Natural killer cell functional genetics and donor-specific antibody-triggered microvascular inflammation

Am J Transplant. 2024 May;24(5):743-754. doi: 10.1016/j.ajt.2023.12.005. Epub 2023 Dec 13.

Abstract

Antibody-mediated rejection (ABMR) is a leading cause of graft failure. Emerging evidence suggests a significant contribution of natural killer (NK) cells to microvascular inflammation (MVI). We investigated the influence of genetically determined NK cell functionality on ABMR development and activity. The study included 86 kidney transplant recipients subjected to systematic biopsies triggered by donor-specific antibody detection. We performed killer immunoglobulin-like receptor typing to predict missing self and genotyped polymorphisms determining NK cell functionality (FCGR3AV/F158 [rs396991], KLRC2wt/del, KLRK1HNK/LNK [rs1049174], rs9916629-C/T). Fifty patients had ABMR with considerable MVI and elevated NK cell transcripts. Missing self was not related to MVI. Only KLRC2wt/wt showed an association (MVI score: 2 [median; interquartile range: 0-3] vs 0 [0-1] in KLRC2wt/del recipients; P = .001) and remained significant in a proportional odds multivariable model (odds ratio, 7.84; 95% confidence interval, 2.37-30.47; P = .001). A sum score incorporating all polymorphisms and missing self did not outperform a score including only KLRC2 and FCGR3A variants, which were predictive in univariable analysis. NK cell genetics did not affect graft functional decline and survival. In conclusion, a functional KLRC2 polymorphism emerged as an independent determinant of ABMR activity, without a considerable contribution of missing self and other NK cell gene polymorphisms.

Keywords: antibody-mediated rejection; gene polymorphisms; kidney transplantation; missing self; natural killer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Biomarkers / analysis
  • Biomarkers / metabolism
  • Female
  • Follow-Up Studies
  • Genotype
  • Graft Rejection* / etiology
  • Graft Rejection* / immunology
  • Graft Rejection* / pathology
  • Graft Survival* / immunology
  • Humans
  • Inflammation* / immunology
  • Isoantibodies* / immunology
  • Kidney Failure, Chronic / genetics
  • Kidney Failure, Chronic / immunology
  • Kidney Failure, Chronic / surgery
  • Kidney Function Tests
  • Kidney Transplantation* / adverse effects
  • Killer Cells, Natural* / immunology
  • Male
  • Microvessels / immunology
  • Microvessels / pathology
  • Middle Aged
  • Prognosis
  • Risk Factors
  • Tissue Donors* / supply & distribution

Substances

  • Isoantibodies
  • Biomarkers