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Niemann-Pick type C (NPC) is a neurodegenerative lysosomal storage disorder caused by defects in the lysosomal proteins NPC1 or NPC2. NPC cells are characterized by reduced lysosomal calcium levels and impaired sphingosine transport from lysosomes. Natural killer (NK) cells kill virally infected/transformed cells via degranulation of lysosome-related organelles. Their trafficking from lymphoid tissues into the circulation is dependent on sphingosine-1-phosphate (S1P) gradients, sensed by S1P receptor 5 (S1P5). We hypothesized that NK-cell function and trafficking could be affected in NPC disease due to the combined effects of the lysosomal calcium defect and sphingosine storage. In an NPC1 mouse model, we found the frequency of NK cells was altered and phenocopied S1P5-deficient mice, consistent with defects in S1P levels. NK cells from NPC1 mice also had a defect in cytotoxicity due to a failure in degranulation of cytotoxic granules, which was associated with reduced lysosomal calcium levels. Affected NPC1 patients and NPC1 heterozygote carriers had reduced NK-cell numbers in their blood and showed similar phenotypic and developmental changes to those observed in the NPC1 mouse. These findings highlight the effects of lysosomal storage on the peripheral immune system.

Original publication

DOI

10.1182/blood-2013-03-488692

Type

Journal article

Journal

Blood

Publication Date

02/01/2014

Volume

123

Pages

51 - 60

Keywords

Adolescent, Adult, Aged, Animals, Calcium, Child, Child, Preschool, Female, Heterozygote, Humans, Infant, Infant, Newborn, Inflammation, Killer Cells, Natural, Leukocytes, Mononuclear, Lysophospholipids, Lysosomes, Male, Mice, Mice, Inbred BALB C, Mice, Transgenic, Middle Aged, Niemann-Pick Disease, Type C, Phenotype, Proteins, Sphingosine, Young Adult