Department of Neurology and.
Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.
JCI Insight. 2021 Jun 8;6(11):147129. doi: 10.1172/jci.insight.147129.
NK cells are innate immune cells implicated in ALS; whether NK cells impact ALS in a sex- and age-specific manner was investigated. Herein, NK cells were depleted in male and female SOD1G93A ALS mice, survival and neuroinflammation were assessed, and data were stratified by sex. NK cell depletion extended survival in female but not male ALS mice with sex-specific effects on spinal cord microglia. In humans, NK cell numbers, NK cell subpopulations, and NK cell surface markers were examined in prospectively blood collected from subjects with ALS and control subjects; longitudinal changes in these metrics were correlated to revised ALS functional rating scale (ALSFRS-R) slope and stratified by sex and age. Expression of NK cell trafficking and cytotoxicity markers was elevated in subjects with ALS, and changes in CXCR3+ NK cells and 7 trafficking and cytotoxicity markers (CD11a, CD11b, CD38, CX3CR1, NKG2D, NKp30, NKp46) correlated with disease progression. Age affected the associations between ALSFRS-R and markers NKG2D and NKp46, whereas sex impacted the NKp30 association. Collectively, these findings suggest that NK cells contribute to ALS progression in a sex- and age-specific manner and demonstrate that age and sex are critical variables when designing and assessing ALS immunotherapy.
自然杀伤（NK）细胞是先天免疫细胞，与肌萎缩侧索硬化症（ALS）有关；本研究旨在探讨 NK 细胞是否以性别和年龄特异性的方式影响 ALS。本研究在雄性和雌性 SOD1G93A ALS 小鼠中耗尽 NK 细胞，评估其生存情况和神经炎症，并按性别分层数据。NK 细胞耗竭可延长雌性 ALS 小鼠的生存时间，但对雄性 ALS 小鼠无此作用，且对脊髓小胶质细胞有性别特异性影响。在人类中，前瞻性采集 ALS 患者和对照受试者的血液样本，检测 NK 细胞数量、NK 细胞亚群和 NK 细胞表面标志物；这些指标的纵向变化与修订后的 ALS 功能评定量表（ALSFRS-R）斜率相关，并按性别和年龄分层。ALS 患者的 NK 细胞迁移和细胞毒性标志物表达上调，CXCR3+NK 细胞和 7 种迁移和细胞毒性标志物（CD11a、CD11b、CD38、CX3CR1、NKG2D、NKp30、NKp46）的变化与疾病进展相关。年龄影响 ALSFRS-R 与标志物 NKG2D 和 NKp46 之间的相关性，而性别影响 NKp30 的相关性。综上，这些发现表明 NK 细胞以性别和年龄特异性的方式促进 ALS 进展，并表明在设计和评估 ALS 免疫疗法时，年龄和性别是关键变量。
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