Fc gammaRIIIa-158V/F polymorphism influences the binding of IgG by natural killer cell Fc gammaRIIIa, independently of the Fc gammaRIIIa-48L/R/H phenotype.
We analyzed a genetic polymorphism of Fc gamma receptor IIIa (CD16) that is present on position 158 (Phe or Val) in the membrane-proximal, IgG-binding domain. With a polymerase chain reaction-based allele-specific restriction analysis assay we genotyped 87 donors and found gene frequencies of 0.57 and 0.43 for Fc gammaRIIIA-158F and -158V, respectively. A clear linkage was observed between the Fc gammaRIIIA-158F and -48L genotypes on the one hand and the Fc gammaRIIIA-158V and -48H or -48R genotypes on the other hand (chi2 test; P < .001). To determine the functional consequences of this Fc gammaRIIIa-158V/F polymorphism, we performed IgG binding experiments with natural killer (NK) cells from genotyped donors. All donors were also typed for the recently described triallelic Fc gammaRIIIa-48L/R/H polymorphism. NK cells were treated with lactic acid to remove cell-associated IgG. Fc gammaRIIIa(NK)-158F bound significantly less IgG1, IgG3, and IgG4 than did Fc gammaRIIIa(NK)-158V, irrespective of the Fc gammaRIIIa-48 phenotype. Moreover, freshly isolated NK cells from Fc gammaRIIIa-158VV individuals carried significantly more cytophilic IgG than did NK cells from Fc gammaRIIIa-158FF individuals. In addition, CD16 monoclonal antibody (MoAb) MEM154 bound more strongly to Fc gammaRIIIa-158V, compared with -158F, again independently of the Fc gammaRIIIa-48 phenotype. The binding of MoAb B73.1 was not influenced by the Fc gammaRIIIa-158V/F polymorphism, but proved to depend solely on the amino acid present at position 48 of Fc gammaRIIIa. In conclusion, the previously reported differences in IgG binding among the three Fc gammaRIIIa-48L/R/H isoforms are a consequence of the linked, biallelic Fc gammaRIIIa-158V/F polymorphism at amino-acid position 158.
Koene
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HR
Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, University of Amsterdam, and Academic Medical Centre.
Kleijer
M
M
Algra
J
J
Roos
D
D
von dem Borne
A E
AE
de Haas
M
M
D000483:Alleles; D000911:Antibodies, Monoclonal / Q000276:immunology; D005838:Genotype; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology*; D010641:Phenotype; D011110:Polymorphism, Genetic; D011485:Protein Binding; D017452:Receptors, IgG / Q000235:genetics* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D017452:Receptors, IgG