Takahashi Fumio, Zhang Chenyang, Hohjoh Hirohiko, Raveney Ben, Yamamura Takashi, Hayashi Nobuhiro, Oki Shinji
Department of Immunology, National Institute of Neuroscience, NCNP, Tokyo, Japan.
School of Life Science and Technology, Tokyo Institute of Technology, Tokyo, Japan.
iScience. 2022 Apr 22;25(5):104278. doi: 10.1016/j.isci.2022.104278. eCollection 2022 May 20.
Neurodegeneration is a process involving both cell autonomous and non-cell autonomous neuron loss, followed by a collapse of neural networks, but its pathogenesis is poorly understood. We have previously demonstrated that Eomes-positive helper T (Eomes + Th) cells recognizing LINE-1(L1)-derived prototypic antigen ORF1 mediate neurotoxicity associated with the neurodegenerative pathology of experimental autoimmune encephalomyelitis (EAE). Here, we show that Eomes + Th cells accumulate in the CNS of mouse models of authentic neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), and secrete the neurotoxic granzyme B after encounter with ORF1 antigen. Multimodal derepression of neuronal L1 transcription is observed in EAE and ALS/AD models during neurodegeneration in active and cell cycle-mediated manner, respectively. These data suggest that the adventitious concurrence of immune-mediated neurodegenerative traits by Eomes + Th cells and ectopic expression of L1-derived antigen(s) in the inflamed CNS may materialize a communal and previously unappreciated pathogenesis of neurodegeneration.
神经退行性变是一个涉及细胞自主和非细胞自主神经元丢失的过程，随后神经网络崩溃，但其发病机制尚不清楚。我们之前已经证明，识别LINE-1（L1）衍生的原型抗原ORF1的Eomes阳性辅助性T（Eomes + Th）细胞介导与实验性自身免疫性脑脊髓炎（EAE）神经退行性病理相关的神经毒性。在这里，我们表明Eomes + Th细胞在包括肌萎缩侧索硬化症（ALS）和阿尔茨海默病（AD）在内的真正神经退行性疾病小鼠模型的中枢神经系统中积累，并在与ORF1抗原相遇后分泌神经毒性颗粒酶B。在EAE和ALS/AD模型中，分别在神经退行性变期间以活跃和细胞周期介导的方式观察到神经元L1转录的多模式去抑制。这些数据表明，Eomes + Th细胞介导的免疫介导神经退行性特征与炎症中枢神经系统中L1衍生抗原的异位表达的偶然同时出现，可能实现一种共同且以前未被认识到的神经退行性变发病机制。
