Maintenance and Reprogramming of Immunoglobulin E Memory

Abstract

Food allergy is an IgE-mediated disease affecting up to 10% of those in Western countries. Clinical reactivity to foods occurs following allergen cross-linking of IgE-FceRI complexes on mast cells and basophils causing rapid degranulation and release of vasoactive mediators. While some food allergies are naturally outgrown (e.g. milk and egg), others typically persist for a lifetime (e.g. peanut). For food allergic patients, the standard of care remains as strict allergen avoidance and use of rescue epinephrine upon accidental exposures. The broad objective of this thesis was to investigate aspects of immunological memory which perpetuate IgE-mediated allergies. In humans, we found that circulating IgE+ memory B cells were extremely rare, positioning memory B cells of other isotypes (e.g. IgG1) as the primary reservoir of IgE responses. IL-4/IL-13 signaling through IL-4Ra was critically required for these non-IgE-expressing memory B cells to replenish the transient IgE pool and, as a result, sensitized mice were fully protected from anaphylaxis upon challenge. Moreover, we demonstrated that IL-4Ra blockade reduced the Th2 dominant cytokine signature while upregulating IFN-y and IL-10. In parallel, we found that allergen-specific B cell responses could be reprogrammed away from an IgE fate. Collectively, this work elucidates key requirements for sustained immunological memory against food allergens and the potential to reprogram its pathogenic fate. These findings may aid in evolving the landscape of food allergy therapeutics.