Fang Sijie, Huang Yazhuo, Zhong Sisi, Li Yangyang, Zhang Yidan, Li Yinwei, Sun Jing, Liu Xingtong, Wang Yang, Zhang Shuo, Xu Tianle, Sun Xiaodong, Gu Ping, Li Dan, Zhou Huifang, Li Bin, Fan Xianqun
Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011, China.
Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China.
J Clin Endocrinol Metab. 2017 Nov 1;102(11):4273-4283. doi: 10.1210/jc.2017-01349.
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).
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.
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.
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.
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.
辅助性T细胞17（Th17）与包括格雷夫斯病在内的多种人类自身免疫性疾病相关，可能在格雷夫斯眼眶病（GO）的发病机制中起关键作用。
研究GO患者和健康受试者中Th17细胞的表型，探讨白细胞介素（IL）-17A调节眼眶成纤维细胞（OFs）的纤维化和脂肪生成情况，并确定Th17细胞与OFs之间的相互作用。
设计/地点/参与者：收集GO患者和健康对照者的血液样本和眼眶组织。
我们进行了多色流式细胞术、免疫组织化学和免疫荧光染色、蛋白质印迹法、PathScan细胞内信号检测、Luminex和酶联免疫吸附测定以及蛋白质质谱分析。
GO患者中表达干扰素-γ和IL-22的Th17细胞增加，这与临床活动评分呈正相关。共刺激分子在GO眼眶中高表达，大多数GO OFs为CD90+。IL-17A促进CD90+ OFs中转化生长因子-β诱导的纤维化，但抑制CD90- OFs中15-脱氧-Δ12,14-前列腺素J2诱导的脂肪生成。Th17细胞促进CD90+和CD90- OFs中促炎细胞因子的分泌。同时，CD90+和CD90- OFs均通过前列腺素E2的产生促进Th17细胞分化，吲哚美辛可减弱这种作用。此外，Th17细胞上调OFs上共刺激分子的表达。
我们的研究结果揭示了IL-17A在GO发生和发展中的致病性。深入解读由CD90和Th17-OF相互作用所描绘的OFs分子基础，将有助于为GO提供更好治疗策略的新方法。
