Activated STING in a Vascular and Pulmonary Syndrome

Abstract

BACKGROUND The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation. METHODS We analyzed the DNA of an index patient with early-onset systemic inflammation, cutaneous vasculopathy, and pulmonary inflammation. We sequenced a candidate gene, TMEM173, encoding the stimulator of interferon genes (STING), in this patient and in five unrelated children with similar clinical phenotypes. Four children were evaluated clinically and immunologically. With the STING ligand cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), we stimulated peripheral-blood mononuclear cells and fibroblasts from patients and controls, as well as commercially obtained endothelial cells, and then assayed transcription of IFNB1, the gene encoding interferon-β, in the stimulated cells. We analyzed IFNB1 reporter levels in HEK293T cells cotransfected with mutant or nonmutant STING constructs. Mutant STING leads to increased phosphorylation of signal transducer and activator of transcription 1 (STAT1), so we tested the effect of Janus kinase (JAK) inhibitors on STAT1 phosphorylation in lymphocytes from the affected children and controls. RESULTS We identified three mutations in exon 5 of TMEM173 in the six patients. Elevated transcription of IFNB1 and other gene targets of STING in peripheral-blood mono-nuclear cells from the patients indicated constitutive activation of the pathway that cannot be further up-regulated with stimulation. On stimulation with cGAMP, fibro-blasts from the patients showed increased transcription of IFNB1 but not of the genes encoding interleukin-1 (IL1), interleukin-6 (IL6), or tumor necrosis factor (TNF). HEK293T cells transfected with mutant constructs show elevated IFNB1 reporter levels. STING is expressed in endothelial cells, and exposure of these cells to cGAMP resulted in endothelial activation and apoptosis. Constitutive up-regulation of phosphorylated STAT1 in patients’ lymphocytes was reduced by JAK inhibitors. CONCLUSIONS STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disease caused by gain-of-function mutations in TMEM173.

Defective removal of ribonucleotides from DNA promotes systemic autoimmunity

“…autoimmunity in AGS and SLE, targeting the IFN axis by type I IFN blockade may be of potential therapeutic efficacy. Indeed, IFN-α antagonists have been tested in SLE patients in clinical trials with promising results (55), while JAK inhibition was recently reported to ameliorate symptoms in patients with the type I IFNdriven STING-associated vasculopathy (56). TREX1 has been implicated in the restriction of retroelements by metabolizing reverse-transcribed retroelement-derived RNA (46), raising the possibility that retroelement-derived RNA/DNA hybrids may act as substrates of RNase H2.…”

Venous thromboembolism in systemic autoimmune diseases: A narrative review with emphasis on primary systemic vasculitides

“…Another recent exciting discovery related to gene mutations and inflammatory vasculopathy is STINGassociated vasclulopathy. 35 The gene mutations in exon 5 of TMEM173, encoding the stimulator of interferon genes (STING) were found in six patients with systemic inflammation, peripheral vascular inflammation and pulmonary manifestations. DVT was not observed in the six patients studied.…”

Treatment of CNS Vasculitis in Children

“…Newly recognized diseases such as early-onset stroke and vasculopathy associated with mutations in adenosine deaminase 2 (ADA2) and activated stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI) are both mimics of CNS vasculitis [69][70][71]. ADA2 mutations have also been described in children with a polyarteritis nodosa [70].…”

“…Treatment with etanercept has been successful in patients with ADA2 mutations [69]. JAK inhibitors have been shown to be effective in vitro in SAVI [71].…”