A study on immunological abnormality in the lysosomal storage disease

Sandhoff病（SD）是溶酶体贮积病的一种原型，是一种严重的神经退行性疾病，由编码溶酶体六糖氨酸酶a和b的β亚基的HEXB基因突变引起。HEXB突变导致溶酶体中未降解底物如GM2和GA2的积累。神经系统异常部分归因于未消化的GM2神经节苷脂和相关脂质在神经元溶酶体中的积累所引起的神经元细胞死亡。然而，最近的一些研究表明，神经节苷脂在神经元中的积累并不能完全解释神经细胞的损伤和寿命的缩短。最近，我们和其他人报道了几例中枢神经系统的免疫异常，这些异常会导致神经元细胞死亡。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关注胸腺事件，以观察SD小鼠发生的自身免疫机制。在SD小鼠晚期，在宏观和显微镜下观察到明显的胸腺退化。大鼠皮层T淋巴细胞数量减少，巨噬细胞明显增多。T淋巴细胞表面含有IgG。巨噬细胞被核碎片和细胞质中未降解的GM2和GA2肿胀。微阵列数据显示B细胞相关基因、巨噬细胞相关基因、趋化因子和th2相关基因上调。从这些结果来看，巨噬细胞通过自身免疫机制包裹携带igg的T淋巴细胞并导致GM2和GA2的积累。因此，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.