Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 25, Pages 10018-10023Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1200941109
Keywords
glucocerebroside; glucosylsphingosine; lysosomal storage disease
Categories
Funding
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [K24DK066306]
- Gaucher Generation Program grant
- NIDDK [R01 DK0804590]
- National Institute on Aging (NIA) [R01 AG023176, AG040132]
- National Institutes of Health [R01DK076674-01A]
- Veterans Administration Merit Award
- Claude D. Pepper Older Americans Independence Center at Yale University School of Medicine (NIA) [P30 AG021342]
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Inherited deficiency of acid beta-glucosidase (GCase) due to biallelic mutations in the GBA (glucosidase, beta, 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.
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