title: Physiological evidence for diversification of IFNα- and IFNβ-mediated response programs in different autoimmune diseases.
abstract: BACKGROUND
  Activation of the type I interferon (IFN) response program is described for several autoimmune diseases, including systemic lupus erythematosus (SLE), multiple sclerosis (MS), myositis (IIM) and rheumatoid arthritis (RA). While IFNα contributes to SLE pathology, IFNβ therapy is often beneficial in MS, implying different immunoregulatory roles for these IFNs. This study was aimed to investigate potential diversification of IFNα-and IFNβ-mediated response programs in autoimmune diseases.
  
  
  METHODS
  Peripheral blood gene expression of 23 prototypical type I IFN response genes (IRGs) was determined in 54 healthy controls (HCs), 69 SLE (47 test, 22 validation), 149 IFNβ-treated MS (71 test, 78 validation), 160 untreated MS, 78 IIM and 76 RA patients. Patients with a type I IFN signature were selected for analysis.
  
  
  RESULTS
  We identified IFNα- and IFNβ-specific response programs (GC-A and GC-B, respectively) in SLE and IFNβ-treated MS patients. Concordantly, the GC-A/GC-B log-ratio was positive for all SLE patients and negative for virtually all IFNβ-treated MS patients, which was confirmed in additional cohorts. Applying this information to other autoimmune diseases, IIM patients displayed positive GC-A/GC-B log-ratios, indicating predominant IFNα activity. The GC-A/GC-B log-ratio in RA was lower and approached zero in part of the patients, implying relative importance of both clusters. Remarkably, GC-A/GC-B log-ratios appeared most heterogeneous in untreated MS; half of the patients displayed GC-A dominance, whereas others showed GC-B dominance or log-ratios near zero.
  
  
  CONCLUSIONS
  Our findings show diversification of the type I IFN response in autoimmune diseases, suggesting different pathogenic roles of the type I IFNs.
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands. td.dejong@vumc.nl.
authors.forename: Tamarah D
authors.initials: TD
authors.lastname: de Jong
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands. s.vosslamber@vumc.nl.
authors.forename: Saskia
authors.initials: S
authors.lastname: Vosslamber
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands. e.mantel@vumc.nl.
authors.forename: Elise
authors.initials: E
authors.lastname: Mantel
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands. s.deridder@vumc.nl.
authors.forename: Sander
authors.initials: S
authors.lastname: de Ridder
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands. j.g.wesseling@durrercenter.nl.
authors.forename: John G
authors.initials: JG
authors.lastname: Wesseling
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands. t.vanderpouwkraan@vumc.nl.
authors.forename: Tineke C T M
authors.initials: TC
authors.lastname: van der Pouw Kraan
authors.affiliation: Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands. c.leurs@vumc.nl.
authors.forename: Cyra
authors.initials: C
authors.lastname: Leurs
authors.affiliation: Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. harald.hegen@i-med.ac.at.
authors.forename: Harald
authors.initials: H
authors.lastname: Hegen
authors.affiliation: Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. Florian.Deisenhammer@tirol-kliniken.at.
authors.forename: Florian
authors.initials: F
authors.lastname: Deisenhammer
authors.affiliation: Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands. j.killestein@vumc.nl.
authors.forename: Joep
authors.initials: J
authors.lastname: Killestein
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden. Ingrid.Lundberg@ki.se.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Lundberg
authors.affiliation: Institute of Rheumatology, Prague, Czech Republic. vencovsky@revma.cz.
authors.forename: Jiri
authors.initials: J
authors.lastname: Vencovsky
authors.affiliation: Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, Reade, Amsterdam, The Netherlands. m.nurmohamed@reade.nl.
authors.forename: Mike T
authors.initials: MT
authors.lastname: Nurmohamed
authors.affiliation: Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, Reade, Amsterdam, The Netherlands. d.v.schaardenburg@reade.nl.
authors.forename: Dirkjan
authors.initials: D
authors.lastname: van Schaardenburg
authors.affiliation: Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, VUmc, Amsterdam, The Netherlands. IEM.Bultink@vumc.nl.
authors.forename: Irene E M
authors.initials: IE
authors.lastname: Bultink
authors.affiliation: Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, VUmc, Amsterdam, The Netherlands. AE.Voskuyl@vumc.nl.
authors.forename: Alexandre E
authors.initials: AE
authors.lastname: Voskuyl
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands. d.pegtel@vumc.nl.
authors.forename: D Michiel
authors.initials: DM
authors.lastname: Pegtel
authors.affiliation: Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, VUmc, Amsterdam, The Netherlands. J.vanderLaken@vumc.nl.
authors.forename: Conny J
authors.initials: CJ
authors.lastname: van der Laken
authors.affiliation: Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, Reade, Amsterdam, The Netherlands. j.bijlsma@vumc.nl.|Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, VUmc, Amsterdam, The Netherlands. j.bijlsma@vumc.nl.
authors.forename: Johannes W J
authors.initials: JW
authors.lastname: Bijlsma
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands. c.verweij@vumc.nl.|Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, VUmc, Amsterdam, The Netherlands. c.verweij@vumc.nl.
authors.forename: Cornelis L
authors.initials: CL
authors.lastname: Verweij
mesh_terms: D000328:Adult; D000368:Aged; D001327:Autoimmune Diseases / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D005260:Female; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D016899:Interferon-beta / Q000627:therapeutic use*; D008180:Lupus Erythematosus, Systemic / Q000097:blood* / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood* / Q000188:drug therapy* / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D016898:Interferon-alpha; D016899:Interferon-beta