Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0014070 (encephalomyelitis)
13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pathogenic role of nitric oxide (NO) in multiple sclerosis (MS) remains controversial. Some groups have reported a pathogenic role of NO in experimental autoimmune encephalomyelitis (EAE), an animal model of some aspects of MS, whereas we and others have found a disease-suppressive effect of NO in EAE. Because the previously used EAE models have a mainly monophasic inflammatory disease course, distinct from MS, we here studied EAE in the DA rat, which better models the demyelinating and relapsing disease course of human MS. The induction of EAE in DA rats led to 1) severe inflammatory infiltrates mainly in the lumbar spinal cord; 2) an up-regulation of the activity of the cytokine-inducible isoform of NO synthases (NOS-II); and 3) increased tissue protein tyrosine nitration, as indicated by peroxynitrite (ONOO(-)), as a marker of nitrosative stress. Sources of superoxide metabolism, i.e., NADPH oxidase, myeloperoxidase, and superoxide dismutase, remained unchanged. Early treatment of animals with aminoguanidine, a relatively selective inhibitor of NOS-II, lowered nitrotyrosine immunoreactivity but at the same time led to more severe disease and pronounced inflammatory infiltrates in the lumbar spinal cord. Our results suggest a rather protective role of NOS-II induction and nitrosative stress in EAE in DA rats and support the hypothesis of a disease-mitigating immunomodulatory role of NO in this animal model of MS.
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PMID:Protective role of the cytokine-inducible isoform of nitric oxide synthase induction and nitrosative stress in experimental autoimmune encephalomyelitis of the DA rat. 1283 62

We have used T cells bearing TCRs that are closely related in sequence as probes to detect conformational variants of peptide-MHC complexes in murine experimental autoimmune encephalomyelitis in H-2(u) mice. The N-terminal epitope of myelin basic protein (MBP) is immunodominant in this model. Our studies have primarily focused on T cell recognition of a position 4 analog of this peptide (MBP1-9[4Y]) complexed with I-A(u). Using site-directed mutagenesis, we have mapped the functionally important complementarity determining region residues of the 1934.4 TCR Valpha domain. One of the resulting mutants (Tyr(95) to alanine in CDR3alpha, Y95A) has interesting properties: relative to the parent wild-type TCR, this mutant poorly recognizes Ag complexes generated by pulsing professional APCs (PL-8 cells) with MBP1-9[4Y] while retaining recognition of MBP1-9[4Y]-pulsed unconventional APCs or insect cell-expressed complexes of I-A(u) containing tethered MBP1-9[4Y]. Insect cell expression of recombinant I-A(u) with covalently tethered class II-associated invariant chain peptide or other peptides which bind relatively weakly, followed by proteolytic cleavage of the peptide linker and replacement by MBP1-9[4Y] in vitro, results in complexes that resemble peptide-pulsed PL-8 cells. Therefore, the distinct conformers can be produced in recombinant form. T cells that can distinguish these two conformers can also be generated by the immunization of H-2(u) mice, indicating that differential recognition of the conformers is observed for responding T cells in vivo. These studies have relevance to understanding the molecular details of T cell recognition in murine experimental autoimmune encephalomyelitis. They are also of particular importance for the effective use of multimeric peptide-MHC complexes to characterize the properties of Ag-specific T cells.
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PMID:T cell recognition of distinct peptide:I-Au conformers in murine experimental autoimmune encephalomyelitis. 1292 95

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or statins are newly identified immunomodulators. In vivo treatment of SJL/J mice with lovastatin reduced the duration and clinical severity of active and passive experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Lovastatin induced the expression of GATA3 and the phosphorylation of STAT6, whereas it inhibited tyrosine phosphorylation of Janus kinase 2, tyrosine kinase 2, and STAT4. Inhibition of the Janus kinase-STAT4 pathway by lovastatin modulated T0 to Th1 differentiation and reduced cytokine (IFN-gamma and TNF-alpha) production, thus inducing Th2 cytokines (IL-4, IL-5, and IL-10). It inhibited T-bet (T box transcription factor) and NF-kappaB in activated T cells and significantly reduced infiltration of CD4- and MHC class II-positive cells to CNS. Further, it stabilized IL-4 production and GATA-3 expression in differentiated Th2 cells, whereas in differentiated Th1 cells it inhibited the expression of T-bet and reduced the production of IFN-gamma. Moreover, lovastatin-exposed macrophage and BV2 (microglia) in allogeneic MLRs induced the production of the anti-inflammatory cytokine IL-10. These observations indicate that the anti-inflammatory effects of lovastatin are mediated via T cells as well as APCs, because it modulates the polarization patterns of naive T cell activation in an APC-independent system. Together, these findings reveal that lovastatin may have possible therapeutic value involving new targets (in both APCs and T cells) for the treatment of multiple sclerosis and other inflammatory diseases.
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PMID:Potential targets of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor for multiple sclerosis therapy. 1470 6

Myelin oligodendrocyte glycoprotein (MOG) is a major experimental autoimmune encephalomyelitis (EAE) antigen in H-2b mice and a potential autoantigen in multiple sclerosis. How well MOG peptides bind to MHC and how TCR recognize the peptide/MHC complex have important implications for thymic selection as well as T cell activation in the periphery. In this study, we have characterized amino acids in the MOG(38-51) peptide important for peptide binding to I-Ab, and for TCR recognition of the peptide/MHC complex. We found that the amino acids R41, F44, R46 and V47 constituted the major TCR contact residues, as alanine substitution at these positions abrogated T cell responses without decreasing their binding affinity to I-Ab. In addition, G38 and W39 were found to be minor TCR contact residues. Finally, substituting tyrosine for alanine at position 40 decreased binding to I-Ab by approximately 50% and prevented induction of T cell responses in C57BL/6J mice upon immunization. Thus, Y40 is the dominant MHC-binding residue of the MOG(38-51) peptide and most likely occupies the p1 pocket of I-Ab. Our results could be useful to design peptides with altered agretopes and epitopes of the MOG(38-51) peptide to study their therapeutic potential in the EAE model.
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PMID:Characterization of MHC- and TCR-binding residues of the myelin oligodendrocyte glycoprotein 38-51 peptide. 1497 Oct 42

Experimental allergic encephalomyelitis (EAE) is a Th1 cell-mediated inflammatory demyelinating autoimmune disease model of multiple sclerosis (MS). Quercetin (3,3'4',5,7-pentahydroxy flavone) is a flavonoid phytoestrogen that has profound anticancer and anti-inflammatory activities. In this study, we show that in vivo treatment of SJL/J mice with quercetin (i.p. 50 or 100 microg every other day) ameliorates EAE in association with the inhibition of IL-12 production and neural antigen-specific Th1 differentiation. In vitro treatment of activated T cells with quercetin blocks IL-12-induced tyrosine phosphorylation of JAK2, TYK2, STAT3, and STAT4, resulting in a decrease in IL-12-induced T cell proliferation and Th1 differentiation. These findings highlight the fact that quercetin ameliorates EAE by blocking IL-12 signaling and Th1 differentiation and suggest its use in the treatment of MS and other Th1 cell-mediated autoimmune diseases.
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PMID:Quercetin, a flavonoid phytoestrogen, ameliorates experimental allergic encephalomyelitis by blocking IL-12 signaling through JAK-STAT pathway in T lymphocyte. 1535 13

The autoreactive response in murine experimental autoimmune encephalomyelitis (EAE) is dominated by an oligoclonal expansion of V beta 8(+) CD4(+) T cells. These T cells recognize the immunodominant N-terminal nonapeptide of myelin basic protein (MBP1-9) associated with the MHC class II molecule, I-A(u). Amongst the autoreactive cells, T cells bearing TCR containing the CDR3 beta motif Asp-Ala-Gly-Gly-Gly-Tyr (DAGGGY) play a dominant role in the disease process. Here we have investigated the molecular basis for antigen recognition by a representative TCR (172.10) that contains the DAGGGY motif. The roles of the three glycines in this motif in the corresponding TCR-peptide-MHC interactions have been analyzed using a combination of site-directed mutagenesis and surface plasmon resonance. Our data show that mutation of either of the first two glycines (G97, G98) to alanine results in soluble, recombinant TCR that do not bind to recombinant antigen at detectable levels. Mutation of the third glycine (G99) of the 172.10 TCR results in a substantial decrease in affinity. The importance of the triple glycines for antigen recognition provides an explanation at the molecular level for the recruitment of T cells bearing the DAGGGY motif into the responding repertoire during EAE induction.
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PMID:The central residues of a T cell receptor sequence motif are key determinants of autoantigen recognition in murine experimental autoimmune encephalomyelitis. 1559 3

Nitric oxide (NO) has been implicated in the pathophysiology of both experimental autoimmune encephalomyelitis and multiple sclerosis (MS). NO-mediated protein damage in MS appears to be confined to large plaques where 3-nitrotyrosine has been detected. To determine whether nitrosative damage takes place beyond visible MS plaques, the occurrence of various NO-triggered protein modifications in normal-appearing white matter (NAWM) of eight MS brains was assessed and compared to that in white matter (WM) of four control brains. As determined by amino acid analysis and western blotting, no evidence of tyrosine nitration was found in the MS samples studied, suggesting that they did not contain appreciable amounts of plaque-derived material. The amino acid composition of total myelin proteins and proteolipid protein (PLP) was also unaltered in the diseased tissue, as was the fatty acid composition of PLP. In addition, we detected no changes in the number of protein free thiols suggesting that oxidation do not occur to any appreciable extent. However, the levels of nitrite in MS-NAWM were higher than those in control WM, while in the MS-gray matter (GM) the concentration of this ion was unaltered. Furthermore, five of the MS samples analyzed, and the same as those with high levels of glial fibrilary acidic protein, showed increased amounts of protein nitrosothiols as determined by the "biotin switch" method. S-nitrosation of GM proteins was again normal. There was no indication of N-nitrosation of tryptophan and N-terminal amino groups in both control and MS tissue. Overall, the data suggests that WM, but not GM, from MS brains is subjected to considerable nitrosative stress. This is the first report to present direct evidence of increased protein S-nitrosation and nitrite content in the brain parenchyma of MS patients.
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PMID:Evidence of nitrosative damage in the brain white matter of patients with multiple sclerosis. 1575 42

SKAP-HOM is a cytosolic adaptor protein representing a specific substrate for the Src family protein tyrosine kinase Fyn. Previously, several groups have provided experimental evidence that SKAP-HOM (most likely in cooperation with the cytosolic adaptor protein ADAP) is involved in regulating leukocyte adhesion. To further assess the physiological role of SKAP-HOM, we investigated the immune system of SKAP-HOM-deficient mice. Our data show that T-cell responses towards a variety of stimuli are unaffected in the absence of SKAP-HOM. Similarly, B-cell receptor (BCR)-mediated total tyrosine phosphorylation and phosphorylation of Erk, p38, and JNK, as well as immunoreceptor-mediated Ca(2+) responses, are normal in SKAP-HOM(-/-) animals. However, despite apparently normal membrane-proximal signaling events, BCR-mediated proliferation is strongly attenuated in the absence of SKAP-HOM(-/-). In addition, adhesion of activated B cells to fibronectin (a ligand for beta1 integrins) as well as to ICAM-1 (a ligand for beta2 integrins) is strongly reduced. In vivo, the loss of SKAP-HOM results in a less severe clinical course of experimental autoimmune encephalomyelitis following immunization of mice with the encephalitogenic peptide of MOG (myelin oligodendrocyte glycoprotein). This is accompanied by strongly reduced serum levels of MOG-specific antibodies and lower MOG-specific T-cell responses. In summary, our data suggest that SKAP-HOM is required for proper activation of the immune system, likely by regulating the cross-talk between immunoreceptors and integrins.
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PMID:Regulation of in vitro and in vivo immune functions by the cytosolic adaptor protein SKAP-HOM. 1613 97

DAP12 is an immunoreceptor tyrosine-based activation motif-bearing membrane adapter molecule expressed by different cell types. Although several receptors associate with DAP12 in murine dendritic cells (DC), the function of these receptors is as yet unknown. Here we report that splenic mature DC with DAP12 overexpression are characterized by an impaired tolerogenic potential. In contrast, inhibition of DAP12 function results in enhanced tolerogenesis and constitutive expression of immunosuppressive tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO). Increased resistance to experimental encephalomyelitis is observed in DAP12 knockin mice, which is dependent on IDO expression. Therefore, DAP12-related receptors act as negative regulators of IDO-mediated tolerance in vivo.
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PMID:Enhanced tryptophan catabolism in the absence of the molecular adapter DAP12. 1620 34

Experimental allergic encephalomyelitis (EAE) is a Th1 cell-mediated autoimmune disease model of multiple sclerosis (MS). IL-12 plays a crucial role in the pathogenesis of EAE/MS and inhibition of IL-12 production or IL-12 signaling was effective in preventing EAE. Cyclooxygenase (COX-2) is a key enzyme promoting inflammation in rheumatoid arthritis and tumor induced angiogenesis. Recent studies have shown that COX-2 inhibitors prevent EAE, however, their mechanism of action is not fully understood. In this study, we show that in vivo treatment (i.p.) with 100 mug COX-2 selective inhibitors (LM01, LM08, LM11, and NS398), on every other day from day 0 to 30, significantly reduced the incidence and severity of EAE in SJL/J and C57BL/6 mice. Further analyses showed that the COX-2 inhibitors reduced neural antigen-induced IL-12 production, T cell proliferation and Th1 differentiation ex vivo and in vitro. The COX-2 inhibitors also decreased IL-12-induced T cell responses through blocking tyrosine phosphorylation of JAK2, TYK2, STAT3, and STAT4 proteins in T cells. These results demonstrate that COX-2 inhibitors ameliorate EAE in association with the modulation of IL-12 signaling through JAK-STAT pathway leading to Th1 differentiation and suggest their use in the treatment of MS and other Th1 cell-mediated autoimmune diseases.
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PMID:COX-2 inhibitors modulate IL-12 signaling through JAK-STAT pathway leading to Th1 response in experimental allergic encephalomyelitis. 1641 5


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