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

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。

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.