Impacts of genetic variation in the Fc gamma receptor locus on functionality of natural killer cells and monocytes - ABSTRACT IgG Antibody (Ab) based therapeutics are becoming more common in treating several diseases, including infections, autoimmune disorders, transplant rejection, and cancer. Abs contain two important domains; the Fab domain mediates binding to a specific antigen, and the Fc domain of an antigen-bound IgG Ab then binds to Fc-gamma receptors (FcRs) expressed on the surface of different immune cells (e.g. NK cells, monocytes) and thereby initiates a broad array of effector functions related to target cell destruction, such as antibody- dependent cellular cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP). However, Ab-based therapies are complicated by what appears to be suboptimal efficacy in a significant number of treated patients. A potential cause for this variability in response to Ab treatment could lie in genetic differences in the FcR locus, which is highly diverse genetically, with (at least) > 20,000 reported single nucleotide polymorphisms (SNPs) plus additional copy number variations (CNVs). Considering the extreme genetic complexity of the FcR locus, we have established a high-throughput assay to systematically screen for functional SNPs in the FcR locus. Based on the existing literature and our own results, we hypothesize that FcR polymorphisms modulate Ab functions across individuals, i.e., the same Ab but with different efficacy, by differentially regulating expression patterns of FcRs in a cell type-specific manner. Here we aim to systematically identify the functional impact of genetic variations in the FcR locus. Aim 1: Identify functional SNPs in the FcR locus that regulate expression of FcRs in human effector cells, and regulatory proteins binding to each SNP. Aim 2: Use the identified FcR SNPs and interacting proteins to derive predictive models for ADCC and ADCP activities. Ab based immune suppressions are routinely used to prevent transplant rejection and often function through ADCC and ADCP based mechanisms. We will enroll a group of 100 transplant patients in parallel with Aim 1, collect blood samples before transplant and measure their ADCC and ADCP activities in vitro. We will build computational models that predict ADCC and ADCP activities in individuals using their FcR genotypes alone, and together with other variables. Aim 3: Determine the impact of FcR genotypes on the efficacy of Ab based immune suppression regimens. After receiving Ab based depletional induction for transplantation, we will assess the contributions of these patients’ FcR genotypes and additional variables to the differences in their depletion efficiency. The expected outcome is to systematically identify functional SNPs in the human FcR locus and their impact on Ab based immunosuppression. This knowledge will further contribute to differentiating mechanisms of antibody-mediated rejection in transplantation and its treatment.
