Αρχειοθήκη ιστολογίου

Αλέξανδρος Γ. Σφακιανάκης
ΩτοΡινοΛαρυγγολόγος
Αναπαύσεως 5
Άγιος Νικόλαος Κρήτη 72100
2841026182
6032607174

Πέμπτη 24 Μαΐου 2018

Severe combined immunodeficiency in Sting V154M/WT mice

Publication date: Available online 23 May 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Delphine Bouis, Peggy Kirstetter, Florent Arbogast, Delphine Lamon, Virginia Delgado, Sophie Jung, Claudine Ebel, Hugues Jacobs, Anne-Marie Knapp, Nadia Jeremiah, Alexandre Belot, Thierry Martin, Yanick J. Crow, Isabelle André-Schmutz, Anne-Sophie Korganow, Frédéric Rieux-Laucat, Pauline Soulas-Sprauel
BackgroundAutosomal 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.ObjectiveThe 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.MethodsWe 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.ResultsIn 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.ConclusionsSting 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.

Teaser

Sting V154M/WT mice develop an IFN-independent severe combined immunodeficiency with hypogammaglobulinemia, a partially IFN-dependent T cell proliferation defect, and variable lung and kidney inflammation, providing new clues in the understanding of STING gain-of-function pathophysiology.


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