小柯机器人

美国西奈山伊坎医学院Ivan Marazzi，Yesai Fstkchyan，Laura Campisi和美国加州大学欧文分校Albert R. La Spada共同合作，近期取得重要工作进展，他们研究发现克隆扩增的CD8T细胞是肌萎缩性侧索硬化-4（ALS4）的特征。相关论文2022年6月22日在线发表于《自然》杂志上。

研究人员利用携带ALS4致病性L389S突变的Setx基因敲入小鼠，描述了一种免疫学特征，该特征由敲入小鼠的中枢神经系统和血液中克隆扩大的终末分化的效应记忆（T_EMRA）CD8 T细胞组成。基因敲入小鼠中抗原特异性CD8 T细胞的频率增加反映了运动神经元疾病的进展，并与抗胶质瘤免疫力相关。

此外，骨髓移植实验表明免疫系统在ALS4神经变性中起关键作用。在ALS4患者中，克隆扩增的T_EMRA CD8 T细胞在外周血中循环。他们的结果提供了ALS4中抗原特异性CD8 T 细胞反应的证据，可用于揭示疾病机制并作为疾病状态的潜在生物标志物。

据介绍，肌萎缩性侧索硬化症(ALS)是一种异质性神经退行性疾病，影响运动神经元和随意肌控制神经元。ALS的异质性包括表现的年龄、进展的速度和症状出现的解剖学部位。特定基因中的致病突变已被确定并定义了ALS1的不同亚型。虽然一些与ALS相关的基因已被证明会影响免疫功能，但特异性免疫特征是否导致了ALS的异质性尚不清楚。肌萎缩性侧索硬化症-4(ALS4)的特点是发病年轻，进展缓慢。ALS4患者在30多岁时表现出运动障碍，大多数人在50多岁时就需要设备来辅助行走。ALS4是由senataxin基因（SETX）突变引起的。

附：英文原文

Title: Clonally expanded CD8 T cells characterize amyotrophic lateral sclerosis-4

Author: Campisi, Laura, Chizari, Shahab, Ho, Jessica S. Y., Gromova, Anastasia, Arnold, Frederic, Mosca, Lorena, Mei, Xueyan, Fstkchyan, Yesai, Torre, Denis, Beharry, Cindy, Garcia-Forn, Marta, Jimnez-Alczar, Miguel, Korobeynikov, Vladislav A., Prazich, Jack, Fayad, Zahi A., Seldin, Marcus M., De Rubeis, Silvia, Bennett, Craig L., Ostrow, Lyle W., Lunetta, Christian, Squatrito, Massimo, Byun, Minji, Shneider, Neil A., Jiang, Ning, La Spada, Albert R., Marazzi, Ivan

Issue&Volume: 2022-06-22

Abstract: Amyotrophic lateral sclerosis (ALS) is a heterogenous neurodegenerative disorder that affects motor neurons and voluntary muscle control1. ALS heterogeneity includes the age of manifestation, the rate of progression and the anatomical sites of symptom onset. Disease-causing mutations in specific genes have been identified and define different subtypes of ALS1. Although several ALS-associated genes have been shown to affect immune functions2, whether specific immune features account for ALS heterogeneity is poorly understood. Amyotrophic lateral sclerosis-4 (ALS4) is characterized by juvenile onset and slow progression3. Patients with ALS4 show motor difficulties by the time that they are in their thirties, and most of them require devices to assist with walking by their fifties. ALS4 is caused by mutations in the senataxin gene (SETX). Here, using Setx knock-in mice that carry the ALS4-causative L389S mutation, we describe an immunological signature that consists of clonally expanded, terminally differentiated effector memory (TEMRA) CD8T cells in the central nervous system and the blood of knock-in mice. Increased frequencies of antigen-specific CD8T cells in knock-in mice mirror the progression of motor neuron disease and correlate with anti-glioma immunity. Furthermore, bone marrow transplantation experiments indicate that the immune system has a key role in ALS4 neurodegeneration. In patients with ALS4, clonally expanded TEMRA CD8T cells circulate in the peripheral blood. Our results provide evidence of an antigen-specific CD8T cell response in ALS4, which could be used to unravel disease mechanisms and as a potential biomarker of disease state.

DOI: 10.1038/s41586-022-04844-5

Source: https://www.nature.com/articles/s41586-022-04844-5

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html