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

K Budding, E A van de Graaf, T. Kardol-Hoefnagel, J C A Broen, J M Kwakkel-van Erp, E-J D Oudijk, D A van Kessel, C E Hack, H G Otten

Research output: Contribution to journalArticleAcademicpeer-review

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, single-nucleotide 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 = 0.016) and monocytes (p = 0.013). Lung endothelial cells with this SNP configuration secreted more profibrotic cytokine IL-6 (p = 0.047) and fibroblast growth factor β (p = 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 = 0.094) and a significantly higher incidence of bronchiolitis obliterans syndrome (p = 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.

Original languageEnglish
Pages (from-to)987-998
JournalAmerican Journal of Transplantation
Volume16
Issue number3
DOIs
Publication statusPublished - Mar 2016

Keywords

  • basic (laboratory) research/science
  • translational research/science
  • lung transplantation/pulmonology
  • immunobiology
  • bronchiolitis obliterans (BOS)
  • complement biology

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