Allergen-specific IgG antibody signaling through FcγRIIb promotes food tolerance

J Allergy Clin Immunol. 2018 Jan;141(1):189-201.e3. doi: 10.1016/j.jaci.2017.03.045. Epub 2017 May 4.

Abstract

Background: Patients with food allergy produce high-titer IgE antibodies that bind to mast cells through FcεRI and trigger immediate hypersensitivity reactions on antigen encounter. Food-specific IgG antibodies arise in the setting of naturally resolving food allergy and accompany the acquisition of food allergen unresponsiveness in oral immunotherapy.

Objective: In this study we sought to delineate the effects of IgG and its inhibitory Fc receptor, FcγRIIb, on both de novo allergen sensitization in naive animals and on established immune responses in the setting of pre-existing food allergy.

Methods: Allergen-specific IgG was administered to mice undergoing sensitization and desensitization to the model food allergen ovalbumin. Cellular and molecular mechanisms were interrogated by using mast cell- and FcγRIIb-deficient mice. The requirement for FcγRII in IgG-mediated inhibition of human mast cells was investigated by using a neutralizing antibody.

Results: Administration of specific IgG to food allergy-prone IL4raF709 mice during initial food exposure prevented the development of IgE antibodies, TH2 responses, and anaphylactic responses on challenge. When given as an adjunct to oral desensitization in mice with established IgE-mediated hypersensitivity, IgG facilitated tolerance restoration, favoring expansion of forkhead box protein 3-positive regulatory T cells along with suppression of existing TH2 and IgE responses. IgG and FcγRIIb suppress adaptive allergic responses through effects on mast cell function.

Conclusion: These findings suggest that allergen-specific IgG antibodies can act to induce and sustain immunologic tolerance to foods.

Keywords: FcγRIIb; IgG; Mast cell; food allergy; oral immunotherapy; regulatory T cell; tolerance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allergens / immunology*
  • Allergens / pharmacology
  • Animals
  • Disease Models, Animal
  • Egg Hypersensitivity / drug therapy
  • Egg Hypersensitivity / genetics
  • Egg Hypersensitivity / immunology*
  • Egg Hypersensitivity / pathology
  • Immune Tolerance*
  • Immunoglobulin G / immunology*
  • Mast Cells / metabolism
  • Mast Cells / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / immunology
  • Receptors, IgG / genetics
  • Receptors, IgG / immunology*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / pathology
  • Th2 Cells / immunology
  • Th2 Cells / pathology

Substances

  • Allergens
  • Fcgr2b protein, mouse
  • Il4ra protein, mouse
  • Immunoglobulin G
  • Receptors, Cell Surface
  • Receptors, IgG