Lifelong memory responses perpetuate humoral TH2 immunity and anaphylaxis in food allergy

Background: A number of food allergies (eg, fish, shellfish, and nuts) are lifelong, without any disease-transforming therapies, and unclear in their underlying immunology. Clinical manifestations of food allergy are largely mediated by IgE. Although persistent IgE titers have been attributed conventionally to long-lived IgE(+) plasma cells (PCs), this has not been directly and comprehensively tested. Objective: We sought to evaluate mechanisms underlying persistent IgE and allergic responses to food allergens. Methods: We used a model of peanut allergy and anaphylaxis, various knockout mice, adoptive transfer experiments, and in vitro assays to identify mechanisms underlying persistent IgE humoral immunity over almost the entire lifespan of the mouse (18-20 months). Results: Contrary to conventional paradigms, our data show that clinically relevant lifelong IgE titers are not sustained by long-lived IgE(+) PCs. Instead, lifelong reactivity is conferred by allergen-specific long-lived memory B cells that replenish the IgE(+) PC compartment. B-cell reactivation requires allergen re-exposure and IL-4 production by CD4 T cells. We define the half-lives of antigen-specific germinal centers (23.3 days), IgE(+) and IgG(1)(+) PCs (60 and 234.4 days, respectively), and clinically relevant cell-bound IgE (67.3 days). Conclusions: These findings can explain lifelong food allergies observed in human subjects as the consequence of allergen exposures that recurrently activate memory B cells and identify these as a therapeutic target with disease-transforming potential.