A study on immunological abnormality in the lysosomal storage disease

桑德霍夫病(SD)是一种严重的神经退行性疾病，由溶酶体氨基己糖苷酶A和B的β亚单位编码的HEXB基因突变引起。HEXB突变导致溶酶体中未降解的底物如GM2和GA2积聚。然而，最近的一些研究表明，神经节苷脂在神经元中的积累不能完全解释神经细胞的损伤和短暂的寿命。最近，我们和其他人报道了中枢神经系统的几种免疫异常，这些异常会导致神经细胞死亡。在本研究中，我们从形态学、流式细胞术和微阵列分析的角度对胸腺事件进行了研究，以了解SD小鼠发生自身免疫的机制。在SD小鼠的终末期，宏观和微观上都注意到明显的胸腺退缩。皮质T淋巴细胞数量减少，巨噬细胞数量明显增加。T淋巴细胞表面有免疫球蛋白G。基因芯片显示巨噬细胞中B细胞相关基因、巨噬细胞相关基因、趋化因子和TH2相关基因表达上调，巨噬细胞通过自身免疫机制吞噬含抗体的T淋巴细胞，导致GM2和GA2积聚。结果，巨噬细胞被激活，以促进自身免疫机制。

Sandhoff disease (SD), a prototype of lysosomal storage diseases, is a severe neurodegenerative disorder caused by mutations in the HEXB gene coding for the β subunit of the lysosomal hexosaminidases A and B. HEXB mutations result in the accumulation of undegraded substrates such as GM2 and GA2 in lysosomes.Neurological abnormalities have been ascribed in part to neuronal cell death caused by the accumulation of both undigested GM2 gangliosides and related lipids in neuronal lysosomes. However, several recent investigations have suggested that ganglioside accumulation in neurons alone cannot completely explain the nerve cell damage and the short life span. Recently we and others have reported several immunological abnormalities in the CNS which would lead to neuronal cell death. In this study we focused on thymic event from the point of morphology, flow cytometry, and microarray analysis to see the autoimmune mechanisms happening in SD mice.In the terminal stage of SD mice, marked thymic involution was noted both macroscopically and microscopically. The number of T lymphocyte in the cortex was decresed and macophage was markedly increased. T lymphocytes contained IgG on their cell surface. Macophages were swollen with nuclear fragments and undegraded GM2 and GA2 in the cytoplasm.The microarray data showed upregulation of B cell-related genes, macrohage-related genes, chemokines and TH2-related genes.From these results, macrophages englobe IgG-bearing T lymphocytes via autoimmune mechanisms and lead to GM2 and GA2 accumulation. As a results, macrophages are activated to facilitate autoimmune mechanisms.