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Am J Transplant. 2016 Mar;16(3):987-98. doi: 10.1111/ajt.13497. Epub 2015 Oct 30.

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

Author information

1
Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
2
Department of Respiratory Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
3
Departments of Rheumatology and Dermatology, University Medical Center Utrecht, Utrecht, The Netherlands.
4
Center of Interstitial Lung Diseases, St. Antonius Hospital, Nieuwegein, The Netherlands.

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.

KEYWORDS:

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

PMID:
26517734
DOI:
10.1111/ajt.13497
[Indexed for MEDLINE]
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