title: Experimentally-derived fibroblast gene signatures identify molecular pathways associated with distinct subsets of systemic sclerosis patients in three independent cohorts.
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.
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH, United States of America.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Johnson
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH, United States of America.
authors.forename: J Matthew
authors.initials: JM
authors.lastname: Mahoney
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH, United States of America.
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Taroni
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH, United States of America.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Sargent
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH, United States of America.
authors.forename: Eleni
authors.initials: E
authors.lastname: Marmarelis
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH, United States of America.
authors.forename: Ming-Ru
authors.initials: MR
authors.lastname: Wu
authors.affiliation: Northwestern University Feinberg School of Medicine, Department of Internal Medicine, Division of Rheumatology, Chicago, IL, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Varga
authors.affiliation: Northwestern University Feinberg School of Medicine, Department of Internal Medicine, Division of Rheumatology, Chicago, IL, United States of America.
authors.forename: Monique E
authors.initials: ME
authors.lastname: Hinchcliff
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH, United States of America.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Whitfield
mesh_terms: D016022:Case-Control Studies; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D008297:Male; D012595:Scleroderma, Systemic / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction