Single Nucleotide Polymorphisms of the High Affinity IgG Receptor FcyRI Reduce Immune Complex Binding and Downstream Effector Functions

Binding of IgG Abs to Fc gamma Rs on immune cells induces Fc gamma R cross-linking that leads to cellular effector functions, such as phagocytosis, Ab-dependent cellular cytotoxicity, and cytokine release. However, polymorphisms in low affinity Fc gamma Rs have been associated with altered avidity toward IgG, thereby substantially impacting clinical outcomes of multimodular therapy when targeting cancer or autoimmune diseases with mAbs as well as the frequency and severity of autoimmune diseases. In this context, we investigated the consequences of three nonsynonymous single nucleotide polymorphisms (SNPs) for the high affinity receptor for IgG, Fc gamma RI. Only SNP V39I, located in the extracellular domain of Fc gamma RI, reduces immune-complex binding of Fc gamma RI whereas monomeric IgG binding is unaffected. This leads to reduced Fc gamma RI effector functions, including Fc receptor gamma-chain signaling and intracellular calcium mobilization. SNPs I301M and I338T, located in the transmembrane or intracellular domain, respectively, have no influence on monomeric IgG or immune complex binding, but FcR gamma signaling is decreased for both SNPs, especially for I338T. We also found that the frequency of these SNPs in a cohort of healthy Dutch individuals is very low within the population. To our knowledge, this study addresses for the first time the biological consequences of SNPs in the high affinity Fc gamma R, and reveals reduction in several Fc gamma RI functions, which have the potential to alter efficacy of therapeutic Abs.