The mutation alone was not enough to cause disease.
For generations, the tragedy of ALS has been understood as a story told entirely within the nervous system — neurons failing, silence spreading through the body. Researchers at Mount Sinai have now revealed that this story has a second narrator: the immune system itself. Published in Nature in June 2022, their work on a juvenile form of the disease demonstrates that motor impairment requires dysfunction in both systems simultaneously, a finding that redraws the map of one of medicine's most stubborn mysteries and asks whether the body's own defenses might one day become part of its rescue.
- ALS has no cure and no effective treatment, and patients face a relentless progression toward paralysis, silence, and respiratory failure — the urgency to find new angles of attack is absolute.
- Decades of neuron-focused research may have been looking at only half the picture, and this discovery forces a fundamental reckoning with what scientists thought they understood about the disease.
- A specific subset of immune cells — CD8 T cells of the TEMRA variety — accumulates in the spinal cord and blood of ALS4 patients, and their concentration tracks directly with how quickly the disease advances.
- Crucially, these immune signatures can be detected through a simple blood draw rather than invasive spinal procedures, making real-time disease monitoring and patient stratification suddenly far more practical.
- The same immune cells that appear to damage motor neurons also seem to protect against brain cancer in animal models, opening an unexpected corridor between ALS research and oncology.
For decades, ALS research has been almost entirely a story about the nervous system — the slow death of motor neurons, the progressive silencing of movement, speech, and breath. A team at Mount Sinai, led by Laura Campisi and Ivan Marazzi alongside neurobiologist Albert La Spada, has now challenged that assumption in work published in Nature in June 2022. Their focus was ALS4, a juvenile and slowly progressive variant linked to mutations in the SETX gene. What they discovered was that the mutation alone was insufficient to cause motor impairment — the genetic defect had to be present in both the nervous system and the immune system at the same time.
The immune dysfunction centered on CD8 T cells, specifically a subset known as TEMRA — terminally differentiated effector memory cells. In ALS4 patients and animal models alike, these cells accumulated at abnormally high levels in the spinal cord and blood, and their concentration correlated directly with disease progression. Using advanced tools including mass cytometry and single-cell sequencing, the team mapped these immune signatures with enough precision to distinguish ALS4 from other disease forms.
The practical implications are significant. These signatures can be identified through a routine blood test rather than an invasive lumbar puncture, raising the possibility of accessible monitoring tools and, eventually, immune-targeted therapies matched to a patient's specific biological profile. The researchers suggest that different ALS subtypes may carry distinct immune fingerprints — a foundation for personalized treatment in a disease that currently offers none.
A secondary finding adds an unexpected dimension: the very TEMRA cells that appear destructive in ALS seem to protect against glioma in mice, creating a potential bridge between neurodegeneration research and cancer therapy. ALS remains without cure, and these findings do not immediately change clinical practice. But by establishing the immune system as a central actor rather than a passive bystander, the Mount Sinai team has opened a question that will drive research for years: if the immune system can be part of the problem, might it also become part of the answer?
For decades, researchers studying amyotrophic lateral sclerosis have trained their focus almost entirely on the brain and spinal cord—the central nervous system where motor neurons die and patients gradually lose the ability to move, speak, swallow, and breathe. A team at Mount Sinai has now upended that assumption. In work published in Nature in June 2022, they demonstrated that the immune system plays an equally fundamental role in at least one form of the disease, fundamentally reshaping how scientists might approach diagnosis and treatment of this devastating condition.
The researchers, led by Laura Campisi and Ivan Marazzi at the Icahn School of Medicine at Mount Sinai, working with neurobiologist Albert La Spada from UC Irvine, focused their investigation on ALS4, a juvenile and slowly progressive variant caused by mutations in a gene called SETX. What they found was striking: the mutation alone was not enough. For motor impairment to develop in their animal models, the genetic defect had to be present in both the nervous system and the immune system simultaneously. This was a departure from the conventional understanding of the disease.
The immune dysfunction they identified centered on a specific type of white blood cell called CD8 T cells. These cells normally serve as the body's cleanup crew, destroying tumor cells and cells infected with pathogens. In ALS4 patients and mice, however, concentrations of a particular subset of these cells—known as TEMRA, or terminally differentiated effector memory cells—accumulated in the spinal cord and circulating blood at abnormally high levels. The researchers found a direct correlation between the abundance of these cells and the progression of disease symptoms.
What makes this discovery particularly practical is accessibility. Detecting these aberrant immune signatures requires only a blood sample, a straightforward procedure compared to extracting cerebrospinal fluid, which demands an invasive lumbar puncture. This opens the possibility of using a simple blood test to track disease progression and potentially identify which patients might benefit from immune-targeted therapies. The Mount Sinai team employed cutting-edge technologies—mass and spectral cytometry and single-cell sequencing—to map these immune signatures with precision, revealing patterns that distinguish ALS4 from other forms of the disease.
The implications extend beyond diagnosis. If different subtypes of ALS carry distinct immune fingerprints, then treatments could theoretically be tailored to match a patient's specific immune profile rather than applying a one-size-fits-all approach. Campisi emphasized the urgency of this line of inquiry: understanding whether neurodegeneration is caused or worsened by immune dysfunction represents a critical gap in current knowledge. The team's work suggests that decades of focusing exclusively on neurons may have missed half the story.
There is an intriguing secondary finding that hints at therapeutic possibilities in unexpected directions. The TEMRA CD8 T cells associated with ALS4, while harmful in the context of motor neuron disease, appear to protect mice against glioma, a type of brain cancer. This observation creates a potential bridge between ALS research and oncology, suggesting that manipulating these immune cells might yield benefits in cancer treatment even as researchers work to neutralize their destructive effects in neurodegeneration.
ALS remains without cure or effective treatment. Patients face progressive paralysis, eventual loss of speech and swallowing, and ultimately respiratory failure. The Mount Sinai findings do not immediately change clinical practice, but they reorient the research landscape. By establishing that the immune system is not a bystander but a central player in at least some forms of ALS, they create a foundation for investigating whether similar immune dysfunction drives other neurodegenerative diseases. The discovery also raises a question that will occupy researchers for years to come: if the immune system can be part of the problem, can it also be part of the solution?
Notable Quotes
We learned that mutations in SETX need to be expressed in both the nervous and immune systems to generate motor impairment in mice, and that dysfunction in the adaptive immune system characterizes ALS4 in mice as well as humans.— Laura Campisi, Assistant Professor of Microbiology, Icahn School of Medicine at Mount Sinai
There is a great need to understand if neurodegeneration is caused or aggravated by immune dysfunction.— Laura Campisi
The Hearth Conversation Another angle on the story
Why did it take so long for researchers to look at the immune system in ALS? Wasn't that an obvious place to check?
It wasn't obvious at all. ALS is fundamentally a disease of motor neurons dying. That's what you see under the microscope, that's what causes the paralysis. The immune system seemed separate—a different compartment. You focus on what you can see failing.
But the Mount Sinai team found that the mutation had to be present in both systems. That's a pretty dramatic shift.
It is. And it suggests that for decades, researchers might have been looking at half the problem. They were treating ALS as purely a nervous system disease when it's actually a conversation between two systems going wrong at once.
The blood test angle seems important. Why does that matter so much?
Because right now, if you want to measure what's happening in a patient's spinal cord, you have to do a lumbar puncture—it's invasive, uncomfortable, not something you repeat casually. A blood test changes everything about how you monitor disease and test whether a treatment is working.
And the cancer connection—that seems almost accidental.
It does, but it's the kind of accident that opens doors. These immune cells are toxic to motor neurons but protective against brain tumors. That's not random. It suggests there's a way to manipulate them, to redirect their activity. That's a research program waiting to happen.