title: High IL-17E and low IL-17C dermal expression identifies a fibrosis-specific motif common to morphea and systemic sclerosis.
abstract: BACKGROUND
  High interleukin (IL)-17A levels are characteristically found in the skin of systemic sclerosis (SSc) individuals. Our aim was to investigate whether the dermal expression of IL-17A and related IL-17 family members (i.e. IL-17C, IL-17E and IL-17F) could distinguish fibrotic from healthy skin and could show similarities in SSc and morphea, two disorders with presumed distinct pathogenesis, but characterized by skin fibrosis.
  
  
  METHODS
  Biopsies were obtained from the involved skin of 14 SSc, 5 morphea and 8 healthy donors (HD) undergoing plastic surgery. Immunohistochemistry/immunofluorescence techniques were coupled to a semi-automated imaging quantification approach to determine the presence of the IL-17 family members in the skin. The in vitro effects induced by the IL-17 family members on fibroblasts from normal and SSc individuals were assessed by ELISA and RIA.
  
  
  RESULTS
  Positive cells for each of the IL-17 isoforms investigated were present in the dermis of all the individuals tested, though with variable frequencies. SSc individuals had increased frequency of IL-17A+ (p = 0.0237) and decreased frequency of IL-17F+ (p = 0.0127) and IL-17C+ cells (p = 0.0008) when compared to HD. Similarly, morphea individuals had less frequent IL-17C+ cells (p = 0.0186) in their skin but showed similar number of IL-17A+ and IL-17F+ cells when compared to HD. Finally, IL-17E+ cells were more numerous in morphea (p = 0.0109) and tended to be more frequent in SSc than in HD. Fibroblast production of IL-6, MMP-1 and MCP-1 was enhanced in a dose-dependent manner in the presence of IL-17E and IL-17F, but not in the presence of IL-17C. None of the cytokine tested had significant effect on type I collagen production. Of interest, in SSc the frequency of both IL-17A and IL-17F positive cells increased with disease duration.
  
  
  CONCLUSIONS
  The frequency of IL-17A and IL-17F distinguish SSc to morphea individuals while dermal expression of IL-17C (low) and IL-17E (high) identifies a fibrosis-specific motif. The specific IL-17C/IL-17E cytokine combination may thus play a role in the development of fibrosis.
authors.affiliation: Immunology and Allergy, University Hospital and School of Medicine, Geneva, Switzerland; Experimental Laboratory of Immunological and Rheumatologic Researches, IRCSS Istituto Auxologico Italiano, Milan, Italy.
authors.forename: Paola Adele
authors.initials: PA
authors.lastname: Lonati
authors.affiliation: Immunology and Allergy, University Hospital and School of Medicine, Geneva, Switzerland; Dermatology, University Hospital and School of Medicine, Geneva, Switzerland.
authors.forename: Nicolò Costantino
authors.initials: NC
authors.lastname: Brembilla
authors.affiliation: Immunology and Allergy, University Hospital and School of Medicine, Geneva, Switzerland.
authors.forename: Elisa
authors.initials: E
authors.lastname: Montanari
authors.affiliation: Dermatology, University Hospital and School of Medicine, Geneva, Switzerland.
authors.forename: Lionel
authors.initials: L
authors.lastname: Fontao
authors.affiliation: Institute of Clinica Medica, Ancona, Italy.
authors.forename: Armando
authors.initials: A
authors.lastname: Gabrielli
authors.affiliation: Rheumatology, Department of Clinical and Experimental Medicine, Second University of Naples, Naples, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Vettori
authors.affiliation: Rheumatology, Department of Clinical and Experimental Medicine, Second University of Naples, Naples, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Valentini
authors.affiliation: Dermatology, University Hospital and School of Medicine, Geneva, Switzerland.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Laffitte
authors.affiliation: Dermatology, University Hospital and School of Medicine, Geneva, Switzerland.
authors.forename: Gurkan
authors.initials: G
authors.lastname: Kaya
authors.affiliation: Experimental Laboratory of Immunological and Rheumatologic Researches, IRCSS Istituto Auxologico Italiano, Milan, Italy; Division of Rheumatology, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
authors.forename: Pier-Luigi
authors.initials: PL
authors.lastname: Meroni
authors.affiliation: Immunology and Allergy, University Hospital and School of Medicine, Geneva, Switzerland.
authors.forename: Carlo
authors.initials: C
authors.lastname: Chizzolini
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D020405:Dermis / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012594:Scleroderma, Localized / Q000378:metabolism* / Q000473:pathology; D012595:Scleroderma, Systemic / Q000378:metabolism* / Q000473:pathology; D055815:Young Adult
chemical_list: D015415:Biomarkers; C486701:IL25 protein, human; D020381:Interleukin-17