血吸虫抗原诱导调节性T细胞调控宿主肝脏免疫病理损害的机制研究

Schistosomiasis, characterized by egg resulted host liver or other important organs granulomas and subsequent fibrosis, is one of the major human parasitic diseases and the mortality rates resulting from this parasitic infection is second only to Malaria in the world. Chronic schistosome infection shows an obvious suppression of host immune responses, restricting pathology in important host organs while allowing long-term survival of parasites. Accumulated results show that some moleculars from parasites or even vaccine components can induce an down-regulation of host immune responses by induction of CD4+CD25+Treg cells, which finally results in the chronicity of the infection or lower effeciency of the vaccinaton. However, the mechanism of Tregs induction during schistosome infection is still unknown. In our previous study, we identified several schistosome japonicum antigens including SjHSP60 and SJMHE1 which significantly induce CD4+CD25+Treg cells. In this study, we are going to investigate the molecular mechanism of the induction of the Treg cells after binding the receptor(s) on APC with SJMHE1 (or its full length antigen SjHSP60). Our findings may be helpful to develop some new stratgies to enhance the immune suppression to control the quick development of liver pathology during schistosome infection and/or enhance the protection of the potential vaccine against schistosome japonicum.

血吸虫病在我国、乃至世界范围内均属最重要的寄生虫病之一，其对宿主的关键致病因素是肝脏内沉积的血吸虫卵引发的持续进展的肝脏免疫病理损害(肝脏虫卵肉芽肿和纤维化)，最终导致肝硬化并引起门脉高压症及各种严重继发损害甚至死亡。感染血吸虫后，宿主可产生具有免疫抑制功能的Treg细胞来抑制肝脏免疫病理损害的进展，使感染成为慢性化，从而实现既有利于宿主存活、最终也有利于血吸虫生存的"双羸"结果。本项目拟在以往的工作基础上，对血吸虫抗原通过诱导APC表达TGF-β来诱导CD4+T细胞分化为Treg细胞的机制进行深入研究，从而较为系统和深入地阐明血吸虫抗原通过诱导Treg细胞来调控血吸虫免疫病理损害的机制，进而加深对包括血吸虫在内的诸多病原微生物感染后调控宿主免疫病理损害机制的认识，为研发血吸虫性肝脏免疫病理损害干预新方法、也最终为血吸虫病等诸多慢性感染性疾病的防治提供重要理论依据和方法。

血吸虫病在我国、乃至世界范围内均属最重要的寄生虫病之一，其对宿主的关键致病因素是沉积在宿主肝脏内的血吸虫卵引发的持续进展的肝脏免疫病理损害(肝脏虫卵肉芽肿和纤维化)，最终导致肝硬化并引起门脉高压症及各种严重继发损害甚至死亡。因此，阐明血吸虫感染后调控宿主肝脏免疫病理发生发展的机制，具有重要的理论及临床指导意义。首先，在本研究中我们发现宿主感染后，血吸虫抗原（尤其是SEA中的SjHSP60）可通过TLR4-Mal-IKK-NF-κB信号轴使主要抗原递呈细胞（APC）如巨噬细胞（MΦ）呈耐受表型并优势表达TGF-β，而TGF-β诱导了CD4+ T细胞转化为CD4+CD25+ 调节性T细胞（Treg细胞），从而对肝脏免疫病理损害进行抑制。同时，我们的初步研究发现，血吸虫感染后诱导的IL-10、以及APC/CD4+T细胞上PD-1L(B7-H1)/PD-1的相互作用，对APC诱导产生Treg细胞、以及Treg细胞的免疫抑制功能均起着调控作用，这应该是宿主免疫系统对免疫应答（免疫病理的发生发展及控制）实施精细调控的可能机制。此外还发现， MΦ的不同表型（活化型/耐受型；M1/M2）、以及影响表型分化的因素，最终均能显著影响初始CD4+ T细胞分化为包括Treg在内的不同亚型（Th1、Th2、Th17、Treg）从而对血吸虫感染免疫病理损害起到不同的调控作用。本研究不仅有助于理论上深入揭示血吸虫感染后宿主免疫系统调控肝脏免疫病理损伤的机制，也有助于研发针对CD4+CD25+ Treg细胞诱导等靶标的新型治疗方法提供理论依据与具有自主知识产权的候选分子。