ALS breakthrough shows fatal disease is driven by immune attack

Researchers have uncovered how the body’s own immune system may be driving the progression of amyotrophic lateral sclerosis, or ALS — a breakthrough that could reshape treatment of the fatal disease.

In a study published Oct. 1 in Nature, scientists at the La Jolla Institute for Immunology and Columbia University showed that immune cells in ALS patients attack a protein found in neurons, triggering inflammation that accelerates nerve cell loss. The protein, known as C9orf72, was the first identified target of such an autoimmune response in ALS.

The research also revealed two distinct patient groups: those whose immune systems mount a strong inflammatory attack and tend to deteriorate quickly, and those with more protective immune responses who live significantly longer. The findings could pave the way for therapies that tamp down harmful activity while boosting protective cells — an approach reminiscent of cancer immunotherapies.

“This is the first study to clearly demonstrate that in people with ALS, there is an autoimmune reaction that targets specific proteins associated with the disease,” said Alessandro Sette, a professor at the institute and co-lead author of the study. The results suggest that the balance between pro- and anti-inflammatory activity “may be a component in the disease progression,” he said.

About 15 people are newly diagnosed with ALS each day in the U.S., where it’s also known as Lou Gehrig’s disease, after the New York Yankees player who died in 1941, two years after his diagnosis. While most patients deteriorate quickly, some, like physicist Stephen Hawking, lived for decades with the illness.

Although immune activation has long been recognized in ALS, the exact triggers behind it were unknown, said Avindra Nath, clinical director at the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, who wasn’t involved in the study.

The new research shows that patients, including those with no family history of the disease, mount immune reactions against the protein C9orf72, Nath said. Those reactions appeared stronger than responses to other ALS-related proteins. He noted that patients with C9orf72 mutations had more pronounced immune activity and tended to live longer, but cautioned that the findings remain correlative.

“The specific mechanisms by which such protection may occur is speculative and further studies are needed,” Nath said.

ALS has long resisted drug development, with only a handful of approved therapies offering modest benefits. By pinpointing a specific immune target, the new study may make it easier for companies to design precision treatments. “It has potential forward paths for intervention in a disease where there is not a lot that people can do, unfortunately,” Sette said.

Similar immune processes are being uncovered in Alzheimer’s disease and Parkinson’s disease, suggesting that autoimmunity may be a common driver of neurodegeneration. Still, researchers cautioned that testing therapies will require new models, and clinical trials remain a long way off.