More active innate immune system tied to faster ALS progression

Blood levels of cells like neutrophils and monocytes may reflect disease course

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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This illustration shows a microscopic view of white blood cells, part of the immune system.

People with amyotrophic lateral sclerosis (ALS) who have a more active innate immune system — the part of the immune system that acts as a first responder to threats — tend to have faster disease progression and poorer survival, a study of large data showed.

Findings suggest that measuring blood levels of certain innate immune cells, or certain ratios of these cells, could help in monitoring ALS progression and in ensuring the disease is being managed appropriately earlier in its course.

“While our results need confirmation … it could be postulated that the evaluation of these readily available and cost-effective peripheral biomarkers could assist clinicians in patients’ management and could also be pivotal in … the identification of subjects with a likely immune dysregulation that could be responders to a targeted treatment,” the researchers wrote.

The study, “The role of peripheral immunity in ALS: a population-based study,” was published in the Annals of Clinical and Translational Neurology.

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Evidence points to inflammation as major player in ALS progression

Although the causes of ALS remain poorly understood, an accumulating body of evidence suggests that increased inflammation plays a key role in driving the disease. Inflammation occurs when the immune system is activated to fight off an infectious threat, but in ALS and other conditions runaway inflammation is damaging.

The immune system can be broadly divided into two groups: innate and adaptive. The innate immune system is the body’s first responders — when an infection or threat is detected, innate immune cells show up and start an inflammatory response. In contrast, cells in the adaptive immune system are slower to act. But they can trigger more powerful inflammatory responses, especially when reacting to a threat they “know” from a previous encounter. In fact, this is how vaccines work.

A team led by scientists at the University of Torino, in Italy, conducted analyses of immune cells in the blood, with the goal of better understanding how immune system abnormalities affect ALS progression.

“A better understanding of the systemic immune response in the context of ALS and frontotemporal dementia (FTD) [a related disease] is not only important to unravel disease mechanism, but potentially to serve as biomarker of disease activity,” the scientists wrote.

The analysis included blood samples from 1,452 people with ALS. Just over half were male, and the median age at disease onset was 69.5 years.

Researchers found that patients with markers of more innate immune activity tended to have faster disease progression. For example, disease progression was typically faster patients with higher levels of neutrophils, a major type of innate immune cell.

These associations were statistically significant even when accounting for other factors like patterns of disease onset and smoking status, and similar results were found in both male and female patients. In analyses stratified by age, these associations were strongest in patients ages 65 to 75, whereas the associations were generally not statistically significant in older or younger patients.

Poorer respiratory health, cognition linked to immune activity, cell counts

In line with faster ALS progression, other analyses showed that patients with more innate immune activity tended to have significantly poorer lung function and shorter survival times. Patients with more advanced disease when they were diagnosed with ALS also generally had higher innate immune activity at diagnosis.

“Our overall and stratified data demonstrated that an increased innate immune system at diagnosis is associated with a more aggressive disease course and confirms that neutrophils are protagonists of inflammatory response in ALS across all age groups and sex,” the researchers wrote.

Other analyses indicated that patients with lower levels of monocytes, another kind of innate immune cell, were significantly more likely to have frontotemporal dementia (FTD) or cognitive symptoms of ALS. In sex-specified analyses, this association was only significant in female patients.

Patients with cognitive difficulties might have fewer monocytes in their blood because more of these immune cells have moved to the brain and are causing inflammation there, the researchers speculated. But they stressed that further work is needed to untangle the relationship between immune activity and cognition in ALS.

“While further evidence is necessary, our data confirm that monocytes may represent an attractive target to study disease-associated neuroinflammatory processes,” the researchers wrote.

Taken together, study findings “add to the growing evidence suggesting that dysregulation of systemic immunity is a common feature among individuals with ALS,” the team concluded.

These findings also underscore that the immune response in ALS “is multifaceted and varies according to the patient’s characteristics,” the researchers added.

“Consequently, a single marker is not sufficient to capture the overall peripheral immune dysregulation and inflammatory status in ALS, and the evaluation of multiple markers is necessary to disentangle the complex underlying mechanism involved in ALS pathogenesis [development] and progression,” they wrote.