Intrinsic Gene Expression Subsets of Diffuse Cutaneous Systemic Sclerosis Are Stable in Serial Skin Biopsies

Department of Genetics, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
Journal of Investigative Dermatology (Impact Factor: 6.37). 02/2012; 132(5):1363-73. DOI: 10.1038/jid.2011.472
Source: PubMed

ABSTRACT 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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Clinical diversity in systemic sclerosis (SSc) reflects multifaceted pathogenesis and the effect of key growth factors or cytokines operating within a disease-specific microenvironment. Dermal interstitial fluid sampling offers the potential to examine local mechanisms and identify proteins expressed within lesional tissue. We used multiplex cytokine analysis to profile the inflammatory and immune activity in the lesions of SSc patients. Dermal interstitial fluid sample from the involved forearm skin, and synchronous plasma samples were collected from SSc patients (n = 26, diffuse cutaneous SSc (DcSSc) n = 20, limited cutaneous SSc (LcSSc) n = 6), and healthy controls (HC) (n = 10) and profiled by Luminex® array for inflammatory cytokines, chemokines, and growth factors. Luminex® profiling of the dermal blister fluid showed increased inflammatory cytokines (median interleukin ( IL)-6 in SSc 39.78 pg/ml, HC 5.51 pg/ml, p = 0.01,median IL-15 in SSc 6.27 pg/ml, HC 4.38 pg/ml, p = 0.03), chemokines (monocyte chemotactic protein (MCP)-3 9.81 pg/ml in SSc, 7.18 pg/ml HC, p = 0.04), and profibrotic growth factors (platelet derived growth factor (PDGF)-AA 10.38 pg/ml versus 6.94 pg/ml in HC, p = 0.03). In general dermal fluid and plasma cytokine levels did not correlate, consistent with predominantly local production of these factors within the dermal lesions, rather than leakage from the serum. In hierarchical clustering and network analysis IL-6 emerged as a key central mediator. Our data confirm that an immuno-inflammatory environment and aberrant vascular repair are intimately linked to fibroblast activation in lesional skin in SSc. This non-invasive method could be used to profile disease activity in the clinic, and identifies key inflammatory or pro-fibrotic proteins that might be targeted therapeutically. Distinct subgroups of SSc may be defined that show innate or adaptive immune cytokine signatures.
    Arthritis research & therapy 03/2015; 17(1):73. DOI:10.1186/s13075-015-0575-8 · 4.12 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Significant advances have been made in understanding the genetic basis of systemic sclerosis (SSc) in recent years. Genomewide association and other large-scale genetic studies have identified 30 largely immunity-related genes which are significantly associated with SSc. We review these studies, along with genomewide expression studies, proteomic studies, genetic mouse models, and insights from rare sclerodermatous diseases. Collectively, these studies have begun to identify pathways that are relevant to SSc pathogenesis. The findings presented in this review illustrate how both genetic and genomic aberrations play important roles in the development of SSc. However, despite these recent discoveries, there remain major gaps between current knowledge of SSc, a unified understanding of pathogenesis, and effective treatment. To this aim, we address the important issue of SSc heterogeneity and discuss how future research needs to address this in order to develop a clearer understanding of this devastating and complex disease.
    Current Rheumatology Reports 03/2015; 17(3):484. DOI:10.1007/s11926-014-0484-x · 2.45 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Genome-wide expression profiling in systemic sclerosis (SSc) has identified four 'intrinsic' subsets of disease (fibroproliferative, inflammatory, limited, and normal-like), each of which shows deregulation of distinct signaling pathways; however, the full set of pathways contributing to this differential gene expression has not been fully elucidated. Here we examine experimentally derived gene expression signatures in dermal fibroblasts for thirteen different signaling pathways implicated in SSc pathogenesis. These data show distinct and overlapping sets of genes induced by each pathway, allowing for a better understanding of the molecular relationship between profibrotic and immune signaling networks. Pathway-specific gene signatures were analyzed across a compendium of microarray datasets consisting of skin biopsies from three independent cohorts representing 80 SSc patients, 4 morphea, and 26 controls. IFNα signaling showed a strong association with early disease, while TGFβ signaling spanned the fibroproliferative and inflammatory subsets, was associated with worse MRSS, and was higher in lesional than non-lesional skin. The fibroproliferative subset was most strongly associated with PDGF signaling, while the inflammatory subset demonstrated strong activation of innate immune pathways including TLR signaling upstream of NF-κB. The limited and normal-like subsets did not show associations with fibrotic and inflammatory mediators such as TGFβ and TNFα. The normal-like subset showed high expression of genes associated with lipid signaling, which was absent in the inflammatory and limited subsets. Together, these data suggest a model by which IFNα is involved in early disease pathology, and disease severity is associated with active TGFβ signaling.
    PLoS ONE 01/2015; 10(1):e0114017. DOI:10.1371/journal.pone.0114017 · 3.53 Impact Factor

Full-text (2 Sources)

Available from
May 21, 2014