Article type:
Research
Estimated read time:
4 mins min read
Published:
26/09/2025
The first description of STING-associated vasculopathy with onset in infancy (SAVI) as an inflammatory interferonopathy caused by DNA variants of the gene TMEM173 which produces the protein Stimulator of Interferon Genes (STING)
Date of publication:
16/2/26
Author:
Roger Brooks
Category:
SAVI clinical
Article body content:
Plain Language
Doctors studied several children who became seriously ill very early in life with ongoing inflammation. These children developed painful skin sores on their fingers, toes, ears, and nose, and many also developed serious lung problems. Usual treatments for inflammation did not work well.
The researchers discovered that these children all had changes (mutations) producing variants of a single gene called TMEM173. This gene controls an important protein involved of the immune system called Stimulator of Interferon Genes (STING), which normally helps the body fight infections. In these children, STING was stuck in the “on” position. This caused the immune system to be overactive all the time, even when there was no infection.
Because the immune system was constantly active, it released too much of a chemical messenger called interferon. Too much interferon can cause damage to small blood vessels and to the lungs and possibly explains why children developed:
· Skin ulcers and tissue loss on fingers, toes, ears, and nose
· Ongoing inflammation
· Lung disease and breathing problems
· Poor growth and serious illness from a very young age
The researchers named this condition STING-associated vasculopathy with onset in infancy (SAVI).
In laboratory tests, the scientists tried medicines called (Janus Kinase) JAK
inhibitors, which block part of the immune signalling pathway. These medicines reduced the abnormal immune activity in patients’ cells. This suggests that these drugs may help treat the disease.
Why it Matters
· It provides a clear genetic explanation for a rare and serious childhood disease.
· It shows that the illness is caused by an overactive immune system, not by infection.
· It opens the possibility of targeted treatments rather than general immune suppression.
· It gives families and doctors a name and diagnosis for the condition (SAVI), which can help with care, research, and support.
Hope for the Future
· The findings suggest that JAK inhibitor drugs could be an effective treatment.
· Targeting the interferon/STING pathway may help not only SAVI patients but also other interferon-driven inflammatory diseases.
· This opens the door to more precise, mechanism-based therapies instead of broad immune suppression.
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Background
Autoinflammatory diseases frequently arise from dysregulation of innate immune signalling pathways. Several early-onset inflammatory syndromes are characterised by excessive type I interferon activity (“interferonopathies”). The authors investigated infants presenting with severe, treatment-refractory systemic inflammation, vasculitic skin lesions, and pulmonary disease in order to identify an underlying genetic and mechanistic cause
What the Study Found
· Whole-exome and targeted sequencing revealed heterozygous de novo mutations clustered in exon 5 of TMEM173.
· These variants produced constitutive activation of STING, independent of ligand stimulation.
· Patient-derived peripheral blood mononuclear cells exhibited a marked interferon-response gene signature and elevated IFNB1 transcription.
· Endothelial cells expressed STING and showed inflammatory activation and apoptosis following STING stimulation, providing a mechanistic basis for vasculopathy.
· Mutant STING constructs transfected into HEK293T cells caused ligand-independent activation of interferon-β reporter genes.
· Constitutive STAT1 phosphorylation was observed in lymphocytes and was reduced in vitro by JAK inhibitors (tofacitinib, ruxolitinib, baricitinib).
Citation Liu Y et al., New Engl J Med. 2014 371:507-18.
Authors Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE, Montealegre Sanchez GA, Tenbrock K, Wittkowski H, Jones OY, Kuehn HS, Lee CCR, DiMattia MA, Cowen EW, Gonzalez B, Palmer I, DiGiovanna JJ, Biancotto A, Kim H, Tsai WL, Trier AM, Huang Y, Stone DL, Hill S, Kim HJ, St. Hilaire C, Gurprasad S, Plass N, Chapelle D, Horkayne-Szakaly I, Foell D, Barysenka A, Candotti F, Holland SM, Hughes JD, Mehmet H, Issekutz AC, Raffeld M, McElwee J, Fontana JR, Minniti CP, Moir S, Kastner DL, Gadina M, Steven AC, Wingfield PT, Brooks SR, Rosenzweig SD, Fleisher TA, Deng Z, Boehm M, Paller AS, Goldbach-Mansky R.
Date of publication 16/7/14 Link 10.1056/NEJMoa1312625