IgG from systemic sclerosis patients induce a profibrosing and serotype-dependent phenotype in normal dermal fibroblast: a multi-omics study
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE178299 | GEO | 2022/06/07
REPOSITORIES: GEO
Similar Datasets
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.
2022-06-29 | PXD025885 | Pride
Project description:Objectives: Eph/Ephrin cell-cell signaling is emerging as a key player in tissue fibrogenesis. The aim of this study was to test the hypothesis that the receptor tyrosine kinase EphB2 mediates dermal fibrosis in systemic sclerosis (SSc). Methods: We assessed normal and SSc human skin biopsies for EphB2 expression. The in vivo role of EphB2 in skin fibrosis was investigated by subjecting EphB2-knockout mice to both bleomycin-induced and tight skin (Tsk1/+) genetic mouse models. EphB2 kinase-dead and overactive point mutant mice were used to evaluate the role of EphB2 forward signaling in bleomycin-induced dermal fibrosis. In vitro studies were performed on dermal fibroblasts from SSc patients and healthy controls, which was followed by in vivo analysis of fibroblast-specific EphB2 deficient mice. Results: Expression of EphB2 is upregulated in SSc skin tissue and explanted SSc dermal fibroblasts compared to healthy controls. EphB2 expression is elevated in two animal models of dermal fibrosis. In mice, EphB2 drives dermal fibrosis in both the bleomycin and the Tsk1/+ models of skin fibrosis. EphB2 forward signaling is a critical mediator of dermal fibrosis. Transforming growth factor-β (TGFβ) cytokines upregulate EphB2 in dermal fibroblasts via non-canonical TGFβ/SMAD signaling and silencing EphB2 in dermal fibroblasts is sufficient to dampen TGFβ-induced fibroblast-to-myofibroblast differentiation. Moreover, mice with fibroblast-specific deletion of EphB2 showed impaired fibroblast-to-myofibroblast differentiation and reduced skin fibrosis upon bleomycin challenge. Conclusion: Our data implicate EphB2 overexpression and kinase-mediated forward signaling in the development of dermal fibrosis in SSc. EphB2 thus represents a potential new therapeutic target for SSc.
2024-04-10 | GSE253089 | GEO
Project description:IgG from systemic sclerosis patients induce a profibrosing and serotype-dependent phenotype in normal dermal fibroblast: a multi-omics study
| PRJNA738391 | ENA
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:Aberrant deposition of extracellular matrix (ECM) resulting in dermal fibrosis is a hallmark of systemic sclerosis (SSc). Evidence suggests that dysfunctional SSc keratinocytes may contribute to fibrosis by altering dermal homeostasis. Whether interleukin-25 (IL-25), an IL-17 family member involved in epithelial/mesenchymal/immune cell interplay takes part in skin fibrosis is unknown. Here we address the role of IL-25 in SSc skin fibrosis. Compared to healthy donor (HD), in SSc and scleroderma-like disorders the epidermis expressed significantly lower levels of IL-25. In epidermal equivalents, IL-25 regulated several molecular pathways related to wound healing and ECM remodeling. Compared to control conditioned medium (CM), the CM from IL-25-primed keratinocytes enhanced the production by fibroblasts of matrix metalloproteinase-1 (MMP-1), IL-6, IL-8 (p< 0.05), but not of type-I collagen (Col-I ) nor fibronectin. However, IL- 25 significantly reduced the production of Col-I when applied directly to fibroblasts. The activation of keratinocytes by IL-25 was receptor-dependent and evident after a very short incubation time (10 min), largely mediated by IL-1, suggesting enhanced and specific release of preformed mediators. These results show that IL-25 participates to skin homeostasis and its decreased expression in SSc may contribute to skin fibrosis by favoring ECM deposition over degradation.
2022-03-31 | GSE168312 | GEO
Project description:Systemic scleroderma (SSc) is an autoimmune disease which results in fibrotic production in the lung. Resultant SSC-pulmonary fibrosis is the main cause of mortality among SSc patients. From high throughput RNAi screening, we uncovered the ubiquitin E3 ligase KLHL42 as a potential pro-fibrotic mediator of TGFb-dependent fibrotic signaling in primary SSc lung fibroblasts. In this analysis, we sought to uncover putative substrates for KLHL42 by comparing SSc lung fibroblasts with control or KLHL42 siRNA prior to TGFb-treatment, lysis, and TUBE precipitation. The resultant pull-down was analyzed with LC-MS/MS.
2020-01-14 | MSV000084800 | MassIVE
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.
2017-01-01 | GSE76806 | GEO
Project description:Systemic sclerosis (SSc) is a perplexing autoimmune disorder, characterized by mysterious causes, high mortality rates, and a lack of effective treatments. The role of abnormal glycosylation in the onset of autoimmune diseases has been recognized for some time. Nonetheless, the intricate details of intact glycopeptides in SSc remain elusive owing to challenges in their detection. In this study, we characterized plasma immunoglobulin G (IgG) intact N-glycopeptides from 30 SSc patients and 30 healthy controls (HCs) via our recently developed intact glycopeptide analysis method GlycoQuant. Twelve differentially expressed intact N-glycopeptides were identified. The correlation of specific intact N-glycopeptides with the clinical features of SSc patients was analyzed. The results revealed a notable increase in the levels of 6 intact N-glycopeptides (IgG2-N3H3F1, IgG2-N3H4F1, IgG2-N4H4F1, IgG2-N4H5F1, IgG2-N5H4F1, and IgG2-N5H5F1) and a decrease in the levels of another set of 6 intact N-glycopeptides (IgG1-N4H3F1, IgG2-N3H6F1A1, IgG2-N4H4F1A1, IgG2-N5H3F1, IgG3-N4H3F1, and IgG3-N4H4F1). These changes in the levels of intact N-glycopeptides are associated with various aspects of SSc, including disease progression, cardiovascular involvement and C-reactive protein in the peripheral blood. In summary, this study offers a detailed overview of the intact N-glycopeptide profile in the peripheral blood of patients with SSc, providing valuable insights that could propel further research into SSc.
2024-11-05 | PXD057509 |
Project description:Systemic sclerosis (SSc) is an autoimmune, connective tissue disease characterized by vasculopathy and fibrosis of the skin and internal organs. Trends in efficacy outcome measures favored tofacitnib. Baseline gene expression in fibroblast and keratinocyte subpopulations indicates interferon (IFN) activated gene expression.
2022-07-26 | GSE209635 | GEO