Regulation of Orbital Fibrosis and Adipogenesis by Pathogenic Th17 Cells in Graves Orbitopathy

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Abstract

Context:

T helper (Th)17 cells are correlated with many human autoimmune disorders, including Graves disease, and may play key roles in the pathogenesis of Graves orbitopathy (GO).

Objective:

To study the phenotype of Th17 cells in patients with GO and healthy subjects, investigate the fibrosis and adipogenesis in orbital fibroblasts (OFs) modulated by interleukin (IL)-17A, and determine the interaction between Th17 cells and OFs.

Design/Setting/Participants:

Blood samples and orbital tissues from GO patients and healthy controls were collected.

Main Outcome Measures:

We conducted multicolor flow cytometry, immunohistochemical and immunofluorescent stainings, Western blotting, a PathScan intracellular signaling assay, Luminex and enzyme-linked immunosorbent assays, and protein mass spectrum.

Results:

Interferon-γ- and IL-22-expressing Th17 cells are increased in GO patients, which are positively related to clinical activity score. Costimulatory molecules are highly expressed in GO orbits and most GO OFs are CD90+. IL-17A promotes TGF-β-induced fibrosis in CD90+ OFs but impedes 15-deoxy-Δ12,14-prostaglandin J2-induced adipogenesis in CD90− OFs. Th17 cells promote proinflammatory cytokine secretion in both CD90+ and CD90− OFs. Meanwhile, both CD90+ and CD90− OFs contribute to Th17 cell differentiation through prostaglandin E2 production, which can be attenuated by indomethacin. Furthermore, Th17 cells upregulate costimulatory molecule expression on OFs.

Conclusion:

Our findings unravel the pathogenicity of IL-17A in the initiation and progression of GO. In-depth interpretation of the molecular basis of OFs delineated by CD90 and Th17-OF interaction will help to afford a novel approach to better therapeutic strategies for GO.

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