Research on the Pathogenesis of Systemic Sclerosis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE308096 | GEO | 2026/04/14
REPOSITORIES: GEO
Similar Datasets
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.
2017-01-01 | GSE76806 | GEO
Project description:Research on the Pathogenesis of Systemic Sclerosis
| PRJNA1328731 | ENA
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 systemic fibrosis, vascular dysfunction, and the presence of antinuclear autoantibodies. In up to 10% of persons with SSc, the target antigens of the antinuclear autoantibodies are unknown. Using IP-MS, we here describe another new target antigen in SSc. We examined a database of IP-MS identifications of 106 persons with SSc from two Belgian academic hospitals [Ghent University Hospital (n=59) and University Hospitals Leuven (n=47)] without autoantibody specificity as tested by commercial assays.TATA-binding protein (TBP)-associated factors (TAFs) were precipitated by sera of four persons (two from Ghent, two from Leuven). Together with TBP, TAFs form the three-lobed transcription factor IID complex (TFIID) (figure 1B). The TFIID complex recognizes core promoter sequences on DNA. The binding of TFIID is the first step of the assembly of the preinitiation complex, which is needed to position RNA polymerase II onto the correct DNA sequence to start transcription. To identify additional cases, we tested samples from individuals with SSc with unidentified autoantibodies from 3 extra hospitals [Cliniques Universitaires Saint-Luc (Belgium) (n=45), Chris Hani Baragwanath Hospital (South Africa) (n=28) and Centre Hospitalier Universitaire d’Angers (France) (n=13)] by IP-MS. Two additional cases precipitating TFIID subunits were identified. In order to confirm the specificity of anti-TIFIID antibodies for SSc, IP-MS was performed in healthy individuals (n=34) and in patients with idiopathic inflammatory myopathy (IIM, n=12), Sjögren’s disease (SjD, n=12), systemic lupus erythematosus (SLE, n=36) and anti-topoisomerase-I-, anti-centromere- or anti-RNA polymerase III-positive SSc (n=28). TAF9, TAF9B and TAF10 were often precipitated in these control samples. In conclusion, we describe TFIID as a new target of autoantibodies in SSc, thereby expanding the spectrum of SSc-associated autoantigens related to transcription.
2025-07-01 | PXD064257 | Pride
Project description:Systemic sclerosis (SSc) is a fibrotic disease with high mortality and SSc-associated pulmonary fibrosis (SSc-PF) as the leading cause of death. SSc shows a significant sex disparity with a sex ratio of 1:3 men to women, yet SSc-PF is more severe in men. This study investigates gene expression differences between men and women with SSc-PF. Whole lung tissues from healthy donors and SSc-PF patients of both sexes were analyzed by RNA sequencing. Selected genes were validated by quantitative polymerase chain reaction (qPCR) and Western blotting analyses. Notably, in whole lung, genes related to extracellular matrix production, such as COL3A1, COL5A1, PDGFA, THBS1, and THBS2, were upregulated in females, while genes that are less-explicitly related to fibrosis, like GNB3, PCSK4, and PCSK7, were upregulated in males. Additionally, normal lung fibroblasts were treated with recombinant TGFβ to determine if there is a differential response in lung fibroblasts depending on sex. This study reveals differentially expressed genes that are unique to female and male SSc-PF patients and identifies potential sex-specific clinical targets.
2026-06-03 | GSE317056 | GEO
Project description:Objectives: To identify key pathways, transcriptional regulators and epigenetic mechanisms underlying conventional dendritic cell (cDC) alteration in Systemic Sclerosis (SSc). Methods: Transcriptomic profiling was performed on CD1c+ cDCs isolated from peripheral blood samples obtained from 12 healthy donors and 48 SSc patients with all major disease subtypes. Differential expression analysis comparing the different SSc subtypes and healthy donors was performed to uncover genes dysregulated in SSc. To identify biologically relevant pathways, a gene co-expression network was built using the Weighted Gene Correlation Network Analysis. We validated the role of key transcriptional regulators using ChIP-sequencing and in vitro functional assays. Results: We identified 17 modules of co-expressed genes in cDCs that correlated with SSc subtypes and key clinical traits. A module of immune regulatory genes was markedly down regulated in patients with the diffuse SSc subtype suffering from severe fibrosis. Gene regulatory network analysis performed on the immune regulatory module predicted NR4A (nuclear receptor 4A) subfamily (NR4A1, NR4A2, NR4A3) genes as the master transcriptional mediators of inflammation. Indeed, ChIP-sequencing analysis of cDCs supported that these NR4A members target numerous differentially expressed genes in SSc cDCs. Inclusion of NR4A receptor agonists in culture-based experiments provided functional proof that dysregulation of NR4As affects cytokine production by cDCs and modulates T-cells activation. Conclusions: NR4A1, NR4A2 and NR4A3 are important regulators of immunosuppressive and fibrosis-associated pathways in SSc cDCs. Thus, the NR4A family represent novel potential targets to restore cDC homeostasis in SSc.
2023-03-22 | GSE186198 | GEO
Project description:Objectives: To identify key pathways, transcriptional regulators and epigenetic mechanisms underlying conventional dendritic cell (cDC) alteration in Systemic Sclerosis (SSc). Methods: Transcriptomic profiling was performed on CD1c+ cDCs isolated from peripheral blood samples obtained from 12 healthy donors and 48 SSc patients with all major disease subtypes. Differential expression analysis comparing the different SSc subtypes and healthy donors was performed to uncover genes dysregulated in SSc. To identify biologically relevant pathways, a gene co-expression network was built using the Weighted Gene Correlation Network Analysis. We validated the role of key transcriptional regulators using ChIP-sequencing and in vitro functional assays. Results: We identified 17 modules of co-expressed genes in cDCs that correlated with SSc subtypes and key clinical traits. A module of immune regulatory genes was markedly down regulated in patients with the diffuse SSc subtype suffering from severe fibrosis. Gene regulatory network analysis performed on the immune regulatory module predicted NR4A (nuclear receptor 4A) subfamily (NR4A1, NR4A2, NR4A3) genes as the master transcriptional mediators of inflammation. Indeed, ChIP-sequencing analysis of cDCs supported that these NR4A members target numerous differentially expressed genes in SSc cDCs. Inclusion of NR4A receptor agonists in culture-based experiments provided functional proof that dysregulation of NR4As affects cytokine production by cDCs and modulates T-cells activation. Conclusions: NR4A1, NR4A2 and NR4A3 are important regulators of immunosuppressive and fibrosis-associated pathways in SSc cDCs. Thus, the NR4A family represent novel potential targets to restore cDC homeostasis in SSc.
2023-03-22 | GSE186197 | 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:Background. The etiology and reasons underlying the ethnic disparities in systemic sclerosis (SSc) remain unknown. African-Americans (AA) are disproportionally affected by SSc, yet dramatically underrepresented in research. The role of DNA methylation in disease risk remains unclear. This analysis was conducted to comprehensive identify differentially methylated loci associated with SSc in AA. Methods. Genomic DNA was isolated from cultured dermal fibroblasts isolated from 15 AA SSc cases and 15 AA controls. All patients met the 2013 ACR/EULAR classification criteria for SSc, most (93%) presenting with diffuse cutaneous SSc. DNA methylation patterns were profiled through reduced representation bisulfite sequencing (RRBS). Alignment and methylation calling were performed using Bismarck v0.16.3 and the GRCh37/hg19 reference genome. Data was filtered, normalized, and analyzed with RnBeads v1.6.1. Differential methylation analysis was conducted on CpG, promoter, gene and system level. Results. We generated DNA methylation data for over 5 million CpGs in each sample and between 10x to 40x coverage in CpGs sites. Using the Combined Score approach implemented in RnBeads, a total of 9 CpG islands, 17 genes and 11 promoters showed significant differential methylation levels between cases and controls at the gene-level. The top differentially methylated genes constitute mostly non-coding RNA genes (42%), followed by pseudogenes (27%), then protein coding genes (19%). Enrichment analysis revealed that both hypo- and hypermethylated genes and their promoter regions were enriched for cell differentiation and immune-related gene ontology terms (hypermethylated regions: mesenchymal cell transition and differentiation; hypomethylated regions: type I IFN signaling). Conclusion. The observed DNA methylation differences between cases and controls support a modest role for DNA methylation differences in mediating susceptibility to SSc in AA. Instead of protein-coding, most differentially methylated genes comprise non-coding RNA genes, supporting a larger contribution of dysregulated regulatory elements to disease. While previous DNA methylation profiling analyses in European-Americans reported an enrichment of extracellular matrix and focal adhesion genes, our data supports a potentially stronger immune-driven etiology in AA.
2021-01-19 | GSE150592 | GEO
Project description:Objectives: Scleroderma (systemic sclerosis, SSc), as a prototypic inflammation-driven fibrotic disease, possesses connective tissue lesions populated with persistently activated myofibroblasts maintained by an mechanotranductive/pro-adhesive signaling loop. Drugs targeting this pathway are therefore of likely therapeutic benefit. The mechanosensitive transcriptional co-activator, yes activated protein-1 (YAP1), is activated in SSc fibroblasts. The terpenoid celastrol has recently been identified as a YAP1 inhibitor: however, if celastrol can alleviate SSc fibrosis is unknown. Methods: Human dermal fibroblasts from healthy individuals and patients with diffuse cutaneous SSc were treated with or without transforming growth factor b1 (TGFb1) in the presence or absence of celastrol. C57BL6J mice were subjected to the inflammatory-driven bleomycin-induced model of skin SSc, in the presence or absence of celastrol. RNA expression was assessed using RNAseq, real-time polymerase chain reaction and spatial transcriptomic analyses. Protein expression was determined using Western blot and enzyme-linked immunosorbent assay. Fibrosis was monitored by hematoxylin and eosin and trichrome staining, and indirect immunofluorescence analysis. Results: In dermal fibroblasts, celastrol impaired the ability of TGFβ1 to induce an SSc-like pattern of gene expression, including the induction of cellular communication network factor 2 (CCN2), collagen I and TGFβ1 protein. Celastrol alleviated the persistent fibrotic phenotype of dermal fibroblasts cultured from lesions of SSc patients. In the bleomycin-induced model of SSc dermatopathology, celastrol inhibited fibrosis and blocked nuclear localization of YAP in myofibroblasts. Conclusion: Our data are consistent with the hypothesis that compounds, such as celastrol, that antagonize the YAP pathway may be potential treatments for SSc skin fibrosis.
2023-11-01 | GSE226760 | GEO