在多发性硬化症中,ODC1限制脑膜B细胞与年龄相关的类似表型和功能:一项人类和实验研究
Jonathan Zurawski1, Alara Tuncer2,3, Martin R Profant2,3
1Brigham and Women's Hospital, Mass General Brigham, Harvard Medical School, Boston, MA 02115.
概括
多氨酸在多发性硬化症 (MS) 期间调节脑膜中的免疫细胞. 甲尼丁脱糖酶 (ODC1) 抑制会影响B细胞和T细胞的反应,影响实验性自身免疫脑膜炎 (EAE) 模型中的疾病严重程度.
科学领域:
- 神经免疫学 神经免疫学
- 细胞的新陈代谢
背景情况:
- 脑膜炎症是多发性硬化症 (MS) 的标志,与较差的临床结果有关.
- 在多发性硬化患者的脑膜和实验性自身免疫脑膜炎 (EAE) 模型中发现富含B细胞的异位淋巴卵泡.
- 在MS和EAE中脑膜B细胞的代谢需求在很大程度上是未知的.
研究的目的:
- 研究氨酸/聚胺通路在MS和EAE中脑膜炎中的作用.
- 阐明Ornithine Decarboxylase 1 (ODC1) 在自我免疫期间调节脑膜B细胞和T细胞反应中的功能.
主要方法:
- 关联多发性硬化患者的7-特斯拉核磁共振扫描脑部扫描与勒普托门功能增强和代谢物.
- 从MOG35-55诱导EAE小鼠分析多胺代谢的硬膜脑膜B细胞.
- 研究ODC1药理抑制对EAE中脑膜免疫细胞的影响.
- 在MOG1-125 EAE模型中检查B细胞特异ODC1删除的后果.
主要成果:
- 在MS患者和EAE小鼠中观察到脑膜炎症和阿尔金因/聚胺途径的代谢物之间的相关性.
- 在EAE小鼠的脑膜B细胞中,ODC1和聚胺代谢减少.
- 抑制ODC1减少了脑膜T细胞,但增加了脑膜B细胞的增殖.
- 针对B细胞的ODC1删除导致B细胞扩张,具有与年龄相关的B细胞类表型,增加MOG特异性IgG,减少突触密度,并恶化EAE疾病.
结论:
- 多氨酸在像MS这样的自身免疫性疾病期间在脑膜内调节B细胞和T细胞反应中发挥着关键的,不同的作用.
- ODC1是脑膜B细胞功能的关键调节者,并影响EAE的整体疾病病理学.
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