IL-33调控的滤泡辅助T细胞在类风湿关节炎中的作用及机制研究

The incidence of rheumatoid arthritis (RA) in China is as high as 0.2% - 0.4%. At present, the pathogenesis of RA is not completely understood. Abnormal activation of autoimmunity, activation of B cells and production of autoantibodies are one of the pathogenesis of RA. In germinal center, follicular helper T cells (Tfh) are the key cells to regulate B cells. Previous studies have shown that the levels of IL-33 and Tfh in peripheral blood of patients with RA are significantly increased. At the same time, some studies have shown that IL-33 can promote the proliferation of Tfh and lead to the loss of immune tolerance. In this current study, ST2 (IL-33 receptor) is highly expressed in Tfh of popliteal lymph nodes in collagen-induced arthritis (CIA). The number of ST2+Tfh in popliteal lymph nodes of CIA mice was significantly higher than that of control group. Therefore, we propose a scientific hypothesis: IL-33 released from synovial epithelial cells after injury binds to ST2 expressed by Tfh in lymph nodes, promotes the proliferation of Tfh cells and then activates B cells, leading to arthritis. This project aims to explore the role and mechanism of Tfh regulated by IL-33 in CIA animal model and RA peripheral blood.

类风湿关节炎(RA)在我国发病率高达0.2%-0.4%，目前其发病机制尚未完全明确。自身免疫的异常激活、B细胞活化和自身抗体的产生是RA的发病机制之一。在生发中心中，滤泡辅助T细胞（Tfh）是调控B细胞的关键细胞。已有研究表明RA患者外周血中IL-33及Tfh水平显著升高，同时有研究表明IL-33可促进Tfh增殖而导致免疫耐受缺失。本项目前期研究发现在胶原诱导关节炎（CIA）中，ST2（IL-33受体）高表达于腘窝淋巴结的Tfh上。同时发现ST2+Tfh数目在CIA小鼠腘窝淋巴结中明显高于对照组。因此我们提出科学假说:滑膜上皮细胞损伤后释放的IL-33与淋巴结中Tfh表达的ST2结合，促进Tfh细胞增殖进而活化B细胞，从而导致关节炎症的发生。本项目拟用CIA动物模型和RA外周血，探索IL-33调控的Tfh在其中发挥的作用及机制。

类风湿性关节炎（RA）是以关节滑膜炎性损伤和骨破坏为特征的慢性自身免疫性疾病，已有研究表明RA患者外周血及关节腔积液中IL-33水平显著升高，这提示IL-33在RA的发病机制中发挥重要作用。Tfh细胞在B细胞向浆细胞转换过程中起重要作用，且与自身免疫疾病密切相关，有研究表明Tfh细胞上存在IL-33受体ST2的表达。在KLH小鼠模型中，我们观察到KLH小鼠受IL-33刺激后，Tfh水平上升，且ST2表达也增高，与之相反的是Tfr细胞比例的下降。在敲除ST2后，KLH小鼠Tfh细胞比例明显减少。证明IL-33能调控Tfh细胞的增殖。在CIA模型中我们观察到，受IL-33刺激后，小鼠腹股沟淋巴结的Tfh细胞升高，Tfh上ST2表达升高。通过流式细胞术与免疫荧光切片观察到，小鼠的生发中心（GC）比例升高，数目增多。而受刺激小鼠关节发病程度以及病理改变都相较未刺激小鼠更加严重。本项目揭示了RA中IL-33能作用于Tfh细胞从而参与到RA的发病机制中，具有重要的理论意义和临床意义。