类风湿关节炎Vγ9Vδ2+ T细胞定向趋化在炎症性骨侵蚀中的作用和机制

Rheumatoid arthritis is characterized by systemic inflammation, cartilage destruction and bone erosion. γδ T cells, as the vinculum of innate immunity and adaptive immunity, can function as antigen-presenting cells, produce a wide array of cytokines and chemokines and crosstalk with adaptive immune cells, thus playing a critical role in autoimmune diseases. It has been reported that increased γδ T cells accumulated in synovial joints of RA. Depletion of γδ T cells before induction of CIA resulted in a significant delay in disease onset and severity, whereas depletion of γδ T cells after development of CIA expedites the onset and severity of arthritis, indicating the involvement of γδ T cells in the pathologic progress of RA. Yet the specific mechanism remains to be clarified. In our preliminary work, we found Vδ2+ T cells decreased in peripheral blood while accumulated in RA synovium. These cells could produce pro-inflammatory cytokines like IL-17 and TNFα and express high levels of chemokines receptors like CCR5 and CXCR3, indicating an increased chemotaxis to joints and a pro-inflammatory feature of Vδ2+ T cells in loci. To explore the pathologic significance of directed chemotaxis of Vδ2+ T cells to joints and the molecular mechanisms of their contributions to cartilage/bone erosion, we initiate the study. Experiments in vitro will focus on the roles of Vδ2+ T in pro-inflammatory cytokines release, adaptive immune cells and fibroblast-like synoviocytes activation, and osteoclasts differentiation. While in CIA mice model, by specific γ chain knock-out, antibody depletion or adoptive transfer, we will verify the roles of γδ T cells in synovium proliferation and inflammatory cartilage destruction in vivo to testify the possibility of specific γδ T target therapy in RA.

类风湿关节炎(RA)以炎症和骨侵蚀为特征。γδT细胞是固有免疫和适应性免疫的纽带，可呈递抗原并产生多种细胞因子和趋化因子作用于适应性免疫。已证实RA滑液和滑膜中有γδT细胞聚集，而胶原诱导关节炎CIA小鼠发病前清除γδT细胞病情减轻，发病后清除则关节炎加重，提示γδT细胞参与RA病理进程，但具体机制不明。我们前期研究发现RA外周血Vδ2+T(Vγ9Vδ2+T)细胞减少而滑液滑膜中增多，趋化因子CCR5和CXCR3上调，分泌IL-17和TNFα能力较强，推测RA Vδ2+T细胞向关节趋化增多并发挥致炎作用，但其是否参与骨/软骨侵蚀尚不明确。研究将从致炎因子释放、效应性免疫细胞活化和破骨细胞(OCs)分化等角度探讨Vδ2+T细胞定向趋化至关节的病理意义及分子信号机制。并在CIA模型中通过特异性敲除γ链、抗体清除和过继性回输等方式验证γδT细胞是否有促炎促OCs分化作用及其作为靶向治疗的可能性。

类风湿关节炎（Rheumatoid arthritis, RA）以多种致炎因子增高和滑膜炎、骨侵蚀为特征，γδT细胞可呈递抗原并产生多种细胞因子和趋化因子。有研究表明RA滑液和滑膜中有γδT细胞聚集，提示γδT细胞参与RA病理进程，但机制不明。本团队发现RA外周血Vδ2+T细胞减少，但增殖和凋亡情况并无改变，其趋化因子受体CCR5和CXCR3表达上调，可分泌IFNγ、IL-17和TNFα；而RA受累关节滑膜和滑液中Vδ2+T细胞增多，滑液中趋化因子MIP-1α, MIP-1β、MIG, IP-10, I-TAC水平增高，提示RA Vδ2+T细胞向关节趋化增多并在局部发挥致炎作用；且RA血清孵育可诱导Vδ2+T细胞趋化因子受体CCR5和CXCR3上调，进一步研究证实主要是TNFα通过激活NF-κB通路发挥此诱导作用。RA患者给予TNFα抑制剂后伴随病情好转可出现外周血Vδ2+T细胞比例恢复和CCR5和CXCR3表达下调。此外发现小鼠肠道特别是小肠固有层有较高比例的γδT细胞，在胶原诱导关节炎（collagen induced arthritis，CIA）小鼠模型中灌胃定植一株可诱导小鼠骨髓来源树突细胞（bone marrow derived dendrtic cells，BMDC）产生IL-10的肠道共生菌Parabacteroides goldsteinii 可减轻小鼠关节炎表型。推测某些肠道共生菌可直接或间接影响肠道免疫细胞包括γδT细胞的功能和应答，但目前尚未对这一机制进行深入探讨和验证。