A study on immunological abnormality in the lysosomal storage disease

山德霍夫病（SD）是溶酶体胆积病的原型，是由编码溶酶体氨基己糖苷酶A和B的β亚基的HEX B基因突变引起的严重神经退行性疾病。HEXB突变导致未降解的底物如GM 2和GA 2在溶酶体中积累。神经系统异常部分归因于神经元溶酶体中未消化的GM 2神经节苷脂和相关脂质的积累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不能完全解释神经细胞损伤和寿命短。最近，我们和其他人报道了几个免疫异常的中枢神经系统，这将导致神经元细胞死亡。本研究从形态学、流式细胞术和基因芯片分析等方面对SD小鼠胸腺事件进行了研究，以探讨其自身免疫机制。皮质T淋巴细胞减少，巨噬细胞明显增多。T淋巴细胞在其细胞表面含有IgG。结果表明，巨噬细胞通过自身免疫机制吞噬携带IgG的T淋巴细胞，并导致GM 2和GA 2的积累，从而导致巨噬细胞内的B细胞相关基因、巨噬细胞相关基因、趋化因子和TH 2相关基因表达上调。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.