Case Report: Novel SAVI-Causing Variants in STING1 Expand the Clinical Disease Spectrum and Suggest a Refined Model of STING Activation

Lin, Bin; Torreggiani, Sofia; Kahle, Dana; Rumsey, Dax G.; Wright, Benjamin L.; Montes-Cano, Marco Antonio; Silveira, Laura Fernández; Alehashemi, Sara; Mitchell, Jacob; Aue, Alexander G.; Ji, Zheng; Jin, Tengchuan; Jesús, Adriana Almeida de; Goldbach‐Mansky, Raphaela

doi:10.3389/fimmu.2021.636225

Cited by 22 publications

(32 citation statements)

References 22 publications

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“…Six case reports (34)(35)(36)(37)(38)(39) and seven case series (40)(41)(42)(43)(44)(45)(46) reporting on SAVI could be identified (full text n = 9, conference abstracts n = 1, letters n = 3). Additional two articles (24,33) reported on the same study population (patients with SAVI, CANDLE, other interferonopathies).…”

Section: Evidence On Effectiveness and Safety For Sting Associated Va...mentioning

confidence: 99%

Effectiveness and Safety of JAK Inhibitors in Autoinflammatory Diseases: A Systematic Review

et al. 2022

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IntroductionAutoinflammatory diseases (AID) are rare diseases presenting with episodes of sterile inflammation. These involve multiple organs and can cause both acute organ damage and serious long-term effects, like amyloidosis. Disease-specific anti-inflammatory therapeutic strategies are established for some AID. However, their clinical course frequently includes relapsing, uncontrolled conditions. Therefore, new therapeutic approaches are needed. Janus Kinase inhibitors (JAKi) block key cytokines of AID pathogenesis and can be a potential option.MethodsA systematic review of the literature in accordance with the PRISMA guidelines was conducted. Three databases (MEDLINE, Embase and Cochrane Central Register of Controlled Trials) were searched for publications regarding the use of JAKi for AID. Data from the included publications was extracted and a narrative synthesis was performed. Criteria for defining treatment response were defined and applied.ResultsWe report data from 38 publications with a total of 101 patients describing the effects of JAKi in AID. Data on Type I Interferonopathies, Adult-Onset Still's Disease (AOSD), Systemic Juvenile Idiopathic Arthritis (sJIA), Familial Mediterranean Fever (FMF), and Behçet's Syndrome (BS) was identified. From a total of 52 patients with type I interferonopathies, in seven patients (7/52, 13.5%) a complete response was achieved, most (35/52, 67.3%) showed a partial response and a minority (10/52, 19.2%) showed no treatment response. For AOSD, a complete or a partial response was achieved by eleven (11/26, 42.3%) patients each. Two sJIA patients achieved complete response (2/4, 50%) and in two cases (2/4, 50%) a partial response was reported. Half of FMF patients showed a complete response and the other half had a partial one (3/6, 50.0%). Amongst BS patients most achieved a partial response (8/13, 61.5%). Five patients showed no response to therapy (5/13, 38.5%). Overall, the most frequent AEs were upper respiratory tract infections (17), pneumonia (10), BK virus viremia (10) and viruria (4), herpes zoster infection (5), viral gastroenteritis (2) and other infections (4).ConclusionThe results from this systematic review show that JAKi can be beneficial in certain AID. The risk of AEs, especially viral infections, should be considered. To accurately assess the risk benefit ratio of JAKi for AID, clinical trials should be conducted.

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Section: Evidence On Effectiveness and Safety For Sting Associated Va...mentioning

confidence: 99%

Effectiveness and Safety of JAK Inhibitors in Autoinflammatory Diseases: A Systematic Review

et al. 2022

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“…STING-associated vasculopathy with onset in infancy is associated with STING mutations, which lead to its spontaneous activation and accidental induction of IFN-I [ 34 , 35 , 36 , 37 ]. Mechanistically, these mutations may trigger a conformational change of STING LBD, mimicking the consequence resulting from cGAMP binding.…”

Section: Discussionmentioning

confidence: 99%

Human STING Is Regulated by an Autoinhibitory Mechanism for Type I Interferon Production

Wang

Zhang

et al. 2022

J Innate Immun

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Stimulator of interferon genes (STING) plays a pivotal role in type I interferon-mediated innate immune response to the cytoplasmic detection of aberrant DNA. STING is a membrane protein localized in endoplasmic reticulum (ER), which upon stimulation translocates to Golgi apparatus and activates downstream signaling cascades. However, the mechanism regulating STING activity and significance of its intracellular traffic are not completely understood. Here we identify a novel region of human STING comprising thirteen residues within its C-terminal tail (CTT) for downstream nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) activation. We also discover that STING CTT fragment can activate downstream signaling regardless of its ER localization. In addition, we reveal that ligand-binding domain (LBD) in the middle of STING binds and confers autoinhibition to its CTT for both NF-κB- and interferon regulatory factor 3-activation. Furthermore, STING LBD can inhibit the interferon-stimulating activity of STING CTT in trans and demonstrate a dominant negative effect on endogenous STING for interferon induction. We thus uncover an important autoinhibitory mechanism modulating STING activity.

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“…The two most frequent STING1 mutations i.e., V155M and N154S, located in the same mutation cluster (including other mutants, such as G166E, V147M or H72N [51]), are assumed to induce STING constitutive activation by promoting the 180 • rotation of the ligand-binding domain, thus resulting in STING oligomerization, independently of any interaction with its ligand cGAMP [52]. Other mutations in the second disease-causing mutation cluster (C206, R281, or R284) are thought to suppress the auto-inhibition of STING oligomerization [14].…”

Section: Savi Pathogenesismentioning

confidence: 99%

Lung Inflammation in STING-Associated Vasculopathy with Onset in Infancy (SAVI)

David

Frémond

2022

Cells

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STING-associated vasculopathy with onset in infancy (SAVI) is a type I interferonopathy caused by gain-of-function mutations in STING1 encoding stimulator of interferon genes (STING) protein. SAVI is characterized by severe inflammatory lung disease, a feature not observed in previously described type I interferonopathies i.e., Mendelian autoinflammatory disorders defined by constitutive activation of the type I interferon (IFN) pathway. Molecular defects in nucleic acid metabolism or sensing are central to the pathophysiology of these diseases, with such defects occurring at any step of the tightly regulated pathway of type I IFN production and signaling (e.g., exonuclease loss of function, RNA-DNA hybrid accumulation, constitutive activation of adaptor proteins such as STING). Among over 30 genotypes, SAVI and COPA syndrome, whose pathophysiology was recently linked to a constitutive activation of STING signaling, are the only type I interferonopathies presenting with predominant lung involvement. Lung disease is the leading cause of morbidity and mortality in these two disorders which do not respond to conventional immunosuppressive therapies and only partially to JAK1/2 inhibitors. In human silicosis, STING-dependent sensing of self-DNA following cell death triggered by silica exposure has been found to drive lung inflammation in mice and human models. These recent findings support a key role for STING and nucleic acid sensing in the homeostasis of intrinsic pulmonary inflammation. However, mechanisms by which monogenic defects in the STING pathway lead to pulmonary damages are not yet fully elucidated, and an improved understanding of such mechanisms is fundamental to improved future patient management. Here, we review the recent insights into the pathophysiology of SAVI and outline our current understanding of self-nucleic acid-mediated lung inflammation in humans.

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Case Report: Novel SAVI-Causing Variants in STING1 Expand the Clinical Disease Spectrum and Suggest a Refined Model of STING Activation

Cited by 22 publications

References 22 publications

Effectiveness and Safety of JAK Inhibitors in Autoinflammatory Diseases: A Systematic Review

Effectiveness and Safety of JAK Inhibitors in Autoinflammatory Diseases: A Systematic Review

Human STING Is Regulated by an Autoinhibitory Mechanism for Type I Interferon Production

Lung Inflammation in STING-Associated Vasculopathy with Onset in Infancy (SAVI)

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