IL-33-ILC2固有免疫途径在细粒棘球蚴持续感染中的作用机制研究

Hydatid diseases seriously affect the health of farmers and herdsmen in the western China. There is not effective prevention measures to control it because its pathogenesis is still unclear. The recently discovered alarmin IL-33 can activate group 2 innate lymphoid cells (ILC2) against infection by inducing type 2 Th cells. But its role has not yet been clarified in the hydatid disease. We found that imbalance of Th1/Th2 and Treg/Teff played the role in the escape of Eg in hosts. This project focuses on immune response mediated by ILC2 and its cytokines. We will observe the changes of IL-33 and relative factor ILC2 in hydatid patients before and after surgery and mice with Eg infection, to clear the relationship between innate immune pathways of IL-33-ILC2 and hydatid disease. And the characteristics of distribution of ILC2 cells and related cytokines around cysts will be observed to analysis the relationship between ILC2 and the formation of cysts and inflammatory reaction. We will analysis the role of innate immune pathways of IL-33-ILC2 on imbalance of subsets of CD4+T cells by blocking with antibody of ST2 during co-culture of ILC2 and CD4+T cells. We focus on regulation of E granulosus antigen to IL-33-ILC2 by observing change character of ILC2 before and after EgB and Eg95 stimulation. This study will provide a new direction for recovering research of E granulosus pathogenesis mechanism and for developing immune strategies against the E granulosus infection by exploring the role of group 2 innate lymphoid cells in hydatid persistent infection.

包虫病严重影响西部农牧民健康，其发病机制不清，阻碍了有效防治措施的进行。固有免疫IL-33和ILC2诱导Th2型应答，参与抗感染免疫，但其在包虫病的作用尚未阐明。前期发现棘球蚴感染引起Th1/Th2和Treg /Teff失衡参与免疫抑制，本项目以ILC2及其因子介导Th2免疫反应为切入点，观察手术前后包虫病患者和Eg感染小鼠的IL-33和ILC2及相关因子的动态变化，明确IL-33/ILC2固有免疫途径与包虫病的关系；通过ILC2与CD4+T细胞培养及抗ST2阻断，分析该途径在CD4+T细胞失衡中的作用；观察包囊周围ILC2分布特点，分析其与包囊形成和炎症反应的关系；用EgB和Eg95调节ILC2，探讨包虫不同抗原与IL-33/ILC2固有免疫的关系；阐明这一新型固有淋巴细胞在棘球蚴持续感染中所起的作用，为设计有效疫苗和以IL-33/ILC2途径为靶点的免疫干预治疗包虫病开拓新思路。

我国是棘球蚴病高发的国家之一，新疆地区以细粒棘球蚴病（CE）多见，也是影响本地区牧民身体健康的因素之一。由于其发病机制不清，阻碍了有效的防控措施和疫苗的研究。最近有一群新发现的固有淋巴细胞(innate lymphoid cells，ILCs) 参与多种生物学作用，在抗菌、促炎、淋巴器官形成和组织修复发挥举足轻重的地位。警报素等因子，可增强Th2反应。本项目开展手术前和手术后的包虫病患者IL-33、ILC2及相关细胞因子与病程状况关系的研究发现IL-33/ILC2在包虫患者升高，手术后明显下降，与CD4+T细胞亚群变化正相关，与疾病进程有关；尤其是sST2在活动性患者中明显升高，可能与预后相关，是重要的生物指标。同时分析棘球蚴感染小鼠ILC2在感染的早、中、晚期数量及表型动态变化，IL-33/ILC2及IL-25/ILC2均与感染的加重有关，观察标本肝脏包囊周围ILC2和IL-13的增加参与了病灶的炎症反应和纤维化，小肠粘膜中ILC2和IL-13等表达升高与粘膜中Tuff细胞的活性有关，尤其是包虫感染时警报素IL-33和IL-25升高，通过与其受体结合，诱导固有免疫IL-33/ILC2调控适应性免疫CD4+T细胞（Th1/Th2和Treg/Teff）的平衡发挥其在棘球蚴致病机制中作用；通过包虫特异性抗原及特异性抗体阻断ST2受体对ILC2增殖的影响，可以减少包虫的感染，可能是防治包虫病的重要靶点，本项目研究初步阐明了这一新型固有淋巴细胞在棘球蚴感染中的免疫作用。