p38调控CARD9(S12N)杂合子等位基因表达不平衡导致ABPA发生的机制研究

变应性支气管肺曲霉病（allergic bronchopulmonary aspergillosis, ABPA）是一种烟曲霉感染后引发Ⅱ型免疫应答的疾病。发病机制未被完全揭示。本课题组已阐明，曲霉刺激CARD9(S12N) 纯合突变的巨噬细胞能引起TH2介导的Ⅱ型免疫应答，诱发ABPA（Nat Immunol, 2018）。申请人前期发现，CARD9(S12N)杂合突变宿主易患ABPA，且杂合巨噬细胞发生等位基因表达不平衡：CARD9(WT) mRNA发生降解，而CARD9(S12N) mRNA降解被抑制。同时p38特异地正调CARD9(WT) mRNA降解过程。为鉴定p38调控等位基因表达不平衡，进而介导杂合巨噬细胞引发Ⅱ型免疫应答的机制，本项目拟确定杂合巨噬细胞能引发Ⅱ型免疫应答，鉴定p38调控等位基因表达不平衡的发生并阐明调控机制，以期为杂合人群ABPA的诊断和治疗提供新策略。

Allergic bronchopulmonary aspergillosis (ABPA) is an allergic inflammatory disorder of Type II immune response caused by Aspergillus fumigatus (Af) infection, pathogenesis of which is still unclear. Our previous results proved that when stimulated with Af, macrophages of homozygous CARD9(S12N) mutantion produce IL-5, induce Type Ⅱ immune response mediated by TH2 and development of ABPA（Nat Immunol, 2018）. In this project, we preliminary found that heterozygous CARD9(S12N) mutation predisposes host to ABPA development as well. In heterozygous macrophages, degradation of CARD9(WT) mRNA and inhibition of CARD9(S12N) mRNA decay results in allelic expression imbalance (AEI)of CARD9. And p38 specifically promotes degradation of CARD9(WT) mRNA. Aiming to provide new diagnosis and treatment strategies of ABPA, we plan to verify that heterozygous macrophages induce Type Ⅱ immune response and that p38 regulate AEI development in macrophage, and to reveal mechanisms of the regulation.