Abstract
The purpose of this study was to explore the skin transcriptional profile in pediatric localized scleroderma (LS) to provide a better understanding of the altered immune and fibrotic pathways promoting disease. LS is a progressive disease of the skin and underlying tissue that causes significant functional disability and disfigurement, especially in developing children. RNA sequencing (RNAseq) technology allows for improved understanding of relevant cellular expression through transcriptome analysis of phases during LS disease progression (more active/inflammatory vs. inactive/fibrotic) and also permits the use of RNA extracted from existing paraffin-embedded skin tissue, which is important in pediatrics. A strong correlation was observed between the comparison of genes expressed between fresh (RNAlater) and paraffinized skin in healthy and LS subjects, supporting the use of paraffinized tissue. LS gene signatures compared to healthy controls showed a distinct expression of an inflammatory response gene signature (IRGS) composed of IFNγ-, IFNα-, and TNFα-associated genes. GSEA© enrichment analysis showed that the IRGS, including interferon-inducible chemokines such as CXCL9, CXCL10, CXCL11, and IFNγ itself, was more highly expressed in LS patients with more inflammatory lesions. The use of paraffinized skin for sequencing was proven to be an effective substitute for fresh skin by comparing gene expression profiles. The prevalence of the IFNγ signature in the lesion biopsies of active LS patients indicates that these genes reflect clinical activity parameters and may be the promoters of early, inflammatory disease.
Highlights
IntroductionLocalized scleroderma (LS), known as morphea, is an autoimmune disease characterized by skin fibrosis and subsequent atrophy (typically in bands along the lines of Blaschko) in the absence of vascular and internal-organ involvement, with an annual incidence of 1–3 per 100,000 children [1]
Localized scleroderma (LS), known as morphea, is an autoimmune disease characterized by skin fibrosis and subsequent atrophy in the absence of vascular and internal-organ involvement, with an annual incidence of 1–3 per 100,000 children [1]
Active disease is defined by cutaneous features, such as erythema, skin thickening, new lesions, and lesion expansion, all captured by validated cutaneous clinical outcome measures including the modified Localized Scleroderma Skin Severity Index and Physician Global Assessment of Activity (PGA-A) [3,4,5]
Summary
Localized scleroderma (LS), known as morphea, is an autoimmune disease characterized by skin fibrosis and subsequent atrophy (typically in bands along the lines of Blaschko) in the absence of vascular and internal-organ involvement, with an annual incidence of 1–3 per 100,000 children [1]. LS progression is biphasic, with an inflammatory active phase that is followed by a fibrotic damage phase distinguished by inflammatory infiltrate of the skin, collagen deposition, and Genetic Signatures in Pediatric LS Skin subsequent thickening of the deep dermis and subcutis, respectively [2]. Active disease is defined by cutaneous features, such as erythema, skin thickening, new lesions, and lesion expansion, all captured by validated cutaneous clinical outcome measures including the modified Localized Scleroderma Skin Severity Index (mLoSSI) and Physician Global Assessment of Activity (PGA-A) [3,4,5]. Since juvenile LS presents during development (mean age of onset 8 years) and can persist for many years (mean disease duration of 13.5 years) [6], morbidity can be substantial. Damage is most prevalent in linear scleroderma, the pre-dominant juvenile LS subtype (60%) [8, 9]
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