CXCL16/CXCR6 and Their Roles in Autoimmune Arthritis

类风湿性关节炎（RA）的病因和发病机制仍不清楚，尽管强烈的 调查趋化因子在吸引和保留炎症关节中的白细胞方面起着关键作用。然而，细胞在关节中定位的精确机制尚不清楚。 本研究的长期目标是了解自身免疫性疾病背景下非淋巴组织中细胞运输和炎症反应的机制。最近我们发现，CXCL 16，一个新发现的趋化因子，及其受体，CXCR 6，高表达在小鼠关节胶原诱导关节炎（CIA），一种动物模型的RA。CXCL 16是具有跨膜结构域的趋化因子家族的第二个成员。受体携带细胞主要是Th 1细胞，显示淋巴外组织归巢潜力，并在RA患者的炎症滑液中富集。用CXCL 16-Ig融合蛋白治疗小鼠显著改善CIA。因此，我们推测CXCL 16/CXCR 6在自身免疫性关节炎的发病机制中起重要作用。该项目将重点关注调节CXCL 16/CXCR 6表达的机制，以及CXCL 16/CXCR 6对 中情局的成立和发展在CIA过程中还将研究优先在Th 1介导的炎性疾病如RA中表达的趋化因子，如CXCR 3和CCR 5，作为比较研究，以进一步阐明CXCL 16/CXCR 6在CIA发病机制中的作用。另外，我们推测CXCL 16/CXCR 6可能介导T细胞、B细胞、巨噬细胞和其他细胞之间的相互作用，这是由于CXCL 16作为一种膜趋化因子的独特结构及其表达模式。将研究CXCL 16/CXCR 6在介导T细胞-抗原呈递细胞中的作用。除了增强我们对类风湿关节中白细胞迁移的理解外，这些研究还有望提供有关趋化因子在调节关节炎中的功能的重要信息。 炎症反应期间淋巴细胞和巨噬细胞的活化和分化。该研究还将为设计自身免疫性关节炎和其他自身免疫性疾病的抗炎剂提供新的靶点

The etiology and pathogenesis of rheumatoid arthritis (RA) remain obscure despite intense investigation. Chemokines play a critical role in attracting and retaining leukocytes in the inflamed joints. However, the precise mechanism for cell positioning in the joints is unclear. The long-term goal of this project is to understand the mechanism of cell trafficking and inflammatory responses in nonlymphoid tissues in the settings of autoimmune diseases. Recently we have found that CXCL16, a newly identified chemokine, and its receptor, CXCR6, are highly expressed in the joints of mice with collagen-induced arthritis (CIA), an animal model of RA. CXCL16 is the second member of the chemokine family with a transmembrane domain. The receptor-bearing cells are mainly Th1 cells, display extralymphoid tissue homing potential and are enriched in inflamed synovial fluid of RA patients. Treatment of mice with CXCL16-lg fusion protein significantly ameliorates CIA. Thus, we hypothesize that CXCL16/CXCR6 play an important role in the pathogenesis of autoimmune arthritis. This project will focus on the mechanisms that regulate CXCL16/CXCR6 expression and the contribution of CXCL16/CXCR6 to the initiation and progression of CIA. Chemokines that are preferentially expressed in Th1-mediated inflammatory disorders like RA, such as CXCR3 and CCR5, will also be investigated during the course of CIA as comparative studies to further elucidate the role of CXCL16/CXCR6 in the pathogenesis of CIA. In addition, we hypothesize that CXCL16/CXCR6 may mediate interactions among T cell, B cells, macrophages and other cells in the affected sites because of the unique structure CXCL16 as a membrane chemokine and its expression pattern. The role of CXCL16/CXCR6 in mediating T cell-antigen presenting cells will be studied. Aside from enhancing our understanding of leukocyte migration in rheumatoid joints, these studies are expected to provide important information regarding chemokine functions in regulating activation and differentiation of lymphocytes and macrophages during inflammatory responses. The study will also provide insights into new targets for designing anti-inflammatory agents in autoimmune arthritis and other autoimmune diseases