Gaucher disease gene GBA functions in immune regulation.
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.
Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520, USA.
Jun
J
Liu
Stephanie
S
Halene
Mei
M
Yang
Jameel
J
Iqbal
Ruhua
R
Yang
Wajahat Z
WZ
Mehal
Wei-Lien
WL
Chuang
Dhanpat
D
Jain
Tony
T
Yuen
Li
L
Sun
Mone
M
Zaidi
Pramod K
PK
Mistry
D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D005776:Gaucher Disease / Q000235:genetics / Q000276:immunology*; D005962:Glucosylceramidase / Q000235:genetics*; D016130:Immunophenotyping; D051379:Mice; D018345:Mice, Knockout
D015703:Antigens, CD; D005962:Glucosylceramidase