su-5402 and Leukodystrophy--Metachromatic

A defect in invariant NKT (iNKT) cell selection was hypothesized in lysosomal storage disorders (LSD). Accumulation of glycosphingolipids (GSL) in LSD could influence lipid loading and/or presentation causing entrapment of endogenous ligand(s) within storage bodies or competition of the selecting ligand(s) by stored lipids for CD1d binding. However, when we analyzed the iNKT cell compartment in newly tested LSD animal models that accumulate GSL, glycoaminoglycans or both, we observed a defective iNKT cell selection only in animals affected by multiple sulfatase deficiency, in which a generalized aberrant T-cell development, rather than a pure iNKT defect, was present. Mice with single lysosomal enzyme deficiencies had normal iNKT cell development. Thus, GSL/glycoaminoglycans storage and lysosomal engulfment are not sufficient for affecting iNKT cell development. Rather, lipid ligand(s) or storage compounds, which are affected in those LSD lacking mature iNKT cells, might indeed be relevant for iNKT cell selection.

Topics: Animals; Cell Count; Cell Differentiation; Disease Models, Animal; Enzyme Inhibitors; Female; Leukodystrophy, Globoid Cell; Leukodystrophy, Metachromatic; Liver; Lymphocytes; Lysosomal Storage Diseases; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Mucopolysaccharidosis I; Multiple Sulfatase Deficiency Disease; Natural Killer T-Cells; Pyrroles; Receptor, Fibroblast Growth Factor, Type 1; Sandhoff Disease; Spleen; Thymus Gland