ICOSL/ICOS信号调控Tfh分化介导日本血吸虫病免疫应答及其免疫病理机制

Schistosomiasis is the immune pathological diseases characterized by the egg-induced granulomatous reaction and secondary fibrosis in host, and their immune pathology mainly exhibit for T cell-mediated delayed hypersensitivity. However, in acute schistosomiasis japonica, the Hoeppli phenomenon are visible around the characteristic egg accompanied antigen/antibody complex composed, which also show that humoral immunity is one of the important factors involved in schistosomiasis . Follicular helper T cells (Tfh), a new discovery of T cell subsets, provide help to B cells and production of high-affinity antibodies and generation of memory B cells. The inducible costimulator (ICOS) is highly expressed in Tfh cells. ICOSL:ICOS interactions are necessary for the activation of T effector cells and Tfh cells. Based on previous studies , it has been found ICOSL:ICOS signal can mediate Th2 and Th17 polarization and regulate the disease process of chronic schistosomiasis, combination with the progress of Tfh. We proposed a hypothesis"ICOSL:ICOS signal is one of the important checkpoints which regulates both cellular immunity and humoral immunity and can also regulate the process of the immune pathology in schistosomiasis". In this program, we intend to application specific ICOSL gene knock-out and ICOS transgenic mouse models of disease to test this hypothesis, and further elucidating the molecular mechanisms of immune response and pathology in schistosomiasis.

血吸虫病是虫卵诱发宿主肉芽肿反应及继发纤维化为特征的免疫病理性疾病。其免疫病理主要表现为T细胞介导的迟发性超敏反应，但在日本血吸虫病急性期可见虫卵周围伴以特征性的抗原/抗体复合物沉着即Hoeppli现象，表明体液免疫也是参与血吸虫致病的重要因素之一。滤泡辅助性T细胞(Tfh)，是新发现的辅助B细胞活化和抗体生成的主要T细胞亚群。高表达协同刺激信号分子ICOS是Tfh的重要特征及介导Tfh分化调节T-B相互作用的重要条件。基于前期研究，已发现ICOSL/ICOS信号可介导血吸虫慢性致病期T细胞亚群Th2和Th17的极化并调节疾病进程，结合Tfh的研究进展，我们提出了"ICOSL/ICOS信号是既调节细胞免疫也可调节体液免疫并调控血吸虫免疫病理进程的重要卡控点之一"的研究假设。本项目拟应用特定的ICOSL敲基因和ICOS转基因小鼠疾病模型验证该假设，深入阐明血吸虫病免疫应答及免疫病理分子机制。

肝脏虫卵肉芽肿炎症和继发性肝纤维化是血吸虫病致病的中心环节，其本质是由CD4+T淋巴细胞持续性对可溶性虫卵抗原产生免疫应答。CD4辅助性T细胞（Th，包括Th1, Th2, Th17, Tregs）介导的体液和细胞免疫应答在抗日本血吸虫的感染和免疫病理的形成发挥着重要的作用。研究表明，ICOS信号与Tfh细胞的分化与功能密切相关,ICOS-ICOSL共刺激信号在慢性炎症和纤维化病变中可能发挥重要作用。本项目应用ICOSL敲基因（ICOSL-/-、ICOSL+/-）、ICOS转基因（ICOS-Tg)及其野生型对照（WT）小鼠建立血吸虫病实验动物模型，探索ICOS-ICOSL共刺激信号在日本血吸虫感染宿主的慢性致病过程中对Tfh分化、极化以及生发中心反应的调控作用及重要信号分子，为深入阐明血吸虫病免疫病理的机制，寻找控制血吸虫性虫病晚期肝纤维化的发生发展的有效途径，提供科学依据。经四年的研究已按计划完成研究内容并取得以下重要研究结果：(1)日本血吸虫感染小鼠慢性致病过程中Tfh介导的免疫应答特征及其免疫调节机制研究:研究结果表明，Tfh增殖及极化与日本血吸虫感染小鼠慢性致病的进程呈显著正相关。Tfh细胞迁移到生发中心通过分泌效应因子IL-21促进B细胞体液免疫应答，而且IL-21因子能促进日本血吸虫感染小鼠的肝虫卵肉芽肿炎症及肝纤维化形成。(2)ICOSL/ICOS信号通路在日本血吸虫感染小鼠慢性致病过程中对Tfh免疫调控作用研究:研究结果表明，阻断ICOS-ICOSL信号通路使得血吸虫性肝纤维化进程得到了一定程度的控制。ICOSL敲除下调了血吸虫感染宿主免疫应答过程中Tfh分化增殖，下调了Th2/Th17/Tfh效应因子的表达，降低了脾脏生发中心反应，即ICOS-ICOSL信号通路可能通过调控Th2、Th17、Tfh免疫应答从而发挥抗血吸虫病肝纤维化的作用。