Early immune system changes in amyotrophic lateral sclerosis correlate with later disease progression

Benjamin J Murdock; Bangyao Zhao; Ian F Webber-Davis; Samuel J Teener; Kristen D Pawlowski; Joshua P Famie; Caroline E Piecuch; Dae Gyu Jang; Eva L Feldman; Lili Zhao; Stephen A Goutman

doi:10.1016/j.medj.2025.100673

Early immune system changes in amyotrophic lateral sclerosis correlate with later disease progression

Med. 2025 Apr 17:100673. doi: 10.1016/j.medj.2025.100673. Online ahead of print.

Affiliations

¹ Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: murdockb@umich.edu.
² Biostatistics Department, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
³ Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.

PMID: 40286795
DOI: 10.1016/j.medj.2025.100673

Abstract

Background: 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.

Methods: 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.

Findings: 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.

Conclusions: 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.

Funding: CReATe Consortium, NIH, Target ALS, DoD, ALSA.

Keywords: ALS; NK cells; Translation to patients; amyotrophic lateral sclerosis; immune system; neuroinflammation.