Elucidation of the mechanisms underlying in the immunological abnormalities of lysosomal storage diseases

阐明溶酶体贮积病免疫学异常的潜在机制

• 批准号: 23790448
• 负责人: YAMAGUCHI Akira
• 金额: $ 2.83万
• 依托单位: Yokohama City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23790448/
• 关键词: ライソゾーム病; 自己抗体; 炎症反応; ケモカイン

We have previously found that the progress neurologic disease induced in SD and hex-/- mice, is associated with the production of pathogenic anti-glycolipid autoantibodies. In this study, we focused immunological abnormalities in the CNS. We employed Real-time PCR analysis to monitor gene expression in the terminal stage of hexb-/- mice and found that gene associated with the immune responses were up-regulated. B lymphocyte chemoattractant CXCL-13 was one of there up-regulated genes and is expressed specifically in the CNS. To determine the role of the CXCL-13, the cxcl-13 gene was additionally disrupted in hexb-/- mice, as it play a key role in the autoimmune disease. Clinical symptoms were improved and life spans were extended in the hexb-/-, cxcl-13-/- mice and the number of neuronal cells was also increased than hexb-/- mice. These findings suggest that the expression of CXCL-13 plays an important role in the pathogenesis of neuropathy in hexb-/- mice and therefore provides a target for novel therapies.

我们以前已经发现，在SD和hex-/-小鼠中诱导的神经系统疾病的进展与致病性抗糖脂自身抗体的产生有关。在这项研究中，我们集中在中枢神经系统的免疫异常。我们采用Real-time PCR技术检测了hexb-/-小鼠免疫终末期的基因表达，发现与免疫应答相关的基因表达上调。B淋巴细胞趋化因子CXCL-13是其中一个表达上调的基因，在中枢神经系统特异性表达。为了确定CXCL-13的作用，在hexb-/-小鼠中另外破坏cxcl-13基因，因为它在自身免疫性疾病中起关键作用。hexb-/-，cxcl-13-/-小鼠的临床症状得到改善，寿命延长，神经细胞数量也比hexb-/-小鼠增加。这些发现表明，CXCL-13的表达在hexb-/-小鼠神经病变的发病机制中起着重要作用，因此为新的治疗提供了靶点。

项目成果

サンドホフ病モデルマウスにおけるα-シヌクレインの機能と病態への関与

参与桑德霍夫病模型小鼠的 α-突触核蛋白功能和病理学

• 作者: 鈴木京子;山口章;神崎誠一;都甲崇;勝瀬大海;青木直哉;河上緒;山口佳代子;幸光範子;藤田雅代;橋本款;山中正二;平安良雄
• 通讯作者: 平安良雄