非断性FAS信号控制着人类B细胞中的mTOR激活和卵泡外成熟
Julian Staniek1,2, Tomas Kalina3, Geoffroy Andrieux4,5
1Department of Rheumatology and Clinical Immunology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Science immunology
|January 12, 2024
概括
缺陷的非光性FAS信号损害了ALPS-FAS中的B细胞分化,通过破坏mTOR通路,导致高血糖球蛋白血症和更少的记忆B细胞.
科学领域:
- 免疫学 免疫学 免疫学
- 细胞生物学 细胞生物学
- 分子医学是分子医学.
背景情况:
- 具有FAS突变的自身免疫淋巴增殖综合征 (ALPS) (ALPS-FAS) 与高糖球蛋白血症有关.
- 矛盾的是,ALPS-FAS患者表现出减少的记忆B细胞分化,尽管FAS表达在生殖中心B细胞上.
研究的目的:
- 调查非亡性FAS信号在ALPSB细胞分化中的作用.
- 阐明ALPS-FAS中受损B细胞命运决定背后的分子机制.
主要方法:
- 来自ALPS-FAS患者的二次淋巴体器官的分析.
- 在体外建模T依赖B细胞激活.
- 评估PI3K/mTOR和B细胞受体 (BCR) 信号通路.
- 调查PTEN核排斥及其对mTOR活动的影响.
主要成果:
- 患有ALPS-FAS的患者表现出记忆B细胞的减少,生殖中心 (GC) B细胞的减少,以及扩大的卵泡外 (EF) B细胞反应.
- 在ALPS-FAS脏B细胞中观察到增强的PI3K/mTOR和BCR信号.
- 在具有FAS能力的细胞中,过渡性FAS结合通过caspase-8介导的PTEN核排斥抑制了mTOR活性,这是ALPS-FAS中缺陷的过程.
- FAS刺激促进了GC启动基因表达,而不是EF反应基因.
结论:
- 非断性FAS信号作为一个分子开关,通过mTOR轴调节EF和GCB细胞命运决定之间的平衡.
- 这种FAS介导的调节电路中的缺陷有助于ALPS-FAS的高玛球蛋白血症和减少记忆B细胞的形成.
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