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 (FcγRs) may influence the capability of donor‐specific antibodies (DSAs) to trigger inflammation. To evaluate the relevance of functional FcγR 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 FcγRIIA(FCGR2A‐H/R131; rs1801274), FcγRIIIA(FCGR3A‐V/F158; rs396991), and FcγRIIIB(FCGR3B‐neutrophil antigen 1 ([NA1]/NA2; rs35139848). Individuals with high‐affinity FCGR3A‐V158alleles (V/V158or V/F158) 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 DSAor capillary C4d. In parallel, there was a trend toward increased macrophage‐ and injury‐repair response–associated transcript subsets. Kidney function over 24 months, however, was not different. In support of a functional role of FcγRIIIApolymorphism, NK92 cells expressing FCGR3A‐V158produced >2 times as much interferon gamma upon incubation with HLAantibody‐coated cells as those expressing FCGR3A‐F158. FcγRIIAand FcγRIIIBpolymorphisms were not associated with allograft morphology. Our data suggest that the presence of high‐affinity FcγRIIIAvariants 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.