自分泌 TNF-α 增加抗髓鞘糖蛋白抗体穿过抗 MAG 神经病血-神经屏障的渗透。
Autocrine TNF-α Increases Penetration of Myelin-Associated Glycoprotein Antibodies Across the Blood-Nerve Barrier in Anti-MAG Neuropathy.
机构信息
From the Department of Neurology and Clinical Neuroscience (R.S., F.S., Y.S., Y.T., Michiaki Koga, T.K.), Yamaguchi University Graduate School of Medicine, Ube; Department of Neurology (Motoi Kuwahara, S.K.), Kindai University Faculty of Medicine, Osaka; Center for Gene Research (Y.M., K.W.), Yamaguchi University, Ube, Japan; and Japan Community Health Care Organization (S.K.).
出版信息
Neurol Neuroimmunol Neuroinflamm. 2023 Feb 21;10(3). doi: 10.1212/NXI.0000000000200086. Print 2023 May.
BACKGROUND AND OBJECTIVES
Deposition of myelin-associated glycoprotein (MAG) immunoglobulin M (IgM) antibodies in the sural nerve is a key feature in anti-MAG neuropathy. Whether the blood-nerve barrier (BNB) is disrupted in anti-MAG neuropathy remains elusive.We aimed to evaluate the effect of sera from anti-MAG neuropathy at the molecular level using our in vitro human BNB model and observe the change of BNB endothelial cells in the sural nerve of anti-MAG neuropathy.
METHODS
Diluted sera from patients with anti-MAG neuropathy (n = 16), monoclonal gammopathies of undetermined significance (MGUS) neuropathy (n = 7), amyotrophic lateral sclerosis (ALS, n = 10), and healthy controls (HCs, n = 10) incubated with human BNB endothelial cells to identify the key molecule of BNB activation using RNA-seq and a high-content imaging system, and exposed with a BNB coculture model to evaluate small molecule/IgG/IgM/anti-MAG antibody permeability.
RESULTS
RNA-seq and the high-content imaging system showed the significant upregulation of tumor necrosis factor (TNF-α) and nuclear factor-kappa B (NF-κB) in BNB endothelial cells after exposure to sera from patients with anti-MAG neuropathy, whereas the serum TNF-α concentration was not changed among the MAG/MGUS/ALS/HC groups. Sera from patients with anti-MAG neuropathy did not increase 10-kDa dextran or IgG permeability but enhanced IgM and anti-MAG antibody permeability. Sural nerve biopsy specimens from patients with anti-MAG neuropathy showed higher TNF-α expression levels in BNB endothelial cells and preservation of the structural integrity of the tight junctions and the presence of more vesicles in BNB endothelial cells. Neutralization of TNF-α reduces IgM/anti-MAG antibody permeability.
DISCUSSION
Sera from individuals with anti-MAG neuropathy increased transcellular IgM/anti-MAG antibody permeability via autocrine TNF-α secretion and NF-κB signaling in the BNB.
背景与目的
髓鞘相关糖蛋白（MAG）免疫球蛋白 M（IgM）抗体在腓肠神经中的沉积是抗 MAG 神经病的一个关键特征。抗 MAG 神经病中血-神经屏障（BNB）是否被破坏仍不清楚。我们旨在使用体外人 BNB 模型从分子水平评估抗 MAG 神经病患者血清的作用，并观察抗 MAG 神经病腓肠神经中 BNB 内皮细胞的变化。
方法
将来自抗 MAG 神经病患者（n=16）、意义未明的单克隆丙种球蛋白病神经病（n=7）、肌萎缩侧索硬化症（ALS，n=10）和健康对照者（n=10）的稀释血清与人类 BNB 内皮细胞孵育，使用 RNA-seq 和高内涵成像系统鉴定 BNB 激活的关键分子，并在 BNB 共培养模型中暴露于血清，以评估小分子/IgG/IgM/抗 MAG 抗体的通透性。
结果
RNA-seq 和高内涵成像系统显示，暴露于抗 MAG 神经病患者血清后，BNB 内皮细胞中肿瘤坏死因子（TNF-α）和核因子-κB（NF-κB）显著上调，而 MAG/MGUS/ALS/HC 组血清 TNF-α 浓度无变化。抗 MAG 神经病患者的血清并未增加 10kDa 葡聚糖或 IgG 的通透性，但增强了 IgM 和抗 MAG 抗体的通透性。抗 MAG 神经病患者的腓肠神经活检标本显示 BNB 内皮细胞中 TNF-α表达水平升高，紧密连接的结构完整性保持不变，BNB 内皮细胞中存在更多囊泡。TNF-α 中和减少了 IgM/抗 MAG 抗体的通透性。
讨论
来自抗 MAG 神经病患者的血清通过 BNB 中的自分泌 TNF-α 分泌和 NF-κB 信号转导增加了跨细胞 IgM/抗 MAG 抗体的通透性。
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