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

• Published in: Journal of allergy and clinical immunology 2021-04, Vol.147 (4), p.1381-1392
• Main Authors: Bruton, Kelly, Spill, Paul, Vohra, Shabana, Baribeau, Owen, Manzoor, Saba, Gadkar, Siyon, Davidson, Malcolm, Walker, Tina D., Koenig, Joshua F.E., Ellenbogen, Yosef, Florescu, Alexandra, Wen, Jianping, Chu, Derek K., Waserman, Susan, Jiménez-Saiz, Rodrigo, Epelman, Slava, Robbins, Clinton, Jordana, Manel
• Format: Article
• Language: English
• Subjects: Allergens; Anaphylaxis; Anaphylaxis - immunology; Animals; Antibodies; Antigens; Blood & organ donations; CD4-Positive T-Lymphocytes - immunology; Cell culture; Cytokines; Cytokines - immunology; Disease Models, Animal; Female; Food allergies; food allergy; Humans; IgE; IL-4 receptor; Immunoglobulin E; Immunoglobulin E - immunology; Immunoglobulin G; Immunologic Memory; Immunological memory; Injections; Interleukin 13; Interleukin 4; Laboratories; Leukocytes, Mononuclear - immunology; Lymphatic system; Lymphocytes B; Memory cells; memory response; Mice; Mice, Inbred C57BL; Peanut Hypersensitivity - immunology; Peripheral blood mononuclear cells; Phenotypes; Plasma cells; Receptors, Interleukin-4 - immunology; TH2 immunity
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2020.11.042

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. Our aim was to investigate the critical requirements for an IgE recall response in peanut allergy. 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. 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. TH2A 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. The findings reported here advance our understanding of events mediating the regeneration of IgE in food allergy.