T cell Response Defects to Commensal Glycoantigens in CGD

描述（由申请人提供）：慢性肉芽肿病（CGD）是一种原发性免疫缺陷，其特征是对机会性感染的易感性增加，反复出现肉芽肿形成和慢性炎症。在正常个体中，微生物的吞噬之后是抗菌活性氧（ROS）的产生，但CGD患者在入侵期间携带先天性缺陷的NADPH氧化酶复合物，该复合物负责ROS的合成，因此无法建立适当的防御。相当大比例的CGD患者还会发生与克罗恩病高度相似的炎症性肠病（IBD），这是由依赖于CD4+ T辅助型1 （TH1）淋巴细胞激活的不适当的适应性自身免疫反应介导的。我们研究了一种新的II类主要组织相容性复合体（MHCII）依赖的T细胞激活荚膜多糖，来自共生细菌脆弱拟杆菌的PSA，可能为cgd相关的IBD提供关键的见解。我们已经发现，T细胞被这些碳水化合物抗原（糖抗原）激活所需的抗原加工机制是由氧化途径介导的，氧化途径在CGD中受损，可能导致T细胞对共生生物缺乏耐受性。因此，本研究有两个具体目的：(1)确定糖抗原刺激的氧化剂产生和CGD中T细胞活化缺陷；(2)确定糖抗原刺激的T细胞在CGD相关IBD中的作用。基于这两个目的，本R21先导研究的重点是分析糖抗原暴露后小鼠和人CGD模型中T细胞刺激和氧化反应的模式，以更清楚地确定共生碳水化合物在肠道炎症性CGD后遗症中的作用。这些发现可能为预防cgd相关肠道炎症的特异性免疫治疗提供了第一个基本原理。公共卫生相关性：本提案的重点是采取第一个机制步骤，以了解T细胞对共生生物表达的碳水化合物抗原的反应在慢性肉芽肿病和相关炎症性肠病中的作用。这些抗原、CGD和IBD之间的直接联系可以通过确定未来治疗干预的特定途径，对CGD患者以及更广泛的IBD患者群体具有深远的意义。

DESCRIPTION (provided by applicant): Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by increased susceptibility to opportunistic infection, recurring granuloma formation, and chronic inflammation. In normal individuals, phagocytosis of microbes is followed by the production of antimicrobial reactive oxygen species (ROS), yet CGD patients carry a congenital defect in the NADPH oxidase complex responsible for ROS synthesis during invasion and thus fail to mount a proper defense. A significant proportion of CGD patients also develop an inflammatory bowel disorder (IBD) highly similar to Crohn's Disease, which is mediated by an inappropriate adaptive autoimmune response that is dependent upon CD4+ T helper type 1 (TH1) lymphocyte activation. Our work with a novel class II major histocompatibility complex (MHCII)-dependent T cell-activating capsular polysaccharide, PSA from the commensal bacteria Bacteroides fragilis, may provide critical insight for CGD-associated IBD. We have discovered that the antigen processing mechanism required for T cell activation by these carbohydrate antigens (glycoantigens) is mediated by the oxidative pathway that is compromised in CGD and may lead to a lack of T cell tolerance to commensal organisms. As such, this proposal is governed by two specific aims: (1) Define the glycoantigen-stimulated oxidant production and T cell activation defects in CGD, and (2) Determine the role for glycoantigen-stimulated T cell in CGD-associated IBD. With these two aims, this R21 pilot study is focused upon analyzing the pattern(s) of T cell stimulation and oxidative responses in mouse and human CGD models upon glycoantigen exposure to more clearly define the role of commensal carbohydrates in gut inflammatory CGD sequelae. These findings could provide the first rationale for specific immunotherapy for the prevention of CGD-associated gut inflammation. PUBLIC HEALTH RELEVANCE: This proposal is focused upon taking the first mechanistic steps in understanding the role of T cell responses to carbohydrate antigens expressed by commensal organisms in chronic granulomatous disease and the associated inflammatory bowel disorders. A direct connection between such antigens, CGD, and IBD could hold profound implications for CGD patients as well as the broader population of IBD sufferers by identifying specific pathways for future therapeutic intervention.