核因子κB受体活化因子配体介导的信号导致日本血吸虫感染小鼠胸腺萎缩进而引起免疫抑制的机制研究

Schistosomiasis remains a major public health problem in many developing countries. Schistosomes need to suppress the host immune system to establish chronic infections. Although immunosuppression induced by schistosomes benefits the host by limiting excessive inflammation and tissue damage, it contributes to increased susceptibility to other pathogens as well as reduced vaccine efficacy. Given the impact of schistosome-elicited immunomodulation both as a risk factor for bacterial, viral, and protozoan coinfection and as a potential therapeutic strategy for multiple inflammatory diseases, it is critical to define the regulatory mechanisms by which schistosome can influence immune responses. Accumulating evidence support the notion that an intact and functional thymus is required for optimal immunity to infection throughout life. Although thymic atrophy is a common feature in infectious diseases, the exact roles of thymic atrophy in infectious diseases remain unclear. Interestingly, our preliminary experiments showed that schistosome infection causes rapid involution of the thymus, which results in decreased thymopoiesis and emigration of naive T cells to the periphery. RANKL expression correlates positively with the process of thymic atrophy, and blockade of RANKL signaling in vivo protects the thymus against inappropriate involution, and restores the output of naïve T cells into the periphery. However, the precise mechanisms responsible for the thymic atrophy seen in schistosomiasis are not completely elucidated, and need to be investigated.

血吸虫病是一种流行广泛、危害严重的寄生虫病。慢性血吸虫感染降低宿主免疫反应在减轻宿主免疫病理损害的同时，还可导致感染慢性化，引起宿主接种疫苗效果差、以及易感染其它病原体。因此，阐明血吸虫感染降低宿主免疫反应的机制，对于预防和治疗血吸虫病和其它合并感染等疾病至关重要。越来越多的证据证实胸腺在维持和调控成年个体免疫反应中具有不可替代的作用。尽管多种感染都可引起胸腺萎缩，但胸腺萎缩在感染性疾病中的作用仍不清楚。我们前期研究发现日本血吸虫感染可引起小鼠胸腺萎缩，外周初始CD4+T细胞数量减少，TCR亲和力下降。伴随胸腺萎缩，核因子κB受体活化因子配体（RANKL）表达水平显著增加，而阻断RANKL信号可减轻日本血吸虫感染导致的胸腺萎缩，恢复外周初始CD4+T细胞数量和TCR亲和力。但是RANKL信号促进日本血吸虫感染小鼠胸腺萎缩，引起免疫抑制的机制有待于进一步研究。

血吸虫病是当前我国乃至世界危害严重的重要寄生虫病之一，全球大约有2亿人被感染。血吸虫感染宿主后，一方面，沉积在肝脏内的虫卵激发的效应性CD4+T细胞反应可导致虫卵肉芽肿等免疫病理损害；另一方面，宿主为了缓解这些免疫病理损害进行的免疫负调控可引起免疫抑制。我们发现RANKL以IL-33依赖性方式诱导血吸虫感染宿主胸腺萎缩，进而引起T细胞免疫抑制。机制上，IL-33通过诱导Pou2f3表达进而促进胸腺簇细胞产生，导致胸腺髓质上皮细胞比例增加，引起胸腺上皮结构异常，造成胸腺萎缩。RANKL除了通过IL-33依赖性的方式诱导血吸虫感染宿主胸腺萎缩外，还可诱导宿主破骨细胞异常增多，进而导致骨质流失增加，引起骨代谢紊乱。另外，我们发现血吸虫感染宿主还可通过CD40信号通过维持B细胞表面CXCR5的表达促进Tfh细胞产生，进而趋化嗜酸性粒细胞至肝脏促进虫卵肉芽肿形成。除此以外，我们发现人脐带MSC来源的EVs可抑制CD4+T细胞反应介导的虫卵肉芽肿反应。这些结果深化了我们对血吸虫致病的认识，为治疗血吸虫病提供潜在靶标。