Sijie Fang1,2,3, Yazhuo Huang1, Sisi Zhong1, Yangyang Li2,3, Yidan Zhang1, Yinwei Li1, Jing Sun1, Xingtong Liu1, Yang Wang1, Shuo Zhang1, Tianle Xu4, Xiaodong Sun5,6, Ping Gu1, Dan Li2,3, Huifang Zhou1, Bin Li2,3, Xianqun Fan1. 1. Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011, China. 2. Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China. 3. Department of Immunology and Microbiology, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China. 4. Discipline of Neuroscience, Department of Anatomy, Histology and Embryology, Collaborative Innovation Center for Brain Science, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China. 5. Department of Ophthalmology, Shanghai First People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200080, China. 6. Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai 200080, China.
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.
Context: T helper (Th)17 cells are correlated with many humanautoimmune 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.
Authors: Peter N Taylor; Lei Zhang; George J Kahaly; Marian Ludgate; Richard W J Lee; Ilaria Muller; Daniel G Ezra; Colin M Dayan Journal: Nat Rev Endocrinol Date: 2019-12-30 Impact factor: 43.330