日本血吸虫虫卵外泌体负向调控免疫应答及其作用机制研究

Schistosomiasis, caused by pathogen schistosome, is an immuological disease characterized by egg granuloma and hepatic fibrosis, and still seriously threatens human health. Granuloma and hepatic fibrosis are closely related to regulation of host immune response caused by egg antigens. However, the specific mechanism of immune response remains unclear, which is a hot spot in current research. Exosomes with variety of functional composition play an important role in intercellular signal transduction and immune regulation. Moreover, the potential value of exosomes in disease diagnosis and therapeutic approaches attracts considerable attention. Exosomes, which were found in excretory-secretory antigens derived from eggs of Schistosoma japonicum, can induce BMDCs (bone-marrow-derived dendritic cells) to produce high levels of IL-10 and downregulate expression of pro-inflammatory cytokines. Importantly, exosomes can antagonize the effect of LPS on BMDCs，which significantly downregulate expression of MHC II and costimulatory molecules. Our aim is to screen and clear mechanisms of novel dendritic cells induced by exosomes derived from eggs to effectively drive Th2 and Treg polarization. Our results will provide a new perspective for the study of immune evasion mechanism of schistosoma and provide new ideas for research on prevention and treatment of schistosomiasis.

血吸虫病是由血吸虫感染引起的以虫卵肉芽肿和肝纤维化为重要特征的免疫性疾病，仍然严重威胁人类健康。肉芽肿和肝纤维化的形成与虫卵抗原调节宿主免疫应答密切相关，然而具体机制仍不明确，是国内外研究的重点。携带多种功能成分的外泌体（exosome）在细胞信号传导和免疫调节中发挥重要作用，并且在疾病诊断和治疗方式上具有潜在应用价值。我们预实验发现，日本血吸虫虫卵排泄分泌物中存在外泌体，且该外泌体可诱导小鼠髓源树突状细胞产生高水平的IL-10并下调促炎性细胞因子表达。更为重要的是，日本血吸虫虫卵源外泌体可有效拮抗LPS诱导的树突状细胞成熟，显著下调树突状细胞表面的MHC II类分子和共刺激分子。本项目拟在此基础上，研究日本血吸虫虫卵外泌体驱使Th2和Treg极化能力，并进一步阐明其负向调控的作用机制。本研究将为血吸虫免疫逃避机制研究提供新视角，为血吸虫病的防治深入研究提供新思路。

血吸虫病是由血吸虫感染引起的以虫卵肉芽肿和肝纤维化为重要特征的免疫性疾病。携带多种功能成分的外泌体在细胞信号传导和免疫调节中发挥重要作用。日本血吸虫虫卵源外泌体在免疫调控及肝纤维化的作用及机制仍不明确。我们早期发现，日本血吸虫虫卵源外泌体能诱导小鼠髓源树突状细胞（BMDC）产生IL-10并下调表面共刺激分子和促炎性细胞因子表达；日本血吸虫虫卵源外泌体可有效拮抗LPS诱导的树突状细胞成熟，显著下调树突状细胞表面的MHC II类分子和共刺激分子。进一步研究发现，日本血吸虫虫卵源外泌体有效激活BMDCs MAPK/NF-κB，呈现明显剂量依赖效应；日本血吸虫虫卵源外泌体里的一些microRNAs可以上调BMDC IL-10和Arg-1等抑炎细胞因子表达。此外，日本血吸虫虫卵源外泌体里的一些microRNAs可以激活大鼠肝星状细胞T6并上调α-SMA、Col-1 α1和Col-3 α1等促纤维化指标。日本血吸虫虫卵源外泌体包含novel miRNA 33 在内的一些microRNAs可以激活人肝星状细胞LX-2并上调α-SMA、Col-1 α1和Col3 α1等促纤维化指标；并且在日本血吸虫感染的小鼠血清和肝脏中发现了novel miR-33 表达的上调。使用agomir novel 33 注射小鼠体内，发现agomir novel 33可显著上调肝脏促纤维化指标α-SMA、Col1α1和Col3α1 的转录水平。更为重要的是，使用antagomir novel 33 可显著减轻日本血吸虫感染小鼠肝脏纤维化水平。本研究将为血吸虫免疫逃避和肝纤维化发病机制研究提供新视角，为血吸虫病的防治深入研究提供新思路。