Study highlights role of natural killer immune cell subsets in ALS
Altered subsets could point to therapeutic targets
Certain subsets of natural killer (NK) cells, a part of the immune system, were elevated in the blood of people with amyotrophic lateral sclerosis (ALS), where they showed altered gene activity and signaling patterns, a study found.
One subset was associated with altered immune signaling, while another was linked to neurodegeneration. Other immune cell types also showed changes suggestive of an overall dysregulated peripheral immune system — the immune system residing outside of the brain and spinal cord — in ALS.
“Our study provides compelling evidence that peripheral immune cells play a major role in ALS pathophysiology [disease processes] and highlights the importance of studying well-defined cell subpopulations to disentangle their precise roles in health and disease, as well as to effectively design novel therapies aimed at modulating the peripheral immune system for the treatment of neurodegenerative diseases,” the researchers wrote.
The study, “Single-cell RNA sequencing highlights the role of distinct natural killer subsets in sporadic amyotrophic lateral sclerosis,” was published in the Journal of Neuroinflammation.
In ALS, the specialized nerve cells involved in muscle control are progressively lost. Neuroinflammation and altered immune dynamics are believed to play a role in this process. Studies have shown that immune cell populations, including NK cells, are altered in the blood of ALS patients, and it’s been suggested that they may be therapeutic targets for the disease.
Natural killer cells in ALS
Immune cells often have multiple subtypes that affect the body in different ways. This isn’t always captured with standard methods used to analyze them, so important information about immune cell dynamics in ALS could be missed, hindering the development of targeted therapeutics.
A newer technique called single-cell RNA sequencing (scRNAseq), which provides a detailed look at the gene activity profile of individual cells, can be used to better profile immune cell subsets and the changes they undergo in a disease state.
In their study, the scientists used scRNAseq to examine and characterize more than 100,000 immune cells isolated from the blood of 14 sporadic ALS patients on riluzole treatment and 14 healthy individuals without cognitive impairment, who served as a control group.
A population of NK cells called CD56-dim NK cells were found at significantly higher levels in the blood of ALS patients compared with healthy controls.
NK cells are involved in destroying other abnormal cells found in the body, such as virus-infected or cancerous cells. CD56-dim NK cells are generally associated with a more mature state that have greater cell-killing, or cytotoxic, abilities.
A certain subpopulation of CD56-dim NK cells, which the researchers dubbed NK_2, was particularly elevated in ALS. These cells also exhibited altered gene activity patterns, with changed genes related to immune responses and immune cell growth, as well as altered cell-to-cell communication patterns, showing signs of increased reception to other immune signals relative to healthy controls.
“Our results highlight that NK_2 cells may be key players in controlling the peripheral immune response in ALS,” the researchers wrote.
Another type of NK cells, called CD56-bright NK cells, also tended to be found at higher levels in ALS patients than in healthy controls. CD56-bright NK cells are associated with a less mature state than their CD56-dim counterparts.
The researchers found a possible association between CD56-bright NK cells and neurodegeneration in ALS.
In statistical models, the proportion of CD56-bright NK cells, along with clinical factors such as disease duration, gender, and a measure of disease severity could explain more than 75% of the variance in levels of neurofilament light chain (NfL), a biomarker of nerve damage that’s elevated in ALS.
Other immune cell types, including classical monocytes and certain T-cells, also showed gene activity changes suggesting an altered immune profile in ALS.
Implications for future therapies
“Altogether, the expansion, gene expression and cell-cell communication alterations of NK_2 cells in ALS blood, and the association of CD56bright NK cells with neurodegeneration may have important implications for the design of therapeutic strategies aimed at depleting or modifying NK cells,” the researchers wrote.
They noted that previous strategies had focused on more broadly targeting NK cells, leading to inconsistent results. Honing in on specific cell subtypes could lead to better therapeutic effects.
“NK cell-based therapeutics should consider the diverse and specialized subpopulations of cells to appropriately and successfully achieve the desired impact,” the team wrote.
Future studies should include blood samples from people with other neurodegenerative diseases to confirm how specific the findings are to ALS, and whether they’re relevant to people with familial forms of ALS, they said.
More in-depth, functional studies are necessary to understand how these cell types may directly influence disease processes, the researchers said. Long-term monitoring of the cells over time, “would provide valuable insights into the role of immune cells during disease progression,” they concluded.
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