T Helper 17 Cells in Primary Sjogren's Syndrome.
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ABSTRACT:
SUBMITTER: Matsui K
PROVIDER: S-EPMC5532573 | biostudies-literature | 2017 Jul
REPOSITORIES: biostudies-literature
Publications
T Helper 17 Cells in Primary Sjögren's Syndrome.
Matsui Kiyoshi K Sano Hajime H
Journal of clinical medicine 20170705 7
Primary Sjögren's syndrome is an autoimmune disease characterized by diffuse infiltration of lymphocytes into exocrine glands and other tissues. The infiltrating lymphocytes have been identified as subsets of B cells and T cells, including T helper 17 cells, T regulatory cells and follicular helper T cells. The role of these cells in the development of the syndrome is now known, as is their impact on the production of proinflammatory cytokines such as IL-6, IL-17, IL-22 and IL-23. In particular, ...[more]
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2013-11-14 | E-MTAB-2073 | biostudies-arrayexpress
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Project description:ObjectivesEnhancer of zeste homolog 2 (EZH2) is an epigenetic regulator that plays an essential role in immune system development and autoimmune diseases. This study aimed to characterize the role of EZH2 in the pathogenesis of primary Sjögren's syndrome (pSS).MethodsWe analyzed EZH2 expression in two transcriptomic datasets of peripheral blood mononuclear cells (PBMCs) from pSS patients and healthy controls. We measured EZH2 expression in CD4+ T cells, CD8+ T cells, and CD19+ B cells from pSS patients and healthy controls and correlated EZH2 expression with clinical parameters. We also examined the activation, proliferation, and T-cell differentiation of CD4+ T cells using the EZH2 inhibitor GSK126, EZH2 siRNA, and EZH2-expressing vector. We further examined the STAT3 signaling pathway after EZH2 inhibition and detected Tfh differentiation in EZH2-overexpressed CD4+ T cells with STAT3 knocked down.ResultsEZH2 was upregulated in GSE164885 and GSE48378. EZH2 expression was higher in pSS CD4+ and CD8+ T cells, and EZH2 expression in circulating pSS CD4+ T cells was positively correlated with IgG, IgA, ESR, RF, and the circulating Tfh population. EZH2 inhibition and silencing EZH2 suppressed activation, proliferation, and Tfh differentiation. Furthermore, overexpressing EZH2 promoted activation, proliferation, and Tfh differentiation in CD4+ T cells. EZH2 inhibition attenuated STAT3 phosphorylation in CD4+ T cells. STAT3 knockdown abrogated EZH2-promoted Tfh differentiation.ConclusionsEZH2 expression was abnormally elevated in pSS CD4+ T cells, which facilitated Tfh differentiation of CD4+ T cells by enhancing STAT3 phosphorylation. EZH2 promotes Tfh differentiation and might be implicated in pSS pathogenesis.
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Project description:ObjectiveA major characteristic of the autoimmune disease primary Sjögren's syndrome (SS) is salivary gland (SG) hypofunction. The inability of resident SG stem cells (SGSCs) to maintain homeostasis and saliva production has never been explained and limits our comprehension of mechanisms underlying primary SS. The present study was undertaken to investigate the role of salivary gland stem cells in hyposalivation in primary SS.MethodsSGSCs were isolated from parotid biopsy samples from controls and patients classified as having primary SS or incomplete primary SS, according to the American College of Rheumatology/European League Against Rheumatism criteria. Self-renewal and differentiation assays were used to determine SGSC regenerative potential, RNA was extracted for sequencing analysis, single telomere length analysis was conducted to determine telomere length, and frozen tissue samples were used for immunohistochemical analysis.ResultsSGSCs isolated from primary SS parotid gland biopsy samples were regeneratively inferior to healthy control specimens. We demonstrated that SGSCs from samples from patients with primary SS are not only lower in number and less able to differentiate, but are likely to be senescent, as revealed by telomere length analysis, RNA sequencing, and immunostaining. We further found that SGSCs exposed to primary SS-associated proinflammatory cytokines we induced to proliferate, express senescence-associated genes, and subsequently differentiate into intercalated duct cells. We also localized p16+ senescent cells to the intercalated ducts in primary SS SG tissue, suggesting a block in SGSC differentiation into acinar cells.ConclusionThis study represents the first characterization of SGSCs in primary SS, and also the first demonstration of a linkage between an autoimmune disease and a parenchymal premature-aging phenotype. The knowledge garnered in this study indicates that disease-modifying antirheumatic drugs used to treat primary SS are not likely to restore saliva production, and should be supplemented with fresh SGSCs to recover saliva production.
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