Published online before print December 28, 2007

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(American Journal of Pathology. 2008;172:98-111.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070404

Clinical and Immunopathologic Alterations in Rhesus Macaques Affected with Globoid Cell Leukodystrophy

Juan T. Borda^*, Xavier Alvarez^*, Mahesh Mohan^*, Marion S. Ratterree, Kathrine Phillippi-Falkenstein, Andrew A. Lackner^* and Bruce A. Bunnell^¶

From the Division of Comparative Pathology,^*Division of Veterinary Medicine,and Division of Gene Therapy,Tulane National Primate Research Center, Tulane University Health Sciences Center, Covington, Louisiana; and the Center of Gene Therapyand Department of Pharmacology,^¶Tulane University Health Sciences Center, Tulane University, New Orleans, Louisiana

Globoid cell leukodystrophy, or Krabbe’s disease, is a severe disorder of the central and peripheral nervous system caused by the absence of galactocerebrosidase (GALC) activity. Herein, we describe the clinical, neuropathological, histochemical, and immunohistological features observed in rhesus macaques affected with Krabbe’s disease. Clinical signs included pronounced muscle tremors of head and limbs, difficulty ambulating, ataxia, hypermetria, proprioceptive deficits, and respiratory abnormalities. Histopathologically, all animals presented with evidence of demyelination in the peripheral and central nervous systems and accumulation of mononuclear and multinuclear globoid cells in the cerebral and cerebellar white matter associated with severe gliosis. Using immunohistochemistry and multi-label confocal microscopy, it was determined that globoid cells were CD68⁺, HAM56⁺, LN5⁺, CD163⁺, IBA-1⁺, and Glut-5⁺, suggesting that both peripheral blood-derived monocytes/macrophages and resident parenchymal microglia gave rise to globoid cells. Interestingly, many of the globoid cells and parenchymal microglia with a more ameboid morphology expressed HLA-DR, indicating immune activation. Increased expression of iNOS, TNF-, and IL-1β were observed in the affected white matter, colocalizing with globoid cells, activated microglia, and astrocytes. Cytokine mRNA levels revealed markedly increased gene expression of CCL2 in the brain of affected macaques. CCL2-expressing cells were detected throughout the affected white matter, colocalizing with GFAP⁺ cells and astrocytes. Collectively, these data suggest that dysregulation of monocyte/macrophage/microglia and up-regulation of certain cytokines may contribute to the pathogenesis of Krabbe’s disease.