Kelly Bruton1, Paul Spill1, Shabana Vohra2, Owen Baribeau1, Saba Manzoor1, Siyon Gadkar1, Malcolm Davidson1, Tina D Walker1, Joshua F E Koenig1, Yosef Ellenbogen3, Alexandra Florescu1, Jianping Wen1, Derek K Chu4, Susan Waserman3, Rodrigo Jiménez-Saiz5, Slava Epelman2, Clinton Robbins2, Manel Jordana6. 1. McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada. 2. Peter Munk Cardiac Centre, Toronto, Ontario, Canada. 3. Department of Medicine, McMaster University, Hamilton, Ontario, Canada. 4. Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada. 5. McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; Centro Nacional de Biotecnología-CSIC, Department of Immunology and Oncology, Madrid, Spain. 6. McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada. Electronic address: jordanam@mcmaster.ca.
Abstract
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. 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. CONCLUSION: The findings reported here advance our understanding of events mediating the regeneration of IgE in food allergy.
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 peanutallergy. METHODS: We used a novel human PBMC culture platform, a mouse model of peanutallergy, 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. 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. CONCLUSION: The findings reported here advance our understanding of events mediating the regeneration of IgE in food allergy.
Authors: M Cecilia Berin; Charuta Agashe; A Wesley Burks; David Chiang; Wendy F Davidson; Peter Dawson; Alexander Grishin; Alice K Henning; Stacie M Jones; Edwin H Kim; Donald Y M Leung; Madhan Masilamani; Amy M Scurlock; Scott H Sicherer; Robert A Wood; Hugh A Sampson Journal: J Allergy Clin Immunol Date: 2021-10-13 Impact factor: 14.290