title: The interferon type I signature is present in systemic sclerosis before overt fibrosis and might contribute to its pathogenesis through high BAFF gene expression and high collagen synthesis.
abstract: Interferon (IFN) signature has been reported in definite systemic sclerosis (SSc) but it has not been characterised in early SSc (EaSSc). We aim at characterising IFN type I signature in SSc before overt skin fibrosis develops.
  
  
  
  The expression of 11 IFN type I inducible genes was tested in whole-blood samples from 30 healthy controls (HCs), 12 subjects with primary Raynaud's phenomenon (RP), 19 patients with EaSSc, 7 patients with definite SSc without cutaneous fibrosis, 21 limited cutaneous SSc and 10 diffuse cutaneous SSc subjects. The correlation between IFN activity in monocytes, B cell activating factor (BAFF) mRNA expression and type III procollagen N-terminal propeptide (PIIINP) serum levels was tested.
  
  
  
  In all the SSc groups, higher IFN scores were observed compared with HC. An IFN score ≥7.09 discriminated HCs from patients with SSc (sensitivity=0.7, specificity=0.88, area under receiving operating characteristic (AUROC)=0.82); the prevalence of an elevated IFN score was: HC=3.3%; RP=33.3%, EaSSc=78.9%, definite SSc=100%, limited cutaneous SSc=42.9%, diffuse cutaneous SSc=70.0%. In monocytes an IFN score ≥4.12 distinguished HCs from patients with fibrotic SSc (sensitivity=0.62, specificity=0.85, AUROC=0.76). Compared with IFN-negative subjects, IFN-positive subjects had higher monocyte BAFF mRNA levels (19.7±5.2 vs 15.20±4.0, p=2.1×10(-5)) and serum PIIINP levels (median=6.0 (IQR 5.4-8.9) vs median=3.9 (IQR 3.3-4.7), p=0.0004).
  
  
  
  An IFN type I signature is observed in patients with SSc from the earliest phases of the disease, even before overt skin fibrosis. The presence of IFN type I signature in monocytes is correlated with BAFF mRNA expression and serum PIIINP levels, supporting a contribution in the pathogenesis and progression of SSc.
authors.affiliation: Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Zana
authors.initials: Z
authors.lastname: Brkic
authors.affiliation: Department of Rheumatology, Clinical Immunology and Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands Department of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Lenny
authors.initials: L
authors.lastname: van Bon
authors.affiliation: Department of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Cossu
authors.affiliation: Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Cornelia G
authors.initials: CG
authors.lastname: van Helden-Meeuwsen
authors.affiliation: Department of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Madelon C
authors.initials: MC
authors.lastname: Vonk
authors.affiliation: Department of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Hanneke
authors.initials: H
authors.lastname: Knaapen
authors.affiliation: Department of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: van den Berg
authors.affiliation: Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Virgil A
authors.initials: VA
authors.lastname: Dalm
authors.affiliation: Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Van Daele
authors.affiliation: Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Severino
authors.affiliation: Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Naomi I
authors.initials: NI
authors.lastname: Maria
authors.affiliation: Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Samara
authors.initials: S
authors.lastname: Guillen
authors.affiliation: Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Willem A
authors.initials: WA
authors.lastname: Dik
authors.affiliation: Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Beretta
authors.affiliation: Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Marjan A
authors.initials: MA
authors.lastname: Versnel
authors.affiliation: Department of Rheumatology, Clinical Immunology and Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Timothy
authors.initials: T
authors.lastname: Radstake
mesh_terms: D000328:Adult; D000368:Aged; D053264:B-Cell Activating Factor / Q000096:biosynthesis* / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D005355:Fibrosis; D005786:Gene Expression Regulation; D006801:Humans; D007370:Interferon Type I / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D010446:Peptide Fragments / Q000096:biosynthesis / Q000097:blood; D011347:Procollagen / Q000096:biosynthesis / Q000097:blood; D012333:RNA, Messenger / Q000235:genetics; D012595:Scleroderma, Systemic / Q000235:genetics* / Q000378:metabolism; D012867:Skin / Q000473:pathology; D059467:Transcriptome
chemical_list: D053264:B-Cell Activating Factor; D007370:Interferon Type I; D010446:Peptide Fragments; D011347:Procollagen; D012333:RNA, Messenger; C505719:TNFSF13B protein, human; C041876:procollagen Type III-N-terminal peptide
keywords: Autoimmune Diseases; Cytokines; Inflammation; Systemic Sclerosis