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)

Theiler's murine encephalomyelitis virus is a picornavirus which induces chronic immune-mediated central nervous system demyelination and virus persistence in susceptible strains of mice. Using murine strains with congeneic recombinant haplotypes, the H-2D region within the class I major histocompatibility complex has been shown to be important in determining susceptibility/resistance to chronic Theiler's murine encephalomyelitis virus infection. We examined the role of H-2D in demyelinating disease with the use of transgenic D8 mice (H-2Dd, resistant haplotype) crossed to susceptible B10.Q (H-2q) and B10.S (H-2s) mice. Expression of the H-2Dd transgene dramatically suppressed demyelination and reduced the number of virus-antigen positive cells in the spinal cord 45 days following infection. More complete protection was observed in transgenic B10.Q (D8+) mice than in transgenic B10.S (D8+) mice. These experiments support the hypothesis that the immunologic basis of resistance by H-2D is determined by effective antigen presentation which prevents virus persistence and subsequent demyelination.
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PMID:H-2 Dd transgene suppresses Theiler's virus-induced demyelination in susceptible strains of mice. 922 47

Experimental autoimmune encephalomyelitis (EAE) serves as a rodent model of the autoimmune disease multiple sclerosis. In mice, EAE is induced by immunizing with spinal cord homogenate, components of the myelin sheath, such as myelin basic protein (MBP) or proteolipid protein (PLP), or peptides derived from these components. EAE can be induced in H-2u or (H-2u x H-2s)F1 mice with the N-terminal peptide of MBP, Ac1-11. Coimmunization with Ac1-11 and Ac1-11[4A], an analog in which lysine at position four is substituted with alanine, prevents EAE. The mechanism of inhibition has not been elucidated, but probably does not work through MHC blockade, T cell anergy or clonal elimination of encephalitogenic T cells. We have isolated T cell clones and hybridomas from (PL/J x SJL/J)F1 mice immunized with either Ac1-11 alone or Ac1-11 and Ac1-11[4A] and analysed these cells for differences in their T cell receptor repertoire and in vitro response. Although T cells elicited by coinjection of Ac1-11 and Ac1-11[4A] expressed TCR that used V alpha and Vbeta gene elements similar to those elicited by Ac1-11 alone, they differed in the sequences of the junctional region of the alpha chain. Most of these T cells also responded less well to Ac1-11 in vitro, suggesting that coinjection of Ac1-11 and Ac1-11[4A] preferentially activates T cells bearing TCR of different affinity for Ac1-11 bound to I-A(u), and which may therefore be less encephalitogenic. Furthermore, our results show that a more diverse repertoire of V alpha and Vbeta genes are elicited by Ac1-11 in (PL/J x SJL/J)F1 mice compared to PL/J and B10.PL mice, providing further evidence that a restricted TCR repertoire is not required for the development of autoimmune disease.
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PMID:Induction of a heterogeneous TCR repertoire in (PL/JXSJL/J)F1 mice by myelin basic protein peptide Ac1-11 and its analog Ac1-11[4A]. 944 77

Vaccination of mice with activated autoantigen-reactive CD4(+) T cells (T cell vaccination, TCV) has been shown to induce protection from the subsequent induction of a variety of experimental autoimmune diseases, including experimental allergic encephalomyelitis (EAE). Although the mechanisms involved in TCV-mediated protection are not completely known, there is some evidence that TCV induces CD8(+) regulatory T cells that are specific for pathogenic CD4(+) T cells. Previously, we demonstrated that, after superantigen administration in vivo, CD8(+) T cells emerge that preferentially lyse and regulate activated autologous CD4(+) T cells in a T cell receptor (TCR) Vbeta-specific manner. This TCR Vbeta-specific regulation is not observed in beta2-microglobulin-deficient mice and is inhibited, in vitro, by antibody to Qa-1. We now show that similar Vbeta8-specific Qa-1-restricted CD8(+) T cells are also induced by TCV with activated CD4(+) Vbeta8(+) T cells. These CD8(+) T cells specifically lyse murine or human transfectants coexpressing Qa-1 and murine TCR Vbeta8. Further, CD8(+) T cell hybridoma clones generated from B10.PL mice vaccinated with a myelin basic protein-specific CD4(+)Vbeta8(+) T cell clone specifically recognize other CD4(+) T cells and T cell tumors that express Vbeta8 and the syngeneic Qa-1(a) but not the allogeneic Qa-1(b) molecule. Thus, Vbeta-specific Qa-1-restricted CD8(+) T cells are induced by activated CD4(+) T cells. We suggest that these CD8(+) T cells may function to specifically regulate activated CD4(+) T cells during immune responses.
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PMID:T cell vaccination induces T cell receptor Vbeta-specific Qa-1-restricted regulatory CD8(+) T cells. 953 72

The role of various MHC genes in determining the progression of multiple sclerosis (MS) remains controversial. The HLA-DR3 gene has been associated with benign relapsing MS in some genetic epidemiologic studies, but with disease progression in others. We induced demyelination in highly susceptible B10.M and B10.Q mice expressing the DR3 (HLA-DRB1*0301) transgene to determine directly the effects of a human transgene by infecting them with Theiler's murine encephalomyelitis virus (TMEV). DR3+ mice experienced a dramatic reduction in the extent and severity of demyelination compared with DR3- littermate controls, whereas anti-TMEV antibody titers, delayed-type hypersensitivity responses, and levels of infectious virus, virus antigen, and virus RNA were similar in both groups. To address a possible mechanism of how the human transgene is reducing virus-induced demyelination, we analyzed cytokine expression in the lesions and also determined whether B10.M mice can respond to peptides derived from the DR3 molecule. Intense staining for IFN-gamma and IL-4, T helper (TH) 1 and TH2 cytokines, respectively, was found in the lesions of TMEV-infected DR3- mice but not in the DR3+ transgenic mice at day 21 after infection. DR3 peptides elicited strong proliferative responses in B10.M mice but not in B10.M (DR3+) mice. These experiments are the first to demonstrate that a human class II DR gene can alter the severity of demyelination in an animal model of MS without influencing viral load. These experiments are consistent with a mechanism by which DR3 reduces demyelination by altering the cytokine expression in the lesions, possibly by deleting T cells involved in virus-induced pathology.
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PMID:Expression of the human histocompatibility leukocyte antigen DR3 transgene reduces the severity of demyelination in a murine model of multiple sclerosis. 954 8

Theiler's murine encephalomyelitis virus causes a chronic demyelinating disease in susceptible strains of mice that is similar to human multiple sclerosis. Several nonmajor histocompatibility complex-linked genes have been implicated as determinants of susceptibility or resistance to either demyelination or virus persistence. In this study, we used linkage analysis of major histocompatibility complex identical H-2d (DBA/2J x B10.D2) F2 intercross mice to identify loci associated with susceptibility to virus-induced demyelinating disease. In a 20-cM region on chromosome 14, we identified four markers, D14Mit54, D14Mit60, D14Mit61, and D14Mit90 that are significantly associated with demyelination. Because two peaks were identified, one near D14Mit54 and one near D14Mit90, it is possible that two loci in this region are involved in controlling demyelination.
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PMID:Chromosome 14 contains determinants that regulate susceptibility to Theiler's virus-induced demyelination in the mouse. 956 Apr 7

Experimental autoimmune encephalomyelitis (EAE), a model for human multiple sclerosis, is an inflammatory disease of the CNS mediated by autoreactive T lymphocytes directed against the neuroantigen, myelin basic protein (MBP). EAE is inducible in the Lewis rat, which exhibits an acute monophasic disease, and in selected mouse strains, which show a remitting-relapsing or chronic course of paralysis. We examined the effects of neuroendocrine modulation by restraint stress on these models of EAE. In Lewis rats, daily cycles of restraint resulted in significant suppression of both clinical and histopathologic changes of EAE. Suppression of EAE was more pronounced in the female than in the male rat, which follows from the higher endogenous corticosterone levels in the female. Mechanistic studies suggested that stress affected the processing of MBP or the T-cell idiotype. In the relapsing murine model of EAE, B10.PL mice were restrained beginning either before MBP challenge or after the establishment of relapsing disease. We observed a striking inhibition of EAE clinical signs in mice stressed before challenge relative to nonstressed controls. Interestingly, approximately 10 days after termination of the stress period, clinical signs returned and were as severe or more severe than in control nonstressed animals. Stress administered after relapsing EAE was established had no protective effect. In vitro parameters revealed that only stress initiated before disease induction significantly reduced the frequency of MBP-specific lymphocytes in the spleen and lymph nodes. Both Th1 and Th2 cytokine responses were suppressed in stressed mice. T-cell receptor transgenic mice exposed to restraint showed a marked decreased in the number and functional activity of transgene-positive lymphocytes. In summary, elevated levels of endogenous neuroendocrine hormones exert a profoundly suppressive effect on both acute and chronic models of autoimmune CNS injury.
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PMID:Neuroendocrine influences on experimental autoimmune encephalomyelitis. 962 97

Experimental allergic encephalomyelitis (EAE), the principal animal model of multiple sclerosis, is a genetically determined phenotype. In this study, analyses of the cumulative disease frequencies in parental, F1 hybrid, and F2 mice, derived from the EAE-susceptible SJL/J strain and the EAE-resistant B10.S/DvTe strain, confirmed that susceptibility to EAE is not inherited as a simple Mendelian trait. Whole genome scanning, using 150 informative microsatellite markers and a panel of 291 affected and 390 unaffected F2 progeny, revealed significant linkage of EAE susceptibility to marker loci on chromosomes 7 (eae4) and 17, distal to H2 (eae5). Quantitative trait loci for EAE severity, duration, and onset were identified on chromosomes 11 (eae6, and eae7), 2 (eae8), 9 (eae9), and 3 (eae10). While each locus reported in this study is important in susceptibility or disease course, interactions between marker loci were not statistically significant in models of genetic control. One locus, eae7, colocalizes to the same region of chromosome II as Orch3 and Idd4, susceptibility loci in autoimmune orchitis and insulin-dependent diabetes mellitus, respectively. Importantly, eae5 and eae7 are syntenic with human chromosomes 6p21 and 17q22, respectively, two regions of potential significance recently identified in human multiple sclerosis genome scans.
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PMID:New genetic loci that control susceptibility and symptoms of experimental allergic encephalomyelitis in inbred mice. 971 54

The genetic susceptibility to collagen-induced arthritis (CIA) in mice, the most commonly used model for rheumatoid arthritis, has been analyzed. The highly susceptible B10.RIII strain was crossed with the resistant RIIIS/J strain and the F2 intercross mice were subjected to genomic screening using microsatellite markers. These strains share the MHC region on chromosome 17, known to be of importance in CIA (this locus is named Mcia1). The same cross has earlier been used to map the major genes outside the MHC controlling chronic relapsing experimental allergic encephalomyelitis (EAE). It was found that the major locus controlling CIA (Mcia2; lod 4.12) was located on chromosome 3 in the same region as one of the major loci controlling EAE (Eae3). The linkage was reproduced in a mouse strain in which the locus was isolated on the B10.RIII background at the N4I2 generation. A second putative locus was identified on chromosome 13 (lod 3.13). The present finding identifies new loci outside the MHC controlling CIA and provides evidence that mouse CIA is controlled by polymorphic genes.
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PMID:Genetic linkage analysis of collagen-induced arthritis in the mouse. 980 1

Experimental allergic encephalomyelitis is an animal model of a T cell-mediated autoimmune disease -- for example, multiple sclerosis. We demonstrated that mice with experimental allergic encephalomyelitis developed retrocochlear hearing loss, and that the lesion of the auditory pathway might be related to T cell receptor Vbeta8-expressing T cells. To investigate whether anti-Vbeta8 antibody could prevent hearing loss, we carried out brain stem auditory evoked potential testing, histologic examinations, and flow cytometry in antibody-treated and control myelin basic protein-immunized B10.PL mice. The antibody was administered just before immunization of myelin basic protein. The disease incidence and severity were significantly reduced in the mice injected with the antibody. The results of brain stem auditory evoked potential testing, histologic examinations, and flow cytometry indicated that the depletion of Vbeta8-expressing T cells brings the prevention of hearing loss, as well as prevention of other neurologic deficits. The development of T cell receptor-specific antibody therapy might help treat retrocochlear hearing loss in multiple sclerosis.
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PMID:Successful prevention of retrocochlear hearing loss in murine experimental allergic encephalomyelitis with T cell receptor Vbeta8-specific antibody. 982 40

Autoimmune diseases can result from the breakdown of regulation and subsequent activation of self-antigenic determinant-reactive T cells. During the evolution of the autoimmune response to myelin basic protein (MBP) in B10.PL mice, several distinct T cell populations expand: the effectors mediating experimental autoimmune encephalomyelitis (EAE) are MBP-reactive, CD4+, and predominantly TCR Vbeta8.2+; in addition, at least two regulatory populations can be detected--one comprised of Vbeta14+ CD4 T cells, reactive to a framework region 3 determinant on the Vbeta8.2 chain, and a second that is CD8+ and reactive to another Vbeta8.2 determinant. The combined action of these two regulatory cell types controls disease-causing effectors, resulting in spontaneous recovery from disease. In this report, we reveal that the cytokine secretion pattern of TCR peptide-specific regulatory CD4 T cells can profoundly influence whether a type 1 or type 2 population predominates among MBP-specific CD4 effectors. The priming of type 1 regulatory T cells results in deviation of the Ag-specific effector T cell population in a type 2 direction and protection from disease. In contrast, induction of type 2 regulatory T cells results in exacerbation of EAE, poor recovery, and an increased frequency of type 1 effectors. Thus, the encephalitogenic potential of the MBP-reactive effector population is crucially and dominantly influenced by the cytokine secretion phenotype of regulatory CD4 T cells. These findings have important implications in understanding peripheral tolerance to self-Ags as well as in the design of TCR-based therapeutic approaches.
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PMID:Induction or protection from experimental autoimmune encephalomyelitis depends on the cytokine secretion profile of TCR peptide-specific regulatory CD4 T cells. 986 85


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