GRP78 抗体与抗髓鞘少突胶质细胞糖蛋白抗体相关疾病中的血脑屏障破坏有关。
GRP78 Antibodies Are Associated With Blood-Brain Barrier Breakdown in Anti-Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disorder.
机构信息
From the Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine (F.S., K.H., C.K., Y.T., Y.S., M.F., T. Maeda, T.K.), Ube; Department of Neurology, Tohoku University Graduate School of Medicine (R.O., T.T., T. Misu), Sendai; Center for Gene Research (Y.M., K.W.), Yamaguchi University (Y.M., K.W.), Ube; Department of Neurology, National Hospital Organization Yonezawa Hospital (T.T.); Department of Neurology, Tohoku Medical and Pharmaceutical University (I.N.), Sendai; and Department of Multiple Sclerosis Therapeutics, Fukushima Medical University (K.F.), Japan.
出版信息
Neurol Neuroimmunol Neuroinflamm. 2021 Nov 1;9(1). doi: 10.1212/NXI.0000000000001038. Print 2022 Jan.
BACKGROUND AND OBJECTIVES
To analyze (1) the effect of immunoglobulin G (IgG) from patients with anti-myelin oligodendrocyte glycoprotein antibody (MOG-Ab)-associated disorder on the blood-brain barrier (BBB) endothelial cells and (2) the positivity of glucose-regulated protein 78 (GRP78) antibodies in MOG-Ab-associated disorders.
METHODS
IgG was purified from sera with patients with MOG-Ab-associated disorder in the acute phase (acute MOG, n = 15), in the stable stage (stable MOG, n = 14), healthy controls (HCs, n = 9), and disease controls (DCs, n = 27). Human brain microvascular endothelial cells (BMECs) were incubated with IgG, and the number of nuclear NF-κB p65-positive cells in BMECs using high-content imaging system and the quantitative messenger RNA change in gene expression over the whole transcriptome using RNA-seq were analyzed. GRP78 antibodies from patient IgGs were detected by Western blotting.
RESULTS
IgG in the acute MOG group significantly induced the nuclear translocation of NF-κB and increased the vascular cell adhesion molecule 1/intercellular adhesion molecule 1 expression/permeability of 10-kDa dextran compared with that from the stable MOG and HC/DC groups. RNA-seq and pathway analysis revealed that NF-κB signaling and oxidative stress (NQO1) play key roles. The NQO1 and Nrf2 protein amounts were significantly decreased after exposure to IgG in the acute MOG group. The rate of GRP78 antibody positivity in the acute MOG group (10/15, 67% [95% confidence interval, 38%-88%]) was significantly higher than that in the stable MOG group (5/14, 36% [13%-65%]), multiple sclerosis group (4/29, 14% [4%-32%]), the DCs (3/27, 11% [2%-29%]), or HCs (0/9, 0%). Removal of GRP78 antibodies from MOG-IgG reduced the effect on NF-κB nuclear translocation and increased permeability.
DISCUSSION
GRP78 antibodies may be associated with BBB dysfunction in MOG-Ab-associated disorder.
背景与目的
分析（1）抗髓鞘少突胶质细胞糖蛋白抗体（MOG-Ab）相关疾病患者的 IgG 对血脑屏障（BBB）内皮细胞的影响，（2）MOG-Ab 相关疾病中葡萄糖调节蛋白 78（GRP78）抗体的阳性率。
方法
从急性期（急性 MOG，n=15）、稳定期（稳定 MOG，n=14）、健康对照组（HC，n=9）和疾病对照组（DC，n=27）的 MOG-Ab 相关疾病患者血清中纯化 IgG。使用高内涵成像系统分析 BMEC 核 NF-κB p65 阳性细胞数量，采用 RNA-seq 分析全转录组基因表达的定量信使 RNA 变化。用 Western blot 检测患者 IgG 中的 GRP78 抗体。
结果
与稳定 MOG 和 HC/DC 组相比，急性 MOG 组 IgG 显著诱导 NF-κB 核转位，并增加血管细胞黏附分子 1/细胞间黏附分子 1 表达/10kDa 葡聚糖的通透性。RNA-seq 和通路分析表明，NF-κB 信号和氧化应激（NQO1）发挥关键作用。在急性 MOG 组 IgG 暴露后，NQO1 和 Nrf2 蛋白量明显减少。急性 MOG 组 GRP78 抗体阳性率（10/15，67%[95%置信区间，38%-88%]）显著高于稳定 MOG 组（5/14，36%[13%-65%]）、多发性硬化组（4/29，14%[4%-32%]）、DC 组（3/27，11%[2%-29%]）或 HC 组（0/9，0%）。从 MOG-IgG 中去除 GRP78 抗体可降低 NF-κB 核转位的作用并增加通透性。
讨论
GRP78 抗体可能与 MOG-Ab 相关疾病的 BBB 功能障碍有关。
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