Kirk John, Plumb Jonnie, Mirakhur Meenakshi, McQuaid Stephen
School of Medicine Inflammation Research Centre, Queen's University of Belfast, Northern Ireland, UK.
J Pathol. 2003 Oct;201(2):319-27. doi: 10.1002/path.1434.
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 O (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.
多发性硬化症（MS）中的血脑屏障（BBB）通透性增加与病变发病机制相关，并且与微血管紧密连接（TJ）的病理学改变有关。本研究量化了TJ病理学改变的不均匀分布及其与BBB渗漏的关联。对14例患者斑块和正常外观白质（NAWM）的冰冻切片，以及6例神经疾病患者和5例正常对照者的白质进行了研究。使用单重和双重免疫荧光以及共聚焦显微镜，在不同病变类型和组织类别中检测与TJ相关的蛋白闭合蛋白-1（ZO-1），并分析其与纤维蛋白原渗漏的关系。对2198个MS血管和1062个对照血管的共聚焦图像数据集进行了分析。在MS的不同病变类型之间以及MS与对照白质之间，检测到TJ异常发生率存在显著差异。这些异常在油红O（ORO）（+）活性斑块中很常见，影响42%的血管段，但在ORO（-）非活性斑块（23%）、NAWM（13%）以及正常（3.7%）和神经疾病对照（8%）中较少见。无论血管大小如何，均发现了类似的模式，这支持了可扩散炎症介质的因果作用。在NAWM和非活性病变中，双重标记显示TJ异常最严重的血管也显示出最严重的纤维蛋白原渗漏。在活性病变中更为明显，在TJ改变最高级别的血管中，41%显示出严重渗漏。得出的结论是，MS中TJ的破坏影响了细胞旁和跨细胞途径，导致了BBB渗漏。非活性病变中的TJ异常和BBB渗漏表明TJ修复失败或病理过程持续存在。在NAWM中，这表明存在病变前改变或继发性损伤。临床上不明显的TJ病理学改变具有预后意义，在规划疾病修饰治疗时应予以考虑。
