Functional Fc gamma receptor gene polymorphisms and donor-specific antibody-triggered microcirculation inflammation

Fc-dependent effector mechanisms may contribute to antibody-mediated rejection (ABMR), and distinct gene polymorphisms modifying the function of Fc gamma receptors (FcRs) may influence the capability of donor-specific antibodies (DSAs) to trigger inflammation. To evaluate the relevance of functional FcR variants in late ABMR, 85 DSA-positive kidney allograft recipients, who were recruited upon antibody screening of 741 prevalent patients, were genotyped for polymorphisms in FcRIIA (FCGR2A-H/R-131; rs1801274), FcRIIIA (FCGR3A-V/F-158; rs396991), and FcRIIIB (FCGR3B-neutrophil antigen 1 ([NA1]/NA2; rs35139848). Individuals with high-affinity FCGR3A-V-158 alleles (V/V-158 or V/F-158) showed a higher rate (and extent) of peritubular capillaritis (ptc) in protocol biopsies than homozygous carriers of the lower-affinity allele (ptc score 1: 53.6% vs 25.9%; P=.018). Associations were independent of C1q-binding to DSA or capillary C4d. In parallel, there was a trend toward increased macrophage- and injury-repair response-associated transcript subsets. Kidney function over 24months, however, was not different. In support of a functional role of FcRIIIA polymorphism, NK92 cells expressing FCGR3A-V-158 produced >2 times as much interferon gamma upon incubation with HLA antibody-coated cells as those expressing FCGR3A-F-158. FcRIIA and FcRIIIB polymorphisms were not associated with allograft morphology. Our data suggest that the presence of high-affinity FcRIIIA variants may favor DSA-triggered microcirculation inflammation. This cross-sectional study performed in kidney transplant recipients with donor-specific antibodies suggests that the presence of high-functional variants of Fc gamma receptor IIIA favors antibody-triggered microcirculation inflammation independent of complement activation, supporting an important role of Fc receptor-dependent mechanisms of injury.