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

Abstract 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. Competing Interest Statement TMC is an Investigator on the ENCORE, LEAP and AMETHIST trials and on Speaker Bureau for Sanofi Specialty Care for which he receives honoraria; he has received no salary from investigator-initiated research supported by Sanofi-Aventis related to this or any other study. A.J.M.F.G. is currently serving as an advisor to Azafaros and Genewity. The remaining authors declare no known competing interests.