Antibodies against citrullinated proteins enhance tissue injury in experimental autoimmune arthritis
Antibodies against citrullinated proteins enhance tissue injury in experimental autoimmune arthritis
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DOI：
10.1172/jci25422
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发表时间：
2006-04-01
影响因子：
15.9
通讯作者：
Holers, VM
中科院分区：
文献类型：
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作者：
Kuhn, KA;Kulik, L;Holers, VM
抗瓜氨酸蛋白抗体是类风湿关节炎的特异性和预测性标志物，尽管这些抗体的病理相关性尚不清楚。为了研究这些自身抗体的意义，使用小鼠胶原诱导的关节炎（CIA）建立瓜氨酸化蛋白抗体反应性的动物模型。在第0天和第21天用牛II型胶原（CII）免疫DBA/1 J小鼠，并且每7天收集血清用于分析。针对CII和环瓜氨酸肽（一种此类瓜氨酸抗原）的抗体在免疫接种后早期出现，然后观察到关节肿胀。此外，这些抗体通过间接免疫荧光和Western印迹分别与大鼠食管中的瓜氨酸聚丝蛋白和瓜氨酸纤维蛋白原特异性结合。为了评估瓜氨酸化蛋白的免疫应答在CIA中的作用，用含瓜氨酸的肽使小鼠耐受，然后用CII进行抗原攻击。与对照组相比，耐受小鼠的疾病严重程度和发病率显著降低。我们还鉴定了对瓜氨酸化纤维蛋白原具有特异性的新型鼠单克隆抗体，其在与次最大剂量的抗CII抗体共同施用时增强关节炎，并在CIA小鼠的发炎滑膜内结合靶点。这些结果表明，抗瓜氨酸化蛋白的抗体主要参与自身免疫性关节炎的发病机制。
Antibodies against citrullinated proteins are specific and predictive markers for rheumatoid arthritis although the pathologic relevance of these antibodies remains unclear. To investigate the significance of these autoantibodies, collagen-induced arthritis (CIA) in mice was used to establish an animal model of antibody reactivity to citrullinated proteins. DBA/1J mice were immunized with bovine type II collagen (CII) at days 0 and 21, and serum was collected every 7 days for analysis. Antibodies against both CII and cyclic citrullinated peptide, one such citrullinated antigen, appeared early after immunization, before joint swelling was observed. Further, these antibodies demonstrated specific binding to citrullinated filaggrin in rat esophagus by indirect immunofluorescence and citrullinated fibrinogen by Western blot. To evaluate the role of immune responses to citrullinated proteins in CIA, mice were tolerized with a citrulline-containing peptide, followed by antigen challenge with CII Tolerized mice demonstrated significantly reduced disease severity and incidence compared with controls. We also identified novel murine monoclonal antibodies specific to citrullinated fibrinogen that enhanced arthritis when coadministered with a submaximal dose of anti-CII antibodies and bound targets within the inflamed synovium of mice with CIA. These results demonstrate that antibodies against citrullinated proteins are centrally involved in the pathogenesis of autoimmune arthritis.