IMMUNOPATHOLOGIC ALTERATIONS IN RHESUS MACAQUES WITH GLOBOID CELL LEUKODYSTROPHY

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。类球形细胞白质营养不良症又称Krabbe病，是由于半乳糖脑苷酶(GALC)活性缺失引起的一种严重的中枢和外周神经系统疾病。这种常染色体隐性遗传病影响人类，并在包括恒河猴在内的许多哺乳动物物种中被描述。本报告描述了Krabbe感染猕猴的临床病理、免疫组织化学和免疫组织学特征。镜下可见单核和多核球状细胞渗入大脑和小脑白质，并伴有髓鞘缺乏。免疫组织化学和多细胞类型特异性标记的多标记共聚焦显微镜显示，小细胞和大细胞均为CD68+、HAM56+、LN5+、CD163、IBA-1和GLUT-5，提示为小胶质细胞起源。诱导型一氧化氮合酶(INOS)在脑白质表达增强，定位于活化的小胶质细胞和球状细胞。小胶质细胞在脑白质营养不良的发病机制中可能起重要作用。INOS的存在和表达增加似乎对少突胶质细胞或髓鞘具有优先毒性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Globoid cell leukodystrophy or Krabbe disease, is a severe disorder of the central and peripheral nervous system caused by the absence galactocerebrosidase (GALC) activity. This autosomal recessive disease affects humans and has been described in a number of mammalian species including the rhesus monkey. In this report, the clinical pathological, immunohistochemical and immunohistological features observed in Krabbe-affected rhesus macaques are described. Upon microscopic examination, the cerebral and cerebellar white matter was infiltrated by mononuclear and multinucleated globoid cells associated with lack of myelin. Using immunohistochemistry and multilabel confocal microscopy with multiple cell-type specific markers, it was determined that both the small and large-size globoid cells were CD68+, HAM56+, LN5+, CD163, IBA-1 and Glut-5 suggesting a microglial origin. Increased expression of inducible nitric oxide synthase (iNOS) was expressed in affected white matter and localized within activated microglia and globoid cells. Increased frequency of activation of microglia in affected areas may play an important role in the pathogenesis of globoid cell leukodystrophy. The presence and increased expression of iNOS seems to be preferentially toxic to oligodendrocytes or myelin.