Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that targets motor neurons, gradually bereaving patients of their ability to control muscle movements. Scientists discovered more than 50 potential disease-causing genes and linked several cellular pathways to ALS, but the syndrome’s diverse clinical and genetic nature make it difficult to predict and interfere with disease progression.1 

Motor neurons, undergoing degeneration in ALS
Researchers discovered a T cell population in mice that mirrors ALS-4 disease progression.

In a recent study published in Nature, Laura Campisi, Ivan Marazzi, and colleagues at Icahn School of Medicine at Mount Sinai discovered an immune cell signature in patients with early onset ALS (ALS-4) that mirrors disease progression and may contribute to neuronal death.2 These findings could have significant implications for ALS diagnostics, prognostics, and therapeutics. 

Laura Campisi joined Marazzi’s laboratory wanting to better understand how the body mounts immune responses. She set out to molecularly profile activated immune cells and discovered several immunity regulators, including SENATAXIN (SETX). Because SETX mutations cause ALS-4, Campisi wondered if ALS might join the suite of other neurodegenerative diseases such as narcolepsy, Alzheimer’s disease, and Parkinson’s disease that scientists recently connected to the immune system.3,4,5,6 

To test whether the immune system plays a role in ALS-4 disease progression, Campisi turned to a mouse model that carries the most common human SETX mutation.7 She replaced their mutated hematopoietic stem cells (HSCs)—progenitors that form immune cells—with wildtype ones and found that they protected against disease. In contrast, replacing healthy HSCs with SETX mutant ones in wildtype mice did not cause disease. This set of experiments showed that mutant HSCs and their progeny contribute to disease, but do not cause disease on their own. “This is extremely strong preclinical evidence that forms a basis for pharmaceutically targeting these cells,” said David Gate, an assistant professor of neurology at Northwestern University, who was not involved in this study. 

See "Raising the Bar for Biomarkers and Early Diagnostics in Neurodegenerative Disease"

Campisi and her colleagues next characterized the immune system in pre-symptomatic mice and discovered an ALS-specific immune cell signature: ALS-4 mice contained more CD8+ T cells in their blood and cerebrospinal fluid (CSF) prior to symptom onset, and this cell population continued to expand as the disease progressed. While Campisi’s team faced pandemic-related difficulties in recruiting enough ALS-4 patients to confirm these findings, they are now teaming up with clinicians to expand their preclinical trials. “We want to follow this [T cell] population in patients to see if they express specific markers that can predict if and when the disease progresses,” Campisi said. 

My hypothesis is that the T cells are autoreactive, so they are reacting against a cellular antigen.
- Laura Campisi, Icahn School of Medicine at Mount Sinai

To find what these T cells responded to, Campisi sequenced them and found that nearly all cells expressed the same T cell receptor, suggesting they bind the same antigen. “The problem is that it is very difficult to find the antigen. I don’t think it is an infection because [the] mice live in a pathogen-free facility. My hypothesis is that the T cells we found are autoreactive, so they are reacting against a cellular antigen,” Campisi said.  

Given that ALS targets motor neurons, Campisi wondered if the ALS-4 T cells promoted disease progression because they react to and are activated by a protein in the brain. To test this hypothesis, Campisi injected ALS-4 mice with brain cancer cells that express neuronal antigens to see if the T cell population would react and confer protection against the cancer type. “It was pretty striking: the tumors became so big in wildtype mice that I had to stop the experiment, but the [mutant] mice that were in the same cage were completely fine, their tumor was not growing,” Campisi said. In contrast, there was no protection against skin-related cancer cells that she injected as a control. The T cells that infiltrated the ALS-4 mice’s brain tumors expressed the same T cell receptor as cells found in their CSF. While Gate cautions that cancer cells typically express many newly created neoantigens, Campisi’s data suggests that the T cell population likely recognizes a brain cell-related antigen.

Campisi’s challenge now lies in identifying the actual antigen and therapeutically targeting these T cells to slow and restrict the disease course. “In ALS, you probably have a defect that starts with neurons, triggering a cascade of events. So, even if you restore what is wrong in neurons, we have to [also] target the other players,” Campisi said.

  1. J.P. Taylor et al., "Decoding ALS: from genes to mechanism,” Nature, 10;539(7628):197-206, 2016.
  2. L. Campisi et al., “Clonally expanded CD8 T cells characterize amyotrophic lateral sclerosis-4,” Nature, 606(7916):945-52, 2022.
  3. A. Rialdi et al., “Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation,” Science, 352(6289):aad7993, 2016.
  4. D. Latorre et al., “T cells in patients with narcolepsy target self-antigens of hypocretin neurons,” Nature, 562(7725):63-68, 2018. 
  5. D. Gate et al., “Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease,” Nature, 577(7790):399-404, 2020.
  6. D. Gate et al., “CD4 T cells contribute to neurodegeneration in Lewy body dementia,” Science, 374(6569):868-74, 2021.
  7. C.L. Bennett et al., "Senataxin mutations elicit motor neuron degeneration phenotypes and yield TDP-43 mislocalization in ALS4 mice and human patients,” Acta Neuropathol, 136:425-43, 2018.
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