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)

Experimental allergic encephalomyelitis (EAE) is induced by T cell-mediated immunity to central nervous system antigens. In H-2u mice, EAE is mediated primarily by T cells specific for residues 1-11 of myelin basic protein (MBP). We demonstrate that differential tolerance to MBP1-11 versus epitopes in MBP121-150 is induced by expression of endogenous MBP, reflecting extreme differences in stability of peptide/MHC complexes. The diverse MBP121-150-specific TCR repertoire can be divided into three fine specificity groups. Two groups were identified in wild-type mice despite extensive tolerance, but the third group was not detected. Activated MBP121-150-specific T cells induce EAE in wild-type mice. Thus, encephalitogenic T cells that escape tolerance either recognize short-lived peptide/MHC complexes or express TCRs with unique specificities for stable complexes.
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PMID:Differential tolerance is induced in T cells recognizing distinct epitopes of myelin basic protein. 962 Jun 78

Molecular mimicry has been suggested as a mode of autoreactive T cell stimulation in autoimmune diseases. Myelin basic protein (MBP) peptide 1-11 induces experimental autoimmune encephalomyelitis (EAE) in susceptible strains of mice. Here we show that a herpesvirus Saimiri (HVS) peptide, AAQRRPSRPFA, with a limited homology to MBP1-11 peptide, ASQKRPSQRHG (underlined letters showing homology), can stimulate a panel of MBP-11-specific T cell hybridomas and more importantly cause EAE in mice. We demonstrate that this is due to cross-recognition of these two peptides by TCRs. Results presented in this communication are the first demonstration that a viral peptide with homology at just 5 amino acids with a self peptide can induce clinical signs of EAE in mice. These findings have important implications in understanding the breakdown of T cell tolerance to self Ags in autoimmune diseases by means of cross-reactivity with unrelated peptides.
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PMID:A viral peptide with limited homology to a self peptide can induce clinical signs of experimental autoimmune encephalomyelitis. 964 7

Multiple sclerosis (MS) is a severe central nervous system disease. Experimental autoimmune encephalomyelitis (EAE) mimics MS in mice. We report that spontaneous development of EAE in RAG-1-deficient mice transgenic for a myelin basic protein (MBP)-specific TCR (TgMBP+/RAG-1-/-) requires expression of the T cell costimulatory molecule CD28. Surprisingly, T cells from CD28-/-TgMBP+/RAG-1-/- mice proliferate and produce IL-2 in response to MBP1-17 peptide in vitro, excluding clonal anergy as the mechanism of CD28-regulated pathogenesis. Proliferation of autoaggressive T cells was dependent on the concentration of the MBP peptide, as was the development of MBP-induced EAE in CD28-deficient PL/J mice. These results provide the first genetic evidence that CD28 costimulation is crucial for MBP-specific T cell activation in vivo and the initiation of spontaneous EAE.
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PMID:CD28 costimulation is crucial for the development of spontaneous autoimmune encephalomyelitis. 1020 86

Myelin basic protein (MBP)-specific T cells play a critical role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a prototype for T cell-mediated autoimmunity. In PL/J and B10.PL mice (H-2(u) haplotype), the immunodominant epitope of MBP is represented by an N-terminal nonameric peptide, MBP1-9. To date, the MBP1-9-specific T cell repertoire has not been analyzed in quantitative terms. In the present study we demonstrate, using MHC class II tetramers, that 15,000-70,000 self-antigen-specific T(h) cells accumulate in the draining lymph nodes following immunization with spinal cord homogenate or MBP1-9. In contrast, MBP1-9-specific T cells are undetectable in unimmunized H-2(u) mice and represent >60% of the CD4 cells in naive mice transgenic for a TCR specific for this epitope. The results suggest that the extremely low affinity of the N-terminal peptide for I-A(u) does not limit the MBP1-9-specific T cells from expanding into a sizeable pool of autoreactive T cells. Therefore, the primary immune response to MBP1-9 does not differ quantitatively from previously reported CD4(+) T cell responses to foreign antigens.
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PMID:Detection of autoreactive T cells in H-2u mice using peptide-MHC multimers. 1105 75

In the current study, cellular and molecular approaches have been used to analyze the biophysical nature of T cell receptor (TCR)-peptide MHC (pMHC) interactions for two autoreactive TCRs. These two TCRs recognize the N-terminal epitope of myelin basic protein (MBP1-11) bound to the MHC class II protein, I-A(u), and are associated with murine experimental autoimmune encephalomyelitis. Mice transgenic for the TCRs have been generated and characterized in other laboratories. These analyses indicate that the mice either develop encephalomyelitis spontaneously (172.10 TCR) or only if immunized with autoantigen in adjuvant (1934.4 TCR). Here, we show that the 172.10 TCR binds MBP1-11:I-A(u) with a 4-5-fold higher affinity than the 1934.4 TCR. Consistent with the higher affinity, 172.10 T hybridoma cells are significantly more responsive to autoantigen than 1934.4 cells. The interaction of the 172.10 TCR with cognate ligand is more entropically unfavorable than that of the 1934.4 TCR, indicating that the 172.10 TCR undergoes greater conformational rearrangements upon ligand binding. The studies therefore suggest a correlation between the strength and plasticity of a TCR-pMHC interaction and the frequency of spontaneous disease in the corresponding TCR transgenic mice. The comparative analysis of these two TCRs has implications for understanding autoreactive T cell recognition and activation.
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PMID:Kinetics and thermodynamics of T cell receptor- autoantigen interactions in murine experimental autoimmune encephalomyelitis. 1139 Oct 2

Intravenous administration of autoantigen is an effective method to induce Ag-specific tolerance against experimental autoimmune encephalomyelitis (EAE). IL-12 is a potent Th1 stimulator and an essential cytokine in the induction of EAE. The role of IL-12 in the induction of i.v. tolerance is not clear. In this study, we induced tolerance by i.v. administering myelin basic protein (MBP) peptide Ac1-11 (MBP1-11) in EAE. We observed significant suppression of IL-12 production by the lymph node cells of MBP1-11-injected mice. To see whether the low level of IL-12 is the cause or effect of tolerance, we administered IL-12 to the EAE mice at the time of i.v. MBP1-11 injection. Exogenous IL-12 abrogated the suppression of clinical and pathological EAE by i.v. tolerance. IL-12 blocked the suppressive effect of i.v. tolerance on the proliferative response to MBP1-11 and MBP1-11-induced production of IL-12 and IFN-gamma. Furthermore, IL-12 completely blocked the i.v. tolerance-induced type 1 T regulatory cell response. These data suggest that i.v. administration of autoantigen results in the suppression of endogenous IL-12 and the consequent switching of the immune response from an immunogenic to a tolerogenic form.
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PMID:The role of IL-12 in the induction of intravenous tolerance in experimental autoimmune encephalomyelitis. 1185 44

Experimental autoimmune encephalomyelitis (EAE) is a CD4 Th1-mediated inflammatory demyelinating disorder of the CNS and a well-established animal model for multiple sclerosis. Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) is a cytosolic tyrosine phosphatase that is involved in regulating the T cell activation cascade from signals initiated through the TCR. To study the role of SHP-1 in EAE pathogenesis, we immunized B10.PL mice heterozygous for deletion of the SHP-1 gene (me(v+/-)) and B10.PL wild-type mice with the immunodominant epitope of myelin basic protein (MBP Ac1-11). T cell proliferation and IFN-gamma production were significantly increased in me(v+/-) mice after immunization with MBP Ac1-11. The frequency of MBP Ac1-11-specific CD4 T cells, analyzed by staining with fluorescently labeled tetramers (MBP1-11[4Y]: I-A(u) complexes), was increased in the draining lymph node cells of me(v+/-) mice compared with wild-type mice. In addition, me(v+/-) mice developed a more severe course of EAE with epitope spreading to proteolipid protein peptide 43-64. Finally, expansion of MBP Ac1-11-specific T cells in response to Ag was enhanced in me(v+/-) T cells, particularly at lower Ag concentrations. These data demonstrate that the level of SHP-1 plays an important role in regulating the activation threshold of autoreactive T cells.
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PMID:Expression of the tyrosine phosphatase SRC homology 2 domain-containing protein tyrosine phosphatase 1 determines T cell activation threshold and severity of experimental autoimmune encephalomyelitis. 1197 Sep 96

Murine experimental allergic encephalomyelitis (EAE) is a useful model for the demyelinating, autoimmune disease multiple sclerosis. In the EAE system, the immunodominant N-terminal epitope of myelin basic protein (MBP) is an unusually short, weakly binding peptide antigen which elicits highly biased TCR chain usage. In the 2.2 A crystal structure of I-A(u)/MBP1-11 complex, only MBP residues 1-7 are bound toward one end of the peptide binding cleft. The fourth residue of MBP1-11 is located in an incompatible p6 pocket of I-A(u), thus explaining the short half-life of I-A(u) complexed with Ac1-11. MBP peptides extended at the C terminus of Ac1-11 result in dramatic affinity increases, likely attributed to register shifting to a higher affinity cryptic epitope, which could potentially mask the presentation of the immunodominant MBP1-11 peptide during thymic education.
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PMID:Structural snapshot of aberrant antigen presentation linked to autoimmunity: the immunodominant epitope of MBP complexed with I-Au. 1215 Aug 94

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 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


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