Department of Neurology and Clinical Neuroscience, Graduate School of Medicine, Yamaguchi University, Ube, Japan.
Department of Neurology and Clinical Neuroscience, Graduate School of Medicine, Yamaguchi University, Ube, Japan/Biogen, Cambridge, MA, USA.
Mult Scler. 2017 Mar;23(3):382-394. doi: 10.1177/1352458516655217. Epub 2016 Jul 11.
Recent studies have revealed that the disruption of the blood-brain barrier (BBB) might contribute to the induction of neurodegeneration in the progressive stage of multiple sclerosis (MS).
We investigated a potential target for the serum auto-antibodies responsible for the BBB impairment in patients with secondary progressive MS (SPMS).
We identified undetermined target antigens in human brain microvascular endothelial cells (BMECs) that reacted with auto-antibodies in sera from SPMS patients using a proteomic approach. In addition, we examined how the identified auto-antibodies compromise the BBB integrity.
We found that 10 of 11 SPMS sera had auto-antibodies against galectin-3, although the patients with other neurological diseases did not have these antibodies. Downregulation of galectin-3 led to elevated intercellular adhesion molecule-1 (ICAM-1) and phospho-nuclear factor-kappa (NFκ) B p65 expression in the BMECs. Exposure to SPMS patients' sera also increased the protein levels of ICAM-1 and phospho-NFκB p65 in BMECs, but these effects induced by anti-galectin-3 immunoreactivity were canceled by the downregulation of galectin-3.
Galectin-3 is a possible immunological target molecule of the pathogenic auto-antibodies and contributes to the persistent BBB breakdown in patients with SPMS. These antibodies may also serve as a novel biomarker for SPMS.
最近的研究表明，血脑屏障（BBB）的破坏可能导致多发性硬化症（MS）进展期的神经退行性变。
我们研究了与继发进展型多发性硬化症（SPMS）患者的 BBB 损伤有关的血清自身抗体的潜在靶标。
我们使用蛋白质组学方法鉴定了与人脑微血管内皮细胞（BMEC）反应的、SPMS 患者血清中自身抗体的未确定靶抗原。此外，我们还研究了鉴定出的自身抗体如何损害 BBB 的完整性。
我们发现 11 份 SPMS 血清中有 10 份含有针对半乳糖凝集素-3 的自身抗体，尽管其他神经系统疾病患者没有这些抗体。半乳糖凝集素-3 的下调导致 BMEC 中细胞间黏附分子-1（ICAM-1）和磷酸核因子-κB p65 的表达升高。SPMS 患者血清的暴露也增加了 BMEC 中 ICAM-1 和磷酸-NFκB p65 的蛋白水平，但半乳糖凝集素-3 下调可消除由抗半乳糖凝集素-3 免疫反应性引起的这些效应。
半乳糖凝集素-3 是致病性自身抗体的可能免疫靶标分子，有助于 SPMS 患者持续的 BBB 破坏。这些抗体也可能成为 SPMS 的一种新型生物标志物。
