title: Modular transcriptional repertoire analyses of adults with systemic lupus erythematosus reveal distinct type I and type II interferon signatures.
abstract: OBJECTIVE
  The role of interferon-α (IFNα) in the pathogenesis of systemic lupus erythematosus (SLE) is strongly supported by gene expression studies. The aim of this study was to improve characterization of the blood IFN signature in adult SLE patients.
  
  
  METHODS
  Consecutive patients were enrolled and followed up prospectively. Microarray data were generated using Illumina BeadChips. A modular transcriptional repertoire was used as a framework for the analysis.
  
  
  RESULTS
  Our repertoire of 260 modules, which consisted of coclustered gene sets, included 3 IFN-annotated modules (M1.2, M3.4, and M5.12) that were strongly up-regulated in SLE patients. A modular IFN signature was observed in 54 of 62 patients (87%) or 131 of all 157 samples (83%). The IFN signature was more complex than expected, with each module displaying a distinct activation threshold (M1.2 < M3.4 < M5.12), thus providing a modular score by which to stratify SLE patients based on the presence of 0, 1, 2, or 3 active IFN modules. A similar gradient in modular IFN signature was observed within patients with clinically quiescent disease, for whom moderate/strong modular scores (2 or 3 active IFN modules) were associated with higher anti-double-stranded DNA titers and lower lymphocyte counts than those in patients with absent/mild modular scores (0 or 1 active IFN modules). Longitudinal analyses revealed both stable (M1.2) and variable (M3.4 and M5.12) components of modular IFN signature over time in single patients. Interestingly, mining of other data sets suggested that M3.4 and M5.12 could also be driven by IFNβ and IFNγ.
  
  
  CONCLUSIONS
  Modular repertoire analysis reveals complex IFN signatures in SLE, which are not restricted to the previous IFNα signature, but which also involve IFNβ and IFNγ.
authors.affiliation: Benaroya Research Institute, Seattle, Washington, and Aix-Marseille University and Hôpital de la Conception, APHM, Marseille, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Chiche
authors.forename: Noémie
authors.initials: N
authors.lastname: Jourde-Chiche
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Whalen
authors.forename: Scott
authors.initials: S
authors.lastname: Presnell
authors.forename: Vivian
authors.initials: V
authors.lastname: Gersuk
authors.forename: Kristen
authors.initials: K
authors.lastname: Dang
authors.forename: Esperanza
authors.initials: E
authors.lastname: Anguiano
authors.forename: Charlie
authors.initials: C
authors.lastname: Quinn
authors.forename: Stéphane
authors.initials: S
authors.lastname: Burtey
authors.forename: Yvon
authors.initials: Y
authors.lastname: Berland
authors.forename: Gilles
authors.initials: G
authors.lastname: Kaplanski
authors.forename: Jean-Robert
authors.initials: JR
authors.lastname: Harle
authors.forename: Virginia
authors.initials: V
authors.lastname: Pascual
authors.forename: Damien
authors.initials: D
authors.lastname: Chaussabel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D007370:Interferon Type I / Q000235:genetics* / Q000378:metabolism; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics* / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D055815:Young Adult
chemical_list: D015415:Biomarkers; D007370:Interferon Type I; D016898:Interferon-alpha; D016899:Interferon-beta; D007371:Interferon-gamma