Tight junctional abnormality in multiple sclerosis white matter affects all calibres of vessel and is associated with blood-brain barrier leakage and active demyelination
Tight junctional abnormality in multiple sclerosis white matter affects all calibres of vessel and is associated with blood-brain barrier leakage and active demyelination
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DOI：
10.1002/path.1434
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发表时间：
2003-10-01
影响因子：
7.3
通讯作者：
McQuaid, S
中科院分区：
文献类型：
--
作者：
Kirk, J;Plumb, J;McQuaid, S
多发性硬化（MS）患者血脑屏障（BBB）通透性增高与病变发病机制相关，并与微血管紧密连接（TJ）病理学有关。本研究量化了TJ病理的不均匀分布及其与BBB渗漏的相关性。对14例患者的斑块和正常白色物质（NAWM）的冰冻切片以及6例神经系统和5例正常对照的白色物质进行了研究。使用单，双免疫荧光和共聚焦显微镜，TJ相关蛋白zonula occludens-1（ZO-1）进行了检查病变类型和组织类别，并与纤维蛋白原渗漏。共聚焦图像数据集进行了分析，为2198 MS和1062对照血管。在MS的不同病变类型之间以及MS和对照白色物质之间检测到TJ异常发生率的显著差异。这些在油红0（ORO）（+）活性斑块中较为常见，影响42%的血管节段，但在ORO-非活性斑块（23%）、NAWM（13%）、正常（3.7%）和神经系统对照（8%）中较不常见。无论血管大小如何，均发现了类似的模式，支持了扩散性炎症介质的因果作用。在NAWM和非活动性病变中，双重标记显示，具有最多TJ异常的血管也显示出最多的纤维蛋白原渗漏。这在活动性病变中甚至更明显，其中TJ改变的最高等级中41%的血管显示严重渗漏。它的结论是，中断TJ在MS中，影响细胞旁和跨细胞路径，有助于血脑屏障泄漏。非活动性病变的TJ异常和BBB渗漏提示TJ修复失败或持续的病理过程。在NAWM中，它提示病变前改变或继发性损伤。临床上不明显的TJ病理具有预后意义，在计划疾病修饰治疗时应予以考虑。版权所有（C）2003约翰威利父子有限公司。
Blood-brain barrier (BBB) hyperpermeability in multiple sclerosis (MS) is associated with lesion pathogenesis and has been linked to pathology in microvascular tight junctions (TJs). This study quantifies the uneven distribution of TJ pathology and its association with BBB leakage. Frozen sections from plaque and normal-appearing white matter (NAWM) in 14 cases were studied together with white matter from six neurological and five normal controls. Using single and double immunofluorescence and confocal microscopy, the TJ-associated protein zonula occludens-1 (ZO-1) was examined across lesion types and tissue categories, and in relation to fibrinogen leakage. Confocal image data sets were analysed for 2198 MS and 1062 control vessels. Significant differences in the incidence of TJ abnormalities were detected between the different lesion types in MS and between MS and control white matter. These were frequent in oil-red 0 (ORO)(+) active plaques, affecting 42% of vessel segments, but less frequent in ORO- inactive plaques (23%), NAWM (13%), and normal (3.7%) and neurological controls (8%). A similar pattern was found irrespective of the vessel size, supporting a causal role for diffusible inflammatory mediators. In both NAWM and inactive lesions, dual labelling showed that vessels with the most TJ abnormality also showed most fibrinogen leakage. This was even more pronounced in active lesions, where 41 % of vessels in the highest grade for TJ alteration showed severe leakage. It is concluded that disruption of TJs in MS, affecting both paracellular and transcellular paths, contributes to BBB leakage. TJ abnormality and BBB leakage in inactive lesions suggests either failure of TJ repair or a continuing pathological process. In NAWM, it suggests either pre-lesional change or secondary damage. Clinically inapparent TJ pathology has prognostic implications and should be considered when planning disease-modifying therapy. Copyright (C) 2003 John Wiley Sons, Ltd.