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Nat Commun. 2017 Dec 19;8(1):2176. doi: 10.1038/s41467-017-01932-3.

Type I interferon-mediated autoinflammation due to DNase II deficiency.

Author information

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. yanickcrow@mac.com.
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. yanickcrow@mac.com.
40
Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, 75015, France. yanickcrow@mac.com.
41
Department of Genetics, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, 75015, France. yanickcrow@mac.com.

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.

PMID:
29259162
PMCID:
PMC5736616
DOI:
10.1038/s41467-017-01932-3
[Indexed for MEDLINE]
Free PMC Article

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