Reviewer #1 (Public Review): The common TMEM173 HAQ, AQ alleles rescue CD4 T cellpenia, restore T-regs, and prevent SAVI (N153S) inflammatory disease in mice

Published: June 13, 2024

The significance of STING (encoded by the TMEM173 gene), in tissue inflammation and cancer immunotherapy has been increasingly recognized. Intriguingly, common human alleles R71H-G230A-R293Q (HAQ) G230A-R293Q (AQ) are carried ∼60% East Asians ∼40% Africans, respectively. Here, we examine modulatory effects HAQ, AQ on STING-associated vasculopathy with onset infancy (SAVI), an autosomal dominant, fatal inflammatory disease caused gain-of-function mutations. CD4 T cellpenia is evident SAVI patients mouse models. Using knock-in mice expressing AQ, Q293, found that Q293 splenocytes resist STING-mediated cell death ex vivo, establishing a critical role residue 293 death. HAQ/SAVI(N153S) AQ/SAVI(N153S) did not have cellpenia. HAQ/SAVI(N153S), more (∼10-fold, ∼20-fold, respectively) T-regs than WT/SAVI(N153S) mice. Remarkably, while they comparable TBK1, IRF3, NFκB activation as WT/SAVI, AQ/SAVI no inflammation, regular body weight, normal lifespan. We propose promotes depleting cells vivo. Billions modern humans dominant alleles. research STING-targeting should consider heterogeneity humans.Teaser: One copy HAQ or gene prevents mutant-caused

Language: Английский

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Reviewer #2 (Public Review): The common TMEM173 HAQ, AQ alleles rescue CD4 T cellpenia, restore T-regs, and prevent SAVI (N153S) inflammatory disease in mice

Published: June 13, 2024

The significance of STING (encoded by the TMEM173 gene), in tissue inflammation and cancer immunotherapy has been increasingly recognized. Intriguingly, common human alleles R71H-G230A-R293Q (HAQ) G230A-R293Q (AQ) are carried ∼60% East Asians ∼40% Africans, respectively. Here, we examine modulatory effects HAQ, AQ on STING-associated vasculopathy with onset infancy (SAVI), an autosomal dominant, fatal inflammatory disease caused gain-of-function mutations. CD4 T cellpenia is evident SAVI patients mouse models. Using knock-in mice expressing AQ, Q293, found that Q293 splenocytes resist STING-mediated cell death ex vivo, establishing a critical role residue 293 death. HAQ/SAVI(N153S) AQ/SAVI(N153S) did not have cellpenia. HAQ/SAVI(N153S), more (∼10-fold, ∼20-fold, respectively) T-regs than WT/SAVI(N153S) mice. Remarkably, while they comparable TBK1, IRF3, NFκB activation as WT/SAVI, AQ/SAVI no inflammation, regular body weight, normal lifespan. We propose promotes depleting cells vivo. Billions modern humans dominant alleles. research STING-targeting should consider heterogeneity humans.Teaser: One copy HAQ or gene prevents mutant-caused

Language: Английский

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Activation of autoreactive lymphocytes in the lung by STING gain-of-function mutation expressing radioresistant cells

JCI Insight, Journal Year: 2024, Volume and Issue: unknown

Published: July 18, 2024

Gain-of-function mutations in the dsDNA sensing adaptor STING lead to a severe autoinflammatory syndrome known as STING-associated vasculopathy with onset Infancy (SAVI). SAVI patients develop interstitial lung disease (ILD) and produce autoantibodies that are commonly associated systemic autoimmune diseases. Mice expressing most common mutation V154M (VM) similarly ILD, but exhibit T B cell lymphopenia, low serum Ig titers, lack autoantibodies. Importantly, lethally irradiated VM hosts reconstituted wildtype (WT) stem cells (WT→VM) still ILD. In this study, we find WT→VM chimeras had restored function, produced autoantibodies, thereby recapitulated loss of tolerance seen patients. Lymphocytes derived from both WT BCR or TCR transgenic (Tg) donors accumulated extravascular tissue WT+Tg→VM mixed chimeras, lymphocyte activation germinal center formation required diverse repertoire. Furthermore, when isolated WTVM were adoptively transferred naïve Rag1-deficient 2º hosts, they trafficked recruited neutrophils. Overall, these findings indicated expression by radioresistant promoted autoreactive then differentiated into potentially pathogenic effector subsets.

Language: Английский

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The common TMEM173 HAQ, AQ alleles rescue CD4 T cellpenia, restore T-regs, and prevent SAVI (N153S) inflammatory disease in mice

Published: Aug. 19, 2024

The significance of STING (encoded by the TMEM173 gene) in tissue inflammation and cancer immunotherapy has been increasingly recognized. Intriguingly, common human alleles R71H-G230A-R293Q ( HAQ) G230A-R293Q AQ ) are carried ∼60% East Asians ∼40% Africans, respectively. Here, we examine modulatory effects HAQ, on STING-associated vasculopathy with onset infancy (SAVI), an autosomal dominant, fatal inflammatory disease caused gain-of-function mutations. CD4 T cellpenia is evident SAVI patients mouse models. Using knock-in mice expressing HAQ , Q293 found that splenocytes resist STING-mediated cell death ex vivo, establishing a critical role residue 293 death. HAQ/SAVI(N153S) AQ/SAVI(N153S) did not have cellpenia. HAQ/SAVI(N153S), more (∼10-fold, ∼20-fold, respectively) T-regs than WT/SAVI(N153S) mice. Remarkably, while they comparable TBK1, IRF3, NFκB activation as WT/SAVI AQ/SAVI no inflammation, regular body weight, normal lifespan. We propose promotes depleting cells vivo . Billions modern humans dominant alleles. research STING-targeting should consider heterogeneity humans.

Language: Английский

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The common Sting1 HAQ, AQ alleles rescue CD4 T cellpenia, restore T-regs, and prevent SAVI (N153S) inflammatory disease in mice

eLife, Journal Year: 2024, Volume and Issue: 13

Published: Sept. 18, 2024

The significance of STING1 gene in tissue inflammation and cancer immunotherapy has been increasingly recognized. Intriguingly, common human alleles R71H-G230A-R293Q ( HAQ ) G230A-R293Q AQ are carried by ~60% East Asians ~40% Africans, respectively. Here, we examine the modulatory effects HAQ, on STING-associated vasculopathy with onset infancy (SAVI), an autosomal dominant, fatal inflammatory disease caused gain-of-function mutations. CD4 T cellpenia is evident SAVI patients mouse models. Using Sting1 knock-in mice expressing , Q293 found that splenocytes resist STING1-mediated cell death ex vivo, establishing a critical role residue 293 death. HAQ/SAVI(N153S AQ/SAVI(N153S did not have cellpenia. HAQ/SAVI(N153S), more (~10-fold, ~20-fold, respectively) T-regs than WT/SAVI(N153S mice. Remarkably, while they comparable TBK1, IRF3, NFκB activation as WT/SAVI AQ/SAVI no inflammation, regular body weight, normal lifespan. We propose promotes depleting cells vivo. Billions modern humans dominant alleles. research STING1-targeting should consider heterogeneity humans.

Language: Английский

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Correcting Autoinflammation in STING-Associated Vasculopathy with Onset in Infancy (SAVI) by Human Stem Cell Genome-Editing

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 21, 2024

Type I interferonopathies comprise a large group of Mendelian autoinflammatory diseases that generally lack effective treatments. STING-associated Vasculitis with onset in Infancy (SAVI) is severe autosomal dominant disease due to gain-of-functon(GOF) mutations the gene STING1, encoding for Stimulator Interferon Response CGAMP Interactor 1 (STING1). SAVI leads multisystemic comprising systemic vasculitis and lung fibrosis. A possible therapeutic approach engineer patient’s hematopoietic system restore interferon homeostasis, thereby preventing chronic inflammation organ damage halting development. Here, we describe “universal” genome editing correction strategy using CRISPR/Cas9 targets stimulator response cGAMP interactor (STING1) at endogenous locus patient-derived induced pluripotent stem cells (iPSCs) human CD34+ progenitor (HSPCs). The engineered SAVI-iPSCs express normal levels STING1 protein following differentiation into monocytes macrophages no longer produce interferon-alpha (IFN-α) basal state. Using SAVI-gene-engineered HSPCs, determined minimum fraction mutant alleles required induce spontaneous IFN-α production, thus establishing threshold necessary rescue disease. Finally, demonstrated HSPCs retain regenerative potential by supporting long-term repopulating capacity multi-lineage transplantation immunocompromised mice. Together, these studies established rationale clinical translation framework correcting other type interferonopathies.

Language: Английский

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The commonTMEM173 HAQ, AQalleles rescue CD4 T cellpenia, restore T-regs, and preventSAVI (N153S)inflammatory disease in mice

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 7, 2023

Abstract The significance of STING (encoded by the TMEM173 gene) in tissue inflammation and cancer immunotherapy has been increasingly recognized. Intriguingly, common human alleles R71H-G230A-R293Q ( HAQ) G230A-R293Q AQ ) are carried ∼60% East Asians ∼40% Africans, respectively. Here, we examine modulatory effects HAQ, on STING-associated vasculopathy with onset infancy (SAVI), an autosomal dominant, fatal inflammatory disease caused gain-of-function mutations. CD4 T cellpenia is evident SAVI patients mouse models. Using knock-in mice expressing HAQ , Q293 found that splenocytes resist STING-mediated cell death ex vivo, establishing a critical role residue 293 death. HAQ/SAVI(N153S) AQ/SAVI(N153S) did not have cellpenia. HAQ/SAVI(N153S), more (∼10-fold, ∼20-fold, respectively) T-regs than WT/SAVI(N153S) mice. Remarkably, while they comparable TBK1, IRF3, NFκB activation as WT/SAVI AQ/SAVI no inflammation, regular body weight, normal lifespan. We propose promotes depleting cells vivo . Billions modern humans dominant alleles. research STING-targeting should consider heterogeneity humans. Teaser Common dominate SAVI(N154S) mutant

Language: Английский

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