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

Authors
  • 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
Type
Published Article
Journal
European Journal of Immunology
Publisher
Wiley
Publication Date
Mar 01, 2014
Volume
44
Issue
3
Pages
905–914
Identifiers
DOI: 10.1002/eji.201343825
PMID: 24285214
Source
Medline
Keywords
License
Unknown

Abstract

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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