Journal
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
Volume 102, Issue 11, Pages 4273-4283Publisher
ENDOCRINE SOC
DOI: 10.1210/jc.2017-01349
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Funding
- National High Technology Research and Development Program (863 Program) [2015AA020311]
- Chinese National Program on Key Basic Research Project [2014CB541800, 2014CB541900]
- National Natural Science Foundation of China [31600971, 81300799, 81320108010, 81570883, 31525008, 81330072, 31300711, 31370863, 31170825, 31200646, 31150110337, 31200647]
- Science and Technology Commission of Shanghai Municipality [14411968000]
- Shanghai Key Grants [14JC1406100, 14JC1493103, 12419A9300]
- Program of Shanghai Academic Research Leader [16XD1403800]
- National Science and Technology Major Projects [2012ZX10002007-003, 2013ZX10003009-002]
- Novo Nordisk
- Shanghai Municipal Education Commission-Gaofeng Clinical Medicine [20152228]
- Shanghai Municipal Hospital Emerging Frontier Technology Joint Research Project [SHDC12012107]
- Shanghai JiaoTong University Medical and Engineering Cross Fund [YG2014MS03]
- Key Project of Shanghai Basic Research [13JC1403800]
- Shanghai Rising Star Program Grant, Chinese Academy of Sciences 100 Talent Program [10QA1407900]
- Program of Shanghai Subject Chief Scientist, Chinese Academy of Sciences 100 Talent Program
- National Science Fund for Distinguished Young Scholars
- Chinese Academy of Sciences Foundation
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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.
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