Foulquier Céline, Sebbag Mireille, Clavel Cyril, Chapuy-Regaud Sabine, Al Badine Roula, Méchin Marie-Claire, Vincent Christian, Nachat Rachida, Yamada Michiyuki, Takahara Hidenari, Simon Michel, Guerrin Marina, Serre Guy
Unité Mixte de Recherche 5165, CNR-Université Toulouse III, Institut Fédératif de Recherche 30 (IFR30), Toulouse, France.
Arthritis Rheum. 2007 Nov;56(11):3541-53. doi: 10.1002/art.22983.
Autoantibodies to citrullinated proteins (ACPAs) are specific for rheumatoid arthritis (RA) and probably are involved in its pathophysiology. Citrullyl residues, posttranslationally generated by peptidyl arginine deiminase (PAD), are indispensable components of ACPA-targeted epitopes. The aim of this study was to identify which PAD isotypes are expressed in the synovial tissue (ST) of patients with RA and are involved in the citrullination of fibrin, the major synovial target of ACPAs.
Expression of all PAD isotypes, including the recently described PAD type 6 (PAD-6), was explored by reverse transcription-polymerase chain reaction and immunoblotting, first in blood-derived mononuclear leukocytes from healthy donors, then in ST samples from 16 patients with RA and 11 control patients (4 with other arthritides and 7 with osteoarthritis [OA]). In ST samples from patients with RA, PADs were localized by immunohistochemistry.
In lymphocytic and monocytic cells and, similarly, in ST samples from patients with RA, the PAD-2, PAD-4, and PAD-6 genes were found to be transcribed, but only PAD-2 and PAD-4 enzymes were detected. PAD-2 was also expressed in ST from control patients, including those with OA, while PAD-4 was preferentially expressed in ST from patients with other arthritides. In RA, the expression levels of PAD-2 and PAD-4 were correlated with the intensity of inflammation (cell infiltration, hypervascularization, and synovial lining hyperplasia), and both enzymes were demonstrable within or in the vicinity of citrullinated fibrin deposits.
PAD-2 and PAD-4 are the only PAD isotypes expressed in the ST of patients with RA and those with other arthritides. Inflammatory cells are a major source, but PAD-4 also comes from hyperplastic synoviocytes. Both isotypes are probably involved in the citrullination of fibrin.
瓜氨酸化蛋白自身抗体（ACPA）对类风湿关节炎（RA）具有特异性，可能参与其病理生理过程。由肽基精氨酸脱氨酶（PAD）翻译后产生的瓜氨酰残基是ACPA靶向表位的必需成分。本研究的目的是确定哪些PAD同种型在RA患者的滑膜组织（ST）中表达，并参与纤维蛋白（ACPA的主要滑膜靶点）的瓜氨酸化。
通过逆转录聚合酶链反应和免疫印迹法，首先在健康供体的血液来源单核白细胞中，然后在16例RA患者和11例对照患者（4例患有其他关节炎，7例患有骨关节炎[OA]）的ST样本中，研究包括最近描述的PAD 6型（PAD-6）在内的所有PAD同种型的表达。在RA患者的ST样本中，通过免疫组织化学对PAD进行定位。
在淋巴细胞和单核细胞中，同样在RA患者的ST样本中，发现PAD-2、PAD-4和PAD-6基因被转录，但仅检测到PAD-2和PAD-4酶。PAD-2也在包括OA患者在内的对照患者的ST中表达，而PAD-4优先在其他关节炎患者的ST中表达。在RA中，PAD-2和PAD-4的表达水平与炎症强度（细胞浸润、血管增生和滑膜衬里增生）相关，并且两种酶在瓜氨酸化纤维蛋白沉积物内或附近均可显示。
PAD-2和PAD-4是在RA患者和其他关节炎患者的ST中表达的仅有的PAD同种型。炎症细胞是主要来源，但PAD-4也来自增生的滑膜细胞。两种同种型可能都参与纤维蛋白的瓜氨酸化。
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