title: Assessment of Type I Interferon Signaling in Pediatric Inflammatory Disease.
abstract: OBJECTIVE
  Increased type I interferon is considered relevant to the pathology of a number of monogenic and complex disorders spanning pediatric rheumatology, neurology, and dermatology. However, no test exists in routine clinical practice to identify enhanced interferon signaling, thus limiting the ability to diagnose and monitor treatment of these diseases. Here, we set out to investigate the use of an assay measuring the expression of a panel of interferon-stimulated genes (ISGs) in children affected by a range of inflammatory diseases.
  
  
  METHODS
  A cohort study was conducted between 2011 and 2016 at the University of Manchester, UK, and the Institut Imagine, Paris, France. RNA PAXgene blood samples and clinical data were collected from controls and symptomatic patients with a genetically confirmed or clinically well-defined inflammatory phenotype. The expression of six ISGs was measured by quantitative polymerase chain reaction, and the median fold change was used to calculate an interferon score (IS) for each subject compared to a previously derived panel of 29 controls (where +2 SD of the control data, an IS of >2.466, is considered as abnormal). Results were correlated with genetic and clinical data.
  
  
  RESULTS
  Nine hundred ninety-two samples were analyzed from 630 individuals comprising symptomatic patients across 24 inflammatory genotypes/phenotypes, unaffected heterozygous carriers, and controls. A consistent upregulation of ISG expression was seen in 13 monogenic conditions (455 samples, 265 patients; median IS 10.73, interquartile range (IQR) 5.90-18.41), juvenile systemic lupus erythematosus (78 samples, 55 patients; median IS 10.60, IQR 3.99-17.27), and juvenile dermatomyositis (101 samples, 59 patients; median IS 9.02, IQR 2.51-21.73) compared to controls (78 samples, 65 subjects; median IS 0.688, IQR 0.427-1.196), heterozygous mutation carriers (89 samples, 76 subjects; median IS 0.862, IQR 0.493-1.942), and individuals with non-molecularly defined autoinflammation (89 samples, 69 patients; median IS 1.07, IQR 0.491-3.74).
  
  
  CONCLUSIONS
  An assessment of six ISGs can be used to define a spectrum of inflammatory diseases related to enhanced type I interferon signaling. If future studies demonstrate that the IS is a reactive biomarker, this measure may prove useful both in the diagnosis and the assessment of treatment efficacy.
authors.affiliation: Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Evolution and Genomic Sciences, University of Manchester, Manchester, UK.
authors.forename: Gillian I
authors.initials: GI
authors.lastname: Rice
authors.affiliation: INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, France.|Sorbonne-Paris-Cité, Institut Imagine, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris Descartes University, Paris, France.|General Pediatrics, Infectious Disease and Internal Medicine Department, Hôpital Robert Debré, AP-HP, Paris, France.|Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Melki
authors.affiliation: INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, France.|Sorbonne-Paris-Cité, Institut Imagine, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris Descartes University, Paris, France.|Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Frémond
authors.affiliation: Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Evolution and Genomic Sciences, University of Manchester, Manchester, UK.|Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Science Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Briggs
authors.affiliation: INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, France.|Sorbonne-Paris-Cité, Institut Imagine, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris Descartes University, Paris, France.
authors.forename: Mathieu P
authors.initials: MP
authors.lastname: Rodero
authors.affiliation: INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, France.|Sorbonne-Paris-Cité, Institut Imagine, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris Descartes University, Paris, France.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kitabayashi
authors.affiliation: Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Evolution and Genomic Sciences, University of Manchester, Manchester, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Oojageer
authors.affiliation: Sorbonne-Paris-Cité, Institut Imagine, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris Descartes University, Paris, France.|Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.|INSERM UMR 1163, Laboratory of Immunogenetics of Pediatric Autoimmunity, Paris, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bader-Meunier
authors.affiliation: Pediatric Rheumatology, Nephrology and Dermatology Department, Hospices Civils de Lyon, Lyon, France.|CIRI, Centre International de Recherche en Infectiologie, INSERM, U1111, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Université Lyon 1, Lyon, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Belot
authors.affiliation: Sorbonne-Paris-Cité, Institut Imagine, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris Descartes University, Paris, France.|Department of Paediatric Dermatology, Reference Centre for Rare Skin Disorders (MAGEC), Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Bodemer
authors.affiliation: Sorbonne-Paris-Cité, Institut Imagine, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris Descartes University, Paris, France.|Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Quartier
authors.affiliation: Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Evolution and Genomic Sciences, University of Manchester, Manchester, UK. yanickcrow@mac.com.|INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, France. yanickcrow@mac.com.|Sorbonne-Paris-Cité, Institut Imagine, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris Descartes University, Paris, France. yanickcrow@mac.com.|Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, 3rd Floor, Room 309, 24 Boulevard du Montparnasse, 75015, Paris, France. yanickcrow@mac.com.
authors.forename: Yanick J
authors.initials: YJ
authors.lastname: Crow
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007249:Inflammation / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism*; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D015415:Biomarkers; D050835:Interferon Regulatory Factors; D007370:Interferon Type I
keywords: Interferon; autoinflammation; autoinflammatory disease; interferonopathy