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)

Infections can trigger or exacerbate the course of Multiple Sclerosis, and both bacterial and viral agents have been implicated. These agents are recognized by host cells via pathogen-associated molecular patterns activating TLRs. We investigated the role that PAMPs play in the animal model Experimental Autoimmune Encephalomyelitis, and found various MyD88-dependent PAMPs can participate as the adjuvant to induce EAE. Studies with IRAK1-deficient mice suggest that signaling through TLRs is not required in the target organ to develop disease. This suggests that PAMPs play an important role in priming of autoreactive T cells in EAE and potentially MS.
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PMID:Multiple toll-like receptor agonists act as potent adjuvants in the induction of autoimmunity. 1636 Aug 85

Theiler's murine encephalomyelitis virus (TMEV) infection in the central nervous system (CNS) induces a demyelinating disease similar to human multiple sclerosis. TMEV infection results in activation of various chemokine and cytokine genes that are important in the initiation of an inflammatory response. We have previously shown that the production of these chemokines and cytokines in astrocytes is induced via the NF-kappaB pathway following TMEV and Coxsackie virus infection. In this study, we investigated whether the NF-kappaB-dependent inflammatory responses after TMEV infection is triggered through TLR3 and/or TLR7. The activation of NF-kappaB or IRF/ISRE, as well as the production of both MCP-1/CCL2 and IL-8/CXCL8, was observed in only TLR3-transfected HEK 293 cells, but not in TLR7-tranfected cells. The potential involvement of TLR3 in mouse embryonic fibroblasts and primary astrocytes was further investigated following transfection with wildtype or dominant negative form of TLRs and MyD88, as well as astrocytes from TLR3- and MyD88-deficient mice. Similarly, the activation of transcription factors and chemokine genes is induced in these mouse cells through primarily TLR3 signaling pathway, but not TLR7 or other MyD88-mediated pathways following TMEV infection. However, the TLR3-mediated cellular activation does not appear to affect the level of viral replication in astrocytes. These results strongly suggest that TLR3-signaling by TMEV alone is sufficient to induce the initial inflammatory cytokine responses that could be very important for the outcome of virus-induced encephalitis and/or demyelinating diseases, such as multiple sclerosis.
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PMID:Induction of chemokine and cytokine genes in astrocytes following infection with Theiler's murine encephalomyelitis virus is mediated by the Toll-like receptor 3. 1658 93

Experimental autoimmune encephalomyelitis is a well-characterized model of cell-mediated autoimmunity. TLRs expressed on APCs recognize microbial components and induce innate immune responses, leading to the elimination of invading infectious agents. Certain TLR agonists have been reported to have adjuvant properties in CNS autoimmune inflammatory demyelination. We report in this study that TLR3 stimulation by polyinosinic-polycytidylic acid, a double-stranded RNA analog, suppresses relapsing demyelination in a murine experimental autoimmune encephalomyelitis model. Disease suppression is associated with the induction of endogenous IFN-beta and the peripheral induction of the CC chemokine CCL2. These data indicate that a preferential activation of the MyD88-independent, type I IFN-inducing TLR pathway has immunoregulatory potential in this organ-specific autoimmune disease.
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PMID:Cutting Edge: TLR3 stimulation suppresses experimental autoimmune encephalomyelitis by inducing endogenous IFN-beta. 1711 17

The IL-12 family of cytokines, which include IL-12, IL-23, and IL-27, play critical roles in the differentiation of Th1 cells and are believed to contribute to the development of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Relatively little is known concerning the expression of IL-12 family cytokines by cells of the CNS, the affected tissue in MS. Previously, we and others demonstrated that peroxisome proliferator-activated receptor (PPAR)-gamma agonists suppress the development of EAE, alter T cell proliferation and phenotype, and suppress the activation of APCs. The present studies demonstrated that PPAR-gamma agonists, including the naturally occurring 15-deoxy-Delta(12,14)-PGJ(2) and the synthetic thiazoladinedione rosiglitazone, inhibited the induction of IL-12p40, IL-12p70 (p35/p40), IL-23 (p19/p40), and IL-27p28 proteins by LPS-stimulated primary microglia. In primary astrocytes, LPS induced the production of IL-12p40, IL-23, and IL-27p28 proteins. However, IL-12p70 production was not detected in these cells. The 15-deoxy-Delta(12,14)-PGJ(2) potently suppressed IL-12p40, IL-23, and IL-27p28 production by primary astrocytes, whereas rosiglitazone suppressed IL-23 and IL-27p28, but not IL-12p40 in these cells. These novel observations suggest that PPAR-gamma agonists modulate the development of EAE, at least in part, by inhibiting the production of IL-12 family cytokines by CNS glia. In addition, we demonstrate that PPAR-gamma agonists inhibit TLR2, MyD88, and CD14 expression in glia, suggesting a possible mechanism by which these agonists modulate IL-12 family cytokine expression. Collectively, these studies suggest that PPAR-gamma agonists may be beneficial in the treatment of MS.
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PMID:Peroxisome proliferator-activated receptor-gamma agonists suppress the production of IL-12 family cytokines by activated glia. 1723 41

The interleukin-12 (IL-12) family of cytokines which includes IL-12, IL-23, and IL-27 play critical roles in T cell differentiation and are important modulators of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Previously, we demonstrated that peroxisome proliferator-activated receptor (PPAR) -alpha agonists suppress the development of EAE. The present studies demonstrated that the PPAR-alpha agonist fenofibrate inhibited the secretion of IL-12p40, IL-12p70 (p35/p40), IL-23 (p19/p40), and IL-27p28 by lipopolysaccharide-stimulated microglia. The cytokines interferon-gamma and tumor necrosis factor-alpha also stimulated IL-12 p40 and IL-27 p28 expression by microglia, which was suppressed by fenofibrate. Furthermore, fenofibrate inhibited microglial expression of CD14 which plays a critical role in TLR signaling, suggesting a mechanism by which this PPAR-alpha agonist regulates the production of these pro-inflammatory molecules. In addition, fenofibrate suppressed the secretion of IL-12p40, IL-23, and IL-27p28 by lipopolysaccharide-stimulated astrocytes. Importantly, fenofibrate suppression of EAE was associated with decreased expression of IL-12 family cytokine mRNAs as well as mRNAs encoding TLR4, CD14, and MyD88 known to play critical roles in MyD88-dependent TLR signaling. These novel observations suggest that PPAR-alpha agonists including fenofibrate may modulate the development of EAE, at least in part, by suppressing the production of IL-12 family cytokines and MyD88-dependent signaling.
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PMID:Peroxisome proliferator-activated receptor-alpha agonist fenofibrate regulates IL-12 family cytokine expression in the CNS: relevance to multiple sclerosis. 1772 29

Innate immune mechanisms essential for priming encephalitogenic T cells in autoimmune neuroinflammation are poorly understood. Experimental autoimmune encephalomyelitis (EAE) is a IL-17-producing Th (Th17) cell-mediated autoimmune disease and an animal model of multiple sclerosis. To investigate how upstream TLR signals influence autoimmune T cell responses, we studied the role of individual TLR and MyD88, the common TLR adaptor molecule, in the initiation of innate and adaptive immune responses in EAE. Wild type (WT) C57BL/6, TLR-deficient and MyD88-deficient mice were immunized with myelin oligodendrocyte glycoprotein (MOG) in CFA. MyD88(-/-) mice were completely EAE resistant. Purified splenic myeloid DC (mDC) from MyD88(-/-) mice expressed much less IL-6 and IL-23, and serum and T cell IL-17 were absent. TLR4(-/-) and TLR9(-/-) mice surprisingly exhibited more severe EAE symptoms than WT mice. IL-6 and IL-23 expression by mDC and Th17 responses were higher in TLR4(-/-) mice, suggesting a regulatory role of TLR4 in priming Th17 cells. IL-6 expression by splenocytes was higher in TLR9(-/-) mice. Our data suggest that MyD88 mediates the induction of mDC IL-6 and IL-23 responses after MOG immunization, which in turn drives IL-17-producing encephalitogenic Th17 cell activation. Importantly, we demonstrate that TLR4 and TLR9 regulate disease severity in MOG-induced EAE.
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PMID:Unexpected regulatory roles of TLR4 and TLR9 in experimental autoimmune encephalomyelitis. 1820 39

TLR sense microbial infections, and control activation of immune responses. Dendritic cells, macrophages, and B lymphocytes express TLR and the TLR-signaling adaptor protein MyD88. The impact of TLR-activated B cells on T cell-mediated inflammation is unknown. In this study, we have used mice carrying B cell-restricted deficiencies in MyD88 or in distinct TLR to examine the impact of TLR-activated B cells on a T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis (EAE). We demonstrate that TLR-signaling in B cells suppresses inflammatory T cell responses (both Th1 and Th17), and stimulates recovery from EAE. Only certain TLR are required on B cells for resolution of EAE, and these are dispensable for disease initiation, indicating that a category of TLR agonists preferentially triggers a suppressive function in B cells and thereby limits autoimmune disease. The TLR agonists controlling the regulatory function of B cells are provided by components of Mycobacterium tuberculosis present in the adjuvant. Thus, MyD88 signaling in B cells antagonizes MyD88 signaling in other cells, which drives differentiation of Th17 cells and is required for induction of EAE. Altogether, our data indicate that B cells link recognition of microbial products via TLR to suppression of a T cell-mediated autoimmune disease.
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PMID:TLR-activated B cells suppress T cell-mediated autoimmunity. 1835

Experimental autoimmune encephalomyelitis (EAE) is a Th17-mediated autoimmune disease and an animal model for multiple sclerosis (MS). Complete Freund's adjuvant (CFA) contains pathogen-associated molecular patterns (PAMPs) that bind toll-like receptors (TLRs), and is necessary to induce EAE. Upstream TLR signals modify innate and adaptive immune responses in EAE. In detail, the common TLR adaptor molecule MyD88 is necessary for induction of EAE, and mediates activation of peripheral myeloid dendritic cells (mDCs) and differentiation of autoimmune Th17 cells. The stimulatory TLRs have not yet been identified for Th17 cells. TLR4 down regulates disease severity in EAE and Th17 cell responses, but promotes Th1 cell responses, which may inhibit the differentiation of Th17 cells. Moreover, treatment with a TLR4 ligand tolerizes mice and prevents EAE. TLR9 down regulates disease severity in myelin oligodendrocyte glycoprotein (MOG)-induced EAE, whereas it promotes disease in MOG(35-55)-induced EAE. Thus MyD88, TLR4 and TLR9 modify the disease process in EAE. Both endogenous and CFA-derived TLR ligands are implicated to modulate the disease process.
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PMID:Regulation of autoimmune encephalomyelitis by toll-like receptors. 1921 Oct 42

MyD88 is an adaptor molecule that functions in the innate signaling induced by proinflammatory adjuvants that interact with TLRs. Mice lacking MyD88, for example, resist active experimental autoimmune encephalomyelitis (EAE) induced by immunization with an encephalitogenic myelin oligodendrocyte glycoprotein (MOG) peptide in CFA. We reasoned that MyD88(-/-) mice, nevertheless, should be susceptible to EAE mediated by adoptive transfer of activated encephalitogenic T cell lines, which do not require adjuvant signaling for their effector functions. We now report, however, that mice lacking MyD88 also resist adoptive EAE mediated by an anti-MOG T cell line that is strongly encephalitogenic in wild-type (WT) mice. The transferred anti-MOG T cells proliferated, secreted INF-gamma, and migrated to the CNS in the MyD88(-/-) mice, as they did in WT mice, but inflammatory infiltrates did not progress and clinical EAE did not develop. The resistance of the MyD88(-/-) mice to adoptive EAE mediated by the otherwise encephalitogenic T cells was found to result from the secretion of IL-10 by recipient T cells of two different specificities: those specific for MOG and those responding to the T cell clone itself-both anticlonotypic and antiergotypic T regulators were detected. IL-10-producing anti-MOG T cells isolated from immunized MyD88(-/-) mice suppressed the induction of active EAE in WT recipients. Moreover, the absence of IL-10 production in MyD88/IL-10 double-knockout mice rendered the mice susceptible to adoptive transfer of EAE. Thus, MyD88 signaling appears to be a key factor in determining the cytokine phenotype of T cells involved in autoimmune inflammation and regulation.
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PMID:IL-10 mediates resistance to adoptive transfer experimental autoimmune encephalomyelitis in MyD88(-/-) mice. 1994 74

B cells regulate autoimmune pathologies and chronic inflammatory conditions such as autoimmune encephalomyelitis and inflammatory bowel disease. The potential counterregulatory role of B cells in balancing pathogen-specific immune responses and the associated immunopathology is less well understood owing to the lack of appropriate persistent infection models. In this paper, we show that B cells have the ability to negatively regulate adaptive immune responses to bacterial pathogens. Using mouse models of infection with Helicobacter felis, a close relative of the human gastrointestinal pathogen H. pylori, we found that B cells activated by Helicobacter TLR-2 ligands induce IL-10-producing CD4(+)CD25(+) T regulatory-1 (Tr-1)-like cells in vitro and in vivo. Tr-1 conversion depends on TCR signaling and a direct T-/B-interaction through CD40/CD40L and CD80/CD28. B cell-induced Tr-1 cells acquire suppressive activity in vitro and suppress excessive gastric Helicobacter-associated immunopathology in vivo. Adoptive cotransfer of MyD88-proficient B cells and Tr-1 cells restores a normal gastric mucosal architecture in MyD88(-/-) and IL-10(-/-) mice in a manner that depends on T cellular, but not B cellular, IL-10 production. Our findings describe a novel mechanism of B cell-dependent Tr-1 cell generation and function in a clinically relevant disease model. In conclusion, we demonstrate that the B cell/Tr-1 cell axis is essential for balancing the control of Helicobacter infection with the prevention of excessive Th1-driven gastric immunopathology, promoting gastric mucosal homeostasis on the one hand and facilitating Helicobacter persistence on the other.
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PMID:TLR-2-activated B cells suppress Helicobacter-induced preneoplastic gastric immunopathology by inducing T regulatory-1 cells. 2114 7


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