Type I interferon-mediated autoinflammation due to DNase II deficiency

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

Mathieu Rodéro (1) , Alessandra Tesser (2) , Eva Bartok (3) , Gillian Rice (4) , Erika Della Mina , Marine M Depp , Benoit Beitz (5) , Vincent Bondet (6) , Nicolas Cagnard (7) , Darragh Duffy (6) , Michael Dussiot (8) , Marie-Louise Frémond , Marco Gattorno (9) , Flavia Guillem (8) , Naoki Kitabayashi (8) , Fabrice Porcheray (5) , Frederic Rieux-Laucat (8) , Luis Seabra , Carolina Uggenti , Stefano Volpi (10) , Leo Zeef (11) , Marie-Alexandra Alyanakian (12) , Jacques Beltrand (8) , Anna Monica Bianco (2) , Nathalie Boddaert (13) , Chantal Brouzes (14) , Sophie Candon , Roberta Caorsi , Marina Charbit (15) , Monique Fabre (16) , Flavio Faletra , Muriel Girard , Annie Harroche , Evelyn Hartmann , Dominique Lasne (14) , Annalisa Marcuzzi , Bénédicte Neven (12) , Patrick Nitschke (17) , Tiffany Pascreau , Serena Pastore , Capucine Picard (18) , Paolo Picco , Elisa Piscianz , Michel Polak (19) , Pierre Quartier (12) , Marion Rabant (20) , Gabriele Stocco (21) , Andrea Taddio , Florence Uettwiller , Erica Valencic , Diego Vozzi , Gunther Hartmann (22) , Winfried Barchet , Olivier Hermine (23) , Brigitte Bader-Meunier (12) , Alberto Tommasini (24) , Yanick Crow (4, 1)

1 Equipe Inserm U1163 - Laboratory of neurogenetics and neuroinflammation
2 Università degli studi di Trieste = University of Trieste
3 University of Bonn
4 Academic Unit of Medical Genetic
5 Microbiology Technology Institute,
6 Immunobiologie des Cellules dendritiques
7 SFR Necker - UMS 3633 / US24 - Structure Fédérative de Recherche Necker
8 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
9 Giannina Gaslini Institute
10 Istituto Giannina Gaslini, Genova
11 University of Manchester [Manchester]
12 Service d'immuno-hématologie pédiatrique [CHU Necker]
13 Service de Radiologie et imagerie médicale [CHU Necker]
14 ERL 8254 - Equipe Inserm U1163 - Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications
15 Service de néphrologie pédiatrique [CHU Necker]
16 Hôpital Bicêtre
17 BIP-D - Plate Forme Paris Descartes de Bioinformatique
18 Centre d'étude des Déficits Immunitaires
19 Service d'endocrinologie, gynécologie et diabétologie pédiatriques [CHU Necker]
20 CHU Necker - Enfants Malades [AP-HP]
21 Department of Life Sciences
22 Institute of Clinical Chemistry and Pharmacology, Center for Integrated Oncology
23 Service d'Hématologie Adulte
24 IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, Italy

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.

Domains: Immunology

Mathieu Rodéro, Alessandra Tesser, Eva Bartok, Gillian Rice, Erika Della Mina, et al.. Type I interferon-mediated autoinflammation due to DNase II deficiency. Nature Communications, 2017, 8 (1), pp.2176. ⟨10.1038/s41467-017-01932-3⟩. ⟨pasteur-01768950⟩