Microbiome dysbiosis is associated with disease duration and increased inflammatory gene expression in systemic sclerosis skin.
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ABSTRACT:
SUBMITTER: Johnson ME
PROVIDER: S-EPMC6366065 | biostudies-literature | 2019 Feb
REPOSITORIES: biostudies-literature
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Project description:ObjectiveTo examine the heterogeneity of global transcriptome patterns in systemic sclerosis (SSc) skin in a large sample of patients with SSc and control subjects.MethodsSkin biopsy specimens obtained from 61 patients enrolled in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) cohort and 36 unaffected control subjects with a similar demographic background were examined by Illumina HumanHT-12 bead arrays. Followup experiments using quantitative polymerase chain reaction and immunohistochemical analysis were also performed.ResultsWe identified 2,754 differentially expressed transcripts in SSc patients compared with controls. Clustering analysis revealed 2 prominent transcriptomes in SSc patients: the keratin and fibroinflammatory signatures. Higher keratin transcript scores were associated with shorter disease duration and interstitial lung disease, while higher fibroinflammatory scores were associated with diffuse cutaneous involvement, a higher skin score at the biopsy site, and a higher modified Rodnan skin thickness score. A subgroup of patients with significantly longer disease duration had a normal-like transcript pattern. Analysis of cell type-specific signature scores revealed remarkable heterogeneity across patients. Significantly higher scores were calculated for fibroblasts (72% of patients), microvascular cells (61%), macrophages (54%), and dendritic cells (DCs) (49%). The majority of samples with significantly higher fibroblast scores (35 of 44 [80%]) had significantly increased macrophage and/or DC scores. Further analysis and immunohistochemical staining indicated that the keratin signature was not a general marker of keratinocyte activation but was in fact associated with an activation pattern in hair and adnexal structures.ConclusionProminent fibroinflammatory and keratin signatures are present in SSc skin. Expression profiles of SSc skin show significant heterogeneity, and this finding might be useful for stratifying patients for targeted therapies or predicting the response to immunosuppression.
| S-EPMC5394431 | biostudies-literature
Project description:ObjectivesDetermine global skin transcriptome patterns of early diffuse systemic sclerosis (SSc) and how they differ from later disease.MethodsSkin biopsy RNA from 48 patients in the Prospective Registry for Early Systemic Sclerosis (PRESS) cohort (mean disease duration 1.3 years) and 33 matched healthy controls was examined by next-generation RNA sequencing. Data were analysed for cell type-specific signatures and compared with similarly obtained data from 55 previously biopsied patients in Genetics versus Environment in Scleroderma Outcomes Study cohort with longer disease duration (mean 7.4 years) and their matched controls. Correlations with histological features and clinical course were also evaluated.ResultsSSc patients in PRESS had a high prevalence of M2 (96%) and M1 (94%) macrophage and CD8 T cell (65%), CD4 T cell (60%) and B cell (69%) signatures. Immunohistochemical staining of immune cell markers correlated with the gene expression-based immune cell signatures. The prevalence of immune cell signatures in early diffuse SSc patients was higher than in patients with longer disease duration. In the multivariable model, adaptive immune cell signatures were significantly associated with shorter disease duration, while fibroblast and macrophage cell type signatures were associated with higher modified Rodnan Skin Score (mRSS). Immune cell signatures also correlated with skin thickness progression rate prior to biopsy, but did not predict subsequent mRSS progression.ConclusionsSkin in early diffuse SSc has prominent innate and adaptive immune cell signatures. As a prominently affected end organ, these signatures reflect the preceding rate of disease progression. These findings could have implications in understanding SSc pathogenesis and clinical trial design.
| S-EPMC7386329 | biostudies-literature
Project description:ObjectiveWe undertook this hypothesis-generating study to identify skin transcripts correlating with severity of interstitial lung disease (ILD) in systemic sclerosis (SSc).MethodsSkin biopsy samples from 59 patients enrolled in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) cohort or an open-label imatinib study (baseline visit) were examined by global gene expression analysis using Illumina HT-12 arrays. Skin transcripts correlating with concomitantly obtained forced vital capacity (FVC) values and the modified Rodnan skin thickness score (MRSS) were identified by quantitative trait analysis. Also, immunofluorescence staining for selected transcripts was performed in affected skin and lung tissue. Plasma levels of CCL2, soluble SELP, and soluble P-selectin glycoprotein ligand 1 (sPSGL-1) were examined in all patients enrolled in the GENISOS cohort (n = 266).ResultsEighty-two skin transcripts correlated significantly with FVC. This gene list distinguished patients with more severe ILD (FVC <70% predicted) in unsupervised hierarchical clustering analysis (P < 0.001). These genes included SELP, CCL2, and matrix metalloproteinase 3, which are involved in extravasation and adhesion of inflammatory cells. Among the FVC correlates, 8 genes (CCL2, HAPLN3, GPR4, ADCYAP1, WARS, CDC25B, PLP1, and STXBP6) also correlated with the MRSS. Immunofluorescence staining revealed that SELP and CCL2 were also overexpressed in affected skin and lung tissue from SSc patients compared to those from controls. Plasma levels of CCL2 and sPSGL-1 correlated with concomitantly obtained FVC values (r = -0.22, P = 0.001 and r = 0.17, P = 0.015, respectively). This relationship was independent of potential confounders (age, sex, ethnicity, smoking status, anti-topoisomerase I positivity, treatment with immunosuppressive agents, MRSS, disease type, and disease duration).ConclusionA limited number of skin transcripts including genes involved in extravasation and adhesion of inflammatory cells correlate with severity of ILD.
| S-EPMC3898704 | biostudies-literature
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:BackgroundThe microbiome alterations are associated with cancer growth and may influence the immune system and response to therapy. Particularly, the gut microbiome has been recently shown to modulate response to melanoma immunotherapy. However, the role of the skin microbiome has not been well explored in the skin tumour microenvironment and the link between the gut microbiome and skin microbiome has not been investigated in melanoma progression. Therefore, the aim of the present study was to examine associations between dysbiosis in the skin and gut microbiome and the melanoma growth using MeLiM porcine model of melanoma progression and spontaneous regression.ResultsParallel analysis of cutaneous microbiota and faecal microbiota of the same individuals was performed in 8 to 12 weeks old MeLiM piglets. The bacterial composition of samples was analysed by high throughput sequencing of the V4-V5 region of the 16S rRNA gene. A significant difference in microbiome diversity and richness between melanoma tissue and healthy skin and between the faecal microbiome of MeLiM piglets and control piglets were observed. Both Principal Coordinate Analysis and Non-metric multidimensional scaling revealed dissimilarities between different bacterial communities. Linear discriminant analysis effect size at the genus level determined different potential biomarkers in multiple bacterial communities. Lactobacillus, Clostridium sensu stricto 1 and Corynebacterium 1 were the most discriminately higher genera in the healthy skin microbiome, while Fusobacterium, Trueperella, Staphylococcus, Streptococcus and Bacteroides were discriminately abundant in melanoma tissue microbiome. Bacteroides, Fusobacterium and Escherichia-Shigella were associated with the faecal microbiota of MeLiM piglets. Potential functional pathways analysis based on the KEGG database indicated significant differences in the predicted profile metabolisms between the healthy skin microbiome and melanoma tissue microbiome. The faecal microbiome of MeLiM piglets was enriched by genes related to membrane transports pathways allowing for the increase of intestinal permeability and alteration of the intestinal mucosal barrier.ConclusionThe associations between melanoma progression and dysbiosis in the skin microbiome as well as dysbiosis in the gut microbiome were identified. Results provide promising information for further studies on the local skin and gut microbiome involvement in melanoma progression and may support the development of new therapeutic approaches.
| S-EPMC8881828 | biostudies-literature
Project description:ObjectiveAt present, there are no clinical or laboratory measures that accurately forecast the progression of skin fibrosis and organ involvement in patients with systemic sclerosis (SSc). The goal of this study was to identify skin biomarkers that could be prognostic for the progression of skin fibrosis in patients with early diffuse cutaneous SSc (dcSSc).MethodsWe analyzed clinical data and gene expression in skin biopsy samples from 38 placebo-treated patients, part of the Roche Safety and Efficacy of Subcutaneous Tocilizumab in Adults with Systemic Sclerosis (FASSCINATE) phase II study of tocilizumab in SSc. RNA samples were analyzed using nCounter. A trajectory model based on a modified Rodnan skin thickness score was used to describe 3 skin disease trajectories over time. We examined the association of skin gene expression with skin score trajectory groups, by chi-square test. Logistic regression was used to examine the prognostic power of each gene identified.ResultsWe found that placebo-treated patients with high expression of messenger RNA for CD14, SERPINE1, IL13RA1, CTGF, and OSMR at baseline were more likely to have progressive skin score trajectories. We also found that those genes were prognostic for the risk of skin progression and that IL13RA1, OSMR, and SERPINE1 performed the best.ConclusionSkin gene expression of biomarkers associated with macrophages (CD14, IL13RA1) and transforming growth factor β activation (SERPINE1, CTGF, OSMR) are prognostic for progressive skin disease in patients with dcSSc. These biomarkers may provide guidance in decision-making about which patients should be considered for aggressive therapies and/or for clinical trials.
| S-EPMC6731768 | biostudies-literature
Project description:Skin biopsy gene expression was analyzed by DNA microarray from 13 diffuse cutaneous systemic sclerosis (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" gene expression subsets described previously, including fibroproliferative, inflammatory, and normal-like groups. Serial skin biopsies showed consistent and non-progressing gene expression over time, and importantly, the patients in the inflammatory subset do not move to the fibroproliferative subset, and vice versa. 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. Collectively, these data emphasize the heterogeneous nature of SSc and demonstrate that the intrinsic subsets are an inherent, reproducible, and stable feature of the disease that is independent of disease duration. Moreover, these data have fundamental importance for the future development of personalized therapy for SSc; drugs targeting inflammation are likely to benefit those patients with an inflammatory signature, whereas drugs targeting fibrosis are likely to benefit those with a fibroproliferative signature.
| S-EPMC3326181 | biostudies-literature
Project description:Fewer than half of patients with systemic sclerosis demonstrate modified Rodnan skin score improvement during mycophenolate mofetil (MMF) treatment. To understand the molecular basis for this observation, we extended our prior studies and characterized molecular and cellular changes in skin biopsies from subjects with systemic sclerosis treated with MMF. Eleven subjects completed ≥24 months of MMF therapy. Two distinct skin gene expression trajectories were observed across six of these subjects. Three of the six subjects showed attenuation of the inflammatory signature by 24 months, paralleling reductions in CCL2 mRNA expression in skin and reduced numbers of macrophages and myeloid dendritic cells in skin biopsies. MMF cessation at 24 months resulted in an increased inflammatory score, increased CCL2 mRNA and protein levels, modified Rodnan skin score rebound, and increased numbers of skin myeloid cells in these subjects. In contrast, three other subjects remained on MMF >24 months and showed a persistent decrease in inflammatory score, decreasing or stable modified Rodnan skin score, CCL2 mRNA reductions, sera CCL2 protein levels trending downward, reduction in monocyte migration, and no increase in skin myeloid cell numbers. These data summarize molecular changes during MMF therapy that suggest reduction of innate immune cell numbers, possibly by attenuating expression of chemokines, including CCL2.
| S-EPMC6590516 | biostudies-literature
Project description:Recent studies in mice have demonstrated that the protein tyrosine phosphatase SHP-1 is a crucial negative regulator of cytokine signaling, inflammatory gene expression, and demyelination in central nervous system. The present study investigates a possible similar role for SHP-1 in the human disease multiple sclerosis (MS). The levels of SHP-1 protein and mRNA in PBMCs of MS patients were significantly lower compared to normal subjects. Moreover, promoter II transcripts, expressed from one of two known promoters, were selectively deficient in MS patients. To examine functional consequences of the lower SHP-1 in PBMCs of MS patients, we measured the intracellular levels of phosphorylated STAT6 (pSTAT6). As expected, MS patients had significantly higher levels of pSTAT6. Accordingly, siRNA to SHP-1 effectively increased the levels of pSTAT6 in PBMCs of controls to levels equal to MS patients. Additionally, transduction of PBMCs with a lentiviral vector expressing SHP-1 lowered pSTAT6 levels. Finally, multiple STAT6-responsive inflammatory genes were increased in PBMCs of MS patients relative to PBMCs of normal subjects. Thus, PBMCs of MS patients display a stable deficiency of SHP-1 expression, heightened STAT6 phosphorylation, and an enhanced state of activation relevant to the mechanisms of inflammatory demyelination.
| S-EPMC2883308 | biostudies-literature
Project description:Cortical tubers in patients with tuberous sclerosis complex are associated with disabling neurological manifestations, including intractable epilepsy. While these malformations are believed to result from the effects of TSC1 or TSC2 gene mutations, the molecular mechanisms leading to tuber formation, as well as the onset of seizures, remain largely unknown. We used the Affymetrix Gene Chip platform to provide the first genome-wide investigation of gene expression in surgically resected tubers, compared with histological normal perituberal tissue from the same patients or autopsy control tissue. We identified 2501 differentially expressed genes in cortical tubers compared with autopsy controls. Expression of genes associated with cell adhesion, for example, VCAM1, integrins and CD44, or with the inflammatory response, including complement factors, serpinA3, CCL2 and several cytokines, was increased in cortical tubers, whereas genes related to synaptic transmission, for example, the glial glutamate transporter GLT-1, and voltage-gated channel activity, exhibited lower expression. Gene expression in perituberal cortex was distinct from autopsy control cortex suggesting that even in the absence of tissue pathology the transcriptome is altered in TSC. Changes in gene expression yield insights into new candidate genes that may contribute to tuber formation or seizure onset, representing new targets for potential therapeutic development.
| S-EPMC2888867 | biostudies-literature