Vascular Immunology Unit, Discipline of Pathology, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia; Central West Neurology and Neurosurgery, Orange, NSW, Australia.
Vascular Immunology Unit, Discipline of Pathology, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia.
J Neuroimmunol. 2020 Dec 15;349:577392. doi: 10.1016/j.jneuroim.2020.577392. Epub 2020 Sep 24.
Multiple sclerosis (MS) is an autoimmune disorder where auto-aggressive T cells target the central nervous system (CNS), causing demyelination. The trans-endothelial migration of leucocytes across the blood-brain barrier (BBB) is one of the earliest CNS events in MS pathogenesis. We examined the effect of the disease state and treatment with fingolimod on the transmigration of peripheral blood mononuclear cells (PBMCs) in an in vitro BBB model. Patients' leucocyte numbers, subsets and phenotypes were assessed by flow cytometry. As expected, fingolimod treatment induced a significant reduction in T cell and B cell numbers compared to untreated MS patients and healthy controls. Interestingly fingolimod led to a marked reduction of CD4+ and a significant increase in CD8 cell numbers. In migrated cells, only CD3 cell numbers were reduced in fingolimod-treated, compared to untreated patients; it had no effect on B cell or monocyte transmigration. T cells were then differentiated into naïve, effector and memory subsets based on their expression of CCR7. This showed that MS patients had increased numbers of effector memory CD4 cells re-expressing CD45RA (TEMRA) and a decrease in central memory (CM) CD8 cells. The former was corrected by fingolimod, while the latter was not. CM CD4 and CD8 cells migrated across BBB more efficiently in fingolimod-treated patients. We found that while fingolimod reduced the proportions of naïve CD19 B cells, it significantly increased the proportions of these cells which migrated. When B cells were further stratified based on CD24, CD27 and CD38 expression, the only effect of fingolimod was an enhancement of CD24CD27 B cell migration, compared to untreated MS patients. The migratory capacities of CD8 Natural Killer (NK), CD8 NK and NK-T cells were also reduced by fingolimod. While the disease-modifying effects of fingolimod are currently explained by its effect on reducing circulating auto-aggressive lymphocytes, our data suggests that fingolimod may also have a direct though differential effect on the trans-endothelial migration of circulating lymphocyte populations.
多发性硬化症 (MS) 是一种自身免疫性疾病，自身攻击性 T 细胞靶向中枢神经系统 (CNS)，导致脱髓鞘。白细胞穿过血脑屏障 (BBB) 的跨内皮迁移是 MS 发病机制中最早的 CNS 事件之一。我们研究了疾病状态和芬戈莫德治疗对体外 BBB 模型中外周血单核细胞 (PBMC) 迁移的影响。通过流式细胞术评估患者白细胞数量、亚群和表型。正如预期的那样，与未经治疗的 MS 患者和健康对照组相比，芬戈莫德治疗显著降低了 T 细胞和 B 细胞数量。有趣的是，芬戈莫德导致 CD4+细胞显著减少，CD8 细胞数量显著增加。与未经治疗的患者相比，在迁移细胞中，只有 CD3 细胞数量在接受芬戈莫德治疗的患者中减少；它对 B 细胞或单核细胞迁移没有影响。然后根据 CCR7 的表达将 T 细胞分为幼稚、效应和记忆亚群。这表明 MS 患者表达 CD45RA（TEMRA）的效应记忆 CD4 细胞数量增加，中央记忆 (CM) CD8 细胞减少。前者被芬戈莫德纠正，后者则没有。CM CD4 和 CD8 细胞在接受芬戈莫德治疗的患者中更有效地穿过 BBB 迁移。我们发现，虽然芬戈莫德降低了幼稚 CD19 B 细胞的比例，但它显著增加了迁移的这些细胞的比例。当根据 CD24、CD27 和 CD38 的表达进一步对 B 细胞进行分层时，与未经治疗的 MS 患者相比，芬戈莫德的唯一作用是增强 CD24CD27 B 细胞的迁移。CD8 自然杀伤 (NK)、CD8 NK 和 NK-T 细胞的迁移能力也被芬戈莫德降低。虽然芬戈莫德的疾病修饰作用目前归因于其减少循环自身攻击性淋巴细胞的作用，但我们的数据表明，芬戈莫德可能对循环淋巴细胞群体的跨内皮迁移也有直接但不同的影响。
