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Differential expression of interferon-induced genes and other tissue-based biomarkers in acute graft-versus-host disease vs. lupus erythematosus in skin.

ABSTRACT: BACKGROUND:In both acute graft-versus-host disease (GVHD) and lupus erythematosus (LE), the patient's own tissues are subjected to immunological assault via complex mechanisms influenced by interferon (IFN) and other cytokines. Although not typically confused clinically, these entities have overlapping histopathological findings in the skin. AIM:To assess whether GVHD can be differentiated from LE using molecular methods on skin specimens. METHODS:We developed a quantitative reverse transcription PCR assay based on previously identified tissue-based biomarkers of cutaneous GVHD, and compared gene expression in GVHD with that in LE. RESULTS:Both entities showed robust expression of IFN-induced genes and of genes encoding proteins involved in antigen presentation, cell signalling and tissue repair. Levels of gene expression differed significantly in GVHD compared with LE, particularly those of IFN-induced genes such as MX1, OAS3, TAP1 and STAT3 (P < 0.01). Three logistic regression models could differentiate the two entities with a high degree of certainty (receiver operating characteristic area under the curve of 1.0). CONCLUSION:The study demonstrates the feasibility of distinguishing between microscopically similar inflammatory dermatoses using tissue-based molecular techniques.

SUBMITTER: Lehman JS

PROVIDER: S-EPMC6445793 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Differential expression of interferon-induced genes and other tissue-based biomarkers in acute graft-versus-host disease vs. lupus erythematosus in skin.

Lehman J S JS Dasari S S Damodaran S S SS El-Azhary R A RA Gibson L E LE Hashmi S K SK Hogan W J WJ Kenderian S J SJ Patnaik M S MS Litzow M R MR Lazarus H M HM Meves A A

Clinical and experimental dermatology 20181002 4

<h4>Background</h4>In both acute graft-versus-host disease (GVHD) and lupus erythematosus (LE), the patient's own tissues are subjected to immunological assault via complex mechanisms influenced by interferon (IFN) and other cytokines. Although not typically confused clinically, these entities have overlapping histopathological findings in the skin.<h4>Aim</h4>To assess whether GVHD can be differentiated from LE using molecular methods on skin specimens.<h4>Methods</h4>We developed a quantitativ ...[more]

PMID: 30280423

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Project description:Allogeneic hematopoietic stem cell transplantation is a curative treatment for numerous hematological malignancies. However, acute graft-versus-host disease (aGvHD) is a major complication affecting 40-70% of all transplant patients, whereby the earliest and most frequent presentation is in the skin. MicroRNAs play a role in varied biological process and have been reported as potential biomarkers for aGvHD. More recently, microRNAs have received added attention as circulatory biomarkers that can be detected in biofluids. In this study, we performed global microRNA expression profiling using a discovery cohort of diagnostic cutaneous aGvHD biopsies (n = 5, stages 1-3) and healthy volunteers (n = 4), in order to identify a signature list of microRNAs that could be used as diagnostic biomarkers for cutaneous aGvHD. Candidate microRNAs (n = 8) were then further investigated in a validation cohort of post-HSCT skin biopsies (n = 17), pre-HSCT skin biopsies (n = 6) and normal controls (n = 6) for their association with aGvHD. Expression of let-7c (p = 0.014), miR-503-5p (p = 0.003), miR-365a-3p (p = 0.02), miR-34a-5p (p < 0.001) and miR-34a-3p (p = 0.006) were significantly differentially expressed between groups and significantly associated with survival outcome in post-HSCT patients (miR-503-5p ROC AUC = 0.83 p = 0.021, Log Rank p = 0.003; miR-34a-3p ROC AUC = 0.93, p = 0.003, Log Rank p = 0.004). There was no association with relapse. A statistical interaction between miR-34a-3p and miR-503-5p (p = 0.016) was diagnostic for aGvHD. Expression levels of the miR-34a-5p protein target p53 were assessed in the epidermis of the skin, and an inverse correlation was identified (r2 = 0.44, p = 0.039). Expression of the validated candidate microRNAs was also assessed at day 28 post-HSCT in the sera of transplant recipients, in order to investigate their potential as circulatory microRNA biomarkers. Expression of miR-503-5p (p = 0.001), miR-34a-5p (p = 0.005), and miR-34a-3p (p = 0.004) was significantly elevated in the sera of patients who developed aGvHD versus no-aGvHD (n = 30) and miR-503-5p was associated with overall survival (OS) (ROC AUC = 0.80, p = 0.04, Log Rank p = 0.041). In conclusion, this investigation reports that microRNA expression levels in clinical skin biopsies, obtained at the time of cutaneous aGvHD onset, show potential as diagnostic biomarkers for aGvHD and as predictive biomarkers for OS. In addition, the same microRNAs can be detected in the circulation and show predictive association with post-HSCT outcomes.

Dataset Information

Differential expression of interferon-induced genes and other tissue-based biomarkers in acute graft-versus-host disease vs. lupus erythematosus in skin.

Publications

Differential expression of interferon-induced genes and other tissue-based biomarkers in acute graft-versus-host disease vs. lupus erythematosus in skin.

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