Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IL-12 is a cytokine detected in active lesions in multiple sclerosis (MS) and promotes the acquisition of a Th1 cytokine profile by CD4+ T cells. Autoreactive T cells recovered from the central nervous system of animals with experimental autoimmune encephalomyelitis (EAE), a disease model for MS, display this phenotype. We demonstrate that human central nervous system-derived microglia, but not astroglia, can produce IL-12 in vitro. Under basal culture conditions, human adult microglia do not express detectable levels of IL-12, although these cells show some degree of activation as assessed by expression of the immunoregulatory surface molecules HLA-DR and B7 as well as low levels of TNF-alpha mRNA. Following activation with LPS, IL-12 p40 mRNA and p70 protein can be readily detected. IL-12 production is preceded by TNF-alpha production and is inhibited by recombinant soluble human TNF receptor (II)-IgG1 fusion protein (shu-TNF-R). These data indicate regulation of IL-12 by an autocrine-dependent feedback loop, providing an additional mechanism whereby shu-TNF-R, now used in clinical trials in MS, may be exerting its effect.
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PMID:Soluble tumor necrosis factor receptor inhibits interleukin 12 production by stimulated human adult microglial cells in vitro. 883 1

To clarify the role of tumor necrosis factor (TNF) in the inflammatory aspects of autoimmunity vs its potential role in the apoptotic elimination of autoreactive effector cells, we assessed the roles of the p55 (TNFR1/Tnfrsf1a/CD120a) and p75 (TNFR2/Tnfrsf1b/CD120b) TNF receptors in the pathogenesis of MOG(35-55)-induced experimental autoimmune encephalomyelitis (EAE). TNFR p55/p75(-/-) double knockout mice were completely resistant to clinical disease. TNFR p55(-/-) single knockout mice were also totally resistant to EAE, exhibiting reduced MOG(35-55)- specific proliferative responses and Th1 cytokine production, despite displaying equivalent DTH responses. Importantly, IL-5 was significantly increased in p55(-/-) mice. In contrast, p75(-/-) knockout mice exhibited exacerbated EAE, enhanced Th1 cytokine production, and enhanced CD4(+) and F4/80(+) CNS infiltration. Thus, p55/TNFR1 is required for the initiation of pathologic disease, whereas p75/TNFR2 may be important in regulating the immune response. These results have important implications for therapies targeting p55 and p75 receptors for treating autoimmune diseases.
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PMID:Divergent roles for p55 and p75 tumor necrosis factor receptors in the pathogenesis of MOG(35-55)-induced experimental autoimmune encephalomyelitis. 1107 4

Mice without secreted TNF but with functional, normally regulated and expressed membrane-bound TNF (memTNF(Delta/Delta) mice) were created by knocking-in the uncleavable Delta 1-9,K11E TNF allele. In contrast to TNF-deficient mice (TNF(-/-)), memTNF supported many features of lymphoid organ structure, except generation of primary B cell follicles. Splenic chemokine expression was near normal. MemTNF-induced apoptosis was mediated through both TNF-R1 and TNF-R2. That memTNF is suboptimal for development of inflammation was revealed in experimental autoimmune encephalomyelitis. Disease severity was reduced in memTNF(Delta/Delta) mice relative to wild-type mice, and the nature of spinal cord infiltrates resembled that in TNF(-/-) mice. We conclude that memTNF supports many processes underlying lymphoid tissue structure, but secreted TNF is needed for optimal inflammatory lesion development.
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PMID:Membrane-bound TNF supports secondary lymphoid organ structure but is subservient to secreted TNF in driving autoimmune inflammation. 1167 36

Lymphotoxin (LT) and tumor necrosis factor (TNF) are important in immune system development and function. LT consists of soluble LT-alpha(3), which binds to TNF-R1 and TNF-R2, and membrane LT-alpha(1)beta(2), which binds to LT-beta-R. We investigated the role of LT and TNF in disease induced by Daniel's (DA) strain of Theiler's murine encephalomyelitis virus (TMEV) since the immune response is believed to be important in both resistance to DA infection as well as mediation of virus-induced demyelination. DA persisted and induced inflammatory demyelination in LT-alpha(-/-) (but not TNF(-/-)) weanling mice of a normally resistant haplotype (C57BL/6), suggesting that LT, but not TNF, is critical for resistance to DA infection. This activity of LT depends on membrane LT-alpha(1)beta(2) and not soluble LT-alpha(3), since DA virus persisted and induced inflammatory demyelination in LT-beta-R(-/-), but not TNF-R1(-/-) or TNF-R2(-/-), mice. The LT-alpha(-/-) and LT-beta-R(-/-) mice failed to mount a virus-specific cytotoxic T cell response. Treatment of weanling C57BL/6 mice with LT-beta-R-Ig, which blocks membrane LT activity, failed to increase susceptibility, suggesting that the LT effect is related to its action on immune system development which is fixed by 3 weeks of age. Our data suggest that membrane LT is important in resistance to DA infection (possibly through interference with CD8+ T cell development and function). There was relatively little demyelination associated with inflammation in LT-alpha(-/-) and LT-beta-R(-/-) mice compared to susceptible SJL mice, suggesting the possibility that LT plays a role in mediating demyelination.
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PMID:Membrane lymphotoxin is required for resistance to Theiler's virus infection. 1288 33

In experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, immunization with myelin Ags leads to demyelination and paralysis. To investigate which molecules are crucial for the pathogenesis of EAE, we specifically assessed the roles of the death receptors Fas and TNF-R1. Mice lacking Fas expression in oligodendrocytes (ODCs) were generated and crossed to TNF-R1-deficient mice. To achieve specific deletion of a loxP-flanked fas allele in ODCs, we generated a new insertion transgene, expressing the Cre recombinase specifically in ODCs. Fas inactivation alone as well as the complete absence of TNF-R1 protected mice partially from EAE induced by the immunization with myelin ODC glycoprotein. The double-deficient mice, however, showed almost no clinical signs of EAE after immunization. Histological analysis revealed that demyelination was suppressed in CNS tissue and that lymphocyte infiltration was notably reduced. We conclude that the death receptors Fas and TNF-R1 are major initiators of ODC apoptosis in EAE. Although only moderate reduction of lymphocyte infiltration into CNS tissue was observed, the absence of these receptors appears to confer protection from demyelination and development of clinical disease.
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PMID:Apoptosis of oligodendrocytes via Fas and TNF-R1 is a key event in the induction of experimental autoimmune encephalomyelitis. 1623 80