Activated STING in a vascular and pulmonary syndrome.
Activated STING in a vascular and pulmonary syndrome.
复制标题
DOI：
10.1056/nejmoa1312625
复制
发表时间：
2014-08-07
期刊：
影响因子：
--
通讯作者：
Goldbach-Mansky R
中科院分区：
文献类型：
--
作者：
Liu Y;Jesus AA;Marrero B;Yang D;Ramsey SE;Sanchez GAM;Tenbrock K;Wittkowski H;Jones OY;Kuehn HS;Lee CR;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
自身炎症性疾病的研究已经揭示了细胞因子失调和炎症的潜在机制。我们分析了早发性全身性炎症、皮肤血管病变和肺部炎症患者的DNA。我们对该患者和5名具有相似临床表型的无关儿童的候选基因TMEM 173进行了测序，该基因编码干扰素刺激因子基因（STING）。4名儿童进行了临床和免疫学评价。使用STING配体环磷酸鸟苷-单磷酸腺苷（cGAMP），我们刺激来自患者和对照的外周血单核细胞和成纤维细胞，以及商业获得的内皮细胞，然后测定受刺激细胞中编码干扰素-β的基因IFNB 1的转录。我们分析了与突变或非突变STING构建体共转染的HEK 293 T细胞中的IFNB 1报告基因水平。突变STING导致信号转导和转录激活因子1（STAT 1）的磷酸化增加，因此我们测试了Janus激酶（JAK）抑制剂对受影响儿童和对照组淋巴细胞中STAT 1磷酸化的影响。我们在6例患者中发现了TMEM 173外显子5的3个突变。患者外周血单核细胞中IFNB 1和STING的其他基因靶点的转录升高表明该途径的组成性激活，不能通过刺激进一步上调。在用cGAMP刺激时，来自患者的成纤维细胞显示IFNB 1的转录增加，但编码白细胞介素-1（IL 1）、白细胞介素-6（IL 6）或肿瘤坏死因子（TNF）的基因的转录没有增加。用突变体构建体转染的HEK 293 T细胞显示升高的IFNB 1报告基因水平。STING在内皮细胞中表达，并且这些细胞暴露于cGAMP导致内皮活化和凋亡。JAK抑制剂降低了患者淋巴细胞中磷酸化STAT 1的组成性上调。婴儿期发作的STING相关血管病变（SAVI）是一种由TMEM 173功能获得性突变引起的自身炎症性疾病。
The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation. 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. 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. STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disease caused by gain-of-function mutations in TMEM173.