Expression of Cyclic GMP-AMP Synthase in Patients With Systemic Lupus Erythematosus
Expression of Cyclic GMP-AMP Synthase in Patients With Systemic Lupus Erythematosus
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DOI：
10.1002/art.40002
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发表时间：
2017-04-01
影响因子：
13.3
通讯作者：
Elkon, Keith B.
中科院分区：
文献类型：
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作者：
An, Jie;Durcan, Laura;Elkon, Keith B.
Objective. I型干扰素（IFN）与系统性红斑狼疮（SLE）和干扰素病如Aicardi-Goutieres综合征的发病机制有关。最近发现的DNA激活的I型IFN途径，环GMP-AMP合酶（cGAS），已与Aicardi-Goutieres综合征和狼疮小鼠模型。本研究的目的是确定cGAS途径是否有助于SLE患者I型IFN的产生。通过系统性红斑狼疮疾病活动指数的雌激素在红斑狼疮中的安全性国家评估版本来测量SLE疾病活动。通过定量聚合酶链反应分析测定cGAS和IFN刺激基因（ISG）的信使RNA表达。采用超高效液相色谱-串联质谱多反应监测法检测环磷酸腺苷（cGAMP）水平。SLE患者外周血单个核细胞（PBMCs）中cGAS的表达显著高于正常对照组（分别为51例和20例，P< 0.01）。cGAS表达与IFN评分呈正相关（P< 0.001）。PBMC中cGAS的表达在体外显示出对I型IFN刺激的剂量响应，与其是ISG一致。通过串联质谱法对cGAMP进行靶向测量，在15%的SLE患者（48例中的7例）中检测到cGAMP，但在正常对照组（19例中的0例）或类风湿性关节炎对照组（22例中的0例）中均未检测到cGAMP。cGAMP阳性的SLE患者疾病活动性高于无cGAMP的SLE患者。在一部分SLE患者中增加的cGAS表达和cGAMP表明cGAS途径应被认为是I型IFN产生的贡献者。尽管更高的cGAS表达可能是暴露于I型IFN的结果，但在疾病活动性增加的患者中检测到cGAMP表明该途径可能参与疾病表达。
Objective. Type I interferon (IFN) is implicated in the pathogenesis of systemic lupus erythematosus (SLE) and interferonopathies such as Aicardi-Goutieres syndrome. A recently discovered DNA-activated type I IFN pathway, cyclic GMP-AMP synthase (cGAS), has been linked to Aicardi-Goutieres syndrome and mouse models of lupus. The aim of this study was to determine whether the cGAS pathway contributes to type I IFN production in patients with SLE.Methods. SLE disease activity was measured by the Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index. Expression of messenger RNA for cGAS and IFN-stimulated genes (ISGs) was determined by quantitative polymerase chain reaction analysis. Cyclic GMP-AMP (cGAMP) levels were examined by multiple reaction monitoring with ultra-performance liquid chromatography tandem mass spectrometry.Results. Expression of cGAS in peripheral blood mononuclear cells (PBMCs) was significantly higher in SLE patients than in normal controls (n=51 and n=20 respectively; P< 0.01). There was a positive correlation between cGAS expression and the IFN score (P< 0.001). The expression of cGAS in PBMCs showed a dose response to type I IFN stimulation in vitro, consistent with it being an ISG. Targeted measurement of cGAMP by tandem mass spectrometry detected cGAMP in 15% of the SLE patients (7 of 48) but none of the normal (0 of 19) or rheumatoid arthritis (0 of 22) controls. Disease activity was higher in SLE patients with cGAMP versus those without cGAMP.Conclusion. Increased cGAS expression and cGAMP in a proportion of SLE patients indicates that the cGAS pathway should be considered as a contributor to type I IFN production. Whereas higher cGAS expression may be a consequence of exposure to type I IFN, detection of cGAMP in patients with increased disease activity indicates potential involvement of this pathway in disease expression.