重组PDCD5蛋白在类风湿关节炎动物模型中的作用及分子机制研究

It was reported that the defect of fibroblast-like synoviocytes (FLS) apoptosis and autoimmune reactions played an important role in the pathogenesis of rheumatoid arthritis (RA). Programmed cell death 5 (PDCD5) is a strong candidate apoptosis-regulating protein because of its known role in programmed cell death. Our previous studies suggested that reduced levels of PDCD5 mRNA and protein were detected in RA synovial tissue (ST) and FLS, and overexpression of PDCD5 could lead to enhanced apoptosis of RA FLS in vitro. We also found that the expression levels of PDCD5 in peripheral blood and synovial fluid of RA patients were negatively correlated with the pathogenic cytokines of RA, such as TNF-α and IL-17, which suggested that PDCD5 could negatively regulate the autoimmunity. On the basis of the above-mentioned study, we will focus on the effects of PDCD5 during the genesis and development of RA using animal models, clarify its regulatory effects on the autoimmunity, and explore its molecular basis and signal pathways. Through this research, we will deepen the understanding in the pathogenesis of RA, and provide laboratory evidences for potential applications of recombinant PDCD5 protein in therapy of RA.

成纤维样滑膜细胞(FLS)的凋亡缺陷以及自身免疫反应是类风湿关节炎(RA)的重要致病机理。人类程序性细胞死亡因子5(PDCD5)对细胞的凋亡具有重要的调控作用。我们前期研究发现，RA患者滑膜组织及FLS细胞中PDCD5的表达出现了异常，并且发现PDCD5能促进体外培养的RA FLS细胞的凋亡。同时我们还发现RA患者外周血及关节滑液中PDCD5的表达水平与TNF-α和IL-17等RA致病性细胞因子存在显著的负相关，提示PDCD5可能参与了RA自身免疫的负性调控。本课题将在上述研究的基础上，着重在RA动物模型上研究重组PDCD5蛋白对RA发生发展的作用，阐明其对RA中自身免疫反应的调控作用，相关分子机制及信号通路。通过这一研究，可以加深对RA致病机理的理解，并为重组PDCD5蛋白在治疗RA疾病中潜在的应用提供实验室依据。

成纤维样滑膜细胞(FLS)的凋亡缺陷以及自身免疫反应是类风湿关节炎(RA)的重要致病机理。人类程序性细胞死亡因子5(PDCD5)对细胞的凋亡具有重要的调控作用。我们前期研究发现，RA患者滑膜组织及FLS细胞中PDCD5的表达出现了异常，并且发现PDCD5能促进体外培养的RA FLS细胞的凋亡。同时我们还发现RA患者外周血及关节滑液中PDCD5的表达水平与TNF-α和IL-17等RA致病性细胞因子存在显著的负相关，提示PDCD5可能参与了RA自身免疫的负性调控。在上述研究的基础上，本课题在动物实验中发现，与关节炎对照小鼠相比，PDCD5转基因小鼠表现出了佐剂诱导性关节炎的进展收到抑制的征象，有明确的临床症状和组织学损伤的减轻。此外，CD4 + IFN-γ+细胞（Th1细胞）和CD4 + IL-17A +细胞（Th17细胞）的占比，以及促炎介质IFN-γ、IL-6、IL-17A、TNF-α的mRNA表达，在PDCD5转基因小鼠中均降低，而CD4 + CD25 + Foxp3 +调节性T细胞（Treg细胞）和抗炎介质IL-4、IL-10均有增加。此外，PDCD5转基因小鼠还表现出IFN-γ、IL-6、IL-17A和TNF-α的血清水平降低，IL-4水平升高。这些结果说明，PDCD5通过改变T淋巴细胞平衡、抑制促炎介质的产生和促进抗炎细胞因子的分泌，发挥了抗炎作用，提示了PDCD5蛋白作为RA的治疗手段的可能。本研究加深了对RA致病机理的理解，并为重组PDCD5蛋白在治疗RA疾病中潜在的应用提供了实验室依据。