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)

Inflammation of the central nervous system (CNS) in experimental autoimmune encephalomyelitis (EAE) starts in the subarachnoid space (SAS) and spreads later to the adjacent CNS parenchyma. To characterize the nature of lesion-forming T cells in situ in more detail, T cells were isolated from the SAS and their surface phenotype and the nucleotide sequence of the junctional region of the T cell receptor (TCR) was determined and compared with those of the lymph node (LN) and spinal cord (SC) T cells. Characteristically, more than 70% of SAS TCR alpha beta + T cells isolated at the early stage of EAE lacked both CD4 and CD8 molecules, whereas those from LN and SC were either CD4+ or CD8+. Analysis of nucleotide sequences of the junctional region of TCR revealed that T cells bearing a sequence identical to that for encephalitogenic T cell clones were found in both SAS and SC. Furthermore, purified CD4-CD8- T cells expressed CD4 molecules after culture. At the same time, these T cells acquired reactivity to myelin basic protein and induced passive EAE in naive animals after adoptive transfer. Our results suggest that CD4-CD8- T cells in the SAS are precursors of lesion-forming T cells in the SC and that phenotype switching takes place during the process of T cell infiltration into the CNS parenchyma. The double-negative nature of these T cells may explain an escape of encephalitogenic T cells from negative selection in T cell differentiation.
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PMID:Characterization of CD4-CD8- T cell receptor alpha beta + T cells appearing in the subarachnoid space of rats with autoimmune encephalomyelitis. 864 13

The natural tendency in T cell-mediated autoimmune conditions to develop focused antigen-specific responses that over-utilize certain T cell receptor (TCR) V region segments prompts the induction of anti-TCR-specific T cells and antibodies that can inhibit the pathogenic T cells and promote recovery from disease. This natural regulatory network can be manipulated by injecting synthetic peptide vaccines that correspond to segments of the over-expressed V genes. In experimental autoimmune encephalomyelitis (EAE), an animal model for the human disease multiple sclerosis (MS), the pathogenic T cells are directed at myelin components, including basic protein (MBP). In some strains such as the Lewis rat and the PL/J mouse, the encephalitogenic BP-specific T cells overexpress a particular V region gene (V beta 8.2) in the TCR. In vivo administration of V beta 8.2 peptides in rats or mice can prevent and treat EAE by boosting regulatory anti-V beta 8.2-specific T cells that inhibit but do not delete the encephalitogenic specificities. This regulation is mediated by soluble factors, suggesting that the presence of regulatory TCR-specific T cells within the target organ (the central nervous system) may inhibit not only the stimulating V beta 8.2 + T cells, but also bystander T cells bearing different V genes. Parallel studies in MS patients have revealed striking V gene biases among BP-specific T cell clones from some patients that provided a rationale for TCR peptide therapy. Injection of V beta 5.2 and V beta 6.1 peptides boosted the frequency of TCR peptide-specific T cells and reduced responses to BP, in some cases with clinical benefit, indicating the presence of an anti-TCR regulatory network in humans that may also be manipulated with TCR peptide therapy.
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PMID:T cell receptor peptides in treatment of autoimmune disease: rationale and potential. 869 26

There are 2 hypotheses for understanding the pathogenesis of multiple sclerosis (MS), viral and autoimmune ones. Although antibodies to many viruses are elevated, an MS-specific virus has not been found and none of conventional viruses has been definitely located in MS lesions. Thus, viruses, if involved, seem to be indirect. Autoimmune encephalomyelitis (EAE) has represented main aspects of MS such as inflammatory demyelinating plaques, spontaneous onset, remission and relapse. This was proven by transgenic mice that express T cell receptor genes of myelin basic protein (MBP)-specific encephalitogenic T cells (Goverman et al, 1993). The animals developed spontaneous EAE and relapsed when kept in the conventional condition. Otherwise, it was necessary to inject bacterial antigens, when they were kept in an SPF condition. We have shown that MBP89-101 specific encephalitogenic T cell clones are polyreactive (Kozovska et al, submitted). In MS, T cell responses to MBP and proteolipid protein (PLP) have been studied and certain T cell immunodominant regions are suggested. Some of the MHC-class II-restricted and MBP peptide-specific T cell clones responded to several viral antigens (Wucherpfenning and Strominger, 1995). Thus, it is highly probable that autoaggressive T cells are polyreactive and activated by viral and other antigens. I believe that this is the central mechanism operating in MS. Before reaching this conclusion, we must show that the MBP- or PLP-specific polyreactive T cells are indeed encephalitogenic. In order to prove this, we must establish an animal model, humanized mice.
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PMID:[A view for understanding the pathogenesis of multiple sclerosis]. 875 41

The mechanism of CD40 ligand (CD40L)-mediated in vivo activation of CD4(+) T cells was examined by investigation of the development of experimental allergic encephalomyelitis (EAE) in CD40L-deficient mice that carried a transgenic T cell receptor specific for myelin basic protein. These mice failed to develop EAE after priming with antigen, and CD4(+) T cells remained quiescent and produced no interferon-gamma (IFN-gamma). T cells were primed to make IFN-gamma and induce EAE by providing these mice with B7.1(+) antigen-presenting cells (APCs). Thus, CD40L is required to induce costimulatory activity on APCs for in vivo activation of CD4(+) T cells to produce IFN-gamma and to evoke autoimmunity.
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PMID:Requirement for CD40 ligand in costimulation induction, T cell activation, and experimental allergic encephalomyelitis. 879 92

We previously identified a superantigen from the exogenous mouse mammary tumor virus carried by FM mice [MMTV (FM)], which can preferentially activate V beta 8.2+ CD4+ T cells by subcutaneous injection. In the present study we investigated the effect of neonatal infection with the virus on the T cell receptor (TCR) beta-chain variable region (V beta) repertoire, T cell immune response, and development of experimental allergic encephalomyelitis (EAE). The infection, surprisingly, resulted in deletion of a large portion of CD4+ T cells including V beta 2+, 6+, 8.1+, 8.3+, and 14+ CD4+ T cells in addition to V beta 8.2+ CD4+ T cells. Nevertheless, the infection marginally affected T cell immune response to various antigens such as ovalbumin (OVA) and alloantigen except the abrogated response to anti-V beta 8.2 antibody-mediated receptor cross-linking. Moreover, the infection exerted a protective effect on the development of EAE in (PL/J x SJL)F1 mice. Thus, MMTV (FM) superantigen has the ability to delete a large portion of CD4+ T cells with broad TCR V beta specificity, including V beta 8.2+ CD4+ T cells, and may have potential as a therapeutic agent against autoimmune diseases.
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PMID:Deletion of CD4+ T cells by mouse mammary tumor virus (FM) superantigen with broad specificity of T cell receptor beta-chain variable region. 880 76

Monoclonal antibodies (mAbs) directed against the V beta chain of the T cell receptor (TCR) of pathogenic T cells have been used to treat acute murine experimental autoimmune encephalomyelitis (EAE) induced by myelin basic protein (BP). We evaluated anti-V beta mAb for the treatment of relapsing EAE (R-EAE) induced in SJL/J mice by the myelin proteolipid protein (PLP) peptide 139-151. Spinal cord mononuclear cells isolated from mice immunized for R-EAE with PLP 139-151 were shown to express a predominance of V beta 2 and V beta 17 during acute and relapsing disease. T cell lines specific for PLP 139-151 were magnetically sorted to express 80-90% V beta 2. These V beta 2-enriched lines induced typical relapsing demyelinating EAE in naive recipient mice. SJL/J mice with R-EAE induced by a PLP 139-151-specific T cell line expressing 88% V beta 2 were treated with anti-V beta 2 mAb. Anti-V beta 2 mAb markedly reduced clinical and histological disease severity when given at the time of cell transfer or when given at clinical disease onset. In contrast, anti-V beta mAbs showed only a mild clinical effect on R-EAE induced by immunization with PLP 139-151 or R-EAE transferred by a PLP 139-151-specific T cell line expressing multiple V beta s. A cocktail of mAbs directed against V beta 2, V beta 4, and V beta 17 significantly reduced the numbers of spinal cord T cells expressing these V beta s during acute EAE but had little effect on disease course, suggesting that pathogenic T cells expressing other V beta s were producing disease. These findings may have implications for the treatment of multiple sclerosis with V beta-selective therapy.
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PMID:Treatment of relapsing autoimmune encephalomyelitis with T cell receptor V beta-specific antibodies when proteolipid protein is the autoantigen. 884 28

The idiotype (Id) of T cells and possibly antibodies are involved in an Id network that may immunoregulate experimental allergic encephalomyelitis (EAE). Thus, the adoptive EAE in PL/J mice responding to myelin basic protein (MBP) peptide acetyl 1-9 can be modulated by monoclonal antibody (mAb) anti-Id generated by immunization with a peptide of inverted hydropathy to MBP peptide 1-9, designated as PBM 9-1. A cross-reactive Id between species can be recognized on the T cell receptor (TCR) of Vb8.2 restricted T cells in either PL/J mice or Lewis rats. The present study was undertaken to examine the vaccine effect of PBM 9-1 presented in the form of a multiple antigen peptide (MAP) to induce active immunity against active EAE in Lewis rats and active or adoptive EAE in PL/J mice. MAP-PBM 9-1 induced an antibody response in both Lewis rats and PL/J mice, but more in the former. A low level of anti-Id antibody, including a low level of reactivity with specific but not control T cells, was also detected in the sera collected before induction of or after recovery from EAE. Active immunization with MAP-PBM 9-1 had a protective effect on relapses of adoptive EAE in PL/J mice and could prevent active EAE in Lewis rats. A relationship was noted between the titer of serum anti-PBM 9-1 Ab and the protective effect of active immunization in Lewis rats. Although the mechanism of effect remains to be clarified, these results suggest that MAP-PBM 9-1 is a nonencephalitogenic candidate for protection against inflammatory demyelination.
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PMID:Active immunization with complementary peptide PBM 9-1: preliminary evidence that it modulates experimental allergic encephalomyelitis in PL/J mice and Lewis rats. 887 4

Early studies of murine experimental autoimmune encephalomyelitis (EAE) induced with myelin basic protein (MBP) divide various mouse strains into either "susceptible" or "resistant" phenotypes. Resistance is defined as lack of encephalitogenic responses after active immunization or adoptive transfer. It is now becoming clear that this unresponsiveness is not due to the inability of T cells to recognize MBP in the context of major histocompatibility complex (MHC) gene products. Using various manipulations, many laboratories are able to induce severe EAE in these strains. We previously reported that a combination of adoptive transfer and subsequent challenge of the recipients with MBP could overcome the resistance in many mouse strains (Shaw et al.: J Neuroimmunol 39:139-150, 1992). This approach now enables us to identify the encephalitogenic epitope and T cell receptor V beta usage in a prototype strain, C57BL/6 (B6). Pepsin-digested MBP fragments first located a major T cell epitope in a polypeptide containing residues 44-88. Overlapping synthetic peptides narrowed this epitope to p60-80. Truncated peptides from the carboxyl- or amino-terminus further mapped a minimal peptide to p67-76. This encephalitogenic epitope appears to be unique to B6 mice. Independent encephalitogenic T cell clones specific for this epitope were also generated. Of six such clones analyzed, five different TCR V beta's were found. Whether unbiased usage of encephalitogenic TCR V beta gene segments in B6 mice is related to its EAE resistant phenotype is not clear at this point.
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PMID:Induction of myelin basic protein-specific experimental autoimmune encephalomyelitis in C57BL/6 mice: mapping of T cell epitopes and T cell receptor V beta gene segment usage. 889 80

Regulation of experimental autoimmune encephalomyelitis (EAE) can be induced by anti-idiotype immunity against T cell receptor (TCR) fragments associated with major histocompatibility complex (MHC) molecules. However, we have recently found that preimmunization with an alpha-chain TCR CDR3 peptide (LYFCAARSNYQL) derived from myelin basic protein (MBP)-specific clones did not suppress but rather augmented the severity of EAE induced by MBP-specific T cells in SJL/J mice. To test whether CDR3 vaccination could control only a highly restricted T cell population, we studied the effect of the peptide against EAE induced by T cells specific for different Ag/MHC ligands and autoimmune diseases affecting non-neural tissues. In contrast to expectations, the peptide was found to augment not only EAE induced by MBP-specific T cells, but also proteolipid protein (PLP)-specific T cell- or PLP peptide-induced EAE in SJL/J mice, and MBP-induced EAE and adjuvant arthritis (AA) in rats. The CDR3 peptide was neither inhibitory nor supportive for Ag-induced activation of an encephalitogenic clone in vitro. In addition, the peptide treatment neither inhibited the induction of Ag-specific T cells nor altered the APC function of spleen cells. These findings, on the one hand, confirm previous results showing TCR peptide-induced enhancement of the disease and, on the other hand, indicate that the TCR CDR3 peptide may control T cells with broader Ag/MHC specificities than could be expected. Structural similarity among TCR idiotypes of autoimmune T cells may partly account for these results.
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PMID:An alpha-chain TCR CDR3 peptide can enhance EAE induced by myelin basic protein or proteolipid protein. 889 82

LER rats are resistant to the active induction of experimental allergic encephalomyelitis (EAE). The mechanism of their resistance to EAE has yet to be defined, although LER rats are susceptible to adoptively transferred EAE. Genetic analysis of LER and the susceptible LEW rat suggests that a gene linked to the T cell receptor (TCR) beta-chain complex contributes to EAE resistance. This result is consistent with the fact that EAE is a T cell mediated disease and one characterized in EAE-susceptible animals by an oligoclonal TCR V beta 8.2+ response. In this report, analysis of TCR transcripts by reverse transcriptase polymerase chain reaction (RT-PCR) and restriction digestion demonstrates that LER lymph nodes, collected on day 10 post-immunization with myelin basic protein (MBP), express both TCR-V beta 8.2 and other TCR beta chains, usually V beta 8.4, whereas LEW animals demonstrate preferential and almost exclusive use of V beta 8.2 TCR. Fluorescence-activated cell sorting (FACS) analyses of anti-MBP T cells confirm that LER T cells express V beta 8.2 TCR to a lesser degree than LEW T cells. Finally, experiments examining the oligo- or polyclonality of the TCRV beta CDR3 region show that the LER response to MBP is polyclonal, while the LEW response to MBP is oligoclonal. Therefore, the cumulative data on the TCR usage profiles in this report suggest that the choice of TCR variable beta-chain may contribute to the resistance seen in the LER rat.
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PMID:Possible mechanism for the TCR beta-chain associated EAE resistance of LER rats. 889 83


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