滤泡辅助性T细胞通过趋化嗜酸性粒细胞来促进血吸虫性肝病发生发展的机制研究

Schistosomiasis remains a major public health problem in many developing countries, which affects approximately 200 million people worldwide. It is well established that the etiopathology during schistosomasis is primarily due to an excessive inflammatory response to eggs, in particular to eggs trapped in liver. Egg-induced liver granuloma, characterized by an eosinophil-rich, CD4+ T helper cell dominated infiltrate, leads to fibrosis and circulatory impairment in host with schistosomiasis. Thus, understanding the mechanisms of granuloma formation is crucial for better schistomiasis treatment. Our previous studies have shown that follicular helper T (Tfh) cells could promote hepatic granuloma formation during S. japonicum infection. However, the mechanism underlying Tfh cell-mediated granuloma formation is still unknown. Strikingly, our preliminary experiments showed that Tfh cells contributed to increase of eosinophils in liver in mice with schistosomiasis and recruited eosinophils in vitro. In addition, Tfh cells had the characteristic ability to produce CXCL12 during schistosome infection. Thus, our preliminary data indicate that Tfh cells may recruit esosinophils into liver to promote the granuloma formation via secretion of CXCL12 in schistosomiasis. Importantly, studying how Tfh cells recruit esosinophils into liver will not only shed light on the mechanisms that promote the liver pathology process in schistosomiasis but may also open novel avenues for the treatment of esosinophil-mediated other diseases.

血吸虫病是当前我国乃至世界最严重的寄生虫病之一，全球大约有2亿人被感染。血吸虫感染造成的核心损害是由肝脏内的虫卵引起肉芽肿，触发并启动了进行性发展的纤维化，最终导致肝硬化、门脉高压症等，甚至危及患者生命。肉芽肿的细胞组分中有50%-60%是嗜酸性粒细胞，其可通过分泌IL-4和IL-13活化肝星状细胞等方式促进纤维化形成。因此，阐明血吸虫性肝病形成的要点之一也就是阐明以嗜酸性粒细胞为主的细胞是如何进入肝脏、聚集于虫卵周围形成肉芽肿并启动纤维化的过程。我们近期预实验结果显示：Tfh细胞分泌CXCL12，不仅在体内可增加肝脏虫卵周围嗜酸性粒细胞的数量，而且在体外也可直接趋化嗜酸性粒细胞。因此，本课题拟通过体外和体内实验，来证明如下科学假说：Tfh细胞可通过分泌CXCL12趋化嗜酸性粒细胞至肝脏促进虫卵肉芽肿形成。我们的研究可深化我们对宿主血吸虫性肝病成因的认识，为治疗血吸虫病提供指导。

血吸虫病是当前我国乃至世界危害人类健康、影响社会经济发展最重要的寄生虫病之一。血吸虫感染后，对宿主造成的最主要的伤害是肝脏中的虫卵引起以嗜酸性粒细胞浸润为主的肉芽肿并继发肝脏纤维化的免疫病理损伤。因此，研究血吸虫感染过程中宿主肝脏虫卵肉芽肿形成机制对于治疗血吸虫病至关重要。滤泡辅助性T细胞（Tfh细胞）是一群独立的CD4+ T细胞亚群，可显著促进血吸虫感染小鼠肝脏虫卵肉芽肿形成，然而具体机制仍不清楚。我们的研究发现Tfh细胞在感染小鼠体内可显著增加肝脏虫卵肉芽肿中嗜酸性粒细胞的数量，从而促进肝脏虫卵肉芽肿形成。进一步研究发现Tfh细胞可通过分泌趋化因子CXCL12趋化嗜酸性粒细胞至日本血吸虫感染小鼠的肝脏中，进而促进肝脏虫卵肉芽肿形成。为了探索日本血吸虫感染过程中，Tfh细胞分泌CXCL12的分子机制，我们用雷帕霉素处理日本血吸虫感染小鼠，发现雷帕霉素可显著抑制日本血吸虫感染小鼠体内CXCL12+ Tfh细胞产生，同时可减轻感染小鼠肝脏虫卵肉芽肿形成。这些结果提示mTOR信号可调控日本血吸虫感染小鼠体内Tfh细胞分泌趋化因子CXCL12。有趣的是，我们的研究还发现mTOR信号不仅可促进CXCL12+ Tfh细胞产生，同时还可抑制Treg细胞形成，最终加重血吸虫性肝病形成。进一步研究发现mTOR信号很有可能是通过glut1分子进而调控Treg细胞与Tfh细胞之间的平衡，最终促进日本血吸虫感染小鼠肝脏虫卵肉芽肿形成。本研究在原有工作基础上，较深入研究了Tfh 细胞趋化嗜酸性粒细胞的分子机制。其不仅可以在理论上深化我们对日本血吸虫感染引起宿主肝脏虫卵肉芽肿成因的认识，还可在实践上以Tfh 细胞为靶标、为治疗血吸虫病提供指导。同时，对研究Tfh 细胞以及嗜酸性粒细胞介导的其它疾病的形成机制也有重要的启示价值。