Delphine Bouis1, Peggy Kirstetter2, Florent Arbogast3, Delphine Lamon1, Virginia Delgado1, Sophie Jung4, Claudine Ebel2, Hugues Jacobs5, Anne-Marie Knapp6, Nadia Jeremiah7, Alexandre Belot8, Thierry Martin9, Yanick J Crow10, Isabelle André-Schmutz11, Anne-Sophie Korganow9, Frédéric Rieux-Laucat12, Pauline Soulas-Sprauel13. 1. CNRS UPR 3572 "Immunopathology and Therapeutic Chemistry"/Laboratory of Excellence Medalis, Institute of Molecular and Cellular Biology (IBMC), Strasbourg, France. 2. Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U964, Illkirch, France; Université de Strasbourg, Illkirch, France. 3. CNRS UPR 3572 "Immunopathology and Therapeutic Chemistry"/Laboratory of Excellence Medalis, Institute of Molecular and Cellular Biology (IBMC), Strasbourg, France; UFR Sciences de la Vie, Université de Strasbourg, Strasbourg, France. 4. CNRS UPR 3572 "Immunopathology and Therapeutic Chemistry"/Laboratory of Excellence Medalis, Institute of Molecular and Cellular Biology (IBMC), Strasbourg, France; Hôpitaux Universitaires de Strasbourg, Pôle de Médecine et de Chirurgie Bucco-dentaires, Centre de référence des maladies rares orales et dentaires (O'Rares) et Université de Strasbourg, Faculté de Chirurgie Dentaire, Strasbourg, France. 5. Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U964, Illkirch, France; Université de Strasbourg, Illkirch, France; Centre National de Recherche Scientifique (CNRS), UMR7104, Illkirch, France; CELPHEDIA, PHENOMIN, Institut Clinique de la Souris (ICS), Illkirch-Graffenstaden, France. 6. CNRS UPR 3572 "Immunopathology and Therapeutic Chemistry"/Laboratory of Excellence Medalis, Institute of Molecular and Cellular Biology (IBMC), Strasbourg, France; UFR Médecine, Université de Strasbourg, Strasbourg, France. 7. Immunity and Cancer Department, Institut Curie, PSL Research University, INSERM U932, Paris, France. 8. Service de Néphrologie, Rhumatologie, Dermatologie pédiatriques, Centre de référence RAISE, HFME, Hospices Civils de Lyon, Lyon, France; INSERM UMR 1111, Université de Lyon, Lyon, France. 9. CNRS UPR 3572 "Immunopathology and Therapeutic Chemistry"/Laboratory of Excellence Medalis, Institute of Molecular and Cellular Biology (IBMC), Strasbourg, France; UFR Médecine, Université de Strasbourg, Strasbourg, France; Department of Clinical Immunology and Internal Medicine, National Reference Center for Autoimmune Diseases, Hôpitaux Universitaires de Strasbourg, Strasbourg, France. 10. INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom. 11. Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France. 12. Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Laboratory of Immunogenetics of Pediatric autoimmune Diseases, INSERM UMR 1163, Paris, France. 13. CNRS UPR 3572 "Immunopathology and Therapeutic Chemistry"/Laboratory of Excellence Medalis, Institute of Molecular and Cellular Biology (IBMC), Strasbourg, France; Department of Clinical Immunology and Internal Medicine, National Reference Center for Autoimmune Diseases, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; UFR Sciences Pharmaceutiques, Université de Strasbourg, Illkirch-Graffenstaden, France. Electronic address: pauline.soulas@ibmc-cnrs.unistra.fr.
Abstract
BACKGROUND: Autosomal dominant gain-of-function mutations in human stimulator of interferon genes (STING) lead to a severe autoinflammatory disease called STING-associated vasculopathy with onset in infancy that is associated with enhanced expression of interferon-stimulated gene transcripts. OBJECTIVE: The goal of this study was to analyze the phenotype of a new mouse model of STING hyperactivation and the role of type I interferons in this system. METHODS: We generated a knock-in model carrying an amino acid substitution (V154M) in mouse STING, corresponding to a recurrent mutation seen in human patients with STING-associated vasculopathy with onset in infancy. Hematopoietic development and tissue histology were analyzed. Lymphocyte activation and proliferation were assessed in vitro. STING V154M/wild-type (WT) mice were crossed to IFN-α/β receptor (IFNAR) knockout mice to evaluate the type I interferon dependence of the mutant Sting phenotype recorded. RESULTS: In STING V154M/WT mice we detected variable expression of inflammatory infiltrates in the lungs and kidneys. These mice showed a marked decrease in survival and developed a severe combined immunodeficiency disease (SCID) affecting B, T, and natural killer cells, with an almost complete lack of antibodies and a significant expansion of monocytes and granulocytes. The blockade in B- and T-cell development was present from early immature stages in bone marrow and thymus. In addition, in vitro experiments revealed an intrinsic proliferative defect of mature T cells. Although the V154M/WT mutant demonstrated increased expression of interferon-stimulated genes, the SCID phenotype was not reversed in STING V154M/WT IFNAR knockout mice. However, the antiproliferative defect in T cells was rescued partially by IFNAR deficiency. CONCLUSIONS: STING gain-of-function mice developed an interferon-independent SCID phenotype with a T-cell, B-cell, and natural killer cell developmental defect and hypogammaglobulinemia that is associated with signs of inflammation in lungs and kidneys. Only the intrinsic proliferative defect of T cells was partially interferon dependent. Crown
BACKGROUND: Autosomal dominant gain-of-function mutations in human stimulator of interferon genes (STING) lead to a severe autoinflammatory disease called STING-associated vasculopathy with onset in infancy that is associated with enhanced expression of interferon-stimulated gene transcripts. OBJECTIVE: The goal of this study was to analyze the phenotype of a new mouse model of STING hyperactivation and the role of type I interferons in this system. METHODS: We generated a knock-in model carrying an amino acid substitution (V154M) in mouse STING, corresponding to a recurrent mutation seen in humanpatients with STING-associated vasculopathy with onset in infancy. Hematopoietic development and tissue histology were analyzed. Lymphocyte activation and proliferation were assessed in vitro. STING V154M/wild-type (WT) mice were crossed to IFN-α/β receptor (IFNAR) knockout mice to evaluate the type I interferon dependence of the mutant Sting phenotype recorded. RESULTS: In STING V154M/WT mice we detected variable expression of inflammatory infiltrates in the lungs and kidneys. These mice showed a marked decrease in survival and developed a severe combined immunodeficiency disease (SCID) affecting B, T, and natural killer cells, with an almost complete lack of antibodies and a significant expansion of monocytes and granulocytes. The blockade in B- and T-cell development was present from early immature stages in bone marrow and thymus. In addition, in vitro experiments revealed an intrinsic proliferative defect of mature T cells. Although the V154M/WT mutant demonstrated increased expression of interferon-stimulated genes, the SCID phenotype was not reversed in STING V154M/WT IFNAR knockout mice. However, the antiproliferative defect in T cells was rescued partially by IFNAR deficiency. CONCLUSIONS: STING gain-of-function mice developed an interferon-independent SCID phenotype with a T-cell, B-cell, and natural killer cell developmental defect and hypogammaglobulinemia that is associated with signs of inflammation in lungs and kidneys. Only the intrinsic proliferative defect of T cells was partially interferon dependent. Crown
Authors: Brock G Bennion; Carys A Croft; Teresa L Ai; Wei Qian; Amber M Menos; Cathrine A Miner; Marie-Louis Frémond; Jean-Marc Doisne; Prabhakar S Andhey; Derek J Platt; Jennifer K Bando; Erin R Wang; Hella Luksch; Thierry J Molina; Elisha D O Roberson; Maxim N Artyomov; Angela Rösen-Wolff; Marco Colonna; Frédéric Rieux-Laucat; James P Di Santo; Bénédicte Neven; Jonathan J Miner Journal: Cell Rep Date: 2020-06-16 Impact factor: 9.423
Authors: Sudesh Pawaria; Kerstin Nündel; Kevin M Gao; Stephanie Moses; Patricia Busto; Kevin Holt; Rohit B Sharma; Michael A Brehm; Ellen M Gravallese; Merav Socolovsky; Anette Christ; Ann Marshak-Rothstein Journal: Arthritis Rheumatol Date: 2019-12-29 Impact factor: 10.995
Authors: Mona Motwani; Sudesh Pawaria; Jennifer Bernier; Stephanie Moses; Kate Henry; Terry Fang; Linda Burkly; Ann Marshak-Rothstein; Katherine A Fitzgerald Journal: Proc Natl Acad Sci U S A Date: 2019-04-03 Impact factor: 11.205
Authors: Chih-Hang Anthony Tang; Avery C Lee; Shiun Chang; Qin Xu; Andong Shao; Yun Lo; Walker T Spalek; Javier A Pinilla-Ibarz; Juan R Del Valle; Chih-Chi Andrew Hu Journal: Cell Mol Immunol Date: 2020-09-30 Impact factor: 11.530
Authors: Christopher J A Duncan; Benjamin J Thompson; Rui Chen; Gillian I Rice; Florian Gothe; Dan F Young; Simon C Lovell; Victoria G Shuttleworth; Vicky Brocklebank; Bronte Corner; Andrew J Skelton; Vincent Bondet; Jonathan Coxhead; Darragh Duffy; Cecile Fourrage; John H Livingston; Julija Pavaine; Edmund Cheesman; Stephania Bitetti; Angela Grainger; Meghan Acres; Barbara A Innes; Aneta Mikulasova; Ruyue Sun; Rafiqul Hussain; Ronnie Wright; Robert Wynn; Mohammed Zarhrate; Leo A H Zeef; Katrina Wood; Stephen M Hughes; Claire L Harris; Karin R Engelhardt; Yanick J Crow; Richard E Randall; David Kavanagh; Sophie Hambleton; Tracy A Briggs Journal: Sci Immunol Date: 2019-12-13