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J Allergy Clin Immunol. 2019 Feb;143(2):712-725.e5. doi: 10.1016/j.jaci.2018.04.034. Epub 2018 May 23.

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

Author information

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.

KEYWORDS:

Severe combined immunodeficiency; V154M; stimulator of interferon genes; type I interferon

PMID:
29800647
DOI:
10.1016/j.jaci.2018.04.034
[Indexed for MEDLINE]

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