Immune system dysfunction in Niemann-Pick type C1 mice

Abstract

Objective To analyze the differences in immune system between Npc1 gene mutant (Npc1-/-) and wild-type (Npc1+ /+ ) mice for better understanding the pathogenesis of Niemann-Pick disease type C1 (NPC1) from an immunological perspective and providing reference for NPC1 treatment in clinic. Methods Body, thymus and spleen weight of Npc1-/-and Npc1+ /+ mice aged (14±2) days, (42±2) days and (63±2) days (Day14±2, Day42±2 and Day63±2) were recorded and the associated organ index were calculated. White blood cell count in peripheral blood of mice aged Day42±2 was examined by routine blood test. Expression of cytokines at mRNA level in mouse peripheral blood was detected by qPCR. Percentages of CD4+ , CD8+ and CD19+ lymphocytes in peripheral blood and spleen of mice aged Day42±2 were measured by flow cytometry. Apoptosis and senescence of spleen in mice aged Day63±2 were examined by immunofluorescence and β-galactosidase staining. Results Compared with Npc1+ /+ mice, there was no significant difference in the weight of spleen and thymus in Npc1-/- mice aged Day14±2; the weight of spleen in Npc1-/- mice aged Day42±2 significantly increased, but the weight of thymus showed a significant decrease; furthermore, both the weight of spleen and thymus in Npc1-/- mice aged Day63±2 significantly decreased; and the body weight of Npc1-/- mice of each age group significantly decreased. Moreover, compared with Npc1+ /+ mice, the absolute number of lymphocytes in the peripheral blood of Npc1-/- mice aged Day42±2 showed no significant difference, but the percentage in whole white blood cells significantly decreased due to the significantly increased neutrophils. Expression of cytokines (IL-1, IL-2, IFN-γ, TNF-α, IL-4, granzyme A and granzyme B) at mRNA level in the peripheral blood leukocytes of Npc1-/- mice aged Day42±2 was abnormal as compared with that in Npc1+ /+ mice. The number of T (CD4+ and CD8+ ) lymphocytes in Npc1-/- mice aged Day42±2 significantly decreased, while the number of B (CD19+ ) lymphocytes increased significantly as compared with those in the Npc1+ /+ mice. Compared with Npc1+ /+ mice, apoptosis and senescence of the spleen in Npc1-/- mice aged Day63±2 aggravated significantly. Conclusion The abnormal lipid metabolism triggered by Npc1 gene mutation causes severe immune dysfunction in Npc1-/- mice. Therefore, immune dysfunction should be taken into full consideration when treating patients with NPC1, which might help improve the life quality and prolong the survival time. Key words: Niemann-Pick disease type C1; Npc1 gene; Immune system dysfunction; Senescence