Antigenic Carbohydrate Structure, Function, and Specificity

描述(申请人提供)：益生菌是以某种方式赋予宿主利益的活的有机体。脆弱类杆菌就是这样一种益生菌，它的荚膜多糖PSA具有免疫调节作用，是一类新的MHC II类呈递的碳水化合物T细胞抗原(糖抗原)的创始成员。口服PSA可恢复Th1/Th2平衡和免疫动态平衡，同时通过诱导调节性T细胞使这些动物不太容易感染炎症性疾病。我们已发表的和初步的数据进一步表明，修饰抗原提呈细胞的N-连接糖链的性质，特别是MHCII，是T细胞递送和识别糖抗原机制的关键方面。这些创新和意想不到的发现表明，通过宿主多糖对共系膜特异性Treg细胞的诱导，免疫稳态可以通过细胞糖基化来调节。在这里，我们提出了三个具体的目标，以获得一个完整的机制和结构上的理解如何宿主糖基化调节糖抗原递呈，外周炎症，并最终在分子，细胞和机体水平上的免疫稳态。我们拟议的实验结果将揭示炎症和糖基化之间通过碳水化合物抗原活性的调节关系，并可能导致药物靶点的确定，以预防和/或治疗哮喘、IBD、动脉粥样硬化和癌症等疾病中正在进行的炎症。

DESCRIPTION (provided by applicant): Probiotics are live organisms that confer a benefit to their host in some fashion. Bacteroides fragilis is one such probiotic by virtue of the immunomodulatory properties of its capsular polysaccharide PSA, the founding member of a novel class of MHC class II-presented carbohydrate T cell antigens (glycoantigens). Oral exposure to PSA in gnotobiotic mice restores the Th1/Th2 balance and immune homeostasis while rendering these animals less susceptible to inflammatory diseases through the induction of regulatory T cells. Our published and preliminary data further demonstrate that the nature of the N-linked glycans decorating antigen presenting cells, and specifically MHCII, is a critical aspect of the mechanism by which glycoantigens are presented and recognized by T cells. These innovative and unexpected findings suggest that immune homeostasis could be regulated by cellular glycosylation by virtue of the impact host glycans have on the induction of commensal-specific Treg cells. Here, we propose three specific aims to obtain a complete mechanistic and structural understanding of how host glycosylation modulates glycoantigen presentation, peripheral inflammation, and ultimately immune homeostasis at the molecular, cellular, and organismal levels. The results from our proposed experiments will reveal regulatory connections between inflammation and glycosylation through carbohydrate antigen activity and could lead to drug target identification to prevent and/or treat ongoing inflammation in diseases as diverse as asthma, IBD, atherosclerosis, and cancer.