Control by Beta 7 integrins of the bacterial triggers of IBD

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7. Project Summary/Abstract The blockade of lymphocyte surface integrins (i.e. natalizumab (α4), vedolizumab (α4β7)) is an FDA-approved strategy for the treatment of inflammatory bowel disease (IBD). Our understanding of their mode of action is incomplete and little emphasis has been placed on their effect on B cells. However, a single dose of vedolizumab in healthy volunteers lowers secretory immunoglobulin (Ig)A (SIgA) and weakens the immunization response to oral cholera vaccine. To address the role of β7 integrins for the migration, localization and function of B cells in IBD, we crossed tumor necrosis factor (TNF)-overproducing mice (TNFΔARE, which develop Crohn’s-like ileitis) and IL10-/- (colitic-prone) with β7-deficient (β7-/-) mice. Unexpectedly, double mutant (TNFΔARE/β7-/-) mice developed accelerated ileitis (earlier onset and worse severity), whereas IL-10-/-β7-/- develop lethal colitis. This phenotype could additionally be induced by an anti-MAdCAM-1(α4β7-ligand) antibody. The accelerated phenotypes were not due to a deficiency of retinoic acid-producing αE(CD103)+ dendritic cells, regulatory T cells, regulatory B cell-derived cytokines or defensins. There was, however, markedly decreased lamina propria (CD19+) B cells, poor localization of IgA+ plasma cells, luminal IgA deficiency, and differences in microbiota composition in co-housed siblings. Furthermore, fecal microbiota transplants from β7-/- mice induced colitis in IL-10-deficient mice, suggesting that an Ig deficit may allow transmissible proliferation of colitogenic pathobionts. Thus, there is a critical need to understand whether sustained blockade of integrins or their ligands may have implications for mucosal immunity. We hypothesize that the acceleration of ileitis and colitis in β7-deficient mice is mediated by impaired B cell migration and suboptimal IgA transcytosis leading to an intestinal immunoglobulin deficit and proliferation of pathobionts. To test these hypotheses, we will examine: 1. the role of B cell recruitment and survival to maintain luminal IgA. 2. How do changes in microbiota composition alter the course and severity of IBD? and 3. Further examine the role of β7 integrin (i.e., αEβ7) for docking of IgA-producing plasma cells with epithelium and optimal IgA transcytosis. This investigation is significant as it begins to address the role of B cells and their unique critical dependence on β7 integrins to home to the intestine and optimally transcytose IgA to maintain the required IgA levels that control certain pathogenic elements of the microbiota during homeostasis and 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 even lead to new interventions to prevent initiation of the dysregulated immune response to the microbiota that triggers IBD.