An unexpected protective role of low affinity allergen-specific IgG via the inhibitory receptor FcγRIIb

Background:Induction of allergen-specific IgG antibodies is a critical parameter for successful specific immunotherapy (SIT). IgG antibodies may inhibit IgE-mediated mast cell activation by direct allergen-neutralization or via the inhibitory receptor FcγRIIb. The affinity of IgE antibodies to the allergen has been shown to be critical for cellular activation.Objective:Here we addressed the question of the affinity thresholds of allergen-specific IgG antibodies for inhibition of mast cell activation by using 2 different monoclonal antibodies against the major cat allergen, Fel d 1, both in vitro and in vivo in mice.Methods:The sequences of the two high-affinity mAbs were back-mutated to germ-line, resulting in low affinity (10-7M) antibodies of the exact same specificity.Results:Using these newly generated recombinant antibodies, we demonstrate that low affinity antibodies are still able to inhibit mast cell activation via FcγRIIb but fail to neutralize the allergen.Conclusion:Antibody affinity dictates the mechanism of mast cell inhibition and IgG antibodies triggering the inhibitory FcγRIIb-pathway may show a broader cross-reactivity pattern than previously thought. This indicates that SIT generates a larger protective umbrella of inhibitory IgG antibodies than previously appreciated