A Promoter Polymorphism in the CD59 Complement Regulatory Protein Gene in Donor Lungs Correlates With a Higher Risk for Chronic Rejection After Lung Transplantation

Abstract

Complement activation leads primarily to membrane attack complex formation and subsequent target cell lysis. Protection against self-damage is regulated by complement regulatory proteins, including CD46, CD55, and CD59. Within their promoter regions, singlenucleotide polymorphisms (SNPs) are present that could influence transcription. We analyzed these SNPs and investigated their influence on protein expression levels. A single SNP configuration in the promoter region of CD59 was found correlating with lower CD59 expression on lung endothelial cells (p ¼ 0.016) and monocytes (p ¼ 0.013). Lung endothelial cells with this SNP configuration secreted more profibrotic cytokine IL-6 (p ¼ 0.047) and fibroblast growth factor b (p ¼ 0.036) on exposure to sublytic complement activation than cells with the opposing configuration, whereas monocytes were more susceptible to antibody-mediated complement lysis (p < 0.0001). Analysis of 137 lung transplant donors indicated that this CD59 SNP configuration correlates with impaired long-term survival (p ¼ 0.094) and a significantly higher incidence of bronchiolitis obliterans syndrome (p ¼ 0.046) in the recipient. These findings support a role for complement in the pathogenesis of this posttransplant complication and are the first to show a deleterious association of a donor CD59 promoter polymorphism in lung transplantation.

Complement Polymorphisms in Kidney Transplantation: Critical in Graft Rejection?

“…Functional experiments indicated that lung endothelial cells and monocytes derived from lung donors with this SNP configuration showed lower CD59 expression and were more susceptible to complement‐mediated cell lysis . None of the polymorphisms within the CD46 and CD55 promoters correlated with incidence of BOS, nor did they correlate with expression levels and susceptibility to complement‐mediated cell lysis . We hypothesize that recipients of kidneys with this CD59 promoter SNP configuration may also be more prone to antibody‐mediated rejection and impaired graft survival.…”

“…Finally, in lung transplantation it was shown that a SNP in the promoter region of CD59 (rs147788946) in lung donors was associated with an increased risk for bronchiolitis obliterans syndrome (BOS) . Functional experiments indicated that lung endothelial cells and monocytes derived from lung donors with this SNP configuration showed lower CD59 expression and were more susceptible to complement‐mediated cell lysis .…”

Results and reflections from the PROfiling Consortium on Antibody Repertoire and Effector functions in kidney transplantation: A mini‐review

“…CD59 inhibits formation of the membrane attack complex by preventing binding of C9 to C5b to C8 complexes. A SNP in the CD59 promotor region (rs147788946) of the donor was associated with higher risk for chronic rejection after lung transplantation . ADCC can be mediated by natural killer cells and to some extent monocytes and neutrophils.…”

Chronic Lung Allograft Dysfunction

“…158 Graft-reactive antibodies induce the activation of the complement system and the degradation of lung tissues. Polymorphism in the complement regulatory protein CD59 has then been associated with the development of BOS, 159 suggesting that harnessing complement activation may control CLAD development. Complement activation has been largely investigated as a potential marker for humoral rejection, via the immunostaining of the complement component 4 (C4d).…”