title: Haplotypes of FcγRIIa and FcγRIIIb polymorphic variants influence IgG-mediated responses in neutrophils.
abstract: Human blood neutrophils normally express two FcγRs (FcγRIIa and FcγRIIIb) that, upon multivalent binding of IgG in immune complexes or on opsonized targets, mediate responses such as phagocytosis, Ab-dependent cellular cytotoxicity, and respiratory burst. Allelic variants have been described for both FcγRIIa (131H/R) and FcγRIIIb (NA1/NA2/SH), with different binding affinity for IgG subclasses. Because neither of these variants acts alone, we have set out to systematically analyze in a large cohort of healthy FCGR2/3-genotyped volunteers how the different haplotypes of neutrophil FcγRs functionally interact. Maximal IgG-induced H2O2 production by neutrophils from individuals with different (homozygous) haplotypes was observed in the following order: 131HH-NA2NA2 > 131RR-NA1NA1 > 131HH-NA1NA1 > 131RR-NA2NA2. Although FcγRIIa 131H is known to bind IgG1 and IgG2 more avidly, no such differences in affinity are known for FcγRIIIb variants. Nonetheless, a remarkable impact of the FcγRIIIb variants on IgG-mediated neutrophil activity was thus demonstrated, which was not explained by differences in FcγR surface expression. The FcγR expression profile was changed by overnight G-CSF/IFN-γ activation of the neutrophils and eliminated any haplotypic impact on the respiratory burst. To our knowledge, our results are the first to provide an integrated functional analysis of neutrophil FcγR haplotypes and suggest that particularly the early phase of IgG-mediated neutrophil reactivity is influenced by FCGR2/3 genotypic variation.
authors.affiliation: Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
authors.forename: Joris
authors.initials: J
authors.lastname: van der Heijden
authors.forename: Sietse
authors.initials: S
authors.lastname: Nagelkerke
authors.forename: Xiwen
authors.initials: X
authors.lastname: Zhao
authors.forename: Judy
authors.initials: J
authors.lastname: Geissler
authors.forename: Theo
authors.initials: T
authors.lastname: Rispens
authors.forename: Timo K
authors.initials: TK
authors.lastname: van den Berg
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kuijpers
mesh_terms: D002478:Cells, Cultured; D005434:Flow Cytometry; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D005787:Gene Frequency; D005838:Genotype; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006239:Haplotypes; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007074:Immunoglobulin G / Q000276:immunology* / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D011110:Polymorphism, Genetic; D017452:Receptors, IgG / Q000235:genetics* / Q000378:metabolism
chemical_list: C428200:FCGR3B protein, human; C080568:Fc gamma receptor IIA; D058851:GPI-Linked Proteins; D007074:Immunoglobulin G; D017452:Receptors, IgG; D016179:Granulocyte Colony-Stimulating Factor; D007371:Interferon-gamma; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases