Single Nucleotide Polymorphisms of the High Affinity IgG Receptor Fc{gamma}RI Reduce Immune Complex Binding and Downstream Effector Functions [IMMUNOGENETICS]

Binding of IgG Abs to FcRs on immune cells induces FcR cross-linking that leads to cellular effector functions, such as phagocytosis, Ab-dependent cellular cytotoxicity, and cytokine release. However, polymorphisms in low affinity FcRs 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, FcRI. Only SNP V39I, located in the extracellular domain of FcRI, reduces immune-complex binding of FcRI whereas monomeric IgG binding is unaffected. This leads to reduced FcRI effector functions, including Fc receptor -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 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 FcR, and reveals reduction in several FcRI functions, which have the potential to alter efficacy of therapeutic Abs.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2xbCiqH