肠道炎症和非经典Th2/Tc2细胞分化在儿童食物过敏中的作用机制研究

Previously we found that inflammatory cytokines suppressed IL-2 expression in CD4+T cells and promoted non-classical Th2 cell differentiation and the development of IgE-mediated food allergy in infants （Sci Transl Med, 2016）. In CD8+ T cells, preliminary data reveal that inflammation promoted fatty acid metabolism and caspase-dependent IL-4 expression. We hypothesize that inflammation and microbial metabolites alter the epigenetic and metabolic state of gastrointestinal resident T cells and mediate mucosal pathology through activation of fatty acid metabolism and caspase-dependent IL-4 expression. We will compare the phenotype and function of blood and gastrointestinal resident T cells in children with and without food allergy, and identify underlying mechanisms through integration of epigenetic and transcriptional data sets. We will confirm fatty acid metabolism and caspase-dependent Th2/Tc2 differentiation pathway in colon mucosa of children with food allergy and in animal models of food-allergy. This will broaden our understanding on the immunopathogenic mechanisms underlie childhood food allergy, and identify potential biomarkers and targets for disease diagnosis and therapy.

我们已发表文章表明炎症细胞因子抑制CD4+ T细胞分泌IL-2，并分化为表达IL－4 的非经典Th2细胞而增加婴幼儿IgE介导的食物过敏的发病风险（Sci Transl Med, 2016）。体外预实验进一步证明，在CD8+ T细胞中，炎症因子促进脂肪酸代谢，并通过激活caspase而生成IL-4。我们假设炎症环境通过改变肠道T细胞的表观遗传和代谢途径，促进肠道T细胞的脂肪酸代谢和caspase－依赖的Th2/Tc2分化而介导肠道黏膜病变。我们将比较过敏和非过敏儿童结肠黏膜和外周血T细胞亚群的表型和功能，阐述T细胞亚群的表观遗传和转录组学特征，并利用过敏儿童结肠黏膜和食物过敏动物模型来验证肠道炎症诱发食物过敏的脂肪酸代谢和caspase活化调控机制。这将增加对食物过敏肠道局部免疫致病机制的了解，为疾病的诊断和治疗提供新的分子标签和药物靶点。

儿童慢性结肠炎及炎症性肠病对婴幼儿的生长发育具有重大影响，但其发病机制尚 不清晰。在本文中，我们分析了儿童未定型慢性结肠炎、克罗恩病和溃疡性结肠炎结肠黏 膜的单细胞聚类、免疫表型和风险基因，证实了这些疾病具有共性致病特征，即环单磷酸腺苷（cAMP）响应通路的减弱。具体表现在，儿童慢性结肠炎及炎症性肠病结肠黏膜中都存在PDE4B（一种水解cAMP的磷酸二酯酶）和TNF高表达的巨噬细胞浸润、CD39+T细胞丰度的下调以及血小板聚集并释放五羟基色胺等。在初步的临床实验中，靶向抑制磷酸二酯酶（PDEs）的药物双嘧达莫可以有效恢复免疫稳态并改善儿童肠道炎症症状。总之，通过对结肠黏膜的系统分析，我们揭示了儿童慢性结肠炎及炎症性肠病的共性发病机制和靶向治疗通路。