Interferon Mutation Causes Fatal Infant Vasculopathy

Liu Y, Jesus AA, Marrero B, et al. Activated STING in a Vascular and Pulmonary Syndrome. N Engl J Med (2014) Published online July 16. doi: 10.1056/NEJMoa1312625

Crow YJ and Casanova J-L. STING-Associated Vasculopathy with Onset in Infancy - A New Interferonopathy. N Engl J Med  (2014) Published online July 16. doi: 10.1056/NEJMe1407246

A single-point mutation has been identified as the cause of a rare pediatric vascular inflammatory disease. This identification has given insights into the inflammatory mechanisms of antiviral defense that are dysregulated in many autoimmune diseases. It also hints at treatments for this fatal disease that is refractory to conventional treatments, and to diseases like it, such as systemic lupus erythematosus, that share an inflammatory pathway.

The mutation is in the TMEM173 gene, which codes for the stimulator of interferon genes (STING) protein. The authors found three different de novo mutations in six patients. These were gain-of-function mutations, which led to chronic induction of type 1 interferon (IFN). This resulted in capillary vasculitis and interstitial lung disease.

The investigators named the disease STING-associated vasculopathy with onset in infancy (SAVI). The clinical syndrome is characterized by a severe cutaneous vasculopathy leading to extensive tissue loss and structural damage, with neonatal-onset systemic inflammation, elevated ESR (erytherocyte sedimentation rate) and elevated CRP (C-reactive protein). Three patients also had major interstitial lung disease.

In the skin, there was a dense neutrophilic inflammatory infiltrate with blood-vessel damage. Lung biopsies showed lymphocytic inflammatory infiltrate resulting in interstitial fibrosis and emphysematious changes. STING was widely expressed in endothelial and alveolar cells. There was increased expression of IFN-stimulated gene transcripts and elevated levels of IFN-induced cytokines in peripheral whole blood.

Patients presented in early infancy with systemic inflammation and violaceous, scaling lesions of fingers, toes, nose, cheeks and ears that progressed to necrosis and did not respond to steroids, disease-modifying anti-rheumatic drugs, intravenous IgG, and other biologics. One patient was alive at age 23 (possibly with a mosaic presentation), one at age 16, but one died at age 14 and one at age 15.

STING, a transmembrane protein in the endoplasmic reticulum, is part of the type 1 IFN response to DNA viruses. In the cytosol, proteins sense double-stranded DNA, and bind to STING, which sends a transcription factor into the nucleus that binds to nuclear DNA and starts transcribing type 1 IFN-α and IFN-β. The IFNs bind to IFN receptors in the same cell and nearby cells to stimulate the JAK-STAT pathway, which also translocates into the nucleus and upregulates IFN transcription. JAK inhibition blocks this feedback loop.

The involvement of the JAK-STAT pathway suggests a therapeutic role for JAK inhibitors, which blocked IFN transcriptions in vitro, and may break the feedback loop that fuels continuous IFN signaling in SAVI. A compassionate use protocol has been  approved for treatment with the JAK inhibitor baricitinib.

Another alternative would be to block STING directly. Blocking STING might also be effective for other diseases that involve type 1 IFN being upregulated by DNA, such as systemic lupus erythematosus.

The IFN-response-gene signature suggests similarities to Aicardi-Gouti̬res syndrome, an early-onset encephalopathy, and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), a proteosome-associated autoinflammatory syndrome. Different defects in the IFN pathway appear to result in overlapping features. At least one version of Aicardi-Gouti̬res syndrome is caused by mutations in IFIH1, a gene encoding MDA5, which responds to RNA in the cytosol Рnot DNA Рand has brain involvement.