Hermansky–Pudlak Syndrome (HPS) is a rare autosomal recessive disorder caused by mutations in the HPS gene encoding the -subunit of the cytosolic adaptor protein AP-3, that functions in organelle biogenesis and protein trafficking. Pearl mice are known to have a mutation in the HPS gene and exhibit characteristics similar to those observed in the human disease, such as prolonged bleeding time, hypopigmentation and pulmonary fibrosis. As AP-3 is required for the efficient presentation of glycolipid antigens and for cytotoxic granule functioning, its mutation can result in immune disfunction. This concept is supported by observations that HPS patients show neutropenia and recurrent infection. In order to examin the role of AP3 in the immune response, we compared the immune repertoire of pearl mice focusing on dendritic cell (DC) compartment. A broad assessment of T, B and NK cell subsets did not reveal major perturbances in pearl mice. The percentages of plasmacytoid DC (pDC) (CD11c+B220+; SiglecH+ DC) and conventional DC (cDC) (CD11c+CD11b+) were comparable in pearl and in wild-type mice. A marked increase of CD1d cell surface expression, important for glycolipid antigens presentation, was evident on pearl T cells, DC and NK cells. To examine the function of DC, cDC and pDC were generate from pearl bone marrow cultures and were challenged with bacterial and viral stimuli. cDC from pearl mice respond to Toll-like receptor stimulation with normal maturation and release of cytokines. On the contrary, pDC from pearl mice secreted significantly low levels of IFN in response to viral stimuli (MCMV, VSV, HSV) or in response to the TLR9 agonist CpG compered to wild type pDC. These results point to a selective defect in pearl pDC and suggest that this alteration may contribute to the increased susceptibility of Hermansky–Pudlak patients to infections.
Defective IFN-alpha production in plasmacytoid dendritic cells from Hermansky-Pudlak mice.
SCUTERA, SARA AGATA CATERINA;LUGANINI, ANNA;GRIBAUDO, Giorgio;MUSSO, Tiziana
2011-01-01
Abstract
Hermansky–Pudlak Syndrome (HPS) is a rare autosomal recessive disorder caused by mutations in the HPS gene encoding the -subunit of the cytosolic adaptor protein AP-3, that functions in organelle biogenesis and protein trafficking. Pearl mice are known to have a mutation in the HPS gene and exhibit characteristics similar to those observed in the human disease, such as prolonged bleeding time, hypopigmentation and pulmonary fibrosis. As AP-3 is required for the efficient presentation of glycolipid antigens and for cytotoxic granule functioning, its mutation can result in immune disfunction. This concept is supported by observations that HPS patients show neutropenia and recurrent infection. In order to examin the role of AP3 in the immune response, we compared the immune repertoire of pearl mice focusing on dendritic cell (DC) compartment. A broad assessment of T, B and NK cell subsets did not reveal major perturbances in pearl mice. The percentages of plasmacytoid DC (pDC) (CD11c+B220+; SiglecH+ DC) and conventional DC (cDC) (CD11c+CD11b+) were comparable in pearl and in wild-type mice. A marked increase of CD1d cell surface expression, important for glycolipid antigens presentation, was evident on pearl T cells, DC and NK cells. To examine the function of DC, cDC and pDC were generate from pearl bone marrow cultures and were challenged with bacterial and viral stimuli. cDC from pearl mice respond to Toll-like receptor stimulation with normal maturation and release of cytokines. On the contrary, pDC from pearl mice secreted significantly low levels of IFN in response to viral stimuli (MCMV, VSV, HSV) or in response to the TLR9 agonist CpG compered to wild type pDC. These results point to a selective defect in pearl pDC and suggest that this alteration may contribute to the increased susceptibility of Hermansky–Pudlak patients to infections.
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
