Aerts, J. M. F. G. | bioRxiv Science

bioRxiv2025

The Role of Glycosphingolipids in Autoimmune Manifestations and Myeloma in Gaucher Disease

Gaucher disease, an inborn error of glucosylceramide recycling, predisposes to haematological malignancies, liver cirrhosis and cancer. Inducible Gaucher disease modelled in susceptible mouse strains showed striking autoimmune hepatitis and cancer development; as reported previously, they also develop monoclonal immunoglobulins and B-cell tumours. Exposure to eliglustat, a therapeutic inhibitor of glucosylceramide biosynthesis, suppressed hepatic disease and occurrence of monoclonal immunoglobulins. To interrogate activation of CD1-restricted T cells by glucosylceramides, we deleted CD1d1/Cd1d2 function in the conditional inducible murine model of Gaucher disease with GBA1 deficiency in haematopoietic cells. Systemic inflammation and autoantibodies in these CD1-/- GCflox/flox Cre+ mice were markedly reduced, and severe liver injury and tumour formation was suppressed; however, occurrence of monoclonal immunoglobulins was unaffected. We suggest that CD1 molecules have distinct actions on tissue homeostasis in this system related to cell-intrinsic activation as well as glycolipid loading and presentation. Our findings implicate glycosphingolipids in the development of autoimmunity and cancer in human Gaucher disease and have broader significance in acquired and genetic disorders affecting sphingolipid expression.

pathology↗

bioRxiv2022

Gaucher Disease Protects Against Tuberculosis

Biallelic mutations in the glucocerebrosidase (GBA1) gene cause Gaucher disease, characterized by lysosomal accumulation of glucosylceramide and glucosylsphingosine in macrophages. This and other lysosomal diseases occur with high frequency in Ashkenazi Jews. It has been proposed that the underlying mutations confer a selective advantage, in particular conferring protection against tuberculosis. Here, using a zebrafish Gaucher disease model, we find that the mutation GBA1 N370S, predominant among Ashkenazi Jews, increases resistance to tuberculosis through the microbicidal activity of glucosylsphingosine in macrophage lysosomes. Consistent with lysosomal accumulation occurring only in homozygotes, heterozygotes remain susceptible to tuberculosis. Thus, our findings reveal a mechanistic basis for protection against tuberculosis by GBA1 N370S and provide biological plausibility for its selection if the relatively mild deleterious effects in homozygotes were offset by significant protection against tuberculosis, a rampant killer of the young in Europe through the Middle Ages into the 19th century. Significance StatementGaucher disease is a recessively inherited disorder in which the lipids glucosylceramide and glucosylsphingosine accumulate in lysosomes of macrophages. Macrophages are the first immune cells to engulf infecting bacteria and we find that glucosylsphingosine increases their ability to kill Mycobacterium tuberculosis that causes tuberculosis. Gaucher disease due to a particular mutation is frequent in Ashkenazi Jews. Since from the middle ages they were often confined to areas of high tuberculosis prevalence, it has been proposed that the mutation prevailed because heterozygotes, who do not accumulate lipids nor manifest Gaucher disease, were protected. Our findings raise the possibility that selection operated on homozygotes manifesting mild forms of Gaucher disease who were protected against tuberculosis which would often have been fatal.

microbiology↗