Huang Qin, Shen Shuqun, Qu Hang, Huang Yu, Wu Danni, Jiang Haishan, Yuan Chao
Department of Rheumatology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Dermatology Hospital, Southern Medical University, Guangzhou 510515, China.
Ann Transl Med. 2020 Jan;8(1):9. doi: 10.21037/atm.2019.12.44.
Previous studies show that the high-mobility group box protein 1 (HMGB1) and the toll-like receptor 4 (TLR4) participate in systemic lupus erythematosus (SLE). The two molecules contribute to the occurrence and persistence of seizures in various disease conditions, such as epilepsy. Since seizures are one of the most severe complications associated with neuropsychiatric SLE (NPSLE), the current study aimed at investigating whether HMGB1 and TLR4 play any role in NPSLE related seizures.
Data from 291 SLE patients and 100 healthy controls (HC) were prospectively collected from 2013 to 2018. The ELISA test was used to determine serum levels of HMGB1 for all patients and HC and cerebrospinal fluid (CSF) levels of NPSLE patients. The expression levels of TLR4 by the peripheral blood monocytes (PBMCs) were determined by real-time PCR of TLR4 mRNA. Binary logistic regression and ROC curve analysis were used to predict NPSLE.
Among the 291 SLE patients, 188 had active disease and were grouped into two, NPSLE (N=86) and Non-NPSLE (N=102) groups. Among the NPSLE patients, 21 had seizure disorders. Serum HMGB1 levels were increased in NPSLE (8.73±0.29 ng/mL) and were associated with disease activity (r=0.6527, P=0.000). Both serum and CSF HMGB1 levels in NPSLE patients with seizure disorders (9.59±0.63 and 2.90±2.29 ng/mL, respectively) were higher than in patients with other neuropsychiatric symptoms (8.45±0.33 and 2.56±1.70 ng/mL, respectively), though without significance. The gene expression of mRNA TLR4 in PBMCs was similar to serum HMGB1 in the investigated groups. Independent predictors of NPSLE were SLEDAI-2k (OR 1.25; 95% CI: 1.155-1.353), serum HMGB1 (OR 1.659; 95% CI: 1.266-2.175), and anti-Rib-P Ab (OR 3.296; 95% CI: 1.013-10.725). ROC curves for the above predictors had a large AUC (95% CI) of 0.936 (0.900-0.971), indicating a good prediction of NPSLE occurrence.
The expression of HMGB1 and TLR4 was increased in NPSLE, but HMGB1 and TLR4 had minimal effect on NPSLE related seizures. The serum levels of HMGB1 were positively correlated with disease activity, and could, therefore, be a potential biomarker of NPSLE for use in future clinical practice.
先前的研究表明，高迁移率族蛋白B1（HMGB1）和Toll样受体4（TLR4）参与系统性红斑狼疮（SLE）。在各种疾病状态下，如癫痫，这两种分子会导致癫痫发作的发生和持续。由于癫痫发作是与神经精神性SLE（NPSLE）相关的最严重并发症之一，当前研究旨在调查HMGB1和TLR4在NPSLE相关癫痫发作中是否发挥作用。
前瞻性收集了2013年至2018年291例SLE患者和100例健康对照（HC）的数据。采用ELISA检测所有患者和HC的血清HMGB1水平以及NPSLE患者的脑脊液（CSF）水平。通过TLR4 mRNA的实时PCR测定外周血单核细胞（PBMCs）中TLR4的表达水平。采用二元逻辑回归和ROC曲线分析预测NPSLE。
在291例SLE患者中，188例疾病活动，分为两组，即NPSLE组（N = 86）和非NPSLE组（N = 102）。在NPSLE患者中，21例有癫痫发作障碍。NPSLE患者血清HMGB1水平升高（8.73±0.29 ng/mL），且与疾病活动相关（r = 0.6527，P = 0.000）。有癫痫发作障碍的NPSLE患者的血清和CSF HMGB1水平（分别为9.59±0.63和2.90±2.29 ng/mL）高于有其他神经精神症状的患者（分别为8.45±0.33和2.56±1.70 ng/mL），但无统计学意义。研究组中PBMCs中mRNA TLR4的基因表达与血清HMGB1相似。NPSLE的独立预测因素为SLEDAI-2k（OR为1.25；95%CI：1.155 - 1.353）、血清HMGB1（OR为1.659；95%CI：1.266 - 2.175）和抗Rib-P抗体（OR为3.296；95%CI：1.013 - 10.725）。上述预测因素的ROC曲线的AUC（95%CI）为0.936（0.900 - 0.971），表明对NPSLE的发生有良好的预测能力。
NPSLE中HMGB1和TLR4的表达增加，但HMGB1和TLR4对NPSLE相关癫痫发作的影响最小。血清HMGB1水平与疾病活动呈正相关，因此可能成为未来临床实践中NPSLE的潜在生物标志物。
