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 expression of a battery of adhesion-related molecules and cytokines was investigated by immunocytochemistry in the central nervous system (CNS) of SJL/J mice sensitized for experimental autoimmune encephalomyelitis (EAE). These molecules consisted of the ligands MECA-325, intercellular adhesion molecule-1, and major histocompatibility complex molecules I and II, plus the receptors lymphocyte function-associated antigen-1, CD8, and CD4. The cytokines comprised interferon-gamma and tumor necrosis factor-alpha. EAE was induced by the adoptive transfer of myelin basic protein-sensitized lymphocytes. MECA-325, a marker for murine high endothelial venules in lymph node tissue, was absent from normal CNS tissue, was expressed at low levels on venules 24 to 48 hours before the onset of clinical signs, rose to maximal levels during acute disease, decreased to preclinical levels during remissions, and rose again during relapses. Intercellular adhesion molecule-1, major histocompatibility antigen-I, and major histocompatibility antigen-II showed similar fluctuations around CNS vessels. The receptors lymphocyte function-associated antigen-1 and CD4 fluctuated in parallel with the above molecules, whereas CD8 remained at a similar low level. Interferon-gamma was present during the acute, remitting, and relapsing phases and was localized to inflammatory cells, whereas tumor necrosis factor occurred at low levels only. Thus, several molecules associated with lymphocyte traffic in lymphoid tissue are selectively expressed in a stage-specific manner within the target organ, the CNS, during EAE. This suggests that the CNS may act as an ancillary organ of the immune system, and that cellular traffic into the CNS during EAE is related to the fluctuating expression of several distinct adhesion-related molecules, frequently co-expressed on the same vessel. The findings may have relevance to the sequence of events in the developing CNS lesion of multiple sclerosis.
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PMID:Adhesion-related molecules in the central nervous system. Upregulation correlates with inflammatory cell influx during relapsing experimental autoimmune encephalomyelitis. 167 55

We have previously found that Lewis rat myelin basic protein (MBP)-reactive lymphocytes (Lc) were cytotoxic in vitro to cultured syngeneic oligodendrocytes (oligos). We report here additional studies to characterize this reaction. The effector lymphocytes in the cytotoxic reaction are also encephalitogenic as evidenced by the capacity of other aliquots of these cells to transfer experimental allergic encephalomyelitis (EAE). We confirmed that the presence of both MBP and antigen-presenting cells (APC) are required for this in vitro cytotoxic effect. This reaction (measured by 51Cr release from labeled oligos) is dose-dependent on the effector/target ratio with marked 51Cr release at a 20/l ratio. Effector/target cell contact is required since: (a) 51Cr release is not significantly increased when effector Lc and oligo are separated by a micropore membrane (28% vs. 24% spontaneous release); (b) no cytotoxic activity is present in the supernatant fluid of a toxic reaction. The adhesion of 51Cr-labeled effector Lc to unlabeled oligo is increased in the presence of both MBP and APC (21 +/- 1.0% of cell adhering) as compared with effector Lc + APC (12 +/- 2.7%), or effector Lc alone (14 +/- 2.8%). Surface expression of class I major histocompatibility complex (MHC) antigens was expressed on the surface of the target oligos during this in vitro cytotoxic reaction. This may explain our previously observed MHC restriction in this reaction. The findings described here may explain some of the in vivo pathogenic events in EAE.
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PMID:Characteristics of in vitro cytotoxic effects of myelin basic protein-reactive T cell lines on syngeneic oligodendrocytes. 168 44

Intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) into susceptible mouse strains produces a chronic demyelinating disease in which mononuclear cell-rich infiltrates in the central nervous system (CNS) are prominent. Current evidence strongly supports an immune-mediated basis for myelin breakdown, with an effector role proposed for TMEV-specific, major histocompatibility complex (MHC) class II-restricted delayed-type hypersensitivity (DTH) responses in which lymphokine-activated macrophages mediate bystander demyelination. The present study examined the possibility that concomitant or later-appearing neuroantigen-specific autoimmune T cell responses, such as those demonstrated in chronic-relapsing experimental allergic encephalomyelitis (R-EAE), may contribute to the demyelinating process following TMEV infection. T cell responses against intact, purified major myelin proteins (myelin basic protein (MBP) and proteolipid protein (PLP], and against altered myelin constituents were readily demonstrable in SJL/J mice with R-EAE, but were not detectable in SJL/J mice with TMEV-induced demyelinating disease. TMEV-infected mice also did not display T cell responses against the peptide fragments of MBP(91-104) and PLP(139-151) recently shown to be encephalitogenic in SJL/J mice. In addition, induction of neuroantigen-specific tolerance to a heterogeneous mixture of CNS antigens, via the i.v. injection of syngeneic SJL/J splenocytes covalently coupled with mouse spinal cord homogenate, resulted in significant suppression of clinical and histologic signs of R-EAE and the accompanying MBP- and PLP-specific DTH responses. In contrast, neuroantigen-specific tolerance failed to alter the development of clinical and histologic signs of TMEV-induced demyelinating disease or the accompanying virus-specific DTH and humoral immune responses. These findings demonstrate that TMEV-induced demyelinating disease can occur in the apparent absence of neuroantigen-specific autoimmune responses. The relationship of the present results to the immunopathology of multiple sclerosis is discussed.
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PMID:Class II-restricted T cell responses in Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease. III. Failure of neuroantigen-specific immune tolerance to affect the clinical course of demyelination. 168 46

Myelin basic protein (MBP) or helper T cells reactive against MBP induce an autoimmune disease, experimental allergic encephalomyelitis, in B10.PL and PL/J inbred mice. In both strains, virtually the entire repertoire of MBP-specific T cells recognize an N-terminal peptide fragment in the context of the I-Au molecule encoded by the major histocompatibility complex (MHC) and utilize a very limited set of T-cell receptor genes. To delineate the nature of the trimolecular complex, consisting of the T-cell receptor, MBP-peptide fragment, and MHC molecule (I-Au), we have synthesized 13 variants of the 9-mer N-terminal immunodominant peptide differing at residue 4 and studied their immune recognition in vitro and in vivo. These substitutions have a striking range of effects on T-cell activation, ability to bind to the MHC molecule, and initiation of immune responses in vivo. An understanding of the autoimmune peptide/MHC/T-cell receptor interactions allowed us to design variant 9-mer peptides that have high affinity for an MHC molecule and are effective in blocking experimental allergic encephalomyelitis, possibly through two distinct mechanisms, peripheral T-cell tolerance and the inhibition of binding of the encephalitogenic peptide to the MHC molecules.
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PMID:Amino acid variations at a single residue in an autoimmune peptide profoundly affect its properties: T-cell activation, major histocompatibility complex binding, and ability to block experimental allergic encephalomyelitis. 900 79

The role of the major histocompatibility complex (MHC) gene products in the genetics of experimental autoimmune encephalomyelitis (EAE) is well established. Here we demonstrate how non-MHC gene products, stimulatory to T cells specific to myelin basic protein (MBP), can affect the MHC control in determining genetic susceptibility or resistance to induction of EAE. I-As-restricted MBP-specific T cells derived from SJL/J mice are shown to cross-react with Mls-2a gene products. The Mls-2a gene product expressed by (SJL/J X BALB/c)F1 mice tolerize T cells recognizing I-As/MBP and favor the development of I-Es/d-restricted MBP-specific T cells mediating EAE in the (SJL/J x BALB/c)F1 mice. These I-Es/d/MBP-specific T cells, cross-reactive with Mls-1a, and the I-As/MBP-specific T cells, cross-reactive with Mls-2a gene products, are both eliminated by self tolerance mechanisms in the H-2-matched (SJL/J X DBA/2)F1 mice, expressing Mls-1a2a gene products, and thereby confer genetic resistance to EAE on the (SJL/J X DBA/2)F1 mice bearing EAE-permissive MHC alleles. These results reflect a developmental selection of a T cell repertoire to the self antigen MBP, imposed by self tolerance to self Mls gene products, which affect the genetic susceptibility to EAE. These studies also demonstrate that self tolerance to Mls gene products can strengthen the tolerance to organ-specific self antigens such as MBP, which may not be expressed or which are absent in the thymus at the time of thymic selection.
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PMID:Minor lymphocyte stimulating (Mls) gene products in mice influence their genetic resistance or susceptibility to induction of autoimmune encephalomyelitis. 168 61

Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated autoimmune disease inducible in rodents by immunization of brain-specific antigens such as myelin basic protein (MBP). It is also well known that various strains of rats differ in their susceptibility to EAE upon active immunization. To elucidate the immune mechanisms of susceptibility and resistance to EAE, we first examined the T cell repertoire for MBP using thymectomized chimeras that possessed thymuses from EAE-susceptible (LEW) or EAE-resistant (BM) strains. It was revealed that T cell specificity of these chimeras was skewed toward that of the grafted thymus. Very interestingly, the chimeras bearing thymuses from the resistant strain developed severe EAE, keeping a hole in the encephalitogenic 68-88 sequence of MBP. These findings suggest that the strain-specific T cell repertoire itself is not involved in the regulation of EAE susceptibility. Furthermore, the analysis of the chimeras reconstituted with F1 T cells and marrow cells from various strains indicates that the major histocompatibility complex (MHC) molecules expressed on accessory cells primarily determine susceptibility or resistance to EAE. We finally showed, using various inbred and congenic rats carrying RT1l or RT1n, that susceptibility to EAE of rats carrying RT1l is heavily influenced by the background genes, whereas resistance to EAE of rats carrying RT1n is primarily regulated by the MHC molecules expressed on accessory cells without influence of the background genes.
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PMID:Analysis of the T cell repertoire for myelin basic protein in thymus-grafted and other types of chimera: evidence that major histocompatibility complex molecules on accessory cells rather than T cell specificity mainly regulate susceptibility to autoimmune encephalomyelitis. 169 40

Autoimmune diseases occur when T lymphocytes become activated on recognizing self antigen linked to the autologous class II molecule of the major histocompatibility complex (MHC). The resulting complex of antigen MHC T-cell receptor could be a target for treatment of autoimmune diseases. Studies in which each component is blocked separately might be limited by interference in non-relevant immune responses that either use the same set of T-cell-receptor V gene segments or are linked to the same MHC. We report here an attack by a specific antibody on the unique antigenic site formed by the binding of two components of the trimolecular complex, the autoantigen bound to the self MHC. We tested its effect in experimental allergic encephalomyelitis, an acute neurological autoimmune disease which is widely regarded as a model for autoimmune disorders and which is mediated by CD4+ T cells recognizing myelin basic protein (BP), or its peptides, in association with self Ia. We made monoclonal antibodies which bound only the complex of BP and I-As. These antibodies blocked the proliferative response in vitro to the encephalitogenic determinant of BP and reduced the response to intact BP, without affecting the response to a nonrelevant antigen-purified protein derivative of tuberculin presented on syngeneic macrophages. They also inhibited experimental allergic encephalomyelitis in H-2s mice. Hence, antibodies directed specifically to the autoantigen-Ia complex, may offer a highly selective and effective treatment in autoimmune diseases.
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PMID:Immunomodulation of experimental allergic encephalomyelitis by antibodies to the antigen-Ia complex. 170 49

T cell lines selected from Lewis rats recovered from experimental autoimmune encephalomyelitis (EAE) respond not only to the immunodominant 72-89 epitope of basic protein (BP), but also to secondary epitopes including the I-A restricted 43-67 region of guinea pig (Gp) BP and the I-E restricted 87-99 sequence of rat (Rt) BP. The current study demonstrates at the clonal level the diversity of T cell responses to Gp- and Rt-BP in EAE-recovered rats. As predicted from the response pattern of BP-selected T cell lines, T cell clones from the lines responded to both the dominant and secondary epitopes of BP. In addition, a new majority clonal type was identified that responded to whole BP but not to epitopes represented on enzymatic cleavage fragments or synthetic peptides spanning the BP molecule. Clones representative of each of the three types of Gp-BP responses were characterized for phenotype, major histocompatibility complex restriction, and biologic activity in vivo. All of the clones were strongly CD4+ and co-expressed CD8 at modest levels as measured by both immunofluorescence and Northern blots. All three T cell specificities were I-A restricted. However, only the 72-89 responsive clone could transfer clinical EAE, due most likely to its unique ability to respond to Rt-BP. In contrast, the Gp-BP 43-67 reactive T cell clone transferred protection against EAE, whereas the whole Gp-BP reactive clone transferred delayed-type hypersensitivity response but was neither encephalitogenic nor protective. Thus, the recovery process from EAE is distinguished by an increased diversity of protective clones as well as innocuous clones that may be spawned as encephalitogenic T cells are regulated.
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PMID:Clonal diversity of basic protein specific T cells in Lewis rats recovered from experimental autoimmune encephalomyelitis. 171 18

Peptide binding and lymph node T cell activation studies have been used to characterize T cell recognition of an encephalitogenic T cell autoantigen from myelin basic protein in mice of the H-2u haplotype. An important role for MHC class II molecules in "determinant selection" is revealed. Amino acids which determine interactions with either the restriction element of the major histocompatibility complex (MHC) or the encephalitogenic T cell receptor are defined. This information enables the design of peptides which bind MHC yet do not crossreact with the autoantigen. Two such peptides compete with the autoantigen for binding to the disease associated class II molecule and inhibit induction of experimental autoimmune encephalomyelitis in H-2u mice. Prospects for peptide mediated therapy are discussed.
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PMID:T cell recognition in experimental autoimmune encephalomyelitis: prospects for immune intervention with synthetic peptides. 171 75

Experimental allergic encephalomyelitis (EAE) is an animal model for the human disease, multiple sclerosis. The LEW rat strain is very susceptible to induction of EAE, whereas the closely related, major histocompatibility complex (MHC)-identical, inbred strain LER is resistant. In this report, the two rat strains have been compared for differences at a number of immunologically relevant loci by restriction fragment length analysis and by nucleotide sequencing. A major difference between the two strains was discovered at the T cell receptor beta chain locus (TcR beta). Both variable (V beta 8) and constant (C beta 1) region elements of TcR beta showed allelic variation between LEW and LER. The known genetic influences in rat models of autoimmunity are currently limited to those encoded by the rat MHC, RT-1. In this study we report our characterization of the allelic differences in TcR beta chains between two rats which differ in their susceptibility to induced EAE, with the goal of understanding the role played by these allelic forms of TcR in the pathogenesis of EAE. The importance of the TcR beta allelic difference in resistance or susceptibility to EAE was assessed in a study of backcross rats scored for both EAE and for the novel LER TcR beta allele. We found that the TcR beta allele from the susceptible strain was present in three out of four susceptible rats, suggesting that it is an important, but not the only, genetic factor in EAE. Supporting this conclusion were the observations that 12 of 13 rats with homozygous LER-derived TCR beta alleles were resistant to EAE.
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PMID:Genetic differences in the T cell receptor alleles of LEW rats and their encephalomyelitis-resistant derivative, LER, and their impact on the inheritance of EAE resistance. 171 10


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