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Low-affinity FcγR interactions can decide the fate of novel human IgG-sensitised red blood cells and platelets

G1Δnab is a mutant human IgG1 constant region with a lower ability to interact with FcγR than the natural IgG constant regions. Radiolabelled RBCs and platelets sensitised with specific G1Δnab Abs were cleared more slowly from human circulation than IgG1-sensitised counterparts. However, non-destruc...

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Autores principales: Armour, Kathryn L, Smith, Cheryl S, Turner, Craig P, Kirton, Christopher M, Wilkes, Anthony M, Hadley, Andrew G, Ghevaert, Cedric, Williamson, Lorna M, Clark, Michael R
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BlackWell Publishing Ltd 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209800/
https://www.ncbi.nlm.nih.gov/pubmed/24285214
http://dx.doi.org/10.1002/eji.201343825
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author Armour, Kathryn L
Smith, Cheryl S
Turner, Craig P
Kirton, Christopher M
Wilkes, Anthony M
Hadley, Andrew G
Ghevaert, Cedric
Williamson, Lorna M
Clark, Michael R
author_facet Armour, Kathryn L
Smith, Cheryl S
Turner, Craig P
Kirton, Christopher M
Wilkes, Anthony M
Hadley, Andrew G
Ghevaert, Cedric
Williamson, Lorna M
Clark, Michael R
author_sort Armour, Kathryn L
collection PubMed
description G1Δnab is a mutant human IgG1 constant region with a lower ability to interact with FcγR than the natural IgG constant regions. Radiolabelled RBCs and platelets sensitised with specific G1Δnab Abs were cleared more slowly from human circulation than IgG1-sensitised counterparts. However, non-destructive splenic retention of G1Δnab-coated RBCs required investigation and plasma radioactivities now suggest this also occurred for platelets sensitised with an IgG1/G1Δnab mixture. In vitro assays with human cells showed that G1Δnab-sensitised RBCs did not cause FcγRI-mediated monocyte activation, FcγRIIIa-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) or macrophage phagocytosis although they did adhere to macrophages. Thus, FcγRII was implicated in the adhesion despite the Δnab mutation reducing the already low-affinity binding to this receptor class. Additional contacts via P-selectin enhance the interaction of sensitised platelets with monocytes and this system provided evidence of FcγRII-dependent activation by G1Δnab. These results emphasise the physiological relevance of low-affinity interactions: It appears that FcγRII interactions of G1Δnab allowed splenic retention of G1Δnab-coated RBCs with inhibitory FcγRIIb binding preventing RBC destruction and that FcγRIIb engagement by G1Δnab on IgG1/G1Δnab-sensitised platelets overcame activation by IgG1. Considering therapeutic blocking Abs, G1Δnab offers lower FcγR binding and a greater bias towards inhibition than IgG2 and IgG4 constant regions.
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spelling pubmed-42098002014-11-14 Low-affinity FcγR interactions can decide the fate of novel human IgG-sensitised red blood cells and platelets Armour, Kathryn L Smith, Cheryl S Turner, Craig P Kirton, Christopher M Wilkes, Anthony M Hadley, Andrew G Ghevaert, Cedric Williamson, Lorna M Clark, Michael R Eur J Immunol Clinical Immunology G1Δnab is a mutant human IgG1 constant region with a lower ability to interact with FcγR than the natural IgG constant regions. Radiolabelled RBCs and platelets sensitised with specific G1Δnab Abs were cleared more slowly from human circulation than IgG1-sensitised counterparts. However, non-destructive splenic retention of G1Δnab-coated RBCs required investigation and plasma radioactivities now suggest this also occurred for platelets sensitised with an IgG1/G1Δnab mixture. In vitro assays with human cells showed that G1Δnab-sensitised RBCs did not cause FcγRI-mediated monocyte activation, FcγRIIIa-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) or macrophage phagocytosis although they did adhere to macrophages. Thus, FcγRII was implicated in the adhesion despite the Δnab mutation reducing the already low-affinity binding to this receptor class. Additional contacts via P-selectin enhance the interaction of sensitised platelets with monocytes and this system provided evidence of FcγRII-dependent activation by G1Δnab. These results emphasise the physiological relevance of low-affinity interactions: It appears that FcγRII interactions of G1Δnab allowed splenic retention of G1Δnab-coated RBCs with inhibitory FcγRIIb binding preventing RBC destruction and that FcγRIIb engagement by G1Δnab on IgG1/G1Δnab-sensitised platelets overcame activation by IgG1. Considering therapeutic blocking Abs, G1Δnab offers lower FcγR binding and a greater bias towards inhibition than IgG2 and IgG4 constant regions. BlackWell Publishing Ltd 2014-03 2014-02-16 /pmc/articles/PMC4209800/ /pubmed/24285214 http://dx.doi.org/10.1002/eji.201343825 Text en © 2013 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim http://creativecommons.org/licenses/by/3.0/ This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Clinical Immunology
Armour, Kathryn L
Smith, Cheryl S
Turner, Craig P
Kirton, Christopher M
Wilkes, Anthony M
Hadley, Andrew G
Ghevaert, Cedric
Williamson, Lorna M
Clark, Michael R
Low-affinity FcγR interactions can decide the fate of novel human IgG-sensitised red blood cells and platelets
title Low-affinity FcγR interactions can decide the fate of novel human IgG-sensitised red blood cells and platelets
title_full Low-affinity FcγR interactions can decide the fate of novel human IgG-sensitised red blood cells and platelets
title_fullStr Low-affinity FcγR interactions can decide the fate of novel human IgG-sensitised red blood cells and platelets
title_full_unstemmed Low-affinity FcγR interactions can decide the fate of novel human IgG-sensitised red blood cells and platelets
title_short Low-affinity FcγR interactions can decide the fate of novel human IgG-sensitised red blood cells and platelets
title_sort low-affinity fcγr interactions can decide the fate of novel human igg-sensitised red blood cells and platelets
topic Clinical Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209800/
https://www.ncbi.nlm.nih.gov/pubmed/24285214
http://dx.doi.org/10.1002/eji.201343825
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