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

An unexpected protective role of low affinity allergen-specific IgG via the inhibitory receptor FcγRIIb
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.
1477-7266
Zha, Lisha
4d0d8a66-cff5-4295-800a-e4794e40f103
Leoratti, Fabiana
cd8a771c-886b-4743-b810-34961a5f0d5d
He, Lichun
8be11f7d-2db8-4f2e-9eb1-eb1330a746af
Mohsen, Mona
d0499da9-ed87-4b77-9dda-b231cce81c50
Stomi, Federico
85247531-494d-430b-863b-87235f99a988
Vogel, Monique
f4e90460-587c-4a19-850e-c583eabc2d75
Bachmann, Martin
7be25ff1-5cb4-4649-a0b7-dda6adf63903
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Zha, Lisha
4d0d8a66-cff5-4295-800a-e4794e40f103
Leoratti, Fabiana
cd8a771c-886b-4743-b810-34961a5f0d5d
He, Lichun
8be11f7d-2db8-4f2e-9eb1-eb1330a746af
Mohsen, Mona
d0499da9-ed87-4b77-9dda-b231cce81c50
Stomi, Federico
85247531-494d-430b-863b-87235f99a988
Vogel, Monique
f4e90460-587c-4a19-850e-c583eabc2d75
Bachmann, Martin
7be25ff1-5cb4-4649-a0b7-dda6adf63903
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c

Zha, Lisha, Leoratti, Fabiana, He, Lichun, Mohsen, Mona, Stomi, Federico, Vogel, Monique, Bachmann, Martin and Cragg, Mark (2018) An unexpected protective role of low affinity allergen-specific IgG via the inhibitory receptor FcγRIIb. Journal of Allergy and Clinical Immunology. (doi:10.1016/j.jaci.2017.09.054).

Record type: Article

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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More information

Accepted/In Press date: 21 September 2017
e-pub ahead of print date: 31 January 2018

Identifiers

Local EPrints ID: 417803
URI: https://eprints.soton.ac.uk/id/eprint/417803
ISSN: 1477-7266
PURE UUID: 831b5f4c-4e52-4508-a9a0-e426ffb719f0
ORCID for Mark Cragg: ORCID iD orcid.org/0000-0003-2077-089X

Catalogue record

Date deposited: 14 Feb 2018 17:30
Last modified: 14 Mar 2019 05:15

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