UMLS:C0014070 - FACTA Search

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Query: UMLS:C0014070 (encephalomyelitis)
13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the human disease multiple sclerosis (MS), the immune mechanisms responsible for selective destruction of central nervous system myelin are unknown. In the common marmoset Callithrix jacchus, a unique demyelinating form of experimental allergic encephalomyelitis resembling MS can be induced by immunization with whole myelin. Here we show that the MS-like lesion can be reproduced by immunization against the extracellular domain of a single myelin protein, myelin/oligodendrocyte glycoprotein (MOG). By contrast, immunization against the quantitatively major myelin proteins myelin basic protein or proteolipid protein results in inflammation but little or no demyelination. Furthermore, in the presence of encephalitogenic (e.g., disease-inducing) T cells, the fully demyelinated lesion is reconstructed by systemic administration of IgG purified from whole myelin-, or MOG-immunized animals, and equally by a monoclonal antibody against MOG, but not by control IgG. Encephalitogenic T cells may contribute to the MS-like lesion through disruption of the blood-brain barrier that permits access of demyelinating antibody into the nervous system. The identification of MOG as a major target antigen for autoimmune demyelination in a nonhuman primate should facilitate development of specific immunotherapies for human MS.
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PMID:Antibody facilitation of multiple sclerosis-like lesions in a nonhuman primate. 867 68

Myelin/oligodendrocyte glycoprotein (MOG) is a minor myelin protein that belongs to the immunoglobulin gene superfamily and evokes demyelination based on immunological response. Localized preferentially at the external surfaces of myelin sheaths, it is one of the primarily target autoantigens in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Elevated MOG content has been found in the myelin fraction of the rabbits affected by the mild form of paralytic tremor (pt) disease, evoked by natural, point mutation in exon 2 of plp gene. A single T-->A transversion results in substitution of histidine36 by glutamine in PLP and it's splicing variant DM-20 molecules. The affected animals, although strictly controlled for pt trait, differ significantly in their phenotypes, distinguished by the severity of neurological symptoms. It was shown that the degree of CNS hypomyelination and deficiency of PLP/DM-20 correlates well with the severity of neurological symptoms and is highest in the most strongly affected animals. Variety of phenotypes generated from pt genotype together with previously observed MOG hyperexpression suggested possible contribution of immunological component to the pt disease. Present studies indicate that MOG expression depends both on the phenotype and the age of affected rabbits and most probably mirrors retardation in myelinogenesis process caused by pt mutation.
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PMID:pt point mutation in plp gene results in hyperexpression of MOG in hypomyelinated rabbit. 878 15

C57BI/6 mice infected with mouse hepatitis virus, strain JHM (MHV-JHM) develop a chronic demyelinating encephalomyelitis. Infectious virus can be isolated only from symptomatic mice. In C57BI/6 mice, two CD8+ T cell epitopes within the MHV-JHM surface glycoprotein were previously identified. Here, we show that mutations in the RNA encoding the immunodominant of the epitopes are present in nearly all virus samples isolated from these mice. Mutations are not present in sequences flanking this epitope or in other CD8+ or CD4+ T cell epitopes. Furthermore, analysis of five peptides corresponding to variant epitopes in direct ex vivo cytotoxicity assays showed that each mutation caused a loss of epitope recognition. These results suggest that escape from CD8+ T cell recognition is necessary for enhanced virus replication and development of clinical disease in these MHV-JHM-infected mice.
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PMID:Cytotoxic T cell-resistant variants are selected in a virus-induced demyelinating disease. 880 80

A comparative pathogenesis study was performed in neonatal mice using a molecularly cloned laboratory variant of Sindbis strain AR339, designated TRSB, and a single-site attenuated mutant of TRSB derived by site-directed mutagenesis of the E2 glycoprotein from Ser to Arg at residue 114 (TRSBr114). TRSB caused 100% mortality with an average survival time of 3.0 +/- 0.7 days, whereas mice inoculated with TRSBr114 exhibited an attenuated disease course with 46% mortality and an extended average survival time of 7.5 +/- 3.4 days for those animals that died. Reduced virulence of TRSBr114 was characterized by delayed appearance of detectable virus, relative to TRSB, and by lower peak virus titers in both sera and brains of infected mice. TRSB infection induced very high peak serum titers of interferon alpha/beta (215,000 units/ml compared to 2100 units/ml for TRSBr114). In situ hybridization analysis demonstrated replication of TRSB in brain, but only minimal histopathological changes and no evidence of encephalitis were observed. However, extensive extraneural lesions and viral replication were found in skin, connective tissue, and muscle. Moreover, dramatic involution of the thymus and loss of hematopoietic tissues were observed in the absence of virus replication at these sites, suggesting the involvement of a systemic physiological stress response in TRSB infection. TRSBr114 infection did not cause thymic lesions. Otherwise, the attenuated mutant demonstrated a similar pattern of tissue and organ involvement, but lesions and positive in situ hybridization signal were much more limited in scope and intensity compared to TRSB. TRSBr114-infected mice developed myositis and encephalomyelitis approximately 6 days postinfection. Therefore, TRSB-infected animals may succumb to an early syndrome associated with the stress response, preventing their survival for a time sufficient for the development of encephalitis. Alternatively, a systemic stress response, as evidenced by thymic involution, may result in immunosuppression, thus contributing to the absence of encephalitis. In any event, the attenuating mutation in the E2 glycoprotein significantly altered the course of Sindbis-induced disease by limiting virus replication and associated damage early in infection. Mutant-infected animals survived beyond Day 4 and progressed to a classical encephalomyelitis from which about half recovered.
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PMID:Fatal Sindbis virus infection of neonatal mice in the absence of encephalitis. 886 1

The pathogenesis of Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease is still controversial. Our hypothesis is that primary infection of oligodendrocytes (OLGs) is not a crucial event in the pathogenesis of demyelination in this model. In fact, it has been proposed that myelin may be destroyed, as an innocent bystander, following an antiviral delayed-type hypersensitivity (DTH) response. This hypothesis would not need widespread oligodendroglial infection, because virus present in other cells would be sufficient to trigger a DTH response. The present study demonstrates that cultured OLGs and astrocytes from susceptible strains of mice (SJL and DBA) and immortalized OLGs can be infected with TMEV in vitro. Infection of OLGs, however, is at very low levels and does not result in overt cytolytic effect. In contrast, infection of immortalized OLGs is very efficient and results in clear cytolysis. Because an important characteristic of DTH responses is the liberation of potentially injurious cytokines into adjacent tissues, we also examined the effects of mouse recombinant tumor necrosis factor-alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha), and interferon-gamma (IFN-gamma) on cultured OLGs and immortalized OLGs. We found that TNF-alpha caused immortalized OLG cytotoxicity in a time- and dose-dependent manner. In contrast, no cytotoxicity was observed on primary OLGs with any of the above cytokines. To determine whether functional effects could be demonstrated on primary OLGs by either virus or cytokines, we measured mRNA expression of different myelin proteins in primary and immortalized OLGs exposed to virus or TNF-alpha. Neither the BeAn strain or the GDVII strain of TMEV interfered with myelin protein mRNA expression in primary OLGs, whereas GDVII virus dramatically reduced myelin OLG glycoprotein (MOG) mRNA in immortalized OLGs. Interestingly, although even high concentrations of TNF-alpha (10,000 U/ml) did not produce primary OLG cytotoxicity, they resulted in a significant reduction in mRNA for both myelin basic protein (MBP) and MOG in these cells. TNF-alpha (at 500 U/ml) also specifically reduced MOG mRNA in immortalized OLGs. Because immortalized OLGs are considered to be arrested at an early stage of maturation, our results suggest that immature OLGs are susceptible to both virus- and cytokine-dependent cytotoxicity, whereas mature OLGs are resistant to cytolysis by either TMEV or cytokines. TNF-alpha, however, is capable of reducing mRNA expression of myelin proteins in primary OLGs; therefore, it may participate in the induction of demyelination, as suggested by the DTH-mediated hypothesis.
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PMID:Effect of Theiler's murine encephalomyelitis virus and cytokines on cultured oligodendrocytes and astrocytes. 887 96

Enzyme immunoassay (EIA) with sixty types of monoclonal antibodies (MAbs) was used to study cross-reactive epitopes on the attenuated and virulent strains of the Eastern equine encephalomyelitis (EEE) and Venezuelan equine encephalomyelitis (VEE) viruses. All three structural proteins of the EEE and VEE viruses were demonstrated to have both cross-reactive and specific antigenic determinants. The glycoprotein E1 of EEE and VEE viruses possesses three cross-reactive epitopes for binding to MAbs. The glycoprotein E2 has a cluster of epitopes for 20 cross-reacting MAbs produced to EEE and VEE viruses. Cross-reactive epitopes were localised within five different sites of glycoprotein E2 of VEE virus and within four sites of that of the EEE virus. There are no cross-neutralising MAbs to the VEE and EEE viruses. Only one type of the protective Mabs was able to cross-protect mice against lethal infection by the virulent strains of the VEE and EEE viruses. Eight MAbs blocked the hemagglutination activity (HA) of both viruses. Antigenic alterations of neutralising and protective sites were revealed for all attenuated strains of the VEE and EEE viruses. Comparative studies of the E2 proteins amino acid sequences show that the antigenic modifications observed with the attenuated strains of the VEE virus may be caused by multiple amino acid changes in positions 7, 62, 120, 192 and 209-213. The escape-variants of the VEE virus obtained with cross-reactive MAbs 7D1, 2D4 and 7A6 have mutations of the E2 protein at positions 59, 212-213 and 232, respectively. Amino acid sequences in these regions of the VEE and EEE viruses are not homologous. These observations indicate that cross-reactive MAbs are capable of recognising discontinuous epitopes on the E2 glycoprotein.
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PMID:Glycoproteins E2 of the Venezuelan and eastern equine encephalomyelitis viruses contain multiple cross-reactive epitopes. 897 33

Recent studies on autoimmune encephalomyelitis and neuritis reveal that many different antigens of the central (CNS) and peripheral nervous system may become targets of an encephalitogenic T-cell response. The aim of this study was to determine the influence of T-cell specificity on the pathology of autoimmune-mediated inflammation in the nervous system. Autoimmune encephalomyelitis was induced by the adoptive transfer of CD4+ T-line cells specific for either myelin basic protein, myelin oligodendrocyte glycoprotein (MOG), myelin-associated glycoprotein, S100 beta, or glial fibrillary acidic protein. The severity of the inflammatory response was antigen- and dose-dependent. With the exception of MOG-specific T-line cells, all autoreactive T-cell lines induced inflammation in the CNS and peripheral nervous system. In the myelin-basic-protein-mediated model, the spinal cord was most severely affected with only minor inflammation in the forebrain. In contrast, both MOG- and myelin-associated-glycoprotein-specific T cells induced a far higher density of lesions in the periventricular and cerebellar white matter. S100 beta- and glial-fibrillary-acidic-protein-specific T cells mediated particularly severe inflammation in the gray matter. In addition to these topographic differences, antigen specificity also influenced the extent of both parenchymal inflammation and macrophage activation in the CNS. However, irrespective of the specificity or number of T cells transferred, the major neuropathologic correlate with disease severity was the absolute number of activated macrophages recruited into the CNS parenchyma (r = 0.9; p < 0.0001). This study suggests that differences in lesion distribution in multiple sclerosis patients may reflect differences in the antigen specificity of an encephalitogenic T-cell response.
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PMID:Experimental autoimmune encephalomyelitis: the antigen specificity of T lymphocytes determines the topography of lesions in the central and peripheral nervous system. 912 Nov 18

Borna disease virus (BDV) is representative of the family of Bornaviridae in the order Mononegavirales (negative-stranded, non-segmented, enveloped RNA viruses). It is the causal agent for Borna disease, characterized as an encephalomyelitis (typical form) in a wide variety of domestic animals (from rodents to birds). Recent information shows the involvement of BDV in the pathogenesis of some human psychiatric disorders. The 8.9-kb viral antigenome codes for five major ORF. The third ORF codes for a 16-kDa protein (matrix protein) that is posttranslationally modified, yielding an N-linked glycoprotein. Our data show that the glycosylated matrix protein exists as a stable tetrameric structure detectable either by electrospray ionization or matrix-assisted laser-desorption ionization mass spectrometry. Under native conditions, the tetramer, with a relative molecular mass of 68 kDa, was isolated from a sediment-free brain suspension of a BDV-infected horse. The 68-kDa entity is stable in the presence of ionic and nonionic detergents but dissociates into subunits when heated. We found that the tetrameric matrix protein inhibits in vitro BDV infection in a dose-dependent manner. In contrast to inhibition of BDV infection with hydrophobic carbohydrate derivatives and protein-bound glycoconjugates, the glycosylated matrix protein is a very potent inhibitor of BDV infection, indicating that this protein represents an essential virus-specific membrane component for viral attachment.
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PMID:The glycosylated matrix protein of Borna disease virus is a tetrameric membrane-bound viral component essential for infection. 921 Apr 91

A primary demyelinating form of experimental allergic encephalomyelitis (EAE) resembling human multiple sclerosis (MS) occurs in Callithrix jacchus marmosets following immunization with human white matter. Participation of a T-cell immune response against myelin basic protein (MBP) in this disease model is supported by observations of increased reactivity against MBP in PBMC and of adoptive transfer of an inflammatory form of EAE by MBP-reactive T-cells. To evaluate the effects of ectopic presentation of MBP on marmoset EAE, animals were vaccinated prior to induction of EAE by subcutaneous injection of attenuated strains of vaccinia virus genetically engineered to contain either the entire coding sequence for human MBP (vT15) or the equine herpes virus glycoprotein gH gene (vAbT249). Vaccination with vT15 was followed by transient cytoplasmic and surface membrane expression of MBP in circulating PBMC (15-45 days). The onset of clinical EAE after immunization (pi) was markedly delayed in vT15-vaccinated animals (37-97 days pi, n = 4) compared to vAbT249-vaccinated controls (14-18 days pi, n = 3). Proliferative responses against MBP but not against vaccinia antigens or phytohemagglutinin were suppressed in protected animals. Thus, development of attenuated live viruses carrying genes for myelin antigens could be useful for induction of immunologic tolerance and for modulation of autoimmune demyelination.
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PMID:Inhibition of allergic encephalomyelitis in marmosets by vaccination with recombinant vaccinia virus encoding for myelin basic protein. 939 84

Alphaviruses infect neurons in the brain and spinal cord and cause acute encephalomyelitis in a variety of mammals. The outcome of infection is determined by whether the neurons survive infection and this, in turn, is determined by the virulence of the virus and the age of the host at the time of infection. We have been studying Sindbis virus (SV) infection of mice as a model system for alphavirus-induced encephalomyelitis. Investigation of intracerebral infection of weanling mice with two different strains of SV has allowed us to analyze the role of the immune response in protection from fatal disease (virulent NSV strain) and in clearance of virus from the nervous system during non-fatal disease (less virulent SV AR339 strain). Neutralizing and non-neutralizing antibodies to the E1 and E2 surface glycoproteins can protect mice from fatal NSV infection when given before or after infection, while T cells are not protective. The mechanism of antibody-mediated protection is not known, but it is likely that more than one mechanism is involved and that different mechanisms are involved in pre-infection and post-infection treatment protection. Clearance of infectious virus from the nervous system of mice during recovery from non-fatal disease is accomplished by antibodies to the E2 glycoprotein. The process does not involve damage to the infected neurons and is independent of complement and mononuclear cells. Bivalent antibody is required and binds to the surface of the infected cell. Initially, release of virus by budding from the cell surface is prevented and, subsequently, intracellular virus replication is inhibited possibly through antiviral mechanisms induced in co-operation with interferon. This non-lytic mechanism for control of virus infection results in the prolonged presence of viral RNA in tissue and the need for prolonged intrathecal synthesis of antiviral antibody by B cells within the central nervous system.
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PMID:The role of antibody in recovery from alphavirus encephalitis. 941 9

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