IMMUNOPATHOLOGIC ALTERATIONS IN RHESUS MACAQUES WITH GLOBOID CELL LEUKODYSTROPHY

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 球样细胞脑白质营养不良或克拉伯病，是一种严重的中枢和外周神经系统疾病所造成的缺乏半乳糖苷酶（GALC）的活动。在这份报告中，临床神经病理学，组织化学和免疫组织化学的特点，观察在蟹影响恒河猴进行了描述。受影响动物的临床体征包括头部和四肢的明显肌肉震颤、行走困难、共济失调、测径过度和呼吸困难。 组织学上，所有动物均表现出外周和中枢神经系统脱髓鞘的证据，以及与重度神经胶质增生相关的大脑和小脑白色物质中单核和多核球状细胞蓄积。使用免疫组织化学和具有多种细胞类型特异性标志物的多标记共聚焦显微镜，确定球状细胞为CD 68+、HAM 56+、LN 5+、CD 163+、IBA-1+和Glut-5+，表明外周血来源的单核细胞/巨噬细胞和驻留的实质小胶质细胞都产生球状细胞。 有趣的是，许多球形细胞以及具有更多变形形态的实质小胶质细胞表达HLA-DR，表明免疫激活。 此外，在受影响的白色物质中观察到iNOS的表达显著增加，并与球状细胞和活化的小胶质细胞共定位。 这提出了单核细胞/巨噬细胞/小胶质细胞的失调可能有助于Krabbe病的发病机制的可能性。

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's disease, is a severe disorder of the central and peripheral nervous system caused by the absence galactocerebrosidase (GALC) activity. In this report, the clinical neuropathological, histochemical and immunohistological features observed in Krabbe-affected rhesus macaques are described. Clinical signs in affected animals include pronounced muscle tremors of head and limbs, difficulty ambulating, ataxia, hypermetria and respiratory difficulties. Histopathologically, all animals presented with evidence of demyelination in the peripheral and central nervous system and accumulation of mononuclear and multinuclear globoid cells in the cerebral and cerebellar white matter associated with severe gliosis. Using immunohistochemistry and multilabel confocal microscopy with multiple cell-type specific markers, it was determined that globoid cells were CD68+, HAM56+, LN5+, CD163+, IBA-1+ and Glut-5+ suggesting that both peripheral blood derived monocyte/macrophages and resident parenchymal microglia give rise to globoid cells. Interestingly, many of the globoid cells as well as parenchymal microglia with a more ameboid morphology expressed HLA-DR indicating immune activation. Furthermore, a marked increase in expression of iNOS was observed in the affected white matter and colocalized with globoid cells and activated microglia. This raises the possibility that dysregulation of monocyte/macrophage/microglia may contribute to the pathogenesis of Krabbe's disease.