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.

FCGR2Cgenotyping by pyrosequencing reveals linkage disequilibrium withFCGR3AV158F andFCGR2AH131R polymorphisms in a Caucasian population

“…These frequencies are concordant with previous results showing that the FCGR2C-ORF allele is present in only half of the 40% of individuals with detectable CD32 + NK cells (i.e., expressing one of the FcγRII). 23 The different genotype frequencies observed in our study ( Table 1) were mostly close to those previously reported in the Caucasian population by Breunis et al and by van der Heijden et al 4 However, Breunis et al 15 did not identify individuals with at least 2 copies of FCGR2C-ORF in their control group, whereas 4.3% and 0.5% had two or three copies of the FCGR2C-ORF allele in our population, respectively. Given the allele and CNV frequencies, all the ORF/STOP combinations expected were observed.…”

“…In our control population, 79.9% of individuals did not express FcγRIIc because they only carry the FCGR2C-STOP allele (149/151) or lack the FCGR2C gene (2/151), whereas 20.1% of them possessed at least one FCGR2C-ORF allele ( Table 1) leading to FcγRIIc expression in those who do not have the additional mutation at the splice sites of intron 7. 4 We also identified an unusual allele combination of FCGRC-ORF/STOP, with 5 copies of FCGR2C-STOP and one copy of FCGR2C-ORF ( Table 1).…”

“…In our control Caucasian population (Table 1), the percentages of individuals with a single copy (11.1%; n = 21) or 3 copies (12.2%; n = 23) of FCGR2C were close to those reported in the previous studies using multiplex ligation-dependent probe amplification. 4,15 It is of note that we identified two individuals with two null alleles corresponding to a total lack of FCGR2C. In our control population, 79.9% of individuals did not express FcγRIIc because they only carry the FCGR2C-STOP allele (149/151) or lack the FCGR2C gene (2/151), whereas 20.1% of them possessed at least one FCGR2C-ORF allele ( Table 1) leading to FcγRIIc expression in those who do not have the additional mutation at the splice sites of intron 7.…”

“…3 Moreover, it has been recently reported that an additional mutation at the splice sites of intron 7 in their FCGR2C-ORF alleles results in another stop codon in ≈20% of the FCGR2C-ORF donors and, therefore, the absence of FcγRIIC expression in these donors. 4 We and others have shown that the FCGR3A-V158F and FCGR2A-H131R polymorphisms are associated with clinical responses to therapeutic mAbs such as rituximab, [5][6][7] cetuximab, 8 or trastuzumab. 9 The better responses observed in 3,4 suggesting that this receptor might also be involved in the anti-tumor responses mediated by cytolytic mAbs.…”

Antibody functional assays as measures of Fc receptor-mediated immunity to HIV - new technologies and their impact on the HIV vaccine field.

“…1). Only about 20% of Caucasians express a functional FcγRIIc on neutrophils, macrophages and NK cells, and its contribution to antibody function has been little studied [109]. This receptor is not present in the macaque.…”