Th17-IgA Axis in Regulation of Intestinal Inflammation

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 DESCRIPTION (provided by applicant): Intestinal mucosal surfaces are protected by a first-line defense mediated by secretory IgA (SIgA). That IgA plays a key role in gut homeostasis is strongly suggested by the observations that in patients with severe IgA deficiency (SlgAD) or common variable immunodeficiency (CVID), impaired IgA production triggers persistent symptoms including gastrointestinal infections. Development of intestinal inflammation and small intestinal nodular lesions is often seen in IgA-deficient patients, a phenomenon attributed to aberrant expansion of commensal bacteria. Multiple signals, including T cell-dependent and -independent pathways, regulate IgA induction. However, the relative importance of each and how they are regulated remain poorly understood. Yet, a better understanding of the IgA response is key to understanding intestinal immune homeostasis and the pathogenesis of inflammatory bowel disease (IBD). Th17 cells, which produce IL-17 (IL-17A), IL-17F, IL-21 and IL-22, have recently been shown to be important in the maintenance of immune homeostasis, in addition to their pro-inflammatory function. Although high amounts of IgA and Th17 cells are both present constitutively in the intestine, there are sparse data that address how each of these systems respond to antigens of the microbiota, or whether these two systems interact in that effort, in regulation of host response to microbiota and the pathogenesis of IBD. In this project, we will investigate how Th17 cells promote intestinal IgA production, and whether Th17 cells regulate the differentiation and maintenance of memory IgA+ B cells. Finally, we will test our hypothesis that in context with intestinal IgA, Th17 cells regulate commensal bacteria colonization and translocation and thus contribute to intestinal homeostasis and protect the intestine from inflammation in response to microbiota. Under the conditions of an impaired intestinal IgA response, disregulated Th17 cells are proinflammatory and able to induce colitis. Upon completion, the proposed studies will establish a novel pathway of Th17 cells through induction of an intestinal IgA response in the regulation of intestinal immune homeostasis and protection of the intestines from inflammation in response to microbiota, as well as the pathogenesis of inflammatory bowel diseases.