title: Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease.
abstract: The type I interferon (IFN) response initiated by detection of nucleic acids is important for antiviral defense but is also associated with specific autoimmune diseases. Mutations in the human 3' repair exonuclease 1 (Trex1) gene cause Aicardi-Goutières syndrome (AGS), an IFN-associated autoimmune disease. However, the source of the type I IFN response and the precise mechanisms of disease in AGS remain unknown. Here, we demonstrate that Trex1 is an essential negative regulator of the STING-dependent antiviral response. We used an in vivo reporter of IFN activity in Trex1-deficient mice to localize the initiation of disease to nonhematopoietic cells. These IFNs drove T cell-mediated inflammation and an autoantibody response that targeted abundant, tissue-restricted autoantigens. However, B cells contributed to mortality independently of T cell-mediated tissue damage. These findings reveal a stepwise progression of autoimmune disease in Trex1-deficient mice, with implications for the treatment of AGS and related disorders.
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, 98195, USA.
authors.forename: Alevtina
authors.initials: A
authors.lastname: Gall
authors.forename: Piper
authors.initials: P
authors.lastname: Treuting
authors.forename: Keith B
authors.initials: KB
authors.lastname: Elkon
authors.forename: Yueh-Ming
authors.initials: YM
authors.lastname: Loo
authors.forename: Michael
authors.initials: M
authors.lastname: Gale
authors.forename: Glen N
authors.initials: GN
authors.lastname: Barber
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Stetson
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000201:enzymology / Q000503:physiopathology*; D020274:Autoimmune Diseases of the Nervous System / Q000503:physiopathology; D015551:Autoimmunity / Q000276:immunology*; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000378:metabolism; D007372:Interferons / Q000502:physiology; D008214:Lymphocytes / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009421:Nervous System Malformations / Q000503:physiopathology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D010750:Phosphoproteins; D007372:Interferons; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1