Integrin αEβ7-dependent IgA transcytosis during homeostasis and IBD

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7. Project Summary Inflammatory bowel disease (IBD) arises in genetically-susceptible individuals when the intestinal immune system loses tolerance to unidentified elements of the commensal microbiota. Plasma cell (PC)-derived secretory immunoglobulin A(sIgA) is one of the main mechanisms through which we are able to coexist with our microbiota. Despite this, insufficient emphasis has been placed on understanding the B cell/immunoglobulin A (IgA) system during IBD. Antibodies that block integrins on the cell surface of white cells have become a widely- used strategy for the treatment of IBD. One of these drugs (vedolizumab), specifically blocks integrin α4β7, a molecule which is critical for the traffic of white cells to the intestine. We find that B cells carry this integrin more than T cells in mice and humans and critically depend on this molecule to traffic to intestine. Therefore, mice that lack the β7 integrin chain have an intestinal B cell deficit and a stool IgA deficit that leads to alterations if their intestinal flora and worse IBD in two chronic IBD mouse models. Although this could be attributed to an integrin α4β7 defect, the luminal IgA deficit persists in mice that lack αEβ7 integrin, although in these mice B cells can reach the intestine normally. We recently found a previously undescribed subset of intestinal PC that express αEβ7, localized primarily to the base of the crypts. We propose that certain intestinal PC express αEβ7, which allows them to dock with intestinal epithelial cells and directly relay IgA for its most efficient transport to the intestinal lumen. We believe that this new mode of IgA transport plays a critical role for the maintenance of IgA in intestinal lumen and therefore on the microbial flora during IBD. In the current proposal we will several address important questions that remain unanswered. 1. Where are these cells located and what is their origin? 2. How do they influence the severity of IBD in mice and 3. What is their contribution on the control of the intestinal bacterial flora during IBD. This investigation is significant as it begins to address the role of B cells and their critical dependence on β7 integrins to home to the intestine and maintain the required IgA levels that control certain pathogenic microbes during IBD. Understanding the role of lymphocyte integrins at the interface between the microbiota and its host may lead to a better understanding of how do current anti-integrin therapeutics work and lead to new interventions to prevent the uncontrolled immune response to the microbiota that triggers IBD.