IgE and allergen-specific immunotherapy-induced IgG4 recognize similar epitopes of Bet v 1, the major allergen of birch pollen

Clin Exp Allergy. 2017 May;47(5):693-703. doi: 10.1111/cea.12835. Epub 2016 Nov 28.

Abstract

Background: Allergen-specific immunotherapy (AIT) with birch pollen generates Bet v 1-specific immunoglobulin (Ig)G4 which blocks IgE-mediated hypersensitivity mechanisms. Whether IgG4 specific for Bet v 1a competes with IgE for identical epitopes or whether novel epitope specificities of IgG4 antibodies are developed is under debate.

Objective: We sought to analyze the epitope specificities of IgE and IgG4 antibodies from sera of patients who received AIT.

Methods: 15 sera of patients (13/15 received AIT) with Bet v 1a-specific IgE and IgG4 were analyzed. The structural arrangements of recombinant (r)Bet v 1a and rBet v 1a_11x , modified in five potential epitopes, were analyzed by circular dichroism and nuclear magnetic resonance spectroscopy. IgE binding to Bet v 1 was assessed by ELISA and mediator release assays. Competitive binding of monoclonal antibodies specific for Bet v 1a and serum IgE/IgG4 to rBet v 1a and serum antibody binding to a non-allergenic Bet v 1-type model protein presenting an individual epitope for IgE was analyzed in ELISA and western blot.

Results: rBet v 1a_11x had a Bet v 1a - similar secondary and tertiary structure. Monomeric dispersion of rBet v 1a_11x was concentration and buffer-dependent. Up to 1500-fold increase in the EC50 for IgE-mediated mediator release induced by rBet v 1a_11x was determined. The reduction of IgE and IgG4 binding to rBet v 1a_11x was comparable in 67% (10/15) of sera. Bet v 1a-specific monoclonal antibodies inhibited binding of serum IgE and IgG4 to 66.1% and 64.9%, respectively. Serum IgE and IgG4 bound specifically to an individual epitope presented by our model protein in 33% (5/15) of sera.

Conclusion and clinical relevance: Patients receiving AIT develop Bet v 1a-specific IgG4 which competes with IgE for partly identical or largely overlapping epitopes. The similarities of epitopes for IgE and IgG4 might stimulate the development of epitope-specific diagnostics and therapeutics.

Keywords: Bet v 1; IgE; IgG4; epitope; immunotherapy.

MeSH terms

  • Animals
  • Antigens, Plant / immunology*
  • Desensitization, Immunologic*
  • Epitopes / immunology*
  • Female
  • Humans
  • Immunoglobulin E* / blood
  • Immunoglobulin E* / immunology
  • Immunoglobulin G* / blood
  • Immunoglobulin G* / immunology
  • Male
  • Mice
  • Rhinitis, Allergic, Seasonal* / blood
  • Rhinitis, Allergic, Seasonal* / immunology
  • Rhinitis, Allergic, Seasonal* / therapy

Substances

  • Antigens, Plant
  • Epitopes
  • Immunoglobulin G
  • Bet v 1 allergen, Betula
  • Immunoglobulin E