Soluble CD59 is a Novel Biomarker for the Prediction of Obstructive Chronic Lung Allograft Dysfunction After Lung Transplantation

Budding, Kevin; Graaf, E.A. van de; Kardol‐Hoefnagel, Tineke; Erp, Johanna M. Kwakkel-van; Luijk, Bart; Oudijk, Erik-Jan; Kessel, Diana A. van; Grutters, Jan C.; Hack, C. E.; Otten, H.G.

doi:10.1038/srep26274

Cited by 27 publications

(26 citation statements)

References 28 publications

(45 reference statements)

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“…While no such validated biomarker currently exists in transplantation, there are complement-related candidates. Soluble CD59 (sCD59), which is associated with cellular damage, including post-myocardial infarction 68 , was found to be elevated in a cohort of patients who developed bronchiolitis obliterans syndrome (BOS) after lung transplantation 69 . Importantly, serum sCD59 concentrations were elevated prior to the clinical diagnosis of BOS in these patients, and sCD59 was determined to be an independent predictor for the development of BOS.…”

Section: Complement and Transplant Rejection Biomarkersmentioning

confidence: 99%

Complement and Transplantation

Horwitz

Chun

Heeger

2019

Clinics in Laboratory Medicine

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Section: Complement and Transplant Rejection Biomarkersmentioning

confidence: 99%

Complement and Transplantation

Horwitz

Chun

Heeger

2019

Clinics in Laboratory Medicine

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“…The validation cohort used in our study revealed the strength of these biomarkers for BOS prediction. They displayed similar performances to predict BOS according to their correlation of expression, with AUC values reaching 0.83, 0.77, and 0.78, respectively, and exceeding the performance of biomarkers already published ( 14 , 34 , 35 ).…”

Section: Discussionmentioning

confidence: 59%

Blood Gene Expression Predicts Bronchiolitis Obliterans Syndrome

Danger¹,

Royer²,

Reboulleau³

et al. 2018

Front. Immunol.

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Bronchiolitis obliterans syndrome (BOS), the main manifestation of chronic lung allograft dysfunction, leads to poor long-term survival after lung transplantation. Identifying predictors of BOS is essential to prevent the progression of dysfunction before irreversible damage occurs. By using a large set of 107 samples from lung recipients, we performed microarray gene expression profiling of whole blood to identify early biomarkers of BOS, including samples from 49 patients with stable function for at least 3 years, 32 samples collected at least 6 months before BOS diagnosis (prediction group), and 26 samples at or after BOS diagnosis (diagnosis group). An independent set from 25 lung recipients was used for validation by quantitative PCR (13 stables, 11 in the prediction group, and 8 in the diagnosis group). We identified 50 transcripts differentially expressed between stable and BOS recipients. Three genes, namely POU class 2 associating factor 1 (POU2AF1), T-cell leukemia/lymphoma protein 1A (TCL1A), and B cell lymphocyte kinase, were validated as predictive biomarkers of BOS more than 6 months before diagnosis, with areas under the curve of 0.83, 0.77, and 0.78 respectively. These genes allow stratification based on BOS risk (log-rank test p < 0.01) and are not associated with time posttransplantation. This is the first published large-scale gene expression analysis of blood after lung transplantation. The three-gene blood signature could provide clinicians with new tools to improve follow-up and adapt treatment of patients likely to develop BOS.

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“…CD59 can be released into the circulation or the interstitial fluid in a soluble form (sCD59) and can be detected in various body fluids including urine, milk, serum, and plasma. 22 – 25 Various studies have designated sCD59 as biomarker for disease activity. Elevated circulating sCD59 concentrations have been found in acute myocardial infarction, and higher serum titers of glycated sCD59 have been described in diabetes mellitus.…”

Section: Resultsmentioning

confidence: 99%

Molecular pathogenesis of human CD59 deficiency

et al. 2018

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ObjectiveTo characterize all 4 mutations described for CD59 congenital deficiency.MethodsThe 4 mutations, p.Cys64Tyr, p.Asp24Val, p.Asp24Valfs*, and p.Ala16Alafs*, were described in 13 individuals with CD59 malfunction. All 13 presented with recurrent Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy, recurrent strokes, and chronic hemolysis. Here, we track the molecular consequences of the 4 mutations and their effects on CD59 expression, localization, glycosylation, degradation, secretion, and function. Mutants were cloned and inserted into plasmids to analyze their expression, localization, and functionality.ResultsImmunolabeling of myc-tagged wild-type (WT) and mutant CD59 proteins revealed cell surface expression of p.Cys64Tyr and p.Asp24Val detected with the myc antibody, but no labeling by anti-CD59 antibodies. In contrast, frameshift mutants p.Asp24Valfs* and p.Ala16Alafs* were detected only intracellularly and did not reach the cell surface. Western blot analysis showed normal glycosylation but mutant-specific secretion patterns. All mutants significantly increased MAC-dependent cell lysis compared with WT. In contrast to CD59 knockout mice previously used to characterize phenotypic effects of CD59 perturbation, all 4 hCD59 mutations generate CD59 proteins that are expressed and may function intracellularly (4) or on the cell membrane (2). None of the 4 CD59 mutants are detected by known anti-CD59 antibodies, including the 2 variants present on the cell membrane. None of the 4 inhibits membrane attack complex (MAC) formation.ConclusionsAll 4 mutants generate nonfunctional CD59, 2 are expressed as cell surface proteins that may function in non–MAC-related interactions and 2 are expressed only intracellularly. Distinct secretion of soluble CD59 may have also a role in disease pathogenesis.

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Soluble CD59 is a Novel Biomarker for the Prediction of Obstructive Chronic Lung Allograft Dysfunction After Lung Transplantation

Cited by 27 publications

References 28 publications

Complement and Transplantation

Complement and Transplantation

Blood Gene Expression Predicts Bronchiolitis Obliterans Syndrome

Molecular pathogenesis of human CD59 deficiency

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