IL-25对血吸虫感染宿主II型免疫应答及慢性期肝脏病理变化的影响及机制研究

Th2 response initiated by schistosome eggs has been believed to be the main reason of liver fibrosis occurred in schistosomiasis. However, at the chronic stage of schistosomiasis while liver fibrosis continues to progress, the overall level of Th2 response in host peripheral lymphoid organs is significantly downregulated. How to explain this paradox? Except for Th2 response, any other factors dictating the liver pathological damage in chronic schistosomiasis remain unknown. IL-25 is known to be an upstream inducing factor for Th2 response. On the other hand, some new types of innate immune cells positive for c-kit but negative on other lineage markers (c-kit+ lineage-) has been found to be activated by IL-25 to enhance innate type II immune response through producing type II cytokine such as IL-13. Our preliminary data showed that the IL-25 mRNA expression in liver of Schistosoma japonicum infected mice is greatly and persistently increased in the process of infection. Strinkingly, the cells with lineage- c-kit+ in the infected liver are also significantly increased. Base on the above, we proposed to utilize IL-25 deficient mice to study whether the persistent presence of IL-25 on the liver contributes to the development of liver pathological changes during chronic schistosomiasis via either maintaining and promoting the local Th2 responsein the liver and/or via increasing the numbers and activities of c-kit+ lineage- cells. This study will help to understand the mechanism which to maintain a moderate host type II immune response and then lead to persistent liver pathological damage when schistosomiasis into the chronic phase. This study will also provide a novel pathway for understand the pathogenesis of type II repsponse associated fibrosis.

血吸虫卵诱导的Th2应答被认为是导致血吸虫性慢性肝纤维化的主要原因。但慢性期时宿主外周的Th2应答已显著降低，为何肝脏病理损害却在持续进展，机制并不清楚。我们发现：血吸虫感染进程中小鼠肝脏局部IL-25mRNA表达呈大幅度持续性增高；与此同时肝脏中lineage-、c-kit+细胞数量亦显著增加。由于IL-25是能促进Th2应答的上源细胞因子，近年来发现它还可以作用于lineage-、c-kit+的新型固有免疫细胞帮助II型免疫应答。因此，本课题拟利用IL-25基因敲除小鼠，进一步研究血吸虫感染时，IL-25是否在肝脏局部通过增加lineage-、c-kit+细胞的数量和功能促进II型固有免疫应答；以及是否通过维持、促进肝脏局部的Th2应答而促进血吸虫性肝纤维化。本研究不仅有助于深入理解血吸虫性肝病的发病机制，也为理解II型免疫应答相关的纤维化疾病的发病机制提供了新的途径。

IL-25是能促进Th2应答的上源性细胞因子，近年来发现它还可以作用于lineage-、c-kit+的新型固有免疫细胞帮助II型免疫应答。本课题利用IL-25基因敲除小鼠，研究血吸虫感染时，IL-25对宿主Th2应答及II型固有免疫应答及慢性期肝脏病理的影响。结果发现：血吸虫感染进程中小鼠肝脏局部IL-25表达大幅度持续性增高，且其来源主要是肝脏局部浸润的免疫细胞。IL-25基因敲除后，脾脏中II型细胞因子IL-4mRNA表达显著下降，脾脏中产生IL-4的Th2细胞的比例无显著变化，但经虫卵抗原刺激后Th2细胞产生的IL-4的水平亦显著降低。提示IL-25并不影响Th2的分化比例，但可以通过帮助Th2细胞产生相应的细胞因子来帮助II性适应性免疫应答。血吸虫感染慢性期，肝脏及脾脏中确有lineage-、c-kit+的新型固有免疫细胞浸润，但IL-25敲除并不显著影响其比例。此外我们还发现：IL-25基因敲除后，血吸虫感染慢性期肝脏中单核来源的髓系抑制性细胞比例显著下降。血吸虫感染的IL-25基因敲除小鼠慢性期肝脏纤维化水平增高。本研究有助于深入理解血吸虫感染过程中宿主的II型免疫应答（包括II型适应性免疫应答及II型固有免疫应答)的发生机制及IL-25在其中发挥的重要作用。