Kennedy Institute of Rheumatology, Charing Cross Campus, Imperial College London, London W6 8LH, UK.
Expert Rev Clin Immunol. 2006 May;2(3):365-75. doi: 10.1586/1744666X.2.3.365.
In the last 10 years, the discovery that antibodies to citrullinated proteins are highly specific for rheumatoid arthritis has led to a model of pathogenesis that ties together the genetic and environmental risk factors for susceptibility and severity of disease. The authors propose that the chronic inflammation is driven by two phases of an immune response. The first phase is the priming of autoimmunity, which may occur many years before the onset of disease and is caused by environmental factors, such as smoking and infectious agents, in the context of disease susceptibility alleles. This may occur in sites outside the joint, such as the respiratory tract. The second phase is the induction of arthritis, which is associated with the generation of citrullinated proteins within the joint, which is then perpetuated as the erosive disease by a local chronic immune response. The identity of candidate synovial citrullinated antigen(s), whether fibrin, vimentin, alpha-enolase, collagen type II or others yet to be described, may be the key to the pathogenesis of the destructive disease characteristic of rheumatoid arthritis. There is emerging evidence that citrullination may already be modified by established therapy in rheumatoid arthritis, but more specific inhibitors of deimination may provide new agents for future treatments.
在过去的 10 年中，人们发现针对瓜氨酸化蛋白的抗体对类风湿关节炎具有高度特异性，这一发现促使人们提出了一种发病机制模型，将疾病易感性和严重程度的遗传和环境风险因素联系在一起。作者提出，慢性炎症是由免疫反应的两个阶段驱动的。第一阶段是自身免疫的启动，这可能发生在疾病发作前多年，是由环境因素（如吸烟和感染因子）在疾病易感等位基因的背景下引起的。这可能发生在关节外的部位，如呼吸道。第二阶段是关节炎的诱导，这与关节内瓜氨酸化蛋白的产生有关，然后由局部慢性免疫反应使侵蚀性疾病持续存在。候选的滑膜瓜氨酸化抗原（无论是纤维蛋白、波形蛋白、α-烯醇酶、II 型胶原还是其他尚未描述的抗原）的身份可能是类风湿关节炎特征性破坏性疾病发病机制的关键。有新的证据表明，瓜氨酸化可能已经被类风湿关节炎的既定治疗所修饰，但更特异性的脱亚胺酶抑制剂可能为未来的治疗提供新的药物。
