Retinoid signals and Th17-mediated pathology

Department of Immunology, National Institute of Neuroscience, NCNP, Tokyo, Japan.
Japanese Journal of Clinical Immunology 03/2009; 32(1):20-8. DOI: 10.2177/jsci.32.20
Source: PubMed


For many years, CD4+ effector T cells were categorized into two subsets: T helper type 1 (Th1) and type 2 (Th2) cells. More recent research has refined this model, delineating further subsets; in particular, Th17 cells, activated CD4+ T cells characterised by the production of the cytokine IL-17. Autoantigen-specific Th17 cells are associated with pathology in a number of animal models of organ-specific autoimmune disease and evidence is mounting that Th17 cells are also critical in human autoimmunity. Retinoids, a family of compounds that bind to and activate retinoic acid receptors (RARs and RXRs), are able to alter CD4+ T cell differentiation in vitro though agonism and antagonism of a range of retinoid receptors. For example, all-trans retinoic acid (ATRA) inhibits Th17 differentiation and instead promotes the upregulation of Foxp3, a key transcription factor in regulatory T cells. Importantly, treatment with retinoids can modulate Th17-mediated autoimmunity: experimental autoimmune encephalomyelitis (EAE), the murine model of multiple sclerosis (MS), is ameliorated by ATRA administration due to suppression of both the differentiation and the function of Th17 cells. In this review, we discuss the unveiled molecular mechanism and the possible clinical application of retinoids for the treatment of human Th17-mediated autoimmune diseases.

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    • "In mouse models, under lymphopenic conditions, TH17 cells can re-differentiate into TH1 cells (Jager et al., 2009). Given that after chemotherapy and radiotherapy, patients with cancer might mimic lymphopenic hosts, and given that there are substantial numbers of IFN-g þ IL-17 þ T cells, TH17 cells could initially express low levels of IFN-g but gradually be converted into TH1 cells in vivo (Klemann et al., 2009). However, although IFN-g inhibits TH17 cell differentiation from naive T cells in mice, TH1 cell derived IFN-g might drive APCs to promote memory TH17 cell expansion through inducing the production of IL-1 and IL-23 by APCs (Mangini et al., 2007; Locksley, 2009). "
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    ABSTRACT: T helper 17 (TH17) cells have well-described roles in autoimmune disease. However, TH17 is not stable in some physiological or pathological courses. Also, TH17 cells can reciprocally modulate and convert into other helper T cell subpopulations. The fully exploring the reciprocal regulatory effects and its immunoregulatory mechanisms are becoming interesting topics in the immunological study. In this review, we summarized reciprocal modulation pattern between TH17 cell and other helper T cell subpopulations in the mouse model of autoimmune diseases and human diseases.
    Journal of Cellular Physiology 01/2011; 226(1):8-13. DOI:10.1002/jcp.22331 · 3.84 Impact Factor
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    • "With the emergence of data supporting the role of Th17 cells as effector cells in EAE [reviewed in (Aranami and Yamamura, 2008; Klemann et al, 2009)], we set out to determine whether modulation of these cells, through the administration of curdlan, would result in modulation of EAE. Since curdlan acts as a Th17 inducer, one would expect exacerbation of EAE upon curdlan administration. "
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    ABSTRACT: Experimental autoimmune encephalomyelitis (EAE), an experimental model for multiple sclerosis, can be induced through inoculation with several different central nervous system (CNS) proteins or peptides. Modulation of EAE, resulting in either protection from EAE or enhancement of EAE, can also be accomplished through either vaccination or DNA immunization with molecular mimics of self-CNS proteins. Previously published data on this method of EAE modulation will be reviewed. New data is presented, which demonstrates that EAE can also be modulated through the administration of the beta-(1,3)-D-glucan, curdlan. Dendritic cells stimulated by curdlan are involved in the differentiation of the interleukin-17 producing subset of CD4(+) T cells that are recognized effector cells in EAE. Using two different systems to study the effects of curdlan on EAE, it was found that curdlan increased the incidence of EAE and/or the severity of the disease course.
    Journal of Neuroimmune Pharmacology 06/2010; 5(2):168-75. DOI:10.1007/s11481-010-9215-x · 4.11 Impact Factor
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    ABSTRACT: Both spinel and plagioclase harzburgites from the Yungbwa ophiolite, southwestern Tibet, have been studied for highly siderophile elements (HSEs) and Re–Os isotopes. The spinel harzburgites can be subdivided into low-Cr# and high-Cr# groups, according to the spinel Cr#. The low-Cr# harzburgites have been estimated to experience with ca. 13% degrees of partial melting, whereas the high-Cr# harzburgites have been subjected to 16–18% degrees of melting. Clinopyroxenes in the low-Cr# harzburgites show depleted REE patterns, indicating they have been negligibly modified by melts. In contrast, both high-Cr# and plagioclase harzburgites have been metasomatized to different extents, as evidenced by the variable enrichment of LREE in their clinopyroxenes. Compositions of the metasomatic agents are of affinities to the subduction-related magmas. The low-Cr# harzburgites have equilibrium temperatures higher than both high-Cr# and plagioclase harzburgites. We explain that the low-Cr# harzburgites represent mantle residues after melt extraction at mid-ocean ridge (MOR), whereas both high-Cr# and plagioclase harzburgites were originated from the supra-subduction zone (SSZ) settings. These different types of mantle peridotites were tectonically juxtaposed during the emplacement of the Yungbwa ophiolite. The low-Cr# harzburgites display consistent highly siderophile element (HSE) patterns with suprachondritic Ru/Ir and Pd/Ir ratios, whereas both high-Cr# and plagioclase harzburgites show fractionated HSE patterns. A high-Cr# harzburgite, GHP-86, is strongly depleted in both Pd and Re. The Yungbwa harzburgites have variable 187Os/188Os ratios ranging from 0.12228 to 0.12876. Sample GHP-86 has the less radiogenic 187Os/188Os ratio, giving a depletion age (TRD) of ∼1Ga. The Re–Os isotope compositions of different types of the Yungbwa harzburgites suggest that their 187Os/188Os ratios have not been remarkably modified by subduction-related melts. Furthermore, subduction modification has not erased the ancient Os signatures in the Yungbwa peridotites. The reason is probably because the primary unradiogenic Os in the Yungbwa harzburgites had not been significantly reduced during the metasomatism. The asthenospheric mantle beneath the Neo-Tethys Ocean, from which the Yungbwa ophiolite was derived, had heterogeneous Os isotope compositions and contained some ancient mantle domains.
    Journal of Asian Earth Sciences 07/2012; 53. DOI:10.1016/j.jseaes.2011.08.010 · 2.74 Impact Factor
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