response, behavioral, neurochemical, neuropathological, cerebrospinal fluid (CSF) and peripheral blood analyses were performed in male adult C57Bl/6 mice exposed to systemic administration of MPTP.
T82510 613369-613780 Sentence denotes The data collected were correlated with longitudinal [at both early (3-24 h) and late (1, 2, 3, 4, 5 and 6 weeks) time points upon MPTP administration] wide gene expression analysis of mRNA species involved in inflammation, immunity, stemness, self-renewal, neural differentiation, migration, DA metabolism and signaling, using TaqMan® Low-Density-based Array (TLDA) in ventral mid brain (VM) and striata (Str).
T58181 613781-614106 Sentence denotes Here we describe that MPTP-induced DA neurodegeneration and self-repair is likely to be associated to a localized biphasic astroglial response, a spatiotemporal recovery of tyrosine hydroxylase (TH) and dopamine transporter (DAT) immunoreactivity (IR) paralleling the spatiotemporal return of synaptosmial DA uptake capacity.
T19612 614107-614251 Sentence denotes Temporal reconstitution of damaged DA cell bodies and axon terminals appeared also paralleled by a switch of nigrostriatal astroglial phenotype.
T39763 614252-614560 Sentence denotes Among a total of 93 mRNA species analysed, we have identified a major time-and region-dependent up-regulation of inflammatory chemokines, such as CCL3/MIP-1a, CXCL10/IP-10, CXCL11-I-TAC and key transcripts involved in DA neurodevelopment, especially the morphogen wingless-type MMTV integration site (Wnt) 1.
T17290 614561-614697 Sentence denotes Activated astrocytes of the VM were identified as potential elements of the Wnt signalling pathway sustaining nigrostriatal self-repair.
T64677 614698-614810 Sentence denotes This work suggests a surprising self-repair ability of the nigrostriatal DA system following MPTP neurotoxicity.
T31937 614811-614944 Sentence denotes It further implicates the MPTP-reactive "in situ" inflammation as key event in the molecular cascade linking tissue injury to repair.
T98888 614945-615166 Sentence denotes A deeper understanding (and manipulation) of the neurodevelopmental cues undergoing recapitulation upon CNS tissue injury is likely to have important implications for the treatment neurodenegerative diseases including PD.
T16227 615167-615287 Sentence denotes Increasing evidence suggests that spinal microglia could be an important player in the pathogenesis of neuropathic pain.
T70439 615288-615512 Sentence denotes We reported previously that peripheral nerve injury induced an early and transient spinal microglial cell proliferation which is in close correlation with spinal microglial activation and the development of neuropathic pain.
T99086 615513-615849 Sentence denotes To further test our hypothesis on the role of new microglia to the genesis of neuropathic pain symptoms, in this study, we investigated the effects of TGF-α1, a potent antiproliferation and anti-inflammatory cytokine on spinal microglia reaction following peripheral nerve injury and the impact on nerve injury induced-hypersensitivity.
T67424 615850-616037 Sentence denotes Rats having a partial ligation on the left sciatic nerve (Seltzer model) had a sharp decrease in paw withdrawal thresholds bilaterally in response to mechanical Von Frey Hair stimulation.
T83238 616038-616143 Sentence denotes Withdrawal latency to heat insults (Hargreaves) was significantly lower unilaterally on the injured side.
T73355 616144-616229 Sentence denotes Correspondingly, following nerve lesion, microgliosis was induced on the spinal cord.
T57972 616230-616461 Sentence denotes A significant increase on the number of BrdU+ cells and the intensity of iba-1 (marker for microglia) immunoreactivity (ir) was observed on the ipsilateral side dorsal horn, with a slight increase on the contralateral side as well.
T28792 616462-616857 Sentence denotes Intrathecal infusion of rat recombinant TGF-β (2 μg and 5 μg) for 14 days, starting on the day of nerve ligation, inhibited spinal microgliosis on the ipsilateral side dorsal horn by a reduction of BrdU+ cells from 22.71 in saline treated rats to 7.6 (2 μg), 10.5(5 μg) in TGF-β1 treated rats, and a reduction on the iba-1 ir intensity (83.21/saline vs. 61.23/2 μg TGF-β and 49.81/ 5 μg TGF-β ).
T48854 616858-617059 Sentence denotes Intrathecal treatment of TGF-β1 reduced partially nerve injury induced mechanical allodynia at both injured and non-injured sides, and completely abolished thermal hyperalgesia at the ipsilateral side.
T44608 617060-617272 Sentence denotes Together, our results suggest that peripheral nerve injury triggered a spinal microglial cell proliferation and these newly generated spinal microglia are involved in the genesis of hypersensitive pain behaviour.
T75211 617273-617786 Sentence denotes Inhibition of spinal glial response with a central TGF-β1 treatment, which is effective in limiting spinal microgliosis, could relieve partially mechanical allodynia, however completely prevented the development of thermal hyperalgesia. which deductively are cytotoxic T lymphocytes, show similarities concerning V-beta/J-beta usage, length of the complementarity determining region 3 (CDR3), and some biochemical characteristics of the CDR3 amino acids suggesting common driving antigen(s) without shared clones.
T74298 617787-617961 Sentence denotes Additionally, these CD8+ T cells persist in the periphery hinting towards either an autoantigen or a persisting viral infection as the antigenic cause of the immune reaction.
T7062 617962-618151 Sentence denotes Taken together, our TCR analysis provides strong evidence for an antigen-driven MHC class-I restricted, CD8+ T cell mediated attack against CNS structures dominating the pathogenesis in RE.
T94011 618152-618301 Sentence denotes Neural progenitor cells (NPC) possess the ability to regenerate new neurons and could be used as a potential therapy for neurodegenerative disorders.
T43591 618302-618430 Sentence denotes In diseases such as multiple sclerosis (MS) and HIVassociated dementia (HAD) this approach may be impacted by activated T cells.
T6248 618431-618550 Sentence denotes In this study, we investigated the effect of activated T cells and granzyme B on NPC proliferation and differentiation.
T29055 618551-618699 Sentence denotes Primary human fetal NPC were treated with supernatants from activated T cells or GB (1-4 nM) in either maintaining medium or differentiating medium.
T61259 618700-618857 Sentence denotes Cell proliferation was studied with BrdU incorporation assay after 24 h and neuronal differentiation by using beta-III-tubulin immunostaining after 4-7 days.
T93937 618858-619029 Sentence denotes The NPC lysates were used detecting the intracellular cyclic AMP (cAMP) by ELISA and the gene expression of Kv1.3, a voltage dependent potassium channel, by real-time PCR.
T71908 619030-619183 Sentence denotes The NPC cultures were also pretreated with pertussis toxin (PTX, 100 ng/ml) or Kv1.3 blocker margatoxin (MgTX, 10 nM) or Kv1.3 siRNA to study mechanisms.
T77205 619184-619337 Sentence denotes Supernatants from activated T cells decreased NPC proliferation and differentiation significantly which were attenuated by immunodepleting GB (P b 0.05).
T90598 619338-619432 Sentence denotes Recombinant GB treatment also decreased both NPC proliferation and differentiation (P b 0.05).
T10620 619433-619594 Sentence denotes GB also decreased cAMP level in the NPC after 20 min of treatment in a dose-dependent manner (P b 0.05) and increased Kv1.3 gene expression after 3 h (P b 0.05).
T15268 619595-619720 Sentence denotes Pretreatment with PTX reversed the GB-induced effect on cAMP and Kv1.3 expression and increased NPC proliferation (P b 0.05).
T37469 619721-619898 Sentence denotes Kv1.3 specific blocker MgTX or siRNA pretreatment also protected NPC neurogenesis against GB treatment as determined by the beta-III-tubulin positive neuron counting (P b 0.05).
T99379 619899-620041 Sentence denotes Kv1.3 siRNA also protected primary human fetal neurons from GB-caused neurite damage as determined by measuring the neurite length (P b 0.05).
T94148 620042-620124 Sentence denotes GB released from activated T cells inhibits NPC proliferation and differentiation.
T66990 620125-620290 Sentence denotes The underlying mechanisms involve a PTX-sensitive Gi-protein-coupled receptor and the subsequent decrease in intracellular level of cAMP and the activation of Kv1.3.
T82593 620291-620454 Sentence denotes Blockade of Kv1.3 provides protection to NPC and neurons and could be used as a potential therapy for T cell-related neurodegenerative diseases such as MS and HAD.
T2807 620456-620674 Sentence denotes Minocycline has been reported to have neuroprotective activity in various animal models of neurological diseases, where a major mechanism for its effectiveness is attributed to the inhibition of microglia inflammation.
T7512 620675-620810 Sentence denotes Much less has been described on the possibility that minocycline could be acting directly on neurons independent of microglia activity.
T84153 620811-621031 Sentence denotes In this study, we tested the protective role of minocycline against H 2 O 2 toxicity in enriched human fetal neurons (HFNs) in the absence of microglia and identified new targets of minocycline using microarray analyses.
T53889 621032-621207 Sentence denotes Furthermore, we demonstrate that an induced enzyme in response to stress, heme oxygenase-1 (HO-1), may be important in the protection of minocycline both in vitro and in vivo.
T56335 621208-621263 Sentence denotes HFNs treated with minocycline were exposed to H 2 O 2 .
T24301 621264-621351 Sentence denotes Relative intensity of neuronal markers was then measured with In-Cell western analysis.
T67140 621352-621430 Sentence denotes Gene expression profiles of the treated HFNs were generated using microarrays.
T41714 621431-621503 Sentence denotes Real-time PCR (RT-PCR) was conducted to validate the microarray results.
T13167 621504-621782 Sentence denotes Using HFNs which contain 85 to 90% neurons and 10-15% astrocytes, but devoid of microglia, we found that H 2 O 2 , kills neurons which was documented by obvious cell loss, and by decreased intensity of neuronal markers and increased active caspase-3 in In-Cell western analyses.
T18170 621783-621846 Sentence denotes Minocycline significantly attenuated these effects of H 2 O 2 .
T22146 621847-621993 Sentence denotes As neurons could therefore be protected by minocycline in the absence of microglia, we subjected HFNs to DNA microarrays using a 14,000 gene chip.
T17498 621994-622216 Sentence denotes Across 14 experiments involving 7 different HFN preparations, we found that many genes were up-regulated by H 2 O 2 and that a minority of these were reduced in expression levels when neurons were protected by minocycline.
T13642 622217-622364 Sentence denotes Of the latter targets, real time PCR and In-Cell western investigations confirmed that HO-1 was up-regulated by H 2 O 2 and reduced by minocycline.
T50479 622365-622492 Sentence denotes Immunohistochemistry for HO-1 showed that neurons and astrocytes were both reactive for this enzyme following H 2 O 2 exposure.
T17571 622493-622634 Sentence denotes The necessity of HO-1 in minocycline protection against H 2 O 2 is currently under investigation using both in vitro and in vivo experiments.
T19404 622635-622884 Sentence denotes We conclude that minocycline confers protective effect of HFNs against H 2 O 2 without the need of microglia activity and that this may involve a hitherto unknown mechanism of minocycline, that of modulating HO-1 levels in neurons and/or astrocytes.
T23810 622885-623116 Sentence denotes The neuroprotective action of estrogen (Es) against 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown in various reports in both female and male mice, however the exact mechanisms of that phenomenon remain obscured.
T87231 623117-623302 Sentence denotes One potential mechanism by which Es may exert this action is by modulating the inflammatory response in nigrostriatal system, which occurs as an early consequence of injury this system.
T64008 623303-623608 Sentence denotes We studied the chronic effects of 17b-estradiol -E2 (0.25 mg per pellet, 21-days release) administered prior (7 days -Experiment 1) to or after (3 days -Experiment 2) MPTP treatment in C57BL male mice (12 months old) on dopaminergic neurons degeneration and inflammatory reaction in nigrostriatal pathway.
T50945 623609-623664 Sentence denotes C57BL mice received 40 mg/kg of MPTP intraperitoneally.
T90639 623665-624026 Sentence denotes We estimated striatal: tyrosine hydroxylase (TH) and glial fibrillary acidic protein (GFAP) content (Western blotting method), cytokines (TNFa, TGFb1, IFNg) and trophic factor (GDNF) gene expression (RT-PCR method), and CD4+ and CD8+ cells influx to nigrostriatal pathway (immunohistochemistry) at 1,7 and 21 (Exp.1) and 7 and 21 (Exp.2) days post intoxication.
T98919 624027-624102 Sentence denotes MPTP treatment reduced striatal TH within 1-21 days following intoxication.
T26290 624103-624224 Sentence denotes We showed that E2 exerted a neuroprotective effect upon nigrostriatal system when administered 7 days prior intoxication.
T5832 624225-624338 Sentence denotes We also observed that E2 protected striatum from MPTP insult when administered on the 3rd day after intoxication.
T26732 624339-624465 Sentence denotes The implantation of E2 pellets after intoxication attenuated the MPTP-induced loss of striatal TH at 7-and 21-day time-points.
T73396 624466-624558 Sentence denotes E2 also decreased the striatal GFAP content, when administered prior and after intoxication.
T37995 624559-624637 Sentence denotes MPTP caused a rapid increase of striatal TGFb1, TNFa and IFNg gene expression.
T95464 624638-624791 Sentence denotes Pre-treatment with E2 decreased the early expression of TGFb1 and IFNg mRNA but failed to suppress the MPTP-induced increase of striatal TNFa mRNA level.
T70673 624792-624920 Sentence denotes E2 pre-treatment also induced an increase of the striatal GDNF gene expression and CD4+ cells influx to the injured brain areas.
T53042 624921-625027 Sentence denotes In contrast, E2 decreased the CD8+ cells infiltration when administered prior and after MPTP intoxication.
T41580 625028-625215 Sentence denotes Our studies suggest that the neuroprotective effects of E2 indicated in MPTP model might mediate through a modulation of both molecular and cellular factors in neuroinflammatory reaction.
T14054 625216-625376 Sentence denotes 10 -Characterization of lysolecithin-induced demyelination, with a focus on the early inflammatory responses and their possible roles Döring Axinia⁎ 1 , Yong V.
T41598 625377-625450 Sentence denotes Wee 1 1 Hotchkiss Brain Institute, University of Calgary, Calgary, Canada
T56282 625451-625705 Sentence denotes Demyelinating diseases of the central nervous system (CNS) such as multiple sclerosis (MS) feature oligodendrocyte (OL) and myelin loss but it is the concordant loss of axons and neurons that is thought to drive the progression of disability in patients.
T35288 625706-625897 Sentence denotes In several studies of MS brain specimens, it has been shown that there is good correspondence of regions of axonal injury with areas containing leukocyte infiltration or microglia activation.
T44772 625898-626017 Sentence denotes In tissue culture studies, products of microglia/macrophage or lymphocytes produce axonal dysfunction and kill neurons.
T90224 626018-626250 Sentence denotes More recently there is an appreciation that some aspects of neuroinflammation can be beneficial, as highlighted by experiments where the significant depletion of microglia/ macrophages in demyelinating models retarded remyelination.
T28246 626251-626474 Sentence denotes The interplay between inflammatory cell subsets, axonal injury and demyelination thus require a closer examination, particularly with the prospect of providing neuroprotection, preventing demyelination, or enhancing repair.
T89489 626475-626590 Sentence denotes We have used a toxin-mediated demyelination of the CNS to characterize the early inflammatory and neural responses.
T87626 626591-626792 Sentence denotes Following the deposition of 1.5% lysolecithin solution into the dorsal column of T3/T4 region of the spinal cord, mice were killed and analysed from 1-7 days after injection using a variety of markers.
T16699 626793-626979 Sentence denotes We find axonal injury (accumulation of β-APP and non-phosphorylated neurofilament) and demyelination (myelin basic protein) to be already evident by 1 day of lysolecithin administration.
T11161 626980-627098 Sentence denotes This time frame corresponded with upregulation of Iba1 immunoreactivity, a marker of microglia/ macrophage activation.
T42943 627099-627185 Sentence denotes We were not able to detect an increase of OLs at the lesion side at these time points.
T35809 627186-627290 Sentence denotes Flow cytometry shows that the macrophage (CD11bCD45high) infiltration is most marked at day 3 of injury.
T15685 627291-627481 Sentence denotes Current experiments are directed at increasing or decreasing the extent and period of microglia/macrophage reactivity and to address the subsequent impact on axonal injury and demyelination.
T85312 627482-627711 Sentence denotes These experiments seek to clarify the beneficial or detrimental roles of immunity, particularly that of microglia/macrophage activation, on the exacerbation of injury, or conversely, the protection and repair of axons and myelin.
T79932 627712-627889 Sentence denotes Preservation of axons in Wallerian degeneration slow (Wld^S) mice has been shown to be beneficial in experimental autoimmune encephalomyelitis (EAE), an autoimmune model for MS.
T85701 627890-628031 Sentence denotes In Wld^S mice, axonal degeneration is delayed due to an increased nicotinamide adenine dinucleotide (NAD) biosynthetic enzyme Nmnat activity.
T17046 628032-628097 Sentence denotes SIRT1 is the downstream effector of the increased Nmnat activity.
T67552 628098-628340 Sentence denotes Resveratrol is a natural polyphenol compound of red wine and has received considerable attention as a chemical responsible for the health benefits of red wine and is currently being tested in clinical trials as a potential therapy for cancer.
T46502 628341-628483 Sentence denotes Resveratrol can enhance SIRT1 activity, potentially resulting in axonal preservation, and exhibit anti-inflammatory and anti-viral activities.
T75434 628484-628654 Sentence denotes We tested whether resveratrol could be therapeutic, possibly by limiting axonal damage in a viral model for MS, Theiler's murine encephalomyelitis virus (TMEV) infection.
T62586 628655-628723 Sentence denotes SJL/J mice were infected intracerebrally with the DA strain of TMEV.
T60940 628724-628922 Sentence denotes Groups of infected mice were fed a diet containing 0.04% resveratrol (20 mg/kg/day) during the acute stage of infection (days 0 to 14) or during the chronic stage (days 21 to 35), or a control diet.
T29200 628923-629082 Sentence denotes Clinically, the mice treated with resveratrol during the acute stage showed more weight gain than control mice at 2 weeks post infection (P b 0.001, by ANOVA).
T30543 629083-629199 Sentence denotes At 5 weeks after infection, central nervous system (CNS) tissues and spleen mononuclear cells (MNCs) were harvested.
T78151 629200-629377 Sentence denotes Conversely, mice treated during the chronic stage tended to have higher clinical and pathological scores than control mice, although they did not reach statistical significance.
T13636 629378-629542 Sentence denotes There were no significant differences in numbers of cells expressing viral antigen in the CNS or MNC proliferative responses to virus among the experimental groups.
T83186 629543-629707 Sentence denotes We speculate that significant weight gain during the acute stage in the early resveratrol treatment group could be due to a neuroprotective property of resveratrol.
T42623 629708-629895 Sentence denotes The potential axonal sparing activity by resveratrol could be of great benefit, since permanent clinical disability in MS results form degenerated axons that do not regenerate in the CNS.
T86799 629896-630183 Sentence denotes 12 -17b-estradiol administration protects against dopamine depletion, down-regulates astroglial activation and modulates cytokine production in the nigro-striatal system in female mice In neurodegenerative disorders an immune system involvement in the pathological process is postulated.
T67902 630184-630377 Sentence denotes The potential role for estrogen (Es) acting as a neuroprotectant of dopaminergic system may be supported by the epidemiological reports showing a gender differences in Parkinson's disease (PD).
T39489 630378-630673 Sentence denotes The aim of the present study was to examine the chronic effects of Es (17b-estradiol, 0.25 mg per pellet, 21-days release) on dopaminergic system and cytokines production in female C57Bl mice (12 months old) in a murine model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
T96478 630674-630766 Sentence denotes Estrogen was administered 7 days prior to (exp.1) or 3 days after MPTP intoxication (exp.2).
T86661 630767-630870 Sentence denotes MPTP (40 mg/kg) was injected to the animals in four intraperitoneal (i.p.) injections at 1-h intervals.
T1825 630871-630955 Sentence denotes Animals were sacrificed by spinal cords dislocation at the different time intervals:
T24883 630956-631029 Sentence denotes 1, 7 and 21 (exp.1) or 7 and 21 days (exp.2) following MPTP intoxication.
T13663 631030-631263 Sentence denotes Striatal dopamine (DA) was quantified by highperformance liquid chromatography (HPLC), glial fibrillary acidic protein (GFAP) expression was measured by Western Blot method, TNFa, IFNg and TGFb mRNA expression was examined by RT-PCR.
T4816 631264-631466 Sentence denotes MPTP treatment decreased DA concentration within 1-21 days, enhanced GFAP expression within 7-21 days, increased TNFa and TGFb mRNA expression at 1 day, and IFNg mRNA at 7 days following MPTP injection.
T23270 631467-631669 Sentence denotes Estradiol exerted a neuroprotective effect upon dopaminergic system (less pronounced MPTP-induced decrease of DA) when administered 7 days prior to MPTP, but not when Es was implanted 3 days after MPTP.
T19059 631670-631833 Sentence denotes Estrogen inhibited GFAP expression at 7 day time point when implanted prior to intoxication and within 7-21 days time points when administered post MPTP injection.
T23535 631834-632015 Sentence denotes Estradiol decreased TNFa and IFNg mRNA expression at 7 day and TGFb mRNA expression at 1 day time point (exp.1), as well as TGFb mRNA expression at 7 day after intoxication (exp.2).
T16074 632016-632162 Sentence denotes Our findings suggest that the neuroprotective effects of Es in MPTP mouse model of PD might be mediated by modulation of an inflammatory reaction.
T53929 632163-632293 Sentence denotes 17b-estradiol may inhibit the activity of astroglial cells and decrease production of inflammatory mediators, including cytokines.
T16139 632294-632406 Sentence denotes The contribution of macrophages to spontaneous recovery from spinal cord injury (SCI) is currently under debate.
T91745 632407-632615 Sentence denotes Macrophages have long been perceived as inhibitory to CNS recovery, but under different conditions these cells can acquire distinct activities whose effect on the tissue varies from destructive to beneficial.
T71417 632616-632712 Sentence denotes We wanted to define the specific contribution of infiltrating monocytes to spinal cord recovery.
T86009 632713-632874 Sentence denotes To that aim we used a unique model that allowed us to identify and subsequently ablate the active blood-derived myeloid cells but sparing the resident microglia.
T99622 632875-633009 Sentence denotes This ablation of monocyte-derived cells found in close proximity to the injured site, resulted in impaired recovery of motor function.
T26462 633010-633072 Sentence denotes Restoration of the monocyte pool restored the healing process.
T14783 633073-633222 Sentence denotes Immunization, which was previously shown to augment recovery from severe spinal cord injury, resulted in enhanced recruitment of these myeloid cells.
T39272 633223-633435 Sentence denotes Importantly, these cells exhibited characteristics of myeloid derived suppressor cells (MDSC) and restricted the local immune response via, at least in part, the anti-inflammatory cytokine interleukin 10 (IL-10).
T49965 633436-633636 Sentence denotes We argue that the discrepancy regarding macrophages contribution to recovery is due, in part, to the heterogeneity of these cells and the need for their timely-regulated response following the insult.
T30111 633637-633809 Sentence denotes This study identifies an essential novel role, in recovery from spinal cord injury, for infiltrating blood-borne monocytes, which can not be provided by resident microglia.
T51243 633810-634098 Sentence denotes 14 -Oral fingolimod (FTY720) suppresses established EAE and allows remyelination Fingolimod (FTY720) is a novel oral immunomodulatory agent that significantly reduced the rate of inflammatory disease activity compared to placebo in patients with relapsing MS in a Phase II clinical trial.
T16905 634099-634247 Sentence denotes Fingolimod is converted in vivo to its active phosphate by sphingosine kinase and then binds to S1P1,3,4 and 5 receptors (S1PRs) with high affinity.
T78901 634248-634483 Sentence denotes Binding of fingolimod to S1P1 on lymphocytes causes their sequestration within peripheral lymph nodes, thus reducing lymphocytic infiltration into the CNS, which is considered an important part of the mechanism of action of fingolimod.
T27523 634484-634639 Sentence denotes In addition, fingolimod readily crosses the blood brain barrier and CNS cells also express S1P receptors, suggesting further direct effects within the CNS.
T392 634640-634793 Sentence denotes In the current experiments we determined if fingolimod can protect from experimental autoimmune encephalomyelitis (EAE) after the onset of demyelination.
T29259 634794-634835 Sentence denotes DA rats were immunized with MOG plus CFA.
T88586 634836-634982 Sentence denotes Fingolimod was administered to rats daily p.o. (0.3 mg/kg) for 9 days beginning at 29 days post immunization or when the 3rd phase of EAE started.
T97011 634983-635122 Sentence denotes The effect of fingolimod on clinical scores, demyelination, inflammation and axonal degeneration was determined by histology and MRI (MTC).
T73071 635123-635210 Sentence denotes Using MTC we established that demyelination was present at the initiation of treatment.
T43103 635211-635359 Sentence denotes Oral administration of fingolimod (2 experiments) to rats with well-established EAE significantly reduced clinical EAE severity compared to vehicle.
T86741 635360-635507 Sentence denotes MTC analysis revealed that white matter loss continued to increase in the vehicle treated animals, but was stabilized by treatment with fingolimod.
T26977 635508-635606 Sentence denotes In some individual lesions we observed a normalization of MTC signals suggestive of remyelination.
T70094 635607-635775 Sentence denotes Histopathological analysis showed a reduction in macrophage and T cell infiltrates in the spinal cord of fingolimodtreated rats, and enhanced myelin and axonal content.
T25594 635776-635918 Sentence denotes These studies demonstrate that fingolimod can reduce EAE severity even if administered in late stage EAE and after the onset of demyelination.
T4442 635919-636032 Sentence denotes This supports the possibility that fingolimod could also have protective effects in the progressive stages of MS.
T8491 636033-636146 Sentence denotes Slaets Helena Stefanie Elisabeth⁎ 1 , Hendriks Jerome 1 , Carmans Sofie 1 , Stinissen Pieter 1 , Hellings Niels 1
T98222 636147-636313 Sentence denotes Leukemia inhibitory factor (LIF) is produced by infiltrating immune cells and glial cells during auto-immune and injury responses in the central nervous system (CNS).
T70431 636314-636469 Sentence denotes During these responses, LIF promotes survival of glial cells and neurons and has immunomodulatory potential, but data on the underlying events are lacking.
T17664 636470-636640 Sentence denotes The goal of this study was to study the mechanisms of LIF-mediated protection of mature oligodendrocytes (OLG) and to determine the effects of LIF on macrophage function.
T60382 636641-636730 Sentence denotes LIF mediated effects were studied in primary rat oligodendrocyte and macrophage cultures.
T68483 636731-636783 Sentence denotes Cell viability was measured by AnnexinV/PI staining.
T98492 636784-636879 Sentence denotes Activation of signalling pathways was analyzed by western blotting and RNAse protection assays.
T71914 636880-636960 Sentence denotes Myelin phagocytosis was determined using DiI-labelled myelin and flow cytometry.
T81913 636961-637185 Sentence denotes We show that LIF protects OLG selectively against the synergistic insult of the proinflammatory cytokines IFNgamma and TNFalpha, while it does not protect against oxidative stress nor against staurosporine induced apoptosis.
T47324 637186-637315 Sentence denotes We further demonstrate that LIF protection is independent of suppressors of cytokine signalling and Bcl-2 mRNA expression levels.
T48919 637316-637604 Sentence denotes Our results indicate that LIF induces a shift in the cellular machinery towards a pro-survival execution program, illustrated by an enhanced expression of isoforms of the anti-apoptotic molecule 14-3-3 and an activation of the Jak/STAT3 and the phosphatidylinositol 3 kinase/Akt pathways.
T12220 637605-637820 Sentence denotes We further demonstrate that LIF modulates macrophage function by inhibiting the production of oxygen radicals and TNFalpha, both mediators of CNS injury in neuroinflammatory diseases such as multiple sclerosis (MS).
T73749 637821-637920 Sentence denotes We show that LIF plays a role in myelin phagocytosis as it stimulates myelin uptake by macrophages.
T86617 637921-638173 Sentence denotes These results demonstrate that LIF has both neuroprotective and anti-inflammatory properties and enhances myelin clearance, implicating it is an important factor in lesion development and limitation in immune mediated demyelinating diseases such as MS.
T42928 638174-638390 Sentence denotes Harada Yohei⁎ 1 , Yawata Izumi 1 , Takeuchi Hideyuki 1 , Sonobe Yoshifumi 1 , Jin Shijie 1 , Doi Yukiko 1 , Liang Jianfeng 1 , Kawanokuchi Jun 1 , Mizuno Tetsuya 1 , Suzumura Akio 1 1 Nagoya University, Nagoya, Japan
T226 638391-638601 Sentence denotes We have shown previously that the most neurotoxic factor from activated microglia is glutamate that is produced by glutaminase utilizing extracellular glutamine as a substrate and released through gap junction.
T41980 638602-639067 Sentence denotes In this study, to elucidate whether or not a similar mechanism is operating in macrophages infiltrating into the central nervous system during inflammatory and demyelinating diseases, we examined the neurotoxicity induced by macrophages in comparison with microglia and experimental allergic encephalomyelitis (EAE), the model of multiple sclerosis, treated with glutaminase inhibitor 6-diazo-5-oxo-L-norleucine (DON) and gap junction inhibitor carbenoxolone (CBX).
T74476 639068-639168 Sentence denotes Microglia were isolated from primary mixed glial cell cultures prepared from neonatal C57BL/6J mice.
T94698 639169-639292 Sentence denotes Peritoneal macrophages elicited with 2 ml of 4% thioglycolate injected intraperitoneally into C57BL/6J mice were collected.
T54546 639293-639359 Sentence denotes Neuronal cultures were prepared from the mice at embryonic day 17.
T59998 639360-639474 Sentence denotes Microglia and macrophages were cultured with 1 micro g/ml LPS for 24 h in the graded concentrations of CBX or DON.
T73124 639475-639588 Sentence denotes Glutamate concentration of the conditioned media was determined with the Glutamate Assay Kit colorimetric method.
T77370 639589-639651 Sentence denotes Inflammatory cytokines and chemokines were detected by RT-PCR.
T49476 639652-639805 Sentence denotes Neurotoxicity in the conditioned media of microglia and macrophages treated with CBX or DON was determined by dye exclusion method with propidium iodide.
T34284 639806-639887 Sentence denotes EAE in C57BL/6J mice were induced by myelin oligodendrocyte glycoprotein peptide.
T24349 639888-639973 Sentence denotes DON and CBX were injected intraperitoneally into the mice every other day from day-2.
T39644 639974-640039 Sentence denotes Microglia and macrophages stimulated with LPS produced glutamate.
T56844 640040-640183 Sentence denotes LPS-stimulated macrophage conditioned media induced robust neurotoxicity, which was completely inhibited by the NMDA receptor antagonist MK801.
T97219 640184-640317 Sentence denotes Both the DON and CBX effectively suppressed glutamate production and subsequent neurotoxicity by activated microglia and macrophages.
T90627 640318-640521 Sentence denotes EAE severity was significantly reduced in 2.0 mg/kg CBX-treated mice, and EAE onset was delayed and EAE severity was significantly reduced in 1.6 mg/kg DON-treated mice compared with PBS-treated control.
T22867 640522-640738 Sentence denotes This study demonstrated that a similar machinery is operating in macrophages as well, and DON and CBX that prevent microgliamediated neurotoxicity should be effective for preventing macrophage-mediated neurotoxicity.
T19371 640739-640839 Sentence denotes Thus, these drugs may be effective therapeutic reagents for inflammatory and demyelinating diseases.
T73110 640840-641018 Sentence denotes We reported that transgenic mice constitutively expressing the B7.2 (CD86) T cell costimulatory ligand on microglia spontaneously develop a T cell-mediated demyelinating disease.
T70466 641019-641218 Sentence denotes We have shown that CD8+ T cells are the primary effector T cell-subset that initiates the pathological process and TCR clonotype mapping demonstrated clonotypic CD8+ T cell expansions within the CNS.
T80538 641219-641401 Sentence denotes To further understand the pathological process that occurs in this animal model, we characterized the phenotypic and functional status of the CD8+ T cells that accumulate in the CNS.
T93873 641402-641587 Sentence denotes The vast majority of the CNS CD8+ T cells displayed phenotypic features of effector-memory cells (CD44hi, CD62-Llo, CD127hi, Ly6Chi, CCR7-) in an activated state (CD43hi, CD69+, CD25+).
T3554 641588-641668 Sentence denotes However, unlike conventional effector cells, they expressed low levels of CD122.
T16512 641669-641804 Sentence denotes A similar memory CD8+ T cell subset (CD122lo, CD62-Llo, CD44hi, CD127hi) was present in increased number in peripheral lymphoid organs.
T33520 641805-641967 Sentence denotes CNS CD8+ T cells exhibited potent cytotoxicity directly ex vivo and were capable of co-producing high levels of IFN-g, TNF-a and IL-2 upon restimulation in vitro.
T11301 641968-642058 Sentence denotes The activating receptor NKG2D was also expressed by a high proportion of CNS CD8+ T cells.
T88522 642059-642291 Sentence denotes High levels of granzyme B were detected directly ex vivo and a significant number of CNS CD8+ T cells also showed surface mobilization of CD107a without restimulation, consistent with active engagement in cytolytic activity in vivo.
T53598 642292-642543 Sentence denotes Our data suggest that the CD8+ T cells that are reactivated in the CNS by B7.2-expressing microglia may originate from the CD122low memory CD8+ T cell subset that has been reported to be maintained through interactions with commensal or self-antigens.
T18511 642544-642655 Sentence denotes The CNS CD8+ T cells are potent effector cells, well equipped to induce tissue injury through various pathways.
T11046 642656-642889 Sentence denotes Transplantation of multipotent neural stem/precursor cells (NPCs) protects the central nervous system (CNS) from inflammatory damage via a number of bystander mechanism(s) alternative to cell replacement, including immune modulation.
T46212 642890-643101 Sentence denotes Here we show that subcutaneous injection of NPCs significantly protects mice from chronic-recurrent autoimmune CNS inflammation via a novel immune-regulatory mechanism occurring within secondary lymphoid organs.
T27895 643102-643229 Sentence denotes Injected NPCs accumulate and survive within draining lymph nodes, where they stably modify the perivascular (micro)environment.
T57069 643230-643428 Sentence denotes Within this context, NPCs restrain dendritic cell function via a bone morphogenetic protein (BMP)-4-dependent mechanism, andin turnprevent the expansion of antigen-specific encephalitogenic T cells.
T13668 643429-643495 Sentence denotes This effect is completely reverted by the BMP-4 antagonist Noggin.
T45387 643496-643717 Sentence denotes Our results suggest a novel tolerogenic mechanism exerted by immune regulatory NPCs in vivo, which may be further exploited to modulate aberrant peripheral immune responses leading to chronic tissue-specific autoimmunity.
T5514 643718-643798 Sentence denotes Stroke is the leading cause of long-term disability in industrialized countries.
T69448 643799-644145 Sentence denotes Here we have investigated the molecular and cellular mechanisms regulating functional recovery of mice subjected to transient (45′) focal cerebral ischemia [e.g., middle cerebral artery occlusion (MCAO)] and transplanted intravenously (i.v.) in the early post-acute phase (namely 72 h after MCAO) with syngenic neural stem/precursor cells (NPCs).
T71341 644146-644326 Sentence denotes Transplanted NPCs selectively accumulated in the periischemic area corresponding to the lateral striatum between 3 and 10 days post-transplantation (dpt) and survived up to 45 dpt.
T4175 644327-644517 Sentence denotes Histopathology revealed that about 0.3% of i.v.-injected NPCs accumulated into the brain, while lower numbers of NPCs were found in peripheral organs (e.g., lung, liver, spleen, and kidney).
T84446 644518-644734 Sentence denotes The great majority of transplanted NPCs accumulating in the brain displayed undifferentiated or only intermediate-differentiated features at 10 dpt, with no NPCs expressing markers of terminal neural differentiation.
T26023 644735-645012 Sentence denotes Starting from 3 dpt, i.v.-injected NPCs induced a gradualthough slow -amelioration of neurological deficits: the clinical improvement in NPC-transplanted MCAO mice compared to Sham-treated controls reached statistical significance from day 15 dpt on and persisted up to 60 dpt.
T7720 645013-645185 Sentence denotes Further neuronal survival, astroglial glial reaction, (neo)angiogenesis and inflammatory reaction were then analysed in the perischemic area at both protein and mRNA level.
T74827 645186-645429 Sentence denotes Neuropathological analysis showed that the i.v. delivery of NPCs is associated to an increase of the number of surviving endogenous neurons, to a significant reduction of the axonal loss as well as to a diminished gliotic scar tissue reaction.
T35346 645430-645614 Sentence denotes Gene expression analysis confirmed the down-regulation of a number of key genes associated with glial proliferation as well as up-regulation of genes controlling the neuronal survival.
T45678 645615-645900 Sentence denotes These preliminary data provide evidence that the post-acute systemic injection of NPCs promotes significant clinico/pathological recovery in mice with experimental MCAO by bystander protection of endogenous hypoxia-injured neurons and inhibition of the astrocytic glial scar formation.
T96644 645901-646117 Sentence denotes Bonnamain Virginie⁎ 1 , Michel Delphine 1 , Nerrière Daguin Véronique 1 , Thinard Reynald 1 , Dugast Anne-Sophie 1 , Brachet Philippe 1 , Anegon Ignacio 1 , Vanhove Bernard 1 , Neveu Isabelle 1 , Naveilhan Philippe 1
T57811 646118-646286 Sentence denotes Porcine neural precursor cells (pNPCs) from fetal brain have been proposed as an alternative to the use of human fetal neuroblasts (NBs) in neurodegenerative disorders.
T3246 646287-646506 Sentence denotes Initially thought as a useful source in cell replacement therapy because of their ability to be expanded in vitro, pNPCs are of a great interest also because of particular immunomodulatory and/or immunogenic properties.
T10624 646507-646686 Sentence denotes Indeed, we recently observed that 40% of the rats transplanted with pNPCs exhibited a healthy graft 63 days post-grafting whereas pNBs grafts were all rejected at this time point.
T71893 646687-646764 Sentence denotes Interestingly, the surviving grafts did not exhibit any sign of inflammation.
T24811 646765-646844 Sentence denotes Immunostaining of activated macrophages/microglial cells with ED1 was negative.
T8445 646845-646961 Sentence denotes In addition, we did not observe any premise of T lymphocyte infiltration as indicated by the absence of R7.3+ cells.
T20212 646962-647133 Sentence denotes To determine potential immunomodulatory properties of NPCs, rat T lymphocytes stimulated with anti-CD3 and anti-CD28 antibodies were mixed with increasing number of pNPCs.
T72418 647134-647207 Sentence denotes Thymidine assays clearly showed that NPCs inhibited T cell proliferation.
T22330 647208-647271 Sentence denotes This inhibitory effect was closely dependent of the cell ratio.
T79244 647272-647441 Sentence denotes We did not find major inhibitory effect at a ratio of 1 pNPC for 4 T cells, but a 50% decrease in the proliferating rate was observed at a ratio of 1 pNPC for 2 T cells.
T72236 647442-647564 Sentence denotes Interestingly, a 90% decrease in the number of proliferating T lymphocytes was observed at a ratio of 2 NPCs for 1 T cell.
T54793 647565-647635 Sentence denotes The same result was obtained with NPCs derived from fetal rat tissues.
T67078 647636-647843 Sentence denotes To determine whether contacts between T cells and NPCs were necessary or if soluble factors were sufficient, NPCs were plated in the upper part of a transwell whereas T cells were cultured in the lower part.
T74917 647844-647893 Sentence denotes Thymidine assays were performed three days later.
T1493 647894-648105 Sentence denotes Inhibitory effect similar to the one observed when the cells were in direct contact was observed indicating that soluble factors released by NPCs are sufficient to inhibit the proliferation of activated T cells.
T19768 648106-648199 Sentence denotes The next step was to search for soluble factors known to interfere with T cell proliferation.
T89086 648200-648406 Sentence denotes RT-PCR and immunocytochemistry analyses revealed the expression of several immunoregulatory molecules by virtually all NPCs, as indicated by their co-localisation with nestin, a marker of neural stem cells.
T29945 648407-648531 Sentence denotes The molecules critical for the immunoregulatory effects of NPCs are currently under investigation using specific inhibitors.
T70385 648532-648767 Sentence denotes Recent characterizations of human mesenchymal stem cells (MSCs) and their role in hematopoiesis and immune modulation suggest that their potential for cell therapy extends beyond their traditional accessory function in HSC engraftment.
T9913 648768-649049 Sentence denotes MSCs, easy to obtain and able to differentiate into multiple lineages such as osteoblasts, adipose tissue, cartilage and stromal cells, contribute significantly to tissue restructuring and immune functioning, in addition to facilitating durable, long-lasting stem cell engraftment.
T39870 649050-649132 Sentence denotes We focus our analysis on immune synapse formation and cytoskeleton reorganization.
T62954 649133-649250 Sentence denotes To investigate cell-cell contact we analysed by confocal microscopy immune synapse formation in the presence of MSCs.
T321 649251-649335 Sentence denotes Furthermore, we study the nature of MSC/DC cell-cell contact by electron microscopy.
T17587 649336-649543 Sentence denotes We found that MSCs impair active immune synapse formation as shown by confocal analysis and we evidenced at electron microscopy two types of intimate contact between MSCs and DCs: gap and adherent junctions.
T78019 649544-649759 Sentence denotes In the same experiments we show that MSC contacts induce a reorganization of DC cytoskeleton by the formation of actin podosomes, these structures are typical of an immature state, and therefore tolerogenic, of DCs.
T45054 649760-650040 Sentence denotes These results suggest that MSCs exert a tolerogenic effect on DCs by mechanism not only mediated by soluble factors, that should be further investigated, but also mediated by cell-cell contact, contact that induces DC cytoskeleton reorganization with formation of actin podosomes.
T51743 650041-650265 Sentence denotes So far, several hypothesis have been made on the mechanisms underlying the tolerogenic effect due to coculturing MSCs and DCs, here we show that short term contacts may induce a tolerogenic phenotype by actin redistribution.
T6351 650266-650407 Sentence denotes We recently reported that mesenchymal stem cells (MSCs) exert a profound inhibitory effect on T cell proliferation both in vivo and in vitro.
T62531 650408-650510 Sentence denotes Subsequently, MSCs were shown to exert similar effects also on B cells, dendritic cells, and NK cells.
T50428 650511-650654 Sentence denotes In addition, MSCs support the recruitment of local precursor cells and provide trophic factors supporting survival and repair of injured cells.
T13516 650655-650738 Sentence denotes These data suggested that MSCs could be used to ameliorate immunomediated diseases.
T58575 650739-650928 Sentence denotes Although it is accepted that MSCs play an important role in maintaining the hematopoietic stem cell in an undifferentiated state, the exact mechanism by which this happens is still unknown.
T35350 650929-651082 Sentence denotes To start addressing that question, we recently characterized the transcriptional profile of purified MSCs and compared it to that of 13 other cell types.
T8775 651083-651187 Sentence denotes We showed that this profile is enriched in transcription factors and component of Wnt signaling pathway.
T81020 651188-651344 Sentence denotes We expand our transcriptional analysis and characterize the signature of MSCs either alone or in co-culture with T cells under different culture conditions.
T19055 651345-651455 Sentence denotes At the end of the period of culture T cells were gently removed from the well leaving adherent MSCs untouched.
T38858 651456-651722 Sentence denotes Pure MSCs exposed to stimuli provided by T cells either proliferating will be analyzed for gene expression upon RNA extraction, amplification and hybridization onto Affymetrix Mouse Genome 430 2.0 arrays according to the manufacturer's instructions (Affymetrix, Inc.
T14562 651723-651931 Sentence denotes Santa Clara, CA).As control groups we utilized resting MSCs, MSCs stimulated by anti-CD3 and anti-CD28 in the absence of T cells as well as T cells stimulated by anti-CD3 and anti-CD28 in the absence of MSCs.
T52885 651932-652171 Sentence denotes For in vivo study, we i.v. injected e-GFP labeled MSCs in C57B/6J mice at the peak of EAE induced with MOG 35-55; animals were followed for 40 days and then brain and spinal cord were removed and stained for immunofluorescence examination.
T87878 652172-652489 Sentence denotes Upon identification of eGFP+ cells under an optical microscope, each cell of interest was captured by laser micro-dissection with the Laser Capture Microdissection. eGFP+ cells were pooled and subjected to RNA extraction, amplification and hybridization onto Affymetrix Mouse Genome 430 2.0 arrays as described above.
T6935 652490-652620 Sentence denotes Emphasis is given to the expression of population-defining transcription factors and differentiation signals under each condition.
T78359 652621-652723 Sentence denotes This analysis resulted in the identification of key molecules with potential therapeutic implications.
T39669 652724-653006 Sentence denotes DCs stimulated with LPS in the presence of MSCs, failed to up-regulate MHC classes I and II and co-stimulatory molecules thus resulting in an impaired capacity of priming CD4+ antigen specific cells. mMSC-treated DCs showed an impaired secretion of the Th1 orienting cytokine IL-12.
T6884 653007-653224 Sentence denotes Furthermore, mMSC significantly decreased DCs surface expression of CCR7, a key receptor for homing into lymph nodes. mMSC-treated DCs down-regulated intracellular components of the antigen processing machinery (APM).
T55034 653225-653423 Sentence denotes In order to dissect the impact of MSCs on LPSmediated activation of DCs through Toll-like Receptor 4 (TLR4) we analyzed by real-time PCR the expression profile of TLRs genes of DCs activated by LPS.
T32162 653424-653541 Sentence denotes We observed a significant down-modulation of key molecules involved in TLR signaling including NF-kB, MAPK and IP-10.
T64914 653542-653723 Sentence denotes These results suggest that mMSC affect adaptive immunity not only through a direct effect on T and B cells but also through an impaired capacity of DCs to properly instruct T cells.
T44126 653724-653955 Sentence denotes Although the pathogenic mechanisms involved in experimental autoimmune encephalomyelitis/multiple sclerosis (EAE/MS) are not well understood, accumulating data suggest that oxidative stress plays a major role in lesion development.
T50233 653956-654088 Sentence denotes Metallothioneins (MTs) are a family of low-molecular weight, cysteine-rich proteins that act in protection against oxidative stress.
T74214 654089-654290 Sentence denotes In the central nervous system (CNS), two neuroprotective antioxidant MT isoforms (MT-I and MT-II), and a brainspecific isoform (MT-III), acting as an inhibitor of neuronal growth, have been identified.
T44900 654291-654404 Sentence denotes The abundance of MT isoforms induced in CNS by tissue injury suggests a role for MTs in several neuropathologies.
T49335 654405-654586 Sentence denotes The present study was aimed at evaluating the expression profiles of the three brain MT isoforms during EAE progression and following murine mesenchymal stem cells (MSCs) treatment.
T23334 654587-654701 Sentence denotes In parallel, oxidative stress conditions were monitored by assessing the activity of the main antioxidant enzymes.
T27435 654702-654797 Sentence denotes Expression of all MT isoforms was significantly increased in EAE mice with respect to controls.
T16045 654798-654985 Sentence denotes A significant up-regulation of MT-I, MT-II and MT-III was observed already at day 11 from the onset of the disease (about a 2-fold induction for each MT with respect to the healthy mice).
T32169 654986-655048 Sentence denotes A further increase in MT transcription was observed at day 40.
T58571 655049-655120 Sentence denotes In mice treated with MSCs, up-regulation of MTs was partially reversed.
T54260 655121-655250 Sentence denotes At day 40 of disease the up-regulation of all MT isoforms decreased to values lower than those observed at day 11 in EAE animals.
T46590 655251-655332 Sentence denotes Changes in CAT and SOD activity parallel those observed in MT expression pattern.
T95606 655333-655552 Sentence denotes The results demonstrate that EAE progression is clearly associated with the development of oxidative stress conditions in the brain, as indicated by increased expression of all MT isoforms and activities of CAT and SOD.
T71005 655553-655704 Sentence denotes Treatment with MSCs significantly reduces both MT upregulation and increased antioxidant enzyme activities accompanying the progression of the disease.
T26761 655705-655910 Sentence denotes Human mesenchymal stem cells (MSC) are endowed with remarkable immunomodulatory properties that resulted in their exploitation for the treatment of immune-mediated diseases such as multiple sclerosis (MS).
T52729 655911-656101 Sentence denotes In this study we addressed their effect on unconventional T cells, namely NKT and gammadelta T cells, which are likely to play a role both in control and pathogenesis of autoimmune diseases.
T26032 656102-656304 Sentence denotes We first studied the effect of MSC on in vitro expansion of both populations from PBMC stimulated with a-Galactosyl Ceramide (for NKT) and Isopentenyl Pyrophosphate (for gammadeltaT cells) respectively.
T64312 656305-656460 Sentence denotes MSC inhibited NKT and gammadelta T cells expansions both in cell-to-cell contact and in trans-well experimental systems without the induction of apoptosis.
T22027 656461-656568 Sentence denotes We observed that such inhibition was partially counteracted by indometacin, an inhibitor of PGE2 synthesis.
T38670 656569-656811 Sentence denotes When we specifically blocked other molecules reported to be involved in the modulation of the immune response by MSC, such as indoleamine2,3-deoxigenase (IDO) and TGFBeta we could not detect any effect on NKT+ and gammadelta+ cells expansion.
T686 656812-656980 Sentence denotes These data indicate that PGE2 represents the soluble factor preferentially involved in the MSC-mediated inhibition of VAlpha24+ VBeta11+ and gammadelta+ cell expansion.
T54319 656981-657139 Sentence denotes We also studied the effects of MSC on OKT3-mediated proliferation, cytokine production and cytotoxic activity of in vitro expanded NKT and gammadelta T cells.
T2016 657140-657355 Sentence denotes MSC moderately inhibited TNFAlpha and IFNgamma production only by NKT while they impaired CD3-mediated proliferation without significantly interfering with the cytotoxic potential of both NKT and gammadelta T cells.
T68133 657356-657439 Sentence denotes In contrast, MSC were lysed by activated gammadelta T cells though TCR recognition.
T14373 657440-657587 Sentence denotes This information is relevant especially for clinical applications of MSC-based therapy like treatment of autoimmune diseases as multiple sclerosis.
T43292 657588-657717 Sentence denotes Hydrogen sulfite (H2S) is generated endogenously in mammalian tissues by the normal processing of sulphur-containing amino acids.
T11117 657718-657810 Sentence denotes Some of its known actions are carried out in the cardiovascular, nervous and immune systems.
T95813 657811-658039 Sentence denotes Besides this endogenous source of H2S, it is known that thermal waters rich in sulphur are precursors of this molecule, and they have been traditionally used in bath therapies because of their beneficial effects on human health.
T71677 658040-658192 Sentence denotes Up to now, all the still scarce scientific studies on this subject have focused on the effects of H2S on the different physiological systems separately.
T50167 658193-658304 Sentence denotes In the present work we have investigated the role of sulfurous thermal waters in the neuroimmune communication.
T48521 658305-658352 Sentence denotes Twelve-month old female ICR-CD1 mice were used.
T26223 658353-658552 Sentence denotes They were divided in two groups: the first (called "sulfurous water group", SG) was submitted to a daily bath of 15 min in sulfurous water, and the second ("control water group", CG) in normal water.
T42106 658553-658615 Sentence denotes The treatments were performed during 4 weeks, 5 days per week.
T30826 658616-658797 Sentence denotes Animal motor condition and neuromuscular vigour were assessed through the tightrope test (% of animals that reach one of the side poles of the rope and % of animals that fall down).
T92261 658798-659006 Sentence denotes In addition, peritoneal leukocytes were obtained and total glutathione levels (nmol/10^6 cells), a key antioxidant of the organism, and natural killer activity (NK, % lysis of tumoural cells) were determined.
T37674 659007-659243 Sentence denotes As regards the tightrope test, mice of the SG group showed higher percentages of reaching one of the side poles situated the end of the rope (50% for SG and 16% for CG) and lower percentages of falling downs (25% for SG and 66% for CG).
T78179 659244-659404 Sentence denotes With respect to total glutathione, SG showed increased levels with respect to the CG group (0.61 ± 0.15 nmol/10^6 cells and 0.41 ± 0.09, respectively p b 0.01).
T68205 659405-659597 Sentence denotes The same tendency was observed in NK activity, since mice of the SG group show a higher percentage of lysis (29 ± 9% for SG and 20 ± 6% for CG, p b 0.05) with respect to those of the CG group.
T76845 659598-659837 Sentence denotes Bath sessions in thermal waters rich in sulphur compounds modulate the neuroimmune relationship by improving in mature mice their neuromuscular coordination and one relevant immune function such as the NK activity in peritoneal leukocytes.
T42340 659838-659907 Sentence denotes In these cells that water also increase the total glutathione levels.
T80636 659908-659998 Sentence denotes These results show a better preservation of homeostasis and health of the treated animals.
T49604 659999-660017 Sentence denotes Financial support:
T50842 660018-660115 Sentence denotes Foundation for Research and Innovation in Medical Hydrology and Spas (Bilbilis Foundation) grant.
T14710 660116-660141 Sentence denotes RETICEF (RD06/0013/0003).
T63682 660142-660708 Sentence denotes We have previously shown that triple-transgenic mice for Alzheimer's disease (3xTgAD; harboring PS1M146V, APPSwe, tauP301L transgenes), which develop plaques and tangles and show genderspecific cognitive and behavioral impairments, also suffer detrimental changes in some key lymphocyte functions, namely proliferation in response to the mitogenes concanavalin A and lipopolysaccharide, natural killer cytotoxic activity of YAC-1 tumoural cells and chemotaxis towards the formylated peptide, in both spleen and thymus, with males showing worse function than females.
T52847 660709-660853 Sentence denotes The regulatory cytokines tumour necrosis factor-α and interleukin-2 in the supernatants of lymphocyte cultures were also altered in 3xTgAD mice.
T57546 660854-660937 Sentence denotes Environmental enrichment (EE) was found to be efficient in improving those changes.
T19466 660938-661043 Sentence denotes In the present work, 3xTgAD and wild type male and female nonand environmentally enriched mice were used.
T29771 661044-661233 Sentence denotes EE began in the adulthood (6 months) and lasted for 5.5 months (house and wheel were maintained permanently, whereas other objects of different shapes and colors were changed every 2 days).
T435 661234-661322 Sentence denotes The animals were sacrificed at the age of 15 months, and thymus and spleen were removed.
T40915 661323-661442 Sentence denotes Lymphocytes were obtained and total glutathione content was measured by enzymatic kinetic spectrophotometric procedure.
T21517 661443-661500 Sentence denotes Plasma corticosterone was determined by radioimmunoassay.
T78964 661501-661672 Sentence denotes The results showed that gender exerted an overall effect on plasma corticosterone, which was higher in females (males 35.83 ± 5.72, females 72.88 ± 4.85 ng/ml, P b 0.001).
T7035 661673-662048 Sentence denotes Further analysis revealed that AD increased corticosterone in males only (non-3xTgAD males 21.90 ± 4.75, 3xTgAD males 79.60 ± 5.07 ng/ml, P b 0.001), and the beneficial effects of the EE decreasing those levels were shown especially in 3xTgAD males (non-environmentally enriched 3xTgAD males 79.60 ± 5.07, environmentally enriched 3xTgAD males 27.85 ± 3.36 ng/ml, P b 0.001).
T35078 662049-662285 Sentence denotes As regards glutathione content, no differences were observed in thymus lymphocytes, whereas gender showed an overall effect on spleen lymphocytes, being higher in females (males 2.37 ± 0.71, females 8.24 ± 0.64 nmol/mg prot, P b 0.001).
T38536 662286-662434 Sentence denotes EE exerted a general effect decreasing the levels of glutathione in spleen lymphocytes (non-EE 6.95 ± 0.68, EE 3.65 ± 0.67 nmol/mg prot, P b 0.001).
T46402 662435-662585 Sentence denotes In conclusion, corticosterone seems to play an important role in the gender-specific immune function and behavioral changes exerted by both AD and EE.
T87518 662586-662703 Sentence denotes The gender differences could contribute to differential development of the disease and therapeutic effects of the EE.
T26636 662704-662817 Sentence denotes Oxidative stress in lymphocytes from old 3xTgAD mice is similar to that of the wild type animals of the same age.
T12710 662818-663008 Sentence denotes However, females show higher glutathione levels in spleen lymphocytes, which could indicate a leveling off mechanism aiming to control the increased oxidative stress that occurs with ageing.
T11543 663009-663167 Sentence denotes EE would be efficient in decreasing the oxidative stress in spleen lymphocytes from old subjects, which would be reflected in lower glutathione levels needed.
T26478 663168-663332 Sentence denotes Therefore, EE stands out as a key strategy to decrease the oxidation and improve the function of the immune system in both healthy and non-healthy elderly subjects.
T49967 663333-663422 Sentence denotes UAB140267, MEC (BFU2005-06777), Research Group UCM-CM (910379), RETICEF (RD06/0013/0003).
T49955 663423-663551 Sentence denotes 3 -Complement inhibition abrogates nerve sodium channel disruption in a rabbit model of Guillain-Barre syndrome-Yuki Nobuhiro⁎ 1
T91088 663552-663695 Sentence denotes Guillain-Barre syndrome is divided into two subtypes, acute inflammatory demyelinating polyneuropathy and acute motor axonal neuropathy (AMAN).
T78410 663696-663825 Sentence denotes Autopsy results indicate complement activation followed by membrane attack formation is an important mechanism for both subtypes.
T15772 663826-663962 Sentence denotes Complement-mediated disruption of voltage-gated sodium channel clusters at the node of Ranvier plays a role in the pathogenesis of AMAN.
T61166 663963-664148 Sentence denotes To examine whether nafamostat mesilate (NM), a serine protease inhibitor exhibiting anti-complement activity, could inhibit complement-mediated Nav disruption in a rabbit model of AMAN.
T23108 664149-664396 Sentence denotes Each AMAN rabbit was intravenously implanted with two osmotic pumps containing NM in 50% dimethyl sulfoxide (treatment group, four rabbits) or 50% dimethyl sulfoxide alone (control group, five rabbits) at a delivery rate of 0.8 mg/kg/h for 7 days.
T94727 664397-664593 Sentence denotes Immunohistochemical analysis was performed to examine the frequency (%) of deposited complement products and disrupted sodium channel clusters at the nodes of Ranvier in the spinal anterior roots.
T85035 664594-664729 Sentence denotes Complement deposition and sodium channel disruption were significantly less frequent in NM-treated rabbits compared to control rabbits.
T2746 664730-664914 Sentence denotes The clinical signs in two rabbits rapidly improved after NM treatment, although there was no significant difference for the total clinical scores between NM-treated and control groups.
T15455 664915-665043 Sentence denotes NM could inhibit complement deposition and consequently prevent complement-mediated sodium channel disruption in the AMAN model.
T73695 665044-665106 Sentence denotes The results provide a rationale for a clinical trial using NM.
T65202 665107-665267 Sentence denotes Microglia, the resident macrophages of the CNS, are implicated in many acute and chronic neurological diseases, including multiple sclerosis, trauma and stroke.
T20294 665268-665455 Sentence denotes While many laboratories are studying the role of activated microglia in CNS pathophysiology, the molecular mechanisms controlling the activation process of microglial are less understood.
T78944 665456-665712 Sentence denotes Recent progress in genetics has identified a new class of RNA molecules called microRNAs (miRNA) involved in gene regulation. miRNAs are single-stranded RNA molecules of ∼ 22 nucleotides complementary to a site in the 3′ untranslated region (UTR) of mRNAs.
T98280 665713-665824 Sentence denotes The annealing of the miRNA to the mRNA either inhibits protein translation or facilitates cleavage of the mRNA.
T24853 665825-665932 Sentence denotes This regulation adds an unexpected layer of complexity to the classic "linear" concept of DNA→mRNA→protein.
T21439 665933-666009 Sentence denotes The functional role of miRNAs in microglial activation is currently unknown.
T72074 666010-666211 Sentence denotes Using miRNA arrays and qRT-PCR for miRNAs we have found a limited number of miRNAs constitutively expressed at high levels, which are most likely involved in the maintenance of the microglia phenotype.
T24566 666212-666332 Sentence denotes Furthermore, we identified several miRNAs which are regulated during microglial activation by LPS/IFN-gamma stimulation.
T78201 666333-666439 Sentence denotes We have correlated the miRNA regulation profiles with parallel mRNA gene array data for target evaluation.
T28277 666440-666597 Sentence denotes To gain insight into the effects of specific miRNAs we used transfection of miRNA mimics to validate the predicted miRNA targets by qRT-PCR and Western blot.
T42427 666598-666663 Sentence denotes miRNAs are an integral part of the microglial activation process.
T82151 666664-666874 Sentence denotes Identification of miRNA specific pathways may constitute new targets for therapeutic intervention in CNS injuries associated with microglial activation such as stroke, multiple sclerosis or Alzheimer's disease.
T97848 666875-667059 Sentence denotes In a study of eleven MS patients and eight healthy controls, Tregs were co-cultured with CD4+CD25-(responder) T cells at 0:1, 1:1, 1:2 and 1:4 ratios in the presence or absence of BLP.
T82704 667060-667133 Sentence denotes We found that BLP reversed Treg suppression at low Treg/responder ratios.
T89672 667134-667350 Sentence denotes In the absence of BLP, Tregs from patients had lower suppressive activity than Tregs from healthy controls at the 1:4 ratio, in agreement with a previously reported defective Treg function in MS (Viglietta et al., J.
T64190 667351-667365 Sentence denotes Exp Med 2004).
T22007 667366-667536 Sentence denotes Preincubation of Tregs or responder cells with BLP before co-culture demonstrated a predominant effect of TLR2 stimulation on Tregs, which were rendered less suppressive.
T62959 667537-667748 Sentence denotes To clarify the dose effect of TLR2 stimulation by BLP on human Treg activity, Tregs were cocultured with responder T cells at 0:1, 1:4, 1:8 and 1:16 ratios in the presence or absence of BLP (0.1, 1 and 5 μg/ml).
T32517 667749-667925 Sentence denotes Suppression of responder cell proliferation by Tregs was significantly reduced by 5 μg/ml BLP compared with 0.1 and 1 μg BLP concentrations at lower Treg/responder cell ratios.
T84981 667926-668035 Sentence denotes By contrast, lower concentrations of BLP did not reduce suppression of responder cell proliferation by Tregs.
T23964 668036-668246 Sentence denotes This study demonstrates the previously uncharacterised nature of Treg responses to different doses of TLR2 stimulation and suggests that infections may facilitate MS exacerbations by suppressing Treg functions.
T53284 668247-668365 Sentence denotes Seventy-four MG patients participated in this study, and they were treated with either FK506 (N = 65) or CyA (N = 22).
T48209 668366-668425 Sentence denotes We measured blood drug concentrations of trough level (C0).
T41078 668426-668508 Sentence denotes The MG-ADL scores were examined in relation to the blood drug concentrations (C0).
T30724 668509-668779 Sentence denotes The mean FK506 C0 for MG patients (n = 38) having the CYP3A5⁎3/⁎3 genotype was significantly higher than those (n=20) having CYP3A5⁎1/⁎3 genotypes (7.05 ng/mL versus 2.87 ng/mL, P = 0.00002) or those ( n = 7) having CYP3A⁎1/⁎1(7.05 ng/mL versus 1.30 ng/mL, P b 0.00035).
T44987 668780-669020 Sentence denotes The improvements of mean MG-ADL scores (beginning→4 months after FK506 administration in MG patients having either CYP3A5⁎3/⁎3 (5.4→3.4 or CYP3A5⁎1/⁎3 (6.2→4.3) genotypes tended to be better than those having CYP3A5⁎1/⁎1 (4.0→3.7 genotypes.
T41625 669021-669128 Sentence denotes But in the CyA concentrations, the comparisons of the CYP3A5 genotypes revealed no significant differences.
T64563 669129-669271 Sentence denotes With MG treatment, comparisons of the CYP3A5 genotypes revealed the significant differences in the FK506 concentrations with ADL improvements.
T31131 669272-669432 Sentence denotes Multiple Sclerosis (MS) is considered an autoimmune disease (AD) and susceptibility to this condition is controlled by multiple genes and environmental factors.
T16793 669433-669506 Sentence denotes Association between MS and other autoimmune disorders has been suggested.
T41852 669507-669719 Sentence denotes Recently, the protein tyrosine phosphatase (PTPN22) 1858CNT gene polymorphism has been proposed as a common susceptibility factor for several autoimmune diseases, but association with MS couldn't be demonstrated.
T295 669720-669813 Sentence denotes 1) To identify coexisting systemic autoimmune features in MS patients and in their relatives.
T6185 669814-669918 Sentence denotes 2) To investigate whether PTPN22 polymorphism was associated with autoimmune features in these patients.
T47923 669919-670022 Sentence denotes A total of 266 patients with definitive MS, according to McDonald criteria, were included in the study.
T22753 670023-670233 Sentence denotes Patients were characterized for the presence of positive family history of AD (group 1); for the coexistence of other autoimmune diseases (group 2) and for the presence of positive serum autoantibody (group 3).
T66526 670234-670311 Sentence denotes Genotyping of the 1858C N T polymorphism was performed using a TaqMan® assay.
T56172 670312-670453 Sentence denotes Twenty nine patients (11%) reported at least one relative with AD such as MS (15), Hashimoto thyroiditis (3), psoriasis (2) and other AD (9).
T3718 670454-670513 Sentence denotes Thirteen patients (5%) reported at least one coexisting AD.
T73238 670514-670601 Sentence denotes Sixty nine patients (26%) had at least one positive serum autoantibody but no other AD.
T38197 670602-670699 Sentence denotes No significant differences in PTPN22 allele frequencies among the different groups were observed.
T48265 670700-670891 Sentence denotes Disregarding the known familiar aggregation of MS, these results do not show an increased frequency of ADs in MS patients and their relatives, compared with the Portuguese general population.
T68045 670892-671061 Sentence denotes The lack of association of AD features with the PTPN22 polymorphism in these patients may be due to lack of statistical power given the small number of cases identified.
T51501 671062-671547 Sentence denotes This study provides no support for the concept that MS might arise on a background of increased susceptibility to autoimmunity, in agreement with the results from a larger Canadian study [ Although specific autoimmune disorders (ADs) are associated with unique clinical and serological features, some overlapping and a tendency towards family aggregation may be explained by the presence of common genetic susceptibility polymorphisms in immune system related genes (HLA-DRB1, PTPN22).
T43845 671548-671656 Sentence denotes It has been hypothesized that these could influence susceptibility, disease course or both in different ADs.
T980 671657-671820 Sentence denotes We previously showed, in our population, that HLA-DRB1⁎15 positive MS patients had better clinical outcome, and also a higher frequency of the PTPN22 1858T allele.
T7154 671821-671980 Sentence denotes To assess the prevalence of coexisting ADs in Portuguese MS patients and their families, and to relate the PTPN22 1858T polymorphism to disease aggressiveness.
T84776 671981-672070 Sentence denotes A total of 160 definitive MS patients, with at least 10 years of disease, were evaluated.
T84677 672071-672290 Sentence denotes Patients were subdivided into 2 groups: patients who maintained an EDSS score of = 3 at 10 years were considered to have 'benign' MS (n = 69); patients with EDSS score N3 were defined as having 'non-benign' MS (n = 81).
T75564 672291-672373 Sentence denotes Genotyping of the PTPN22 1858CNT polymorphism was performed using a TaqMan® assay.
T43273 672374-672529 Sentence denotes Families: eleven 'benign' patients reported at least one first degree relative with an AD, compared to five 'non-benign' patients (16% vs. 6.2%, p = 0.06).
T73966 672530-672579 Sentence denotes These were mostly due to MS familiar aggregation.
T99737 672580-672674 Sentence denotes Coexisting AD: four 'benign' and four 'non-benign' patients had coexisting AD (5.8% vs. 4.9%).
T76221 672675-672801 Sentence denotes The PTPN22 1858T phenotype frequency was higher in 'benign' than in 'non-benign' patients (18.1% vs. 8%, p = 0.054, OR = 2.5).
T92616 672802-672975 Sentence denotes The PTPN22 1858T variant, previously associated with increased susceptibility to autoimmunity (but not with MS), seems to be associated with a good prognosis in MS patients.
T50119 672976-673285 Sentence denotes This, together with the observed higher frequency of autoimmune diseases in the relatives of patients with benign course, suggests that different pathogenic pathways are implicated in this subgroup of patients, or alternatively, that genetic factors related to autoimmunity modulate the course of the disease.
T54946 673286-673430 Sentence denotes Murine experimental autoimmune encephalomyelitis (EAE) is an induced, autoimmune, demyelinating disease model for human multiple sclerosis (MS).
T48860 673431-673530 Sentence denotes Copaxone is an approved immunomodulatory therapy for MS that was discovered through studies in EAE.
T46322 673531-673641 Sentence denotes It is thought that the main mode of action of Copaxone is the induction of a Th1 to Th2 shift in CD4+ T-cells.
T13989 673642-673861 Sentence denotes We have shown that, in human MS, Copaxone therapy induces an upregulation of cytotoxic, suppressor CD8+ T-cell responses, suggesting that these cells are integrally involved in mediating the immune effects of this drug.
T97032 673862-673949 Sentence denotes In this study, we show that Copaxone induces robust CD8+ T-cell responses even in mice.
T30664 673950-674192 Sentence denotes Whereas Copaxone immunization ameliorates the clinical and histologic severity of EAE in wild type C57/BL6 mice, such protection is not observed in CD8(−/−) mice, indicating that CD8+ T cells are required in mediating the effects of Copaxone.
T54023 674193-674420 Sentence denotes Moreover, adoptive transfer of CD8+ T-cells from Copaxone-immunized (but not OVA-immunized) mice results in amelioration of EAE in CD8(−/−) and wildtype mice, suggesting therapeutic potential for Copaxone-specific CD8+ T-cells.
T34355 674421-674543 Sentence denotes These cells appear to mediate their effects through a cytotoxic/suppressor mechanism, similar to our findings in human MS.
T26489 674544-674745 Sentence denotes In conclusion, our studies provide strong evidence that the in vivo induction of immune modulatory CD8+ T-cells is an essential step in mediating therapeutic protection during autoimmune demyelination.
T77628 674746-674871 Sentence denotes In the past decade, several new radioligands have been developed for positron emission tomography for potential clinical use.
T98200 674872-675053 Sentence denotes Since microglia play important roles in health and disease, studying their activation states with such radioligands may prove useful for assessing disease prognosis and progression.
T99742 675054-675290 Sentence denotes Radioligands that bind to the translocator protein of 18 kDa (TSPO), formerly known as the peripheral benzodiazepine receptor, are currently being scrutinized, but the protein expression of TSPO in human brain has not been well-studied.
T35626 675291-675362 Sentence denotes In addition, the cell types that express TSPO in vivo has been debated.
T94460 675363-675632 Sentence denotes Autoradiography used in combination with immunohistochemistry (IHC) for cell-specific markers on autopsy tissue or in animal models has shown that microglia are the main cell type that upregulate the TSPO, but astrocytes are a cell type of interest for some conditions.
T96277 675633-675791 Sentence denotes The purpose of this study is to detect the protein expression of TSPO in normal and diseased human brain via IHC and to delineate the cells that express TSPO.
T93031 675792-675920 Sentence denotes We have assessed the expression of TSPO via IHC using two antibodies, one polyclonal and one monoclonal, developed against TSPO.
T23404 675921-676133 Sentence denotes The two antibodies have good agreement and show mild staining in normal brain, but elevated staining in pathologic conditions such as Alzheimer's disease, multiple sclerosis, ischemic stroke and HIV encephalitis.
T22547 676134-676266 Sentence denotes Microglia and macrophages appear to be the main cell types expressing TSPO, although limited astrocyte expression was also observed.
T76528 676267-676398 Sentence denotes The IHC of TSPO will be useful in animal models of inflammation and will shed light on the conditions that govern its upregulation.
T6729 676399-676528 Sentence denotes Future studies will look into regional expression of TSPO and may probe the timing of upregulation of TSPO with in vitro studies.
T56312 676529-676592 Sentence denotes Tongue muscle atrophy is relatively common in MuSK-MG patients.
T34091 676593-676675 Sentence denotes However, these are not clear whether tongue muscle atrophy can be reversed or not.
T43010 676676-676787 Sentence denotes We observed retrospectively a change of the tongue atrophy before and after immunosuppressive treatment by MRI.
T21838 676788-676917 Sentence denotes We observed retrospectively a change of the tongue atrophy before and after immunosuppressive treatment by MRI from 2002 to 2008.
T33609 676918-677077 Sentence denotes In retrospective evaluation with mid-sagittal MRI, numbers of cross sectional areas of tongue are; 2088 mm 2 in 2002, 1401 mm 2 in 2005, and 1736 mm 2 in 2008.
T99530 677078-677184 Sentence denotes In MuSK-MG, immune-modulating treatments can result in dramatic clinical recovery, even after long course.
T17129 677185-677228 Sentence denotes Tongue muscle atrophy can be reversed, too.
T10831 677229-677406 Sentence denotes 12 -Meningeal myeloid cells as middlemen between T cell deficiency and depressive behavior - Peripheral immune status is tightly linked to central nervous system (CNS) function.
T80404 677407-677511 Sentence denotes Original studies showed that T cells have a beneficial effect on neuronal survival following CNS injury.
T35601 677512-677600 Sentence denotes More recently, the role of the immune system has been extended to normal brain function.
T12362 677601-677720 Sentence denotes T cells have been implicated in cognitive function and adult neurogenesis, two major aspects of adult brain plasticity.
T28677 677721-677895 Sentence denotes Severe combined immune deficient (SCID) mice exhibit reduced neurogenesis and cognitive impairment as examined on spatial learning and memory tasks, (e.g. Morris Water maze).
T69164 677896-678047 Sentence denotes Moreover, depletion of the immune system in wild type (WT) mice followed by bone marrow transplantation from SCID mice also impairs cognitive function.
T34219 678048-678127 Sentence denotes T cell transfusion restores cognitive function and neurogenesis in both groups.
T51226 678128-678202 Sentence denotes Thus, the immune system affects aspects of brain plasticity and cognition.
T99184 678203-678328 Sentence denotes This led us to examine the effect immunodeprivation might have on the ability of the brain to withstand stressful conditions.
T95891 678329-678462 Sentence denotes We assayed SCID and WT mice using the forced swim test (FST), in which increased immobility is indicative of a "depressed" phenotype.
T15135 678463-678539 Sentence denotes Here we show that SCID mice are strikingly more immobile than WT in the FST.
T85244 678540-678637 Sentence denotes We assayed SCID and WT mice in an open field assay and found no differences in baseline activity.
T22256 678638-678704 Sentence denotes We then examined the population of meningeal cells in both groups.
T42337 678705-678929 Sentence denotes Immunohistochemical observations revealed that although the numbers of meningeal macrophages/monocytes (CD11b+CD11c−) were comparable in both groups, the numbers of MHCII positive cells were significantly lower in SCID mice.
T34319 678930-679036 Sentence denotes When meningeal isolations were examined by flow cytometry, the reduced MHCII expression was substantiated.
T37491 679037-679225 Sentence denotes Moreover, we found that meningeal macrophages/ monocytes from SCID mice show an increased pro-inflammatory phenotype, characterized by expression of cytokines such as IFNγ, TNFa, and IL1β.
T88113 679226-679342 Sentence denotes We propose that the lack of mature and active T cells leads to a skewed pro-inflammatory phenotype of myeloid cells.
T86571 679343-679465 Sentence denotes As a consequence, this leads to accumulation of pro-inflammatory cytokines in meninges and finally to depressive behavior.
T23470 679466-679662 Sentence denotes These results may shed new light on the "etiology" of depressive behavior in chemotherapy patients, the elderly, HIV-dementia, and other conditions, all tightly associated with T cell dysfunction.
T49752 679663-679834 Sentence denotes If found true in the abovementioned conditions, our study might lead to development of new therapeutic approaches for depression, based on modulation of adaptive immunity.
T62463 679835-680194 Sentence denotes 13 -The pathway of CX3CR1 and fractalkine interaction is involved in the leukocytes infiltration on experimental autoimmune encephalomyelitis in mice -Muramoto Kenzo⁎ 2 , Kuboi Yoshikazu 2 , Ogasawara Hideaki 1 , Rikitsu Etsuko 1 , Mizuno Keiko 1 , Nishimura Miyuki 1 , Imai Toshio 1 1 Kan research institute, Kobe, Japan 2 Eisai Co., LTD., Tsukuba-shi, Japan
T32327 680195-680367 Sentence denotes Leukocytes migration to central nervous system is involved in severity of the demyelinating diseases multiple sclerosis and experimental autoimmune encephalomyelitis (EAE).
T54099 680368-680461 Sentence denotes Fractalkine (FKN, CX3CL1) is a unique chemokine with unique chemokine/mucin hybrid structure.
T93602 680462-680595 Sentence denotes CX3CR1, the solo receptor for CX3CL1, is expressed on microglia, monocyte/macrophage, dendritic cells and cytotoxic/effector T cells.
T7759 680596-680740 Sentence denotes It was reported that Fractalkine and CX3CR1 were constitutively expressed in several region of the CNS and this interaction was involved in EAE.
T90643 680741-680887 Sentence denotes To clarify the role of CX3CR1/FKN pathway on EAE model, the effect of anti-FKN monoclonal antibody (mAb) on an EAE model was investigated in mice.
T93867 680888-681018 Sentence denotes Anti-FKN mAb was administered every other day from 6 days after the sensitization with MOG (myeline-oligodendrocyte-glycoprotein).
T65044 681019-681137 Sentence denotes The administration of anti-FKN mAb at the dose of 0.5 mg/mice significantly inhibited the development of EAE symptoms.
T13782 681138-681203 Sentence denotes The infiltrated cells into the spinal cord were analyzed by FACS.
T13961 681204-681320 Sentence denotes These infiltrated cells including T cell, dendritic cells and so on was decreased by administration of anti-FKN mAb.
T34913 681321-681425 Sentence denotes The mRNA levels of inflammatory and immune genes in spinal cord were analyzed by real-time PCR analysis.
T91420 681426-681604 Sentence denotes The elevation of mRNA such as leukocytes markers (CD45, CD4, CD8, CD11c), cytokines and chemokines were observed in an EAE model and suppressed by administration of anti-FKN mAb.
T35997 681605-681764 Sentence denotes The immunohistochemical analysis also showed the inhibitory effect of anti-FKN mAb on infiltration of leukocytes into spinal cords and activation of microglia.
T74052 681765-681895 Sentence denotes This anti-FKN mAb also showed therapeutic effect when it was administered after the induction of disease in PLP-induced EAE model.
T39036 681896-682051 Sentence denotes These results suggested CX3CR1/FKN pathway facilitates the development EAE through leukocyte migration into spinal cord on both of acute and chronic phase.
T49610 682052-682418 Sentence denotes 14 -Modulation of the HIV-1 infected microglial proteome by astrocytes - Astrocytes are brain homeostatic regulators that modulate a broad range of neural functions including regulating extracellular glutamate and neuronal networks, controlling neuronal activities and neurogenesis and secretory a broad range of growth factors including neurotrophins and cytokines.
T91833 682419-682660 Sentence denotes In neurological diseases such as those caused by human immunodeficiency virus (HIV-1) infection astrocytes affect mononuclear phagocyte (MP; perivascular and tissue macrophages and microglia) function and the secretion of neurotoxic factors.
T10022 682661-682739 Sentence denotes Nonetheless, little is known about MP-astrocytes communicate during infection.
T44192 682740-682801 Sentence denotes To examine these questions we employed a proteomics approach.
T29402 682802-682893 Sentence denotes Our primary method of profiling was 2-dimensional gel electrophoresis with DIGE technology.
T758 682894-683026 Sentence denotes Protein identification was accomplished using nano-LC-MS/MS (LTQ Orbitrap, Thermo Scientific) sequencing of tryptic digest peptides.
T24639 683027-683086 Sentence denotes The primary method of validation was Western blot analysis.
T13117 683087-683225 Sentence denotes We examined differential regulation of HIV-1 infected MP proteins during co-cultivation with astrocytes and confirmed by Western blotting.
T86644 683226-683302 Sentence denotes These revealed the differential regulation of redox and structural proteins.
T60700 683303-683453 Sentence denotes Preliminary results demonstrated that gelsolin, leukotriene A4 hydrolase, and adenylyl cyclase-associated proteins were decreased in MP by astrocytes.
T78864 683454-683545 Sentence denotes Increases in annexin, carbonyl reductase and calreticulin precursor proteins were observed.
T10012 683546-683685 Sentence denotes We conclude astrocytes significantly affect the MP proteome following HIV-1 infection and as such can affect disease onset and progression.
T96797 683686-683766 Sentence denotes 15 -Anti-leukocyte adhesion therapy for the treatment of seizures and epilepsy -
T26238 683768-683863 Sentence denotes A seizure is a paroxysmal hypersynchronous discharge from central nervous system (CNS) neurons.
T78986 683864-684006 Sentence denotes Repeated seizures can lead by unknown mechanisms to epilepsy, a chronic neurological disorder that affects 1% of the general world population.
T15969 684007-684205 Sentence denotes Both experimental and clinical data indicate that repeated seizure activity can lead to the chronic recurrent seizures of epilepsy, but the mechanisms responsible for this transition remain unclear.
T11511 684206-684318 Sentence denotes Our GOAL was to study the role of leukocyte trafficking mechanisms in the pathogenesis of seizures and epilepsy.
T51009 684319-684384 Sentence denotes Epilepsy was induced by injection of C57Bl mice with pilocarpine.
T15078 684385-684482 Sentence denotes Intravital microscopy and in vivo staining were performed in cortical brain vessels postseizures.
T98880 684483-684652 Sentence denotes Magnetic resonance imaging, confocal microscopy, immunohistochemistry, telemetry, power spectrum analysis, behavioral evaluation and cognitive tests were also performed.
T79252 684653-684889 Sentence denotes In mouse models of epilepsy, seizures caused elevated expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-and P-selectin on brain vessels and recruitment of leukocytes to the brain.
T90814 684890-685187 Sentence denotes Intravital microscopy revealed enhanced granulocyte and Th1 lymphocyte rolling and arrest in brain vessels after seizures and these leukocyte-vascular interactions were inhibited by blockade of the leukocyte mucin P-selectin glycoprotein ligand-1 (PSGL-1) or integrins alpha4beta1 and alphaLbeta2.
T5429 685188-685339 Sentence denotes Treatment of mice with anti-alpha4-integrin or anti-alphaL integrin mAb dramatically reduced acute and chronic seizure activity induced by pilocarpine.
T98393 685340-685490 Sentence denotes Genetic deficiency of PSGL-1 or of the alpha1-3-fucosyltransferases, enzymes involved in the glycosylation of PSGL-1, also inhibited seizure activity.
T12950 685491-685581 Sentence denotes Neutrophil depletion reduced seizure induction and spontaneous recurrent seizures as well.
T77281 685582-685824 Sentence denotes Blood-brain barrier (BBB) leakage was induced by seizures, but was drastically reduced in anti-alpha4 treated or PSGL-1 or FucT deficient animals, establishing a pathogenetic link between leukocyte adhesion, BBB damage and seizure generation.
T33086 685825-685944 Sentence denotes Our results suggest leukocyte recruitment mechanisms as potential targets for the prevention and treatment of epilepsy.
T54255 685945-686030 Sentence denotes Monocytes human immunodeficiency virus type 1 (HIV-1) infection is highly restricted.
T66166 686031-686129 Sentence denotes Such virus-cell exposure is thought to have limited consequence on the physiology of the monocyte.
T12469 686130-686269 Sentence denotes With the advent of functional proteomics the tools are available to investigate the consequences to cell function following HIV-1 exposure.
T75874 686270-686430 Sentence denotes To this end we investigated changes to the proteome of the plasma membrane (PM) to monocytes and monocyte-derived macrophages (MDM) 7 days after virus exposure.
T7939 686431-686580 Sentence denotes Viable human monocyte PM was labeled with CyDye fluorophores and lysed the subjected to two dimensional differential ingel electrophoresis (2D DIGE).
T84957 686581-686664 Sentence denotes This was used to compare PM proteomes of unaffected and HIV-1ADA exposed monocytes.
T81045 686665-686849 Sentence denotes Tandem mass spectrometry (LC/MS-MS) assay showed that 45% of the PM proteome was changed after HIV-1 exposure with differentially expressed proteins showing higher than 2 fold changes.
T84033 686850-686939 Sentence denotes Of these proteins 20% were redox proteins linked to PM protection from respiratory burst.
T414 686940-687127 Sentence denotes Heat shock protein 70 (HSP70), leukotriene hydrolase A4 (LTHA4) and biliverdin reductase (BVR) were representative upregulated PM proteins that are known to protect against free radicals.
T63226 687128-687319 Sentence denotes Confocal images, flow cytometry analyses of HIVexposed and control permeabilized and control cells showed these proteins were upregulated and translocated to the PM in virusexposed monocytes.
T95531 687320-687456 Sentence denotes Western blot and flow cytometry assays of PM and cytozolic fractions stained against HSP70, LTHA4 and BVR confirmed the 2D DIGE results.
T99261 687457-687757 Sentence denotes We next investigated whether the translocation of the three proteins to the plasma membrane was specific to HIV-1 and whether use of PM protecting antioxidants such as tocopherol acetate and sanguinarine attenuate the oxidative burst in monocytes and alter levels of the proteins under investigation.
T27643 687758-687978 Sentence denotes The alterations in the metabolic and redox systems provide an insight into cell-pathogen interactions and of compensatory events between engagement of pathogen killing host defenses and modulation of a respiratory burst.
T11455 687979-688081 Sentence denotes Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS).
T32032 688082-688196 Sentence denotes MS is thought to be a T-cellmediated disease, although the major focus of prior research has been on CD4+ T-cells.
T9526 688197-688325 Sentence denotes We have shown previously that MS patients and healthy subjects harbor CNS-specific CD8+ T-cells with a mixed functional profile.
T73516 688326-688420 Sentence denotes The roles of these CD8+ T-cells in the pathogenesis and/or regulation of MS are still unclear.
T38876 688421-688609 Sentence denotes We have also shown that untreated MS patients show an overall deficit in the immune suppressive ability of CD8+ T-cells, which is corrected following glatiramer acetate (Copaxone) therapy.
T20001 688610-688776 Sentence denotes In the current study, we addressed the role of CNS-targeted CD8+ T-cells in MS patients by developing a novel, flow cytometry-based in vitro immune suppression assay.
T90291 688777-688923 Sentence denotes First, we confirmed the validity of this approach by replicating the suppression by CD4+CD25+ regulatory T-cells ("T-regs") from healthy subjects.
T54563 688924-689011 Sentence denotes We observed a deficit of CD4+CD25+ T-reg-mediated suppression in untreated MS patients.
T75001 689012-689141 Sentence denotes Moreover, MS patients also had an overall deficit in CD8+ T-cellmediated suppression in Copaxone-or anti-CD3-stimulated cultures.
T28658 689142-689400 Sentence denotes Interestingly, CD8+ T-cells from MS patients and healthy controls subjects that were targeted against CNS autoantigens, but not those specific for control antigens, exhibited regulatory ability, in that they suppressed the proliferation of CD4+CD25− T-cells.
T31555 689401-689607 Sentence denotes In conclusion, our results not only confirm that MS is a disease of perturbed immune regulation but also provide the first evidence that CNS-specific CD8+ T-cells may have a regulatory role in this disease.
T2816 689608-689814 Sentence denotes 18 -MicroRNAs regulate brain to body anti-inflammatory signaling - MicroRNAs (miRs) contribute to both neuronal and immune cell fate, but their involvement in inter-tissue communication remained unexplored.
T94201 689815-689956 Sentence denotes Here, we report a role for the acetylcholinesterase (AChE) mRNA-targeting miRs 132, 182⁎ in regulating brain-to-body control of inflammation.
T95121 689957-690293 Sentence denotes We show increases in miRs 132, 182⁎ and decreases in AChE in human leukocytes exposed to bacterial endotoxin, reduced AChE and inflammation following treatment with mimics of miRs 132, 182⁎, and impaired cholinergic anti-inflammatory regulation in leukocytes from mice over-expressing 3′-UTR-null AChE devoid of miR-responding elements.
T61113 690294-690530 Sentence denotes Our findings identify AChE mRNA-targeting miRs as functional regulators of brain to body signaling, opening avenues for studying the neuro-immune dialogue and for post-transcriptional therapeutic interventions in inflammatory reactions.
T31969 690531-690663 Sentence denotes 19 -TLR3 and TLR4 are innate antiviral immune receptors in human microglia -Suh Hyeon-Sook⁎ 1 , Zhao Meng-Liang 1 , Belbin Thomas J.
T57676 690664-690862 Sentence denotes 1 More than 80% of patients with typical generalized myasthenia gravis (MG) have auto-antibodies against the acetylcholine receptor (AChR) at the postsynaptic membrane of the neuromuscular junction.
T18864 690863-690983 Sentence denotes Early-onset MG is frequently associated with thymic abnormalities and the myasthenia often ameliorates after thymectomy.
T67956 690984-691144 Sentence denotes To characterize the autoreactive antibodies that are produced in the thymus, memory B lymphocytes were isolated from the thymus of MG patients and immortalized.
T81525 691145-691282 Sentence denotes Immortalization of B cells by Epstein Barr Virus (EBV) transformation provides a tool to characterize the auto-antibodies in MG patients.
T39202 691283-691410 Sentence denotes To overcome the low efficiency of EBV-based immortalization, the polyclonal B cell activator CpG 2006 was added to the B cells.
T87128 691411-691498 Sentence denotes 60 IgGpositive B cell clones were cultured for the production of monoclonal antibodies.
T74871 691499-691619 Sentence denotes Screening of clones by immunohistochemistry on muscle tissue showed immunoreactivity to striated muscle proteins in 30%.
T95634 691620-691710 Sentence denotes Nevertheless, no anti-AChR antibody producing B-cell was found in our immortalized clones.
T67305 691711-691829 Sentence denotes To further study the specificity of the non positive striated muscle antibodies we performed protein array techniques.
T43419 691830-692065 Sentence denotes In conclusion, the increased immortalization efficiency of EBV transformation by the addition of a polyclonal B cell activator allowed us to immortalize memory B cells from MG patients and subsequently to produce monoclonal antibodies.
T23682 692066-692186 Sentence denotes Interestingly we showed that the thymus does not contain an enriched population of mature B-cells with AChR specificity.
T94445 692187-692401 Sentence denotes Finally, with this improved method further insights into the pathology of this autoimmune disease might be obtained by helping to identify autoantibodies in both seropositive and in double seronegative MG patients.
T22291 692402-692548 Sentence denotes Antibodies play a central role in immunity by forming an interface with the innate immune system and, typically, mediate proinflammatory activity.
T59130 692549-692709 Sentence denotes We investigated the role of a novel posttranslational modification that leads to anti-inflammatory activity of antibodies of immunoglobulin G, isotype 4 (IgG4).
T32034 692710-692930 Sentence denotes IgG4 antibodies are dynamic molecules that exchange Fab arms by swapping a heavy chain and attached light chain (half-molecule) with a heavy-light chain pair from another molecule, which results in bispecific antibodies.
T29848 692931-693070 Sentence denotes The anti-inflammatory property of IgG4 antibodies was tested in vivo in a rhesus monkey model of experimental autoimmune myasthenia gravis.
T32228 693071-693229 Sentence denotes Passive transfer of a pathogenic, patient-derived, IgG1 antibody against acetylcholine receptor (AChR) induced autoimmune myasthenia gravis in rhesus monkeys.
T33493 693230-693442 Sentence denotes Immunoprohylaxis with an IgG4 anti-AChR antibody prevented IgG1-induced myasthenia gravis as well as the characteristic structural damage and accompanying electro-physiological changes to neuromuscular junctions.
T64416 693443-693592 Sentence denotes IgG4 Fab arm exchange was shown to dampen receptor down-modulation, which may prevent disease by reducing receptor cross-linking and internalization.
T53461 693593-693757 Sentence denotes IgG4 Fab arm exchange is suggested to be an important biological mechanism that provides the basis for the anti-inflammatory activity attributed to IgG4 antibodies.
T65104 693758-693962 Sentence denotes Our study provides clues for novel approaches for the development of antigen-specific immunotherapeutic treatments for patients suffering from MG and possibly other antibody-mediated autoimmune disorders.
T64568 693963-694068 Sentence denotes Multiple sclerosis (MS) is an immune-mediated, demyelinating disease of the central nervous system (CNS).
T66470 694069-694307 Sentence denotes While MS and its animal model, experimental autoimmune encephalomyelitis (EAE) are thought to be mediated and regulated by CD4+ Tcells, several reports from us and others show that CD8+ T cells play an important role in MS/EAE immunology.
T14106 694308-694452 Sentence denotes Glatiramer acetate (GA, Copaxone) is an immunomodulatory MS therapy that is believed to mediate its effects through Th1 to Th2 immune deviation.
T9042 694453-694654 Sentence denotes We have shown that GA therapy induces robust CD8+ T cell responses, which are suppressor and cytotoxic in nature and may mediate immune effects through HLA-E-mediated killing of activated CD4+ T cells.
T84701 694655-694751 Sentence denotes We further show that CD8+ T cells are, in fact, essential in mediating the effects of GA on EAE.
T47964 694752-694829 Sentence denotes We also address the role of CNS-specific CD8+ T cells in the disease process.
T48354 694830-694995 Sentence denotes While these cells are widely believed to be pathogenic in nature, we show that both in human MS and in EAE, CNS-targeted CD8+ T cells have an immune suppressor role.
T11076 694996-695132 Sentence denotes We also demonstrate that untreated MS patients are functionally deficient in not only CD4+, but also CD8+, regulatory T cells (T reg s).
T20424 695133-695252 Sentence denotes Interestingly, all human CD4+ and CD8+ T cells attain a transient FOXP3+ state following multiple modes of stimulation.
T56434 695253-695370 Sentence denotes Importantly, in this state they behave unequivocally like bonafide T reg s as assessed by in vitro suppressor assays.
T31628 695371-695498 Sentence denotes Thus, we believe that MS is a disease of perturbed immune regulation characterized by the inability to sustain induced T reg s.
T91566 695499-695697 Sentence denotes We are therefore evaluating the interplay between antigen presenting cells and T cells to dissect the ability of immune populations to modulate T cell development into suppressor vs. effector cells.
T27028 695698-695780 Sentence denotes These studies were supported by grant awards from the NIH and National MS Society.
T68687 695781-695836 Sentence denotes NJK is a Harry Weaver Neuroscience Scholar of the NMSS.
T91519 695837-695860 Sentence denotes CONCURRENT SYMPOSIUM 1:
T30733 695861-695926 Sentence denotes Neuroprotective strategies in neuroimmunologic disease Chairs: S.
T5361 695927-695937 Sentence denotes Khoury, S.
T25661 695938-695943 Sentence denotes Appel
T42432 695944-696005 Sentence denotes Interactions between the immune system and neural stern cells
T56684 696006-696203 Sentence denotes Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA Multiple sclerosis (MS) is an autoimmune disease that causes demyelination and axonal damage in the central nervous system.
T82539 696204-696379 Sentence denotes The majority of the patients experience relapsing-remitting symptoms followed by a secondary progressive phase leading to permanent disability once chronic disease has set in.
T1242 696380-696443 Sentence denotes The current treatment of MS relies on immunologic manipulation.
T25750 696444-696531 Sentence denotes However, it is becoming clear that repair should be considered as a goal for treatment.
T57132 696532-696676 Sentence denotes Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS, and provides a powerful tool for investigating the pathogenesis of MS.
T16137 696677-696829 Sentence denotes Although current evidence shows that remyelination and regeneration occur spontaneously to some extent, it is not nearly sufficient enough in MS or EAE.
T5095 696830-697006 Sentence denotes Remyelinating oligodendrocytes arise from differentiation of neural progenitors and lack of progenitor function has been proposed to play a role in remyelination failure in MS.
T42975 697007-697212 Sentence denotes Understanding how inflammation can impact the function of neural stem cells (NSCs) acutely and chronically is critical for the development of therapeutic strategies targeting endogenous and exogenous NSCs.
T54396 697213-697264 Sentence denotes T cell astrocyte crosstalk in health and disease J.
T70213 697265-697378 Sentence denotes Kipnis Recent evidence suggests that T cells can influence neuronal plasticity by supporting learning and memory.
T38015 697379-697549 Sentence denotes For example, T celldepleted mice exhibit impaired cognitive performance, which could be reversed following injection of exogenous T cells from genetically matched donors.
T89047 697550-697647 Sentence denotes The mechanisms underlying the beneficial effects of T cells in the brain are not well understood.
T32639 697648-697776 Sentence denotes We now suggest that cognitive impairment is a result of a malfunctioning meningeal immune surveillance in T cell deficient mice.
T82466 697777-697962 Sentence denotes Myeloid cells, occupying subarachnoid and ventricular spaces, exhibit a skewed pro-inflammatory phenotype in the absence of T cells and produce high levels of proinflammatory cytokines.
T3320 697963-698108 Sentence denotes Pro-inflammatory cytokines produced by meningeal myeloid cells are proposed to diffuse into brain parenchyma and to affect astroglial activation.
T40982 698109-698292 Sentence denotes Immune deficient mice possess higher levels of activated astrocytes along with a reduced expression of the synaptogenic protein, thrombospondin1 (TSP1), as compared to wild type mice.
T46187 698293-698397 Sentence denotes Moreover, immune deficient mice have fewer hippocampal synapses when compared to wild type counterparts.
T51113 698398-698707 Sentence denotes We show that while anti-inflammatory cytokine, interleukin (IL)-4, increases TSP1 expression in astrocytes, pro-inflammatory cytokines, such as IL-1beta and TNF-alpha inhibit its expression, which is, supposedly, responsible for reduced synapses and for cognitive impairment observed in immune deficient mice.
T91774 698708-698951 Sentence denotes Our results not only shed a light on a potential mechanism underlying cognitive dysfunctions associated with immune decline but might also lead to a development of new future therapies for cognitive and mental conditions that target meningeal.
T86251 698952-699115 Sentence denotes Neuroinflammation, marked by gliosis and infiltrating T-cells, is a prominent pathological feature in human ALS as well as in models of neurodegenerative diseases.
T9686 699116-699333 Sentence denotes Transgenic mice ubiquitously overexpressing mutant Cu 2+ /Zn 2+ superoxide dismutase (mSOD1), a chronic neurodegenerative model of inherited amyotrophic lateral sclerosis (ALS), exhibit such neuroinflammatory changes.
T90728 699334-699619 Sentence denotes We have documented that the innate immune system plays a pivotal role in determining the rate of disease progression in mSOD1 mice by demonstrating that microglia either lacking or with reduced mSOD1 expression enhance motoneuron protection and slow disease progression in such models.
T59019 699620-699770 Sentence denotes These studies were carried out in mice that are unable to develop myeloid cells, but in which both peripheral and central immune systems are modified.
T16393 699771-700072 Sentence denotes To provide evidence for a potential role of the adaptive immune system in these models, we bred mSOD1 mice with RAG2 −/− mice that are unable to develop mature and functional T-and B-cells. mSOD1/ RAG2 −/− mice died earlier than mSOD1/RAG2 +/− mice, and no T-cells were present within the spinal cord.
T20020 700073-700108 Sentence denotes The onset of disease was unchanged.
T39897 700109-700276 Sentence denotes Following irradiation and transplantation with mSOD1 or WT-derived bone marrow, survival was extended in mSOD1/RAG2 −/− mice, to ages identical to mSOD1/RAG2 +/− mice.
T15861 700277-700497 Sentence denotes Immunohistochemical analyses of spinal cord sections demonstrated that CD4+ T-cells had been restored by BMT, but there was no evidence for the presence of B cells either in mSOD1/RAG2 −/− mice or in mSOD1/RAG2 +/− mice.
T12582 700498-700680 Sentence denotes When CD4 −/− mice were crossed with mSOD1 mice, the CD4 −/− /mSOD1 mice died earlier than CD4 +/− /mSOD1 mice, confirming the importance of CD4+ T-cells in mediating neuroprotection.
T34936 700681-700875 Sentence denotes Mice lacking functional T-cells, or CD4+ T-cells also had increased mRNA levels for pro-inflammatory cytokines and NOX2, and decreased levels of trophic factors and glial glutamate transporters.
T75913 700876-701123 Sentence denotes Bone marrow transplants reconstituted mice with T-cells, prolonged survival, suppressed cytotoxicity, decreased mRNA levels for pro-inflammatory cytokines and NOX2, and increased mRNA expression of trophic factors and glial glutamate transporters.
T70354 701124-701307 Sentence denotes These results demonstrate for the first time in a model of chronic neurodegeneration that CD4+ Tcells may provide neuroprotection by modulating the trophic/ cytotoxic balance of glia.
T55448 701308-701447 Sentence denotes These glial/T-cell interactions establish a novel target for therapeutic intervention in ALS and possibly other neurodegenerative diseases.
T16801 701448-701471 Sentence denotes Regenerating the brain:
T88847 701472-701501 Sentence denotes The role of neural stem cells
T94782 701502-701725 Sentence denotes Neuroimmunology Unit -Institute of Experimental neurology (INSpe), DIBIT -San Raffaele Hospital, Milan, Italy Inflammation and degeneration are the usual pathological processes occurring in the central nervous system (CNS).
T19402 701726-701883 Sentence denotes They are only apparently distinct process because as soon as the pathological process becomes chronic they have the tendency to become strictly interrelated.
T39718 701884-702035 Sentence denotes As such, primary neurodegeneration triggers a secondary inflammatory reaction while primary inflammatory reactions lead to neurodegenerative phenomena.
T51282 702036-702240 Sentence denotes Several molecular and cellular events sustaining intrinsic brain repair mechanismsoccurring within the CNS as a consequence of chronic inflammatory and/or degenerative processeshave been described so far.
T38598 702241-702392 Sentence denotes They can be divided into three distinctalthough strictly interrelatedcategories: inflammation-driven processes, CNS plasticity and neuro (glio)genesis.
T60024 702393-702598 Sentence denotes By one hand, humoral and cellular inflammatory components shift sense (function) over time from a tissue-damaging mode to a mode promoting tissue repair (e.g. neurotrophic support from inflammatory cells).
T29926 702599-702810 Sentence denotes By the other hand, the recruitment of alternative "non-damaged" functioning neuronal pathways (cortical maps)occurring mainly via axonal branching and synaptogenesis takes place as a consequence of brain damage.
T26097 702811-702984 Sentence denotes Whether or not (and to what extent) the recapitulation of precise developmental pathways underlies the whole phenomenon of brain plasticity is still matter of investigation.
T51145 702985-703315 Sentence denotes Finally, endogenous neural stem/precursor cells (NPCs)the self-renewing and multipotent cells of the CNS capable of driving neurogenesis and gliogenesis in adult lifemay adapt targeted migration into damaged areas and promote repair via several mechanisms of action (e.g. neuro and gliogenesis, immunomodulation, neuroprotection).
T84051 703316-703577 Sentence denotes It is still a matter of investigation whether (or not) equally robust brain repair/protection can occur following the recruitment within the CNS of trans-differentiating stem cells of a different embryonic origin (e.g. developmental plasticity vs. cell fusion).
T62737 703578-703811 Sentence denotes Multiple sclerosis (MS)the most common demyelinating disease of the CNS affecting young adultsis an autoimmune disease encompassing both inflammatory (myelin and axon destruction) and degenerative (axonal and neuronal loss) features.
T5528 703812-703906 Sentence denotes Spontaneous brain repair (remyelination) occurs early during MS evolution but fails over time.
T53899 703907-704134 Sentence denotes Recent evidence clearly indicate that there are immunological, developmental and cellular events aiming at restoring tissue integrity in MS patients that operate early during disease evolution but lose their efficacy over time.
T1183 704135-704341 Sentence denotes This supports the ensuing idea that MS progression can be viewed as a dysfunction of the intrinsic brain repair mechanisms rather than caused by an uncontrolled, and still undiscovered, pathogenic alien(s).
T18860 704342-704494 Sentence denotes Antibodies against nicotinic acetylcholine receptors (AChR) are implicated in myasthenia gravis as well as in autoimmune autonomic ganglionopathy (AAG).
T52642 704495-704580 Sentence denotes AAG presents as severe generalized sympathetic and parasympathetic autonomic failure.
T34322 704581-704678 Sentence denotes This disorder is also known as acute pandysautonomia or idiopathic subacute autonomic neuropathy.
T46672 704679-704779 Sentence denotes The most disabling manifestations are orthostatic hypotension (OH) and gastrointestinal dysmotility.
T12813 704780-705004 Sentence denotes An autoimmune pathogenesis was suggested by the subacute onset, frequent association with antecedent viral illness, occasional association with cancer or other autoimmune disorders, and spontaneous recovery in some patients.
T70004 705005-705081 Sentence denotes Many cases have a rapid onset, but others have a chronic progressive course.
T22782 705082-705300 Sentence denotes Several clinical and experimental observations indicate that AAG is an antibody-mediated disorder. (1) About 50% of AAG patients have high levels of serum antibodies specific for the neuronal AChR in autonomic ganglia.
T68252 705301-705393 Sentence denotes This ganglionic (α3-type) AChR mediates fast synaptic transmission in all autonomic ganglia.
T79146 705394-705593 Sentence denotes Ganglionic AChR antibodies found in AAG patients are distinct from muscle AChR antibodies found in patients with MG. (2) Ganglionic AChR antibody levels correlate with severity of autonomic deficits.
T43670 705594-705730 Sentence denotes Patients with high antibody levels have a combination of OH, dry eyes and dry mouth, Adies pupil, gastroparesis, and neurogenic bladder.
T45742 705731-705944 Sentence denotes Patients with low antibody levels may have mild or restricted autonomic deficits or postural tachycardia syndrome (POTS). (3) Removal of antibodies using plasmapheresis may result in dramatic clinical improvement.
T46420 705945-706205 Sentence denotes (4) Induction of ganglionic AChR antibodies in rabbits by immunization leads to experimental AAG which reproduces many of the cardinal features of the human disease. (5) Passive transfer of ganglionic AChR antibodies to mice causes transient autonomic failure.
T92444 706206-706496 Sentence denotes In electrophysiological studies, ganglionic AChR antibodies produce a reduction in ganglionic AChR current in cultured neuroblastoma cells, inhibit synaptic transmission in isolated autonomic ganglia due to a reduction in the amplitude of the cholinergic excitatory postsynaptic potentials.
T93326 706497-706616 Sentence denotes AAG is an antibody-mediated channelopathy that produces a severe, but potentially treatable, form of autonomic failure.
T9584 706617-706691 Sentence denotes Department of Neurology, Kinki University School of Medicine, Osaka, Japan
T92901 706692-706775 Sentence denotes Anti-ganglioside antibodies are frequently present in some autoimmune neuropathies.
T35188 706776-706878 Sentence denotes In particular, they are present in about 60% of the acute-phase sera of Guillain-Barré syndrome (GBS).
T4896 706879-707026 Sentence denotes Some of them may be directly involved in the pathogenetic mechanisms by biding to the regions where the respective target ganglioside is localized.
T75921 707027-707242 Sentence denotes We have recently found the presence of the IgG antibody that specifically recognizes a new conformational epitope formed by two gangliosides (ganglioside complex, GSC) in the acute-phase sera from some GBS patients.
T83428 707243-707371 Sentence denotes The IgG antibodies against GD1a/GD1b and/or GD1b/GT1b complexes are associated with severe GBS requiring artificial ventilation.
T51869 707372-707560 Sentence denotes In contrast, the binding activity of the antibody highly specific to GD1b is weaker towards GSC comprising GD1b than to GD1b alone because GD1b undergoes conformational change in that GSC.
T6492 707561-707627 Sentence denotes GD1b is localized in large sensory neurons in dorsal root ganglia.
T74187 707628-707721 Sentence denotes Monospecific anti-GD1b IgG has been shown as a causative factor of sensory ataxic neuropathy.
T20285 707722-707802 Sentence denotes However, GBS patients with monospecific anti-GD1b IgG do not always have ataxia.
T83603 707803-707936 Sentence denotes We investigated whether the reactivities of anti-GD1b IgG to such GSCs are different between GBS with ataxia and that without ataxia.
T75150 707937-708110 Sentence denotes As a result, the reactivities to GD1b mixed with GD1a, GT1b, GQ1b and GalNAc-GD1a were significantly more reduced in ataxic patients than in non-ataxic patients (p b 0.001).
T59515 708111-708198 Sentence denotes It suggests that the IgG antibodies associated with ataxia are highly specific to GD1b.
T2961 708199-708283 Sentence denotes Thus, highly specific anti-GD1b IgG may bind to GD1b tightly to cause ataxia in GBS.
T80423 708284-708367 Sentence denotes Most of the patients with Miller Fisher syndrome (MFS) have anti-GQ1b IgG antibody.
T4069 708368-708517 Sentence denotes Our recent investigation showed that some MFS patients have antibodies with higher titer against GSCs including GQ1b; such as GQ1b/GM1 and GQ1b/GD1a.
T91106 708518-708714 Sentence denotes Based on the results of anti-GSC antibody assay, there are three types of IgG antibodies in MFS; those specific to GQ1b itself, those specific to GQ1b/GM1 complex, and those specific to GQ1b/GD1a.
T30270 708715-708905 Sentence denotes Gangliosides along with other components as cholesterol are known to form lipid rafts, in which the carbohydrate portions of two different gangliosides may form a new conformational epitope.
T20929 708906-709011 Sentence denotes Within the rafts, gangliosides are considered to interact with important receptors or signal transducers.
T81763 709012-709150 Sentence denotes More study is needed to elucidate the mechanisms how the antibodies against gangliosides or ganglioside complexes cause nerve dysfunction.
T99535 709151-709269 Sentence denotes Increasing evidence suggests that CD8 + T cells play an important role in the pathogenesis of multiple sclerosis (MS).
T53080 709270-709482 Sentence denotes CD8 + T cells are found in greater number than CD4 + T cells in acute and chronic MS lesions, and preferential oligoclonal expansion of CD8 + T cells has been observed in the blood, CSF and brains of MS patients.
T72291 709483-709643 Sentence denotes Furthermore, therapeutic depletion of CD4 + T cells did not improve disease in MS patients, however, depleting all lymphocytes reduced new lesions and relapses.
T20694 709644-709825 Sentence denotes We have previously demonstrated in a murine model that CD8 + T cells specific for myelin basic protein (MBP) induce central nervous system (CNS) autoimmunity upon adoptive transfer.
T16920 709826-710022 Sentence denotes To investigate the pathogenesis of MBP-specific CD8 + T cell-mediated autoimmune disease, we generated T cell receptor (TCR) transgenic models using two different MBP-specific CD8 + T cell clones.
T75275 710023-710215 Sentence denotes One model exhibits strong central tolerance while the other model exhibits a unique form of tolerance that allows MBP-specific CD8 + T cells to populate the periphery without inducing disease.
T32964 710216-710437 Sentence denotes Using the first model, we show that negative selection is mediated in the thymus by cross-presentation of MBP by non-bone marrow derived cells, and by synthesis and direct presentation of MBP by bone marrow-derived cells.
T3993 710438-710611 Sentence denotes Using the second model, we demonstrate that the unique state of tolerance, which is maintained during exposure to many immunogenic stimuli, can be broken by viral infection.
T73182 710612-710776 Sentence denotes Our data indicate that the ability of viral infection to trigger disease depends upon expression of endogenous TCR chains on the MBP-specific TCRtransgenic T cells.
T55083 710777-710992 Sentence denotes Expression of a particular endogenous TCR alpha chain confers specificity to a viral epitope, and T cell activation via the virusspecific TCR allows the T cells to respond to endogenous MBP using the transgenic TCR.
T19050 710993-711102 Sentence denotes Interestingly, viral infection of CD4 + MBP-specific TCR transgenic mice does not trigger autoimmune disease.
T55006 711103-711242 Sentence denotes These data provide a potential mechanism by which infectious agents may activate myelin-specific CD8 + T cells to trigger CNS autoimmunity.
T54218 711243-711305 Sentence denotes The dual-face role of alpha B-crystallin in multiple sclerosis
T15156 711306-711366 Sentence denotes Hans van Noort, Delta Crystallon BV, Leiden, The Netherlands
T41131 711367-711446 Sentence denotes The role of T cells in multiple sclerosis (MS) has remained somewhat confusing.
T84035 711447-711609 Sentence denotes On the one hand, infiltrated and locally activated T cells against one or more central nervous system (CNS) antigens are likely to be crucial in lesion formation.
T14170 711610-711753 Sentence denotes On the other hand, no abnormality in the T-cell repertoire of MS patients appears to exist which would explain an autoimmune attack on the CNS.
T93070 711754-712006 Sentence denotes These seemingly paradoxical elements can be reconciled by assuming that MS lesions do not result from an autoimmune attack by an abnormal immune system, but instead, by autoimmune provocation driven by a neurodegenerative process within the CNS itself.
T1541 712007-712079 Sentence denotes Data on the role of alpha B-crystallin (CRYAB) support the latter model.
T3401 712080-712252 Sentence denotes In response to stress of various kinds, glial cells including oligodendrocytes produce strongly increased levels of CRYAB, whose prime intracellular role is anti-apoptotic.
T55248 712253-712464 Sentence denotes Even before lymphocyte infiltration is apparent in the CNS of MS patients, CRYAB accumulation occurs in glial cells, reflecting some form of neurodegenerative stress in the absence of peripheral immune elements.
T62896 712465-712563 Sentence denotes CRYAB is also secreted and as a chaperokine it triggers microglia to produce TNF-alpha and RANTES.
T16696 712564-712617 Sentence denotes By doing so, CRYAB helps recruit immune surveillance.
T95212 712618-712650 Sentence denotes The point is to protect the CNS.
T75122 712651-712797 Sentence denotes Neuroinflammation in CRYAB-deficient mice causes more damage than in normal mice, and soluble CRYAB itself prevents or inhibits neuroinflammation.
T53585 712798-712911 Sentence denotes Unfortunately, however, humans are selectively immune reactive to CRYAB, much more so than to other CNS antigens.
T32319 712912-713084 Sentence denotes In MS patients and healthy subjects alike, marked numbers of pro-inflammatory memory T cells against CRYAB are present in the circulation, as well as anti-CRYAB antibodies.
T86252 713085-713204 Sentence denotes This immune-reactive state is therefore common in humans and thought to be a bystander effect of prior viral infection.
T61729 713205-713343 Sentence denotes Combining these data suggests that immune surveillance provoked by a stressed CNS will inadvertently recruit also CRYAB-reactive elements.
T58017 713344-713566 Sentence denotes Since local antigen-presenting cells in the CNS of MS patients offer high levels of CRYAB they could well trigger an inflammatory reaction which overwhelms the originally protective role of CRYAB, and creates an MS lesion.
T18337 713567-713777 Sentence denotes While therefore common among humans and not the cause of MS per se, we consider CRYAB-reactive T cells to be the key elements which locally fuel an inflammatory lesion, when provoked to do so by a stressed CNS.
T77439 713778-713863 Sentence denotes As a possible solution, CRYAB itself may be used to eliminate the T cells against it.
T91202 713864-713967 Sentence denotes Controversial debate continues as to whether T cells are able to promote central nervous system repair.
T40772 713968-714301 Sentence denotes It has been suggested that T cell injections and vaccination strategies with encephalitogenic antigens contribute to protection from secondary damage after noninflammatory brain and spinal cord injury, however, these studies have been challenged by recent findings demonstrating that the approach includes severe detrimental effects.
T35872 714302-714494 Sentence denotes These contradictory data suggest that a specific molecular crosstalk between the immune system and the nervous system critically determines the ultimate outcome of T cell actions in the brain.
T90440 714495-714612 Sentence denotes Here, we have investigated the use of T cells and their marker cytokine IL-4 for the treatment of spinal cord injury.
T56736 714613-714785 Sentence denotes Here we report that IL-4, released by T cells independent of their antigen specificity, stimulates substantial fiber regrowth in the lesioned brain and spinal cord in vivo.
T42487 714786-715053 Sentence denotes IL 4 receptor −/− animals, mice with selective mutations in the IL-4 signal transduction cascade, inhibitory antibodies, and delivery of IL-4 both in vitro and in vivo were used to identify this cytokine as the molecule responsible for T cell mediated axon outgrowth.
T70230 715054-715213 Sentence denotes We could show that IL-4-dependent AKT/MAPK pathways are crucial for T cell-mediated axon regeneration, while the classical Stat-6 pathway does not play a role.
T90564 715214-715383 Sentence denotes This effect was not the result of increased local release of neurotrophins but of T cells conveying regeneration via IL 4 dependent modulation of neurotrophin signaling.
T88514 715384-715505 Sentence denotes Locomotion analysis revealed significantly improved neurological outcome after lesion in mice treated with IL-4+ T cells.
T90032 715506-715649 Sentence denotes Our results feature IL-4 as a key player in T cell mediated axon reorganization and open the door to the design of novel CNS repair strategies.
T85603 715650-715871 Sentence denotes Demyelination of central nervous system (CNS) axons can cause devastating neurological impairment, but is often followed by myelin repair, which restores function and protects irreplaceable nerve fibres from degenerating.
T33230 715872-715990 Sentence denotes For example, inflammatory demyelinating lesions of multiple sclerosis (MS) are repaired in many, but not all patients.
T72111 715991-716116 Sentence denotes Although strategies to promote myelin repair are eagerly sought, factors that govern remyelination in vivo have been elusive.
T3171 716117-716232 Sentence denotes Chemokine receptor CXCR2 facilitates inflammatory demyelination, by promoting myeloid leukocyte entry into the CNS.
T9345 716233-716305 Sentence denotes Blocking CXCR2 on these cells might suppress inflammatory tissue damage.
T8996 716306-716471 Sentence denotes During postnatal CNS organogenesis, however, CXCR2 positions oligodendrocyte progenitor cells (OPCs) in the spinal cord, to receive timely growth-factor stimulation.
T83344 716472-716642 Sentence denotes CXCR2 is present in clinical and experimental demyelinating lesions, raising the question whether reengaging CXCR2's developmental properties might enhance remyelination.
T73748 716643-716725 Sentence denotes If that were the case, inhibiting CXCR2 signalling could antagonize tissue repair.
T34127 716726-716827 Sentence denotes We show that the action of CXCR2 towards non-hematopoietic cells, unexpectedly, delays myelin repair.
T53533 716828-716954 Sentence denotes Bone marrow chimeric mice (Cxcr2ht to Cxcr2 wt and Cxcr2ht to Cxcr2ko) were subjected to two distinct models of myelin injury.
T74570 716955-717033 Sentence denotes In both cases, myelin repair was more efficient in Cxcr2ht to Cxcr2ko animals.
T3989 717034-717172 Sentence denotes OPCs in demyelinated lesions of Cxcr2ko recipient proliferated earlier and more vigorously than in tissues from Cxcr2wt recipient animals.
T39230 717173-717322 Sentence denotes In-vitro demyelinated CNS slice cultures also showed faster myelin repair when CXCR2 was blocked with neutralizing antibodies or genetically deleted.
T80036 717323-717419 Sentence denotes We propose that CXCR2-dependent developmental cues function aberrantly during CNS myelin repair.
T61179 717420-717609 Sentence denotes Instead, our results suggest that CXCR2-inactivation permits optimal spatiotemporal positioning of OPCs in demyelinating lesions, to receive local proliferative and differentiating signals.
T67966 717610-717794 Sentence denotes Given its actions towards inflammatory myeloid leukocytes and non-hematopoietic cells, our present findings identify CXCR2 as a unique drug target for clinical demyelinating disorders.
T52200 717795-717971 Sentence denotes Four different patterns of demyelination have been described in active demyelinating lesions of multiple sclerosis (MS) patients that were biopsied shortly after disease onset.
T77224 717972-718060 Sentence denotes These patterns were suggested to represent heterogeneity of the underlying pathogenesis.
T21137 718061-718225 Sentence denotes The aim of the present study was to determine if lesion heterogeneity also exists in an unselected collection of autopsy material from patients with established MS.
T25756 718226-718435 Sentence denotes All post-mortem MS brain tissue available in the VU medical center was assessed for the presence of active demyelinating lesions using magnetic resonance imaging (MRI)-guided sampling and immunohistochemistry.
T85554 718436-718799 Sentence denotes Tissue blocks containing active demyelinating lesionsdefined by the presence of activated macrophages containing intracellular myelin proteinswere evaluated for the presence of complement and antibody deposition, oligodendrocyte apoptosis, differential loss of myelin proteins and hypoxia-like damage using histology, immunohistochemistry and confocal microscopy.
T22365 718800-718885 Sentence denotes Sixty-three tissue blocks from 27 MS patients contained active demyelinating lesions.
T97392 718886-719004 Sentence denotes Blocks with active demyelinating lesions were compared to blocks with active (non-demyelinating) and inactive lesions.
T22606 719005-719120 Sentence denotes Deposition of antibodies and activated complement components was consistently associated with active demyelination.
T26128 719121-719218 Sentence denotes Antibodies and complement colocalized with myelin proteins in phagocytic vesicles in macrophages.
T69778 719219-719359 Sentence denotes This pattern was observed in all tissue blocks containing active demyelinating lesions, lesion heterogeneity between patients was not found.
T73240 719360-719503 Sentence denotes Preferential loss of myelin proteins, extensive hypoxialike damage and oligodendrocyte apoptosis were absent or very rare in our tissue sample.
T87861 719504-719616 Sentence denotes We conclude that the immunopathological appearance of active demyelinating lesions in established MS is uniform.
T32803 719617-719806 Sentence denotes Initial heterogeneity of demyelinating lesions in the earliest phase of MS lesion formation may disappear over time as different pathways converge in one general mechanism of demyelination.
T95027 719807-720029 Sentence denotes Consistent presence of complement, antibodies and Fcgamma receptors in phagocytic macrophages suggests that antibody-and complement mediated myelin phagocytosis is the dominant mechanism of demyelination in established MS.
T62433 720030-720267 Sentence denotes Metalloproteinase-disintegrins (ADAMs) represent a family of membrane-anchored metalloproteinases with both proteolytic and disintegrin characteristics, playing an important role in the development and neurobiology of the nervous system.
T97371 720268-720414 Sentence denotes ADAMs have been implicated in ectodomain shedding of surface proteins, growth factors, and remodeling of components of extracellular matrix (ECM).
T51312 720415-720546 Sentence denotes In the present study, we investigated the role of ADAMs in axonal outgrowth and myelination of the peripheral nervous system (PNS).
T86922 720547-720623 Sentence denotes Rat dorsal root ganglia (DRG) and Schwann cells (SCs) were studied in vitro.
T52247 720624-720779 Sentence denotes Expression patterns of ADAM7, -8, -10, -12, -17, -19, -28, and -33, which were predicted to be active metalloproteinases, were investigated in SCs by qPCR.
T86516 720780-720949 Sentence denotes Furthermore, mRNA analysis was performed in the co-culture of DRG and SCs, from the day 1 after seeding the cells up to day 21 after induction of myelination using qPCR.
T48669 720950-721000 Sentence denotes Protein expression was assessed by immunostaining.
T83059 721001-721227 Sentence denotes The involvement of ADAM10 in the process of axonal outgrowth and myelination was studied in greater details by applying the hydroxamate-based inhibitor GI254023X during the pre-myelination stage as well as myelination process.
T24467 721228-721304 Sentence denotes The mean length of the axons was measured and compared to the control group.
T51541 721305-721399 Sentence denotes Using western blotting, P0 protein expression level was used as a marker for myelin synthesis.
T15687 721400-721490 Sentence denotes Among all ADAMs investigated, ADAM10 revealed the highest level of mRNA expression in SCs.
T93041 721491-721598 Sentence denotes ADAM10 mRNA level was up-regulated consistently (p b 0.001) in DRG-SCs co-cultures after seeding the cells.
T9951 721599-721667 Sentence denotes Neurons as well as SCs widely expressed ADAM10 at the protein level.
T90282 721668-721813 Sentence denotes In neurons, the expression of ADAM10 was exclusively limited to the axons during the pre-myelination stage in which axonal outgrowth takes place.
T53030 721814-721986 Sentence denotes Inhibition with GI254023X resulted in a significant dosedependent decrease in the mean length of the axons (p b 0.0001), leading to nearly no outgrowth at the highest dose.
T16012 721987-722193 Sentence denotes The cultures treated with GI254023X from the beginning of the seeding, significantly expressed much less P0 in comparison to those inhibited from the beginning of myelination induction and the control ones.
T37371 722194-722267 Sentence denotes Our data suggest that ADAMs are differentially expressed in DRGs and SCs.
T61413 722268-722379 Sentence denotes Among all ADAMs investigated, ADAM10 seems to play a critical role in axonal outgrowth in the peripheral nerve.
T55141 722381-722554 Sentence denotes While inflammation can damage the CNS, there is an increasing appreciation that there are beneficial aspects of neuroinflammation that can promote neuroprotection or repair.
T26794 722555-722708 Sentence denotes In particular, leukocytes are sources of neurotrophic factors and they could be used to deliver a multitude of neurotrophic factors into the injured CNS.
T59611 722709-722832 Sentence denotes The challenge of harnessing beneficial aspects of neuroinflammation is how to avoid its potential detrimental consequences.
T71263 722833-723014 Sentence denotes The multiple sclerosis (MS) medication, glatiramer acetate (GA), has been shown to be an immuno-modulator through mechanisms including the generation of CD4+ T helper 2 (Th2) cells.
T94380 723015-723272 Sentence denotes Th2 cells produce anti-inflammatory cytokines such as interleukin-5 (IL-5), are not toxic to neurons, and they have been shown to produce BDNF in an animal model of MS, experimental autoimmune encephalomyelitis (Aharoni et al., PNAS 102:19045-19050, 2005) .
T41063 723273-723400 Sentence denotes Thus, there is the prospect of harnessing beneficial inflammation for repair by using cells that are generated/modulated by GA.
T5609 723401-723447 Sentence denotes Remyelination may occur in spinal cord injury.
T32114 723448-723592 Sentence denotes The process of remyelination requires the generation of oligodendrocyte precursor cells (OPCs) that mature into myelin forming oligodendrocytes.
T61912 723593-723767 Sentence denotes Several growth factors are involved in the generation of OPCs, and important ones include insulin-like growth factor-1 (IGF-1), plateletderived growth factor (PDGF) and BDNF.
T70915 723768-723877 Sentence denotes Here, we have addressed whether GA-reactive Th2 cells or GA-treated macrophages produce these growth factors.
T78889 723878-724039 Sentence denotes We have also examined whether GA treatment of mice with a demyelinating injury to the spinal cord could promote the generation of OPCs and remyelination in vivo.
T85589 724040-724308 Sentence denotes Our results show that GA-reactive Th2 cells and GA-treated macrophages have elevated levels of growth factors, particularly IGF-1, and that the conditioned medium from GA-reactive T cells promotes the maturation of OPCs from progenitors cultured from E15 mouse brains.
T83452 724309-724615 Sentence denotes Moreover, demyelinated mice injected daily with GA for the first 7 days have increased number of OPCs around the injury site at day 7 compared to vehicle-treated animals, correspondent with elevated mRNA levels for growth factors and a polarization of inflammatory markers to one that is anti-inflammatory.
T7515 724616-724703 Sentence denotes Finally, we determined that GA increased indices of remyelination 28 days after injury.
T42398 724704-724853 Sentence denotes These experiments highlight the feasibility of promoting spinal cord repair through harnessing beneficial inflammation, using medications such as GA.
T27412 724854-724952 Sentence denotes Pregnancy reduces multiple sclerosis (MS) disease activity, especially during the third trimester.
T20113 724953-725038 Sentence denotes This mitigation is often followed by a relapse within the first 3 months post-partum.
T47949 725039-725137 Sentence denotes The biological mechanisms underlying this amelioration and rebound disease largely remain unclear.
T27754 725138-725244 Sentence denotes The Dutch MS pregnancy study aims to identify biological parameters of MS disease course during pregnancy.
T26243 725245-725408 Sentence denotes The first parameter addressed focused on antigen presenting cells (APC) which drive autoreactive T cells and therefore play a major role in MS disease progression.
T36608 725409-725531 Sentence denotes The second parameter addressed the analysis of Treg versus T helper 17 (Th17) cell subsets during the course of pregnancy.
T92087 725532-725666 Sentence denotes Using Affymetrix microarray, gene expression of CD14+ cells from pregnant MS patients and from pregnant healthy controls was compared.
T95380 725667-725807 Sentence denotes Using stringent statistical analysis five inflammation related genes, CD64, STAT1, JAK2, CD38 and SLAMF7 were upregulated more than twofold.
T97958 725808-725892 Sentence denotes Furthermore 4 genes, IL-8, FCER1A, PTX3, CXCL2 were downregulated more than twofold.
T67150 725893-725944 Sentence denotes The microarray data was confirmed by qPCR analysis.
T26583 725945-726034 Sentence denotes Multicolor flowcytometry analysis was performed in order to identify Treg and Th17 cells.
T49148 726035-726134 Sentence denotes Preliminary results indicate that frequencies of Treg and Th17 are altered in pregnant MS patients.
T75398 726135-726226 Sentence denotes Overall the data shows differential gene expression in APC in MS patients during pregnancy.
T25139 726227-726358 Sentence denotes Furthermore preliminary data suggests that pregnancy influences the numbers of Th17 and Treg cells in MS patients during pregnancy.
T97427 726359-726462 Sentence denotes The Dutch MS pregnancy study contributes to the further understanding of the complex MS disease course.
T82128 726463-726684 Sentence denotes P-selectin glycoprotein ligand-1 (PSGL-1) and alpha (1,3) fucosyltransferases (FucT), enzymes that glycosylate PSGL-1 and control its binding capacity, are involved in the migration of leukocytes in sites of inflammation.
T62515 726685-726910 Sentence denotes Although some previous studies have shown that PSGL-1 ligands have also a protective role in models of autoimmune diseases, some controversies emerged from studies performed in experimental autoimmune encephalomyelitis (EAE).
T13203 726911-727006 Sentence denotes Our goal was to clarify the role of mucin PSGL-1 and glycosylation-dependent mechanisms in EAE.
T54359 727007-727027 Sentence denotes Among other METHODS:
T21694 727028-727106 Sentence denotes Two photon microscopy was performed in draining lymph nodes of immunized mice.
T15713 727107-727179 Sentence denotes Proliferation and bioplex assays for cytokine production were performed.
T59228 727180-727284 Sentence denotes Adhesive interactions were quantified in inflamed brain microcirculation by using intravital microscopy.
T37474 727285-727419 Sentence denotes MOG35-55 specific T cells produced from FucT-VII−/− and PSGL-1 −/− mice transferred a significantly more severe disease than WT cells.
T61370 727420-727667 Sentence denotes Co-cultures performed with CD4+CD25+ Tregs and effector T cells showed that deficiency of PSGL-1 and FucT-VII leads to a marked decrease of suppression capacity on the proliferation and production of pro-inflammatory cytokines by effector T cells.
T37081 727668-728072 Sentence denotes Two-photon microscopy experiments performed inside draining lymph nodes of EAE mice show that the locomotion of FucT-VII and PSGL-1 deficient MOG-specific T cells is significantly decreased while the arrest coefficient is increased when compared to WT effector T cells suggesting that the lack of PSGL-1 and FucT activity leads to prolonged contacts with DCs and increased activation of effector T cells.
T47670 728073-728195 Sentence denotes Moreover, FucT-VII deficient Tregs displayed altered behavior by increased average velocity and mean motility coefficient.
T16537 728196-728356 Sentence denotes In addition to these dysfunctions, Tregs from FucT-VII−/− and PSGL-1−/− mice presented decreased migration capacity to inflamed brain when compared to WT Tregs.
T11855 728357-728537 Sentence denotes Moreover, intravital microscopy experiments showed that FucT-VII and PSGL-1 deficient Tregs display a dramatic decrease of adhesive interactions in inflamed brain microcirculation.
T65127 728538-728652 Sentence denotes Finally, Tregs deficient in PSGL-1 and FucT-VII have a reduced capacity to suppress EAE when compared to WT cells.
T1007 728653-728925 Sentence denotes Our data suggest that PSGL-1 and fucosyltransferase activity have multiple roles in the censorship of EAE by CD4+CD25+ Tregs by participating to cell-cell contacts required for efficient suppression in lymph nodes and by controlling Treg migration into the inflamed brain.
T3894 728926-729077 Sentence denotes Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by inflammation, myelin damage, and axonal degeneration.
T38691 729078-729213 Sentence denotes MS disease relapses are markedly decreased during pregnancy with the greatest reduction in disease observed during the third trimester.
T34863 729214-729315 Sentence denotes We have studied pregnancy in the murine model of MS, experimental autoimmune encephalomyelitis (EAE).
T51569 729316-729407 Sentence denotes Disease severity is significantly reduced when pregnancy is induced during established EAE.
T22983 729408-729528 Sentence denotes We also observed a post-partum flare in disease scores, with EAE suppression only occurring during the gestation period.
T95832 729529-729611 Sentence denotes A serum factor has been implicated as the primary mediator of disease suppression.
T59256 729612-729741 Sentence denotes Exosomes are small lipid-bound microvesicles that are found in peripheral blood and are important in intercellular communication.
T21023 729742-729900 Sentence denotes Exosomes are able to modulate the immune response by relaying molecular signals from their cell of origin to target cells bearing specific adhesion molecules.
T23540 729901-730009 Sentence denotes We have shown that pregnancy-associated exosomes are able to suppress antigen-specific T cell proliferation.
T83997 730010-730115 Sentence denotes We have also observed that the concentration of circulating serum exosomes is increased during pregnancy.
T98673 730116-730264 Sentence denotes Exosomes are hypothesized to dampen immune responses during pregnancy to protect the semiallogeneic fetus, causing a global immunosuppressive state.
T666 730265-730423 Sentence denotes Thus, we examined exosomal proteins that are known to influence T cell activity such as Fas ligand, heat shock protein 70, TGF-β, IL-10, IL-17, and IFN-gamma.
T6726 730424-730671 Sentence denotes Harnessing the mechanism by which exosomes suppress immunity, and consequently EAE, can have extraordinary implications for therapy development in MS. (Supported by NIH grant AI 064320, National MS Society grant RG3272 and NIH grant T32 AI055411).
T12256 730672-731052 Sentence denotes 3 -CD4+FOXP3+ T regulatory cells inhibit experimental autoimmune encephalomyelitis via distinct IL-10 dependent and IL-10 independent mechanisms Davidson Todd⁎ 1 , Shevach Ethan 1 1 National Institute of Allergy and Infectious Disease, NIH, Bethesda, MD, United States CD4+Foxp3+ T regulatory cells (Tregs) are important for controlling a diverse array of immunological responses.
T96601 731053-731241 Sentence denotes Adoptive transfer of these cells into mice results in protection from experimental autoimmune encephalomyelitis (EAE) while depletion of this population results in exacerbation of disease.
T44676 731242-731392 Sentence denotes Tregs have been shown to produce IL-10, a cytokine with immunosuppressive potential that may be important in their ability to inhibit disease in vivo.
T78536 731393-731525 Sentence denotes Adoptive transfer of IL-10−/− T-regs does not inhibit EAE, underlining the importance of this cytokine in Treg mediated suppression.
T94084 731526-731802 Sentence denotes Tracking of adoptively transferred congenically labeled Tregs demonstrated their presence not only in the lymph nodes and spleen, but also in the CNS at time-points both before and after the onset of clinical symptoms, suggesting a role in preventing immune responses in situ.
T24631 731803-731995 Sentence denotes Analysis of IL-10 production by intracellular staining indicated that Tregs do not produce IL-10 in either lymph nodes or spleen but rather express this cytokine almost exclusively in the CNS.
T30105 731996-732237 Sentence denotes Consistent with this result, we found antigen specific TGF-β induced Tregs are capable of limiting the proliferation and activation of effector cells in the draining lymph nodes of immunized mice, but that this effect does not require IL-10.
T1971 732238-732290 Sentence denotes Thus, Tregs inhibit EAE via two distinct mechanisms.
T3524 732291-732383 Sentence denotes The first being an IL-10 independent mechanism whereby Tregs inhibit priming in lymph nodes.
T7075 732384-732483 Sentence denotes The second, IL-10 dependent mechanism requires production of this cytokine by Tregs within the CNS.
T78196 732485-732609 Sentence denotes A rational approach to treat autoimmune diseases such as multiple sclerosis (MS) requires the restoration of self tolerance.
T66441 732610-732740 Sentence denotes We hypothesize that over-representation of self-constituents in the thymus is required to avoid autoimmunity and by extension, MS.
T72245 732741-732865 Sentence denotes As such we have exploited thymus-based tolerance mechanisms to purge autoreactive T-cells and to reinstall immune tolerance.
T68215 732866-733191 Sentence denotes Thus the central aim of this study was to assess whether intrathymic delivery of a recombinant lentiviral vector (LV) engineered to overexpress myelin oligodendrocyte glycoprotein (MOG), a key autoantigen in MS, ameliorates the signs of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice, an animal model for MS.
T87000 733192-733383 Sentence denotes Animals were intrathymically injected with concentrated lentiviral vectors engineered to express MOG (LV-MOG) or the hydrogen potassium ATPase -an irrelevant autoantigen (LV-HKATPase) or PBS.
T74484 733384-733447 Sentence denotes As a further control aged-matched naive animals were also used.
T66905 733448-733587 Sentence denotes Animals were subsequently immunized with the encaphalotogenic MOG35-55 peptide 12 weeks post-treatment and monitored for a further 6 weeks.
T58752 733588-733661 Sentence denotes Thereafter, animals were humanely killed and tissues and organs analyzed.
T44902 733662-733825 Sentence denotes Neurological assessment indicated that untreated and control animals injected with LV-HKATPase or with PBS, developed fulminant symptoms of EAE after immunization.
T30987 733826-733927 Sentence denotes In contrast, animals receiving the therapeutic LV-MOG vector manifest significantly reduced symptoms.
T73588 733928-734096 Sentence denotes Histological analysis of the brain and spinal cords from control animals showed inflammatory lesions that correlated with severe areas of demyelination and axonal loss.
T94468 734097-734274 Sentence denotes Notably LV-MOG-treated animals demonstrated significantly fewer cellular infiltrates that corresponded with a lower number of demyelinating areas with little, or no axonal loss.
T14820 734275-734460 Sentence denotes Functional in vitro activity of MOG35-55-stimulated T cell responses from LV-MOG-treated animals demonstrated a 34% to 50% decrease in proliferative responses in comparison to controls.
T40776 734461-734704 Sentence denotes Finally, quantification of cytokine immunoreactivity in activated spleen cell supernatants revealed that the T-cell pro-inflammatory differentiation cytokine, IL-6, was significantly reduced in LV-MOG treated animals in comparison to controls.
T88388 734705-734847 Sentence denotes Collectively these data indicate that intrathymic delivery of a LV-MOG represents a novel form of tolerance induction for the treatment of MS.
T12991 734848-734976 Sentence denotes Our approach further adds to the armamentarium of nontoxic gene-based strategies for the treatment of this debilitating disease.
T70228 734977-735139 Sentence denotes Th17 cells represent an highly proinflammatory population that have been recently shown to play a crucial role in autoimmune diseases, such as Multiple Sclerosis.
T86489 735140-735292 Sentence denotes The break of the balance that generally exists between the effector lymphocytes and the T regulatory compartment, has been associated with autoimmunity.
T47434 735293-735421 Sentence denotes We have recently detected a strong immunosuppressive function within the CD4+CD25HighCD39+ subpopulation of Treg cells in human.
T8949 735422-735516 Sentence denotes Furthermore we showed that this subset of T cell was decreased in Multiple Sclerosis patients.
T58468 735517-735788 Sentence denotes The aim of this study is to characterize effector T cell subsets which release proinflammatory cytokines such as IL17 and IFNgamma as well as CD39+ Treg cells in healthy individuals age matched with patients affected by the relapsing-remitting form of Multiple Sclerosis.
T16200 735789-735951 Sentence denotes We performed a multicolor cytometric analysis and assays in vitro in order to phenotipically and functionally characterized the cells populations mentioned above.
T23175 735952-736164 Sentence denotes Surprisingly we found, within the CD25high cells, IFN-gamma+ and IL-17+ T cell lymphocytes, suggesting that recently activated proinflammatory cells contaminate the pool of Treg cells in the CD25high compartment.
T27866 736165-736369 Sentence denotes Interestingly these Th1 and Th17 cells were confined in the CD39 negative T cell population thus confirming that CD39 expression represent a valuable marker for Treg cells within the CD25high compartment.
T75777 736370-736492 Sentence denotes We then monitored the frequency of both CD39-Th1 and Th17 cells and CD39+ Treg cells in healthy donors and in MS patients.
T42908 736493-736701 Sentence denotes We found that the decrease of the frequency of the CD39+ cells among the CD25high subset in these patients is associated to an increase in the CD39-CD25high effector cells releasing proinflammatory cytokines.
T8319 736702-736844 Sentence denotes Our results highlighted a contamination within the CD25high regulatory compartment by recently activated effector T cell lymphocytes in human.
T79612 736845-737062 Sentence denotes Furthermore the analysis of the frequency of these populations suggest that in MS patients the equilibrium between effector cells and regulatory subsets is shifted towards the proinflammatory cytokine producing cells.
T80521 737063-737114 Sentence denotes The implications of our findings will be discussed.
T80622 737115-737267 Sentence denotes Esposito Marianna⁎ 1 , Ruffini Francesca 1 , Bellone Matteo 1 , Martino Gianvito 1 , Furlan Roberto 1 1 San Raffaele Scientific Institute, Milano, Italy
T5090 737268-737516 Sentence denotes Rapamycin is a novel macrolide immunosuppressive drug, widely used in preventing clinical allograft rejection, and has been previously reported to efficiently suppress autoimmune diseases by increasing CD4+Foxp3+ Treg cell number and functionality.
T8984 737517-737678 Sentence denotes While its effect has been extensively characterized in vitro, the in vivo effect on the level and function of Treg cell population is still awaiting elucidation.
T59295 737679-737935 Sentence denotes We have treated SJL mice affected by relapsing EAE induced by immunization with PLP139-151, with rapamycin using different administration routes, including oral, and schedules, and studied its effect on clinical, pathological, and immunological parameters.
T68784 737936-738085 Sentence denotes We found that rapamycin treatment, independently from the route and schedule of administration, significantly ameliorates the clinical course of EAE.
T67186 738086-738183 Sentence denotes The protective effect was confirmed also by the finding of reduced demyelination and axonal loss.
T90704 738184-738387 Sentence denotes The therapeutic effect of rapamycin was associated to a decrease of infiltrating CNS cells, especially macrophages, but not with an increase of Treg cells, or in the CNS or in peripheral lymphoid organs.
T22892 738388-738636 Sentence denotes Rapamycin administration, however, was associated with decreased proliferation and inhibited release of IFN-gamma and IL-17 by antigen-specific T cells in draining lymph nodes and spleens from EAE rapa-treated mice as compared to the control group.
T73059 738637-738904 Sentence denotes These pre-clinical results indicate rapamycin as an efficient drug in controlling experimentally induced autoimmune responses, provide evidence of the immunological mechanism, and suggest this compound as a plausible candidate for the treatment of multiple sclerosis.
T60035 738905-739188 Sentence denotes Natalizumab is a humanized monoclonal antibody directed against alpha-4-integrin, which reduces the relapse rate and MRI evidence of disease activity in patients with multiple sclerosis (MS) by blocking the transmigration of T cells and B cells into the central nervous system (CNS).
T99190 739189-739296 Sentence denotes Little is know about effects of natalizumab on the activation stage and function of circulating leukocytes.
T21548 739297-739557 Sentence denotes We used flow cytometry to study the phenotype of peripheral blood mononuclear cells (PBMCs) in 28 patients with relapsing-remitting MS (21 females and seven males) before and during treatment with natalizumab (Tysabri, Biogen Idec Inc; 300 mg IV once a month).
T59634 739558-739658 Sentence denotes Blood was obtained at baseline and immediately before natalizumab infusions at month 1, 3, 6 and 12.
T90405 739659-739780 Sentence denotes None of the patients had been treated with any immunomodulatory drugs for at least 1 month before inclusion in the study.
T28222 739781-739983 Sentence denotes PBMCs were stained directly ex vivo and after in vitro stimulation with anti-CD3 and anti-CD28 (for studies of CD4+ and CD8+ T cells) or IFN-g and LPS (for studies of CD19+ B cells and CD14+ monocytes).
T85287 739984-740087 Sentence denotes The pretreatment measurement was compared to the on-treatment measurements using a mixed effects model.
T55158 740088-740317 Sentence denotes We observed that the expression of IFN-g increased on all cell types under study (CD4+, CD8+, CD19+ and CD14+ cells) early after initiation of natalizumab treatment and remained elevated throughout the follow-up (p b 0.05-0.005).
T75828 740318-740522 Sentence denotes In addition, CD4+ T cells expressed higher levels of TNF-a (p b 0.05), while stimulated CD19+ B cells displayed increased expression of TNF-a, IL-6 and IL-23 (p b 0.05-0.005) during natalizumab treatment.
T75248 740523-740706 Sentence denotes The expression of CCR5 and CCR6, two chemokine receptors associated with previously activated effectormemory cells were also increased during natalizumab treatment (p b 0.005-0.0005).
T95735 740707-740875 Sentence denotes The frequency of CCR6+/CD4+ T cells doubled during the first month of treatment, while increased frequencies of CCR5+/CD8+ T cells were detected later during treatment.
T343 740876-741103 Sentence denotes In conclusion, we observed increased numbers of leukocytes expressing proinflammatory cytokines in peripheral blood during natalizumab treatment, presumably due to sequestration of activated cells in the peripheral circulation.
T6529 741104-741302 Sentence denotes An accumulation of potentially aggressive leukocytes in blood may lead to rapid influx of inflammatory cells to the CNS after discontinuation of natalizumab treatment and may be of clinical concern.
T62687 741303-741528 Sentence denotes 2 -Different chaperone usage by IL-12 AND IL-23 during their assembly reveals novel targets for intervention with cytokine secretion in neuroinflammation IL-12, IL-23 and IL-27 are members of a unique dimeric cytokine family.
T9311 741529-741637 Sentence denotes IL-12 is composed of disulphide-linked p40 and p35 while IL-23 is composed of disulphide-linked p40 and p19.
T9054 741638-741769 Sentence denotes In addition, the p40 subunit can homodimerize to form p80, a cytokine with as yet poorly understood chemotactic activity in humans.
T29459 741770-741990 Sentence denotes The promiscuity of the p40 subunit is indicative for complex regulatory mechanisms operating at the level of partner selection, assembly and maturation during folding in the endoplasmic reticulum (ER) prior to secretion.
T46052 741991-742096 Sentence denotes IL-12 is involved in Th1 differentiation while IL-23 induces development of IL-17-secreting CD4+ T cells.
T83804 742097-742215 Sentence denotes Both cytokines are linked to stages in the development and maintenance of CNS inflammation, such as seen in MS or EAE.
T59258 742216-742430 Sentence denotes All known therapeutic agents, including the mAb ustekinumab or drugs interfering with transcription of the p40 subunit via inhibition of NFkappab, block simultaneously IL-12, p80, p40 and IL-23 via the p40 subunit.
T28208 742431-742525 Sentence denotes As yet, no drugs are available that can selectively interfere with either IL-12, p80 or IL-23.
T96602 742526-742672 Sentence denotes We investigated the assembly stages of these cytokines using in-lab established recombinant cell lines specifically producing IL-12, p80 or IL-23.
T77130 742673-742901 Sentence denotes We identified geldanamycin and its more soluble version 17-AAG as drugs capable of blocking secretion of IL-12 and p80, through a mechanism involving the ER chaperone GRP94 rather than the cytosolic homologue HSP90 (IC50 50 nM).
T33798 742902-743020 Sentence denotes Geldanamycin/17-AAG did not inhibit IL-23 secretion nor secretion of p40 monomers at tested concentrations up to 1 μM.
T90535 743021-743109 Sentence denotes Geldanamycin is a benzoquinone ansamycin that has been shown to inhibit HSP90 and GRP94.
T35639 743110-743289 Sentence denotes In immunoprecipitation experiments geldanamycin/17-AAG inhibited interaction of p80 with GRP94. siRNA knockdown of GRP94 completely abolished p80 secretion, but not that of IL-23.
T58712 743290-743369 Sentence denotes Other GRP94 inhibitors including herbimycin A and radicicol also inhibited p80.
T22728 743370-743479 Sentence denotes Geldanamycin research has concentrated on its ability to target cancer cells susceptible to Hsp90 inhibition.
T75922 743480-743598 Sentence denotes Our work shows that the ER chaperone GRP94 is vital for folding of IL-12 and p80 but dispensible for folding of IL-23.
T88526 743599-743683 Sentence denotes Experiments are underway in our lab to test geldanamycin/17-AAG in EAE models of MS.
T21110 743684-743795 Sentence denotes A full comparative proteomic analysis of the ER "foldosomes" of IL-12, p80, IL-23 and IL-27 is being performed.
T50253 743796-743941 Sentence denotes Natalizumab, a humanized anti-a4 integrin monoclonal antibody, reduces relapses and disease progression in patients with multiple sclerosis (MS).
T93658 743942-744155 Sentence denotes Whereas its presumed mode of action is inhibition of T cell/monocyte entry into the brain, little is known about its specific effect on B cells, which are increasingly recognized to participate in MS pathogenesis.
T85810 744156-744342 Sentence denotes We obtained serial blood samples from 17 patients before and during natalizumab therapy for MS for up to 16 months, and blood samples from 10 untreated MS patients and 13 healthy donors.
T72452 744343-744481 Sentence denotes We determined numbers of mature and immature lymphocyte subsets by flow cytometry for CD3, CD4, CD8, CD19, CD138, and CD10 in 111 samples.
T27729 744482-744676 Sentence denotes We analyzed marker transcripts for immature hematopoietic cells by quantitative PCR for CD34, Vpre-beta-1 (pre-B lymphocyte gene 1) and DNTT (terminal deoxynucleotidyltransferase) in 65 samples.
T30646 744677-744836 Sentence denotes Natalizumab therapy increased CD19+ mature B cells more than other lymphocytes/monocytes in blood (2.8-fold versus1.3-1.8-fold increase in cells/µl; pb 0.01)).
T64894 744837-744924 Sentence denotes Even greater was the increase of immature CD19+ CD10+ pre-B cells (7.4-fold; p b 0.01).
T1286 744925-744991 Sentence denotes This pattern remained stable during treatment for up to 16 months.
T52923 744992-745097 Sentence denotes Transcripts of lymphocyte precursors (Vpre-beta-1 and DNTT) were elevated more than transcripts for CD34.
T45618 745098-745328 Sentence denotes Circulating B cells and especially pre-B cell are most prominently elevated among the studied immune cell subsets, raising the possibility that the effects and side effects of natalizumab are partly mediated by actions on B cells.
T47627 745329-745502 Sentence denotes This longitudinal systematic gene expression study focuses on multiple sclerosis (MS) and the effects of medication by subcutaneous recombinant Interferon-beta-1a (IFNβ-1a).
T30361 745503-745691 Sentence denotes It is the aim to attain human peripheral blood derived gene transcripts that are differentially regulated throughout therapy and to infer accessory regulatory pathways of the applied drug.
T12116 745692-745877 Sentence denotes Employing the Affymetrix HGU133Plus2.0 array (55.000 transcript species), we performed a full genome study monitoring 12 RRMS patients receiving IFNβ-1a (s.c.) over a period of 2 years.
T96747 745878-746086 Sentence denotes Peripheral blood samples were collected and directly processed (Ficoll) before first treatment (t0) and correspondingly before each upcoming injection after 2 days (t1), 4 weeks (t2), 1 (t3) and 2 (t4) years.
T96842 746087-746420 Sentence denotes Transcriptome analyses were realized including data curation by MAS 5.0 (Absent-and No change-calls, respectively), probeset quality by GeneAnnot (specificity and sensitivity) and a self-made algorithm (intensity dependent fold change criterion) as well as available R software packages (paired t-test, principal component analysis).
T76852 746421-746549 Sentence denotes Gene regulatory network inference and transcription factor binding site identification (TRANSFAC, JASPAR) analyses are underway.
T44696 746550-746865 Sentence denotes Consistently upregulated throughout analyzed time points were four genes, namely interferon-induced protein 44 (IFI44) and SP110 nuclear body protein (alias IFI41), protein associated with topoisomerase II homolog 2 (PATL2; DNA transcription and replication related), and CD20 antigen-like 1 (MS4A4A) (3 probesets).
T32035 746866-746961 Sentence denotes Groups of functionally related genes changed over time in the majority of analyzed individuals.
T88369 746962-747173 Sentence denotes Whereas earlier during therapy mainly typical IFNβ induced genes were filtered, such as IFIT-1, -2, -3, -5, MX-1, -2, OAS-1, -2, -3, -L, other sets of up-regulated genes (FCRL1, TCL1A) dominate at years 1 and 2.
T36079 747174-747236 Sentence denotes Only HERC6 and JUP were consistently upregulated until 1 year.
T16223 747237-747424 Sentence denotes Of interest are up-regulated killer cell genes (KLRF1, KLRD1, KIR2DL3, KIR2DS2, KIR3DL-1, -2, -3) at 2 days, and downregulated integrin genes (ITGA2B, ITGB-3, -5) at 1 month post-therapy.
T37445 747425-747521 Sentence denotes Filtered genes represent promising candidates to be actively involved in IFNβ regulated effects.
T34976 747522-747648 Sentence denotes The dynamic expression changes of individual RNA profiles reflect the intertwining of disease and therapy course complexities.
T66138 747649-747718 Sentence denotes 5 -Diversity in the major ass B-cell epitope among different mammals:
T96167 747719-747864 Sentence denotes Affect on vaccine design, safety, and efficacy of immunotherapy for Alzheimer's disease Cribbs David⁎ 1 , Head Elizabeth 1 , Vasilevko Vitaly 1 1
T75166 747865-748143 Sentence denotes The failure of the first immunotherapy trial in Alzheimer's disease (AD) patients, due to meningoencephalitis in a few patients that received the AN1792 vaccine has provided an opportunity to develop novel second-generation vaccines that reduce the potential for adverse events.
T74383 748144-748314 Sentence denotes The translational effectiveness of immunotherapy for AD is likely to be dependent on how well animal models predict the type of immune response that will occur in humans.
T49435 748315-748484 Sentence denotes Notably, the evidence from the AN1792 clinical trial indicates that the overwhelming antibody response was to the free N-terminus of the amyloid-beta (Aβ) peptide (DAE).
T65066 748485-748612 Sentence denotes However, previous studies in mice identified an internal sequence, EFRH, near the N-terminus as the major B-cell epitope in Aβ.
T35552 748613-748832 Sentence denotes Importantly, anti-Aβ antibodies generated in mice bind the amyloid precursor protein (APP), which is expressed on the surface of cells, whereas the antibodies generated in the AN1792 clinical trial do not recognize APP.
T66712 748833-748959 Sentence denotes Thus differences in the B cell epitope may have significant consequences for the efficacy, as well as safety of immunotherapy.
T2361 748960-749105 Sentence denotes To explore the diversity of immune responses in mammals, we immunized mice, rats, guinea pigs, rabbits, goats, and dogs with the AN-1792 vaccine.
T2902 749106-749294 Sentence denotes We then performed fine epitope mapping to determine the major anti-Aβ B-cell epitopes, and Western blot analysis to determine whether the anti-Aβ antibodies cross-reacted with amyloid APP.
T76838 749295-749502 Sentence denotes Surprisingly, we found that the major anti-Aβ B-cell epitope in mice, rats, a goat and guinea pigs is located in an internal sequence of Aβ1-42, and serum from these species recognizes APP on a Western blot.
T55621 749503-749756 Sentence denotes Conversely, anti-Aβ antibodies from monkeys, canines and rabbits all closely resembled the reported immune response in humans by recognizing only the free N-terminus of Aβ1-42, which is dependent on the free aspartic acid at position one of the peptide.
T72597 749757-749838 Sentence denotes As expected, the serum from these species does not recognize APP by Western blot.
T8631 749839-749977 Sentence denotes Thus, careful selection of animal models for testing new vaccine candidates may facilitate effective translation to human clinical trials.
T20787 749978-750226 Sentence denotes Moreover, developing immunogens that induce neo-epitope antibodies that recognize free N-or C-terminal, or naturally occurring truncated forms of Aβ, but not APP, may improve the safety as well as the efficacy of new active immunization approaches.
T83153 750227-750388 Sentence denotes Neural stem/precursor cells (NPCs) have the capacity to self-renew and generate functional differentiated cells (e.g., neurons, astrocytes and oligodendrocytes).
T45378 750389-750538 Sentence denotes Due to their plasticity, NPCs could potentially be implemented in cell-based therapy to treat neurodegenerative diseases, such as multiple sclerosis.
T27385 750539-750716 Sentence denotes Besides the beneficial role provided by cell replacement, NPCs exert neuroprotection from inflammatory damage acting through multiple mechanisms alternative to cell replacement.
T42878 750717-750851 Sentence denotes Transplantation of NPCs in mice with experimental autoimmune encephalomyelitis (EAE), has been demonstrated to ameliorate the disease.
T97534 750852-751000 Sentence denotes NPCs injected intravenously or subcutaneously migrate in the central nervous system (CNS) but also accumulate, survive and persist in non-CNS sites.
T86179 751001-751093 Sentence denotes Undifferentiated NPCs are found within lymph nodes even after 100 days from transplantation.
T20336 751094-751168 Sentence denotes At these peripheral districts, NPCs seem to have immunomodulatory effects.
T56130 751169-751309 Sentence denotes Indeed, NPCs inhibit the activation of dendritic cells (DC) and prevent the expansion of antigen-specific encephalitogenic T cells in vitro.
T27075 751310-751456 Sentence denotes To elucidate the crosstalk between NPCs and cells of the immune system, we are performing the ex vivo characterization of EAE mouse lymphnode DCs.
T86411 751457-751587 Sentence denotes DC subsets from different body districts of NPC-injected or not treated mice were analyzed, especially for their activation state.
T68772 751588-751777 Sentence denotes Given the extensive data and insights obtained from the mouse system, our aim is to extend these studies to human NPCs from fetal human brain, also with the perspective of a clinical trial.
T77100 751778-751916 Sentence denotes Immunomodulatory properties have already been demonstrated for human mesenchymal stem cells, although the exact mechanisms remain elusive.
T1994 751917-752019 Sentence denotes There are clearly other genes that are crucial in the development of HSE that have yet to be revealed.
T79079 752020-752245 Sentence denotes The identification of other genes involved in HSE will present important biological and medical implications, providing a dissection of immunity to HSV-1 in natural conditions and a rational understanding of HSE pathogenesis.
T94799 752246-752555 Sentence denotes Hosking Martin⁎ 1 , Lane Thomas 1 1 University of California, Irvine, Irvine, United States Inoculation with the neurotropic JHM strain of mouse hepatitis virus (JHMV) into the central nervous system (CNS) of mice results in an acute encephalomyelitis associated with an immune-mediated demyelinating disease.
T84606 752556-752796 Sentence denotes JHMV infection induces transcription of the chemokine receptor CXCR2 and signaling ligands CXCL1 and CXCL2 during acute and chronic disease yet the functional significance of these molecules to either host defense or defense is not defined.
T41443 752797-752951 Sentence denotes Therefore, the goals of this study were to define the functional role of ELR+ chemokines in host defense and disease following viral infection of the CNS.
T29608 752952-753213 Sentence denotes Treatment with anti-CXCR2 antibody during acute disease abrogated blood-brain barrier (BBB) breakdown associated with diminished MMP-9 expression and virus-specific T cell infiltration correlating with elevated viral titers in the brain and increased mortality.
T51753 753214-753430 Sentence denotes Silencing CXCR2 signaling during chronic disease was associated with increased mortality independent of either viral recrudescence, modulating leukocyte entry into the CNS, or affecting the severity of demyelination.
T76446 753431-753562 Sentence denotes However, anti-CXCR2 treatment resulted in increased numbers of TUNEL-positive oligodendrocytes and oligodendrocyte precursor cells.
T1607 753563-753737 Sentence denotes Cultures of oligodendrocytes were protected from apoptosis in response to exposure to MHV following inclusion of the CXCR2 ligands CXCL1 and CXCL2 in a dose-dependent manner.
T9755 753738-754019 Sentence denotes These findings reveal previously unrecognized and differential roles for ELR+ chemokines in host defense by increasing BBB permeability during acute disease and protecting cells of the oligodendrocyte lineage from apoptosis during a chronic neuroinflammatory demyelinating disease.
T59464 754020-754232 Sentence denotes The migration of lymphocytes into the central nervous system (CNS) during viral encephalitis is hindered by the blood-brain barrier (BBB) such that most infiltrating cells remain localized to perivascular spaces.
T12139 754233-754351 Sentence denotes This sequestration of leukocytes away from the parenchyma is believed to protect the CNS from immunopathologic injury.
T44146 754352-754651 Sentence denotes Infections of the CNS with highly cytopathic neurotropic viruses, such as West Nile virus (WNV), however, require the parenchymal penetration of T lymphocytes for virus clearance and survival, suggesting that perivascular localization might hinder antiviral immune responses during WNV encephalitis.
T34254 754652-754942 Sentence denotes Using human and murine brain specimens from individuals with WNV encephalitis, we evaluated the expression of CXCL12 and its receptor, CXCR4, at the BBB and tested the hypothesis that inhibition of CXCR4 would promote T lymphocyte entry into the CNS parenchyma and increase viral clearance.
T96288 754943-755197 Sentence denotes Antagonism of CXCR4 significantly improved survival from lethal infection through enhanced intraparenchymal migration of WNV-specific CD8+ T cells within the brain, leading to reduced viral loads and, surprisingly, decreased immunopathology at this site.
T91811 755198-755378 Sentence denotes The benefits of enhanced CD8+ T cell infiltration suggest that pharmacologic targeting of CXCR4 may have therapeutic utility for the treatment of acute viral infections of the CNS.
T78877 755379-755672 Sentence denotes 6 -Both TLR2 and TLR4 are required for the effective immune response in Staphylococcus aureus-induced experimental murine brain abscess - Toll-like receptors (TLRs) play central roles in the innate reaction to bacterial products, and transmit specific immune responses against these pathogens.
T18790 755673-755806 Sentence denotes TLRs are expressed on numerous cell types including innate immune cells, and on astrocytes, neurons, and microglial cells of the CNS.
T230 755807-755903 Sentence denotes Lipoproteins and lipopolysaccharides are specifically recognized by TLR2 and TLR4, respectively.
T49096 755904-756002 Sentence denotes We examined the in vivo role of TLR2 and TLR4 in Staphylococcus (S.) aureus-induced brain abscess.
T97325 756003-756228 Sentence denotes After intracerebral inoculation with bacteria, we performed survival studies followed by histopathological qualitative and flow-cytometrical quantitative as well as molecular qPCR studies on relevant chemokines and cytokines.
T5159 756229-756324 Sentence denotes Phenotypically, 87% of TLR2−/− mice, and 43% of TLR4−/− mice died, while all WT mice recovered.
T48277 756325-756440 Sentence denotes Clearance of bacteria from the CNS was significantly delayed in TLR2−/− mice as compared to TLR4−/− and WT animals.
T11310 756441-756576 Sentence denotes Recruitment of granulocytes and macrophages to the CNS, as well as microglial activation and expansion was upregulated in TLR2−/− mice.
T41252 756577-756716 Sentence denotes While inflammation persisted especially in the CNS of TLR2−/−, but also of TLR4−/− mice, WT mice terminated the infection more effectively.
T73371 756717-756972 Sentence denotes Collectively, these data show that the immune response to experimental S. aureus-induced brain abscess depends crucially on the recognition of S. aureus by TLR2, but that TLR4 is also required for an optimal intracerebral immune response in this disorder.
T64765 756973-757245 Sentence denotes Although there is no curable treatment for Alzheimer disease (AD), based on the growing understanding of the pathological mechanisms, several novel therapeutic strategies are being developed, and it is widely accepted that Aβ immunotherapy is one of the potential methods.
T92688 757246-757410 Sentence denotes Active and passive Aβ immunotherapies can reduce AD-like pathology and improve cognitive performance in animal models of the disease and potentially in AD patients.
T69657 757411-757624 Sentence denotes Hock et al. (2004) suggested that tissue amyloid plaque immuno-reactive (TAPIR) antibodies correlated well with the slower cognitive decline in AD patients who had received active immunization with Aβ and aduvant.
T49072 757625-757716 Sentence denotes Thus, we wished to develop such monoclonal antibody for passive immunization therapy in AD.
T40027 757717-757982 Sentence denotes We used a hybridoma technique to develop a TAPIR-like anti-human Aβ mouse monoclonal antibody, characterized it in vitro and evaluated its therapeutic effects on 18 months old APP transgenic Tg2576 mice by intraperitoneal administration of the antibody for 8 weeks.
T13090 757983-758140 Sentence denotes The obtained monoclonal antibody, 3.4A10 was an IgG2b isotype, and recognized Nterminal portion of Aβ1-42 without binding denatured or native AβPP fragments.
T71763 758141-758268 Sentence denotes It had higher affinity to Aβ1-42 than to Aβ1-40 (the dissociation constant was 5.64 × 10-11 M and 3.77 × 10-8 M, respectively).
T58576 758269-758426 Sentence denotes It stained preferably the peripheral part of senile plaques of AD brain sections and recognized the plaque core less than 4G8 (7.5% versus 14.93%, P b 0.05).
T41322 758427-758573 Sentence denotes It inhibited the Aβ1-42 fibril formation as well as degraded pre-aggregated Aβ1-42 peptide in a thioflavin T fluorescence spectrophotometry assay.
T43695 758574-758876 Sentence denotes It decreased amyloid burden compared to the control group by a quantitative image analysis (P b 0.05) and significantly reduced Aβ42 levels rather than Aβ40 levels in brain lysates by a quantitative ELISA assay as well as the Aβ⁎56 oligomer (12mer) in TBS fraction of the brain lysates by western blot.
T37601 758877-759007 Sentence denotes 3.4A10 entered brain and decorated some plaques, which is surrounded by more Iba1-positive microglia after 8 weeks administration.
T49838 759008-759136 Sentence denotes 3.4A10 therapy did not induce lymphocytic infiltration and obvious increase in microhemorrhage examined by Berlin blue staining.
T9262 759137-759260 Sentence denotes 3.4A10 is a TAPIR-like anti-human amyloid monoclonal antibody to Aβ, and has a potential of therapeutic application for AD.
T63863 759261-759450 Sentence denotes Recent genetic studies show an independent role of HLA class-I genes in conferring susceptibility to chronic human inflammatory diseases such as type-1 diabetes and multiple sclerosis (MS).
T44935 759451-759616 Sentence denotes These data provide strong incentive to further investigate the contribution of MHC class-I-restricted CD8 T cells in the induction and development of these diseases.
T71268 759617-759848 Sentence denotes We are investigating the contribution of MHC class-I restricted CD8 T cells in mouse models of central nervous system inflammation in which CD8 T cells specifically target oligodendrocytes, the primary cellular target of MS lesion.
T69869 759849-760090 Sentence denotes To assess the pathogenic impact of CD8 T cells on oligodendrocytes, we generated mice, referred as double knock in (DKI) mice, in which the well-studied model antigen influenza hemagglutinin (HA) is selectively expressed on oligodendrocytes.
T69910 760091-760254 Sentence denotes Introduction of HA-specific CD8 T cells by TCR transgenesis did not result in any sign of central or peripheral tolerance, or any CNS pathology in the DKI animals.
T10278 760255-760420 Sentence denotes The exclusive expression of HA in oligodendrocytes, and the resulting lack of T-cell silencing, is very reminiscent of some natural myelin self-antigens such as MOG.
T32031 760421-760589 Sentence denotes Transfer of pre-activated HA-specific CD8 T cells from CL4 TCR transgenic mice in DKI recipients led to inflammatory lesions in the optic nerve, spinal cord, and brain.
T74935 760590-760760 Sentence denotes These lesions associating CD8 Tcell infiltration with focal loss of oligodendrocytes, demyelination, and microglia activation, were very reminiscent of active MS lesions.
T67095 760761-760870 Sentence denotes In order to trace these HA-specific CD8 T cells in vivo, we labeled them with green florescent protein (GFP).
T30538 760871-761164 Sentence denotes Staining for GFP and Granzyme B revealed that HA-specific Tc1 cells containing Granzyme B granules were detected within CNS lesions of DKI mice, some of the Granzyme B+ T cells were found in close apposition to carbonic anhydrase II or cyclic nucleotide 3′ phosphodiesterase+ oligodendrocytes.
T78715 761165-761294 Sentence denotes We also detected GFP+ Tc1 cells with polarized Granzyme B+ granules facing an oligodendrocyte, suggesting directed degranulation.
T56648 761295-761515 Sentence denotes These findings can provide important new insights with regard to CNS tissue damage mediated by CD8 T cells specific for a sequestered antigen and in extension for the understanding of the role of CD8 T cells in human MS.
T93952 761516-761770 Sentence denotes 3 -Tim-3:Galectin-9 pathway protects against CNS autoimmunity by expanding myeloid-derived suppressor cells Tim-3 is a cell surface molecule expressed on IFN-g-producing Th1 cells; upon interaction with its ligand, galectin-9, it terminates Th1 immunity.
T23975 761771-761934 Sentence denotes Tim-3/Tim-3 ligand interactions also play an important role in immune tolerance as mice treated with Tim-3 Ig fusion protein and Tim-3−/− mice cannot be tolerized.
T65732 761935-762042 Sentence denotes Here we sought to study more precisely the mechanism by which Tim-3 induces tolerance in the immune system.
T95334 762043-762124 Sentence denotes We therefore generated mouse strains that overexpress either Tim-3 or galectin-9.
T98195 762125-762343 Sentence denotes We find that in both strains T cell responses are suppressed and that this is associated with an increased frequency of CD11b+Ly-6G+ cells that exhibit morphology consistent with myeloidderived suppressor cells (MDSC).
T60559 762344-762636 Sentence denotes We further find that Tim-3 transgenic mice are protected from Experimental Autoimmune Encephalomyelitis (EAE), a murine model for multiple sclerosis (MS), and that protection from disease is associated with an increased frequency of MDSC among central nervous system (CNS)-infiltrating cells.
T88470 762637-762776 Sentence denotes Lastly, we find that loss of Tim-3 reverses the MDSC expansion observed in Galectin-9 transgenic mice and restores normal immune responses.
T77283 762777-762914 Sentence denotes MDSC accumulate in large numbers in cancer patients and in tumor-bearing mice in which they are potent inhibitors of anti-tumor immunity.
T55277 762915-763018 Sentence denotes Accumulation of MDSC has also been observed after exposure to bacterial, parasitic, and viral antigens.
T22676 763019-763158 Sentence denotes Despite the biological importance of MDSC in regulating immune responses, the molecular pathways that expand and regulate MDSC are unknown.
T62377 763159-763313 Sentence denotes It is known that IFN-g plays an important role as MDSC fail to accumulate in IFN-g Receptor−/− mice and require IFN-g for activating suppressor functions.
T59058 763314-763443 Sentence denotes Here, we have made a novel observation that the Tim-3/galectin-9 pathway plays a role in the expansion and/or activation of MDSC.
T6132 763444-763628 Sentence denotes As Tim-3 is a cell surface receptor expressed on IFN-g secreting Th1 cells, our findings are consistent with the previous studies implicating IFN-g in MDSC-mediated immune suppression.
T35012 763629-763851 Sentence denotes Since MSC have been shown to divert immune responses in autoimmune, cancer, and infectious diseases, targeting of the galectin-9-Tim-3 pathway may represent an important therapeutic target in many immune-mediated diseases.
T58314 763852-764035 Sentence denotes 4 -CNS-specific, autoreactive CD8+ T cells have a regulatory role in autoimmune demyelination -York Nathan⁎ 1 , Mendoza Jason 1 , Benagh Andrew 1 , Firan Mihail 1 , Karandikar Nitin 1
T80158 764036-764218 Sentence denotes A great deal of our current knowledge about the immune pathogenesis of multiple sclerosis (MS) derives from work in its murine model, experimental autoimmune encephalomyelitis (EAE).
T70607 764219-764423 Sentence denotes The vast majority of studies in MS and EAE have focused on the role of CD4+ T-cells in these diseases, with the underlying assumption that they are CD4+ Th1-mediated and Th2-regulated autoimmune diseases.
T53319 764424-764537 Sentence denotes However, several reports from us and others have implicated an important role for CD8+ T-cells in these diseases.
T83608 764538-764637 Sentence denotes In this study, we specifically dissected the role of autoreactive, CNSspecific CD8+ T-cells in EAE.
T80703 764638-764778 Sentence denotes Similar to our observations in human MS, we saw robust induction of CNS-specific CD8+ T-cell responses in several established models of EAE.
T93954 764779-764910 Sentence denotes However, unlike some recent reports, these CD8+ T cells, when purified, were unable to adoptively transfer disease into naïve mice.
T51763 764911-765051 Sentence denotes Thus, in vitro activated MOG35-55-specific CD4+ T-cells, but not CD8+ T-cells, were capable of adoptively transferring EAE to naïve B6 mice.
T7164 765052-765216 Sentence denotes In contrast, transfer of MOG-stimulated CD8+ T-cells resulted in inhibition of EAE induction, suggesting a regulatory, rather than pathogenic, role for these cells.
T38084 765217-765322 Sentence denotes MOG-loaded target cells were specifically killed in MOG-immunized mice in a CD8+ T-cell-dependent manner.
T37760 765323-765495 Sentence denotes Both CD4+ T cells as well as CD4-depleted APC were appropriate cytolytic targets of MOG-specific CD8+ T cells, suggesting a cytotoxic/ suppressor mechanism for these cells.
T93503 765496-765655 Sentence denotes In conclusion, our studies reveal a novel immune regulatory function for CNS-specific CD8+ T-cells that are reproducibly generated during the induction of EAE.
T21642 765656-765779 Sentence denotes The neuropathology of Parkinson's disease (PD) includes microglial inflammatory responses and T cell modulation of disease.
T19401 765780-765962 Sentence denotes We previously showed that nitration of alpha-synuclein creates novel antigenic epitopes capable of inducing both innate and adaptive immune responses that exacerbate PD pathobiology.
T49753 765963-766114 Sentence denotes We now demonstrate that the pathogenic activities of nitrated alpha-synuclein-mediated immunity are attenuated by CD4+CD25+ regulatory T cells (Tregs).
T47902 766115-766350 Sentence denotes Mice immunized with nitrated alpha-synuclein generate robust T cell proliferative and pro-inflammatory secretory responses, and transfer of these cells to MPTP-intoxicated recipients exacerbates microglial-associated neurodegeneration.
T35292 766351-766564 Sentence denotes We now show that transfer of T cells from mice injected with tolerogenic doses of vasoactive intestinal peptide (VIP) to MPTP-intoxicated recipients attenuates microglial activation and promotes neuronal survival.
T90657 766565-766660 Sentence denotes These T cells also show enhanced regulatory function and anti-inflammatory secretory responses.
T16737 766661-766885 Sentence denotes Surprisingly, we found that pooled splenocytes from synuclein-immunized and VIP-injected donors afforded greater neuroprotection upon adoptive transfer to MPTP-intoxicated recipients than those from VIP-treated donors alone.
T86518 766886-766974 Sentence denotes This was due in part to greater suppressive capabilities of Tregs within the population.
T30101 766975-767306 Sentence denotes Using both proteomic and cell biological assays, we found that Tregs were capable of modulating microglial neurotoxic activities through regulation of phagocytosis and induction of redox-active enzymes and bioenergetic proteins in activated microglia while suppressing reactive oxygen species and nuclear factor kappa B activation.
T12774 767307-767452 Sentence denotes The data demonstrate that the effects of Tregs on nitrated alphasynuclein-mediated immune activities are multifaceted and of therapeutic benefit.
T24676 767453-767659 Sentence denotes 6 -Primary oligodendrocyte death does not cause autoimmunity - The presence of axon growth inhibitors in the adult CNS also appears to play a prominent role in limiting axonal regeneration after CNS injury.
T25969 767660-767752 Sentence denotes Growth inhibitors include both CNS myelin-derived and astrocyte glial-scar derived proteins.
T52335 767753-767890 Sentence denotes The Nogo protein is a significant component of this inhibition, since CNS myelin lacking Nogo possesses reduced axonal growth inhibition.
T90450 767891-768051 Sentence denotes Axonal regeneration and improved recovery is observed in certain strains of genetically engineered mice lacking the Nogo protein after spinal cord injury (SCI).
T45949 768052-768225 Sentence denotes Since the degree of regeneration varies with age and mutation, Nogo appears to collaborate with other factors appear to determine the degree of fiber regeneration after SCI.
T8475 768226-768435 Sentence denotes In mice lacking two other myelin proteins, myelin associated glycoprotein (MAG) and olgodendrocyte myelin glycoprotein (OMgp), as well as Nogo, there is greater recovery after axonal damage in the spinal cord.
T13471 768436-768491 Sentence denotes An axonal receptor for Nogo (NgR1) has been identified.
T55353 768492-768600 Sentence denotes This one receptor also mediates inhibition of axonal outgrowth by two other myelin inhibitors, MAG and OMgp.
T51926 768601-768672 Sentence denotes A short NEP1-40 peptide functions as a NgR antagonist of Nogo function.
T56638 768673-768763 Sentence denotes Administration of this peptide promotes significant axonal regeneration in the rodent SCI.
T81967 768764-768935 Sentence denotes Moreover, this regeneration allows improved walking function and the treatment succeeds even when the compound is administered systemically, up to a week after the injury.
T19245 768936-769090 Sentence denotes To block all NgR function, the extracellular domain of the receptor was delivered to mice with SCI by transgenic means and to rats with SCI intrathecally.
T64569 769091-769185 Sentence denotes The degree of fiber sprouting was moderately greater than with the selective NEP1-40 blockade.
T57587 769186-769332 Sentence denotes Mice lacking NgR1 also show enhanced plasticity of the raphespinal and rubrospinal (but not corticospinal) fiber systems after spinal cord injury.
T84191 769333-769494 Sentence denotes In contrast to poor regeneration of cut corticospinal fibers, the growth of contralateral spared corticospinal fibers is robustly increased in mice lacking NgR1.
T83373 769495-769640 Sentence denotes Further work demonstrates that Nogo/NgR blockade after stroke promotes axonal sprouting and improves functional neurological recovery in rodents.
T54351 769641-769789 Sentence denotes While these myelin inhibitors limit axon regeneration after injury they play a physiological role in limiting brain experience-dependent plasticity.
T42312 769790-770009 Sentence denotes Advances in understanding the molecular determinants of axonal growth within the adult CNS are likely to lead to therapeutic methods to promote neurological recovery after acquired injuries of the brain and spinal cord.
T87317 770010-770116 Sentence denotes Clinical trials of oncolytic viruses (OVs) for cancers have revealed that these agents are well tolerated.
T88640 770117-770174 Sentence denotes However, clear-cut evidence of efficacy has been elusive.
T34224 770175-770306 Sentence denotes A fundamental issue continues to limit the efficacy of cancer virotherapy: the response of the host to the ongoing viral infection.
T15850 770307-770567 Sentence denotes This response occurs at the level of intracellular tumor defenses to the viral infection, extracellular stromal reactions to the propagating virus, and, importantly, active host defenses consisting of innate immune as well as inflammatory angiogenic responses.
T56933 770568-770713 Sentence denotes The combination of these host responses severely limit and curtail tumor cell infection and viral replication, thus limiting anticancer efficacy.
T10561 770714-770889 Sentence denotes We thus believe that such host responses will have to be circumvented, even temporarily and/or partially, in order to fulfill the promising anticancer effects of these agents.
T41137 770890-771082 Sentence denotes Immune privilege and a paucity of dendritic cells (DC) in the brain contribute to immunological ignorance against glioblastoma multiforme (GBM), an aggressive intracranial primary brain tumor.
T33215 771083-771389 Sentence denotes Herein we uncovered that activation of GBM antigenspecific T-cell dependent immune responses were mediated through the release of endogenous high-mobility-group box 1 (HMGB1) from dying tumor cells in response to herpes simplex type 1 thymidine kinase (TK) gene therapy, chemotherapy and radiation therapy.
T86660 771390-771553 Sentence denotes Tumor-derived HMGB1 activated TLR2 signaling on GBM infiltrating, bone marrow derived DCs, which induced a systemic CD8+ T cell dependent anti-GBM immune response.
T93885 771554-771673 Sentence denotes DCs were recruited to the tumors following intratumoral expression of Fms-like Tyrosine Kinase 3 ligand (Flt3L) and TK.
T69229 771674-771772 Sentence denotes Using chimeric mice we demonstrated that tumor infiltrating DCs were derived from the bone marrow.
T52457 771773-771919 Sentence denotes TLR2 signaling was required for the infiltration of DC into the tumor and for the subsequent activation of DCs for efficient antigen presentation.
T14224 771920-772175 Sentence denotes ELISPOT and antigen specific T-cell proliferation assays indicated that clonal expansion of tumor antigen specific T-lymphocytes was induced by treatment of glioma bearing mice with Ad-Flt3L and Ad-TK (+GCV); crucially, this did not occur in TLR2−/− mice.
T49917 772176-772280 Sentence denotes We then identified the endogenous TLR2 ligand responsible for TLR2 activation on tumor infiltrating DCs.
T33444 772281-772414 Sentence denotes HMGB1 was released from tumor cells in vitro, in response to Ad-TK (+GCV) and in the serum of GBM bearing Ad-TK treated mice in vivo.
T44603 772415-772646 Sentence denotes TLR2 signaling induced by media from Ad-TK (+GCV) treated tumor cells; could be blocked with either glycyrrhizin, which binds to both of the box domains on HMGB1 and prevents subsequent HMGB1 signaling, or with antibodies to HMGB1.
T52790 772647-772720 Sentence denotes These data indicate that HMGB1 is an endogenous, GBM derived TLR2 ligand.
T85888 772721-773004 Sentence denotes Administration of either glycyrrhizin or anti-HMGB1 immunoglobulins to tumor bearing, Ad-Flt3L and Ad-TK treated mice, abolished GBM regression and long term survival, highlighting the critical role played by HMGB1-mediated TLR2 signaling to elicit T-cell dependent tumor regression.
T75354 773005-773202 Sentence denotes In summary, our data provide the first experimental evidence for the role of TLR2 signalling, and its endogenous ligand, i.e., HMGB1, in regulating immune surveillance against brain tumor antigens.
T91586 773203-773311 Sentence denotes The discovery of a central role for HMGB1 and TLR2 signalling in overcoming immune ignorance to brain tumor.
T2734 773312-773445 Sentence denotes Epilepsy has an incidence of about 1-3%, affecting an estimated 2.5 million Americans and more than 50 million individuals worldwide.
T14490 773446-773486 Sentence denotes Seizures can occur singly or temporally.
T32172 773487-773595 Sentence denotes Seizure disorders in some adults and children are often associated with infections such as viral infections.
T92187 773596-773719 Sentence denotes Many of these infectiontriggered seizure disorders are often refractory to many currently established anti-epileptic drugs.
T50070 773720-773807 Sentence denotes About 30% of patients with epilepsy are refractory to current anti-seizure medications.
T50472 773808-773985 Sentence denotes The goal is to define and characterize a novel virus infection-induced seizure model in C57BL/6 mice and determine the virus-host interactions that lead to seizure and epilepsy.
T98870 773986-774105 Sentence denotes C57BL/6 mice were infected with the DA virus (DAV) strain of Theiler's murine encephalomyelitis virus or mock infected.
T13455 774106-774309 Sentence denotes Mice were followed for seizures, weight change, body temperature, motor function (righting reflex, rotorod) and neurologic changes including inflammation, perivascular cuffing and pyknotic/dying neurons.
T14227 774310-774421 Sentence denotes In addition, various knockout mice were infected to determine the role for IL-1, TNF-alpha, IL-6 and IFN-gamma.
T16209 774422-774488 Sentence denotes C57BL/6 mice are susceptible to seizures induced by DAV infection.
T84058 774489-774569 Sentence denotes Approximately 50% of C57BL/6 mice develop acute behavior seizures 3-10 days p.i.
T93708 774570-774671 Sentence denotes Following a variable latent period, about half of the seized mice had spontaneous seizures, epilepsy.
T58736 774672-774732 Sentence denotes Motor function and coordination are impaired in seized mice.
T18780 774733-774842 Sentence denotes Pyramidal neuron pyknosis/death and inflammatory changes in the hippocampus correlated with seizure activity.
T17440 774843-775049 Sentence denotes IL-1R1 and MyD88 deficient mice developed seizures in similar numbers to wild-type infected mice but fewer numbers of infected IL-6 and TNF-R1 deficient mice developed seizures than wild-type infected mice.
T2015 775050-775143 Sentence denotes Interestingly more IFN-gammaR deficient mice developed seizures than wild-type infected mice.
T20363 775144-775216 Sentence denotes Cytokine mRNA levels were monitored by array analyses and real-time PCR.
T30178 775217-775305 Sentence denotes Innate immune responses to infection by DAV results in neuronal cell death and seizures.
T64380 775306-775386 Sentence denotes These seizures resolve and then following a latent period mice develop epilepsy.
T93340 775387-775566 Sentence denotes The characterization of this model will enable the investigation of viral and immune contributions in the central nervous system to the development of seizure disorders in humans.
T18596 775567-775590 Sentence denotes Immunological synapses:
T30741 775591-775668 Sentence denotes The cellular and molecular biology of antiviral immune responses in the brain
T89472 775669-775956 Sentence denotes Board of Governors' Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, and Depts. of Medicine, and Molecular and Medical Pharmacology, Brain Research Institute, and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine; UCLA, Los Angeles, CA, United States
T56378 775957-776184 Sentence denotes Immunological synapses (ISs) mediate cell to cell communication in the immune system; in the brain, they mediate communication between anti-viral T cells and infected brain cells, and between antitumor T cells and brain tumors.
T43629 776185-776304 Sentence denotes Adaptive immune responses clear adenovirally infected cells from the brain, or brain tumor cells, with high efficiency.
T86323 776305-776572 Sentence denotes In order to unravel the cell and molecular biology of T cell mediated clearance of virally infected cells from the brain, we have developed a novel approach to elucidate the communication pathways between T cells and infected brain cells, or brain tumor glioma cells.
T11698 776573-776751 Sentence denotes We previously demonstrated that T cell-mediated clearance of virally infected cells in the brain is IFNγ dependent, and does eventually lead to the death of infected brain cells.
T68933 776752-776890 Sentence denotes We have also shown that ISs mediate intercellular communication between T-cells and infected target antigen presenting cells in the brain.
T32894 776891-777031 Sentence denotes We have demonstrated the polarization of IFNγ in CD8 T cells which had established close synaptic contacts with virally infected astrocytes.
T67313 777032-777289 Sentence denotes To determine whether IFNγ only acts exclusively on target cells contacted by T cells, or whether it is secreted non-specifically into the extracellular space within the brain, we developed a novel method to detect vectorial IFNγ release at the level of ISs.
T7182 777290-777578 Sentence denotes Here we describe the construction of novel adenoviral bi-cistronic vectors encoding a constitutively expressed gene (e.g. eGFP; used as a marker to identify infected brain cells), and a second gene under the control of the IFNγ inducible GAS element (e.g. Cre recombinase, or luciferase).
T18085 777579-777675 Sentence denotes These vectors were tested both in vitro and in vivo for IFNγ inducible reporter gene expression.
T42104 777676-778058 Sentence denotes When injected into Rosa26 mice the antiviral T cells induced the expression of β-galactosidase, indicating that they established contacts with infected cells and released IFNγ, which induced expression of Cre, and removal of the STOP codon within the Rosa26 locus that allowed expression of β-galactosidase; the release of IFNγ at immunological synapses is currently being examined.
T65198 778059-778405 Sentence denotes Our method allows us to utilize IFNγ regulated transgene expression as a means to elucidate the existence of targeted vectorial release of T cell cytokines, and to evaluate the function of immunological synapses in orchestrating the function of neuro-immunological circuits during antiviral and anti-tumoral immune responses in the brain in vivo.
T1829 778406-778425 Sentence denotes Support: NINDS/NIH.
T82392 778426-778567 Sentence denotes While viral infections can promote or diminish autoimmunity in type 1 diabetes (T1D), their relationship with this disease is not understood.
T72435 778568-778687 Sentence denotes We found that prevention of autoimmune diabetes by acute viral infection results from regulation of antiviral immunity.
T22044 778688-779048 Sentence denotes Following challenge during the prediabetic phase with lymphocytic choriomeningitis virus (LCMV), Programmed death-ligand 1 (PD-L1) is increased while PD-1-expressing autoreactive CD8 + T cells decline and CD4 + CD25 + regulatory T cells (Tregs) are enhanced in terms of number, TGF-β production and capacity to control T1D even when disease is virally induced.
T76899 779049-779221 Sentence denotes PD-L1 up-regulation delays overt diabetes and facilitates the action of virally enhanced Tregs in a synergistic phenomenon enabled by inflammation and Toll-like receptor 2.
T56944 779222-779371 Sentence denotes These results reconcile current discordance about the role of viruses in T1D and provide novel insight into disease etiology and potential treatment.
T64610 779372-779449 Sentence denotes Innate immune evasion mechanisms of neurovirulent murine coronavirus Susan R.
T45928 779450-779631 Sentence denotes Weiss The neurovirulent murine coronavirus, mouse hepatitis virus (MHV), possesses mechanisms to ensure propagation and persistence despite the existence of host defense strategies.
T61848 779632-779778 Sentence denotes The type I IFN response is an important host defense in vivo as demonstrated by the increased susceptibility to MHV of IFN receptor knockout mice.
T54007 779779-779955 Sentence denotes We have shown that MHV induces IFN-β mRNA synthesis, albeit only at very late times post-infection, but does not induce IFN-β protein synthesis in mouse L2 fibroblast cultures.
T46242 779956-780080 Sentence denotes The only cell type, prior to our studies, reported to produce type I IFN in response to MHV is plasmacytoid dendritic cells.
T13915 780081-780358 Sentence denotes However, we have observed that, while MHV does not induce IFN-β in several types of primary cell cultures derived from the murine central nervous system, it does induce IFN-β in macrophages/microglia in the brain as well as in cultures of bone marrow derived macrophages (BMM).
T55902 780359-780433 Sentence denotes Furthermore MHV induction of IFN-β, at least in BMM, is dependent on MDA5.
T43119 780434-780699 Sentence denotes We and others have reported that MHV is highly resistant to the antiviral effects of IFNs in fibroblast cultures, but that coinfection with MHV, does not provide protection to the IFN-sensitive Sendai virus when IFN is administered prior to MHV-Sendai co-infection.
T6302 780700-780883 Sentence denotes However, pre-treatment of cells with MHV, can provide protection from the anti-viral effect of IFN-β on Sendai, but not on other IFN sensitive viruses including NDV, Sindbis, and VSV.
T41398 780884-781056 Sentence denotes Using a reporter linked to an interferon-stimulated response element (ISRE), we found that MHV infection prevents activation of the ISRE by IFN-α/β and by Sendai infection.
T58115 781057-781254 Sentence denotes Interestingly, MHV does not prevent translocation of STAT1 to the nucleus following IFN-β treatment, suggesting that MHV is able to actively block STAT1 at a later step such as binding to the ISRE.
T83962 781255-781362 Sentence denotes Similarly, MHV prevents type I interferon independent activation by Sendai of an ISRE driven reporter gene.
T54134 781363-781510 Sentence denotes However, it does not inhibit translocation of IRF-3 to the nucleus, suggesting that binding of IRF-3 to the ISRE may be inhibited by MHV infection.
T82655 781511-781693 Sentence denotes Using quantitative real-time PCR, we have shown that MHV-infection can downregulate a number of wellcharacterized ISGs important for recognition of viral dsRNA and antiviral defense.
T85117 781694-781858 Sentence denotes We are currently investigating the significance of these IFN-induced genes in the defense against MHV and the mechanism by which MHV downregulates their expression.
T10860 781859-782053 Sentence denotes Peroxisome proliferator-activated receptors (PPAR) belong to a family of nuclear hormone receptors involved in inflammation, lipid and glucose metabolism, cell proliferation and differentiation.
T16614 782054-782226 Sentence denotes Previous work from our laboratory has examined the efficacy of using a PPARg agonist after spinal cord injury (SCI) and noted modest behavioral and anatomical improvements.
T96774 782227-782481 Sentence denotes In this study, we examined the expression pattern after SCI of PPARd, the most prevalent PPAR isotype in the central nervous system where it is involved in brain lipid metabolism, differentiation of oligodendrocyte progenitor cells (OPC) and myelination.
T55716 782482-782638 Sentence denotes It also appears to play a protective role in certain disease models like experimental autoimmune encephalomyelitis (EAE), Parkinson's and cerebral ischemia.
T93436 782639-782772 Sentence denotes In this study we used a rat spinal contusion model to investigate whether PPARd expression is changed after spinal cord injury (SCI).
T84420 782773-782950 Sentence denotes Contusive SCI was performed at the T8 level on Sprague-Dawley rats and spinal cord tissue was collected at 1-28 day post-injury (dpi); uninjured spinal cords served as controls.
T42383 782951-783077 Sentence denotes Cross-sections spanning the injury site were used to examine the number, distribution and phenotype of cells expressing PPARd.
T72617 783078-783179 Sentence denotes It was observed that after injury, PPARd+ cell numbers gradually increased throughout the first week.
T16640 783180-783288 Sentence denotes By 7 dpi, expression levels were significantly elevated and reached almost twice that of uninjured controls.
T79457 783289-783344 Sentence denotes Cell numbers remained elevated through at least 28 dpi.
T65346 783345-783470 Sentence denotes PPARd was localized primarily in neurons, NG2+ cells (putative oligodendrocyte progenitors), oligodendrocytes and astrocytes.
T62690 783471-783606 Sentence denotes This rise in expression could reflect an endogenous neuroprotective mechanism that may influence cell survival and promote myelination.
T32494 783607-783829 Sentence denotes Future studies will examine whether providing a PPARd agonist after SCI is beneficial and will test the role of endogenous PPARd signaling in CNS repair by performing SCI and demyelination injuries in PPARd knock-out mice.
T90106 783830-783908 Sentence denotes Supported by Christopher and Dana Reeve Foundation, NS043494 and P30-NS045758.
T71916 783909-784180 Sentence denotes Alzheimer Research Laboratory, Case Western Reserve University, Department of Neurosciences, Cleveland, OH, United States Alzheimer's disease (AD) is typified by deposition of Aβ peptides in the brain owing to an imbalance between production and clearance of Aβ peptides.
T37022 784181-784407 Sentence denotes Apolipoprotein E isoforms are associated with age-related risk for Alzheimer's disease and play critical roles in Aβ homeostasis in the brain although the basis of this remains a central unanswered question in AD pathogenesis.
T91188 784408-784576 Sentence denotes Liver X Receptors (LXRs) are ligandactivated transcription factors that regulate basal and inducible expression of the key cholesterol homeostatic genes ABCA1 and ApoE.
T88501 784577-784657 Sentence denotes Importantly, LXRs also act as potent inhibitors of inflammatory gene expression.
T68361 784658-784735 Sentence denotes We report that LXR signaling impacts the development of AD-related pathology.
T93690 784736-784978 Sentence denotes Oral treatment of one year old Tg2576 mice with the LXR agonist GW3965 resulted in a significant reduction in amyloid plaque burden and Abeta peptide levels in the brain that was accompanied by suppression of microglial-mediated inflammation.
T16804 784979-785134 Sentence denotes Genetic loss of either Lxrα or Lxrβ in APP/PS1 transgenic mice results in increased amyloid plaque load and a significantly enhanced inflammatory response.
T5967 785135-785241 Sentence denotes These findings demonstrate that LXRs play critical roles in Abeta clearance and deposition from the brain.
T15009 785242-785350 Sentence denotes Importantly, LXR agonist treatment of Tg2576 mice dramatically attenuated behavioral deficits in these mice.
T55812 785351-785524 Sentence denotes LXR activation enhanced the clearance of Aβ by facilitating the proteolytic degradation of soluble Abeta by neprilysin and IDE through an ABCA1 and ApoE-dependent mechanism.
T10061 785525-785636 Sentence denotes The capacity of ApoE to promote Abeta degradation is dependent upon the ApoE isoform and its lipidation status.
T73875 785637-785846 Sentence denotes These data demonstrate a novel mechanism through which ApoE facilitates the clearance of Abeta peptides from the brain and suggest that LXR agonists may represent a novel therapy for AD through this mechanism.
T92534 785847-785973 Sentence denotes The enhanced expression of lipidated forms of ApoE, through the activation of liver X receptors, stimulates Abeta degradation.
T85524 785974-786109 Sentence denotes Indeed, aged Tg2576 mice treated with the LXR agonist GW3965 exhibited a dramatic reduction in brain Aβ peptide levels and plaque load.
T32723 786110-786196 Sentence denotes LXR agonist treatment also reversed contextual memory deficits observed in these mice.
T42466 786197-786329 Sentence denotes We report that ApoE plays a previously unappreciated role in facilitating the proteolytic clearance of soluble Abeta from the brain.
T85625 786330-786441 Sentence denotes Abnormal or excessive inflammation is thought to contribute to the progression of neurodegenerative conditions.
T49446 786442-786656 Sentence denotes Although this topic has been widely studied in both basic and clinical enterprises, the mechanisms of brain inflammation and indeed the relationship between neurodegeneration and inflammation are poorly understood.
T80421 786657-786803 Sentence denotes Microglia are the principal brain-resident immunocompetent cells, and are relatively potent sources of reactive oxygen and nitrogen intermediates.
T87327 786804-786979 Sentence denotes Thus, experiments were designed to better understand the intricate relationship between intracellular oxidative pathways in microglia and intercellular inflammatory signaling.
T46728 786980-787154 Sentence denotes To this end, the production and/or disposition of oxygen free radicals in microglia were manipulated to determine the resultant effects on oxidative and inflammatory indices.
T30402 787155-787358 Sentence denotes Data show that the production of intracellular oxidants in microglia and macrophages is generally crucial to the subsequent production and release of cytokines and the adoption of a neurotoxic phenotype.
T71886 787359-787672 Sentence denotes However, the development of significant oxidative stress in microglia can also be associated with decreases in the release of inflammatory mediators, and the ability of free radicals to control inflammatory signaling in microglia/macrophages may be based on oxidative alterations to the multicatalytic proteasome.
T51881 787673-788020 Sentence denotes Together, these findings suggest that free radical production in brainresident monocytic cells could be a key mechanism regulating brain inflammation in response to various stimuli, and that interventions aimed at free radical regulation in microglia may provide novel and effective therapeutic avenues to ameliorate neurotoxic brain inflammation.
T64311 788021-788077 Sentence denotes Supported by RO1 NS046267, P20 RR15592, and P01 DA19398.
T94921 788078-788166 Sentence denotes The biological significance of post-traumatic spinal cord inflammation is controversial.
T13131 788167-788299 Sentence denotes Resident microglia and infiltrating leukocytes (e.g., monocytes/T-cells) cause neuronal cell death, axonal injury and demyelination.
T81797 788300-788410 Sentence denotes However, these same cells can promote neuron survival, axon regeneration, remyelination and revascularization.
T24535 788411-788656 Sentence denotes Over the past few years, we have used numerous strategies to manipulate resident and recruited immune cells in an effort to understand their reparative and injurious function in the context of rodent models of traumatic spinal cord injury (SCI).
T22993 788657-788992 Sentence denotes Data will be presented that illustrate the conflicting effects of activated CNS macrophages with an emphasis on newer data that suggest a role for a subset of toll-like receptors (TLRs) in regulating various aspects of CNS repair (e.g., axonal regeneration, remyelination, gliosis) and/or down-regulating destructive neuroinflammation.
T39012 788993-789161 Sentence denotes Myelin-reactive and non-CNS reactive lymphocytes are also recruited to the injured spinal cord where they have been reported to have beneficial and detrimental effects.
T60699 789162-789286 Sentence denotes Data will be presented illustrating the pathogenic potential of B lymphocytes and self-reactive antibodies in models of SCI.
T26673 789287-789374 Sentence denotes The experimental limitations and clinical implications of these data will be discussed.
T37057 789375-789420 Sentence denotes Supported by NIH grants NS37846 and NS047175.
T22743 789421-789483 Sentence denotes Therapeutic strategies against microglia-induced neurotoxicity
T37237 789484-789655 Sentence denotes Department of Neuroimmunology, RIEM, Nagoya University, Nagoya, Japan Accumulation of activated microglia and reactive astrocytes were observed around degenerated neurons.
T51621 789656-789780 Sentence denotes Cytokines from these activated glial cells may be involved in the pathophysiology of neuronal degeneration and regeneration.
T48402 789781-789860 Sentence denotes In this study, we have examined the neurotoxicity by microglia-derived factors.
T94813 789861-789927 Sentence denotes The most neurotoxic factor from activated microglia was glutamate.
T75048 789928-789992 Sentence denotes All the recombinant cytokines examined was not toxic to neurons.
T2 789993-790164 Sentence denotes However, TNF-a exerted neurotoxicity via inducing glutamate in microglia and IFN-g induced minor neurotoxicity that was mediated through IFN-g-R and AMPA receptor complex.
T13757 790165-790346 Sentence denotes Upon stimulation with TNF-a, microglia produced glutamate by glutaminase using extracellular glutamine, and released it through gap-junction, but not through glutamate transporters.
T42244 790347-790452 Sentence denotes Both glutaminase and gap-junction inhibitors suppressed glutamate release and neurotoxicity by microglia.
T91914 790453-790635 Sentence denotes We then examined whether glutaminase inhibitor (6-diazo-5-oxo-L-norleucine: DON) and gapjunction inhibitor (Carbenoxolone: CBX) suppress neuronal damage in vivo, using animal models.
T82582 790636-790830 Sentence denotes Both DON and CBX significantly suppressed delayed neuronal cell death in hippocampus after brain ischemia, and also increased survival of the animal model of amyotrophic lateral sclerosis (ALS).
T7020 790831-790979 Sentence denotes Blockade of the unique mechanisms in glutamate production and release by microglia may be useful therapeutic strategy against neuronal degeneration.