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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:143

Article

Bouis, Delphine¹  Kirstetter, Peggy^2,3,4  Arbogast, Florent^1,5  Lamon, Delphine¹  Delgado, Virginia¹  Jung, Sophie^1,6,7  Ebel, Claudine^2,3,4  Jacobs, Hugues^2,3,4,8,9  Knapp, Anne-Marie^1,10  Jeremiah, Nadia¹¹  Belot, Alexandre^12,13  Martin, Thierry^1,10,14  Crow, Yanick J.^15,16,17  Andre-Schmutz, Isabelle^16,18  Korganow, Anne-Sophie^1,10,14  Rieux-Laucat, Frederic^16,19  Soulas-Sprauel, Pauline^1,14,20 

[1] Inst Mol & Cellular Biol IBMC, CNRS, Lab Excellence Medalis, UPR Immunopathol & Therapeut Chem 3572, Strasbourg, France

[2] IGBMC, Illkirch Graffenstaden, France

[3] INSERM, U964, Illkirch Graffenstaden, France

[4] Univ Strasbourg, Illkirch Graffenstaden, France

[5] Univ Strasbourg, UFR Sci Vie, Strasbourg, France

[6] Hop Univ Strasbourg, Pole Med & Chirurg Buccodent, Ctr Reference Malad Rares Orales & Dent ORares, Strasbourg, France

[7] Univ Strasbourg, Fac Chirurg Dent, Strasbourg, France

[8] CNRS, UMR7104, Illkirch Graffenstaden, France

[9] PHENOMIN, CELPHEDIA, ICS, Illkirch Graffenstaden, France

[10] Univ Strasbourg, UFR Med, Strasbourg, France

[11] PSL Res Univ, INSERM, U932, Immun & Canc Dept,Inst Curie, Paris, France

[12] Hosp Civils Lyon, HFME, Ctr Reference RAISE, Serv Nephrol,Rhumatol,Dermatol,Pediat, Lyon, France

[13] Univ Lyon, INSERM, UMR 1111, Lyon, France

[14] Hop Univ Strasbourg, Natl Reference Ctr Autoimmune Dis, Dept Clin Immunol & Internal Med, Strasbourg, France

[15] INSERM, UMR 1163, Lab Neurogenet & Neuroinflammat, Paris, France

[16] Paris Descartes Sorbonne Paris Cite Univ, Imagine Inst, Paris, France

[17] Univ Edinburgh, Ctr Genom & Expt Med, MRC Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland

[18] INSERM, UMR 1163, Lab Human Lymphohematopoiesis, Paris, France

[19] INSERM, UMR 1163, Lab Immunogenet Pediat Autoimmune Dis, Paris, France

[20] Univ Strasbourg, UFR Sci Pharmaceut, Illkirch Graffenstaden, France

关键词: Severe combined immunodeficiency;    stimulator of interferon genes;    V154M;    type I interferon;   

DOI  :  10.1016/j.jaci.2018.04.034

来源: Elsevier

【 摘 要 】

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-alpha/beta 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.

【 授权许可】

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