Sanquin Research and Landsteiner Laboratory, Department of Blood Cell Research, Academic Medical Center, University of Amsterdam, 1066 CX Amsterdam, The Netherlands.
J Immunol. 2012 Feb 1;188(3):1318-24. doi: 10.4049/jimmunol.1003945. Epub 2011 Dec 23.
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.
不同 FcγR 对 IgG 的激活和抑制信号之间的平衡确保了许多炎症反应的体内平衡。FCGR2C 是编码激活型 FcγRIIa（CD32a）和抑制型 FcγRIIb（CD32b）的 FCGR2A 和 FCGR2B 基因不等交换的产物。FCGR2C 外显子 3 中的单核苷酸多态性（SNP）导致激活型 FcγRIIc（CD32c）（FCGR2C 开放阅读框 [ORF]）的表达或由于终止密码子（FCGR2C-Stop）而不存在。现在已经在白细胞上鉴定出两种额外的 FcγRIIb/c 表达变体。在“非经典”FCGR2C-ORF 等位基因的情况下，由于外显子 7 附近的新剪接位点突变导致另一个终止密码子，FcγRIIc 的表达出乎意料地缺失。在具有 FCGR2C-Stop 等位基因的个体中，在 NK 细胞上检测到 FcγRIIb，而 NK 细胞通常缺乏这种蛋白。具有这些非经典 FCGR2C-Stop 等位基因的个体携带 FCGR2C-FCGR3B 的缺失，该缺失延伸到相邻 FCGR2B 基因的启动子区域，并可能在 NK 细胞中删除 FCGR2B 启动子中的负调节元件。NK 细胞上的 FcγRIIb 表达有效地抑制了 Ab 依赖性细胞毒性试验中 FcγRIIIa（CD16a）介导的杀伤。我们的发现表明，FcγR 表达的变化更为广泛且以前未被注意到，这与免疫和炎症有关。
