Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Microglia are the resident macrophage-like population in the CNS. Microglia remain quiescent until injury or infection activates the cells to perform effector inflammatory and APC functions. Our previous studies have shown that microglia infected with a neurotropic strain of Theiler's murine encephalomyelitis virus secreted innate immune cytokines and up-regulated costimulatory molecules and MHC class II, enabling the cells to present viral and myelin Ags to CD4+ T cells. Recently, TLRs have been shown to recognize pathogen-associated molecular patterns and initiate innate immune responses upon interaction with infectious agents. We examined TLR expression on brain microglia and their functional responses upon stimulation with various TLR agonists. We report that mouse microglia express mRNA for all of the recently identified TLRs, TLR1-9, used for recognition of bacterial and viral molecular patterns. Furthermore, stimulation of quiescent microglia with various TLR agonists, including LPS (TLR4), peptidoglycan (TLR2), polyinosinic-polycytidylic acid (TLR3), CpG DNA (TLR9), and infection with viable Theiler's murine encephalomyelitis virus, activated the cells to up-regulate unique patterns of innate and effector immune cytokines and chemokines at the mRNA and protein levels. In addition, TLR stimulation activated up-regulation of MHC class II and costimulatory molecules, enabling the microglia to efficiently present myelin Ags to CD4+ T cells. Thus, microglia appear to be a unique and important component of both the innate and adaptive immune response, providing the CNS with a means to rapidly and efficiently respond to a wide variety of pathogens.
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PMID:Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. 1535 40

The course of autoimmune inflammatory diseases of the central nervous system (CNS) can be influenced by infections. Here we assessed the disease-modulating effects of the most frequent respiratory pathogen Streptococcus pneumonia on the course of experimental autoimmune encephalomyelitis (EAE). Mice were immunized with myelin oligodendrocyte glycoprotein 35-55 (MOG(35-55)) peptide, challenged intraperitoneally with live S. pneumoniae type 3, and then treated with ceftriaxone. EAE was monitored by a clinical score for 35 days after immunization. EAE was unaltered in mice infected with S. pneumoniae 2 days before and 21 days after the first MOG(35-55) injection but was more severe in animals infected 7 days after the first MOG(35-55) injection. The antigen-driven systemic T-cell response was unaltered, and the intraspinal Th1 cytokine mRNA concentrations at the peak of disease were unchanged. The composition of CNS-infiltrating cells and subsequent tissue destruction were only slightly increased after S. pneumoniae infection. In contrast, the serum levels of tumor necrosis factor alpha and interleukin-6 and spinal interleukin-6 levels were elevated, and the expression of major histocompatibility complex class II molecules, CD80, and CD86 on splenic dendritic cells were enhanced early after infection. Serum cytokine concentrations were not elevated, and EAE was not aggravated by S. pneumoniae infection in Toll-like receptor 2 (TLR2)-deficient mice. In conclusion, infection with S. pneumoniae worsens EAE probably by elevation of proinflammatory cytokines and activation of dendritic cells in the systemic circulation via TLR2 and cross talk through the blood-brain barrier.
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PMID:Streptococcus pneumoniae Infection aggravates experimental autoimmune encephalomyelitis via Toll-like receptor 2. 1686 72

Recent studies claim a central role for Toll-like receptor (TLR) ligands in stimulating autoimmune disease by activation of antigen-presenting cells in the target organ, but it is unclear if and how TLR ligands reach target organs. Most evidence comes from rodent models, and it is uncertain whether this principle holds in primates. Here we identify which cells contain peptidoglycan (PGN) in multiple sclerosis brain and in two nonhuman primate experimental autoimmune encephalomyelitis (EAE) models with different disease courses: acute (rhesus monkey) versus chronic disease (marmoset). Because persistence of TLR ligands in the central nervous system might be consequential for disease progression, we also determined the expression of two major PGN-degrading enzymes, ie, lysozyme and N-acetylmuramyl-l-alanine amidase. Distinct phagocyte subsets, including granulocytes, macrophages, and dendritic cells, contained PGN in the brain and coexpressed the inflammatory cytokine interleukin-12. The number of phagocytes carrying PGN increased in acute and chronic EAE compared with control animals, with the highest number of PGN-containing cells in acute EAE brain. Lytic enzymes were scarcely expressed in monkey and multiple sclerosis brain, favoring PGN persistence. PGN stimulated interleukin-12p70 release by leukocytes from all three primate species. The presence of PGN in the inflamed brain may have major implications because TLR2/Nod ligation potentially promotes inflammation and disease progression.
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PMID:Phagocytes containing a disease-promoting Toll-like receptor/Nod ligand are present in the brain during demyelinating disease in primates. 1707 91

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

Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the CNS, most frequently starting with a series of bouts, each followed by complete remission and then a secondary, progressive phase during which the neurological deficit increases steadily. The underlying molecular mechanisms responsible for disease progression are still unclear. Herein, we demonstrate that high mobility group box chromosomal protein 1 (HMGB1), a DNA-binding protein with proinflammatory properties, is evident in active lesions of MS and experimental autoimmune encephalomyelitis (EAE) and that HMGB1 levels correlate with active inflammation. Furthermore, the expression of the innate HMGB1 receptors--receptor for advanced glycation end products, TLR2, and TLR4--was also highly increased in MS and rodent EAE. Additionally, in vitro activation of rodent CNS-derived microglia and bone marrow-derived macrophages demonstrated that microglia were equally as capable as macrophages of translocating HMGB1 following LPS/IFN-gamma stimulation. Significant expression of HMGB1 and its receptors on accumulating activated macrophages and resident microglia may thus provide a positive feedback loop that amplifies the inflammatory response during MS and EAE pathogenesis.
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PMID:Pivotal advance: HMGB1 expression in active lesions of human and experimental multiple sclerosis. 1864 48

Activation of Toll-like receptors (TLR) contributes to the initiation and maintenance of chronic inflammation in autoimmune diseases, yet repeated exposure to a TLR agonist can induce hyporesponsiveness to subsequent TLR stimulation. Here, we used a synthetic TLR7 agonist, 9-benzyl-8-hydroxy-2-(2-methoxyethoxy) adenine (SM360320, 1V136) to study TLR7 induced attenuation of inflammatory responses and its application to autoimmune diseases. Repeated low dose administration of this TLR7 agonist induced hyporesponsiveness or tolerance to TLR2, -7, and -9 activators and limited the course of neural inflammation in an experimental allergic encephalomyelitis model. The hyporesponsiveness did not depend on T or B lymphocytes, but did require bone marrow derived cells. In addition, TLR7 tolerance reduced inflammation in a passive antibody mediated arthritis model. TLR7 tolerance did not cause global immunosuppression, because susceptibility to Listeria monocytogenes infection was not altered. The mechanism of TLR7 tolerance involved the up-regulation of 2 inhibitors of TLR signaling: Interleukin 1 Receptor Associated Kinase (IRAK) M, and Src homology 2 domain-containing inositol polyphosphate phosphatase (SHIP)-1. These findings suggest that induction of TLR7 tolerance might be a new therapeutic approach to subdue inflammation in autoimmune diseases.
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PMID:Prevention of autoimmune disease by induction of tolerance to Toll-like receptor 7. 1918 97

Theiler's murine encephalomyelitis virus (TMEV) infection directly induces many proinflammatory genes, including type I interferon (IFN) and a variety of cytokine genes. These virus-induced cytokines are a critical factor in developing TMEV-induced demyelinating disease. We have previously reported that the major activation signal for the cytokine genes is mediated via TLR3. In this study, we describe that TLR2 is upregulated via TLR3 signal and cooperatively participates in the expression of IL-6, IL-1beta, CCL2, and CCL5 genes following TMEV infection. The expression of these genes was significantly impaired in both TLR2-deficient and TLR3-deficient primary astrocytes. However, the induction of type I IFNs was not affected by TLR2 deficiency in the primary cells. TMEV infection led to TLR2-mediated NF-kappaB activation, but not IRF3 or IRF7 activation, critical for type I IFN production. More importantly, TLR3 was required for TMEV-induced early TLR2 upregulation in primary astrocytes leading to the production of TLR2-dependent cytokines such as IL-6. Interestingly, soluble factor(s) produced via TLR2/3-dependent signals appears to be partially associated with the downstream cytokine production. These results indicate that TMEV utilizes TLR3-induced TLR2 to induce inflammatory cytokines, which are critical to the development of immune-mediated demyelinating disease.
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PMID:Theiler's virus infection induces TLR3-dependent upregulation of TLR2 critical for proinflammatory cytokine production. 1919 35

Multiple sclerosis is an inflammatory disease of the central nervous system that begins as a relapsing-remitting disease (RRMS) and is followed by a progressive phase (SPMS). The progressive phase causes the greatest disability and has no effective therapy, but the processes that drive SPMS are mostly unknown. Here we found higher serum concentrations of 15alpha-hydroxicholestene (15-HC) in patients with SPMS and in mice with secondary progressive experimental autoimmune encephalomyelitis (EAE) but not in patients with RRMS. In mice, 15-HC activated microglia, macrophages and astrocytes through a pathway involving Toll-like receptor 2 (TLR2) and poly(ADP-ribose) polymerase 1 (PARP-1). PARP-1 activity was higher in monocytes of patients with SPMS, and PARP-1 inhibition suppressed the progression of EAE. Thus, the TLR2-PARP-1 pathway is a potential new therapeutic target in SPMS.
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PMID:Toll-like receptor 2 and poly(ADP-ribose) polymerase 1 promote central nervous system neuroinflammation in progressive EAE. 2168 47

TLRs are a class of conserved pattern recognition receptors that are used by cells of the innate immune system. Recent studies have demonstrated the expression of TLRs on both human and mouse T cells raising the possibility that TLRs play a direct role in adaptive immunity. TLR2 is activated primarily by bacterial wall components including peptidoglycan and lipoproteins. Several studies have shown that mouse regulatory T (Treg) cells express TLR2 and claimed that engagement of TLR2 by synthetic ligands reversed their suppressive function. In contrary, enhancement of Treg function was observed following engagement of TLR2 on human Treg. We have reexamined the expression and function of TLR2 on mouse Treg purified from Foxp3-GFP knock-in mice. TLR2 ligation by TLR2 agonist, the synthetic bacterial lipoprotein Pam3CSK4, enhanced the proliferative responses of both conventional T cells and Treg in response to TLR stimulation in the absence of APC. Treatment of Foxp3+ Treg with Pam3CSK4 did not alter their suppressive function in vitro or in vivo and did not reduce their level of Foxp3 expression. An additional effect of TLR2 stimulation of Treg was induction of Bcl-x(L) resulting in enhanced survival in vitro. Treatment of mice with the TLR2 agonist enhanced the Ag-driven proliferation of Treg in vivo, but did not abolish their ability to suppress the development of experimental autoimmune encephalomyelitis. Development of methods to selectively stimulate TLR2 on Treg may lead to a novel approaches for the treatment of autoimmune diseases.
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PMID:Engagement of TLR2 does not reverse the suppressor function of mouse regulatory T cells, but promotes their survival. 1974 87

Recent reports suggest that commensal bacteria may play a down-regulatory role in autoimmune disease. In the present studies, we demonstrate that phosphorylated dihydroceramides, uniquely structured lipids derived from the common human oral bacterium Porphyromonas gingivalis and from bacteria commonly found in the gastrointestinal tract and other organs, are capable of enhancing autoimmunity. We have previously reported that these lipids have proinflammatory effects on human fibroblasts in vitro and, in preliminary studies, have recovered these lipids from surgically removed human carotid atheroma, suggesting that they may play a role in human inflammatory disease. To investigate whether these lipids have functional effects on autoimmunity, we administered phosphorylated dihydroceramides to mice with the murine model of multiple sclerosis, experimental allergic encephalomyelitis (EAE). We find that these lipids, and particularly the phosphoethanolamine dihydroceramide (PE DHC) fraction, significantly enhanced EAE. Mechanistically, PE DHC enhances EAE in mice lacking natural killer T cells, fails to enhance EAE in Toll-like receptor 2 (TLR2)-deficient mice and, in vitro, induces dendritic cell interleukin-6 secretion in a TLR2-dependent manner. Finally, PE DHC-treated mice with EAE demonstrate a decreased percentage of spinal cord Foxp3+ T cells, suggesting that these lipids may affect regulatory aspects of adaptive immune responses. Overall, our results suggest that phosphorylated dihydroceramides derived from common human bacteria function as TLR2 ligands and may play a previously unrecognized role in human autoimmune diseases.
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PMID:Unique lipids from a common human bacterium represent a new class of Toll-like receptor 2 ligands capable of enhancing autoimmunity. 1985 Aug 90


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