Pathways of Adaptive Immune Activation During Sensitization and Recall in Food Allergy

Abstract

Approximately 10% of North Americans have at least one food allergy. Allergic reactions to foods are mediated by IgE antibodies which, upon allergen exposure, are crosslinked on the surface of mast cells and basophils, resulting in degranulation. The granule contents of mast cells and basophils are responsible for the diverse signs and symptoms of food allergy, including hives, itchiness, edema, vomiting, diarrhea, and a potentially lethal form of systemic shock called anaphylaxis. The clinical recommendation for food allergic Canadians is strict allergen avoidance, and emergency epinephrine use upon an accidental exposure. There are presently no disease modifying therapeutic options for allergic Canadians. The work in this PhD thesis focuses on the pathways which result in the production and memory of allergen-specific IgE. Using murine models of food allergy and anaphylaxis, we have delineated pathways of early allergic sensitization which may occur prior to allergic patients presenting in the clinic during the first allergic reaction. We have demonstrated that CD4+ T cell activation can occur in the absence of B cell activation, but can hold the memory of IgE responses persistently, potentially for a lifetime. Upon re-exposure to the allergen, CD4+ T cells can activate naïve B cells, which pursue either direct or sequential isotype switching to IgE, both resulting in clinical reactivity against food allergens. Our findings will inform future diagnostic and prognostic tests in pre-allergic patients, and to design novel therapeutics with disease modifying capacity in humans.