| Autor: |
Bouis, Delphine, Kirstetter, Peggy, Arbogast, Florent, Lamon, Delphine, Delgado, Virginia, Jung, Sophie, Ebel, Claudine, Jacobs, Hugues, Knapp, Anne-Marie, Jeremiah, Nadia, Belot, Alexandre, Martin, Thierry, Crow, Yanick J, André-Schmutz, Isabelle, Korganow, Anne-Sophie, Rieux-Laucat, Frédéric, Soulas-Sprauel, Pauline |
| Jazyk: |
angličtina |
| Rok vydání: |
2018 |
| Předmět: |
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| Zdroj: |
Bouis, D, Kirstetter, P, Arbogast, F, Lamon, D, Delgado, V, Jung, S, Ebel, C, Jacobs, H, Knapp, A-M, Jeremiah, N, Belot, A, Martin, T, Crow, Y J, André-Schmutz, I, Korganow, A-S, Rieux-Laucat, F & Soulas-Sprauel, P 2018, ' Severe combined immunodeficiency in Sting V154M/WT mice ', Journal of Allergy and Clinical Immunology . https://doi.org/10.1016/j.jaci.2018.04.034 |
| Popis: |
BACKGROUND: Autosomal dominant gain-of-function (GOF) mutations in human STING (Stimulator of Interferon Genes) lead to a severe autoinflammatory disease called SAVI (STING Associated Vasculopathy with onset in Infancy), associated with enhanced expression of interferon (IFN) stimulated gene (ISG) 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 IFN 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 SAVI. Hematopoietic development and tissue histology were analyzed. Lymphocyte activation and proliferation were assessed in vitro. Sting V154M/WT mice were crossed to IFNAR (IFNα/β Receptor) knock-out mice in order to evaluate the type I IFN-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 NK 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. Whilst the V154M/WT mutant demonstrated increased expression of ISGs, the SCID phenotype was not reversed in Sting V154M/WT IFNAR knock-out mice. However, the anti-proliferative defect in T cells was partially rescued by IFNAR deficiency.CONCLUSIONS: Sting GOF mice developed an IFN-independent SCID phenotype with a T, B and NK cell developmental defect and hypogammaglobulinemia, associated with signs of inflammation in lungs and kidneys. Only the intrinsic proliferative defect of T cells was, partially, IFN-dependent. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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