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

Matthias Diebold; Hannes Vietzen; Andreas Heinzel; Susanne Haindl; Carsten T Herz; Katharina Mayer; Konstantin Doberer; Alexander Kainz; Ingrid Faé; Sabine Wenda; Laura M Kühner; Sarah M Berger; Elisabeth Puchhammer-Stöckl; Nicolas Kozakowski; Stefan Schaub; Philip F Halloran; Georg A Böhmig

doi:10.1016/j.ajt.2023.12.005

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

Am J Transplant. 2023 Dec 13:S1600-6135(23)00904-8. doi: 10.1016/j.ajt.2023.12.005. Online ahead of print.

Authors

Matthias Diebold¹, Hannes Vietzen², Andreas Heinzel³, Susanne Haindl³, Carsten T Herz³, Katharina Mayer³, Konstantin Doberer³, Alexander Kainz³, Ingrid Faé⁴, Sabine Wenda⁴, Laura M Kühner², Sarah M Berger², Elisabeth Puchhammer-Stöckl², Nicolas Kozakowski⁵, Stefan Schaub⁶, Philip F Halloran⁷, Georg A Böhmig⁸

Affiliations

¹ Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, University of Basel, Basel, Switzerland.
² Center for Virology, Medical University of Vienna, Vienna, Austria.
³ Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
⁴ Department of Blood Group Serology and Transfusion Medicine, Medical University Vienna, Vienna, Austria.
⁵ Department of Pathology, Medical University of Vienna, Vienna, Austria.
⁶ Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, University of Basel, Basel, Switzerland.
⁷ Alberta Transplant Applied Genomics Centre, ATAGC, University of Alberta, Edmonton, Alberta, Canada.
⁸ Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria. Electronic address: georg.boehmig@meduniwien.ac.at.

PMID: 38097018
DOI: 10.1016/j.ajt.2023.12.005

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 (FCGR3A^V/F158 [rs396991], KLRC2^wt/del, KLRK1^HNK/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 KLRC2^wt/wt showed an association (MVI score: 2 [median; interquartile range: 0-3] vs 0 [0-1] in KLRC2^wt/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.