Wang Jiajia, Cheng Qiyao, Wang Xia, Zu Beibei, Xu Jianhua, Xu Yuanhong, Zuo Xianbo, Shen Yujun, Wang Jing, Shen Yuxian
School of Basic Medical Sciences (JW, QC, XW, YS, YS), Anhui Medical University, Hefei, China; Institute of Biopharmaceutics (JW, QC, XW, YS, YS), Anhui Medical University, Hefei, China; Rheumatism Immunity Branch of Xuzhou Central Hospital (BZ), Xuzhou, China; First Affiliated Hospital (JX, YX, XZ), Anhui Medical University, Hefei, China; School of Pharmacy (QC), Anhui Medical University, Hefei, China; and School of Public Health (JW), Anhui Medical University, Hefei, China.
Am J Med Sci. 2014 Dec;348(6):465-73. doi: 10.1097/MAJ.0000000000000328.
Systemic lupus erythematosus (SLE) is an autoimmune disease with uncertain pathogenesis. Endoplasmic reticulum (ER) stress has close correlations with inflammation and/or immune diseases. However, it is unknown whether aberrant ER stress is involved in SLE pathogenesis. We aimed to characterize the ER stress-related genes in patients with SLE and analyzed their correlations with the disease. Peripheral blood leucocytes were isolated from 76 well-characterized patients with SLE and 69 healthy controls. ER stress-related genes were determined at transcription level by absolute quantitative real-time polymerase chain reaction. Stepwise regression and correlation analysis were used to analyze the relationships between SLE disease and ER stress. Abnormal unfolded protein responses were found in patients with SLE with the downregulation of inositol-requiring enzyme 1 (IRE1), pancreatic ER kinase (PERK) and CCAAT/enhancer-binding protein homologous protein (CHOP) and upregulation of XBP1, XBP1s and MANF. In the patients with SLE disease activity index (SLEDAI) <12, PERK and MANF expressions were significantly decreased, compared with the patients with severe SLE (SLEDAI ≥ 12). However, there was no significant change in ATF6 mRNA expression in the patients with SLE. Negative correlation between IRE1/XBP1 and SLEDAI was observed in lower SLEDAI score group. Negative correlations between CHOP and anti-dsDNA antibody, MANF and antinuclear antibody were observed in high-SLEDAI score group. We also found that antinuclear antibody and anti-dsDNA antibodies correlated with SLEDAI in a weak positive manner. SLEDAI was negatively related with C3 level. SLEDAI and anti-dsDNA antibody showed modestly positive correlation with urine protein. These findings suggest that the abnormal unfolded protein responses, especially IRE1/XBP1 and PERK/CHOP axes, may contribute to SLE pathogenesis, which may be potential diagnosis indicators or treatment targets.
系统性红斑狼疮（SLE）是一种发病机制不明的自身免疫性疾病。内质网（ER）应激与炎症和/或免疫疾病密切相关。然而，异常的内质网应激是否参与SLE发病机制尚不清楚。我们旨在鉴定SLE患者中与内质网应激相关的基因，并分析它们与该疾病的相关性。从76例特征明确的SLE患者和69例健康对照中分离外周血白细胞。通过绝对定量实时聚合酶链反应在转录水平测定内质网应激相关基因。采用逐步回归和相关分析来分析SLE疾病与内质网应激之间的关系。在SLE患者中发现异常的未折叠蛋白反应，其中肌醇需求酶1（IRE1）、胰腺内质网激酶（PERK）和CCAAT/增强子结合蛋白同源蛋白（CHOP）下调，而XBP1、XBP1s和MANF上调。在SLE疾病活动指数（SLEDAI）<12的患者中，与重度SLE患者（SLEDAI≥12）相比，PERK和MANF表达显著降低。然而，SLE患者中ATF6 mRNA表达无显著变化。在较低SLEDAI评分组中观察到IRE1/XBP1与SLEDAI呈负相关。在高SLEDAI评分组中观察到CHOP与抗双链DNA抗体、MANF与抗核抗体呈负相关。我们还发现抗核抗体和抗双链DNA抗体与SLEDAI呈弱正相关。SLEDAI与C3水平呈负相关。SLEDAI和抗双链DNA抗体与尿蛋白呈中度正相关。这些发现表明，异常的未折叠蛋白反应，尤其是IRE1/XBP1和PERK/CHOP轴，可能有助于SLE发病机制，这可能是潜在的诊断指标或治疗靶点。
