Regulation of mucosal IgA and allergic inflammation by intestinal epithelial cells

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 DESCRIPTION (provided by applicant): Epithelial cells lining mucosal surfaces represent the first barrier of the host against exogenous products and pathogens. Intestinal epithelial cells (IEC) have been extensively studied for their role in the digestion and selective absorption of ingested food molecules. IEC produce cytokines that influence the differentiation of classical antigen presenting and other innate cells and subsequently, shape adaptive immune responses. These cells also express the receptor for polymeric immunoglobulins, which allows the transport of polymeric IgA across the epithelium and their secretion as secretory IgA antibodies in the lumen. However, the role of IEC in allergic responses remains poorly understood and it remains unclear how specific signaling pathways in IEC affect allergic sensitization in the GI tract and impact allergic responses at distant mucosal sites such as the airways. We will address the overall hypothesis that selected innate signaling pathway in intestinal epithelial cells shape allergen-specific antibody isotype responses and promote IgA antibodies, which can prevent the development, or reduce the magnitude of allergic inflammation at distant sites. Using genetically modified mice and pharmaceutical inhibitors of the selected innate signaling pathway we propose to 1) address how activation of the non-canonical NFB signaling in intestinal epithelial cells regulate adaptive immune response during allergic sensitization; 2) Establish mechanisms of protection against allergic inflammation by IgA and IgA+ B cells.