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.
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.
| Ryan, Sean O; Johnson, Jenny L; Cobb, Brian A (2013) Neutrophils confer T cell resistance to myeloid-derived suppressor cell-mediated suppression to promote chronic inflammation. J Immunol 190:5037-47 |
| Rabinovich, Gabriel A; van Kooyk, Yvette; Cobb, Brian A (2012) Glycobiology of immune responses. Ann N Y Acad Sci 1253:1-15 |
| Lewis, Colleen J; Cobb, Brian A (2011) Adaptive immune defects against glycoantigens in chronic granulomatous disease via dysregulated nitric oxide production. Eur J Immunol 41:2562-72 |
| Lewis, Colleen J; Cobb, Brian A (2010) Carbohydrate oxidation acidifies endosomes, regulating antigen processing and TLR9 signaling. J Immunol 184:3789-800 |
