Type I interferon-mediated autoinflammation due to DNase II deficiency

  • Nat Commun. 2017 Dec 19;8(1):2176. doi: 10.1038/s41467-017-01932-3.
Mathieu P Rodero  1 ,  Alessandra Tesser  2 ,  Eva Bartok  3 ,  Gillian I Rice  4 ,  Erika Della Mina  1 ,  Marine Depp  1 ,  Benoit Beitz  5 ,  Vincent Bondet  6  7 ,  Nicolas Cagnard  8 ,  Darragh Duffy  6  7  9 ,  Michael Dussiot  10 ,  Marie-Louise Frémond  1 ,  Marco Gattorno  11 ,  Flavia Guillem  10 ,  Naoki Kitabayashi  1 ,  Fabrice Porcheray  5 ,  Frederic Rieux-Laucat  12  13 ,  Luis Seabra  1 ,  Carolina Uggenti  1 ,  Stefano Volpi  11 ,  Leo A H Zeef  14 ,  Marie-Alexandra Alyanakian  15 ,  Jacques Beltrand  16  17 ,  Anna Monica Bianco  18 ,  Nathalie Boddaert  19  20 ,  Chantal Brouzes  21 ,  Sophie Candon  15  22 ,  Roberta Caorsi  11 ,  Marina Charbit  23 ,  Monique Fabre  24 ,  Flavio Faletra  25 ,  Muriel Girard  20  26 ,  Annie Harroche  27 ,  Evelyn Hartmann  3  28 ,  Dominique Lasne  29  30 ,  Annalisa Marcuzzi  2 ,  Bénédicte Neven  12  13  31 ,  Patrick Nitschke  8  20 ,  Tiffany Pascreau  29  30 ,  Serena Pastore  18 ,  Capucine Picard  31  32  33  34 ,  Paolo Picco  11 ,  Elisa Piscianz  2 ,  Michel Polak  16  17 ,  Pierre Quartier  12  13  31 ,  Marion Rabant  24 ,  Gabriele Stocco  35 ,  Andrea Taddio  2  18 ,  Florence Uettwiller  12  13  31 ,  Erica Valencic  18 ,  Diego Vozzi  25 ,  Gunther Hartmann  3 ,  Winfried Barchet  3  36 ,  Olivier Hermine  10  37 ,  Brigitte Bader-Meunier  13  31 ,  Alberto Tommasini  18 ,  Yanick J Crow  38  39  40  41
Affiliations
  • 1. INSERM UMR1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, 75015, France.
  • 2. Department of Medicine, Surgery, and Health Sciences, University of Trieste, Trieste, 34149, Italy.
  • 3. Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, 53127, Germany.
  • 4. Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UK.
  • 5. Bioaster, Immunomonitoring Unit, Paris, 75015, France.
  • 6. Immunobiology of Dendritic Cells, Institut Pasteur, Paris, 75015, France.
  • 7. INSERM U1223, Paris, 75015, France.
  • 8. Plateforme Bio-informatique, Université Paris Descartes-Structure, Fédérative de Recherche Necker, INSERM US24/CNRS, UMS 3633, Paris, 75015, France.
  • 9. Centre for Translational Research, Institut Pasteur, Paris, 75015, France.
  • 10. INSERM UMR 1163, CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, Imagine Institute, Université Paris Descartes, Sorbonne Paris-Cité et Assistance publique-Hôpitaux de Paris, Hôpital Necker, Paris, France, Laboratory of Excellence GR-ex, Paris, 75015, France.
  • 11. Unita' Operativa Pediatria 2, Istituto Giannina Gaslini, Genova, 16147, Italy.
  • 12. Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, 75015, France.
  • 13. Laboratory of Immunogenetics of Pediatric Autoimmunity, INSERM UMR 1163, Paris, 75015, France.
  • 14. Bioinformatics Core Facility, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK.
  • 15. Laboratoire d'Immunologie Biologique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, 75015, France.
  • 16. Service d'endocrinologie, Gynécologie et Diabétologie Pédiatriques, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, 75015, France.
  • 17. INSERM U1016, Institut IMAGINE, Université Paris Descartes, Paris, 75015, France.
  • 18. Institute for Maternal and Child Health-IRCCS "Burlo Garofolo"- Trieste, Trieste, 34137, Italy.
  • 19. Pediatric Radiology Department, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, 75015, France.
  • 20. INSERM UMR1163, Imagine Institute, Paris Descartes University, Paris, 75015, France.
  • 21. Department of Biological Haematology, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, 75015, France.
  • 22. Institut Necker-Enfants Malades, INSERM U1151-CNRS UMR 8253, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, 75015, France.
  • 23. Pediatric Nephrology Department, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, 75015, France.
  • 24. Pathology Department, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, 75015, France.
  • 25. Department of Advanced Diagnostic and Clinical Trials, Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", Trieste, 34137, Italy.
  • 26. Pediatric Hepatology Unit, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, 75015, France.
  • 27. Service d'hématologie-Centre de Traitement de l'Hémophilie, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, 75015, France.
  • 28. Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Bonn, Bonn, 53105, Germany.
  • 29. INSERM UMR_S1176, Univ. Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, Paris, 94276, France.
  • 30. Laboratoire d'Hématologie, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, 75015, France.
  • 31. Pediatric Immunology-Hematology and Rheumatology Unit, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, 75015, France.
  • 32. Study Center for Primary Immunodeficiencies, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, 75015, France.
  • 33. Necker Medical School, Paris, 75015, France.
  • 34. INSERM UMR1163, Laboratory of Lymphocyte Activation and Susceptibility to EBV, Imagine Institute, Paris Descartes University, Paris, 75015, France.
  • 35. Department of Life Sciences, University of Trieste, Trieste, 34128, Italy.
  • 36. German Center for Infection Research (DZIF), Cologne-Bonn, Bonn, 53127, Germany.
  • 37. Service d'hématologie, Faculté de Médecine Paris Descartes, Sorbonne Paris-Cité et Assistance Publique-Hôpitaux de Paris Hôpital Necker, Paris, 75015, France.
  • 38. INSERM UMR1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, 75015, France. [email protected].
  • 39. Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UK. [email protected].
  • 40. Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, 75015, France. [email protected].
  • 41. Department of Genetics, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, 75015, France. [email protected].
PMID: 29259162 DOI: 10.1038/s41467-017-01932-3
Abstract

Microbial nucleic acid recognition serves as the major stimulus to an Antiviral response, implying a requirement to limit the misrepresentation of self nucleic acids as non-self and the induction of autoinflammation. By systematic screening using a panel of interferon-stimulated genes we identify two siblings and a singleton variably demonstrating severe neonatal anemia, membranoproliferative glomerulonephritis, liver fibrosis, deforming arthropathy and increased anti-DNA antibodies. In both families we identify biallelic mutations in DNASE2, associated with a loss of DNase II Endonuclease activity. We record increased interferon Alpha protein levels using digital ELISA, enhanced interferon signaling by RNA-Seq analysis and constitutive upregulation of phosphorylated STAT1 and STAT3 in patient lymphocytes and monocytes. A hematological disease transcriptomic signature and increased numbers of erythroblasts are recorded in patient peripheral blood, suggesting that interferon might have a particular effect on hematopoiesis. These data define a type I interferonopathy due to DNase II deficiency in humans.