类风湿关节炎（RA)是以慢性关节炎症和骨破坏为特征的自身免疫性疾病。近期本课题组首次发现，白细胞免疫球蛋白样受体A3（LILRA3）与RA遗传易感性和骨破坏显著相关，有关研究结果已发表于风湿病学权威杂志Arthritis & Rheumatism。但目前尚无有关LILRA3功能和参与RA致病机制的研究报道。前期工作我们已进一步发现：LILRA3在RA患者关节滑液中呈特异性表达；体外LILRA3可直接诱导破骨细胞的分化，并促进RA患者滑膜成纤维细胞（RASF）的活化。课题组拟进一步研究LILRA3对RASF 活化和破骨细胞分化的作用机制；并通过LILRA3转基因鼠的研究,为理解LILRA3在关节炎中的作用机制提供直接依据。本课题将从分子、细胞、RA患者和动物模型四个层面探讨LILRA3对RA的致病作用, 为深入理解RA发病机制提供新线索, 也可能为RA治疗提供新的干预靶点。

Rheumatoid arthritis (RA) is an autoimmune diseases characterized by chronic inflammation, joint erosion and destruction, and ultimately disability. The etiology of RA remains obscure. Previously, we have found that the leukocyte immunoglobulin-like receptor A3 (LILRA3) was strongly associated with RA susceptibility and joint destruction in RA patients. However, so far the function of LILRA3 remains elusive. Our preliminary results indicated that RA patients showed striking elevated expression of LILRA3 in synovial fluid, compared to osteoarthritis (OA) patients. For the first time, we domenstrated that LILRA3 could directly induce osteoclast differentiation and synovial fibroblasts (SF) activation in vitro. To better understand the molecular mechanisms of LILRA3 contributed to RA pathgenesis, we aim to further study i) the role of LILRA3 and its possible interaction with RANKL/M-CSF in osteoclast differentiation; ii) the role of LILRA3 and its possible interaction with TNF/IL-1 in SF activation; iii) by generating LILRA3 transgenic mice, we are able to show the direct evidence of LILRA3 contributing to RA susceptibility and severity. Our study may provide new clue in understanding of RA pathogenesis and novel target for RA treatment.