CD155-TIGIT-MyD88信号在促进血吸虫病肝纤维化中的作用及机制研究

Schistosomiasis is a chronic helminthic disease that affects approximately 200 million people worldwidely. After Schistosoma japonicum infection, parasite eggs are trapped in host liver and granulomas are induced to form around eggs. Severe granuloma subsequently results in serious liver fibrosis and circulatory impairment chronically. It is important to fully elucidate the mechanisms of the granuloma formation and fibrosis. Previous studies have proven that type II immune response including its typical cytokine IL-4 is one of essential roles for granuloma formation and fibrosis during schistosome infection. However, it remains unclear what factors are involved in facilitating type 2 immune response in the liver. . Although the underline mechanisms are still unknown, recent literatures and our preliminary studies suggest that enrichment of TIGIT+Treg cells in the liver contribute to the type II immune polarization in liver by inhibition of Th1 but facilitating Th2 cell generation. Our preliminary study also suggests that CD155, the ligand of TIGIT, is much higher expressed in the liver than that in spleen and lymph nods. In addition, we also show that MyD88 is probably involved in the expansion of TIGIT+Treg cells in the liver.. In this study, we plan to further confirm that CD155 drives the enrichment of TIGIT+Treg cells in liver by CD155-TIGIT-MyD88 axis to maintain the type 2 immune polarization in liver. In addition, we plan to elucidate the underline molecular mechanisms including the interaction of TIGIT and MyD88 pathway, and the underline signaling after TIGIT-MyD88 activation. Our results will not only be helpful for better understanding the complicate causes of type 2 immune propensity in the liver fibrosis in schistosomiasis, but also provide potential targets for the interventions of liver fibrosis-associated diseases.

血吸虫病是当前我国乃至世界最严重的寄生虫病之一，每年造成的严重致病、甚至死亡数以万计，其主要原因之一为II型免疫应答介导的宿主肝纤维化所致。迄今，大量研究证明肝脏损伤后可通过复杂的机制诱导以Th2细胞及IL-4为重要代表的显著的II型免疫应答倾向。其成因除血吸虫抗原诱导外，近年研究提示，其中一个重要原因可能在于肝内富集的TIGIT+Treg细胞通过抑制Th1促进Th2细胞分化及效应，但机制并不清楚。文献及我们的前期研究提示，肝脏局部高表达的CD155可能通过激活TIGIT+Treg细胞的TIGIT信号，并通过Myd88信号使TIGIT+Treg细胞扩增并在肝脏内富集，从而参与维持肝脏II型免疫倾向。因此，本课题拟进一步证实上述科学假说，并继续深挖TIGIT信号与Myd88信号的交集机制、以及下游分子机制，为理解肝脏II型免疫倾向的复杂成因及发掘潜在干预措施提供一个新的理论依据。

血吸虫病是当前我国乃至世界最严重的慢性寄生虫病之一，每年造成的严重致病、甚至死亡数以万计，其主要原因之一为感染早期血吸虫抗原诱导的强烈I型免疫应答介导的肝细胞免疫损伤以及后期过快过强的II型免疫应答介导的宿主肝纤维化所致。然而，宿主的免疫调控可有效控制感染后的肝脏免疫损害，其调控因素较为复杂，近年的研究、以及我们的前期研究均提示其重要因素之一可能在于肝脏中富集的TIGIT+Treg细胞，其可在抑制Th1等I型免疫反应而形成II型免疫反应优势的同时有效发挥整体免疫抑制作用，使得宿主肝脏内长期处于缓慢纤维化修复期而不会快速导致肝硬化，但是，相关调控机制并不清楚。. 通过本课题的研究，我们证明了血吸虫感染宿主可通过TIGIT控制I型免疫反应以增强II型免疫应答并富集Treg细胞，从而减轻早期宿主肝细胞的免疫损害并进入纤维修复期，其中，重点揭示了血吸虫感染宿主肝脏高表达TIGIT的配体CD155，CD155通过激活TIGIT+Treg细胞使其表达向肝趋化因子受体（CXCR3、CCR6、CCR2等），使肝脏中富集大量具有较强免疫抑制活性的TIGIT+Treg细胞，从而有效形成并维持优势II型免疫及宿主肝脏内免疫负调控环境。此外，还发现MyD88可能通过调控其配体CD155表达促进了TIGIT和ST2信号（促进ST2表达），从而共同促进并维持Treg细胞活性（表面功能分子及增殖能力）。我们还揭示了血吸虫感染宿主体内与免疫负调控相关的TIGIT与PD-1两个分子的表达之间可能存在相互负调控，从而在机体内或局部形成持续稳定的免疫负调控状态。. 本课题在理论上不仅加深了对血吸虫感染宿主肝脏免疫调控和病理损害控制的认识，还对其他慢性感染、甚至肿瘤中共同存在的免疫负调控问题的研究也有一定借鉴意义。此外，我们阐明的基于Th1及Treg细胞通过高表达TIGIT以削弱I型、加强II型免疫反应并加强免疫负调控的这一理论，为今后血吸感染所致肝细胞损害的临床免疫学控制提供了潜在干预靶点，甚至对控制其他组织炎性损害或激活肿瘤组织免疫也有重要参考价值。