Genetic variation in human Fc gamma receptors: Functional consequences of polymorphisms and copy number variation

Fc gamma receptors (FcγRs) are receptors for immunoglobulin G (IgG), the most abundant of five classes of antibodies. They are expressed on almost all immune cells and mediate a range of cellular functions, such as phagocytosis, antibody-dependent cellular cytotoxicity, activation of the NADPH-oxidase and the release of cytokines. The genes encoding FcγRs are subject to considerable inter-individual genetic variation. These genetic variations occur in several forms, e.g. from single nucleotide polymorphisms (SNPs) and polymorphic variants that differ from each other in more than one nucleotide, to copy number variation (CNV), where large stretches of DNA, covering one to three complete FcγR genes, are deleted or inserted at the FCGR2/3 locus at chromosome 1q23. Commonly, these genetic variations result in differences in expression and/or function.
In this thesis, we have described several novel as well as previously known genetic variations in FcγRs and their functional and/or clinical importance. We have shown that the effect of polymorphisms do not necessarily only affect the receptor itself, but can also influence the cooperation with other FcγRs. Moreover, we have shown how another protein, SIRPα, can inhibit signaling by FcγRs.
The knowledge with respect to the genotype-phenotype relationships among FcγRs described in this thesis serves as a paradigm for understanding this balance of signals in a bigger context, and it is anticipated that a deeper understanding of this will give insight into inter-individual differences in immunoreactivity and the susceptibility for the development of autoimmune diseases or cancer.