Project description:We here used whole blood gene expression profiling to differentiate SSc patients from healthy controls (HC) and to identify a specific gene expression and predictive genes for SSc-overlap syndromes.
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.
Project description:Murine GVH-SSc dorsal scapular skin samples were analyzed to determine the effect of IFNAR-1 inhibition on gene expression at day 14 and day 28. Gene expression in GVH-SSc skin from mice treated with a neutralizing IFNAR-1 antibody was compared to that in GVH-SSc skin from mice treated with isotype IgG, with skin from syngeneic graft controls as reference.
Project description:Murine GVH-SSc dorsal scapular skin samples were analyzed to determine the effect of IFNAR-1 inhibition on gene expression at day 14 and day 28. Gene expression in GVH-SSc skin from mice treated with a neutralizing IFNAR-1 antibody was compared to that in GVH-SSc skin from mice treated with isotype IgG, with skin from syngeneic graft controls as reference. For each timepoint, the following samples were analyzed: syngeneic control (n=4); GVH-SSc isotype (n=4); GVH-SSc anti-IFNAR-1 (n=4)
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.
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.
Project description:Human scleroderma skin derived fibroblast were treated with LiCL. This is a study of differential gene expression between LiCl treated SSc group and untreated SSc group.