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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.

Author information

1
Department of Internal Medicine 3, Institute for Clinical Immunology, Friedrich-Alexander University, Erlangen-Nuremberg, Germany.
2
Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
3
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada.
4
Department of Pathology, Medical University of Vienna, Vienna, Austria.
5
Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
6
Department of Paediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
7
Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander University, Erlangen-Nuremberg, Germany.
8
Alberta Transplant Applied Genomics Centre, ATAGC, University of Alberta, Edmonton, AB, Canada.

Abstract

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

PMID:
29478298
DOI:
10.1111/ajt.14710

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