STING-associated vasculopathy with onset in infancy
Autosomal dominant pattern is the inheritance manner of this condition
SpecialtyMedical genetics
CausesMutations 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.

Other features include myositis and joint stiffness. Some children experience hyper mobility, and joint pain.

Imaging:

Chest X-rays show sign consistent with interstitial lung disease.

Bloods:

Anemia, leukopenia, thrombocytosis, T cell lymphopenia with normal B cells and hypergammaglobulinemia may occur.

Autoantibodies may be present including antinuclear, antiphospholipid, and anticardiolipin antibodies.

The erythrocyte sedimentation rate and C reactive protein levels tend to be raised.

Biopsies:

Skin biopsies show inflammation of the capillaries and microthrombosis. Immunoglobulin M and C3 deposition may be present.

Lung biopsies show fibrosing alveolitis, follicular hyperplasia, B-cell germinal centers and interstitial fibrosis. Some children demonstrate pulmonary alveolar protianosis on Lavage.

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.

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.

Diagnosis

The condition may be suspected on clinical grounds. The diagnosis is made by sequencing the TMEM173 gene.

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.

Epidemiology

This condition is considered rare, with 9 cases reported in the literature up to 2019.

Research

This disease was first described in 2014.[3] 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)[4] 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.[5] SAVI mice also develop lung disease that depends on adaptive immunity, but not on the type I interferon receptor.[6] 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.[7] Lung disease in SAVI mice also can be regulated by microbes,[8] 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.[9] 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.[10]

References

  1. ↑ Reference, Genetics Home. "SAVI". Genetics Home Reference. Retrieved 2019-02-21.
  2. ↑ Jeremiah N, Neven B, Gentili M, Callebaut I, Maschalidi S, Stolzenberg M-C, Goudin N, Fremond, M-L, Nitschke P, Molina TJ, Blanche S, Picard C, Rice GI, Crow YJ, Manel N, Fischer A, Bader-Meunier B, Rieux-Laucat, F (2014) Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations. J Clin Invest 124: 5516-5520
  3. ↑ Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE, Montealegre Sanchez GA, Tenbrock K, Wittkowski H, Jones OY, Kuehn HS, Lee C-C R, DiMattia M A, and 40 others. Activated STING in a vascular and pulmonary syndrome. New Eng J Med 371: 507-518
  4. ↑ Miner, Jonathan J.; Yan, Nan; Platt, Derek J.; Wu, Jianjun; Gonugunta, Vijay K.; Sakai, Tomomi; Miner, Cathrine A.; Smith, Amber M.; Ai, Teresa L. (2017-11-06). "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.
  5. ↑ Miner, Jonathan J.; Baldridge, Megan T.; Smith, Amber M.; Platt, Derek J.; Miner, Cathrine A.; Ai, Teresa L.; Ingle, Harshad; Bennion, Brock G. (2019-02-15). "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.
  6. ↑ Luksch, Hella; Stinson, W. Alexander; Platt, Derek J.; Qian, Wei; Kalugotla, Gowri; Miner, Cathrine A.; Bennion, Brock G.; Gerbaulet, Alexander; Rösen-Wolff, Angela; Miner, Jonathan J. (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.
  7. ↑ Bennion, Brock G.; Croft, Carys A.; Ai, Teresa L.; Qian, Wei; Menos, Amber M.; Miner, Cathrine A.; Frémond, Marie-Louis; Doisne, Jean-Marc; Andhey, Prabhakar S.; Platt, Derek J.; Bando, Jennifer K. (2020-06-16). "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.
  8. ↑ Platt, Derek J.; Lawrence, Dylan; Rodgers, Rachel; Schriefer, Lawrence; Qian, Wei; Miner, Cathrine A.; Menos, Amber M.; Kennedy, Elizabeth A.; Peterson, Stefan T.; Stinson, W. Alexander; Baldridge, Megan T. (2021-05-11). "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.
  9. ↑ "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 2021-12-31.
  10. ↑ Motwani, Mona; Pawaria, Sudesh; Bernier, Jennifer; Moses, Stephanie; Henry, Kate; Fang, Terry; Burkly, Linda; Marshak-Rothstein, Ann; Fitzgerald, Katherine A. (2019-04-16). "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.
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