Immune checkpoints may predict ALS severity, progression
Proteins elevated in those with more severe symptoms, study finds
Immune checkpoint proteins — proteins that help regulate immune response — were elevated on T-cells and in the blood of people with amyotrophic lateral sclerosis (ALS), a small study found, suggesting they may play a role in how the disease develops.
The increases were associated with more severe ALS symptoms and higher levels of neurofilament light chain (NfL), a marker of nerve cell damage. The findings suggest that measuring these proteins could aid in earlier diagnosis of ALS and help predict the speed of disease progression.
The study, “Immune checkpoint changes correlate with the progression and prognosis of amyotrophic lateral sclerosis,” was published in the Annals of Medicine.
ALS occurs due to the degeneration of motor neurons, the nerve cells in the brain and spinal cord that control voluntary movement. What exactly causes ALS is unclear, but dysfunction in immune regulation, including how immune cells respond to inflammation, may contribute to disease progression.
Measuring protein checkpoints in ALS
Immune checkpoints help regulate immune responses by either activating or inhibiting them. The researchers, in China, looked at whether levels of immune checkpoints change in the context of ALS.
The study involved 46 adults diagnosed with ALS and 26 healthy individuals as controls. In people with ALS, the proportion of CD4-positive T-cells — a subset of T-cells — that had PD-1 on their surface was significantly higher than in controls (8.36% vs. 5.15%). PD-1 is an immune checkpoint that helps prevent the immune system from becoming overactive.
Over the course of a year, patients with a proportion of PD-1-positive T-cells higher than 8% experienced significantly faster progression compared with those with fewer of those cells. Survival did not differ between the two groups.
To better understand changes in immune checkpoints, the researchers used a Luminex multiplex immunoassay test to measure 14 other proteins in the blood of 44 adults with ALS, 30 healthy individuals, and 19 adults with other neurological diseases.
Four soluble proteins (PD-1, BTLA, CTLA-4, and CD27) were higher in ALS patients than in the other two groups. Soluble TIM-3, a type of immune checkpoint, was linked to more severe disease — the higher the levels of that protein, the lower the Revised ALS Functional Rating Scale (ALSFRS-R) scores. This scale measures how well a patient performs everyday activities. Lower scores indicate more severe symptoms.
When immune checkpoints are present on the surface of immune cells, they are considered membrane-bound; when released into the bloodstream, they are referred to as soluble.
“Both membrane-bound and soluble PD-1 were significantly elevated in ALS patients and correlated with disease progression. Cells expressing high levels of PD-1 may represent a population of exhausted [T-cells],” the researchers wrote.
Levels of PD-1 can increase when T-cells are repeatedly prompted to mount an immune response. PD-1 normally acts like a brake to prevent the immune system from overreacting. However, when its levels remain high, T-cells may become exhausted and no longer function well.
Soluble PD-L1 — a protein that binds to PD-1 — was higher in patients with more severe symptoms (lower ALSFRS-R scores) and in those with signs of more damage to nerve cells (higher levels of NfL). However, these relationships did not remain significant after adjusting for other factors.
While the study “evaluates a broad spectrum of immune checkpoints in ALS simultaneously … the detailed mechanisms by which [blood] immune checkpoints are related to the immune response in ALS remain to be elucidated,” the researchers concluded.
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