Yamaguchi, A. et al. Possible role of autoantibodies in the pathophysiology of GM2 gangliosidoses. J. Clin. Invest. 113, 200-208

Yokohama City University, Yokohama, Kanagawa, Japan
Journal of Clinical Investigation (Impact Factor: 13.22). 02/2004; 113(2):200-8. DOI: 10.1172/JCI19639
Source: PubMed


Mice containing a disruption of the Hexb gene have provided a useful model system for the study of the human lysosomal storage disorder known as Sandhoff disease (SD). Hexb(-/-) mice rapidly develop a progressive neurologic disease of ganglioside GM2 and GA2 storage. Our study revealed that the disease states in this model are associated with the appearance of antiganglioside autoantibodies. Both elevation of serum antiganglioside autoantibodies and IgG deposition to CNS neurons were found in the advanced stages of the disease in Hexb(-/-) mice; serum transfer from these mice showed IgG binding to neurons. To determine the role of these autoantibodies, the Fc receptor gamma gene (FcR gamma) was additionally disrupted in Hexb(-/-) mice, as it plays a key role in immune complex-mediated autoimmune diseases. Clinical symptoms were improved and life spans were extended in the Hexb(-/-)FcR gamma(-/-) mice; the number of apoptotic cells was also decreased. The level of ganglioside accumulation, however, did not change. IgG deposition was also confirmed in the brain of an autopsied SD patient. Taken together, these findings suggest that the production of autoantibodies plays an important role in the pathogenesis of neuropathy in SD and therefore provides a target for novel therapies.

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    • "It is widely postulated that the CNS is the main pathological target of GM2 gangliosidosis. However, we have previously found that the production of autoantibodies plays an important role in the pathogenesis of neuropathy in Sandhoff disease [10]. In our present study, we observed a dramatic involution of the thymus in 15 week old Hexb−/−FcRγ+/+ mouse. "
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    ABSTRACT: Sandhoff 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. 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 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. These 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.
    Full-text · Article · Aug 2010 · PLoS ONE
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    • "Most data suggest that this is due to activation of the innate immune system, with microglial cells and macrophages playing a prominent role [21] [22]. However, additional involvement of autoimmune pathophysiology has also been suggested in a small number of studies [23]. Targeting inflammation has been proven to be of therapeutic benefit; preventing macrophage recruitment to the brain in a mouse model of Sandhoff disease extended life span of these mice [24], as did treatment with non-steroidal anti-inflammatory drugs (NSAIDs) [25]. "
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    ABSTRACT: There are over 40 human disease states that are caused by defects in various aspects of lysosomal function. Over the past two decades there has been dramatic progress in the development and evaluation of therapies for lysosomal storage disorders, several of which are now in routine clinical use or in clinical trials. The greatest current challenge is in developing effective therapies for treating the CNS manifestations of these complex disorders. In this article, we will review the current therapies/approaches being considered for treating lysosomal storage diseases and give a perspective on the scientific, medical, social and ethical issues they raise.
    Full-text · Article · Oct 2008 · Biochimica et Biophysica Acta
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    • "Varied findings for the same test may be attributable to different genetic backgrounds (the original mice were not purebred and colony breeding schemes have differed between reports) and/or to different experimental parameters. Evidence for onset of motor incoordination as early as 60–70 days in LSDs, as we have detected using the balance beam test, is uncommon [15] [27] [28]. The use of this test, not previously employed on Sandhoff mice, should be particularly valuable to evaluation of efficacy in therapeutic strategies involving early intervention. "
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    ABSTRACT: Mouse models of lysosomal storage diseases, including Sandhoff disease, are frequently employed to test therapies directed at the central nervous system. We backbred such mice and conducted a behavioral test battery which included sensorimotor and cognitive assessments. This is the first report of short-term memory deficits in a murine model of Sandhoff disease. We also document early onset of motor deficits using the balance beam test.
    Full-text · Article · Jul 2008 · Behavioural Brain Research
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