Skin gene expression is prognostic for the trajectory of skin disease in patients with diffuse cutaneous systemic sclerosis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE106358 | GEO | 2018/06/04
REPOSITORIES: GEO
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Project description:Background: Only a subset of patients with systemic sclerosis (SSc) demonstrate improvement in modified Rodnan skin score (mRSS) during mycophenolate mofetil (MMF) treatment. Here we investigated the molecular and cellular effects in skin associated with MMF therapy in subjects who demonstrated or lacked clinical improvement. Methods: Clinical and skin gene expression data were obtained genome-wide from baseline and longitudinal (6-, 12-, 24-, and 36-mo) biopsies in 33 MMF-treated subjects with SSc. Clinical improvement was defined as mRSS reduction ≥ 25%. An inflammatory signature score was calculated for each patient sample using single-sample gene set enrichment analysis (ssGSEA). Cell type specific changes during treatment were characterized. Results: Eleven subjects with SSc completed at least 24 months of MMF therapy and were termed ‘completers’. Two distinct gene expression patterns were observed that corresponded to MMF treatment status. Three subjects showed attenuation of the inflammatory signature by 24 months, paralleling reductions in activated dendritic cells. MMF cessation at 24 months resulted in an inflammatory signature rebound paralleling mRSS increase. Three subjects that remained on MMF showed persistent inflammatory signature reductions with decreasing or stable mRSS. The remaining six completers either did not fulfill minimum mRSS (n=5), and/or lacked a baseline inflammatory signature (n=4). Conclusions: An elevated inflammatory skin gene expression signature is associated with clinical improvement during MMF therapy. Inflammation returned upon MMF discontinuation with concomitant mRSS increase. These data summarize MMF’s molecular effects in skin and support MMF therapy for longer than 24 months in patients who demonstrate clinical response.
2017-01-01 | GSE76885 | GEO
Project description:Systemic sclerosis (SSc) is an incurable autoimmune disease with high morbidity and mortality rates, with no effective treatment. Here, we conducted a population scale single-cell genomic analysis of skin and blood samples of 56 healthy controls, and 97 SSc patients at different stages of disease. We found immune compartment activation in only a subset of diffuse SSc patients, but global dysregulation of the stromal compartment, including a novel subset of LGR5+ scleroderma associated fibroblasts (ScAF). ScAF cells are mainly localized in the deep reticular dermis of healthy subjects and are dramatically perturbed morphologically and molecularly in SSc patients. Single-cell multiome profiling of the epigenetic and transcriptional landscapes of stromal cells in healthy subjects and SSc patients, revealed ScAF-specific markers, pathways, and transcription factors important in disease development. Systematic analysis combining the clinical metadata and molecular features of the patients, associates specific ScAF targets with disease pathogenesis and SSc clinical traits. Our study provides a high-resolution atlas of the entire spectrum of sclerodermatous skin, proposing a paradigm shift in the understanding of SSc disease and facilitating the development of new biomarkers and therapeutic strategies for SSc.
2022-04-04 | GSE195452 | GEO
Project description:Systemic sclerosis (SSc) is characterized by vascular damage, autoimmunity and fibrosis and is associated with highly variable clinical presentation and disease course. Aberrant transforming growth factor-ß (TGF-ß) signaling via the early immediate transcription factor Egr-1 is implicated in the pathogenesis of SSc. To shed light on the role of Egr-1 in fibrosis, regulation of gene expression in human skin fibroblasts overexpressing Egr-1 was examined by genome-wide expression analysis. Over 600 genes were found to be regulated by Egr-1. The Egr-1-responsive gene signature is largely comprised of genes involved in cell proliferation, TGF-ß signaling, wound healing, extracellular matrix synthesis and vascular development. Expression of the Egr-1 responsive genes was evaluated in a microarray dataset comprising skin biopsies from 17 patients with scleroderma and six healthy controls (GEO GSE9285; PMID 18648520). The “Egr-1 responsive gene signature” was enriched in the ‘diffuse-proliferation’ subset of skin biopsies in the patients with diffuse cutaneous SSc (dcSSc), but was not associated with other forms of scleroderma, or with healthy controls. Skin biopsies from patients with scleroderma can provide more insights into the relevant pathological processes in the subset of disease and could be developed into a diagnostic tool for identifying a subset of diffuse scleroderma patients who may be responsive to Egr-1 therapy. Cultures of primary fibroblasts from neonatal foreskin treated by Egr1 and Tgfb1 were measured at 24 and 48 hours. Control samples without any treatment were also measured at the same time points. Two biological replicates per condition/time point were measured using the Illumina HumanRef-8 V2 Expression BeadChip.
2011-10-25 | E-GEOD-27165 | biostudies-arrayexpress
Project description:To investigate the miRNA signature in the serum of systemic sclerosis (SSc) patients. The levels of 758 miRNAs were evaluated in the serum of 26 SSc patients as compared to 9 healthy controls by using an Openarray platform. Patients fulfilling the ACR/EULAR 2013 classification criteria were classified in relation to the extent of skin fibrosis as limited cutaneous (lcSSc) or diffuse cutaneous SSc (dcSSc); patients fulfilling the classification criteria without skin fibrosis will be referred to as non-cutaneous SSc (ncSSc). MicroRNAs (miRNAs) are regulatory molecules, which have been addressed as potential biomarkers and therapeutic targets in rheumatic diseases. Here, we investigated the miRNA signature in the serum of systemic sclerosis (SSc) patients and we further assessed their expression in early stages of the disease.The levels of 758 miRNAs were evaluated in the serum of 26 SSc patients as compared to 9 healthy controls by using an Openarray platform. Three miRNAs were examined in an additional cohort of 107 SSc patients and 24 healthy donors by single qPCR. MiR-483-5p expression was further analysed in the serum of patients with localized scleroderma (LoS) (n=22), systemic lupus erythematosus (SLE) (n=33) and primary Sjögren’s syndrome (pSS) (n=23). The function of miR-483-5p was examined by transfecting miR-483-5p into primary human dermal fibroblasts and pulmonary endothelial cells.30 miRNAs were significantly increased in patients with SSc. Of these, miR-483-5p showed reproducibly higher levels in an independent SSc cohort and was also elevated in patients with preclinical-SSc symptoms (early SSc). Notably, miR-483-5p was not differentially expressed in patients with SLE or pSS, whereas it was up-regulated in LoS, indicating that this miRNA could be involved in the development of skin fibrosis. Consistently, miR-483-5p overexpression in fibroblasts and endothelial cells modulated the expression of fibrosis-related genes.Our findings showed that miR-483-5p is up-regulated in the serum of SSc patients, from the early stages of the disease onwards, and indicated its potential function as a fine regulator of fibrosis in SSc.
2018-02-15 | GSE108918 | GEO
Project description:Systemic sclerosis (SSc) is a rare but devastating disease of fibrosis impacting the dermis and multiple organ systems. The prevalence ranges from 4 to 489 cases per million individuals with ten year mortality rates reported around 18 percent. Survival is related to the extent of skin involvement, yet the precise mechanisms driving skin fibrosis in SSc remain unknown. In this study, we analyzed the shared and unique transcriptomic profiles of SSc and normal keratinocytes.
2018-03-21 | GSE81072 | GEO
Project description:Systemic sclerosis (SSc) shows complex clinical manifestations including progressive skin and internal organ fibrosis. SSc can be divided into 'intrinsic subsets' by gene expression suggesting patient-specific heterogeneity in pathogenesis or temporal evolution of disease. Here we validate these subsets using an independent patient population, and test whether the genes vary over time with patients changing subsets as disease progresses, or if the genes are a stable feature of the patients within each subset. Skin biopsies were analyzed from 13 dSSc patients enrolled in an open label study of rituximab, 9 dSSc patients not treated with rituximab, and 9 healthy controls. These data recapitulate the patient 'intrinsic subsets' described previously with gene expression associated with cell proliferation, inflammatory processes, and a normal-like group. Serial skin biopsies showed consistent and non-progressing gene expression. We were unable to detect significant differences in gene expression before and after rituximab treatment, consistent with an apparent lack of clinical response. Serial biopsies from each patient stayed within the same gene expression subset regardless of treatment regimen or the time point at which they were taken. This demonstrates the intrinsic subsets are an inherent, reproducible and stable feature of SSc that is independent of disease duration. Skin biopsies were analyzed from 13 dSSc patients enrolled in an open label study of rituximab, 9 dSSc patients not treated with rituximab, and 9 healthy controls.
2012-03-23 | E-GEOD-32413 | biostudies-arrayexpress
Project description:Systemic sclerosis (SSc) is characterized by vascular damage, autoimmunity and fibrosis and is associated with highly variable clinical presentation and disease course. Aberrant transforming growth factor-ß (TGF-ß) signaling via the early immediate transcription factor Egr-1 is implicated in the pathogenesis of SSc. To shed light on the role of Egr-1 in fibrosis, regulation of gene expression in human skin fibroblasts overexpressing Egr-1 was examined by genome-wide expression analysis. Over 600 genes were found to be regulated by Egr-1. The Egr-1-responsive gene signature is largely comprised of genes involved in cell proliferation, TGF-ß signaling, wound healing, extracellular matrix synthesis and vascular development. Expression of the Egr-1 responsive genes was evaluated in a microarray dataset comprising skin biopsies from 17 patients with scleroderma and six healthy controls (GEO GSE9285; PMID 18648520). The “Egr-1 responsive gene signature” was enriched in the ‘diffuse-proliferation’ subset of skin biopsies in the patients with diffuse cutaneous SSc (dcSSc), but was not associated with other forms of scleroderma, or with healthy controls. Skin biopsies from patients with scleroderma can provide more insights into the relevant pathological processes in the subset of disease and could be developed into a diagnostic tool for identifying a subset of diffuse scleroderma patients who may be responsive to Egr-1 therapy.
2011-10-26 | GSE27165 | GEO
Project description:Skin and lung fibrosis in systemic sclerosis (SSc) is driven by myofibroblasts, alpha-smooth muscle actin (SMA) expressing cells that produce matrix as well as increase tension on surrounding tissues. Myofibroblast progenitors have been described to arise from a variety of cell types in murine fibrosis models, but relatively modest insight is available as to their source and differentiation in fibrotic human diseases. We utilize single cell RNA-sequencing to examine the transcriptome changes that occur in fibroblasts in SSc skin and during myofibroblast differentiation. We show that dermal myofibroblasts arise from an SFRP2/DPP4-expressing progenitor fibroblast population. In SSc skin, fibroblasts undergo global changes in gene expression, including SFRP2-expressing fibroblasts, which globally upregulate expression of markers, such as PRSS23 and THBS1. However, only a fraction of SSc fibroblasts differentiate into myofibroblasts, as shown by expression of additional markers, such as SFRP4 and FNDC1. These results indicate that myofibroblasts derive from a specific fibroblast subpopulation in SSc skin, that their differentiation proceeds in two stages and that other fibroblast populations also shift transcriptomes in SSc skin, suggesting a cytokine driven process. The myofibroblast transcriptome implicates upstream transcription factors that should help further unravel the drivers of myofibroblast differentiation.
2021-05-20 | GSE138669 | GEO
Project description:339 total forearm skin biopsies were obtained from 113 unique SSc patients and 44 matched healthy controls. 105 SSc patients had a 2nd biopsy, 76 patients had a 3rd biopsy, and 1 patient had a 4th biopsy. Global gene expression profiling was performed, and differentially expressed genes and cell type-specific signatures in SSc were evaluated for relationships to skin thickness and other clinical variables. Changes in skin gene expression over time were analyzed by mixed effects models and principal component analysis. Immunohistochemical staining was performed to validate conclusions. Skin thickness in SSc is related to dysregulated immune cell and fibroblast gene expression. Skin gene expression changes over time in early diffuse SSc, with a tendency towards normalization.
2022-02-01 | GSE181549 | GEO
Project description:Systemic sclerosis (SSc) is characterized by intractable multiorgan fibrosis caused by vascular and immune dysfunction. Currently, effective therapeutic options for patients with SSc are limited. Nitrate, an abundant nutrient in the diet, has been demonstrated to be preventative and therapeutic for several diseases. To determine whether nitrate can slow or reverse SSc progression, topical application of nitrate delivered by dissolving microneedles was used to treat a bleomycin (BLM)-induced dermal fibrosis mouse model. In this study, nitrate considerably attenuated dermal thickness, stiffness, and collagen deposition.To examine the nitrate regulation of gene expression at the genome-wide level, bulk RNA sequencing of skin was performed. Bulk RNA sequencing of skin revealed that Cd4 was a key hub gene in SSc nitrate therapy. Additionally, BLM-induced cytokines and chemokines were inhibited by nitrate, and CD4+ T cells infiltration markedly declined. Il4, Il6, Il13, and Tgfb expression in CD4+ T cells isolated from skin biopsies also significantly decreased. Mechanistically, Il1rl1, a type2 immune response inducer, was markedly repressed in isolated CD4+ T cells and dermal tissues after nitrate treatment. Remarkably, compared with wild type mice, mice lacking Il1rl1 showed impaired transcriptional profiles after intradermal BLM injection. Adoptive transfer of ST2+CD4+ T cells promoted bleomycin-induced Rag2-/- mice dermal fibrosis. Collectively, these findings demonstrate that nitrate targeting ST2+CD4+ T cells is an effective therapeutic option for SSc.
2024-06-04 | GSE264187 | GEO