Interrupting reactivation of immunologic memory diverts the allergic response and prevents anaphylaxis

BACKGROUND: IgE production against innocuous food antigens can result in anaphylaxis, a severe life-threatening consequence of allergic reactions. The maintenance of IgE immunity is primarily facilitated by IgG⁺ memory B cells, as IgE⁺ memory B cells and IgE⁺ plasma cells are extremely scarce and short-lived, respectively. OBJECTIVE: Our aim was to investigate the critical requirements for an IgE recall response in peanut allergy. METHODS: We used a novel human PBMC culture platform, a mouse model of peanut allergy, and various experimental readouts to assess the IgE recall response in the presence and absence of IL-4Rα blockade. RESULTS: In human PBMCs, we have demonstrated that blockade of IL-4/IL-13 signaling aborted IgE production after activation of a recall response and skewed the cytokine response away from a dominant type 2 signature. T_H2A cells, identified by single-cell RNA sequencing, expanded with peanut stimulation and maintained their pathogenic phenotype in spite of IL-4Rα blockade. In mice with allergy, anti-IL-4Rα provided long-lasting suppression of the IgE recall response beyond antibody treatment and fully protected against anaphylaxis. CONCLUSION: The findings reported here advance our understanding of events mediating the regeneration of IgE in food allergy.