变态反应性支气管肺曲霉菌病（Allergic Bronchopulmonary Aspergillosis, ABPA)的主要免疫应答为激活Th2细胞极化，分泌IL-4、IL-5和IL-13, 导致血清IgE和曲霉特异IgE升高以及肺支气管嗜酸性粒细胞大量浸润。目前ABPA 的发病机制尚不清楚，原发性免疫缺陷被认为是ABPA的主要诱发因素。申请人前期研究发现CARD9基因缺失小鼠感染烟曲霉菌发生ABPA；CARD9主要表达在髓系来源固有免疫细胞中，是C型凝集素受体下游传递活化信号的重要接头蛋白。本项目拟深入研究CARD9基因缺失通过影响固有免疫细胞的分化及功能驱动Th2细胞极化最终引起ABPA发生的分子机制，并筛查临床ABPA病人CARD9基因的原发性变异，最终阐明CARD9基因原发性变异导致ABPA发病的分子机制，为ABPA的早期临床诊断提供依据，以及ABPA的治疗提供新靶点和治疗策略。

Allergic bronchopulmonary aspergillosis (ABPA) are most frequently caused by Aspergillus fumigatus (A. fumigatus). ABPA is a disease in which Th2 CD4+T-cell responses play a critical role in the development of an asthma-like disease with pulmonary hypersensitivity and compromised lung function. Activated Th2 cells can secrete cytokines such as IL-4, IL-5 and IL-13 leading to IgE isotype switching of B-cells, increased secretion of A. fumigatus-specific IgG, IgE and total IgE antibodies, and pulmonary eosinophilic influx. Genetic association studies have shown that primary immunodeficiency leads to a predisposition to develop ABPA. The caspase recruitment domain-containing protein 9 (CARD9) is the critical adaptor protein that operates downstream of several C-type lectin receptors including Dectin-1, Dectin-2, and Dectin-3, which are critical for host innate immune responses against fungal infection. Our Preliminary data showed that CARD9-deficient mice developed ABPA after infection with A. fumigatus. In this project, we aimed to clarify that CARD9-deficient DCs activated by A. fumigatus prime Th2 cell polarization and lead to the development of ABPA. Furthermore, we aimed to identify the associations between gene polymorphisms and genetic errors of CARD9 and an increased incidence of ABPA, which will have significant impact on improving early diagnosis and treatment strategies.