STING-associated vasculopathy with onset in infancy

STING-associated vasculopathy with onset in infancy
Autosomal dominant pattern is the inheritance manner of this condition
Specialty	Medical genetics
Causes	Mutations in the TMEM173 gene

STING-associated vasculopathy with onset in infancy (SAVI) ^[1] is a rare autoinflammatory vasculopathy associated with the stimulator of interferon genes (STING) protein and characterised by severe skin lesions and interstitial lung disease.

Signs and symptoms

The onset is in infancy. The skin lesions occur on cheeks, nose, fingers, toes and soles. ^[2] They may vary in appearance but frequently develop into non-healing ulcers. Interstitial lung disease is also common. Some individuals may not experience any obvious skin issues. All affected children fail to thrive.^{[ citation needed ]}

Other features include myositis and joint stiffness. Some children experience hyper mobility, and joint pain.^{[ citation needed ]}

Imaging:

Chest X-rays show sign consistent with interstitial lung disease.^{[ citation needed ]}

Bloods:

Anemia, leukopenia, thrombocytosis, T cell lymphopenia with normal B cells and hypergammaglobulinemia may occur. ^{[ citation needed ]}

Autoantibodies may be present including antinuclear, antiphospholipid, and anticardiolipin antibodies.^{[ citation needed ]}

The erythrocyte sedimentation rate and C reactive protein levels tend to be raised. ^{[ citation needed ]}

Biopsies:

Skin biopsies show inflammation of the capillaries and microthrombosis. Immunoglobulin M and C3 deposition may be present.^{[ citation needed ]}

Lung biopsies show fibrosing alveolitis, follicular hyperplasia, B-cell germinal centers and interstitial fibrosis. Some children demonstrate pulmonary alveolar protianosis on Lavage.^{[ citation needed ]}

Genetics

This condition is due to mutations in the TMEM173 gene. This gene is located on the long arm of chromosome 5 (5q31.2) and encodes the stimulator of interferon genes (STING) protein. There are 3 disease causing mutations in the dimerization domain of STING that cause SAVI; V155M, N154S, and V147L.^{[ citation needed ]}

Pathopysiology

This only partly understood. The wild type protein (STING) is normally found in the cytoplasm of the cell. The mutant forms are located in the Golgi apparatus.^{[ citation needed ]} While SAVI is primarily driven by constitutive STING activation and type I interferon overproduction, recent research indicates that STING can also induce necroptosis. A study showed that STING signaling engages ZBP1-mediated necroptosis independently of TNFR1 and FADD, suggesting this mechanism may contribute to inflammatory pathology in STING-related diseases. ^[3]

Diagnosis

The condition may be suspected on clinical grounds. The diagnosis is made by sequencing the TMEM173 gene.^{[ citation needed ]}

Treatment

No specific treatment is known. Management is supportive. Research into the efficacy of a subgroup of medications known as JAK inhibitors (such as Baricitinib) has been studied at the National Institutes of Health, starting in 2014.^{[ citation needed ]} A study showed that genetic deletion of Necroptosis components significantly imporved the survival of the SAVI preclinical murine model N153S suggesting that inhibitor of this inflammatory cell death pathway could represent a potential therapeutic strategy. ^[3]

Epidemiology

This condition is considered rare, with 9 cases reported in the literature up to 2019.^{[ citation needed ]}

Research

This disease was first described in 2014. ^[4] In 2017 a group led by Dr. Jonathan Miner generated the first mouse model of SAVI. Dr. Miner's research team used CRISPR/Cas9 genome editing to introduce a mutation into the mouse STING gene (STING1) ^[5] that was analogous to a human SAVI-associated mutation. These mice, known as STING N153S or SAVI mice, developed spontaneous lung disease and a severe immunodeficiency to a herpesviruses. ^[6] SAVI mice also develop lung disease that depends on adaptive immunity, but not on the type I interferon receptor. ^[7] Whereas SAVI mice also lack lymph nodes and have reduced numbers of innate lymphoid cells (ILCs), patients with SAVI do have lymph nodes despite also having reduced numbers of ILCs. ^[8] Lung disease in SAVI mice also can be regulated by microbes, ^[9] which might reflect the capacity of STING to detect or be regulated by microbial metabolites. The Miner laboratory subsequently moved to the University of Pennsylvania (Penn), where research on mechanisms of STING-associated autoimmunity has continued. ^[10] Other laboratories including those of Kate Fitzgerald (UMass) and Angela Rosen-Wolff (TU Dresden), independently generated the same SAVI mice, as well as additional models, and made similar findings with regard to the role of type I interferon in the mouse model of SAVI. ^[11]

References

1. "STING-associated vasculopathy with onset in infancy". MedlinePlus. Retrieved 21 February 2019.
2. Jeremiah N, Neven B, Gentili M, Callebaut I, Maschalidi S, Stolzenberg MC, et al. (2014). "Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations". J Clin Invest. 124 (12): 5516–5520. doi:10.1172/JCI79100. PMID   25401470.
3. Kelepouras K, Saggau J, Bonasera D, Kiefer C, Locci F, Rakhsh-Khorshid H, et al. (2025). "STING induces ZBP1-mediated necroptosis independently of TNFR1 and FADD". Nature. doi:10.1038/s41586-025-09536-4. PMID   40834903.
4. Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE, Montealegre Sanchez GA, et al. (2014). "Activated STING in a vascular and pulmonary syndrome". New Eng J Med. 371 (6): 507–518. doi:10.1056/NEJMoa1312625. PMC   4174543 . PMID   25029335.
5. Miner JJ, Yan N, Platt DJ, Wu J, Gonugunta VK, Sakai T, et al. (6 November 2017). "STING-associated vasculopathy develops independently of IRF3 in mice". Journal of Experimental Medicine. 214 (11): 3279–3292. doi:10.1084/jem.20171351. ISSN   0022-1007. PMC   5679177 . PMID   28951494.
6. Miner JJ, Baldridge MT, Smith AM, Platt DJ, Miner CA, Ai TL, et al. (15 February 2019). "A Human Gain-of-Function STING Mutation Causes Immunodeficiency and Gammaherpesvirus-Induced Pulmonary Fibrosis in Mice". Journal of Virology. 93 (4): e01806–18. doi:10.1128/JVI.01806-18. ISSN   0022-538X. PMC   6364005 . PMID   30463976.
7. Luksch H, Stinson WA, Platt DJ, Qian W, Kalugotla G, Miner CA, et al. (July 2019). "STING-associated lung disease in mice relies on T cells but not type I interferon". The Journal of Allergy and Clinical Immunology. 144 (1): 254–266.e8. doi:10.1016/j.jaci.2019.01.044. ISSN   1097-6825. PMC   6612314 . PMID   30772497.
8. Bennion BG, Croft CA, Ai TL, Qian W, Menos AM, Miner CA, et al. (16 June 2020). "STING Gain-of-Function Disrupts Lymph Node Organogenesis and Innate Lymphoid Cell Development in Mice". Cell Reports. 31 (11): 107771. doi:10.1016/j.celrep.2020.107771. ISSN   2211-1247. PMC   7372600 . PMID   32553167.
9. Platt DJ, Lawrence D, Rodgers R, Schriefer L, Qian W, Miner CA, et al. (11 May 2021). "Transferrable protection by gut microbes against STING-associated lung disease". Cell Reports. 35 (6): 109113. doi:10.1016/j.celrep.2021.109113. ISSN   2211-1247. PMC   8477380 . PMID   33979608.
10. "The Miner Lab studies rare diseases and antiviral immunity | Miner Lab | Perelman School of Medicine at the University of Pennsylvania". www.med.upenn.edu. Retrieved 31 December 2021.
11. Motwani M, Pawaria S, Bernier J, Moses S, Henry K, Fang T, et al. (16 April 2019). "Hierarchy of clinical manifestations in SAVI N153S and V154M mouse models". Proceedings of the National Academy of Sciences of the United States of America. 116 (16): 7941–7950. Bibcode:2019PNAS..116.7941M. doi: 10.1073/pnas.1818281116 . ISSN   1091-6490. PMC   6475399 . PMID   30944222.