Summary: New research suggests amyotrophic lateral sclerosis (ALS) may have an autoimmune component. Scientists found that CD4+ T cells in people with ALS recognize and attack neuron-associated proteins, a discovery that helps explain rapid disease progression in some patients and points toward immune-focused treatment strategies.
Importantly, patients who showed a stronger presence of anti-inflammatory CD4+ T cells had substantially longer predicted survival, indicating a protective immune response that could be harnessed therapeutically.
Key Facts
- Autoimmune association: People with ALS exhibit CD4+ T cell responses directed at neuronal proteins, consistent with autoimmune activity.
- Two patient groups identified: One group shows predominantly inflammatory T cell responses and shorter survival projections; another group combines inflammatory responses with higher anti-inflammatory T cell levels and longer projected survival.
- Therapeutic implications: Adjusting the balance between inflammatory and regulatory CD4+ T cells may slow progression and enable new, targeted treatments.
Source: La Jolla Institute
Background
Approximately 5,000 Americans receive an ALS diagnosis each year. The disease typically progresses rapidly, and about half of diagnosed patients die within 14 to 18 months, most commonly due to respiratory failure. The underlying causes of ALS have been unclear, but neuroinflammation and immune involvement have long been observed in affected tissues.
Researchers at La Jolla Institute for Immunology (LJI) and Columbia University Irving Medical Center report evidence that ALS can include an autoimmune reaction. The team discovered that CD4+ T cells from people with ALS recognize a neuronal protein called C9orf72 and mount a response against it. That targeted recognition — an immune response against the body’s own protein — is a defining feature of autoimmune disease.
“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 Irving Medical Center.
The investigators mapped the antigenic regions of C9orf72 recognized by CD4+ T cells and characterized the cytokine profile of those T cells. They found that C9orf72-specific CD4+ T cells preferentially release cytokines such as IL-5 and IL-10, with IL-10–associated responses notably higher in donors who have a longer predicted survival.
Two patient groups with different immune balances and survival outcomes
ALS shows wide variability in progression. While many patients decline quickly, a smaller fraction survive many years after diagnosis. The research team evaluated T cell responses across patients and identified two immunological patterns that correlate with different survival projections.
The first group demonstrated strongly inflammatory CD4+ T cell responses that react vigorously to C9orf72, corresponding to shorter predicted survival. The second group, while also mounting inflammatory responses, had higher numbers of anti-inflammatory or regulatory CD4+ T cells. That regulatory response correlated with significantly longer predicted survival.
Regulatory CD4+ T cells normally curb immune responses after infections or inflammation to prevent damage to healthy tissue. The researchers propose that in ALS, a disrupted balance between inflammatory and counter-inflammatory CD4+ T cells may accelerate neuronal damage in patients lacking a sufficient regulatory response.
“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 finding suggests that enhancing regulatory T cell functions could be an avenue to slow disease progression.
Implications for treatment and future research
Identifying C9orf72 as a target for autoimmune T cell responses provides a focused target for precision immunotherapies. Therapies that increase anti-inflammatory CD4+ T cell activity or otherwise rebalance T cell responses may reduce harmful neuroinflammation and extend patient survival.
Study first author Tanner Michaelis noted that knowing the specific antigen recognized by these immune cells opens the door to antigen-specific approaches and improved therapeutic design. The investigators also suggested the approach could be relevant to other neurodegenerative diseases in which immune cells contribute to neuronal loss.
This work contributes to an expanding body of evidence in neuroimmunology showing immune involvement in neurodegenerative disorders. According to the authors, immune cell participation appears to be a common feature across several diseases characterized by neuron death.
Additional authors of the study, titled “Autoimmune response to C9orf72 protein in amyotrophic lateral sclerosis,” include Cecilia S. Lindestam Arlehamn, April Frazier, James D. Berry, Merit Cudkowicz, Namita Goyal, Christina Fournier, Allison Snyder, Justin Y. Kwan, Jody Crook, Elizabeth J. Phillips, Simon A. Mallal, John Ravits, Karen S. Marder, and John Sidney.
Funding: The study received support from La Jolla Institute, Kyowa Kirin North America, the Swedish Research Council (grant 2024-00175), the Freedom Together Foundation, and in part from the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health.
A: The study shows that ALS involves an autoimmune component in which CD4+ T cells target the neuronal protein C9orf72, supporting the idea that immune responses contribute to disease pathology.
A: Patients fell into two groups—those with predominantly inflammatory T cell responses and shorter predicted survival, and those with additional anti-inflammatory CD4+ T cell activity and longer predicted survival.
A: Enhancing regulatory or anti-inflammatory CD4+ T cell responses and reducing harmful inflammation may offer new therapeutic strategies to slow ALS progression.
About this ALS and neurology research news
Author: Madeline McCurry-Schmidt
Source: La Jolla Institute
Contact: Madeline McCurry-Schmidt – La Jolla Institute
Image: Image credit: Neuroscience News
Original Research: Open access. “Autoimmune response to C9orf72 protein in amyotrophic lateral sclerosis” by Gina Kirchweger et al., published in Nature.
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder marked by motor neuron loss. A hallmark of affected tissue is neuroinflammation, including increased T cell infiltration and microglial activation, especially in the spinal cord. While autoimmune mechanisms have long been suspected in ALS, until now there had been no clearly identified antigen driving such responses.
This study demonstrates that ALS is associated with CD4+ T cell recognition of the C9orf72 antigen and defines the specific epitopes involved. The C9orf72-specific responses are mediated by CD4+ T cells that favor production of IL-5 and IL-10, with IL-10–linked responses greater in donors who have a longer predicted survival time.
These findings support the hypothesis that neuroinflammation and an imbalance between inflammatory and counter-inflammatory T cell responses play important roles in ALS progression. They underscore the potential for therapeutic strategies aimed at enhancing regulatory T cell activity or employing antigen-specific approaches to develop precision treatments for ALS.