Background: Allergy is a global disease with overall frequencies of >20%. Symptoms vary from irritating local itching to life-threatening systemic anaphylaxis. Even though allergies are allergen-specific, there is a wide range of cross-reactivities (eg apple and latex) that remain largely unexplained. Given the abilities of low-affinity IgG antibodies to inhibit mast cells activation, here we elucidate the minimal affinity of IgE antibodies to induce type I hypersensitivity.
Methods: Three mature (high-affinity) IgE antibodies recognizing three distinct epitopes on Fel d 1, the major cat allergen, were back-mutated to germline conformation, resulting in binding to Fel d 1 with low affinity. The ability of these IgE antibodies to activate mast cells in vitro and in vivo was tested.
Results: We demonstrate that affinities as low as 10-7 M are sufficient to activate mast cells in vitro and drive allergic reactions in vivo. Low-affinity IgE antibodies are able to do so, since they bind allergens bivalently on the surface of mast cells, leading to high-avidity interactions.
Conclusions: These results suggest that the underlying mechanism of allergen cross-reactivity may be low-affinity but high-avidity binding between IgE antibodies and cross-reactive allergen.
Keywords: IgE antibody; affinity; allergen cross-reactivity; allergy; avidity; specificity.
© 2021 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.