Skin biopsy expression from the faSScinate phase 2 study of tocilizumab in systemic sclerosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE249550 | GEO | 2023/12/10
REPOSITORIES: GEO
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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) is an autoimmune disease characterized by clinical heterogeneity, multi-organ involvement, and complex genetic risk. Here, we report the first multi-tissue meta-analysis of ten independent SSc gene expression datasets. We identify a common immune-fibrotic expression axis across all tissues that is associated with the most severe disease phenotypes. The coexpression patterns conserved across tissues and phenotypes were used to query functional genomic networks, which allowed us to identify common and tissue-specific disease drivers. We find evidence of pro-fibrotic macrophages (MØs) in SSc end-target organs. Prominent genes in the skin functional genomic network are associated with SSc genetic risk and are modulated by immunosuppressive treatment in clinical improvers. These data suggest the interactions between T lymphocytes and MØs are a critical driver of disease and implicate MØs as central to SSc pathogenesis. In total, this study presents a mechanism for fibrosis in SSc end-target tissues, a set of putative therapeutic targets for modulating SSc, and a framework for multi-tissue functional genomic studies of complex human disease.
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Project description:Skin systemic sclerosis (Scleroderma, SSc) is an autoimmune disease while its epigenetic regulatory mechanism is not known. We surveyed the genome-wide active regulatory elements in fresh human skin cells, using Assay of Transposase Accessible Chromatin with sequencing (ATAC-seq) in longitudinal skin from healthy volunteers and affected and unaffected skin from patients with SSc. We created robust pipelines that enable accurate single molecule counting and allelic discrimination from clinical material in vivo without clonal expansion. We generated high-resolution epigenetic regulomes of 9 cell types in normal and SSc skins, and identified 106044 cell type specific accessible sites. Motif analysis of these peaks predicted known and novel transcription factors regulating each cell type. For each cell type, we discovered thousands of accessible sites are differential in normal versus unaffected and affected skin from patients with SSc. We predicted novel transcription factors regulating SSc in a cell type specific manner, and predicted the relative contributions of each cell type in driving skin SSc. ATAC-seq also revealed novel elements that escape X chromosome inactivation, which coordinately impact genes with immune function.
2020-10-20 | GSE99702 | GEO
Project description:Autoantibodies (Aab) are frequent in systemic sclerosis (SSc). While recognized as potent biomarkers, their pathogenic role is much debated. This study explored the effect of purified IgG from SSc patients on the phenotype and function of healthy dermal fibroblast (FB) using an innovative multi-omics approach.
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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.
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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 a complex and still unclear rare disease associated with fibrosis in multiple organs. Microbiota has recently emerged as an important environmental factor in SSc pathogenesis, either at gut, oral and skin level.
2023-12-28 | GSE200486 | GEO
Project description:Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is the leading cause of death in patients with systemic sclerosis (SSc) with unclear pathogenesis and limited treatment options. Evidence strongly supports an important role for profibrotic, SPP1-expressing macrophages in SSc-ILD. We sought to define the transcriptome and chromatin structural changes of SPP1 SSc-ILD macrophages, so as to better understand their role in promoting fibrosis and to identify transcription factors associated with open chromatin driving their altered phenotype.
2022-09-02 | GSE212109 | GEO
Project description:Currently, there are no clinical or laboratory measures that accurately predict progression of skin fibrosis and organ involvement in patients with systemic sclerosis (SSc). The goal of this study is to identify skin biomarkers in early diffuse cutaneous SSc patients, to prognosticate the progression of skin fibrosis. We found that skin gene expression of biomarkers associated with macrophages (CD14, IL13RA1) and TGFβ activation (SERPINE1, CTGF, OSMR) are prognostic for progressive skin disease. These biomarkers might help to guide decisions about which patients should be considered for aggressive therapies and/or for clinical trials.
2018-06-04 | GSE106358 | GEO
Project description:Objective: Pulmonary complications in systemic sclerosis (SSc), including pulmonary fibrosis (PF) and pulmonary arterial hypertension (PAH), are the leading cause of mortality. We compared the molecular fingerprint of SSc lung tissues and matching primary lung fibroblasts to those of normal donors, and patients with idiopathic pulmonary fibrosis (IPF) and idiopathic pulmonary arterial hypertension (IPAH). Methods: Lung tissues were obtained from 33 patients with SSc who underwent lung transplantation. Tissues and cells from a subgroup of SSc patients with predominantly PF or PAH were compared to those from normal donors, patients with IPF, or IPAH. Microarray data was analyzed using Efficiency Analysis for determination of optimal data processing methods. Real time PCR and immunohistochemistry were used to confirm differential levels of mRNA and protein, respectively. Results: We identified a consensus of 242 and 335 genes that were differentially expressed in lungs and primary fibroblasts, respectively. Enriched function groups in SSc-PF and IPF lungs included fibrosis, insulin-like growth factor signaling and caveolin-mediated endocytosis. Functional groups shared by SSc-PAH and IPAH lungs included antigen presentation, chemokine activity, and IL-17 signaling. Conclusion: Using microarray analysis on carefully phenotyped SSc and comparator lung tissues, we demonstrated distinct molecular profiles in tissues and fibroblasts of patients with SSc-associated lung disease compared to idiopathic forms of lung disease. Unique molecular signatures were generated that are disease- (SSc) and phenotype- (PF vs PAH) specific. These signatures provide new insights into pathogenesis and potential therapeutic targets for SSc lung disease. Lung tissues were obtained from 33 patients with SSc who underwent lung transplantation. Tissues and cells from a subgroup of SSc patients with predominantly PF or PAH were compared to those from normal donors, patients with IPF, or IPAH. Microarray data was analyzed using Efficiency Analysis for determination of optimal data processing methods. Real time PCR and immunohistochemistry were used to confirm differential levels of mRNA and protein, respectively.
2013-06-21 | E-GEOD-48149 | biostudies-arrayexpress