NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis.
NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis.
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DOI：
10.1126/scitranslmed.3005580
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发表时间：
2013-03-27
影响因子：
17.1
通讯作者：
Kaplan MJ
中科院分区：
文献类型：
--
作者：
Khandpur R;Carmona-Rivera C;Vivekanandan-Giri A;Gizinski A;Yalavarthi S;Knight JS;Friday S;Li S;Patel RM;Subramanian V;Thompson P;Chen P;Fox DA;Pennathur S;Kaplan MJ
导致类风湿性关节炎（RA）发展的早期事件尚不清楚，但瓜氨酸化抗原（ACPA）自身抗体的形成被认为是一个关键的致病现象。从患有各种自身免疫性疾病的患者分离的中性粒细胞显示增强的细胞外陷阱形成（NET），这是一种使自身抗原和免疫刺激分子外化的现象。我们研究了异常NETosis是否发生在RA中，确定其触发因素并检查其有害的炎症后果。与健康对照组和骨关节炎患者的中性粒细胞相比，在循环和滑液RA中性粒细胞中观察到增强的NETosis。此外，网状中性粒细胞浸润RA滑膜组织、类风湿结节和皮肤。NETosis与ACPA的存在和水平以及全身炎症标志物相关。RA血清和免疫球蛋白组分RA患者与高水平的ACPA和/或类风湿因子显着增强NETosis，这些自身抗体诱导的NET显示不同的蛋白质含量。在NETosis期间，中性粒细胞外化与RA发病机制有关的瓜氨酸化自身抗原，而抗瓜氨酸化波形蛋白抗体有效诱导NET形成。炎性细胞因子IL-17 A和TNF-α诱导RA中性粒细胞NETosis。反过来，NET显着增强RA和OA滑膜成纤维细胞的炎症反应，包括诱导IL-6，IL-8，趋化因子和粘附分子。这些观察结果表明，通过瓜氨酸化自身抗原和免疫刺激分子的外化，可能促进关节和外周的异常适应性和先天性免疫应答，并使这种疾病的致病机制永久化，加速了NETosis在RA发病机制中的作用。
The early events leading to the development of rheumatoid arthritis (RA) remain unclear but formation of autoantibodies to citrullinated antigens (ACPA) is considered a key pathogenic phenomenon. Neutrophils isolated from patients with various autoimmune diseases display enhanced extracellular trap formation (NETs), a phenomenon that externalizes autoantigens and immunostimulatory molecules. We investigated whether aberrant NETosis occurs in RA, determined its triggers and examined its deleterious inflammatory consequences. Enhanced NETosis was observed in circulating and synovial fluid RA neutrophils, compared to neutrophils from healthy controls and from patients with osteoarthritis. Further, netting neutrophils infiltrated RA synovial tissue, rheumatoid nodules and skin. NETosis correlated with ACPA presence and levels and with systemic inflammatory markers. RA sera and immunoglobulin fractions from RA patients with high levels of ACPA and/or rheumatoid factor significantly enhanced NETosis, and the NETs induced by these autoantibodies displayed distinct protein content. During NETosis, neutrophils externalized citrullinated autoantigens implicated in RA pathogenesis, whereas anti-citrullinated vimentin antibodies potently induced NET formation. The inflammatory cytokines IL-17A and TNF-α induced NETosis in RA neutrophils. In turn, NETs significantly augmented inflammatory responses in RA and OA synovial fibroblasts, including induction of IL-6, IL-8, chemokines and adhesion molecules. These observations implicate accelerated NETosis in RA pathogenesis, through externalization of citrullinated autoantigens and immunostimulatory molecules that may promote aberrant adaptive and innate immune responses in the joint and in the periphery, and perpetuate pathogenic mechanisms in this disease.
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DOI：
10.1084/jem.20100239
发表时间：
2010-08-30
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Li P;Li M;Lindberg MR;Kennett MJ;Xiong N;Wang Y
通讯作者：
Wang Y
DOI：
10.4049/jimmunol.1100123
发表时间：
2011-07-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Lin AM;Rubin CJ;Khandpur R;Wang JY;Riblett M;Yalavarthi S;Villanueva EC;Shah P;Kaplan MJ;Bruce AT
通讯作者：
Bruce AT
影响因子：
2.7
作者：
Gupta, AK;Hasler, P;Hahn, S
通讯作者：
Hahn, S
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
4.9
作者：
Kinloch, Andrew;Tatzer, Verena;Wait, Robin;Peston, David;Lundberg, Karin;Donatien, Phillipe;Moyes, David;Taylor, Peter C;Venables, Patrick J
通讯作者：
Venables, Patrick J