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

Am J Transplant. 2018 Sep;18(9):2261-2273. doi: 10.1111/ajt.14710. Epub 2018 Mar 30.


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-V158 alleles (V/V158 or 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 DSA or 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 FcγRIIIA polymorphism, NK92 cells expressing FCGR3A-V158 produced >2 times as much interferon gamma upon incubation with HLA antibody-coated cells as those expressing FCGR3A-F158 . FcγRIIA and FcγRIIIB polymorphisms were not associated with allograft morphology. Our data suggest that the presence of high-affinity FcγRIIIA variants may favor DSA-triggered microcirculation inflammation.

Keywords: alloantibody; genetics; histocompatibility; kidney transplantation/nephrology; protocol biopsy; rejection: antibody-mediated (ABMR); translational research/science.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cross-Sectional Studies
  • Female
  • Follow-Up Studies
  • GPI-Linked Proteins / genetics
  • Genotype
  • Graft Rejection / diagnosis*
  • Graft Rejection / etiology
  • Graft Survival
  • Humans
  • Inflammation / diagnosis*
  • Inflammation / etiology
  • Isoantibodies / adverse effects*
  • Kidney Failure, Chronic / genetics
  • Kidney Failure, Chronic / surgery
  • Kidney Transplantation / adverse effects*
  • Male
  • Microcirculation
  • Middle Aged
  • Polymorphism, Genetic*
  • Postoperative Complications
  • Prognosis
  • Receptors, IgG / genetics*
  • Risk Factors
  • Tissue Donors


  • FCGR2A protein, human
  • FCGR3A protein, human
  • FCGR3B protein, human
  • GPI-Linked Proteins
  • Isoantibodies
  • Receptors, IgG