循环Tfh细胞调控B细胞影响IgE的产生在哮喘病理过程中的作用机制研究

Abnormality in IgE pathway is one of the pathogenesis of asthma. While T cell help for the pathologic abundance of IgE has long been considered as a Th2 property, recent studies have identified follicular helper T (Tfh) cells as the specialized subset indispensible for providing cognate help to B cells during germinal centers (GCs). Furthermore, the more recent work presents clear evidence that human blood CD4+CXCR5+ T cells named circulating Tfh (cTfh) cells are counterparts of Tfh cells in GCs. Our preliminary study found that cTfh cells indeed expanded in acute asthma patients and positively correlated with total IgE in the blood. Thus, we postulate that cTfh cells may play an important role in the pathogenesis of asthma by modulating IgE production. To testify the assumption, a fundamental platform for phenotypic and functional characterization of cTfh cells in vitro will be established. By analyzing the capacity of cTfh cells to modulate IgE production, the biological significance of these cells in the pathogenesis of asthma will expectedly be revealed. Finally, in attempting to better understand the role of cTfh cells in a more physiological environment, the model of ovalbumin-induced asthma mice will be used. Our studies will help to provide insights into the pathogenesis and perhaps identify novel therapeutic targets for asthma.

IgE异常增高是哮喘发病机制之一。传统观点认为Th2细胞介导IgE异常增高。新近研究表明，定位于淋巴滤泡的滤泡辅助性T(Tfh)细胞才是辅助B细胞发挥免疫效应的最主要T细胞群体，其功能远大于已被公认的Th2细胞。最新研究发现外周血循环Tfh (cTfh)细胞具有与Tfh细胞相似的表型和功能，可间接反映Tfh细胞功能状态。我们前期研究发现哮喘患者cTfh细胞比例明显高于健康对照组，且cTfh细胞比例与哮喘患者血清总IgE水平呈正相关。据此我们推测，cTfh细胞通过活化B细胞影响IgE的产生参与哮喘疾病进程。为证实这一假说，我们将首先通过体外实验对cTfh细胞及其效应分子在促进B细胞活化后IgE产生中的作用进行序贯性研究，阐明哮喘发病新机制；其次观察过继转移cTfh细胞对哮喘小鼠发病的影响，进一步在体内实验中明确cTfh细胞在哮喘病理过程中的作用。本研究可为哮喘发病机制及该病防治提供新思路。

IgE异常增高是哮喘发病机制之一。新近研究表明，定位于淋巴滤泡的滤泡辅助性T(Tfh)细胞才是辅助B细胞发挥免疫效应的最主要T细胞群体，其功能远大于已被公认的Th2细胞。最新研究发现外周血循环Tfh (cTfh)细胞具有与Tfh细胞相似的表型和功能，可间接反映Tfh细胞功能状态。本研究的主要目的是探明cTfh细胞是否通过活化B细胞影响IgE的产生参与哮喘疾病进程。研究结果发现不同严重程度哮喘、哮喘不同类型的患者cTfh细胞数量、表型发生改变。同时过敏性哮喘患者外周血cTfh细胞胞内细胞因子表达谱发生改变。哮喘患者cTfh细胞三种亚群存在极化偏移现象，极化偏移的cTfh2细胞水平、cTfh2（%）/ cTfh1（%）比值均与患者血清总IgE水平呈正相关。体外实验发现cTfh细胞可以通过IL-4、IL-21活化B细胞影响IgE的产生。本研究结果阐明cTfh细胞通过活化B细胞影响IgE的产生参与哮喘病理过程，为哮喘发病机制提供新线索，并可能为后续药物靶点设计及该病防治开拓新思路和提供理论依据。