Kinetics, cross-reactivity, and specificity of Bet v 1-specific IgG4 antibodies induced by immunotherapy with birch pollen.
BACKGROUND
IgE antibodies specific for the major birch pollen allergen frequently cross-react with Bet v 1 homologous food proteins, for example Cor a 1 in hazelnut and Mal d 1 in apple. Specific immunotherapy with birch pollen (BP-SIT) induces IgG4 antibodies that inhibit IgE binding to Bet v 1. However, information on cross-reactivity of BP-SIT-induced Bet v 1-specific IgG4 antibodies with food allergens is limited. In this study, we investigated the kinetics of production, cross-reactivity, and IgE-blocking activity of Bet v 1-specific IgG4 antibodies emerging during conventional BP-SIT and whether IgG4-epitopes overlapped with IgE epitopes.


METHODS
IgE and IgG4 levels specific for Bet v 1, Mal d 1, and Cor a 1 were determined in 42 birch pollen-allergic patients before and during BP-SIT. Inhibition of IgE binding was studied by IgE-facilitated antigen-binding assays and basophil activation tests. Furthermore, inhibition of IgE-mediated activation of food allergen-reactive Bet v 1-specific T-cell lines was assessed. Competitive immunoscreening of phage-displayed peptides was applied to select mimotopes recognized by IgE and IgG4 antibodies, respectively. The resulting mimotopes were mapped on the surface of the 3D structure of the allergens using a computer-based algorithm.


RESULTS
BP-SIT significantly increased Bet v 1- and food allergen-reactive IgG4 antibodies. In parallel, allergen-specific IgE levels decreased significantly. Sera containing food allergen-reactive IgG4 antibodies inhibited IgE binding, basophil activation, and IgE-mediated food allergen-induced T-cell proliferation. Predicted IgE and IgG4 epitopes on all allergens showed high overlap.


CONCLUSIONS
Our results indicate that BP-SIT may induce Bet v 1-specific IgG4 antibodies that cross-react with related food allergens and inhibit IgE binding by epitope competition.
Department of Pathophysiology and Allergy Research and Christian Doppler Laboratory for Immunomodulation, Medical University of Vienna, Vienna, Austria.
B
B
Subbarayal
D
D
Schiller
C
C
Möbs
N W
NW
de Jong
C
C
Ebner
N
N
Reider
D
D
Bartel
J
J
Lidholm
W
W
Pfützner
R
R
Gerth van Wijk
S
S
Vieths
B
B
Bohle
D000293:Adolescent; D000328:Adult; D000485:Allergens / Q000276:immunology*; D019138:Antibodies, Blocking / Q000187:drug effects; D000918:Antibody Specificity / Q000276:immunology*; D052179:Antigens, Plant / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D029662:Betula / Q000276:immunology*; D002460:Cell Line; D002648:Child; D003429:Cross Reactions / Q000276:immunology; D003888:Desensitization, Immunologic / Q000379:methods*; D005512:Food Hypersensitivity / Q000276:immunology*; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis / Q000378:metabolism; D007074:Immunoglobulin G / Q000096:biosynthesis* / Q000378:metabolism; D008875:Middle Aged; D011058:Pollen / Q000276:immunology*; D055815:Young Adult
D000485:Allergens; D019138:Antibodies, Blocking; D052179:Antigens, Plant; D007074:Immunoglobulin G; C061312:Bet v 1 allergen, Betula; D007073:Immunoglobulin E
IgE; IgG4; birch pollen allergy; blocking antibodies; specific immunotherapy