Severe combined immunodeficiency in stimulator of interferon genes (STING) V154M/wild-type mice

Autor: Claudine Ebel, Anne-Marie Knapp, Virginia Delgado, Isabelle André-Schmutz, Anne-Sophie Korganow, Pauline Soulas-Sprauel, Delphine Bouis, Delphine Lamon, Nadia Jeremiah, Florent Arbogast, Peggy Kirstetter, Alexandre Belot, Thierry Martin, Frédéric Rieux-Laucat, Yanick J. Crow, Hugues Jacobs, Sophie Jung
Přispěvatelé: CCSD, Accord Elsevier, Immunopathologie et chimie thérapeutique (ICT), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Les Hôpitaux Universitaires de Strasbourg (HUS), Institut Clinique de la Souris (ICS), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Edinburgh, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Rok vydání: 2017
Předmět:
0301 basic medicine
stimulator of interferon genes
[SDV]Life Sciences [q-bio]
T-Lymphocytes
Immunology
Receptor
Interferon alpha-beta
Biology
Natural killer cell
03 medical and health sciences
Mice
0302 clinical medicine
Interferon
Agammaglobulinemia
Sciences du Vivant [q-bio]/Biologie cellulaire
medicine
Immunology and Allergy
Animals
Humans
Sciences du Vivant [q-bio]/Immunologie
Inflammation
Mice
Knockout
Severe combined immunodeficiency
B-Lymphocytes
Interferon-stimulated gene
Wild type
Membrane Proteins
Cell Differentiation
V154M
medicine.disease
eye diseases
3. Good health
[SDV] Life Sciences [q-bio]
Killer Cells
Natural
Mice
Inbred C57BL
Sting
Disease Models
Animal
030104 developmental biology
medicine.anatomical_structure
Stimulator of interferon genes
Knockout mouse
Interferon Type I
Mutation
type I interferon
Severe Combined Immunodeficiency
030215 immunology
medicine.drug
Zdroj: Journal of Allergy and Clinical Immunology
Journal of Allergy and Clinical Immunology, 2019, 143 (2), pp.712-725.e5. ⟨10.1016/j.jaci.2018.04.034⟩
Journal of Allergy and Clinical Immunology, Elsevier, 2019, 143 (2), pp.712-725.e5. ⟨10.1016/j.jaci.2018.04.034⟩
ISSN: 1097-6825
0091-6749
Popis: International audience; 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.
Databáze: OpenAIRE
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