FCGR2C Q13 and FCGR3A V176 alleles jointly associate with worse natural killer cell-mediated antibody-dependent cellular cytotoxicity and microvascular inflammation in kidney allograft antibody-mediated rejection

Abstract

Natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) is a major mechanism of humoral allograft injury. FCGR3A V¹⁷⁶/F¹⁷⁶ polymorphism influences ADCC activity. Additionally, NK cell FcγRIIc expression, dictated by the Q¹³/STP¹³ polymorphism, was never investigated in kidney transplantation. To assess the clinical relevance of FCGR2C Q¹³/STP¹³ polymorphism in conjunction with FCGR3A V¹⁷⁶/F¹⁷⁶ polymorphism, 242 kidney transplant recipients were genotyped. NK cell Fc gamma receptor (FcγR) expression and ADCC activity were assessed. RNA sequencing was performed on kidney allograft biopsies to explore the presence of infiltrating FcγR+ NK cells. The FCGR2C Q¹³ allele was enriched in antibody-mediated rejection patients. FcγRIIc Q¹³+ NK cells had higher ADCC activity than FcγRIIc Q¹³- NK cells. In combination with the high-affinity FCGR3A V¹⁷⁶ allele, Q¹³+V¹⁷⁶+ NK cells were the most functionally potent. Q¹³+ was associated with worse microvascular inflammation and a higher risk of allograft loss. Among V¹⁷⁶- patients, previously described in the literature as lower-risk patients, Q¹³+V¹⁷⁶- showed a lower graft survival than Q¹³-V¹⁷⁶- patients. In antibody-mediated rejection biopsies, FCGR2C transcripts were enriched and associated with ADCC-related transcripts. Our results suggest that FCGR2C Q¹³ in addition to FCGR3A V¹⁷⁶ is a significant risk allele that may enhance NK cell-mediated ADCC and contribute to allograft injury and poor survival.

Keywords: Fc gamma receptor; alloantibody; allograft injury; antibody-mediated rejection; cytotoxicity; kidney transplantation; natural killer cell.