Sera from patients with multifocal motor neuropathy disrupt the blood-nerve barrier
Sera from patients with multifocal motor neuropathy disrupt the blood-nerve barrier
复制标题
DOI：
10.1136/jnnp-2013-305405
复制
发表时间：
2014-05-01
影响因子：
11
通讯作者：
Kanda, Takashi
中科院分区：
文献类型：
--
作者：
Shimizu, Fumitaka;Omoto, Masatoshi;Kanda, Takashi
目的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过程中的关键步骤。本研究的目的是确定MMN患者的血清是否可以打开BNB，以及患者血清中哪种成分对这种破坏最重要。方法研究MMN患者、肌萎缩性侧索硬化症患者和对照组血清对人周围神经微血管内皮细胞（PnMECs）紧密连接蛋白和血管细胞粘附分子-1 （VCAM-1）表达以及跨内皮电阻（TEER）的影响。结果MMN患者血清中claudin-5蛋白表达降低，TEER水平降低。然而，在应用抗血管内皮生长因子（anti-VEGF）中和抗体后，这种效果被逆转。暴露于MMN患者血清后，pnmec分泌的VEGF显著增加。MMN患者的血清也通过上调核因子κ B （nf - κ B）信号传导而增加VCAM-1蛋白的表达。从MMN血清中纯化的免疫球蛋白G降低了claudin-5的表达，增加了pnmec中VCAM-1的表达。结论MMN患者的血清可能通过pnmec中自分泌VEGF或暴露于MMN血清中含有的针对pnmec的自身抗体而破坏BNB功能。MMN血清中抗pnmec的自身抗体可通过上调VCAM-1表达激活BNB，从而允许大量循环炎症细胞进入周围神经系统。
Objective 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.Methods 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).Results 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-kappa B) signalling. The immunoglobulin G purified from MMN sera decreased the expression of claudin-5 and increased the VCAM-1 expression in PnMECs.Conclusions 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.