T cell Response Defects to Commensal Glycoantigens in CGD

描述（由申请方提供）：慢性肉芽肿病（CGD）是一种原发性免疫缺陷，其特征为对机会性感染的易感性增加、复发性肉芽肿形成和慢性炎症。在正常个体中，微生物的吞噬作用之后是抗微生物活性氧（ROS）的产生，然而CGD患者在入侵期间负责ROS合成的NADPH氧化酶复合物中携带先天性缺陷，因此无法进行适当的防御。相当大比例的CGD患者还发展出与克罗恩病高度相似的炎性肠病（IBD），其由依赖于CD4+ T辅助1型（TH1）淋巴细胞活化的不适当的适应性自身免疫应答介导。我们的工作与一种新的II类主要组织相容性复合体（MHCII）依赖性T细胞活化荚膜多糖，PSA从肠道细菌脆弱类杆菌，可能提供关键的见解CGD相关的IBD。我们已经发现，这些碳水化合物抗原（糖抗原）激活T细胞所需的抗原加工机制是由CGD中受损的氧化途径介导的，并可能导致T细胞缺乏对微生物的耐受性。因此，该提议由两个具体目标支配：（1）定义CGD中糖抗原刺激的氧化剂产生和T细胞活化缺陷，以及（2）确定糖抗原刺激的T细胞在CGD相关IBD中的作用。出于这两个目的，该R21初步研究重点分析了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，以更清楚地定义糖基碳水化合物在肠道炎性CGD后遗症中的作用。这些发现可以为预防CGD相关肠道炎症的特异性免疫疗法提供第一个理论基础。公共卫生相关性：该建议的重点是采取第一个机械步骤，在理解的作用，T细胞反应的碳水化合物抗原表达的微生物在慢性肉芽肿性疾病和相关的炎症性肠病。这些抗原，CGD和IBD之间的直接联系可能对CGD患者以及更广泛的IBD患者群体产生深远的影响，通过确定未来治疗干预的特定途径。

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.