Murdock Benjamin J, Zhao Bangyao, Webber-Davis Ian F, Teener Samuel J, Pawlowski Kristen D, Famie Joshua P, Piecuch Caroline E, Jang Dae Gyu, Feldman Eva L, Zhao Lili, Goutman Stephen A
Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
Biostatistics Department, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
Med. 2025 Aug 8;6(8):100673. doi: 10.1016/j.medj.2025.100673. Epub 2025 Apr 25.
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with no cure and limited treatment options. The immune system is implicated in disease pathology, unlocking a potential therapeutic avenue. However, it is unclear whether immune changes are a cause or consequence of disease progression.
Peripheral immune cells were longitudinally measured at monthly intervals in 55 ALS and 50 control participants. 22 peripheral immune markers in the blood were assessed using flow cytometry, and clinical progression was assessed using the revised ALS functional rating scale (ALSFRS-R). Individual immune markers, their trajectories, and overall variability were compared in ALS versus control participants; ALS participants were also stratified by clinical progression rates and assessed similarly across progression groups. Finally, a novel, lagged linear regression model correlated the rate of immune changes to subsequent downstream ALSFRS-R changes.
Numerous immune markers were dysregulated in ALS versus control participants, with altered levels, trajectories, or variability in immune populations and surface markers. ALS participants had increased immune variability relative to control participants; within ALS participants, faster progressors overall had decreased marker variability. Finally, natural killer (NK) cell numbers, NK cell subpopulations, and NK cell surface markers were significantly associated with downstream ALS progression.
The immune system is dysregulated in ALS and more consistently dysregulated in faster ALS progression, and immune dysregulation occurs upstream of clinical changes. These findings suggest that the immune system is a causal factor of ALS progression in human patients.
CReATe Consortium, NIH, Target ALS, DoD, ALSA.
肌萎缩侧索硬化症（ALS）是一种致命的运动神经元疾病，目前无法治愈且治疗选择有限。免疫系统与疾病病理相关，这为潜在的治疗途径提供了可能。然而，尚不清楚免疫变化是疾病进展的原因还是结果。
对55名ALS患者和50名对照参与者每月进行一次外周免疫细胞的纵向测量。使用流式细胞术评估血液中的22种外周免疫标志物，并使用修订的ALS功能评定量表（ALSFRS-R）评估临床进展。比较ALS患者与对照参与者的个体免疫标志物、其变化轨迹以及总体变异性；ALS患者还按临床进展率分层，并在各进展组中进行类似评估。最后，采用一种新的滞后线性回归模型，将免疫变化率与随后下游的ALSFRS-R变化相关联。
与对照参与者相比，ALS患者中有多种免疫标志物失调，免疫细胞群体和表面标志物的水平、变化轨迹或变异性均发生改变。与对照参与者相比，ALS患者的免疫变异性增加；在ALS患者中，总体进展较快者的标志物变异性降低。最后，自然杀伤（NK）细胞数量、NK细胞亚群和NK细胞表面标志物与下游ALS进展显著相关。
ALS患者的免疫系统失调，在进展较快的ALS患者中失调更为一致，且免疫失调发生在临床变化之前。这些发现表明，免疫系统是人类患者ALS进展的一个因果因素。
CReATe联盟、美国国立卫生研究院、靶向ALS、美国国防部、肌萎缩侧索硬化症协会。
