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 are implicated in CNS autoimmune diseases. We show that mice with targeted-deletion of Stat3 in CD4(+) T cells (CD4(Stat3)(-/-)) do not develop experimental autoimmune uveoretinitis (EAU) or experimental autoimmune encephalomyelitis. Defective Th17 differentiation noted in CD4(Stat3)(-/-) mice is compensated by exaggerated increases in Foxp3-, IL-10-, IL-4-, and IFN-gamma-expressing T cells, suggesting critical roles of STAT3 in shaping Ag-specific CD4(+) T cell repertoire. In mice with EAU, a high percentage of IL-17-expressing T cells in their peripheral lymphoid organs also secrete IFN-gamma while these double-expressors are absent in CD4(Stat3)(-/-) and wild-type mice without EAU, raising the intriguing possibility that uveitis maybe mediated by Th17 and IL-17-expressing Th1 cells. Resistance of Stat3-deficient mice to EAU derives in part from an inability of uveitogenic Th17 and Th1 cells to enter eyes or brain of the CD4(Stat3)(-/-) mouse because of the reduction in the expression of activated alpha4/beta1 integrins on CD4(Stat3)(-/-) T cells. Adoptive transfer of activated interphotoreceptor retinoid-binding protein-specific uveitogenic T cells induced in CD4(Stat3)(-/-) mice a severe EAU characterized by development of retinal folds, infiltration of inflammatory cells into the retina, and destruction of retinal architecture, underscoring our contention that the loss of STAT3 in CD4(+) T cells results in an intrinsic developmental defect that renders CD4(Stat3)(-/-) resistant to CNS inflammatory diseases. STAT3 requirement for IL-17 production by Th17, generation of double positive T cells expressing IL-17 and IFN-gamma, and for T cell trafficking into CNS tissues suggests that STAT3 may be a therapeutic target for modulating uveitis, sceritis, or multiple sclerosis.
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PMID:Loss of STAT3 in CD4+ T cells prevents development of experimental autoimmune diseases. 1842 28

Multiple sclerosis (MS) is a CD4+ T cell-mediated autoimmune disease affecting the central nervous system. It was largely accepted that Th1 cells driven by IL-12 were pathogenic T cells in human MS and experimental autoimmune encephalomyelitis, an animal model of MS. Recent data have established that IL-17-producing CD4+ T cells, driven by IL-23 and referred to as Th17 cells, play a pivotal role in the pathogenesis of EAE. A combination of TGF-beta and IL-6 induce Th17 cell lineage commitment via expression of transcription factor RORgammat. Th17 cells and induced Foxp3+ T regulatory cells are in reciprocal position in the T cell lineage commitment governed by TGF-beta and IL-6. The vitamin A metabolite retinoic acid is involved in this process via TGF-beta dependent induction of Foxp3. We have demonstrated that human Th17 cells could be identified as CCR2+ CCR5- memory CD4+ T cells. It is becoming clear that IL-23/Th17 axis also plays an important role in the pathogenesis of various human autoimmune diseases including MS. Additionally, accumulating evidences raise a possibility that CCR2 on Th17 cells may be a therapeutic target in MS.
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PMID:Th17 Cells and autoimmune encephalomyelitis (EAE/MS). 1842 64

The identification of novel helper T (Th) cell subsets, i.e., IL-17-producing Th cells (Th17 cells) and regulatory T cells (Treg cells), provided new insight into our understanding of the molecular mechanisms involved in the development of infectious and autoimmune diseases as well as immune responses, and thus led to revision of the classic Th1/Th2 paradigm. Several current lines of evidence from gene-deficient mice indicate that IL-17 and Th17 cells, but not IFN-gamma and Th1 cells, are responsible for the development of autoimmune diseases such as murine arthritis and encephalomyelitis, which have classically been considered to be Th1-mediated disorders. Th17 cells may also contribute to the pathogenesis of classically recognized Th2-mediated allergic disorders. In this review, we summarize the current knowledge regarding IL-17 and Th17 cells and discuss their potential roles in the pathogenesis of allergic disorders.
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PMID:Th17 and allergy. 1842 65

Triptolide (TPT), a diterpenoid triepoxide, is the major component isolated from the Chinese herb Tripterygium wilfordii Hook. f. Previous studies have shown that TPT has immunosuppressive properties and is effective in prolonging graft survival and suppressing autoimmune responses. The aim of this study was to investigate the protective effect of TPT in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Treatment of C57BL/6 mice with TPT from the date of EAE induction significantly delayed EAE onset and suppressed disease severity, accompanied with reduced inflammation and demyelination in the central nervous system. TPT treatment lead to a significant inhibition of the mRNA expression of both Th1/Th(IL-17) and Th2 cytokines in spleen mononuclear cells (MNC) as well as in spinal cord tissues. In addition, the expression of Forkhead box p3 (Foxp3) was up-regulated in spleen MNC after TPT treatment. Furthermore, we detected apparent inhibition of nuclear factor-kappa B (NF-kappaB)-DNA binding activity, increased expression of the inhibitor of nuclear factor-kappa Balpha (IkappaBalpha) and decreased expression of pIkappaBalpha in spleen MNC in TPT-treated EAE mice. Taken together, these findings indicate that TPT has profound immunoregulatory functions and potential protective values for the treatment of autoimmune inflammatory disorders.
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PMID:Triptolide modulates T-cell inflammatory responses and ameliorates experimental autoimmune encephalomyelitis. 1843 25

Interleukin (IL)-6 is a pleiotropic cytokine that has crucial roles in the regulation of immune response, inflammation and hematopoiesis. Recently, a new inflammatory helper T cell subset which produces IL-17A (IL-17), termed Th17 cells was identified and has been reported to be involved in the development and pathogenesis of collagen induced arthritis (CIA) and experimental autoimmune encephalomyelitis (EAE), which are known as the mouse model of rheumatoid arthritis and multiple sclerosis, respectively. It has been demonstrated that IL-6 together with TGF-beta induces the differentiation of Th17 cells from naive helper T cells in vitro. However, IL-6 independent pathway of Th17 differentiation has also been reported, suggesting that the role of IL-6 in vivo in these diseases remains unclear. With the treatment of anti-IL-6R antibody in CIA and EAE, we could suppress the differentiation of antigen specific Th17 cells and the onset of diseases. These results indicate that IL-6 is involved in the induction of Th17 cells in vivo, and anti-IL-6R antibody might be a promising therapy of Th17-mediated autoimmune diseases.
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PMID:[Role of IL-6 in the development and pathogenesis of CIA and EAE]. 1844 9

Plasmacytoid dendritic cells (pDCs) have both stimulatory and regulatory effects on T cells. pDCs are a major CNS-infiltrating dendritic cell population during experimental autoimmune encephalomyelitis but, unlike myeloid dendritic cells, have a minor role in T cell activation and epitope spreading. We show that depletion of pDCs during either the acute or relapse phases of experimental autoimmune encephalomyelitis resulted in exacerbation of disease severity. pDC depletion significantly enhanced CNS but not peripheral CD4(+) T cell activation, as well as IL-17 and IFN-gamma production. Moreover, CNS pDCs suppressed CNS myeloid dendritic cell-driven production of IL-17, IFN-gamma, and IL-10 in an IDO-independent manner. The data demonstrate that pDCs play a critical regulatory role in negatively regulating pathogenic CNS CD4(+) T cell responses, highlighting a new role for pDCs in inflammatory autoimmune disease.
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PMID:Cutting edge: central nervous system plasmacytoid dendritic cells regulate the severity of relapsing experimental autoimmune encephalomyelitis. 1845 61

Recent studies have suggested that IL-21 is a key factor in the development of IL-17-producing CD4 T cells (Th17) and that the induction of experimental autoimmune encephalomyelitis, which depends on mounting an efficient Th17 response, is reportedly impaired in the absence of IL-21 signaling. In this study, we provide supportive in vitro evidence that IL-21 can drive Th17 responses in conjunction with TGF-beta. However, more importantly we also demonstrate, using IL-21- and IL-21R-deficient mice, that IL-21 is not essential for the differentiation of Th17 cells in vitro and in vivo. Moreover, we show that IL-21- and IL-21R-deficient mice are highly susceptible to experimental autoimmune encephalomyelitis with disease scores that were comparable, or even higher at the peak of disease, to those of control mice. Thus, our results challenge the notion that IL-21 is a key factor in driving Th17 immunity and disease.
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PMID:Cutting edge: IL-21 is not essential for Th17 differentiation or experimental autoimmune encephalomyelitis. 1849 Jul 6

CD4(+)CD25(+) regulatory T cells (Tregs) are essential for maintaining self-tolerance and immune homeostasis. Here we characterize a novel subset of CD4(+)CD25(+) Tregs that express latency-associated peptide (LAP) on their cell surface (CD4(+)CD25(+)LAP(+) cells). CD4(+)CD25(+)LAP(+) cells express elevated levels of Foxp3 and Treg-associated molecules (CTLA4, glucocorticoid-induced TNFR-related gene), secrete TGFbeta, and express both cell surface TGFbeta and surface receptors for TGFbeta. In vitro, the suppressive function of CD4(+)CD25(+)LAP(+) cells is both cell contact and soluble factor dependent; this contrasts with CD4(+)CD25(+)LAP(-) cells, which are mainly cell contact dependent. In a model of experimental autoimmune encephalomyelitis, CD4(+)CD25(+)LAP(+) cells exhibit more potent suppressive activity than CD4(+)CD25(+)LAP(-) cells, and the suppression is TGFbeta dependent. We further show that CD4(+)CD25(+)LAP(+) cells suppress myelin oligodendrocyte glycoprotein-specific immune responses by inducing Foxp3 and by inhibiting IL-17 production. Our findings demonstrate that CD4(+)CD25(+) Tregs are a heterogeneous population and that the CD4(+)CD25(+) subset that expresses LAP functions in a TGFbeta-dependent manner and has greater in vivo suppressive properties. Our work helps elucidate the ambiguity concerning the role of TGFbeta in CD4(+)CD25(+) Treg-mediated suppression and indicates that LAP is an authentic marker able to identify a TGFbeta-expressing CD4(+)CD25(+) Treg subset.
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PMID:Latency-associated peptide identifies a novel CD4+CD25+ regulatory T cell subset with TGFbeta-mediated function and enhanced suppression of experimental autoimmune encephalomyelitis. 1849 Jul 32

Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, has long been thought to be mediated by Th1 CD4(+) T cells. Using adoptive transfer techniques, transfer of CNS specific Th1 T cells was sufficient to induce EAE in naive mice. However, recent studies found a vital role for IL-17 in induction of EAE. These studies suggested that a fraction of IL-17-producing T cells that contaminate Th1 polarized cell lines are largely responsible for initiation of EAE. In this study, we tracked the appearance and cytokine production capacity of adoptively transferred cells within the CNS of mice throughout EAE disease. IL-17-producing, adoptively transferred cells were not enriched over the low percentages present in vitro. Thus, there was no selective recruitment and/or preferential proliferation of adoptively transferred IL-17-producing cells during the induction of EAE. Instead a large number of CNS infiltrating host T cells in mice with EAE were capable of producing IL-17 following ex vivo stimulation. The IL-17-producing T cells contained both alphabeta and gammadelta TCR(+) T cells with a CD4(+)CD8(-) or CD4(-)CD8(-) phenotype. These cells concentrated within the CNS within 3 days of adoptive transfer, and appeared to play a role in EAE induction as adoptive transfer of Th1 lines derived from wild-type mice into IL-17-deficient mice induced reduced EAE clinical outcomes. This study demonstrates that an encephalitogenic Th1 cell line induces recruitment of host IL-17-producing T cells to the CNS during the initiation of EAE and that these cells contribute to the incidence and severity of disease.
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PMID:Host T cells are the main producers of IL-17 within the central nervous system during initiation of experimental autoimmune encephalomyelitis induced by adoptive transfer of Th1 cell lines. 1852 70

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) mediated by Th17 and Th1 cells. DNA microarray analysis previously showed that NR4A2, an orphan nuclear receptor, is strongly up-regulated in the peripheral blood T cells of MS. Here, we report that NR4A2 plays a pivotal role for mediating cytokine production from pathogenic T cells. In experimental autoimmune encephalomyelitis (EAE), an animal model of MS, NR4A2, was selectively up-regulated in the T cells isolated from the CNS. Strikingly, a forced expression of NR4A2 augmented promoter activities of IL-17 and IFN-gamma genes, leading to an excessive production of these cytokines. Conversely, treatment with siRNA for NR4A2, resulted in a significant reduction in the production of IL-17 and IFN-gamma. Furthermore, treatment with NR4A2 siRNA reduced the ability of encephalitogenic T cells to transfer EAE in recipient mice. Thus, NR4A2 is an essential transcription factor for triggering the inflammatory cascade of MS/EAE and may serve as a therapeutic target.
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PMID:Orphan nuclear receptor NR4A2 expressed in T cells from multiple sclerosis mediates production of inflammatory cytokines. 1855 Aug 28


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