The adaptive immune response to food antigens in the gut

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Food allergy affects approximately 8% of US children. The most severe form of food allergy results in anaphylaxis, which can be life-threatening. Currently only one FDA-approved therapy for peanut allergy exists, which is oral immunotherapy (OIT). Other food allergies lack approved treatments. Although a promising intervention, peanut OIT does not work for all children, often only mitigates anaphylaxis risk temporarily and can itself cause life-threating reactions. Therefore most patients must try to avoid food allergens to prevent allergic reactions. New strategies to treat food allergies are needed; however, progress is stymied because we lack a mechanistic understanding of the factors that attenuate allergy to food. Food-antigen specific immunoglobulin E (IgE) is a central mediator of anaphylactic reactions. In contrast, gut IgA to food antigens is presumed to be beneficial as part of a tolerogenic response. However, it is still unknown how IgA to food is induced and how this cellular mechanism is related to induction of food-specific IgE. Our preliminary data demonstrate that despite potentially opposing functions, food-specific IgA and IgE are often co-produced in children with food allergy. Indeed we find in mouse models that many of the immune stimuli that induce IgE are the same ones that induce IgA. Our preliminary data challenge the current, but untested, paradigm that the steady state/tolerogenic response to food antigens involves IgA . Our goal is to identify how food- specific gut IgA is induced, its relationship to food-specific IgE and to define the role of IgA in food allergy. To mechanistically define the role of T cell subsets we created new mouse models to selectively knockout specific T cell subsets along with particular effector functions. These models will also enable us to test the isolated role of food-specific IgA in the gut by eliminating the select T cell subset that drives food-specific IgA without impacting microbe-specific IgA or food-specific IgE. To definitively identify the role of IgA in food allergy, we also developed new mouse models that isolate IgA from IgE production to food. To define the clonal relationship of food-specific IgA and IgE B cells early after peanut immunization we established collaborations with bioinformatics experts in B cell receptor repertoire analyses. Finally, we developed a method to detect peanut- and egg-white-specific IgA in human stool samples and will use these assays to characterize the food- specific gut IgA response in atopic children and separately, children undergoing oral immunotherapy with peanut. Our preliminary studies demonstrate that the generation of food-specific IgA occurs through an entirely novel immunological pathway, distinct mechanistically from microbe-specific-IgA and physically from food- specific IgE and question current models of how IgA might mitigate the allergic response to food. If successful, our experiments will define the fundamental immunologic rules that govern the production of food-reactive IgE and IgA and thereby identify new therapeutic and diagnostic possibilities for those with food allergy. 1