title: Loss of Trex1 in Dendritic Cells Is Sufficient To Trigger Systemic Autoimmunity.
abstract: Defects of the intracellular enzyme 3' repair exonuclease 1 (Trex1) cause the rare autoimmune condition Aicardi-Goutières syndrome and are associated with systemic lupus erythematosus. Trex1(-/-) mice develop type I IFN-driven autoimmunity, resulting from activation of the cytoplasmic DNA sensor cyclic GMP-AMP synthase by a nucleic acid substrate of Trex1 that remains unknown. To identify cell types responsible for initiation of autoimmunity, we generated conditional Trex1 knockout mice. Loss of Trex1 in dendritic cells was sufficient to cause IFN release and autoimmunity, whereas Trex1-deficient keratinocytes and microglia produced IFN but did not induce inflammation. In contrast, B cells, cardiomyocytes, neurons, and astrocytes did not show any detectable response to the inactivation of Trex1. Thus, individual cell types differentially respond to the loss of Trex1, and Trex1 expression in dendritic cells is essential to prevent breakdown of self-tolerance ensuing from aberrant detection of endogenous DNA.
authors: Institute for Immunology, Faculty of Medicine Carl Gustav Carus, University of Technology, 01307 Dresden, Germany;
authors: Katrin
authors: K
authors: Peschke
authors: Institute for Immunology, Faculty of Medicine Carl Gustav Carus, University of Technology, 01307 Dresden, Germany;
authors: Martin
authors: M
authors: Achleitner
authors: Institute of Neuropathology, University of Freiburg, 79106 Freiburg, Germany;
authors: Kathrin
authors: K
authors: Frenzel
authors: Institute for Immunology, Faculty of Medicine Carl Gustav Carus, University of Technology, 01307 Dresden, Germany;
authors: Alexander
authors: A
authors: Gerbaulet
authors: Institute for Immunology, Faculty of Medicine Carl Gustav Carus, University of Technology, 01307 Dresden, Germany;
authors: Servi Remzi
authors: 0000-0003-1970-6807
authors: SR
authors: Ada
authors: Institute of Neuropathology, University of Freiburg, 79106 Freiburg, Germany;
authors: Nicolas
authors: N
authors: Zeller
authors: Institute for Laboratory Animal Science, Hannover Medical School, 30625 Hannover, Germany; Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, 30625 Hannover, Germany;
authors: Stefan
authors: S
authors: Lienenklaus
authors: Deep Sequencing Group SFB655, Biotechnology Center, University of Technology, 01307 Dresden, Germany;
authors: Mathias
authors: 0000-0002-3274-7163
authors: M
authors: Lesche
authors: Department of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, University of Technology, 01307 Dresden, Germany;
authors: Claire
authors: 0000-0002-1063-5830
authors: C
authors: Poulet
authors: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany;
authors: Ronald
authors: 0000-0003-2084-5150
authors: R
authors: Naumann
authors: Deep Sequencing Group SFB655, Biotechnology Center, University of Technology, 01307 Dresden, Germany;
authors: Andreas
authors: 0000-0002-2668-8371
authors: A
authors: Dahl
authors: Department of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, University of Technology, 01307 Dresden, Germany;
authors: Ursula
authors: U
authors: Ravens
authors: Department of Dermatology, Faculty of Medicine Carl Gustav Carus, University of Technology, 01307 Dresden, Germany;
authors: Claudia
authors: C
authors: Günther
authors: Faculty of Life Sciences, University of Manchester, Manchester M13 9PL, United Kingdom; and.
authors: Werner
authors: 0000-0002-1297-9725
authors: W
authors: Müller
authors: Institute of Neuropathology, University of Freiburg, 79106 Freiburg, Germany;
authors: Klaus-Peter
authors: KP
authors: Knobeloch
authors: Institute of Neuropathology, University of Freiburg, 79106 Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany.
authors: Marco
authors: M
authors: Prinz
authors: Institute for Immunology, Faculty of Medicine Carl Gustav Carus, University of Technology, 01307 Dresden, Germany;
authors: Axel
authors: A
authors: Roers
authors: Institute for Immunology, Faculty of Medicine Carl Gustav Carus, University of Technology, 01307 Dresden, Germany; rayk.behrendt@tu-dresden.de.
authors: Rayk
authors: 0000-0002-1091-2877
authors: R
authors: Behrendt
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000502:physiology; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000502:physiology; D001921:Brain / Q000276:immunology; D003713:Dendritic Cells / Q000502:physiology*; D005090:Exodeoxyribonucleases / Q000172:deficiency / Q000502:physiology*; D007370:Interferon Type I / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000172:deficiency / Q000502:physiology*
chemical_list: D018941:Antigens, CD19; C000604812:CD19 antigen, mouse; D007370:Interferon Type I; D010750:Phosphoproteins; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1