Immune system holds the key to why some ALS patients live longer

Amyotrophic lateral sclerosis (ALS) remains one of medicine’s most perplexing conditions. Known for its devastating progression, it strips away the body’s ability to move, speak, and eventually breathe.

Each year, thousands of Americans are diagnosed, with survival often measured in months rather than years.

Despite decades of research, its origins remain elusive. Now, new insights are reshaping how scientists think about the disease, pointing to the immune system as a central player.

ALS and immune attack

Researchers at the La Jolla Institute for Immunology and Columbia University have shown that immune cells called CD4+ T cells mistakenly attack proteins in neurons.

“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 LJI Professor Alessandro Sette, who co-led the study with Professor David Sulzer of Columbia University.

They discovered that these cells react strongly to a protein called C9orf72, a known risk factor for ALS. This immune misfire resembles patterns seen in other autoimmune diseases, reframing ALS as part of a broader spectrum of self-directed immune disorders.

Why ALS moves fast

Amyotrophic lateral sclerosis usually progresses with startling speed, leaving little time for treatment.

“There is an autoimmune component to ALS, and this study gives us clues as to why the disease progresses so rapidly,” said Sulzer. “This research also gives us a possible direction for disease treatment.”

The new perspective connects ALS progression to a cycle of persistent inflammation. Instead of resolving, immune activity keeps fueling neuronal damage. This theory helps explain why some patients decline so quickly while others survive for years.

Survival odds differ

While most patients lose function within two years, some defy the odds. Lou Gehrig lived only a short time after diagnosis, but Stephen Hawking lived for decades. Until now, the reasons for these striking differences were poorly understood.

The research suggests the immune system may tip the balance. Patients with highly inflammatory T cells tend to have shorter survival times. By contrast, those who also produce protective anti-inflammatory T cells may experience slower disease progression.

Dual immune roles in ALS

This protective response echoes how the immune system works during infections. In viral battles, inflammatory T cells eliminate infected cells, while anti-inflammatory T cells restore balance once the threat is gone. In ALS, a similar counter-response may soften the damage.

“This protective T-cell response is strongest in people with a longer predicted survival time,” said Emil Johansson, a visiting scientist in the Sette Lab.

The findings imply that the immune system is not only destructive but also holds the power to slow disease – depending on which arm dominates.

Expanded disease theory

The uploaded research goes deeper into this concept. It argues that ALS should not be seen purely as a disorder of motor neurons but as a disease of disrupted communication between the nervous and immune systems.

The paper emphasizes that toxic immune activation contributes directly to neurodegeneration. It proposes that immune surveillance mechanisms, which usually protect the brain, break down in ALS, leading to runaway inflammation.

Another theoretical insight is that different ALS subtypes could emerge from the balance – or imbalance – between inflammatory and regulatory immune responses.

This could unify genetic and environmental observations under one framework: immune dysfunction as the common pathway that determines how fast the disease unfolds.

ALS treatment possibilities

The new direction raises the possibility of immune-based therapies. If doctors can encourage protective T-cell activity while dampening harmful inflammation, ALS progression might slow.

“Hopefully, now that we know the specific target of these immune cells, we can make more effective therapies for ALS,” said LJI research technician Tanner Michaelis, first author of the study.

“This approach may also apply to additional disorders such as Parkinson’s, Huntington’s, and Alzheimer’s,” said Sette.

Wider disease connections

The immune system’s role in neurodegeneration is gaining recognition. Parkinson’s disease, Huntington’s, and Alzheimer’s all show signs of immune involvement.

“There are several neurodegenerative diseases where we now have clear evidence of immune cell involvement,” said Sette. “This is turning out to be more of a rule of neurodegenerative diseases – rather than an exception.”

By placing ALS within this larger framework, scientists hope not only to explain its mysteries but also to uncover shared therapeutic strategies across multiple brain disorders.

The study is published in the journal Nature.

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