title: Microarray study reveals a transforming growth factor-β-dependent mechanism of fibrosis in discoid lupus erythematosus.
abstract: BACKGROUND
  Discoid lupus erythematosus (DLE) is characterized by scarring lesions that develop and perpetuate fibrotic lesions. These are not observed in subacute cutaneous lupus erythematosus (SCLE). The pathophysiological basis of this is currently unknown.
  
  
  OBJECTIVE
  To identify contradistinctive signalling pathways and cellular signatures between the two type of lupus, with a focus on the molecular mechanisms leading to fibrosis.
  
  
  METHODS
  We conducted a gene expression microarray analysis in lesional and nonlesional skin biopsy specimens of patients with DLE (n = 10) and SCLE (n = 10). Confirmatory reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry were performed on selected transcripts in a new cohort of paraffin-embedded skin biopsies (n = 20). Changes over time of a group of selected inflammatory and fibrotic genes were also evaluated in a second biopsy taken 12 weeks later. In vitro functional studies were performed in primary isolated fibroblasts.
  
  
  RESULTS
  Compared with nonlesional skin, DLE samples expressed a distinctive T-cell gene signature. DLE samples displayed a significant CD4 T-cell enrichment with an imbalance towards T helper 1 cytokine predominance and a relative increased forkhead box (FOX)P3 response. RT-qPCR and immunochemical analysis over time showed a progressive increment of fibrotic markers and persistent FOXP3 recruitment. Ex vivo upregulation of SERPINE1, MMP9, TGFBR1, phosphorylated SMAD3 and TGFB1 suggested a transforming growth factor (TGF)-β-dependent mechanism of fibrosis in DLE, also confirmed by the results observed following in vitro stimulation with TGF-β.
  
  
  CONCLUSIONS
  These results highlight major pathogenic pathways in DLE and provide novel molecular targets for the development of new therapies. The data suggest the existence of a TGF-β-dependent pathway inducing fibrosis in DLE.
authors.affiliation: Department of Medicine, Systemic Autoimmune Diseases Unit, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Solé
authors.affiliation: Department of Immunology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Gimenez-Barcons
authors.affiliation: Department of Pathology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Ferrer
authors.affiliation: Department of Medicine, Systemic Autoimmune Diseases Unit, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Ordi-Ros
authors.affiliation: Department of Medicine, Systemic Autoimmune Diseases Unit, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Cortés-Hernández
mesh_terms: D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology; D005355:Fibrosis / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D008178:Lupus Erythematosus, Cutaneous / Q000235:genetics* / Q000378:metabolism; D008179:Lupus Erythematosus, Discoid / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000378:metabolism / Q000473:pathology*; D051900:Smad3 Protein / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism / Q000502:physiology; D046888:Tissue Array Analysis; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D005819:Genetic Markers; D017395:Plasminogen Activator Inhibitor 1; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins; C051321:SERPINE1 protein, human; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human