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    Hierarchy of clinical manifestations in SAVI N153S and V154M mouse models

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    Authors
    Motwani, Mona
    Pawaria, Sudesh
    Bernier, Jennifer
    Moses, Stephanie
    Henry, Kate
    Fang, Terry
    Burkly, Linda
    Marshak-Rothstein, Ann
    Fitzgerald, Katherine A.
    UMass Chan Affiliations
    Department of Medicine, Division of Rheumatology
    Program in Innate Immunity, Department of Medicine, Division of Infectious Diseases and Immunology
    Document Type
    Journal Article
    Publication Date
    2019-04-16
    Keywords
    SAVI
    STING
    T cells
    cell death
    type I interferonopathies
    Immunology and Infectious Disease
    Infectious Disease
    
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    Link to Full Text
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475399/
    Abstract
    Studies over the past decade have revealed a central role for innate immune sensors in autoimmune and autoinflammatory diseases. cGAS, a cytosolic DNA sensor, detects both foreign and host DNA and generates a second-messenger cGAMP, which in turn binds and activates stimulator of IFN genes (STING), leading to induction of type I interferons and inflammatory cytokines. Recently, gain-of-function mutations in STING have been identified in patients with STING-associated vasculopathy with onset in infancy (SAVI). SAVI patients present with early-onset systemic inflammation and interstitial lung disease, resulting in pulmonary fibrosis and respiratory failure. Here, we describe two independent SAVI mouse models, harboring the two most common mutations found in patients. A direct comparison of these strains reveals a hierarchy of immune abnormalities, lung inflammation and fibrosis, which do not depend on either IFN-alpha/beta receptor signaling or mixed lineage kinase domain-like pseudokinase (MLKL)-dependent necroptotic cell death pathways. Furthermore, radiation chimera experiments reveal how bone marrow from the V154M mutant mice transfer disease to the WT host, whereas the N153S does not, indicating mutation-specific disease outcomes. Moreover, using radiation chimeras we find that T cell lymphopenia depends on T cell-intrinsic expression of the SAVI mutation. Collectively, these mutant mice recapitulate many of the disease features seen in SAVI patients and highlight mutation-specific functions of STING that shed light on the heterogeneity observed in SAVI patients.
    Source

    Motwani M, Pawaria S, Bernier J, Moses S, Henry K, Fang T, Burkly L, Marshak-Rothstein A, Fitzgerald KA. Hierarchy of clinical manifestations in SAVI N153S and V154M mouse models. Proc Natl Acad Sci U S A. 2019 Apr 16;116(16):7941-7950. doi: 10.1073/pnas.1818281116. Epub 2019 Apr 3. PMID: 30944222; PMCID: PMC6475399. Link to article on publisher's site

    DOI
    10.1073/pnas.1818281116
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/35188
    PubMed ID
    30944222
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    ae974a485f413a2113503eed53cd6c53
    10.1073/pnas.1818281116
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