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 dominant immune response to rat myelin basic protein in H-2u mice is directed against the acetylated, N-terminal peptide Ac1-11 (AcASQKR-PSQRHG). This peptide causes encephalomyelitis on injection into mice of the H-2u haplotype. Only two residues of the peptide are required for ligation of the TCR from an Ac1-11-specific T cell hybridoma. Proline at position 6 could not be substituted by any other L-amino acid, whereas glutamine at position 3 could be replaced by phenylalanine, histidine, methionine, or tyrosine. Cross-reactive recognition of these residues appears to be specific, because increasing the affinity of each analogue for its MHC restriction element, by replacing lysine with tyrosine at position 4, did not alter the pattern of cross-reactivity. For the majority of substitutions at this position, a lack of stimulation could not be explained by failure to bind to I-Au. However, competition binding studies showed that introduction of proline at position 3 reduced the efficacy of binding to I-Au. Cross-reactive analogues of Ac1-11 were injected into H-2u mice to test the extent to which cross-reactive T cell activation might lead to autoimmune disease in this model. An analogue containing methionine at position 3 caused clinical experimental autoimmune encephalomyelitis in a small percentage of H-2u mice.
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PMID:Cross-reactive antigen recognition by an encephalitogenic T cell receptor. Implications for T cell biology and autoimmunity. 138 32

Myelin/oligodendrocyte glycoprotein (MOG) is a primary target autoantigen in experimental autoimmune encephalomyelitis, a widely used animal model for autoimmune demyelinating diseases such as multiple sclerosis. We have isolated several rat MOG cDNAs and confirmed their identity by comparison with MOG N-terminal peptide sequence. As expected, MOG mRNA expression is CNS-specific and peaks during active myelination. Our studies show that full length MOG mRNA is approximately 1.6 kb and encodes a signal peptide of 27 amino acids, followed by 218 residues for mature MOG (24,962 MW). A single site for N-glycosylation is found at Asn-31. Rather than the ubiquitous AAUAAA polyadenylation signal, a series of three overlapping, rare poly A signals were identified. The N-terminal half of mature MOG shares 52% identity with bovine butyrophilin, a possible lipid receptor. This same region has 39% identity with chicken B-G antigen, a major histocompatibility complex antigen involved in B cell selection and immune repertoire development. We show that both MOG and butyrophilin, each exhibiting a single Ig-like variable region domain, meet criteria for inclusion in the immunoglobulin superfamily. Moreover, MOG appears to represent a unique member of this superfamily in that it possesses two potential transmembrane domains, in contrast to a single membrane-spanning domain or glycophospholipid anchor found in all other members of Ig superfamily members.
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PMID:Myelin/oligodendrocyte glycoprotein is a unique member of the immunoglobulin superfamily. 145 82

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

Experimental allergic encephalomyelitis (EAE) serves as a model for autoimmune diseases mediated by T lymphocytes. Following sensitization to rat, mouse or guinea pig myelin basic protein (MBP) in complete Freund's adjuvant, inbred mouse strains PL/J (H-2u), SJL/J (H-2s) and (PL/J X SJL/J)F1((PLSJ)F1) develop EAE. Whereas sensitization to the N-terminal 37 amino-acid peptide of rat or guinea pig MBP [MBP(1-37)] induces EAE in PL/J mice, immunization to the C-terminal peptide (89-169) leads to EAE in SJL/J mice. The immune response to MBP in (PLSJ)F1 mice is not co-dominant; sensitization to the N-terminal peptide induces EAE, while sensitization to the C-terminal peptide does not. We have generated MBP-specific T-cell clones restricted to class II (Ia) antigens of the major histocompatibility complex (MHC) from PL/J and (PLSJ)F1 mice following sensitization to rat MBP. Two such I-Au-restricted T-cell clones that proliferate in response to the encephalitogenic N-terminal MBP peptide and recognize a shared determinant with mouse (self) MBP cause paralysis in 100% of (PLSJ)F1 mice tested. Paralysis is induced even when recipients are injected with as few as 1 X 10(5) cloned T cells. Relapsing paralysis followed in two-thirds of the recipients after recovery from acute paralysis, whereas one-third developed chronic persistent paralysis, a form of EAE not usually seen. Histopathology revealed intense perivascular inflammation, demyelination and remyelination within the central nervous system of paralysed mice. The experimental disease induced with these clones shares important features with human demyelinating diseases such as multiple sclerosis. This is the first demonstration that T-cell clones that respond to a defined self-antigen can induce clinical and histological autoimmune disease.
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PMID:T-cell clones specific for myelin basic protein induce chronic relapsing paralysis and demyelination. 241 63

Class II-restricted T cell clones specific for myelin basic protein (MBP) have been generated from PL/J and (PL/J X SJL/J)F1 [((PLSJ)F1] mice following sensitization to rat MBP. Of 17 T cell clones generated from (PLSJ)F1 mice, 5 are I-Au(A alpha uA beta u) restricted, one is restricted to I-As(A alpha sA beta s), 10 are restricted to hybrid I-A(u X s)F1 (A alpha sA beta u) determinants, and one clone is restricted to hybrid I-E(u X s) (E alpha uE beta s) molecules. Thus, of 16 I-A-restricted T cell clones generated from (PLSJ)F1 mice, only one is I-As-restricted, reflecting a lack of priming to MBP in association with I-As. T cell clones restricted to I-Au and to I-E (E alpha u E beta s) molecules recognize mouse (self) MBP. Furthermore, only the five T cell clones restricted to I-Au molecules recognize a determinant in common with mouse (self) MBP within the encephalitogenic N-terminal peptide. Three such I-Au restricted T cell clones, derived independently, cause paralysis in 100% of (PL/J X SJL/J)F1 mice tested. Acute, chronic unremitting, and chronic relapsing paralysis are all induced following injection of these clones. Administration of greater numbers of cloned T cells causes acute and fatal experimental allergic encephalomyelitis, while administration of lower numbers of cloned T cells is associated with chronic unremitting and relapsing paralysis. Paralysis induced with T cell clones shares many clinical, immunologic, and histologic aspects with human demyelinating diseases such as multiple sclerosis. Histopathology reveals perivascular lymphocytic infiltration, demyelination, and remyelination. These studies demonstrate the utility of T cell clones for analyzing the association between class II major histocompatibility complex molecules and disease susceptibility.
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PMID:Encephalitogenic T cell clones specific for myelin basic protein. An unusual bias in antigen recognition. 241 64

PL/J mice developed chronic relapsing experimental allergic encephalomyelitis (EAE) after receiving syngeneic guinea pig basic protein (GPBP)-immune lymph node cells or spleen cells which were cultured in the presence of GPBP or the encephalitogenic N-terminal peptide of GPBP. The presence of L3T4+ cells and in vitro proliferation in response to GPBP are required for the successful transfer. Pathologically, passively transferred EAE in the virus-free PL/J strain was characterized by an infiltration in the central nervous system by small lymphocytes, followed by the appearance of macrophages, and subsequently by primary demyelination. These findings were similar to those previously observed in chronic relapsing EAE in SJL/J mice. However, in some experiments pathologic examination of the spinal cord showed large demyelinating lesions which were necrotic and infiltrated with eosinophilic polymorphonuclear leukocytes. Sera from mice with this pathology contained antibodies to murine hepatitis virus and extensive search identified a few areas of coronavirus replication. The pathology of autoimmune mediated demyelination may be altered in the presence of coronavirus infection but the clinical pattern of EAE expression did not differ between virus-free and coronavirus-infected mice.
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PMID:Adoptively transferred acute and chronic relapsing autoimmune encephalomyelitis in the PL/J mouse and observations on altered pathology by intercurrent virus infection. 282 23

The N-terminal peptide (Ac1-9) of myelin basic protein (MBP) is the immunodominant encephalitogenic epitope in H-2u mice. Previous studies have defined the role of amino acid residue 4 in binding to I-Au. Accordingly, substitutions at this residue have generated peptides spanning a wide range of affinities for the MHC. In the present study, we have tested the tolerogenicity of three of these peptides. Ac1-9, Ac1-9[4A] and Ac1-9[4Y], by administering these to mice i.p. in the absence of adjuvant. Significantly, mice treated with the high affinity analogues Ac1-9[4A] and Ac1-9[4Y] prior to immunization became less susceptible to Ac1-9-induced experimental autoimmune encephalomyelitis (EAE), whereas those given the low affinity peptide Ac1-9 were only moderately protected. T cell priming, as assessed by in vitro proliferative and lymphokine assays, demonstrated a direct correlation between the level of disease inhibition and T cell unresponsiveness. In treatment studies, Ac1-9 and Ac1-9[4Y] were also shown to be effective when given on the first day of disease onset. Priming of T cells, when measured by proliferation in vitro, however, became more resistant to inactivation when soluble peptides were administered close to the day of assay. Kinetic studies revealed that tolerance could be achieved in primed mice but that this takes time to develop.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Affinity for class II MHC determines the extent to which soluble peptides tolerize autoreactive T cells in naive and primed adult mice--implications for autoimmunity. 749 32

The acetylated N-terminal peptide of myelin basic protein (MBP) is the immunodominant T cell epitope in the induction of experimental autoimmune encephalomyelitis in the I-Au- and I-Ak-expressing mouse strains. We used a direct binding assay to examine the kinetics of binding and dissociation of a series of MBP peptide analogues with the affinity-purified class II MHC molecules I-Au and I-Ak. We observe much faster in vitro rates of binding and dissociation than has been reported previously for other immunogenic peptides at neutral pH. The kinetics also reveal inactivation of the peptide-free class II MHC molecules. These results are consistent with previously proposed mechanisms for tolerance escape and autoimmune disease.
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PMID:Myelin basic protein peptide complexes with the class II MHC molecules I-Au and I-Ak form and dissociate rapidly at neutral pH. 753 2

This study explores antigen administration via mucosal surfaces as a potential means of inducing antigen-specific non-responsiveness in experimental autoimmune encephalomyelitis (EAE). In the H-2u mouse model of EAE, the acetylated N-terminal peptide of myelin basic protein represents a dominant T cell epitope which on its own is sufficient to induce disease. Oral administration of the encephalitogenic peptide over a wide range of doses failed to induce oral tolerance to EAE. In marked contrast, a single intranasal dose of this peptide (Ac1-9 or Ac1-11) profoundly inhibited EAE when administered prior to disease induction. We investigated this phenomenon further by using two analogues of Ac1-11 with alanine or tyrosine at position 4 which display higher affinity binding to the I-Au molecule than the original peptide with lysine at this position. There was a positive correlation between the degree of protection from EAE and the affinity of individual peptides for class II MHC. Peptide inhalation inhibited not only EAE induced by subcutaneous injection of the encephalitogenic peptide but also disease induced by a complex mixture of potential auto-antigens such as spinal cord homogenate. Thus, in contrast to oral tolerance, nonresponsiveness by peptide inhalation is inducible with the encephalitogenic peptide in the absence of additional regulatory epitopes. The finding that a single epitope may protect against EAE induced with whole spinal cord homogenate implies, however, that regulatory mechanisms affecting additional potential self-epitopes may play a significant role.
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PMID:Inhibition of experimental autoimmune encephalomyelitis by inhalation but not oral administration of the encephalitogenic peptide: influence of MHC binding affinity. 769 44

Orally administered antigens induce a state of immunologic hyporesponsiveness termed oral tolerance. Different mechanisms are involved in mediating oral tolerance depending on the dose fed. Low doses of antigen generate cytokine-secreting regulatory cells, whereas high doses induce anergy or deletion. We used mice transgenic for a T-cell receptor (TCR) derived from an encephalitogenic T-cell clone specific for the acetylated N-terminal peptide of myelin basic protein (MBP) Ac-1-11 plus I-Au to test whether a regulatory T cell could be generated from the same precursor cell as that of an encephalitogenic Th1 cell and whether the induction was dose dependent. The MBP TCR transgenic mice primarily have T cells of a precursor phenotype that produce interleukin 2 (IL-2) with little interferon gamma (IFN-gamma), IL-4, or transforming growth factor beta (TGF-beta). We fed transgenic animals a low-dose (1 mg x 5) or high-dose (25 mg x 1) regimen of mouse MBP and without further immunization spleen cells were tested for cytokine production. Low-dose feeding induced prominent secretion of IL-4, IL-10, and TGF-beta, whereas minimal secretion of these cytokines was observed with high-dose feeding. Little or no change was seen in proliferation or IL-2/IFN-gamma secretion in fed animals irrespective of the dose. To demonstrate in vivo functional activity of the cytokine-secreting cells generated by oral antigen, spleen cells from low-dose-fed animals were adoptively transferred into naive (PLJ x SJL)F1 mice that were then immunized for the development of experimental autoimmune encephalomyelitis (EAE). Marked suppression of EAE was observed when T cells were transferred from MBP-fed transgenic animals but not from animals that were not fed. In contrast to oral tolerization, s.c. immunization of transgenic animals with MBP in complete Freund's adjuvant induced IFN-gamma-secreting Th1 cells in vitro and experimental encephalomyelitis in vivo. Despite the large number of cells reactive to MBP in the transgenic animals, EAE was also suppressed by low-dose feeding of MBP prior to immunization. These results demonstrate that MBP-specific T cells can differentiate in vivo into encephalitogenic or regulatory T cells depending upon the context by which they are exposed to antigen.
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PMID:Oral tolerance in myelin basic protein T-cell receptor transgenic mice: suppression of autoimmune encephalomyelitis and dose-dependent induction of regulatory cells. 855 44


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