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)

Following intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV), susceptible mouse strains develop a chronic demyelinating disease characterized histologically by mononuclear cell-rich infiltrates in the central nervous system (CNS). An immune-mediated basis for this disease is strongly supported by previous studies demonstrating a correlation between clinical disease susceptibility, the presence of particular H-2 region genotypes, and the development of chronically elevated levels of TMEV-specific, MHC class II-restricted delayed-type hypersensitivity (DTH). The present study compared disease susceptibility in (B10.S X SJL)F1 and (B10.S(26R) X SJL)F1 mice which differ only at the D region of the H-2 complex. The data conclusively demonstrates a major influence for homozygosity of H-2s alleles at the H-2D region (the murine equivalent of the human class I HLA-A, B, and C genes) in determining disease susceptibility, as measured by either clinical or histopathological endpoints. In addition, disease susceptibility strongly correlated with the development of high levels of TMEV-specific DTH in the susceptible (B10.S X SJL)F1 strain. However, disease susceptibility did not appear to correlate with TMEV titers in the CNS, TMEV-specific humoral (ELISA and neutralizing) immune responses, or virus-specific splenic T cell proliferative responses. These findings lend additional support to our hypothesis that CNS myelin damage is mediated by a TMEV-specific DTH response. The possible role of class I-restricted responses in the demyelinating process is discussed and murine TMEV-induced demyelinating disease is compared with experimental allergic encephalomyelitis as relevant animal models for human multiple sclerosis.
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PMID:The Theiler's murine encephalomyelitis virus (TMEV) model for multiple sclerosis shows a strong influence of the murine equivalents of HLA-A, B, and C. 358 35

Acute experimental allergic encephalomyelitis (EAE) is an autoimmune disease involving the central nervous system (CNS) that can be elicited in susceptible strains of mice by the subcutaneous inoculation of mouse spinal cord homogenate (MSCH) in conjunction with complete Freund's adjuvant. In order to localize the physiological compartment conveying susceptibility to mice for EAE induction, hematopoietic radiation chimeras were prepared between the highly responsive SJL and low responder B10.S strains. Upon challenge with SJL MSCH preparations, high incidence of clinical disease was exhibited by B10.S----SJL chimeras but not by SJL----B10.S mice, suggesting that non-bone-marrow-derived factors were influencing development of disease. The incidence of histological lesions in the CNS was high for virtually all experimental and control groups except normal B10.S and B10.S----B10.S reconstituted mice. In contrast, challenge with B10.S MSCH induced a high clinical incidence of EAE in both B10.S----SJL and SJL----B10.S chimeras, indicating a possible interstrain difference in the immunogenicity of relevant CNS antigens.
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PMID:Acute experimental allergic encephalomyelitis in radiation bone marrow chimeras between high and low susceptible strains of mice. 378 73

The expression of acute experimental autoimmune encephalomyelitis (EAE) in mice is controlled by several dominant genes, H-2 and histamine sensitization genes. SJL/J and SWR/J, which are H-2s and H-2q, respectively, are susceptible to EAE and sensitive to Bordetella pertussis histamine-sensitizing factor (HSF), which produces a vasoactive amine hypersensitivity. Other H-2s or H-2q strains such as A.SW, B10.Q and several others do not develop acute EAE and are not sensitive to B. pertussis HSF. One strain tested, DDD (KsIsD?) is HSF sensitive but does not develop EAE (presumably because it lacks the appropriate responder H-2 haplotype). However, F1 hybrids between B10.S and DDD are sensitive to HSF and develop EAE. The induction and effector phases of acute EAE are apparently controlled by the combination of H-2 and HSF genes. A combination of the correct H-2 hapotype and histamine sensitivity is required for the development of acute EAE.
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PMID:Acute autoimmune encephalomyelitis in mice. II. Susceptibility is controlled by the combination of H-2 and histamine sensitization genes. 680 29

Recent experiments have shown that during the course of chronic experimental allergic encephalomyelitis, there is a shift in the determinant hierarchy away from the dominant to other subdominant and cryptic self determinants. It was therefore of interest to define the pattern of dominance for mouse myelin basic protein in the three commonly used experimental allergic encephalomyelitis model strains of mice, i.e., B10.PL, SJL/J, and (SJL x B10.PL)F1. Our studies indicate that many cryptic determinants are demonstrable, which only activate T cells on injection as individual peptides and not with the native protein. The core amino acid residues of the various determinants are defined and range in size between 5 and 10 amino acids. Interestingly, there is a bias toward H-2u-restricted response vis-a-vis the H-2s-restricted response in the (SJL x B10.PL)F1 strain. The TCR V beta 8.2 gene segment was not predominantly used for responses to other determinants, although some B10.PL and (SJL x B10.PL)F1 cell lines expressed V beta 8.2 more than others. This study represents the most comprehensive analysis so far of the pattern of dominant and cryptic proliferative T cell determinants and their core sequences for mouse myelin basic protein.
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PMID:T cell determinant structure of myelin basic protein in B10.PL, SJL/J, and their F1S. 751 56

Models of T cell recognition suggest that amino acid residues in the CDR3 region of the T cell receptor (TCR) alpha or beta chain directly contact the major histocompatibility complex-bound peptide, and thus are crucial for providing peptide specificity. T cells derived from B10.PL or PL/J mice of H-2u haplotype, use only D beta 2 and J beta 2 gene segments in the recognition of the dominant determinant, Ac1-9/Au, of myelin basic protein (MBP). New Zealand White (NZW) mice, with identical class II H-2u genes (I-A and I-E), carry an 8.8-kb deletion in their TCR beta chain locus encompassing D beta 2 and J beta 2 gene segments. How does this deletion of the crucial D beta 2-J beta 2 region in NZW mice influence specific responses to Ac1-9/Au as well as to other known Au or Eu determinants of MBP? We found that these mice respond very poorly to the dominant Ac1-9/Au and to the subdominant 31-50/Eu determinant in in vitro proliferation assays as well as in their in vivo capacity to induce experimental autoimmune encephalomyelitis. This loss of response is apparently owing to the absence of high avidity TCRs with essential CDR3 residues contributed by D beta 2 or J beta 2 gene segments. These data reveal constraints in the recognition of certain antigenic structures, and further support a TCR-recognition model in which CDR3 residues of the TCR alpha and beta chains constitute the antigenic peptide-binding sites on the TCR molecule. Implications for autoimmune manifestations contributed by NZW genes in (NZB x NZW)F1 disease are also discussed.
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PMID:Holes in the T cell repertoire to myelin basic protein owing to the absence of the D beta 2-J beta 2 gene cluster: implications for T cell receptor recognition and autoimmunity. 751 12

B10.RIII mice develop chronic and relapsing experimental autoimmune encephalomyelitis (EAE) after immunization with the myelin basic protein (MBP) peptide 89-101 (VHFFKNIVTPRTP). To investigate the basis for the chronicity of the disease, the subsequent development of an immune responses to other parts of the MBP protein were investigated. Onset of disease occurs 9-25 days after immunization with MBP89-101. T cell responses towards a series of MBP peptides were assessed in an enzyme-linked immunospot assay detecting single cells secreting IFN-gamma. There were responses not only to MBP89-101, but also towards peptides derived from sequences outside of MBP89-101. These peptides were of two kinds: those with sequences completely outside the 89-101 stretch of MBP; and those sharing a short sequence with MBP89-101 depending on alternative splicing of MBP mRNA. Immunization with these peptides also produced chronic EAE and a spreading of the immune response to other MBP peptides. Immunization with stepped peptides around the relevant region (MBP87-110) showed that peptides sharing a 6-amino-acid motif induced EAE after immunization. After MBP89-101 peptide immunization, T cells isolated from lymph nodes did not cross-react in vitro to the other peptides sharing this motif. We suggest that one mechanism for the development of relapses during the disease course is the recruitment of new T cells with specificity for MBP peptides not derived from the peptide used for immunization. This is the first time such a mechanism has been demonstrated in a chronic autoimmune disease model.
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PMID:Spreading of the immune response to different myelin basic protein peptides in chronic experimental autoimmune encephalomyelitis in B10.RIII mice. 754 12

B10.RIII mice develop chronic and relapsing experimental autoimmune encephalomyelitis (EAE) after immunization with the myelin basic protein (MBP) peptide 89-101. The disease is associated with the major histocompatibility complex (MHC) (eae1). We have now investigated the importance of non-MHC regions for the EAE susceptibility in a cross between RIIIS/J and B10.RIII mice which share the MHC region but differ in disease susceptibility. Linkage analysis using microsatellite markers spanning the genome identified a region (eae2) on chromosome 15 which showed linkage to disease (P = 0.0002). Our data also suggest linkage to a second region (eae3) on chromosome 3 (P = 0.0024), and provide evidence for locus interactions between eae2 and eae3. These results provide clues to the genetic basis of multiple sclerosis.
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PMID:Identification of murine loci associated with susceptibility to chronic experimental autoimmune encephalomyelitis. 754 92

A high proportion of peptide 1-11 specific T cells from H-2u (V beta 8+, H-2u) mice express the V beta 8 TCR chain. Peptide 89-101 is immunodominant for B10.RIII (V beta 8+, H-2r) mice; thus, it was of interest to determine whether V beta 8 TCR would be over-represented in a population of peptide 89-101-specific T cells of this strain. Second, it was asked whether MBP peptides other than 89-101 would induce EAE in these mice. Of 70 B10.RIII(71NS)/SnJ mice immunized with mouse myelin basic protein (MBP), 32 of 41 males (78%) and 11 of 29 females (38%) showed clinical signs of experimental allergic encephalomyelitis (EAE). All mice immunized with peptide 89-101 showed clinical signs. One of six mice immunized with peptide 91-103 showed clinical signs, and 9 of 16 mice, all males, responded with EAE when immunized with peptide 38-88. No clinical EAE was observed in mice immunized with peptide 43-67, 68-88, 55-74, 1-37 or 1-20. A peptide 89-101-specific T cell line was established. At the initial stimulation the line was 29% V beta 8+ versus 21% in normal controls, and the line did not transfer EAE adoptively. After five in vitro stimulations, the percentage of V beta 8+ T cells had increased to 54%, and the line was encephalitogenic. Encephalitogenicity was partially blocked by anti-V beta 8 monoclonal antibody. Thus, over-representation of V beta 8+ TCR by encephalitogenic peptide-specific T cells is not limited to peptide 1-11-specific T cells from H-2u mice.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Epitope specificity and TCR V beta gene utilization in the encephalitogenic response of B10.RIII(71NS)/SnJ mice. 767 20

Traditionally, statistical analyses of multiple limiting dilution analyses have used linear regression in comparing the fit of each analysis to a single-hit Poisson model. Multiple analyses can, however, result in an inflated type I error leading to spurious rejection of the null hypothesis. Logistic regression was used as an umbrella statistic to analyze eight limiting dilution analyses for antigen-reactive T cells from two mouse strains (SJL/J; B10.S), at two priming doses of antigen, for each of two antigens (porcine myelin basic protein, PMBP; purified protein derivative of M. tuberculosis, PPD) used to induce experimental allergic encephalomyelitis (EAE). This proved superior to traditional methods: six of the eight strain/dose/antigen combinations were consistent with a viable model, whereas only three of eight were consistent with the Poisson single-hit model. Moreover, only three of the resultant 32 standardized residual values (four per group times eight groups) fell outside the 95% confidence interval. Logistic regression, therefore, is recommended when nominal dependent measures can be structured as a function of more than one independent variable.
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PMID:Use of logistic regression in comparing multiple limiting dilution analyses of antigen-reactive T cells. 768 Mar 68

Experimental allergic encephalomyelitis (EAE) is a prototype for CD4+ T cell-mediated autoimmune diseases. Immunization with myelin basic protein (MBP) in B10.PL mice results in EAE, and a majority of animals recover permanently from the disease. Most MBP-reactive encephalitogenic T cells recognize an immunodominant NH2-terminal peptide, Ac1-9, and predominantly use the T cell receptor (TCR) V beta 8.2 gene segment. Here we report that in mice recovering from MBP-induced EAE, peripheral T cells proliferate in response to a single immunodominant TCR peptide from the V beta 8.2 chain (amino acids 76-101), indicating natural priming during the course of the disease. Cloned T cells, specific for this TCR peptide, specifically downregulate proliferative responses to Ac1-9 in vivo and also protect mice from MBP-induced EAE. These regulatory T cells express CD4 molecules and recognize a dominant peptide from the TCR variable framework region of V beta 8.2, in the context of the major histocompatibility complex class II molecule, I-Au, and predominantly use the TCR V beta 14 gene segment. This is the first demonstration of the physiological induction of TCR peptide-specific CD4+ T cells that result from MBP immunization and that are revealed only during the recovery from disease. The downregulation of disease-causing T cells by TCR peptide-specific T cells offers a mechanism for antigen-specific, network-induced recovery from autoimmune disease.
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PMID:The involvement of T cell receptor peptide-specific regulatory CD4+ T cells in recovery from antigen-induced autoimmune disease. 768 92


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