Fc-dependent effector mechanisms may play an important role in antibody-mediated rejection (ABMR). Distinct gene polymorphisms may determine the function of Fc gamma receptors (FcγR), potentially influencing donor-specific antibody (DSA)-mediated injury. Here, we investigated whether high-activity variants of activating FcγR influence the capability of DSA to trigger rejection. The study included 85 DSA-positive kidney allograft recipients subjected to protocol biopsies after a median of 5 years post-transplantation, recruited upon ABMR screening of 741 prevalent patients. Subjects were genotyped for functional polymorphisms in FcγRIIA (H/R₁₃₁), FcγRIIIA (V/F₁₅₈), and FcγRIIIB (NA1/NA2). Individuals with at least one high-affinity FcγRIIIA-V₁₅₈ allele (V/V₁₅₈ or V/F₁₅₈) showed a higher rate of peritubular capillaritis contrasted to homozygous carriers of the low risk allele (ptc score ≥1: 53.6% vs. 25.9%; P=0.018), higher ptc scores [median (IQR): 1 (0-2) vs. 0 (0-1); P=0.038], and increased macrophage- and injury-repair response–associated transcript subsets determined by transcriptomics. Associations with peritubular capillaritis persisted after adjustment of the C1q-binding capability of DSA or capillary C4d. There were, however, no significant differences regarding transplant glomerulopathy or allograft function over 24 months. FcγRIIA and FcγRIIIB polymorphisms were not associated with biopsy results or clinical endpoints. We conclude that high-affinity FcγRIIIA variants may enhance the susceptibility of allografts to DSA-triggered inflammation/injury.

CITATION INFORMATION: Arnold M-.L., Kainz A., Eskandary F., Kozakowski N., Wahrmann M., Haslacher H., Oberbauer R., Heilos A., Spriewald B., Hidalgo L., Halloran P., Bohmig G. Functional Fc Gamma Receptor Gene Polymorphisms and Donor-Specific Antibody-Triggered Transplant Injury Am J Transplant. 2017;17 (suppl 3).

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