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dc.contributor.authorMotwani, Mona
dc.contributor.authorPawaria, Sudesh
dc.contributor.authorBernier, Jennifer
dc.contributor.authorMoses, Stephanie
dc.contributor.authorHenry, Kate
dc.contributor.authorFang, Terry
dc.contributor.authorBurkly, Linda
dc.contributor.authorMarshak-Rothstein, Ann
dc.contributor.authorFitzgerald, Katherine A.
dc.date2022-08-11T08:09:10.000
dc.date.accessioned2022-08-23T16:20:01Z
dc.date.available2022-08-23T16:20:01Z
dc.date.issued2019-04-16
dc.date.submitted2020-04-08
dc.identifier.citation<p>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. <a href="https://doi.org/10.1073/pnas.1818281116">Link to article on publisher's site</a></p>
dc.identifier.issn0027-8424 (Linking)
dc.identifier.doi10.1073/pnas.1818281116
dc.identifier.pmid30944222
dc.identifier.urihttp://hdl.handle.net/20.500.14038/35188
dc.description.abstractStudies 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.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=30944222&dopt=Abstract">Link to Article in PubMed</a></p>
dc.relation.urlhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475399/
dc.subjectSAVI
dc.subjectSTING
dc.subjectT cells
dc.subjectcell death
dc.subjecttype I interferonopathies
dc.subjectImmunology and Infectious Disease
dc.subjectInfectious Disease
dc.titleHierarchy of clinical manifestations in SAVI N153S and V154M mouse models
dc.typeJournal Article
dc.source.journaltitleProceedings of the National Academy of Sciences of the United States of America
dc.source.volume116
dc.source.issue16
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1427&amp;context=infdis_pp&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/infdis_pp/414
dc.identifier.contextkey17313943
refterms.dateFOA2022-08-23T16:20:02Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathinfdis_pp/414
dc.contributor.departmentDepartment of Medicine, Division of Rheumatology
dc.contributor.departmentProgram in Innate Immunity, Department of Medicine, Division of Infectious Diseases and Immunology
dc.source.pages7941-7950


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