Severe combined immunodeficiency in stimulator of interferon genes (STING) V154M/wild-type mice.
Agammaglobulinemia
Animals
B-Lymphocytes
/ physiology
Cell Differentiation
/ genetics
Disease Models, Animal
Humans
Inflammation
/ genetics
Interferon Type I
/ metabolism
Killer Cells, Natural
/ immunology
Membrane Proteins
/ genetics
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation
/ genetics
Receptor, Interferon alpha-beta
/ genetics
Severe Combined Immunodeficiency
/ genetics
T-Lymphocytes
/ physiology
Severe combined immunodeficiency
V154M
stimulator of interferon genes
type I interferon
Journal
The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
09
10
2017
revised:
24
02
2018
accepted:
03
04
2018
pubmed:
26
5
2018
medline:
26
2
2020
entrez:
26
5
2018
Statut:
ppublish
Résumé
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. 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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 29800647
pii: S0091-6749(18)30758-9
doi: 10.1016/j.jaci.2018.04.034
pii:
doi:
Substances chimiques
Ifnar1 protein, mouse
0
Interferon Type I
0
Membrane Proteins
0
Sting1 protein, mouse
0
Receptor, Interferon alpha-beta
156986-95-7
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
712-725.e5Informations de copyright
Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.