Phenotypic Variation in IgG Receptors by Nonclassical FCGR2C Alleles

The balance between activating and inhibitory signals from the different Fc gamma Rs 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 Fc gamma RIIa (CD32a) and inhibitory Fc gamma RIIb (CD32b), respectively. A single nucleotide polymorphism (SNP) in exon 3 of FCGR2C results in either expression of the activating Fc gamma RIIc (CD32c) (FCGR2C-open reading frame [ORF]) or its absence because of a stop codon (FCGR2C-Stop). Two additional variations in Fc gamma RIIb/c expression on leukocytes have now been identified. In case of nonclassical FCGR2C-ORF alleles, Fc gamma RIIc 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 Fc gamma RIIb 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. Fc gamma RIIb expression on NK cells effectively inhibited killing mediated by Fc gamma RIIIa (CD16a) in Ab-dependent cytotoxicity tests. Our findings demonstrate a more extensive and previously unnoticed variation in Fc gamma R expression with relevance to immunity and inflammation. The Journal of Immunology, 2012, 188: 1318-1324.