Gaq对类风湿关节炎Th1Th2细胞分化的调控作用及其机制研究

Gαq是Gq蛋白的α功能亚基，在信号转导中发挥着重要的作用。先前的研究报道，Gαq调控DC的游走和B细胞的凋亡；更有意义的是，Gαq-KO骨髓嵌合鼠在骨髓移植四个月后，自发表现出炎症性关节炎的症状。临床研究也表明，Gαq在类风湿关节炎（RA）患者外周血的表达明显降低，并且与疾病活动度相关。以上研究结果确立了Gαq在免疫调控和RA发病中的重要作用。由于Gαq-KO骨髓嵌合鼠自发炎症性关节炎，并且Th1/Th2失衡在RA发病中发挥着重要的作用，因此推测Gαq可能调控类风湿关节炎患者Th1Th2细胞的分化。预实验结果表明，与同龄WT骨髓嵌合鼠相比，Gαq-KO骨髓嵌合鼠在自发炎症性关节炎之前和之后，Th1细胞的比例都是显著升高的，Th2细胞无显著变化。本研究将深入研究Gαq对类风湿关节炎患者Th1Th2细胞分化的调控；并利用Gαq基因敲除小鼠，深入研究Gαq调控Th1Th2细胞分化的分子机制。

Gαq, the alpha subunit of Gq G protein, is an important signal transducer. It has been reported that Gαq regulated DC migration and B cell survival. More importantly, Gαq -KO bone marrow chimeras with Gαq deficiency only in their immune system could spontaneously develop manifestations of systemic autoimmune disease with high titer anti-nuclear antibody (ANA) and inflammatory arthritis. We also found that the protein and mRNA expression levels of Gαq in peripheral blood lymphocytes (PBLs) of rheumatoid arthritis (RA) patients were significantly lower compared with healthy controls. These results confirmed the important role of Gαq in the pathogenesis of rheumatoid arthritis. As Gαq-KO bone marrow chimeras will spontaneously develop inflammatory arthritis and Th1/Th2 imbalance is important in the pathogenesis of RA, Gαq may regulate the Th1Th2 differentiation in RA patients. With this idea, we detected the percentage of Th1 and Th2 cell in Gαq-KO bone marrow chimeras before and after suffering from arthritis. The result showed that, in comparing to WT bone marrow chimeras, the percentage of Th1 cell was both significantly increased in these Gαq-KO bone marrow chimeras. Based on these findings, we hypothesize Gαq may regulate the Th1Th2 differentiation in RA patients. To prove our hypothesis, we first study the differentiation of high, low and normal Gαq expression Naive CD4+ T cells from RA patients to Th1Th2 cells. Naive CD4+ T cells from healthy individuals will be used as controls. Then we use Gαq-KO mice to study the role of Gαq in Th1Th2 differentiation and address the underlying molecular mechanisms. The success of this study will deepen our knowledge in the role of Gαq in immune regulation and pathogenesis of rheumatoid arthritis.