Abstract
BackgroundSandhoff disease is a lysosomal storage disorder characterized by the absence of β-hexosaminidase and storage of GM2 ganglioside and related glycolipids. We have previously found that the progressive neurologic disease induced in Hexb −/− mice, an animal model for Sandhoff disease, is associated with the production of pathogenic anti-glycolipid autoantibodies.Methodology/Principal FindingsIn our current study, we report on the alterations in the thymus during the development of mild to severe progressive neurologic disease. The thymus from Hexb −/− 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+/CD8− 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 is expressed specifically in the thymus. B1 cells were also found to have increased in the thy mus. It is significant that these alterations in the thymus were reduced in FcRγ additionally disrupted Hexb −/− mice.Conclusions/SignificanceThese results suggest that the FcRγ chain may render the usually poorly immunogenic thymus into an organ prone to autoimmune responses, including the chemotaxis of B1 cells toward CXCL13.
Highlights
Lysosomal storage disorders (LSDs) arise from functional defects in one or more of the proteins essential to normal lysosome function
As with many of the other LSDs, neurodegeneration is a prominent feature of Sandhoff disease (SD) and since the neurons accumulate a large amount of GM2 ganglioside and GA2 relative to other tissues in this disease, it is generally thought that the nervous system is its main pathological target
Flow cytometric analysis further revealed that CD4+/CD8+ immature T cell ratio was dramatically decreased in the 15 week old Hexb2/2FcRc+/+ thymus compared with that of the Hexb+/2FcRc+/+ mice (5.8% vs. 88.0%), whereas the CD4+/CD82 and CD42/CD8+ T cell ratios were markedly increased (Fig. 1C top panel)
Summary
Lysosomal storage disorders (LSDs) arise from functional defects in one or more of the proteins essential to normal lysosome function. This typically involves the enzymes that play a critical role in the intracellular digestion of glycoproteins, glycolipids, glycosaminoglycans, or other macromolecules [1]. Mutations in the HEXA gene cause Tay-Sachs disease, whereas mutations in the HEXB gene cause Sandhoff disease (SD) [1]. 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 antiglycolipid autoantibodies
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