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

Abstract

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.

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Identifiers

ORCID for Mark Cragg: orcid.org/0000-0003-2077-089X

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