University of Washington, Seattle.
University of Manchester, Manchester, UK.
Arthritis Rheumatol. 2017 Apr;69(4):800-807. doi: 10.1002/art.40002. Epub 2017 Mar 7.
Type I interferon (IFN) is implicated in the pathogenesis of systemic lupus erythematosus (SLE) and interferonopathies such as Aicardi-Goutières syndrome. A recently discovered DNA-activated type I IFN pathway, cyclic GMP-AMP synthase (cGAS), has been linked to Aicardi-Goutières 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.
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.
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.
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.
I 型干扰素（IFN）参与了系统性红斑狼疮（SLE）和干扰素病（如 Aicardi-Goutières 综合征）的发病机制。最近发现的 DNA 激活的 I 型 IFN 途径，环鸟苷酸-腺苷酸合酶（cGAS），与 Aicardi-Goutières 综合征和狼疮的小鼠模型有关。本研究旨在确定 cGAS 途径是否有助于 SLE 患者产生 I 型 IFN。
通过红斑狼疮性疾病活动指数的安全性评估（Safety of Estrogens in Lupus Erythematosus National Assessment version）来衡量 SLE 的疾病活动。通过定量聚合酶链反应分析来测定 cGAS 和 IFN 刺激基因（ISGs）的信使 RNA 表达。通过超高效液相色谱串联质谱法的多重反应监测来检查环鸟苷酸-腺苷酸（cGAMP）的水平。
SLE 患者外周血单个核细胞（PBMCs）中 cGAS 的表达明显高于正常对照组（n=51 和 n=20；P<0.01）。cGAS 表达与 IFN 评分呈正相关（P<0.001）。cGAS 在 PBMCs 中的表达对体外 I 型 IFN 刺激呈剂量反应，与其作为 ISG一致。串联质谱法对 cGAMP 的靶向测量在 15%的 SLE 患者（48 例中的 7 例）中检测到 cGAMP，但在正常对照（19 例中均未检测到）或类风湿关节炎（22 例中均未检测到）对照中均未检测到。cGAMP 阳性的 SLE 患者的疾病活动度更高。
一部分 SLE 患者中 cGAS 表达和 cGAMP 的增加表明 cGAS 途径应被视为产生 I 型 IFN 的原因之一。虽然更高的 cGAS 表达可能是暴露于 I 型 IFN 的结果，但在疾病活动增加的患者中检测到 cGAMP 表明该途径可能参与疾病的表达。
