血吸虫感染宿主诱导Tfh细胞来促进肝脏免疫病理损害的机制研究

Schistosomiasis is a chronic helminthic disease that affects approximately 200 million people worldwidely. After S. 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 mechanism of the granuloma formation. Previous studies proved that type II response and its cytokine IL-4 are essential for granuloma formation during schistosome infection. However, recent study suggested that Tfh cells are induced and are the predominant source of IL-4 during helminth infection. In addition, latest studies directly showed that Tfh cells are induced during schistosome infection and most IL-4-producing CD4+ T cells in response to Schistosoma mansoni antigens are Tfh cells. However, it is not yet clear whether Tfh cells, as the other CD4+ T cell populations (Th1, Th2, Th17 and Treg cells) do, are involved in the development of liver pathology during schistosome infection. In this study, we plan not only to prove that Tfh cells play a critical role of promoting the hepatic granuloma formation and liver injury, but also to elucidate the possible mechanisms of Tfh cell generation in schistosome-infected mice. We believe that our results would indicate a therapeutic potential to target a Tfh cell induction axis in liver pathology caused by schistosome infection.

血吸虫病在我国、乃至世界范围内属最重要的寄生虫病之一，其关键致病原因是虫卵沉积于宿主肝脏内引起免疫病理损害――虫卵肉芽肿并继发肝纤维化，最终导致门脉高压及各种严重的并发症甚至死亡。血吸虫性肝脏免疫病理损害的机制极为复杂、尚不明确，因而也缺乏有效的临床干预方法。一直以来研究均认为II类免疫应答及其关键细胞因子IL-4是促进血吸虫性肝脏免疫病理损害发生发展的关键因素。然而，近年来，最新的免疫学研究发现Tfh细胞有可能才是真正的促进致病因素。本课题拟在以往的工作基础上，围绕Tfh应答这一关键致病因素开展研究，确证Tfh细胞在血吸虫感染后宿主肝脏的虫卵肉芽肿纤维化病理损害发生发展中起到核心致病作用，并深入阐明血吸虫感染后宿主Tfh细胞的诱导产生机制，从而更深入地从理论上阐明血吸虫性肝脏免疫病理损害发生发展的核心机制，进而为针对Tfh细胞诱导环节的血吸虫病临床治疗新方法的研究提供理论依据。

血吸虫病在我国、乃至世界范围内属最重要的寄生虫病之一，其关键致病原因是虫卵沉积于宿主肝脏内引起免疫病理损害―虫卵肉芽肿并继发肝纤维化，最终导致门脉高压及各种严重的并发症甚至死亡。血吸虫性肝脏免疫病理损害的机制极为复杂、尚不明确，因而也缺乏有效的临床干预方法。本课题在以往的工作基础上，围绕Tfh应答这一关键致病因素，从流行区血吸虫病患者和血吸虫感染小鼠两方面开展了大量研究。.首先，我们在血吸虫感染小鼠和血吸虫病流行区患者中证实了Tfh细胞与肝脏免疫病理损害明显相关，并以血吸虫感染的Tfh细胞缺陷小鼠证明了Tfh细胞在促进宿主肝脏免疫病理损害发生发展中起到核心致病作用：Tfh细胞可通过分泌CCL12趋化CXCR4受体阳性的嗜酸性粒细胞参与形成肝内虫卵肉芽肿和纤维化；同时，Tfh细胞促进宿主产生抗体，从而出现抗体水平与肝脏免疫病理损害程度呈正相关关系；此外，还发现Tfh细胞可高水平分泌RANKL促进慢性血吸虫病患者骨质疏松的发生发展。.随后，我们发现血吸虫感染诱导小鼠产生的IL-7可抑制虫卵抗原诱导的巨噬细胞凋亡而使肝脏内巨噬细胞数量迅速增多；巨噬细胞SRA、TLR2/4等受体可与虫卵抗原结合，并作为APC诱导CD4+T初始细胞分化为Tfh、Treg、Th2等亚群共同调控肝脏免疫病理进程。.最后，我们证明了血吸虫抗原可促进小鼠T细胞表达CD40L，CD40L激活APC内CD40信号后使APC表面高表达CXCR5和ICOSL，ICOSL与T细胞表面受体ICOS结合后促使T细胞表达CXCR5，最终使共同表达CXCR5的CD4+T细胞与APC共定位于淋巴滤泡相同部位、直接接触并分化为Tfh细胞，但同时虫卵抗原还可能通过激活mTOR-Glut1抑制Tfh细胞的分化。.本研究更深入地从理论上阐明了血吸虫病肝脏免疫病理损害发生发展的核心机制，进而为针对Tfh细胞诱导环节的血吸虫病临床治疗新方法的研究提供了理论依据。