Center of Experimental Rheumatology, University Hospital Zurich/Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Gloriastrasse 23-25, CH-8091 Zurich, Switzerland.
Mol Immunol. 2009 Nov;47(1):12-8. doi: 10.1016/j.molimm.2009.01.010. Epub 2009 Feb 15.
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by the progressive and irreversible destruction of joints. RA remains an incurable condition, although a new class of drugs, biologicals, have made a major breakthrough in targeting and/or eliminating the immune cells, including T cells, B cells and monocytes/macrophages from the joints. That we cannot (yet?) cure the disease is most likely due to the lack of therapeutic targeting the endogenously activated RA synovial fibroblasts (RASF). Most interestingly, RASF express Toll-like receptors (TLRs) 1-6 rendering them prone to activation by exogenous and endogenous TLR ligands and resulting in the production of numerous powerful chemokines and cytokines. These factors are responsible for the repopulation of immune cells in the joints after ceasing cell depleting therapies. To characterize the molecular mechanisms of synovial activation, a new approach studying the epigenetic characteristics of RASF has been recently undertaken. Thereby, the pattern of histone acetylation, DNA methylation and gene expression regulating microRNA are being explored. Since auto-antibodies have the most predictive and diagnostic value for RA, it is challenging to study more comprehensively the contribution of auto-antibodies to the disease. A new screening technique, serological analysis of recombinant human cDNA expression library (SEREX), adapted from cancer research allowed for the identification of novel auto-antibodies in RA, including anti-serpin E2 auto-antibodies. The serpin E2 auto-antibodies were found to inhibit the activity of serpin E2 and have potentially a functional role in the disease. The recent findings in the field of innate immunity, epigenetics and autoimmunity related to the pathogenesis of RA are in the scope of this review.
类风湿关节炎（RA）是一种慢性炎症性自身免疫性疾病，其特征是关节进行性和不可逆转的破坏。尽管一类新的药物——生物制剂——在靶向和/或消除关节中的免疫细胞（包括 T 细胞、B 细胞和单核细胞/巨噬细胞）方面取得了重大突破，但 RA 仍然是一种无法治愈的疾病。我们不能（尚未？）治愈这种疾病，很可能是因为缺乏针对内源性激活的 RA 滑膜成纤维细胞（RASF）的治疗靶点。最有趣的是，RASF 表达 Toll 样受体（TLR）1-6，使它们容易被外源性和内源性 TLR 配体激活，并导致产生许多强大的趋化因子和细胞因子。这些因子负责在停止细胞耗竭治疗后，使免疫细胞重新在关节中定居。为了表征滑膜激活的分子机制，最近采用了一种新的研究方法来研究 RASF 的表观遗传特征。由此，正在探索调节 microRNA 的组蛋白乙酰化、DNA 甲基化和基因表达模式。由于自身抗体对 RA 具有最具预测性和诊断价值，因此研究自身抗体对疾病的贡献具有挑战性。一种新的筛选技术，即重组人 cDNA 表达文库的血清学分析（SEREX），源自癌症研究，允许在 RA 中鉴定新的自身抗体，包括抗丝氨酸蛋白酶 E2 自身抗体。发现丝氨酸蛋白酶 E2 自身抗体抑制丝氨酸蛋白酶 E2 的活性，并在疾病中具有潜在的功能作用。本文综述了与 RA 发病机制相关的先天免疫、表观遗传学和自身免疫领域的最新发现。
