Autoimmune Target Identified in ALS

Researchers at the La Jolla Institute for Immunology (LJI), collaborating with colleagues at Columbia University, identified a specific immune target implicated in amyotrophic lateral sclerosis (ALS). ALS has long been linked to inflammation in the brain and spinal cord, but this research helped clarify what exactly the immune system may be reacting to.

The study found that immune cells called CD4 T cells mistakenly recognize a normal nervous-system protein, C9orf72, as a threat. This type of “self-attack” is a defining feature of autoimmune disease and provides direct evidence that autoimmune mechanisms may contribute to ALS.

People with ALS who carry genetic changes in the C9orf72 gene showed much stronger immune reactions to the protein.

This connects a known genetic risk factor for ALS with abnormal immune activity, demonstrating how genetics and the immune system may work together to influence disease progression.

The researchers also observed important differences in immune responses between patients. Some immune cells produced inflammatory signals, while others produced signals that help calm inflammation. People with higher levels of these calming immune responses were predicted to live longer, suggesting that certain immune activity may help slow disease progression.

Overall, the findings support a growing view in neuroimmunology that ALS may involve both harmful and protective immune responses, and that future treatments could focus on reducing damaging inflammation while strengthening the immune system’s regulatory and protective roles.

Citation

Michaelis, T., Lindestam Arlehamn, C. S., Johansson, E., Frazier, A., Berry, J. D., Cudkowicz, M., Goyal, N. A., Fournier, C., Snyder, A., Kwan, J. Y., Crook, J., Phillips, E. J., Mallal, S. A., Ravits, J., Marder, K. S., Sidney, J., Sulzer, D., & Sette, A. (2025). Autoimmune response to C9orf72 protein in amyotrophic lateral sclerosis. Nature, 647(8091), 970–978. https://doi.org/10.1038/s41586-025-09588-6