Thymic Alterations in GM2 Gangliosidoses Model Mice
Thymic Alterations in GM2 Gangliosidoses Model Mice
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DOI：
10.1371/journal.pone.0012105
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发表时间：
2010-08-10
期刊：
影响因子：
3.7
通讯作者：
Yamanaka, Shoji
中科院分区：
文献类型：
--
作者：
Kanzaki, Seiichi;Yamaguchi, Akira;Yamanaka, Shoji
背景：桑德霍夫病是一种溶酶体贮积症，其特征是缺乏 β-己糖胺酶以及 GM2 神经节苷脂和相关糖脂的贮积。我们之前发现，Hexb(-/-) 小鼠（桑德霍夫病的动物模型）诱导的进行性神经系统疾病与致病性抗糖脂自身抗体的产生有关。方法/主要发现：在我们目前的研究中，我们报告了轻度至重度进行性神经系统疾病发展过程中胸腺的变化。大于15周龄的Hexb(-/-)小鼠的胸腺显示未成熟CD4(+)/CD8(+) T细胞百分比显着下降，而CD4(+)/CD8(-) T细胞数量显着增加。在复旧过程中，发现凋亡的胸腺细胞和 T 细胞的 IgG 沉积水平均有所增加，同时明显观察到巨噬细胞肿胀，特别是在皮质中。我们采用 cDNA 微阵列分析来监测退化过程中的基因表达，发现与免疫反应相关的基因上调，特别是在巨噬细胞中表达的基因。 CXCL13 是这些上调基因之一，并且在胸腺中特异性表达。胸腺中的 B1 细胞也有所增加。值得注意的是，在 FcR gamma 额外破坏的 Hexb(-/-) 小鼠中，胸腺中的这些变化减少了。结论/意义：这些结果表明，FcR gamma 链可能使通常免疫原性较差的胸腺变成容易发生自身免疫反应的器官，包括 B1 细胞对 CXCL13 的趋化性。
Background: Sandhoff disease is a lysosomal storage disorder characterized by the absence of beta-hexosaminidase and storage of GM2 ganglioside and related glycolipids. We have previously found that the progressive neurologic disease induced in Hexb(-/-) mice, an animal model for Sandhoff disease, is associated with the production of pathogenic anti-glycolipid autoantibodies.Methodology/Principal Findings: In our current study, we report on the alterations in the thymus during the development of mild to severe progressive neurologic disease. The thymus from Hexb(-/-) mice of greater than 15 weeks of age showed a marked decrease in the percentage of immature CD4(+)/CD8(+) T cells and a significantly increased number of CD4(+)/CD8(-) T cells. During involution, the levels of both apoptotic thymic cells and IgG deposits to T cells were found to have increased, whilst swollen macrophages were prominently observed, particularly in the cortex. We employed cDNA microarray analysis to monitor gene expression during the involution process and found that genes associated with the immune responses were upregulated, particularly those expressed in macrophages. CXCL13 was one of these upregulated genes and is expressed specifically in the thymus. B1 cells were also found to have increased in the thy mus. It is significant that these alterations in the thymus were reduced in FcR gamma additionally disrupted Hexb(-/-) mice.Conclusions/Significance: These results suggest that the FcR gamma chain may render the usually poorly immunogenic thymus into an organ prone to autoimmune responses, including the chemotaxis of B1 cells toward CXCL13.