Identification of galectin-3 as a possible antibody target for secondary progressive multiple sclerosis
Identification of galectin-3 as a possible antibody target for secondary progressive multiple sclerosis
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DOI：
10.1177/1352458516655217
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发表时间：
2017-03-01
影响因子：
5.8
通讯作者：
Kanda, Takashi
中科院分区：
文献类型：
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作者：
Nishihara, Hideaki;Shimizu, Fumitaka;Kanda, Takashi
背景资料：近年来的研究表明，血脑屏障（blood-brain barrier，BBB）的破坏可能参与了多发性硬化（multiple sclerosis，MS）进展期神经退行性变的诱导。目的：探讨继发性进展性MS（secondary progressive MS，SPMS）患者血脑屏障（BBB）受损的血清自身抗体的潜在靶点。我们使用蛋白质组学方法鉴定了人脑微血管内皮细胞（BMEC）中与SPMS患者血清中自身抗体反应的未确定靶抗原。此外，我们研究了如何识别的自身抗体妥协的BBB integrity.Results：我们发现，10 11 SPMS血清有抗半乳糖凝集素-3的自身抗体，虽然与其他神经系统疾病的患者没有这些抗体。半乳糖凝集素-3下调导致BMEC中细胞间粘附分子-1（ICAM-1）和磷酸化核因子-κ（NF）B p65表达升高。SPMS患者血清暴露后，BMEC中ICAM-1和磷酸化NFB p65蛋白水平升高，但抗Galectin-3免疫反应性的这种作用被Galectin-3的下调所抵消。结论：Galectin-3可能是SPMS患者致病性自身抗体的免疫靶分子，参与了持续性BBB破坏。这些抗体也可以作为SPMS的新生物标志物。
Background: 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).Objective: We investigated a potential target for the serum auto-antibodies responsible for the BBB impairment in patients with secondary progressive MS (SPMS).Methods: 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.Results: 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 (NF) B p65 expression in the BMECs. Exposure to SPMS patients' sera also increased the protein levels of ICAM-1 and phospho-NFB p65 in BMECs, but these effects induced by anti-galectin-3 immunoreactivity were canceled by the downregulation of galectin-3.Conclusion: 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.