Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, , Ube, Yamaguchi, Japan.
J Neurol Neurosurg Psychiatry. 2014 May;85(5):526-37. doi: 10.1136/jnnp-2013-305405. Epub 2013 Aug 7.
In multifocal motor neuropathy (MMN), the destruction of the blood-nerve barrier (BNB) has been considered to be the key step in the disease process. The purpose of the present study was to ascertain whether sera from patients with MMN can open the BNB, and which component of patient sera is the most important for this disruption.
We evaluated the effects of sera from patients with MMN, patients with amyotrophic lateral sclerosis, and control subjects on the expression of tight junction proteins and vascular cell adhesion molecule-1 (VCAM-1), and on the transendothelial electrical resistance (TEER) in human peripheral nerve microvascular endothelial cells (PnMECs).
The sera from patients with MMN decreased the claudin-5 protein expression and the TEER in PnMECs. However, this effect was reversed after application of an anti-vascular endothelial growth factor (anti-VEGF) neutralising antibody. The VEGF secreted by PnMECs was significantly increased after exposure to the sera from patients with MMN. The sera from patients with MMN also increased the VCAM-1 protein expression by upregulating the nuclear factor kappa-B (NF-κB) signalling. The immunoglobulin G purified from MMN sera decreased the expression of claudin-5 and increased the VCAM-1 expression in PnMECs.
The sera from MMN patients may disrupt the BNB function via the autocrine secretion of VEGF in PnMECs, or the exposure to autoantibodies against PnMECs that are contained in the MMN sera. Autoantibodies against PnMECs in MMN sera may activate the BNB by upregulating the VCAM-1 expression, thereby allowing for the entry of a large number of circulating inflammatory cells into the peripheral nervous system.
在多灶性运动神经病（MMN）中，血神经屏障（BNB）的破坏被认为是疾病进程中的关键步骤。本研究旨在确定 MMN 患者的血清是否可以打开 BNB，以及患者血清中的哪个成分对此破坏最为重要。
我们评估了 MMN 患者、肌萎缩侧索硬化症（ALS）患者和对照者的血清对人周围神经微血管内皮细胞（PnMEC）中紧密连接蛋白和血管细胞黏附分子-1（VCAM-1）表达以及跨内皮电阻（TEER）的影响。
MMN 患者的血清降低了 PnMEC 中 Claudin-5 蛋白表达和 TEER。然而，在用抗血管内皮生长因子（anti-VEGF）中和抗体处理后，这种作用被逆转。PnMEC 暴露于 MMN 患者的血清后，VEGF 分泌显著增加。MMN 患者的血清还通过上调核因子 kappa-B（NF-κB）信号通路增加了 VCAM-1 蛋白表达。从 MMN 血清中纯化的免疫球蛋白 G 降低了 Claudin-5 的表达，并增加了 PnMEC 中的 VCAM-1 表达。
MMN 患者的血清可能通过 PnMEC 中 VEGF 的自分泌或通过暴露于包含在 MMN 血清中的针对 PnMEC 的自身抗体来破坏 BNB 功能。MMN 血清中的针对 PnMEC 的自身抗体可能通过上调 VCAM-1 表达来激活 BNB，从而允许大量循环炎症细胞进入周围神经系统。
