Wines, Bruce D., Vanderven, Hillary A., Esparon, Sandra E., Kristensen, Anne B., Kent, Stephen J., and Hogarth, P. Mark (2016) Dimeric FcγR ectodomains as probes of the Fc receptor function of anti-influenza virus IgG. Journal of Immunology, 197 (4). pp. 1507-1516.

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Abstract

Ab-dependent cellular cytotoxicity, phagocytosis, and Ag presentation are key mechanisms of action of Abs arising in vaccine or naturally acquired immunity, as well of therapeutic mAbs. Cells expressing the low-affinity Fc gamma Rs (Fc gamma RII or CD32 and Fc gamma RIII or CD16) are activated for these functions when receptors are aggregated following the binding of IgG-opsonized targets. Despite the diversity of the Fc receptor proteins, IgG ligands, and potential responding cell types, the induction of all Fc gamma R-mediated responses by opsonized targets requires the presentation of multiple Fc regions in close proximity to each other. We demonstrated that such "near-neighbor" Fc regions can be detected using defined recombinant soluble (rs) dimeric low-affinity ectodomains (rsFc gamma R) that have an absolute binding requirement for the simultaneous engagement of two IgG Fc regions. Like cell surface-expressed Fc gamma Rs, the binding of dimeric rsFc gamma R ectodomains to Ab immune complexes was affected by Ab subclass, presentation, opsonization density, Fc fucosylation, or mutation. The activation of an NK cell line and primary NK cells by human IgG-opsonized influenza A hemagglutinin correlated with dimeric rsFc gamma RIIIa binding activity but not with Ab titer. Furthermore, the dimeric rsFc gamma R binding assay sensitively detected greater Fc receptor activity to pandemic H1N1 hemagglutinin after the swine influenza pandemic of 2009 in pooled human polyclonal IgG. Thus these dimeric rsFc gamma R ectodomains are validated, defined probes that should prove valuable in measuring the immune-activating capacity of IgG Abs elicited by infection or vaccination or experimentally derived IgG and its variants.

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