NKT细胞在屋尘提取物暴露预防过敏性哮喘中的作用和机制研究

The prevalence of asthma is increasing dramatically in association with rapid urbanization. Absence of environmental exposure is generally believed to be one of the likely causes. Previous studies showed house dust extract (HDE), containing a wide variety of molecules derived from microbes, could protect against OVA-induced asthma depending on Toll-like receptors. Recent evidence indicated iNKT cell, type I natural killer cell, have a role in pathological mechanism of asthma. However, homeostasis of iNKT cells established depending on pathways of CD1d molecular is important in protective immunity against asthma, although the exact molecular mechanism is yet unknown. Our study suggested low prevalence of childhood asthma was found in rural Conghua compared to urban Guangzhou. HDEs from the two regions showed different composition of microorganism and lipid molecules. αGalCer, a kind of glycolipid, could exacerbate symptoms of OVA-induce asthmatic mice, whereas HDE from rural families could protect against asthma. Therefore, this study is designed to reveal the immune regulation mechanism of glycolipids against lung iNKT homeostasis using HDEs from rural and urban families and to clarify 1) the mechanism of HDEs activating human iNKT cells in vitro and lung iNKT homeostasis in vivo as well as tendency of cytokines production. This study may provide theoretical and experimental foundation for research and development of early interventions against asthma.

哮喘患病率随城市化进程逐渐升高，微生物暴露缺乏是可能原因之一。以往研究表明，过敏原诱导的哮喘模型中，屋尘提取物（包含多种微生物成分）暴露依赖Toll样受体途径产生免疫保护。最新证据表明，iNKT（I型自然杀伤T）细胞参与哮喘病理机制，但能够通过CD1d分子依赖途径建立iNKT细胞稳态，并介导免疫保护，其具体分子机制尚不清楚。我们发现，从化农村儿童哮喘发病率显著低于广州市区，城乡屋尘中微生物种类和脂质成分显著不同，糖脂αGalCer暴露加重过敏性哮喘小鼠症状，而农村屋尘提取物暴露降低哮喘症状。因此，本项目从屋尘提取物糖脂对肺部iNKT细胞稳态的免疫调节思路出发，以城乡不同屋尘提取物为样本，应用人iNKT细胞和和OVA致敏哮喘模型，阐明屋尘提取物激活iNKT细胞、肺部iNKT稳态以及IFN-γ等细胞因子分泌倾向在预防过敏性哮喘中的作用和分子机制，为研发有效的早期预防措施提供理论和实验依据。

哮喘患病率随城市化进程逐渐升高，微生物暴露缺乏是可能原因之一。以往研究表明，过敏原诱导的哮喘模型中，屋尘提取物（包含多种微生物成分）暴露依赖Toll样受体途径产生免 疫保护。最新证据表明，iNKT（I型自然杀伤T）细胞参与哮喘病理机制，但能够通过CD1d分子依赖途径建立iNKT细胞稳态，并介导免疫保护，其具体分子机制尚不清楚。本项目从屋尘提取物糖脂对肺部iNKT细胞稳态的免疫调节思路出发，以城乡不同屋尘提取物为样本，应用人iNKT细胞和和OVA致敏哮喘模型，阐明屋尘提取物激活iNKT细胞、肺部iNKT稳态以及IFN-γ 等细胞因子分泌倾向在预防过敏性哮喘中的作用和分子机制，为研发有效的早期预防措施提供理论和实验依据。本项目采用脂质组学分析城乡儿童卧室床尘样品中的脂质差异，发现城乡儿童卧室床尘中的差异脂质主要为鞘脂类、甘油磷脂、甘油糖脂和Fatty Acyls；通过屋尘螨滴鼻构建过敏性哮喘小鼠模型，发现农村来源屋尘提取物持续低剂量滴鼻暴露可以明显抑制OVA诱导的过敏性哮喘反应。本研究发表学术论文3篇，包括1篇SCI论文（Allergy杂志）。