Zha, Lisha; De Souza Leoratti, Fabiana Maria; He, Lichun; Mohsen, Mona Omar Mahmoud; Cragg, Mark; Storni, Federico Lorenzo; Vogel, Monique; Bachmann, Martin (2018). An unexpected protective role of low-affinity allergen-specific IgG through the inhibitory receptor FcγRIIb. The Journal of allergy and clinical immunology, 142(5), 1529-1536.e6. Elsevier 10.1016/j.jaci.2017.09.054
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BACKGROUND
Induction of allergen-specific IgG antibodies is a critical parameter for successful allergen-specific immunotherapy. IgG antibodies can inhibit IgE-mediated mast cell activation through direct allergen neutralization or through 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 affinity thresholds of allergen-specific IgG antibodies for inhibition of mast cell activation using 2 different mAbs against the major cat allergen Fel d 1 both in vitro and in vivo in mice.
METHODS
Sequences of the 2 high-affinity mAbs were back-mutated to germline, resulting in low-affinity (10 mol/L) 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 through FcγRIIb but do not neutralize the allergen.
CONCLUSION
Antibody affinity dictates the mechanism of mast cell inhibition, and IgG antibodies triggering the inhibitory FcγRIIb pathway can show a broader cross-reactivity pattern than previously thought. This indicates that allergen-specific immunotherapy generates a larger protective umbrella of inhibitory IgG antibodies than previously appreciated.
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