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 DA strain of Theiler's murine encephalomyelitis virus persists in the white matter of the spinal cords of susceptible mice. Previous results showed that the difference in susceptibility to viral persistence between the susceptible SJL/J strain and the resistant B10.S strain was due to multiple non-H-2 loci. The respective roles of hematopoietic and nonhematopoietic cells in this difference have been evaluated with bone marrow chimeras. The results show that non-H-2 loci with a major effect on susceptibility are expressed in hematopoietic cells. However, the study of the SJL.B10-D10Mit180-D10Mit74 congenic line suggests that other loci expressed in nonhematopoietic cells also play a role.
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PMID:Bone marrow chimeras reveal non-H-2 hematopoietic control of susceptibility to Theiler's virus persistent infection. 1199 10

We investigated the role of the immune system in protecting against virus-induced demyelination by generating lines of transgenic B10 (H-2(b)) congenic mice expressing three independent contiguous coding regions of the Theiler's murine encephalomyelitis virus (TMEV) under the control of a class I major histocompatibility complex (MHC) promoter. TMEV infection of normally resistant B10 mice results in virus clearance and development of inflammatory demyelination in the spinal cord. Transgenic expression of the viral capsid genes resulted in inactivation of virus-specific CD8(+) T lymphocytes (class I MHC immune function) directed against the relevant peptides, but it did not affect production of virus capsid-specific antibodies or lymphocyte proliferation to the virus antigen (class II MHC immune functions). Following intracerebral infection with TMEV, all three lines of mice survived the acute encephalitis but transgenic mice expressing VP1 (or the cluster of virus capsid proteins [VP4, VP2, and VP3] mapping to the left of VP1 in the TMEV genome) developed virus persistence and subsequent demyelination in spinal cord white matter. Transgenic mice expressing noncapsid proteins mapping to the right of VP1 (2A, 2B, 2C, 3A, 3B, 3C, and 3D) cleared the virus and did not develop demyelination. These results are consistent with the hypothesis that virus capsid gene products of TMEV stimulate class I-restricted CD8(+) T-cell immune responses, which are important for virus clearance and for protection against myelin destruction. Presented within the context of self-antigens, inactivation of these cells by ubiquitous expression of relevant virus capsid peptides partially inhibited resistance to virus-induced demyelination.
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PMID:Transgenic expression of Theiler's murine encephalomyelitis virus genes in H-2(b) mice inhibits resistance to virus-induced demyelination. 1209 92

The development of clinical symptoms in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) involves T-cell activation and migration into the central nervous system, production of glial-derived inflammatory molecules, and demyelination and axonal damage. Ligands of the peroxisome proliferator-activated receptor (PPAR) exert anti-inflammatory effects on glial cells, reduce proliferation and activation of T cells, and induce myelin gene expression. We demonstrate in two models of EAE that orally administered PPARgamma ligand pioglitazone reduced the incidence and severity of monophasic, chronic disease in C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein peptide and of relapsing disease in B10.Pl mice immunized with myelin basic protein. Pioglitazone also reduced clinical signs when it was provided after disease onset. Clinical symptoms were reduced by two other PPARgamma agonists, suggesting a role for PPARgamma activation in protective effects. The suppression of clinical signs was paralleled by decreased lymphocyte infiltration, lessened demyelination, reduced chemokine and cytokine expression, and increased inhibitor of kappa B (IkB) expression in the brain. Pioglitazone also reduced the antigen-dependent interferon-gamma production from EAE-derived T cells. These results suggest that orally administered PPARgamma agonists could provide therapeutic benefit in demyelinating disease.
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PMID:Peroxisome proliferator-activated receptor-gamma agonists prevent experimental autoimmune encephalomyelitis. 1211 74

Experimental allergic encephalomyelitis (EAE), a Th1 polarized demyelinating disease of the central nervous system (CNS), shares many pathological and clinical similarities with multiple sclerosis (MS), and thus represents an attractive animal model for this disease. The goal of this study was to evaluate the suppressive effects of fluasterone (HE2500), a synthetic androstene derivative, and androstenetriol (HE2200), a natural androstene hormone on EAE. SJL mice were immunized with proteolipid protein (PLP) 139-151 peptide/CFA to induce EAE. Starting on day -7, animals were given daily injections (s.c.) of derivatives (3.0 mg) in vehicle, or vehicle alone for 33 days. Both HE2500 and HE2200 significantly delayed the onset, reduced the peak clinical score and cumulative disease index of EAE, and prevented or significantly attenuated relapses. Lower doses or other routes of administration were less effective. Moreover, T cells from treated mice had significantly reduced PLP 139-151-specific T cell proliferation responses and reduced numbers of TNF-alpha- and IFN-gamma-producing cells in the CNS. Daily treatment of B10.PL mice with HE2500, starting on day 0, completely prevented the development of disease in these animals. Finally, SJL mice treated with HE2500 at EAE onset showed significantly reduced mean clinical scores. Thus, these compounds, which have been reported to have a few androgenic or estrogenic side effects, appear to have a potent inhibitory activity in EAE. These observations suggest that HE2500 and/or HE2200 limit the production of autoimmune Th1 associated cytokines, and ultimately may be beneficial for patients with MS or other autoimmune diseases.
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PMID:A synthetic androstene derivative and a natural androstene metabolite inhibit relapsing-remitting EAE. 1222 95

Adenovirus vectors are increasingly being used for genetic vaccination and may prove highly suitable for intervention in different pathological conditions due to their capacity to generate high level, transient gene expression. In this study, we report the use of a recombinant adenovirus vector to induce regulatory responses for the prevention of autoimmune diseases through transient expression of a TCR beta-chain. Immunization of B10.PL mice with a recombinant adenovirus expressing the TCR Vbeta8.2 chain (Ad5E1 mVbeta8.2), resulted in induction of regulatory type 1 CD4 T cells, directed against the framework region 3 determinant within the B5 peptide (aa 76-101) of the Vbeta8.2 chain. This determinant is readily processed and displayed in an I-A(u) context, on ambient APC. Transient genetic delivery of the TCR Vbeta8.2 chain protected mice from Ag-induced experimental autoimmune encephalomyelitis. However, when the Ad5E1 mVbeta8.2 vector was coadministered with either an IL-4- or IL-10-expressing vector, regulation was disrupted and disease was exacerbated. These results highlight the importance of the Th1-like cytokine requirement necessary for the generation and activity of effective regulatory T cells in this model of experimental autoimmune encephalomyelitis.
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PMID:Protection against experimental autoimmune encephalomyelitis generated by a recombinant adenovirus vector expressing the V beta 8.2 TCR is disrupted by coadministration with vectors expressing either IL-4 or -10. 1251 39

The B10.RIII mouse strain (H-2(r)) develops chronic experimental autoimmune encephalomyelitis (EAE) upon immunization with the myelin basic protein 89-101 peptide. EAE was induced and studied in a backcross between B10.RIII and the EAE-resistant RIIIS/J strain (H-2(r)), and a complete genome scan with microsatellite markers was performed. Five loci were significantly linked to different traits and clinical subtypes of EAE on chromosomes 1, 5, 11, 15, and 16, three of the loci having sex specificity. The quantitative trait locus on chromosome 15 partly overlapped with the Eae2 locus, previously identified in crosses between the B10.RIII and RIIIS/J mouse strains. The loci on chromosomes 11 and 16 overlapped with Eae loci identified in other mouse crosses. By analyzing the backcross animals for lymphocyte phenotypes, the proportion of B and T cells in addition to the levels of CD4(+)CD8(-) and CD4(-)CD8(+) T cells and the CD4(+)/CD8(+) ratio in spleen were linked to different loci on chromosomes 1, 2, 3, 5, 6, 11, and 15. On chromosome 16, we found significant linkage to spleen cell proliferation. Several linkages overlapped with the quantitative trait loci for disease phenotypes. The identification of subphenotypes that are linked to the same loci as disease traits could be most useful in the search for candidate genes and biological pathways involved in the pathological process.
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PMID:Novel quantitative trait loci controlling development of experimental autoimmune encephalomyelitis and proportion of lymphocyte subpopulations. 1251 69

Experimental allergic encephalomyelitis (EAE) is an animal model for multiple sclerosis induced by stimulating myelin basic protein (MBP)-specific T cells. The MBP-specific repertoire in B10.PL mice is shaped by tolerance mechanisms that eliminate MBP121-150-specific T cells. In contrast, MBPAc1-11-specific T cells escape tolerance and constitute the encephalitogenic repertoire. To determine if this differential tolerance is caused by differences in the abundance of MBP epitopes generated by processing, MBP peptides were eluted from I-Au complexes and analyzed by mass spectrometry. Peptides were identified from both the NH2-terminal and MBP121-150 regions. Unexpectedly, MBPAc1-18 and Ac1-17, which contain the MBPAc1-11 epitope, were much more abundant than MBP121-150 peptides. The results demonstrate that competition between two I-Au binding registers, a low affinity register defined by MBPAc1-11 and a high affinity register defined by MBP5-16, prevents most of the NH2-terminal naturally processed peptides from binding in the MBPAc1-11 register. The small fraction of MBPAc1-18 bound in the MBPAc1-11 register is not sufficient to induce tolerance but provides a ligand for MBPAc1-11-specific T cells during disease. These results provide a basis for both the lack of tolerance to MBPAc1-11 and the ability of this epitope to become a target during autoimmunity.
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PMID:Competition between two MHC binding registers in a single peptide processed from myelin basic protein influences tolerance and susceptibility to autoimmunity. 1275 72

Determinations of the effects of iron status on the immune system are complicated by the fact that microorganisms and immune cells both utilize iron. To determine the role of iron in immune function, we utilized a model [experimental autoimmune encephalomyelitis (EAE)] in which a strong antigen-specific CD4+ T-cell response develops in the absence of infection. EAE is an autoimmune disease frequently used as a model for the human disease multiple sclerosis (MS). EAE was induced in B10.PL mice fed low iron (1 mg/kg), normal iron (10 mg/kg) or high iron (160 mg/kg) diets that were replete in all other nutrients. Liver iron measurements verified iron status, i.e., low iron mice had 1.9 micro mol/g tissue, normal iron mice, 3.27 micro mol/g tissue and high iron mice, 5.35 micro mol/g tissue. EAE symptoms were most severe in normal iron mice, and EAE did not develop in low iron mice. The incidence of EAE was 71% in normal iron mice, 62% in iron-overloaded mice and 0% in iron-deficient mice. Two of seven mice in the normal iron group developed severe EAE and were euthanized. None of the iron-overloaded mice developed severe EAE. Other measures of EAE severity were similar in the normal and iron-overloaded mice. The data suggest that iron deficiency provides protection from the development of EAE and that iron excess with its potential contribution to free radical formation was not an important factor. The mechanism of EAE inhibition in iron-deficient mice likely involves the delivery and metabolism of iron for optimal CD4+ T-cell development.
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PMID:Iron-deficient mice fail to develop autoimmune encephalomyelitis. 1288 50

The induction of organ-specific autoimmune diseases, such as experimental allergic encephalomyelitis (EAE) the principal animal model of multiple sclerosis (MS), relies on the use of complete Freund's adjuvant (CFA) emulsions. In this study we report that the physical structure of the particles comprising neuroantigen-CFA emulsions significantly influences the genetic control of the incidence and sexual dimorphism seen in EAE. Immunization of (B10.S/SgMcdJ x SJL/J) F(2) mice segregating the quantitative trait loci (QTL) controlling EAE in susceptible SJL/J and resistant B10.S/SgMcdJ mice with emulsions consisting of particles where the Mycobacterium tuberculosis and neuroantigens are localized on the phase surfaces led to severe EAE in 98.8% of the mice, overriding all sex-specific and non-sex-specific genetic checkpoints. In contrast, F(2) mice immunized with emulsions where the bacterial products and encephalitogens are buried inside the water/oil vesicles exhibited a significant reduction in disease incidence (7.5%) and a sexual dimorphism (5% male versus 10% female). A genome scan identified QTL on chromosomes 7 and 11 controlling the sexual dimorphism as a function of the physical structure of the emulsion. The chromosome 11 QTL co-localizes with eae6b, and with Il12b and heptatitis A virus cellular receptor 2 (Havcr2, formerly known as Timd3), both of which are candidate genes for this QTL. Sequence analysis of the SJL/J and B10.S/SgMcdJ alleles indicates that both gene products are structurally monomorphic. Expression analysis also excluded both as candidates for this sex-specific QTL. These results reinforce the importance of gene-environment interactions in initiating and propagating autoimmune disease of the central nervous system, particularly in the context of susceptibility to MS and disease heterogeneity.
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PMID:Genetic analysis of the influence of neuroantigen-complete Freund's adjuvant emulsion structures on the sexual dimorphism and susceptibility to experimental allergic encephalomyelitis. 1450 69

Self-reactivity is potentially so devastating to the organism that a variety of regulatory devices have evolved to control it. One broadly used strategy is that employing the processed T cell receptor (TCR) as a target for TCR-specific regulatory cells. In several autoimmune models, feedback regulation employing both CD4+ and CD8+ T cells of TCR specificity can be shown to occur and to account for remission from the transient disease state, or for its prevention. We will focus here on the experimental autoimmune encephalomyelitis (EAE) model in the B10.PL (H-2u) mouse. In this model, the acetylated 1-9 N-terminal antigenic determinant from myelin basic protein (MBP) induces a transient paralytic disease owing to the activation of self-directed, high-affinity, CD4+ T cells. Although the response is multiclonal, a particularly aggressive member of this repertoire, bearing a Vbeta8.2,Jbeta2.7 receptor, which we have termed a 'driver clone', appears to be largely responsible for the disease process. A CD4+ T cell directed against a TCR determinant in the framework region of the Vbeta chain, and a CD8+ T cell directed against an upstream, distinct framework determinant, both of which are necessary for regulation, bring about a reversal of the disease process. To accomplish this, there must be a Th1 milieu during the induction of regulation, which is provided in part by the CD4+ regulatory cells themselves. To act as a target, the Vbeta8.2 MBP-reactive T cell must be activated, and the Th1 driver clone(s) is down-regulated via apoptotic killing, leaving a group of Th2, MBP-specific clones of weak affinity, which themselves may help in perpetuating long-term regulation. Similar results are also found in the collagen arthritis and NOD diabetes models.
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PMID:Seven surprises in the TCR-centred regulation of immune responsiveness in an autoimmune system. 1460 18


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