IMMUNOPATHOLOGIC ALTERATIONS IN RHESUS MACAQUES WITH GLOBOID CELL LEUKODYSTROPHY

患有球状细胞脑白质营养不良的恒河猴的免疫病理学改变

• 批准号: 7562332
• 负责人: JUAN BORDA
• 金额: $ 3.04万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7562332
• 关键词: Affect; Animals; Ataxia; Cells; Cerebrum; Clinical; Computer Retrieval of Information on Scientific Projects Database; Confocal Microscopy; Demyelinations; Disease; Funding; Gliosis; Globoid cell leukodystrophy; Grant; HLA-DR Antigens; Head; Immune; Immunohistochemistry; Institution; Limb structure; Macaca mulatta; Microglia; Mononuclear; Morphology; Muscle Tremors; Neuraxis; Pathogenesis; Peripheral; Peripheral Nervous System; Reporting; Research; Research Personnel; Resources; Source; United States National Institutes of Health; cell type; galactosylceramidase; macrophage; monocyte; peripheral blood; respiratory; white matter

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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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。本报告描述了Krabbe感染猕猴的临床神经病理、组织化学和免疫组织学特征。受影响动物的临床症状包括明显的头部和四肢肌肉震颤、行走困难、共济失调、宫缩乏力和呼吸困难。在组织病理学上，所有动物都表现出周围和中枢神经系统脱髓鞘的证据，脑和小脑白质中单核和多核球状细胞聚集，与严重的胶质增生有关。应用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，确定球状细胞为CD68+、HAM56+、LN5+、CD163+、IBA-1+和GLUT-5+，提示外周血来源的单核/巨噬细胞和驻留的实质小胶质细胞共同形成了球状细胞。有趣的是，许多球状细胞以及具有更多阿米巴形态的实质小胶质细胞表达人类白细胞抗原-DR，表明免疫激活。此外，iNOS在受累白质中的表达明显增加，并与球状细胞和激活的小胶质细胞共存。这增加了单核/巨噬细胞/小胶质细胞的失调可能参与了Krabbe病的发病机制。