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Background: Sandhoff disease is a lysosomal storage disorder characterized by the absence of b-hexosaminidase and storage of GM2 ganglioside and related glycolipids. We have previously found that the progressive neurologic disease induced in Hexb2/2 mice, an animal model for Sandhoff disease, is associated with the production of pathogenic anti-glycolipid autoantibodies. Methodology/Principal Findings: In our current study, we report on the alterations in the thymus during the development of mild to severe progressive neurologic disease. The thymus from Hexb2/2 mice of greater than 15 weeks of age showed a marked decrease in the percentage of immature CD4+/CD8+ T cells and a significantly increased number of CD4+/CD82 T cells. During involution, the levels of both apoptotic thymic cells and IgG deposits to T cells were found to have increased, whilst swollen macrophages were prominently observed, particularly in the cortex. We employed cDNA microarray analysis to monitor gene expression during the involution process and found that genes associated with the immune responses were upregulated, particularly those expressed in macrophages. CXCL13 was one of these upregulated genes and i