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)

The Notch receptor and its ligands are involved in myelination in central nervous system (CNS) development. Re-expression of this pathway in the adult CNS has been proposed to hamper remyelination in multiple sclerosis. Previous studies also revealed that pharmacological inhibition of Notch signaling ameliorates experimental autoimmune encephalomyelitis (EAE). However, in a recent study in toxin-induced demyelination constituents of the Notch signaling pathway were demonstrated in remyelinating lesions indicating that remyelination may occur in the presence of Notch signaling. We examined the expression of Notch1-immunoreactivity (IR) and Jagged1-IR in EAE induced by myelin-oligodendrocyte glycoprotein (MOG). In this model, the combined action of T cells, antibodies and the complement cascade yields a pathology closely reflecting multiple sclerosis. Notch1 and its ligand Jagged1 were differentially expressed in the lesions of MOG-EAE. Notch1-IR on macrophages was highest in actively demyelinating and lowest in remyelinating lesions. The amount of Notch1-positive astrocytes increased during the lesion evolution from demyelination to remyelination. Notch1-positive oligodendrocytes were exclusively present in remyelinating lesions and not found in lesions without signs of remyelination. Astrocytes represented the major source of Jagged1-IR in demyelination and remyelination. In conclusion, our study proves that constituents of the Notch pathway are expressed in remyelination in an animal model of T-cell- and antibody-mediated CNS demyelination. Thus, it is unlikely, at least in the paradigm of MOG-EAE, that Notch signaling is responsible for a failure of remyelination.
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PMID:Notch1 and its ligand Jagged1 are present in remyelination in a T-cell- and antibody-mediated model of inflammatory demyelination. 1713 49

Notch signaling plays an important role during T cell development in the thymus and in T cell activation but the role of Notch in autoimmunity is not clear. We investigated the role of Jagged1 and Delta1 in experimental autoimmune encephalomyelitis. During experimental autoimmune encephalomyelitis, Delta1 expression is up-regulated on dendritic cells and B cells after priming while Jagged1 is up-regulated only on dendritic cells. Administration of anti-Jagged1 Ab exacerbated clinical disease while that of anti-Delta1 Ab reduced the severity of the clinical disease. In contrast, administration of Jagged1-Fc protected from disease, that of Delta1-Fc exacerbated disease. Treatment with Jagged1-Fc was associated with increased IL-10-producing Ag-specific cells in the CNS, while anti-Jagged1 decreased the frequency of IL-10-producing cells. Treatment with Delta1-Fc increased Th1 cells in the CNS, while anti-Delta-1 decreased the frequency of Th1 cells. Manipulation of Delta1 or Jagged1 had no effect on the frequency of Th17 cells or FoxP3(+) cells. Moreover, Jagged1 may play a role in CNS homeostasis because murine astrocytes specifically express Jagged1 that is up-regulated by TGF-beta, whereas IFN-gamma, TNF-alpha, and IL-17 decrease Jagged1 expression. Our study provides novel data about differential roles of Notch ligands in regulating inflammation in the periphery as well as in the CNS.
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PMID:JAGGED1 and delta1 differentially regulate the outcome of experimental autoimmune encephalomyelitis. 1794 72

Understanding complex diseases will benefit the recognition of the properties of the gene networks that control biological functions. Here, we set out to model the gene network that controls T-cell activation in humans, which is critical for the development of autoimmune diseases such as Multiple Sclerosis (MS). The network was established on the basis of the quantitative expression from 104 individuals of 20 genes of the immune system, as well as on biological information from the Ingenuity database and Bayesian inference. Of the 31 links (gene interactions) identified in the network, 18 were identified in the Ingenuity database and 13 were new and we validated 7 of 8 interactions experimentally. In the MS patients network, we found an increase in the weight of gene interactions related to Th1 function and a decrease in those related to Treg and Th2 function. Indeed, we found that IFN-ss therapy induces changes in gene interactions related to T cell proliferation and adhesion, although these gene interactions were not restored to levels similar to controls. Finally, we identify JAG1 as a new therapeutic target whose differential behaviour in the MS network was not modified by immunomodulatory therapy. In vitro treatment with a Jagged1 agonist peptide modulated the T-cell activation network in PBMCs from patients with MS. Moreover, treatment of mice with experimental autoimmune encephalomyelitis with the Jagged1 agonist ameliorated the disease course, and modulated Th2, Th1 and Treg function. This study illustrates how network analysis can predict therapeutic targets for immune intervention and identified the immunomodulatory properties of Jagged1 making it a new therapeutic target for MS and other autoimmune diseases.
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PMID:A network analysis of the human T-cell activation gene network identifies JAGGED1 as a therapeutic target for autoimmune diseases. 1803 Mar 50

Multiple sclerosis (MS) is an inflammatory disease of the CNS that is associated with demyelination and axonal loss, resulting in severe neurological handicap. Current MS therapies mostly target neuroinflammation but have only a little impact on CNS myelin repair. Progress toward treatments that enhance remyelination would therefore represent major advances in MS treatment. Here, we examined the ability of TFA-12, a new synthetic compound belonging to tocopherol long-chain fatty alcohols, to promote oligodendrocyte regeneration and remyelination in experimental models of MS. We showed that TFA-12 significantly ameliorates neurological deficit and severity of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE) in mice. Histological evaluation of mouse EAE spinal cords showed that TFA-12 treatment reduces inflammation, astrogliosis, and myelin loss. Additionally, we demonstrated that TFA-12 accelerates remyelination of focal demyelinated lesions induced by lysolecithin injections. We also found that this compound induces the differentiation of oligodendrocyte precursor cells into mature oligodendrocytes through the inhibition of the Notch/Jagged1 signaling pathway. Altogether, our data provide important proof of principle indicating that TFA-12 could be a potential therapeutic compound for myelin repair in MS.
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PMID:Tocopherol derivative TFA-12 promotes myelin repair in experimental models of multiple sclerosis. 2384 31

Oligodendrocytes are a type of glial cells that ensheath multiple neuronal axons and form myelin. Under pathological conditions, such as multiple sclerosis (MS), inflammatory damage to myelin and oligodendrocytes leads to demyelination. Although the demyelinated regions can partially resolve functional deficits through remyelination, however, as the disease progresses, remyelination typically becomes incomplete and ultimately fails. One possible explanation for this failure is the activation of the Notch pathway in MS lesions, which impedes oligodendrocyte precursor cells (OPCs) at maturation. This leads to a potential target for remyelination. Here, we have identified a compound Yhhu4952 that promoted the maturation of cultured OPCs in a dose-dependent and time-dependent manner. Neonatal rats showed a significant increase in the expression of myelin basic protein (MBP) and the prevalence of mature oligodendrocytes in the corpus callosum after Yhhu4952 treatment. The compound was also effective in promoting remyelination in cuprizone-induced demyelination model and improving severity scores in experimental autoimmune encephalomyelitis (EAE) model. Mechanism studies revealed that Yhhu4952 promotes OPC differentiation through the inhibition of the Jagged1-Notch1 pathway. These findings suggest Yhhu4952 is potentially useful for proceeding oligodendrocyte differentiation and remyelination.
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PMID:N-Phenylquinazolin-2-amine Yhhu4952 as a novel promotor for oligodendrocyte differentiation and myelination. 3023 49