Blood-brain barrier tight junction disruption in human immunodeficiency virus-1 encephalitis
Blood-brain barrier tight junction disruption in human immunodeficiency virus-1 encephalitis
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DOI：
10.1016/s0002-9440(10)65511-3
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发表时间：
1999-12-01
影响因子：
6
通讯作者：
Achim, CL
中科院分区：
文献类型：
--
作者：
Dallasta, LM;Pisarov, LA;Achim, CL
血脑屏障（BBB）在调节通过中枢神经系统（CNS）的细胞运输中起关键作用，这是由于几种独特的解剖学特征，包括在细胞之间形成不可渗透的密封的内皮间紧密连接的存在。先前的研究表明，在人类免疫缺陷病毒性脑炎（HIVE）的血脑屏障扰动;然而，这些渗透性变化的基础及其与人类免疫缺陷病毒1型（HIV-1）感染的单核细胞浸润的关系（该疾病发病机制中的关键事件）仍不清楚。在这项研究中，我们检查了来自HIV-1血清阴性患者和HIV-1感染患者的CNS组织，通过对紧密连接膜蛋白、闭合蛋白和闭合小带-1（ZO-1）的免疫组织化学分析，在有和没有脑炎的情况下，用于BBB完整性的改变。在死于HIVE的患者中，在皮质下白色物质、基底节的血管内观察到明显的紧密连接破坏（P < 0.001），表现为occludin和ZO-1免疫反应性的断裂或缺失。这些改变也与激活的HIV-1感染的脑巨噬细胞的积累、纤维蛋白原渗漏和显著的星形细胞增多有关。相反，与HIV血清阴性患者或HIV-1感染无脑炎患者相比，HIVE患者的小脑组织无显著变化（P > 0.05）。我们的研究结果表明，紧密连接破坏是HIVE的一个关键特征，它发生在与活化的HIV-1感染的巨噬细胞血管周围积聚、血清蛋白外渗和显著的星形胶质细胞增生相关的组织病理学改变区域。我们认为，破坏这一关键的血脑屏障结构是HIV-1感染的单核细胞进入中枢神经系统的主要途径。
The blood-brain barrier (BBB) plays a critical role in regulating cell trafficking through the central nervous system (CNS) due to several unique anatomical features, including the presence of interendothelial tight junctions that form impermeable seals between the cells. Previous studies have demonstrated BBB perturbations during human immunodeficiency virus encephalitis (HIVE); however, the basis of these permeability changes and its relationship to infiltration of human immunodeficiency virus type 1 (HIV-1)-infected monocytes, a critical event in the pathogenesis of the disease, remains unclear, In this study, we examined CNS tissue from HIV-1-seronegative patients and HIV-1-infected patients, both with and without encephalitis, for alterations in BBB integrity via immunohistochemical analysis of the tight junction membrane proteins, occludin and zonula occludens-1 (ZO-1). Significant tight junction disruption (P < 0.001), as demonstrated by fragmentation or absence of immunoreactivity for occludin and ZO-1, was observed within vessels from subcortical white matter, basal ganglia, and, to a lesser extent, cortical gray matter in patients who died with HIVE. These alterations were also associated with accumulation of activated, HIV-1-infected brain macrophages, fibrinogen leakage, and marked astrocytosis. In contrast, no significant changes (P > 0.05) were observed in cerebellar tissue from patients with HIVE compared to HIV-seronegative patients or HIV-1-infected patients without encephalitis. Our findings demonstrate that tight junction disruption is a key feature of HIVE that occurs in regions of histopathological alterations in association with perivascular accumulation of activated HIV-1-infected macrophages, serum protein extravasation, and marked astrocytosis. We propose that disruption of this key BBB structure serves as the main route of HIV-1-infected monocyte entry into the CNS.