title: Presence of an interferon signature in individuals who are anti-nuclear antibody positive lacking a systemic autoimmune rheumatic disease diagnosis.
abstract: Elevated levels of type I interferons (IFNs) are a characteristic feature of the systemic autoimmune rheumatic diseases (SARDs) and are thought to play an important pathogenic role. However, it is unknown whether these elevations are seen in anti-nuclear antibody-positive (ANA+) individuals who lack sufficient criteria for a SARD diagnosis. We examined IFN-induced gene expression in asymptomatic ANA+individuals and patients with undifferentiated connective tissue disease (UCTD) to address this question.
  
  
  
  Healthy ANA-control subjects and ANA+titre (≥1:160 by immunofluorescence) participants meeting no criteria, meeting at least one criterion (UCTD) or meeting SARD classification criteria were recruited. Whole peripheral blood IFN-induced and BAFF gene expression were quantified using NanoString technology. The normalized levels of five IFN-induced genes were summed to produce an IFN5 score.
  
  
  
  The mean IFN5 scores were increased in all ANA+participant subsets as compared with healthy control subjects. We found that 36.8% of asymptomatic ANA+and 50% of UCTD participants had IFN5 scores >2 SD above the mean for healthy control subjects. In all ANA+subsets, the IFN5 score correlated with the presence of anti-Ro/La antibodies. In the asymptomatic ANA+subset, this score also correlated with the ANA titre, whereas in the other ANA+subsets, it correlated with the number of different ANA specificities. Development of new SARD criteria was seen in individuals with normal and high IFN5 scores.
  
  
  
  An IFN signature is seen in a significant proportion of ANA+individuals and appears to be associated with ANA titre and type of autoantibodies, rather than with the presence or development of clinical SARD symptoms.
authors.affiliation: Krembil Research Institute, University Health Network, Toronto, ON, Canada. jwither@uhnres.utoronto.ca.|Division of Rheumatology, University Health Network, Toronto, ON, Canada. jwither@uhnres.utoronto.ca.|Department of Medicine, University of Toronto, Toronto, ON, Canada. jwither@uhnres.utoronto.ca.|Department of Immunology, University of Toronto, Toronto, ON, Canada. jwither@uhnres.utoronto.ca.|Toronto Western Hospital, 1E-420, 399 Bathurst Street, Toronto, ON, M5T 2S8, Canada. jwither@uhnres.utoronto.ca.
authors.forename: Joan
authors.identifier: 0000-0001-5961-9228
authors.initials: J
authors.lastname: Wither
authors.affiliation: Division of Rheumatology, University Health Network, Toronto, ON, Canada.|Department of Medicine, University of Toronto, Toronto, ON, Canada.|Division of Rheumatology, Mount Sinai Hospital, Toronto, ON, Canada.|Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada.
authors.forename: Sindhu R
authors.initials: SR
authors.lastname: Johnson
authors.affiliation: Krembil Research Institute, University Health Network, Toronto, ON, Canada.
authors.forename: Tony
authors.initials: T
authors.lastname: Liu
authors.affiliation: Krembil Research Institute, University Health Network, Toronto, ON, Canada.
authors.forename: Babak
authors.initials: B
authors.lastname: Noamani
authors.affiliation: Krembil Research Institute, University Health Network, Toronto, ON, Canada.
authors.forename: Dennisse
authors.initials: D
authors.lastname: Bonilla
authors.affiliation: Lakeridge Heath Services, Oshawa, ON, Canada.
authors.forename: Larissa
authors.initials: L
authors.lastname: Lisnevskaia
authors.affiliation: Division of Rheumatology, Hospital for Sick Children, Toronto, ON, Canada.|Department of Pediatrics, University of Toronto, Toronto, ON, Canada.
authors.forename: Earl
authors.initials: E
authors.lastname: Silverman
authors.affiliation: Division of Rheumatology, University Health Network, Toronto, ON, Canada.|Department of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: Arthur
authors.initials: A
authors.lastname: Bookman
authors.affiliation: Krembil Research Institute, University Health Network, Toronto, ON, Canada.
authors.forename: Carolina
authors.initials: C
authors.lastname: Landolt-Marticorena
mesh_terms: D000328:Adult; D000368:Aged; D000974:Antibodies, Antinuclear / Q000276:immunology*; D001327:Autoimmune Diseases / Q000175:diagnosis / Q000235:genetics / Q000276:immunology*; D053264:B-Cell Activating Factor / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression / Q000235:genetics / Q000276:immunology; D006801:Humans; D007370:Interferon Type I / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D049294:Phospholipid Transfer Proteins / Q000235:genetics / Q000276:immunology; D012216:Rheumatic Diseases / Q000175:diagnosis / Q000235:genetics / Q000276:immunology*; D019892:eIF-2 Kinase / Q000235:genetics / Q000276:immunology
chemical_list: D000974:Antibodies, Antinuclear; D053264:B-Cell Activating Factor; D007370:Interferon Type I; C493422:PLSCR1 protein, human; D049294:Phospholipid Transfer Proteins; C505719:TNFSF13B protein, human; C000602769:EIF2AK2 protein, human; D019892:eIF-2 Kinase
keywords: Anti-nuclear antibodies; Interferon; Pre-clinical; Systemic autoimmune rheumatic disease