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)

Mast cells and their potent chemical mediators are known to initiate and modulate a number of important inflammatory cascades. With respect to the central nervous system, the role of mast cells as participants in the promotion and resolution of inflammation has been widely underestimated. Mast cell-derived histamine, serotonin, kallikreins, and tumor necrosis factor-alpha (TNF-alpha) can enhance microvascular permeability, leukocyte rolling, adhesion, and extravasation of inflammatory cells into the brain and spinal cord. Mast cell mediators may play an important role in autoimmune encephalomyelitis and multiple sclerosis by promoting the entry of autoreactive T cells and the recruitment of nonspecific monocytes across the blood:brain barrier.
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PMID:Hypothesis: a possible role for mast cells and their inflammatory mediators in the pathogenesis of autoimmune encephalomyelitis. 887 94

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

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease of the central nervous system (CNS) that is mediated by T helper 1 (Th1) CD4+ T cells. Lewis rats can be protected from actively induced EAE by coimmunization with the encephalitogenic myelin basic protein (MBP) epitope 73-84 and its single alanine-substituted analog 1028. Although analog 1028 cannot induce either active or passive EAE, it does elicit a Th1-like response that is cross-reactive with MBP73-84. Analog 1028 can effectively inhibit clinical EAE in a dose-dependent manner when rats are coimmunized with the encephalitogenic peptide MBP73-84 and 1028 in complete Freund adjuvant (CFA). Stimulation of cells from MBP73-84:1028-coimmunized protected rats proliferate and secrete interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) in vitro in response to MBP73-84. Furthermore, coimmunized protected rats harbor a population of MBP73-84-reactive potentially encephalitogenic T cells, because splenocytes from these rats can be stimulated to transfer passive EAE to naive recipients. Thus, the protection of coimmunized rats by analog 1028 is not due to the inhibition of priming of MBP73-84-reactive T cells or alteration of the cytokine secretion profile of the MBP73-84-reactive cell population. Rather, MBP73-84-reactive potentially encephalitogenic T cells are primed in these protected animals.
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PMID:Encephalitogenic T cells are present in Lewis rats protected from autoimmune encephalomyelitis by coimmunization with MBP73-84 and its analog. 887 5

Impairment of the blood-brain barrier (BBB) in experimental autoimmune encephalomyelitis (EAE) has been frequently attributed to disruption, without much consideration of saturable transport processes. In mice with EAE, we studied the permeability of the BBB to radioactively labeled albumin and sucrose, markers of BBB disruption, and tumor necrosis factor-alpha (TNF-alpha), a cytokine transported across the BBB by a saturable system and thought to play a role in the pathogenesis of EAE. Permeation of the BBB was increased to all three substances during the acutely ill stage, was greatest in the lumbar spine, and returned to normal with recovery. The change in BBB permeability to sucrose was greater than to the larger albumin and is consistent with a partial disruption of the BBB. The enhanced permeability to TNF-alpha was comparable to that for sucrose, even though TNF-alpha is similar in size to albumin. This paradoxically high uptake of TNF-alpha could be explained by an enhancement of its endogenous saturable transport system. Thus the changes in BBB function during EAE extend beyond disruption to include changes in the saturable transport systems for substances involved in the disease process.
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PMID:Differential permeability of the BBB in acute EAE: enhanced transport of TNT-alpha. 889 50

Demyelination of axons in the central nervous system (CNS) during multiple sclerosis (MS) and its animal model experimental allergic encephalomyelitis (EAE) is a result of phagocytosis and digestion by macrophages (M phi) and the local release of inflammatory mediators like tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO). We have investigated the process of myelin phagocytosis by M phi in vitro using flow cytometric analysis. The binding and uptake of CNS-derived myelin was dose dependent, was abolished in the presence of EDTA and was enhanced after opsonization with complement. The phagocytosis of opsonized myelin could be inhibited by antibodies directed against complement receptor type 3 (CR3). Furthermore, CR3 also contributes to phagocytosis of non-opsonized myelin, e.g. under serum-free conditions. The phagocytosis of CNS-derived myelin induced the production of substantial amounts of TNF-alpha and NO by the M phi. Our results indicate an important role for CR3 in myelin phagocytosis. The induction of TNF-alpha and NO which accompanies this phagocytosis may further contribute to the overall process of demyelination during MS or EAE.
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PMID:Macrophage phagocytosis of myelin in vitro determined by flow cytometry: phagocytosis is mediated by CR3 and induces production of tumor necrosis factor-alpha and nitric oxide. 889 23

The effect of pentoxifylline (PTX) on experimental allergic encephalomyelitis (EAE) in mice, a known animal model of multiple sclerosis (MS), was investigated. PTX was orally administrated at 10, 40 and 100 mg/kg/day, respectively. Although oral PTX at these doses had no significant effect on the incidence and severity of EAE, oral PTX (40 mg/kg/day) alone produced a significant delay in the onset of EAE. Semiquantitative reverse transcriptase-polymerase chain reaction analysis revealed that PTX at this dose reduced the mRNA levels for tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta and IL-6 in peripheral blood mononuclear cells (PBMC) of mice with EAE. A histopathological study showed that PTX treatment delayed infiltration of inflammatory cells in the central nervous system (CNS) of mice with EAE. These results indicated that the tolerable dose of PTX had a suppressive effect on the induction phase of EAE by modulating cytokine production in PBMC but had no effect on the severity of EAE. The findings in the present study with animals suggested that a tolerable dose of PTX might prolong the intervals between relapses in MS, but might not improve the clinical sign and symptoms of MS.
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PMID:Pentoxifylline delays the onset of experimental allergic encephalomyelitis in mice by modulating cytokine production in peripheral blood mononuclear cells. 895 77

Multiple sclerosis (MS) is a chronic demyelinating disease affecting the central nervous system (CNS) principally in young adults. Although its etiology is as yet unknown current evidence suggests that tissue damage is mediated by autoimmune T cells. The examination of an experimental animal model for MS, experimental allergic encephalomyelitis (EAE), has demonstrated that myelin basic protein (MBP)- or proteolipid protein (PLP)-specific T cells mediate the destruction of CNS myelin. In recent years, elegant studies in EAE have shown that encephalitogenic T cells recognize short peptides of MBP or PLP in the context of MHC/HLA-class II molecules, express a restricted number of T cell receptor (TCR) molecules and secrete interferon-gamma and tumor necrosis factor-alpha/beta. Understanding the pathogenetic steps in lesion development at the molecular level led to highly specific immunotherapies for EAE targeting each individual molecule. It has been the hope of many investigators that immunological events resembling those in EAE can be found in patients with MS and that the specific immunotherapies effective in EAE could also be applied to MS. However, to date, the evidence for a unique immunological abnormality in MS is not strong. Although MBP- and PLP-specific T cells with properties similar to those that are encephalitogenic in animals can be isolated from patients, they are not specific for MS and occur with similar frequency in controls. In addition, the variability in specificity and TCR usage has raised questions regarding the relevance of these cells in patients. The importance of the T cell responses to myelin antigens in MS may not be established until the effects of abrogating their activity through specific therapies targeting the trimolecular complex (TMC) have been demonstrated. Consequently, attention has begun to focus on modifying the biology of the MS lesion rather than targeting the initiating event at the level of the TMC, and the success of this approach is reflected by the effect of interferon-beta on lesion development in MS. The recent approval for the use of interferon-beta for the treatment of relapsing-remitting MS has raised great interest in examining novel strategies for immunotherapies in MS. The basic concepts as well as the current candidates for such new immunotherapies will be outlined in this short review.
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PMID:Experimental immunotherapies for multiple sclerosis. 898 75

Myelin basic protein (MBP)-specific T cells are implicated in the pathogenesis of multiple sclerosis and are targets of selective immunotherapies. However, autoantigen-specific T cells can also be isolated from healthy individuals. Their functional potential is unknown and obviously cannot be tested in humans. We approached this question in a closely related primate species, the rhesus monkey. CD4+ T cell lines specific for MBP were isolated from normal rhesus monkeys using the same primary limiting dilution technique that is now widely used to generate human autoreactive T cell clones in vitro. Three different epitopes were recognized by three rhesus T cell lines isolated from three different monkeys. Upon activation, all lines produced interferon-gamma, interleukin-2, tumor necrosis factor-alpha, and granulocyte/macrophage colony-stimulating factor but neither interleukin-4 nor transforming growth factor-beta. The MBP-specific T cells were injected intravenously without adjuvant into the nonirradiated autologous monkey. One of the three rhesus monkeys developed an encephalomyelitis with a pleocytosis in the spinal fluid and perivascular infiltrates in the leptomeninges, spinal nerve roots and cerebral cortex. The data demonstrate that the normal immune repertoire of a primate species contains MBP-specific CD4+ T cells that are able to induce an autoimmune encephalomyelitis upon transfer into the nonirradiated autologous recipient.
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PMID:Encephalitogenic potential of myelin basic protein-specific T cells isolated from normal rhesus macaques. 903 60

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease of the central nervous system that can be induced by immunization with myelin basic protein (MBP)/complete Freund's adjuvant and serves as a model for multiple sclerosis. Recent studies have suggested that cytokines play a crucial role in the clinical course of EAE. To clarify the roles of cytokines in EAE, we examined levels of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta1 (TGF-beta1) and interleukin-10 (IL-10) mRNA in isolates from infiltrating inflammatory cells in EAE lesions induced in Lewis rats. The non-radioactive and sensitive competitive PCR method was employed to quantify the relative amounts of cytokine mRNA. Levels of both IFN-gamma and TNF-alpha mRNA were increased at the early stage of EAE and rapidly decreased at the peak stage. On the other hand, TGF-beta1 mRNA was demonstrated throughout the course of EAE as well as under normal conditions and its amount paralleled the severity of EAE. IL-10 mRNA was detected by reverse transcription polymerase chain reaction (RT-PCR) under normal conditions, but was below the level of detection of competitive PCR. IL-10 mRNA expression peaked at the early stage of EAE and declined gradually thereafter. Taken together, these results suggest that IFN-gamma and TNF-alpha might play a crucial role in the development of EAE. Furthermore, it appears that the peak expression of IL-10 mRNA at the early stage and the following marked TGF-beta1 expression at the peak stage might represent an important endogenous mechanism to limit the extent of inflammation and to prevent relapse in the course of acute monophasic EAE.
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PMID:Competitive PCR quantification of pro- and anti-inflammatory cytokine mRNA in the central nervous system during autoimmune encephalomyelitis. 905 77

Cells of the central nervous system (CNS) normally do not express detectable levels of major histocompatibility complex (MHC) Class I antigens. However, MHC Class I expression can be induced after virus infection. We tested the hypothesis that virus-induced Class I expression is mediated by lymphocytes or cytokines using lymphocyte- and cytokine-deficient mice. We used Theiler's murine encephalomyelitis virus (TMEV), which induces CNS demyelination that maps genetically to the D region of MHC Class I and is associated with high levels of Class I products. TMEV infection of severe combined immunodeficiency (SCID) and recombination activation gene-1-deficient mice, which lack B and T lymphocytes, resulted in equivalent H-2D and H-2K expression in brain and spinal cord, according to analysis of the area and intensity of immunoperoxidase staining. Class I antigens were demonstrated as early as 6 hours after infection, and they were more widely distributed than viral RNA, indicating that expression was induced indirectly via a soluble factor. To determine whether cytokines induced the expression, we infected mice lacking receptors for interferon-alpha/beta (IFN-alpha/beta R (-/-)), interferon-gamma (IFN-gamma R(-/-)), and tumor necrosis factor-alpha (TNFRp55(-/-)). TMEV-infected IFN-gamma R(-/-) and TN-FRp55(-/-) mice expressed Class I antigens in the CNS, whereas IFN-alpha/beta R(-/-) mice did not, establishing that IFN-alpha/beta mediated the expression. In contrast to the equivalent expression in SCID mice, we observed greater area and higher intensity of H-2D versus H-2K antigens in infected SCID mice reconstituted with normal spleen cells. Collectively, the data indicate that after TMEV infection, early generalized MHC Class I expression is mediated by IFN-alpha/beta independently of lymphocytes, but the differential regulation of H-2D over H-2K may be controlled by B and/or T lymphocytes.
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PMID:Interferon alpha/beta mediates early virus-induced expression of H-2D and H-2K in the central nervous system. 925 80

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