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)

TH17 cells play an essential role in the development of both human multiple sclerosis and animal experimental autoimmune encephalomyelitis (EAE). Nevertheless, it is not well understood how the pathogenicity of TH17 cells is controlled in the autoimmune neuroinflammation. In vitro, we found Lumican (Lum), an extracellular matrix (ECM) protein, is selectively expressed by TH17 cells among tested murine TH subsets. Lum deficiency leads to earlier onset and enhanced severity of EAE. This enhanced disease in Lum-deficient mice is associated with increased production of IL-17 and IL-21 and decreased TH17 cell apoptosis. Dysregulation in cytokine production appears to be specific to TH17 cells as TH1 and TH2 cell polarization and/or cytokine production were unaltered. Furthermore, adoptive transfer of myelin oligodendrocyte glycoprotein specific TH17 cells derived from Lum-deficient mice led to earlier onset and increased severity of disease compared to controls highlighting a TH17-cell-intrinsic effect of Lum. Taken together, our results suggest that Lum negatively regulates encephalitic TH17 cells, implicating a potential therapeutic pathway in TH17 cell mediated autoimmune and inflammatory diseases.
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PMID:Lumican negatively controls the pathogenicity of murine encephalitic TH17 cells. 2768 97

Multiple sclerosis is a chronic inflammatory central nervous system (CNS) disease, which affects about 1 in 1000 individuals in the western world. It has been suggested that this relatively high prevalence is linked to a high level of hygiene, i.e. a reduced exposure to various microorganisms, including parasites. Parasites are known to employ different immunomodulatory and antiinflammatory strategies, which enable them to evade destruction by the immune system. We have investigated the immunomodulation by the swine whipworm, Trichuris suis, by measuring the impact of oral administration of T. suis ova as well as of intraperitoneal administration of T. suis excretory/secretory products on the development and progression of experimental autoimmune encephalomyelitis - an animal model that shares clinical and pathological characteristics with multiple sclerosis. Intraperitoneal administration of excretory/secretory products before disease onset, resulted in a significant decrease in disease severity as well as markedly reduced TH1 and TH17 T-cell responses, centrally in the spinal cord as well as in the periphery, i.e. the spleen. Thus, parenteral administration of T. suis-derived products results in a skewing of the immune response with a significant impact on disease severity in a CNS inflammatory disease model.
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PMID:Trichuris suis secrete products that reduce disease severity in a multiple sclerosis model. 2803 Mar 34

Autoimmunity and inflammation are controlled in part by regulatory B (Breg) cells, including the recently identified IL-10-competent B10 cell subset that represents 1%-3% of mouse spleen B cells. In this study, the influence of irradiation on Breg/B10 cell generation and IL-10 production mediated by TLR9 signaling pathways was investigated. Spleen and peritoneal cavity Breg/B10 cell frequencies were significantly expanded three weeks after sub-total body irradiation (sub-TBI, 5Gy or 10Gy) in adult male wild type (WT) C57BL/6(B6) mice but not in TLR9-/- mice. TLR9 agonist ODN1826 stimulation in vitro for 5h induced more B10 cells to express cytoplasmic IL-10 in sub-TBI WT mice than in TLR9-/- mice. Prolonged ODN1826 stimulation (48h) induced additional spleen CD19hiCD5+CD1dhi B cells to express IL-10. TLR9-dependent signaling molecules, MyD88, TRAF6 and IRF8 are involved in sub-TBI induced Breg/B10 cells development and expansion. Furthermore, using a mouse model for multiple sclerosis, we show here that sub-TBI induced Breg/B10 cells dramatically inhibit disease onset and severity when transferred into mice with established experimental autoimmune encephalomyelitis (EAE). Adoptively transferred sub-TBI induced Breg cells significantly suppress inflammatory T cell responses of TH17 and TH1 types in EAE mice. In conclusion, sub-TBI can drive Breg/B10 cell development and expansion, which could be used as a novel tool for suppressing undesirable immunity. The ex vivo expansion and reinfusion of autologous Breg/B10 cells may provide a novel and effective in vivo treatment for severe autoimmune diseases that are resistant to current therapies.
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PMID:TLR9 mediated regulatory B10 cell amplification following sub-total body irradiation: Implications in attenuating EAE. 2811 75

N-acetylglucosamine (GlcNAc) branching of Asn (N)-linked glycans inhibits pro-inflammatory T cell responses and models of autoimmune diseases such as Multiple Sclerosis (MS). Metabolism controls N-glycan branching in T cells by regulating de novo hexosamine pathway biosynthesis of UDP-GlcNAc, the donor substrate for the Golgi branching enzymes. Activated T cells switch metabolism from oxidative phosphorylation to aerobic glycolysis and glutaminolysis. This reduces flux of glucose and glutamine into the hexosamine pathway, thereby inhibiting de novo UDP-GlcNAc synthesis and N-glycan branching. Salvage of GlcNAc into the hexosamine pathway overcomes this metabolic suppression to restore UDP-GlcNAc synthesis and N-glycan branching, thereby promoting anti-inflammatory T regulatory (Treg) over pro-inflammatory T helper (TH) 17 and TH1 differentiation to suppress autoimmunity. However, GlcNAc activity is limited by the lack of a cell surface transporter and requires high doses to enter cells via macropinocytosis. Here we report that GlcNAc-6-acetate is a superior pro-drug form of GlcNAc. Acetylation of amino-sugars improves cell membrane permeability, with subsequent de-acetylation by cytoplasmic esterases allowing salvage into the hexosamine pathway. Per- and bi-acetylation of GlcNAc led to toxicity in T cells, whereas mono-acetylation at only the 6 > 3 position raised N-glycan branching greater than GlcNAc without inducing significant toxicity. GlcNAc-6-acetate inhibited T cell activation/proliferation, TH1/TH17 responses and disease progression in Experimental Autoimmune Encephalomyelitis (EAE), a mouse model of MS. Thus, GlcNAc-6-Acetate may provide an improved therapeutic approach to raise N-glycan branching, inhibit pro-inflammatory T cell responses and treat autoimmune diseases such as MS.
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PMID:Increasing cell permeability of N-acetylglucosamine via 6-acetylation enhances capacity to suppress T-helper 1 (TH1)/TH17 responses and autoimmunity. 3091 78


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