Ma N, Madigan M C, Chan-Ling T, Hunt N H
Department of Pathology, University of Sydney, NSW, Australia.
Glia. 1997 Feb;19(2):135-51. doi: 10.1002/(sici)1098-1136(199702)19:2<135::aid-glia5>3.0.co;2-#.
We examined the optic nerve, as an analogous tissue to brain white matter, to assess possible relationships between changes in the blood-nerve barrier, axonal integrity, and astrocyte morphology in the central nervous system during fatal murine cerebral malaria (FMCM). In the FMCM model, namely, CBA mice infected with Plasmodium berghei ANKA, neurological symptoms begin around day 5 post-inoculation (p.i.) and mice become increasingly ill by day 7 p.i., at which time they lapse into coma and die. Using intravascular perfusion with horseradish peroxidase combined with light and electron microscopy, and GFAP immunohistochemistry, the optic nerves in malaria-infected mice were found to display i) breakdown of the blood-nerve barrier, detectable as early as day 3 p.i. (about 2 days before the onset of neurological symptoms) increasing to peak severity by day 7 p.i.; ii) monocytosis, vascular congestion, and monocyte adherence to the endothelium in the microvasculature during the later stages of the disease process; iii) an increased incidence of patchy axonal demyelination and degeneration, mostly associated with vascular changes and astrogliosis, beginning at day 5 p.i. and more evident by day 7 p.i.; and iv) an increased intensity of GFAP immunostaining, detectable from day 3 p.i. and peaking at day 7 p.i. These optic nerve changes were always seen in the infected individuals, though they varied in intensity. The temporal and anatomical coincidence between the compromised blood-nerve barrier, monocyte adherence to the vascular endothelium, astrocyte changes, neuronal degeneration, and demyelination in the optic nerve in FMCM suggests that these factors are mechanistically inter-related. These findings are consistent with the proposed immunopathological nature of FMCM and provide further evidence for the pivotal role of the CNS microvasculature in the disease process. This is the first investigation of involvement of the optic nerve in FMCM and the first demonstration, to our knowledge, of loss of axonal viability in this condition in any CNS tissue. The observed demyelination is consistent with reports by other workers on such changes in the brain in human cerebral malaria.
我们将视神经作为与脑白质类似的组织进行研究，以评估在致命性鼠脑型疟疾（FMCM）期间中枢神经系统中血-神经屏障变化、轴突完整性和星形胶质细胞形态之间的可能关系。在FMCM模型中，即感染伯氏疟原虫ANKA的CBA小鼠，神经症状在接种后（p.i.）约第5天开始出现，到接种后第7天小鼠病情逐渐加重，此时它们陷入昏迷并死亡。通过使用辣根过氧化物酶进行血管内灌注并结合光镜和电镜检查，以及GFAP免疫组织化学方法，发现感染疟疾的小鼠视神经表现出：i）血-神经屏障破坏，最早在接种后第3天（约在神经症状出现前2天）即可检测到，到接种后第7天严重程度达到峰值；ii）在疾病后期，微脉管系统中出现单核细胞增多、血管充血以及单核细胞黏附于内皮细胞；iii）散在性轴突脱髓鞘和变性的发生率增加，大多与血管变化和星形胶质细胞增生有关，从接种后第5天开始出现，到接种后第7天更为明显；iv）GFAP免疫染色强度增加，从接种后第3天可检测到，在接种后第7天达到峰值。这些视神经变化在受感染个体中总是可见，尽管其强度有所不同。FMCM中视神经的血-神经屏障受损、单核细胞黏附于血管内皮、星形胶质细胞变化、神经元变性和脱髓鞘之间在时间和解剖学上的一致性表明这些因素在机制上相互关联。这些发现与FMCM所提出的免疫病理学性质一致，并为中枢神经系统微脉管系统在疾病过程中的关键作用提供了进一步证据。这是首次对视神经在FMCM中的参与情况进行研究，据我们所知，也是首次证明在这种情况下任何中枢神经系统组织中轴突活力丧失。观察到的脱髓鞘现象与其他研究人员关于人类脑型疟疾中大脑此类变化的报道一致。
