Kennedy Institute of Rheumatology, Imperial College London, London, UK.
FEBS Lett. 2011 Dec 1;585(23):3681-8. doi: 10.1016/j.febslet.2011.06.006. Epub 2011 Jun 23.
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by synovial inflammation and destruction of joints. Over 20 years ago, tumour necrosis factor alpha (TNFα) was identified as a key player in a cytokine network, whose multifunctional effects could account for both the inflammation and destruction in RA. The remarkable efficacy of TNF inhibitors in the treatment of RA has resulted in extensive research addressing the regulation of TNFα production responsible for this excessive production. The discovery of autoimmunity to citrullinated protein/peptide antigens (ACPA) has led the concept that ACPA may be the essential link between disease susceptibility factors and the production of TNFα, which ultimately accounts for the disease phenotype. In this review we will consider (1) the mechanisms of citrullination, both physiological and pathological, (2) how known genetic and environmental factors could drive this peculiar form of autoimmunity and (3) how the immune response could lead to excessive production of TNFα by the synovial cells and ultimately to the disease phenotype (Fig. 1).
类风湿关节炎（RA）是一种慢性自身免疫性疾病，其特征为滑膜炎症和关节破坏。二十多年前，肿瘤坏死因子-α（TNFα）被确定为细胞因子网络中的关键因子，其多功能作用可以解释 RA 中的炎症和破坏。TNF 抑制剂在 RA 治疗中的显著疗效促使人们广泛研究负责这种过度产生的 TNFα产生的调节。对瓜氨酸化蛋白/肽抗原（ACPA）自身免疫的发现导致了这样一种概念，即 ACPA 可能是疾病易感性因素与 TNFα产生之间的必要联系，而 TNFα最终导致了疾病表型。在这篇综述中，我们将考虑（1）瓜氨酸化的生理和病理机制，（2）已知的遗传和环境因素如何驱动这种特殊形式的自身免疫，以及（3）免疫反应如何导致滑膜细胞过度产生 TNFα，并最终导致疾病表型（图 1）。
