title: Phenotypic variation in IgG receptors by nonclassical FCGR2C alleles.
abstract: The balance between activating and inhibitory signals from the different FcγRs for IgG ensures homeostasis of many inflammatory responses. FCGR2C is the product of an unequal crossover of the FCGR2A and FCGR2B genes encoding the activating FcγRIIa (CD32a) and inhibitory FcγRIIb (CD32b), respectively. A single nucleotide polymorphism (SNP) in exon 3 of FCGR2C results in either expression of the activating FcγRIIc (CD32c) (FCGR2C-open reading frame [ORF]) or its absence because of a stop codon (FCGR2C-Stop). Two additional variations in FcγRIIb/c expression on leukocytes have now been identified. In case of "nonclassical" FCGR2C-ORF alleles, FcγRIIc expression was unexpectedly absent, because of novel splice site mutations near exon 7 leading to another stop codon. In some individuals with FCGR2C-Stop alleles FcγRIIb was detected on NK cells, which normally are devoid of this protein. Individuals with these nonclassical FCGR2C-Stop alleles carried a deletion of FCGR2C-FCGR3B that extends into the promoter region of the adjacent FCGR2B gene and probably deletes a negative regulatory element in the FCGR2B promoter in NK cells. FcγRIIb expression on NK cells effectively inhibited killing mediated by FcγRIIIa (CD16a) in Ab-dependent cytotoxicity tests. Our findings demonstrate a more extensive and previously unnoticed variation in FcγR expression with relevance to immunity and inflammation.
authors.affiliation: Sanquin Research and Landsteiner Laboratory, Department of Blood Cell Research, Academic Medical Center, University of Amsterdam, 1066 CX Amsterdam, The Netherlands. joris.vanderheijden@sanquin.nl
authors.forename: Joris
authors.initials: J
authors.lastname: van der Heijden
authors.forename: Willemijn B
authors.initials: WB
authors.lastname: Breunis
authors.forename: Judy
authors.initials: J
authors.lastname: Geissler
authors.forename: Martin
authors.initials: M
authors.lastname: de Boer
authors.forename: Timo K
authors.initials: TK
authors.lastname: van den Berg
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kuijpers
mesh_terms: D000483:Alleles; D005786:Gene Expression Regulation / Q000276:immunology; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017452:Receptors, IgG / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C445323:FCGR2A protein, human; C499173:FCGR2B protein, human; C080572:Fc gamma receptor IIC; D017452:Receptors, IgG