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

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

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Department of Internal Medicine 3, Institute for Clinical Immunology, Friedrich-Alexander University, Erlangen-Nuremberg, Germany.
Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada.
Department of Pathology, Medical University of Vienna, Vienna, Austria.
Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
Department of Paediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander University, Erlangen-Nuremberg, Germany.
Alberta Transplant Applied Genomics Centre, ATAGC, University of Alberta, Edmonton, AB, Canada.


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.


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


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