Peptidyl arginine deiminase type 2 (PAD‐2) and PAD‐4 but not PAD‐1, PAD‐3, and PAD‐6 are expressed in rheumatoid arthritis synovium in close association with tissue inflammation

作者：Céline Foulquier, Mireille Sebbag, C Clavel, Sabine Chapuy‐Regaud, Roula Al Badine, Marie‐Claire Méchin, Christian Vincent, Rachida Nachat, Michiyuki Yamada, Hidenari Takahara, Michel Simon, Marina Guerrin, Guy Serre · 发表于：Arthritis & Rheumatism · 年份：2007 · DOI：10.1002/art.22983 · 被引用次数：384 · 研究领域：Rheumatoid Arthritis Research and Therapies、Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis、Osteoarthritis Treatment and Mechanisms

OBJECTIVE: 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. METHODS: 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. RESULTS: 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 hyperplasi...