T cell Response Defects to Commensal Glycoantigens in CGD

CGD 中 T 细胞对共生糖抗原的反应缺陷

• 批准号: 7533265
• 负责人: Brian A Cobb
• 金额: $ 19.63万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-20 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7533265
• 关键词: Adoptive Transfer; Animal Model; Animals; Antigen-Presenting Cells; Antigens; Autoimmune Responses; Bacteroides fragilis; Biochemistry; Bystander Suppression; CD4 Positive T Lymphocytes; Carbohydrates; Cells; Cellular biology; Chronic; Chronic Granulomatous Disease; Complex; Congenital Abnormality; Crohn' s disease; Data; Defect; Development; Disease; Disease model; Equilibrium; Exposure to; Failure; Figs - dietary; Fluorescence; Foundations; Future; Gnotobiotic; Granuloma; Granulomatous; Histocompatibility Antigens Class II; Human; Immune; Immune response; Immunologic Deficiency Syndromes; Immunotherapy; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Interleukin-10; Knock-out; Lead; Life; Link; Lymphocyte; Lymphocyte Activation; Lymphoid Tissue; Maintenance; Major Histocompatibility Complex; Mediating; Microbe; Mus; NADPH Oxidase; Opportunistic Infections; Organism; Ovalbumin; Oxidants; Pathway interactions; Patients; Pattern; Phagocytosis; Phenotype; Pilot Projects; Play; Polysaccharides; Population; Predisposition; Prevention; Process; Production; Public Health; Reactive Oxygen Species; Role; Surface; T-Cell Activation; T-Lymphocyte; Therapeutic Intervention; Work; antigen processing; antimicrobial; base; commensal microbes; insight; killings; novel; oxidation; prevent; response

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.

描述(申请人提供)：慢性肉芽肿病(CGD)是一种以机会性感染易感性增加、复发肉芽肿形成和慢性炎症为特征的原发免疫缺陷。在正常人中，吞噬微生物之后会产生抗菌活性氧物种(ROS)，但CGD患者在入侵过程中负责合成ROS的NADPH氧化酶复合体存在先天缺陷，因此无法进行适当的防御。相当大比例的CGD患者还患上与克罗恩病高度相似的炎症性肠病(IBD)，这种疾病是由一种不适当的适应性自身免疫反应介导的，这种反应依赖于CD4+T辅助细胞1型(TH1)淋巴细胞的激活。我们对共生细菌脆弱类杆菌的一种新的依赖于II类主要组织相容性复合体(MHCII)的激活T细胞的囊膜多糖PSA的工作，可能为CGD相关的IBD提供关键的洞察力。我们发现，这些碳水化合物抗原(糖抗原)激活T细胞所需的抗原处理机制是由CGD中受损的氧化途径介导的，可能导致T细胞对共生生物缺乏耐受性。因此，这一建议有两个特定的目标：(1)明确糖抗原刺激的氧化剂产生和T细胞激活缺陷在CGD中的作用；(2)确定糖抗原刺激的T细胞在CGD相关性IBD中的作用。带着这两个目标，本R21先导研究集中于分析糖抗原暴露下小鼠和人CGD模型中T细胞刺激和氧化反应的模式(S)，以更清楚地确定共生碳水化合物在肠炎性CGD后遗症中的作用。这些发现可能为特异性免疫疗法预防CGD相关性肠炎提供第一个理论基础。公共卫生相关性：这项建议的重点是采取第一个机械性步骤，了解T细胞对共生生物表达的碳水化合物抗原在慢性肉芽肿疾病和相关炎症性肠道疾病中的作用。这种抗原、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患者产生深远的影响。