Thymic Alterations in GM2 Gangliosidoses Model Mice

Kanzaki, Seiichi; Yamaguchi, Akira; Yamaguchi, Kayoko; Kojima, Yoshitsugu; Suzuki, Kyoko; Koumitsu, Noriko; Nagashima, Yoji; Nagahama, Kiyotaka; Ehara, Michiko; Hirayasu, Yoshio; Ryo, Akihide; Aoki, Ichiro; Yamanaka, Shōji

doi:10.1371/journal.pone.0012105

Cited by 11 publications

(6 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These effects can, at least in part, be attributed to the antiproliferative effects of the accumulated lipids (41). Similar immune phenotypes have been described in other inherited lipidosis (43,44). Thus, on a broader note, the studies underscore the importance of defining the role of aberrant immunity and the interactions between lipids and immune cells in genetic lipidosis and reversal of immune dysregulation as an additional therapeutic target (45).…”

Section: Discussionmentioning

confidence: 60%

Gaucher disease geneGBAfunctions in immune regulation

Liu

Halene

Yang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Inherited deficiency of acid β-glucosidase (GCase) due to biallelic mutations in the GBA (glucosidase, β, acid) gene causes the classic manifestations of Gaucher disease (GD) involving the viscera, the skeleton, and the lungs. Clinical observations point to immune defects in GD beyond the accumulation of activated macrophages engorged with lysosomal glucosylceramide. Here, we show a plethora of immune cell aberrations in mice in which the GBA gene is deleted conditionally in hematopoietic stem cells (HSCs). The thymus exhibited the earliest and most striking alterations reminiscent of impaired T-cell maturation, aberrant B-cell recruitment, enhanced antigen presentation, and impaired egress of mature thymocytes. These changes correlated strongly with disease severity. In contrast to the profound defects in the thymus, there were only limited cellular defects in peripheral lymphoid organs, mainly restricted to mice with severe disease. The cellular changes in GCase deficiency were accompanied by elevated T-helper (Th)1 and Th2 cytokines that also tracked with disease severity. Finally, the proliferation of GCase-deficient HSCs was inhibited significantly by both GL1 and Lyso-GL1, suggesting that the “supply” of early thymic progenitors from bone marrow may, in fact, be reduced in GBA deficiency. The results not only point to a fundamental role for GBA in immune regulation but also suggest that GBA mutations in GD may cause widespread immune dysregulation through the accumulation of substrates.

show abstract

Section: Discussionmentioning

confidence: 60%

Gaucher disease geneGBAfunctions in immune regulation

Liu

Halene

Yang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…cats treated with vectors expressing human Hex had marked cellular infiltrates apparent as vascular cuffs consisting primarily of B lymphocytes, whereas SD cats treated with the same vectors demonstrated little or no infiltrate. A differential immune response to the same AAV vectors may result from immune defects in affected animals, such as premature thymic involution caused in part by a ganglioside-mediated apoptotic cascade, as reported in cats with GM1 gangliosidosis [21][22][23] and in SD mice 24,25 and cats (data not shown). Though decreased thymus size is measurable only in late-stage disease, increased thymocyte apoptosis and other changes are present in early to middle disease stages, perhaps contributing to the diminished immune response of AAV-treated SD cats.…”

Section: Discussionmentioning

confidence: 79%

Therapeutic Response in Feline Sandhoff Disease Despite Immunity to Intracranial Gene Therapy

et al. 2013

View full text Add to dashboard Cite

Salutary responses to adeno-associated viral (AAV) gene therapy have been reported in the mouse model of Sandhoff disease (SD), a neurodegenerative lysosomal storage disease caused by deficiency of β-N-acetylhexosaminidase (Hex). While untreated mice reach the humane endpoint by 4.1 months of age, mice treated by a single intracranial injection of vectors expressing human hexosaminidase may live a normal life span of 2 years. When treated with the same therapeutic vectors used in mice, two cats with SD lived to 7.0 and 8.2 months of age, compared with an untreated life span of 4.5 ± 0.5 months (n = 11). Because a pronounced humoral immune response to both the AAV1 vectors and human hexosaminidase was documented, feline cDNAs for the hexosaminidase α- and β-subunits were cloned into AAVrh8 vectors. Cats treated with vectors expressing feline hexosaminidase produced enzymatic activity >75-fold normal at the brain injection site with little evidence of an immune infiltrate. Affected cats treated with feline-specific vectors by bilateral injection of the thalamus lived to 10.4 ± 3.7 months of age (n = 3), or 2.3 times as long as untreated cats. These studies support the therapeutic potential of AAV vectors for SD and underscore the importance of species-specific cDNAs for translational research.

show abstract

“…Hexb −/− / Fcrγ −/− mice exhibit a partial recovery of the thymic mass and attenuation of disease progression, including the production of autoantibodies. In the case of SD mice, Kanzaki et al reported that thymic alteration in SD mice is partially dependent of the FcRγ chain, including severe decreases in CD4 + /CD8 + T cells and chemotaxis of B1 cells toward CXCL13 in the thymus (Kanzaki et al 2010). These findings suggested that the production of autoantibodies can be attributed to thymic alterations.…”

Section: Discussionmentioning

confidence: 99%

Thymic involution and corticosterone level in Sandhoff disease model mice: new aspects the pathogenesis of GM2 gangliosidosis

Matsuoka

Tsuji

Taki

et al. 2011

J of Inher Metab Disea

View full text Add to dashboard Cite

Sandhoff disease (SD) is a lysosomal disease caused by a mutation of the HEXB gene associated with excessive accumulation of GM2 ganglioside (GM2) in lysosomes and neurological manifestations. Production of autoantibodies against the accumulated gangliosides has been reported to be involved in the progressive pathogenesis of GM2 gangliosidosis, although the underlying mechanism has not been fully elucidated. The thymus is the key organ in the acquired immune system including the development of autoantibodies. We showed here that thymic involution and an increase in cell death in the organ occur in SD model mice at a late stage of the pathogenesis. Dramatic increases in the populations of Annexin-V(+) cells and terminal deoxynucletidyl transferase dUTP nick end labeling (TUNEL) (+) cells were observed throughout the thymuses of 15-week old SD mice. Enhanced caspase-3/7 activation, but not that of caspase-1/4, -6 ,-8, or -9, was also demonstrated. Furthermore, the serum level of corticosterone, a potent inducer of apoptosis of thymocytes, was elevated during the same period of apoptosis. Our studies suggested that an increase in endocrine corticosterone may be one of the causes that accelerate the apoptosis of thymocytes leading to thymic involution in GM2 gangliosidosis, and thus can be used as a disease marker for evaluation of the thymic condition and disease progression.

show abstract

Thymic Alterations in GM2 Gangliosidoses Model Mice

Cited by 11 publications

References 49 publications

Gaucher disease geneGBAfunctions in immune regulation

Gaucher disease geneGBAfunctions in immune regulation

Therapeutic Response in Feline Sandhoff Disease Despite Immunity to Intracranial Gene Therapy

Thymic involution and corticosterone level in Sandhoff disease model mice: new aspects the pathogenesis of GM2 gangliosidosis

Contact Info

Product

Resources

About