Qiang Fu1, Qiuying He2, Qian Dong1, Jinye Xie2, Yiyun Geng2, Hui Han2, Yanhua Huang2, Jianqiang Lu2, Zhijie Zeng2, Weijia Wang3, Kang Chen4, Xiaoxia Zhan5. 1. Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-sen University, 2 Zhongshan Road, Guangzhou 510080, Guangdong, China. 2. Department of Laboratory Medicine, Zhongshan Hospital of Sun Yat-sen University, 2 Sunwendong Road, Zhongshan 528403, Guangdong, China. 3. Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-sen University, 2 Zhongshan Road, Guangzhou 510080, Guangdong, China. Electronic address: wwj0760@163.com. 4. Department of Laboratory Medicine, Zhongshan Hospital of Sun Yat-sen University, 2 Sunwendong Road, Zhongshan 528403, Guangdong, China. Electronic address: ck521620@163.com. 5. Department of Laboratory Medicine, Zhongshan Hospital of Sun Yat-sen University, 2 Sunwendong Road, Zhongshan 528403, Guangdong, China. Electronic address: xiaoxiazhan14@163.com.
Abstract
BACKGROUND: Diverse clinical and serological manifestations of systemic lupus erythematosus (SLE) compromise its diagnosis and treatment. A more reliable biomarker for SLE, which can play a critical role in either diagnosis, monitoring the disease progress or evaluating the response to treatment for individualized therapeutic, is necessary. DNA sensor is an important mediator of inflammation in systemic autoimmune diseases. However, the potential role for DNA sensor as disease activity biomarkers for SLE remained obscure. We detected the aberrant activation of DNA sensors and the corresponding IFN-β response in SLE patients, and to evaluate their potential role as disease biomarkers for SLE. METHODS: We quantified the expressions of IFN-I and DNA sensor, such as cGAS, IFI16, DDX41, DAI and their down-stream adaptor STING in PBMC derived from patients with SLE (n = 100), healthy controls (HCs) (n = 62) by real-time PCR. The relationships between the expression of cGAS or IFI16 and clinical features in SLE patients were investigated. ROC curve analysis was performed to examine the predictive value of cGAS and IFI16 in SLE diagnosis, disease activity monitoring, specific organ manifestation and therapeutic response. RNA interference-mediated depletion of IFI16 or cGAS was conducted to evaluate their impact on IFN-I response. RESULTS: The expressions of cGAS and IFI16 were significantly higher in PBMC from SLE patients, closely correlated with the SLEDAI scores and high anti-dsDNA antibody titers. While the AUC for cGAS (0.767) was less than that of IFI16 and IFN-β, the AUC for IFI16 (0.856) and IFN-β (0.856) were similar. Expression of cGAS and IFI16 combine with IFN-β in PBMC showed high sensitivity (89.2%) and specificity (89.1%) for discrimination between mild and moderate/severe disease activity in SLE. Higher expression of IFI16 was association with ocular disorder in SLE patients. Neither IFI16 nor cGAS was a reliable indicator of therapeutic response. RNA interference-mediated depletion of IFI16 or cGAS prevented active SLE serum-induced upregulating in both IFN-α and IFN-β. CONCLUSIONS: High expression levels of cGAS and IFI16 in PBMC from SLE patients correlated strongly with disease activity. Both cGAS and IFI16 mediated signaling pathway were account for the robust production of IFN-β. Expression of cGAS and IFI16 combined with IFN-β in PBMC might serve as potential biomarkers for early diagnosis and monitoring disease activity in SLE.
BACKGROUND: Diverse clinical and serological manifestations of systemic lupus erythematosus (SLE) compromise its diagnosis and treatment. A more reliable biomarker for SLE, which can play a critical role in either diagnosis, monitoring the disease progress or evaluating the response to treatment for individualized therapeutic, is necessary. DNA sensor is an important mediator of inflammation in systemic autoimmune diseases. However, the potential role for DNA sensor as disease activity biomarkers for SLE remained obscure. We detected the aberrant activation of DNA sensors and the corresponding IFN-β response in SLE patients, and to evaluate their potential role as disease biomarkers for SLE. METHODS: We quantified the expressions of IFN-I and DNA sensor, such as cGAS, IFI16, DDX41, DAI and their down-stream adaptor STING in PBMC derived from patients with SLE (n = 100), healthy controls (HCs) (n = 62) by real-time PCR. The relationships between the expression of cGAS or IFI16 and clinical features in SLE patients were investigated. ROC curve analysis was performed to examine the predictive value of cGAS and IFI16 in SLE diagnosis, disease activity monitoring, specific organ manifestation and therapeutic response. RNA interference-mediated depletion of IFI16 or cGAS was conducted to evaluate their impact on IFN-I response. RESULTS: The expressions of cGAS and IFI16 were significantly higher in PBMC from SLE patients, closely correlated with the SLEDAI scores and high anti-dsDNA antibody titers. While the AUC for cGAS (0.767) was less than that of IFI16 and IFN-β, the AUC for IFI16 (0.856) and IFN-β (0.856) were similar. Expression of cGAS and IFI16 combine with IFN-β in PBMC showed high sensitivity (89.2%) and specificity (89.1%) for discrimination between mild and moderate/severe disease activity in SLE. Higher expression of IFI16 was association with ocular disorder in SLE patients. Neither IFI16 nor cGAS was a reliable indicator of therapeutic response. RNA interference-mediated depletion of IFI16 or cGAS prevented active SLE serum-induced upregulating in both IFN-α and IFN-β. CONCLUSIONS: High expression levels of cGAS and IFI16 in PBMC from SLE patients correlated strongly with disease activity. Both cGAS and IFI16 mediated signaling pathway were account for the robust production of IFN-β. Expression of cGAS and IFI16 combined with IFN-β in PBMC might serve as potential biomarkers for early diagnosis and monitoring disease activity in SLE.