Mixed IgG Fc immune complexes exhibit blended binding profiles and refine FcR affinity estimates
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved..
Immunoglobulin G (IgG) antibodies coordinate immune effector responses by interacting with effector cells via fragment crystallizable γ (Fcγ) receptors. The IgG Fc domain directs effector responses through subclass and glycosylation variation. Although each Fc variant has been extensively characterized in isolation, during immune responses, IgG is almost always produced in Fc mixtures. How this influences effector responses has not been examined. Here, we measure Fcγ receptor binding to mixed Fc immune complexes. Binding of these mixtures falls along a continuum between pure cases and quantitatively matches a mechanistic model, except for several low-affinity interactions mostly involving IgG2. We find that the binding model provides refined estimates of their affinities. Finally, we demonstrate that the model predicts effector cell-elicited platelet depletion in humanized mice. Contrary to previous views, IgG2 exhibits appreciable binding through avidity, though it is insufficient to induce effector responses. Overall, this work demonstrates a quantitative framework for modeling mixed IgG Fc-effector cell regulation.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:42 |
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| Enthalten in: |
Cell reports - 42(2023), 7 vom: 25. Juli, Seite 112734 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Tan, Zhixin Cyrillus [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 31.07.2023 Date Revised 07.08.2023 published: Print-Electronic UpdateOf: bioRxiv. 2023 Feb 15;:. - PMID 36824734 Citation Status MEDLINE |
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| doi: |
10.1016/j.celrep.2023.112734 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM35922671X |
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| 245 | 1 | 0 | |a Mixed IgG Fc immune complexes exhibit blended binding profiles and refine FcR affinity estimates |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a UpdateOf: bioRxiv. 2023 Feb 15;:. - PMID 36824734 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Immunoglobulin G (IgG) antibodies coordinate immune effector responses by interacting with effector cells via fragment crystallizable γ (Fcγ) receptors. The IgG Fc domain directs effector responses through subclass and glycosylation variation. Although each Fc variant has been extensively characterized in isolation, during immune responses, IgG is almost always produced in Fc mixtures. How this influences effector responses has not been examined. Here, we measure Fcγ receptor binding to mixed Fc immune complexes. Binding of these mixtures falls along a continuum between pure cases and quantitatively matches a mechanistic model, except for several low-affinity interactions mostly involving IgG2. We find that the binding model provides refined estimates of their affinities. Finally, we demonstrate that the model predicts effector cell-elicited platelet depletion in humanized mice. Contrary to previous views, IgG2 exhibits appreciable binding through avidity, though it is insufficient to induce effector responses. Overall, this work demonstrates a quantitative framework for modeling mixed IgG Fc-effector cell regulation | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a CP: Immunology | |
| 650 | 4 | |a Fcγ | |
| 650 | 4 | |a affinity | |
| 650 | 4 | |a antibodies | |
| 650 | 4 | |a avidity | |
| 650 | 4 | |a effector function | |
| 650 | 4 | |a immunology | |
| 650 | 4 | |a receptors | |
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| 650 | 7 | |a Immunoglobulin G |2 NLM | |
| 650 | 7 | |a Immunoglobulin Fc Fragments |2 NLM | |
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| 700 | 1 | |a Biburger, Markus |e verfasserin |4 aut | |
| 700 | 1 | |a Varghese, Prabha |e verfasserin |4 aut | |
| 700 | 1 | |a Lees, Stephen |e verfasserin |4 aut | |
| 700 | 1 | |a Nimmerjahn, Falk |e verfasserin |4 aut | |
| 700 | 1 | |a Meyer, Aaron S |e verfasserin |4 aut | |
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