Bell Luisa, Koeniger Tobias, Tacke Sabine, Kuerten Stefanie
Department of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany.
Institute of Anatomy and Cell Biology, Friedrich Alexander University Erlangen-Nürnberg (FAU), Krankenhausstr. 9, 91054, Erlangen, Bavaria, Germany.
Histochem Cell Biol. 2019 Jun;151(6):489-499. doi: 10.1007/s00418-019-01768-6. Epub 2019 Jan 21.
Recent studies with B-cell-depleting antibodies have demonstrated clinical success in the treatment of multiple sclerosis (MS) patients. While these antibodies efficiently target B cells in the blood, it is unclear how effective they are in the central nervous system (CNS), especially in the context of limited blood-brain barrier (BBB) permeability and the ongoing discussion on the relevance of B-cell aggregate formation in the brains of SP-MS patients. The aim of this study was to evaluate BBB integrity in the context of B-cell-dependent neuroinflammation in a mouse model of MS. C57BL/6 mice were actively immunized with either myelin oligodendrocyte glycoprotein peptide 35-55 to induce T-cell-dependent experimental autoimmune encephalomyelitis (EAE), or with the myelin basic protein-proteolipid protein fusion protein MP4 for additional B-cell dependence. BBB integrity was assessed using Evans Blue or fluorescein isothiocyanate-dextran injection, respectively, in combination with immunofluorescence staining for key components of the BBB. In both EAE models, tracer leakage into the CNS parenchyma was observed indicating BBB leakiness. Yet, intensity and distribution patterns of leakage differed between the two models. There was no difference in the severity of BBB damage comparing acute and chronic MP4-induced EAE, but the formation of B-cell aggregates was associated with local BBB impairment in this model. This study underscores that a leaky BBB is a characteristic feature of EAE, but it also suggests that extent and region specificity of BBB damage differs between individual EAE models that vary in the underlying immunopathology.
近期使用B细胞耗竭抗体的研究已证明在治疗多发性硬化症（MS）患者方面取得了临床成功。虽然这些抗体能有效靶向血液中的B细胞，但它们在中枢神经系统（CNS）中的有效性尚不清楚，尤其是在血脑屏障（BBB）通透性有限以及对继发进展型多发性硬化症（SP-MS）患者大脑中B细胞聚集体形成的相关性持续讨论的背景下。本研究的目的是在MS小鼠模型中评估B细胞依赖性神经炎症背景下的血脑屏障完整性。C57BL/6小鼠分别用髓鞘少突胶质细胞糖蛋白肽35 - 55主动免疫以诱导T细胞依赖性实验性自身免疫性脑脊髓炎（EAE），或用髓鞘碱性蛋白 - 蛋白脂蛋白融合蛋白MP4进行免疫以增加对B细胞的依赖性。分别通过注射伊文思蓝或异硫氰酸荧光素 - 葡聚糖，并结合对血脑屏障关键成分的免疫荧光染色来评估血脑屏障的完整性。在两种EAE模型中，均观察到示踪剂渗漏到中枢神经系统实质中，表明血脑屏障存在渗漏。然而，两种模型中渗漏的强度和分布模式有所不同。比较急性和慢性MP4诱导的EAE，血脑屏障损伤的严重程度没有差异，但在该模型中B细胞聚集体的形成与局部血脑屏障损伤有关。本研究强调血脑屏障渗漏是EAE的一个特征，但也表明在基础免疫病理学不同的个体EAE模型中，血脑屏障损伤的程度和区域特异性存在差异。
