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

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

doi:10.1016/j.jaci.2018.04.034

Cited by 74 publications

(86 citation statements)

References 43 publications

(76 reference statements)

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“…S2A). This was consistent with the findings of other investigators who also observed a minimal ISG signature as a result of SAVI mutations (16,17). This result was surprising because murine models of two additional STING-dependent type I interferonopathies, TREX1-deficient mice (5) or DNase II-deficient mice (19), had robust ISG signatures.…”

Section: Savi Mutant Mice Have Elevated Type I Ifn and Inflammatory Genesupporting

confidence: 92%

“…Despite the severe phenotypes of many SAVI patients, the same mutation in different individuals can have very different clinical manifestations (13)(14)(15). Thus, a better understanding of how, when, and where overactivation of STING causes sterile inflammation is clearly needed and animal models have been developed by investigators to explore these questions (16,17). Unexpectedly, murine models of the two most common SAVI mutations appear to reflect different aspects of the human disease: the N153S mutant mice purportedly develop skin disease while the V154M mice were found to develop variable levels of lung inflammation.…”

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confidence: 99%

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Hierarchy of clinical manifestations in SAVI N153S and V154M mouse models

Motwani

Pawaria

Bernier

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

100

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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-offunction 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-α/β receptor signaling or mixed lineage kinase domainlike 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. STING | SAVI | type I interferonopathies | T cells | cell death N ucleic acids are readily detected by nucleic acid sensors that survey cells for signs of infection or tissue damage. Engagement of a diverse collection of RNA and DNA sensors trigger host-defense responses to curb pathogen replication and initiate beneficial repair responses to tissue injury. The DNA sensor cGAS (cGMP-AMP synthase) is a nucleotidyl transferase that detects double-stranded DNA and generates a novel secondmessenger 2′-5′cGMP-AMP (cGAMP). cGAMP binds stimulator of IFN genes (STING), causing its dimerization leading to activation of TBK1/IRF3 and IKK/NF-κB, pathways resulting in the induction of type I IFNs and proinflammatory cytokines, respectively (1). DNases outside cells (DNase I), within the phagolysosomal compartment (DNase II) or cytosol (DNase III/Trex1), ensure that in healthy individuals self nucleic acids do not trigger DNA sensors (2). Inappropriate clearance of DNA and its subsequent detection by DNA sensors underlies the pathogenesis of debilitating human diseases, such as Aicardi-Goutiéres syndrome (3). A subset of Aicardi-Goutiéres syndrome patients have mutations in Trex1, a 3′-5′ exonuclease that degrades DNA, which accumulates from endogenous retroelements (4, 5).Gain-of-function (GOF) mutations in components of RNA and DNA sensing pathways can also result in severe autoinflammatory and autoimmune diseases. Examples include the GOF mutations in DDX58 (RIG-I) and ...

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Section: Savi Mutant Mice Have Elevated Type I Ifn and Inflammatory Genesupporting

confidence: 92%

mentioning

confidence: 99%

Hierarchy of clinical manifestations in SAVI N153S and V154M mouse models

Motwani

Pawaria

Bernier

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

100

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“…Interestingly, the most frequent virus isolated was rhinovirus, which may be a direct consequence of effective type I IFN inhibition by ruxolitinib at least in respiratory epithelial cells, where IFN-β is required to control rhinovirus [16,17]. On the other end, these infections might result from a cumulative effect of the drug with the reported developmental and in vitro proliferative defects of STING mutant T lymphocytes [18,19]. Considering the severity of lung disease and the lymphopenia ( Table 2) present before ruxolitinib treatment, P2 was started on antibiotic prophylaxis with Bactrim and Azithromycin; that, however, did not seem to prevent the febrile episodes, mostly if not always caused by viral pathogens.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Adverse Events During Janus Kinase Inhibitor Treatment of SAVI Syndrome

et al. 2019

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Objectives Mutations affecting the TMEM173 gene cause STING-associated vasculopathy with onset in infancy (SAVI). No standard immunosuppressive treatment approach is able to control disease progression in patients with SAVI. We studied the efficacy and safety of targeting type I IFN signaling with the Janus kinase inhibitor, ruxolitinib. Methods We used DNA sequencing to identify mutations in TMEM173 in patients with peripheral blood type I IFN signature. The JAK1/2 inhibitor ruxolitinib was administered on an off-label basis. Results We identified three patients with SAVI presenting with skin involvement and progressive severe interstitial lung disease. Indirect echocardiographic signs of pulmonary hypertension were present in one case. Following treatment with ruxolitinib, we observed improvements of respiratory function including increased forced vital capacity in two patients, with discontinuation of oxygen therapy and resolution of echocardiographic abnormalities in one case. Efficacy was persistent in one patient and only transitory in the other two patients. Clinical control of skin complications was obtained, and one patient discontinued steroid Stefano Volpi and Antonella Insalaco contributed equally.Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10875-019-00645-0) contains supplementary material, which is available to authorized users. treatment. One patient, who presented with kidney involvement, showed resolution of hematuria. One patient experienced increased recurrence of severe viral respiratory infections. Monitoring of peripheral blood type I interferon signature during ruxolitinib treatment did not show a stable decrease. Conclusions We conclude that targeting type I IFN receptor signaling may represent a promising therapeutic option for a subset of patients with SAVI syndrome and severe lung involvement. However, the occurrence of viral respiratory infection might represent an important cautionary note for the application of such form of treatment.

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“…Stimulator of interferon genes -associated vasculopathy with onset in infancy (SAVI) is a typical STING-related hereditary inflammatory type-I interferonopathy, and is manifested by interstitial lung disease, dermatomyositis and arthritis. Its pathology is featured by leukocytoclastic vasculitis and microthrombotic angiopathy of small dermal vessels (166,167) and patients can also suffer from lymphopenia (166)(167)(168)(169). The etiology of SAVI is a gain of function (GOF) mutant in STING which leads to constitutive STING activation without CDNs stimulation (166).…”

Section: Cgas-sting Pathway In Autoimmune or Inflammatory Diseasesmentioning

confidence: 99%

“…The inhibitory role of cGAS-STING in inflammation is also attributed to its apoptosis-triggering role. In some subtypes of SAVI and mouse models, apoptosis of blood-vessel endothelial cells or bronchial epithelial cells and leucopenia can be observed (especially T-cell lymphopenia) (166,169,170). When the STING signal is stimulated, apoptosis occurs more frequently in normal or cancerous T cells (119).…”

Section: Cgas-sting Pathway In Autoimmune or Inflammatory Diseasesmentioning

confidence: 99%

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

2020

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Double-stranded DNA (dsDNA) sensor cyclic-GMP-AMP synthase (cGAS) along with the downstream stimulator of interferon genes (STING) acting as essential immunesurveillance mediators have become hot topics of research. The intrinsic function of the cGAS-STING pathway facilitates type-I interferon (IFN) inflammatory signaling responses and other cellular processes such as autophagy, cell survival, senescence. cGAS-STING pathway interplays with other innate immune pathways, by which it participates in regulating infection, inflammatory disease, and cancer. The therapeutic approaches targeting this pathway show promise for future translation into clinical applications. Here, we present a review of the important previous works and recent advances regarding the cGAS-STING pathway, and provide a comprehensive understanding of the modulatory pattern of the cGAS-STING pathway under multifarious pathologic states.

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

Cited by 74 publications

References 43 publications

Hierarchy of clinical manifestations in SAVI N153S and V154M mouse models

Hierarchy of clinical manifestations in SAVI N153S and V154M mouse models

Efficacy and Adverse Events During Janus Kinase Inhibitor Treatment of SAVI Syndrome

Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response

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