Rheumatoid arthritis and citrullination.
Rheumatoid arthritis and citrullination.
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DOI：
10.1097/bor.0000000000000452
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发表时间：
2018-01
影响因子：
5.1
通讯作者：
Andrade F
中科院分区：
文献类型：
--
作者：
Darrah E;Andrade F
瓜氨酸化失调是驱动瓜氨酸化蛋白抗体产生和维持的关键因素，这是类风湿关节炎（RA）的标志。本文综述了近年来有关类风湿性关节炎瓜氨酸化抗原来源的文献。对类风湿性关节炎患者滑液（SF）的研究为了解类风湿性关节炎关节中积累的瓜氨酸化蛋白（类风湿性关节炎瓜氨酸组）的身份及其产生的控制机制提供了重要的见解。瓜氨酸化酶（肽精氨酸脱亚胺酶，PADs）受到严格控制以限制其过度活化。钙和氧化还原条件是PAD活性的重要调节因子。研究表明，类风湿性关节炎的瓜氨酸化在细胞内和细胞外都是失调的。在中性粒细胞中，宿主（即穿孔素和膜攻击复合体）和细菌（即毒素）成孔蛋白诱导显著的钙内流、细胞溶解和pad的过度激活，这可能分别在RA关节和疾病起始的关节外部位维持高尿酸水平。在严重RA患者的血液循环中也发现了结合和激活PAD4的自身抗体。由于细胞外环境是氧化的，已知的条件是使pad失活，RA中有效的细胞外瓜氨酸化可能需要垂死细胞不断释放活性酶，并可能被pad激活的自身抗体加速。了解pad如何在RA患者中过度激活以及瓜氨酸化蛋白（即瓜氨酸组）的产生，对于确定负责抗瓜氨酸化蛋白免疫反应的发展和维持的途径是重要的。
Dysregulated citrullination is a key element that drives the production and maintenance of antibodies to citrullinated proteins, a hallmark in rheumatoid arthritis (RA). This article reviews recent literature on the origin of citrullinated antigens in RA. The study of synovial fluid (SF) from patients with RA has provide important insights into the identity of citrullinated proteins that accumulate in the RA joint (the RA citrullinome) and mechanisms that control their generation. Citrullinating enzymes (peptidylarginine deiminases, PADs) are tightly controlled to limit their hyperactivation. Calcium and redox conditions are important regulators of PAD activity. Studies suggest that citrullination is dysregulated both intra- and extracellularly in RA. In neutrophils, host (i.e. perforin and the membrane attack complex) and bacterial (i.e. toxins) pore-forming proteins induce prominent calcium influx, cytolysis and hyperactivation of PADs, which likely maintain hypercitrullination in the RA joint and at extra-articular sites of disease initiation, respectively. Autoantibodies that bind and activate PAD4 have also been identified in the circulation of patients with severe RA. Since the extracellular environment is oxidizing, conditions that are known to inactivate PADs, efficient extracellular citrullination in RA probably requires the constant release of active enzymes from dying cells and may be accelerated by PAD-activating autoantibodies. Understanding how PADs are hyperactivated in patients with RA and the array of citrullinated proteins generated (i.e. the citrullinome), is important to identifying pathways responsible for the development and maintenance of anti-citrullinated protein immune responses.