title: Lifelong memory responses perpetuate humoral TH2 immunity and anaphylaxis in food allergy.
abstract: 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 IgG1+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.
authors.affiliation: McMaster Immunology Research Centre (MIRC), Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Jiménez-Saiz
authors.affiliation: McMaster Immunology Research Centre (MIRC), Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Derek K
authors.initials: DK
authors.lastname: Chu
authors.affiliation: McMaster Immunology Research Centre (MIRC), Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Talveer S
authors.initials: TS
authors.lastname: Mandur
authors.affiliation: McMaster Immunology Research Centre (MIRC), Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Tina D
authors.initials: TD
authors.lastname: Walker
authors.affiliation: McMaster Immunology Research Centre (MIRC), Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Gordon
authors.affiliation: McMaster Immunology Research Centre (MIRC), Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Roopali
authors.initials: R
authors.lastname: Chaudhary
authors.affiliation: McMaster Immunology Research Centre (MIRC), Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Joshua
authors.initials: J
authors.lastname: Koenig
authors.affiliation: McMaster Immunology Research Centre (MIRC), Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: Saliba
authors.affiliation: McMaster Immunology Research Centre (MIRC), Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Galipeau
authors.affiliation: Departments of Immunology and Medicine, Roswell Park Cancer Institute, Buffalo, NY.
authors.forename: Adam
authors.initials: A
authors.lastname: Utley
authors.affiliation: Department of Microbiology & Immunology, McGill University, Montreal, Quebec, Canada.
authors.forename: Irah L
authors.initials: IL
authors.lastname: King
authors.affiliation: Departments of Immunology and Medicine, Roswell Park Cancer Institute, Buffalo, NY.
authors.forename: Kelvin
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Respiratory, Inflammation & Autoimmunity, MedImmune, Gaithersburg, Md.
authors.forename: Rachel
authors.initials: R
authors.lastname: Ettinger
authors.affiliation: Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Susan
authors.initials: S
authors.lastname: Waserman
authors.affiliation: Department of Respiratory, Inflammation & Autoimmunity, MedImmune, Gaithersburg, Md.
authors.forename: Roland
authors.initials: R
authors.lastname: Kolbeck
authors.affiliation: McMaster Immunology Research Centre (MIRC), Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada. Electronic address: jordanam@mcmaster.ca.
authors.forename: Manel
authors.initials: M
authors.lastname: Jordana
mesh_terms: D000485:Allergens / Q000276:immunology; D000707:Anaphylaxis / Q000276:immunology*; D000818:Animals; D010367:Arachis / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D005512:Food Hypersensitivity / Q000276:immunology*; D006801:Humans; D056724:Immunity, Humoral; D007073:Immunoglobulin E / Q000378:metabolism; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D000485:Allergens; D007073:Immunoglobulin E
keywords: IgE; IgG(1); T(H)2; anaphylaxis; food allergy; germinal centers; mast cells; memory B cells; peanut allergy; plasma cells