(Press-News.org)
A team of researchers from the Sant Pau Research Institute (IR Sant Pau) has published a study in the Journal of Neuroinflammation that, for the first time, examines in depth the role of the peripheral immune system in amyotrophic lateral sclerosis (ALS) at the single-cell level. Their findings suggest that immune system cells—particularly two subpopulations of Natural Killer (NK) cells—may play a crucial part in the development and progression of this neurodegenerative disease.
ALS is a condition that causes the progressive degeneration of motor neurones, leading to a loss of muscle function and, eventually, affecting vital functions such as breathing. At present, there is still no curative treatment or sufficiently effective therapy to halt its progression, and the estimated average survival after diagnosis is between 3 and 5 years.
First detailed analysis of the immune system in ALS
Although the role of the immune system had already been demonstrated in diseases such as Alzheimer’s, until now, there had not been a similarly in-depth study confirming this significance for ALS. “It was suspected that there could be an immunological component involved in the disease, but it had not been demonstrated in depth at the cellular level,” explains Dr Oriol Dols, a researcher in the Neurobiology of Dementias group and Memory Unit at IR Sant Pau, who coordinated the study.
To address this challenge, 14 patients with sporadic ALS—i.e. with no known genetic mutations explaining the condition (around 90% of ALS cases)—were recruited and their immune profile compared with that of 14 healthy individuals who served as a control group.
Using single-cell RNA sequencing—a technique that allows researchers to analyse gene expression in individual cells—the scientists were able to study over 100,000 immune cells from peripheral blood one by one, detecting highly specific cellular and genetic alterations in each subpopulation of lymphocytes, monocytes and, notably, NK cells.
Altered NK cell subpopulations
NK cells are primarily known for their role in defending against viral infections or tumour cells. However, this study showed an abnormal increase in certain subpopulations of NK cells in ALS patients, which also presented a hyperactivated state.
“The key finding is that not only are NK cells increased overall, but there are two very specific subpopulations with different implications,” notes Dr Dols. One of these subpopulations appears to exert a modulatory effect on other immune cells, such as CD8 or CD4 T lymphocytes; the other is closely associated with neurodegenerative processes, as evidenced by a connection with neurofilament levels, a marker of neuronal damage. “This suggests that these NK cells might directly influence motor neurone injury,” adds the specialist.
Changes also in monocytes and T lymphocytes
In addition to NK cells, the study reveals alterations in subpopulations of monocytes and CD8 T lymphocytes with an increased capacity for antigen presentation. Altogether, this indicates a global immune system imbalance that may contribute to a neuroinflammatory environment and speed up the death of motor neurones.
“Knowing that the peripheral immune system is involved in ALS opens up new lines of inquiry: from the search for blood biomarkers to facilitate earlier diagnosis, to prospective therapies targeting these specific subpopulations,” says Esther Álvarez-Sánchez, also a researcher in the Neurobiology of Dementias group and Memory Unit at IR Sant Pau, and first author of the article.
At present, there is no approved drug that specifically modulates NK cells or T lymphocytes in the context of ALS, so these findings represent an initial step towards developing more targeted and combined treatments.
Next steps and impact
This study was carried out with the largest cohort so far analysed by single-cell RNA sequencing in ALS (14 patients and 14 controls). The statistical outcomes confirm the robustness of the immune differences detected, and the team is already conducting a longitudinal follow-up of the same patients one year later to gauge how the immune profile evolves.
Likewise, in vitro experiments are being designed to combine patients’ NK cells with motor neurones, to decipher which specific signals trigger the hyperactivation of these subpopulations and how they relate to neuronal death. “Understanding the mechanism that drives part of the immune system to become ‘uncontrolled’ is essential, and we must also explore how to modulate it without impairing the beneficial functions of these cells,” explains Dr Dols.
Although this work does not immediately translate into a treatment, the identification of key immune subpopulations in ALS is a promising step forward. “Just as in cancer we have learned to regulate the immune response to combat tumours, in ALS we are moving towards the idea of combining therapies addressing both neurodegeneration and the altered immune response,” concludes Dr Dols.
END
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