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

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 withGOand 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-gamma-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-beta-induced fibrosis in CD90(+) OFs but impedes 15deoxy-Delta(12,14)-prostaglandin J(2)-induced adipogenesis in CD902 OFs. Th17 cells promote proinflammatory cytokine secretion in both CD90(+) and CD902 OFs. Meanwhile, both CD90(+) and CD902 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.