Bregs调控Th1/Th17/Tregs平衡在特发性肺纤维化中的作用机制研究。

Idiopathic pulmonary fibrosis (IPF) is a highly heterogeneous and lethal pathological process with limited therapeutic options, which is the most common and severe of the idiopathic interstitial pneumonias (IIPs). The pathogenesis of IPF is a complex process with continual injury, chronic inflammation and wound healing response. It has been reported that Th1, Th2, Th17 and Tregs were important in pulmonary fibrosis. The mechanisms for differentiation from naive CD4+T to Th1, Th2, Th17 and Tregs are still unknown in IPF. IL-10-producing B cells, also known as regulatory B cells (Bregs), play a key role in controlling airway inflammation, autoimmunity,and cancer. According to our preliminary experiments, the numbers of Bregs increased in IPF patients or bleomycin-induced pulmonary fibrosis mouse model. This suggested that the immune regulation of Bregs may be crucial for differentiation of Th1, Th2, Th17 and Tregs in the pathogenesis of IPF. In this study, we will investigate the immune regulatory mechanisms of Bregs to direct the differentiation of naive CD4+ T cell in IPF patients and bleomycin-induced fibrosis mouse model. Mice lacking Bregs will be used to determine the role of Bregs for the pathogenesis of IPF and the key signaling molecules for Bregs. This study can provide more detailed and integrated understanding of the cellular and molecular mechanisms of idiopathic pulmonary fibrosis. It can help pave the way for effective therapeutics for this devastating and complex disease.

特发性肺纤维化是一种最常见和最严重间质性肺疾病，一般是由损伤、免疫炎症反应及组织修复持续叠加所致。越来越多的证据表明，初始CD4+ T细胞来源的Th1、Th2、Th17及Tregs参与了特发性肺纤维化发病进程。 调节性B细胞（regulatory B cells, Bregs）是一类新发现的负调节免疫细胞，已经发现Bregs通过调控T细胞分化在类风湿关节炎、多发性硬化症等自身免疫性疾病中发挥着重要的免疫调控作用，但尚无报道Bregs是否在特发性肺纤维化中起何作用。我们初步数据表明在特发性肺纤维化患者及博来霉素诱导肺纤维化小鼠模型中，Bregs数量显著上调，提示Bregs可能在特发性肺纤维化中发挥重要作用。本项目将进一步从分子、细胞水平及临床样本研究特发性肺纤维化中Bregs对T细胞分化的免疫调控作用。该研究将不仅加深我们对特发性肺纤维化发病机制的了解，而且可为临床治疗提供理论及实验依据。

特发性肺纤维化是一种最常见和最严重间质性肺疾病，一般是由损伤、免疫炎症反应及组织修复持续叠加所致。越来越多的证据表明，初始CD4+ T 细胞来源的Th1、Th2、Th17 及Tregs 参与了特发性肺纤维化发病进程。 调节性B 细胞（regulatory B cells, Bregs）是一类新发现的负调节免疫细胞，已经发现Bregs 通过调控T 细胞分化在类风湿关节炎、多发性硬化症等自身免疫性疾病中发挥着重要的免疫调控作用，但尚无报道Bregs 是否在特发性肺纤维化中起何作用。本研究发现IPF患者在不同疾病进展阶段免疫功能状态存在明显差别，急性加重期IPF患者Bregs（包括B10）、Tregs都显著低于稳定期IPF患者，同时Th1、Th17细胞均显著高于稳定期IPF患者，以上结果提示AE-IPF患者处于严重免疫失衡状态，而Bregs在此过程中可能起着重要作用。我们应用博来霉素建立小鼠肺纤维化及急性加重模型，同时应用CD22抗体中和Bregs，发现Bregs消除可缓解小鼠肺纤维化及急性加重模型炎症及纤维化程度；该研究将不仅加深我们对特发性肺纤维化发病机制的了解，而且调节性B细胞可能做为临床治疗特发性肺纤维化及急性加重的新的靶点，从而为临床干预治疗IPF及急性加重提供新的思路和策略。