Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012 Jun 19;109(25):10018-23.
doi: 10.1073/pnas.1200941109. Epub 2012 Jun 4.

Gaucher disease gene GBA functions in immune regulation

Jun Liu  1 , Stephanie Halene, Mei Yang, Jameel Iqbal, Ruhua Yang, Wajahat Z Mehal, Wei-Lien Chuang, Dhanpat Jain, Tony Yuen, Li Sun, Mone Zaidi, Pramod K Mistry
Affiliations

Gaucher disease gene GBA functions in immune regulation

Jun Liu et al. Proc Natl Acad Sci U S A. .

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Immune cell dysfunction in GBA1-deficient mice is organ-specific. Immunophenotyping of DP immune cells from the thymus (A), spleen (B), and lymph nodes (C and D) of GBA1-deficient (GD) and control (WT) mice, showing organ-specific differences in selected cell populations. Statistical analysis was performed by Student’s t test comparing WT and GD (n = 6 mice; *P < 0.05; **P < 0.01).
Fig. 2.
Fig. 2.
Profound changes in thymic immune cells in GBA1-deficient mice correlate with disease severity. Gated FACS analysis of immune cells from the thymus of GBA1-deficient (GD) vs. control mice (A–H), showing the effect of moderate and severe disease (as shown), classified on the basis of spleen weight (see Results). Analysis was performed using either double or single markers, as shown. At least six mice were used.
Fig. 3.
Fig. 3.
Changes in immune cell composition in the spleen and lymph nodes are less profound and occur only in severe disease. Gated FACS analysis of immune cells from the spleen (A–F) and lymph nodes (superficial cervical, axillary, mesenteric, and inguinal nodes) (G–L) of GBA1-deficient (GD) vs. control mice, showing the effect of moderate and severe disease (as shown), classified on the basis of spleen weight (see Results). Analysis was performed using either double or single markers, as shown. At least six mice were used.
Fig. 4.
Fig. 4.
High levels of lipid substrates impair hematopoiesis. (A and B) Correlation of splenomegaly with splenic glucosylceramide (GL1) (A) or glucosylsphingosine (Lyso-GL1) (B) levels. Spleen weight expressed as a multiple (N) of spleen weight of age-matched control mice (control spleen weight = 0.29 ± 0.07% body weight). Statistics were as follows: GL1, r2 = 0.22 and P = 0.014; Lyso-GL1, r2 = 0.48 and P = 0.00004. (C) Proliferation assay on bone marrow stem cells isolated from WT or GBA1-deficient (Mx1-Cre+/−/GBAfl/fl) (GD) mice (n = 5 mice; bone marrow pooled) and treated with either vehicle (DMSO, red), GL1 (green), and Lyso-GL1 (blue). The resultant progenitor, LT-HSCs, ST-HSCs, and MPP were cultured and cell numbers counted on days 0, 5, and 10 (see Materials and Methods).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Grabowski GA, Petsko GA, Kolodny EH. Gaucher Disease. The Online Metabolic and Molecular Bases of Inherited Disease. 2010. Chapter 146, eds Valle D, et al. Available at www.ommbid.com.
    1. Korkotian E, et al. Elevation of intracellular glucosylceramide levels results in an increase in endoplasmic reticulum density and in functional calcium stores in cultured neurons. J Biol Chem. 1999;274:21673–21678. - PubMed
    1. Mistry PK, et al. Glucocerebrosidase gene-deficient mouse recapitulates Gaucher disease displaying cellular and molecular dysregulation beyond the macrophage. Proc Natl Acad Sci USA. 2010;107:19473–19478. - PMC - PubMed
    1. Hůlková H, et al. Abnormal nonstoring capillary endothelium: A novel feature of Gaucher disease. Ultrastructural study of dermal capillaries. J Inherit Metab Dis. 2010;33:69–78. - PMC - PubMed
    1. Elleder M. Glucosylceramide transfer from lysosomes—the missing link in molecular pathology of glucosylceramidase deficiency: A hypothesis based on existing data. J Inherit Metab Dis. 2006;29:707–715. - PubMed

Publication types