Evidence is emerging that amyotrophic lateral sclerosis (ALS) may have an autoimmune component — a finding that, if confirmed, could shape the development of new therapies and prognostic tools.

Investigators found that individuals with ALS mount autoimmune T-cell responses against a protein known as C9orf72, which is expressed in neurons and is the most common genetic cause of ALS.

“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,” co-lead author Alessandro Sette, Dr.Biol.Sci., with the La Jolla Institute for Immunology in La Jolla, California, said in a statement.

However, outside experts urged caution in interpreting the results and said it would be premature to label ALS as an autoimmune disorder.

The study was published online on October 1 in Nature.

C9orf72 Protein a ‘Major Target’

ALS is a progressive neurodegenerative disorder that destroys motor neurons, typically leading to paralysis and death, and has a mean life expectancy of approximately 4 years.

Signs of neuroinflammation have been observed in affected tissues, including increased T-cell infiltration and activation of microglia, particularly in the spinal cord, but a clear target for immune attack had not been identified, until now, the investigators noted.

In the analysis of peripheral blood mononuclear cells from whole-blood donations from 40 individuals with ALS and 28 age- and sex-matched healthy control participants, the researchers identified C9orf72 as a “major target” of ALS-associated T-cell autoreactivity.

They found that ALS is associated with recognition of the C9orf72 antigen and mapped specific epitopes that are recognized. “Notably, a significant and selective increase in overall responses to the C9orf72 peptide pool was observed in participants with ALS,” they reported.

These responses were mediated largely by CD4+ T cells that preferentially release interleukin (IL) 5, a proinflammatory cytokine, and IL-10, a potent anti-inflammatory cytokine.

Anti-inflammatory IL-10-mediated responses were associated with a longer predicted survival time, “raising the possibility that enhancing this anti-inflammatory component might provide therapeutic benefits,” the authors wrote.

The autoreactive T-cell response was found broadly in individuals with ALS but was particularly high in carriers of C9orf72 mutant alleles. Mutations in C9orf72 are present in 40% of familial ALS cases and about 10% of sporadic cases.

“Our results reinforce the previous hypothesis that neuroinflammation has an important role in ALS disease progression, possibly because of a disrupted balance of inflammatory and counter-inflammatory T-cell responses,” Sette and colleagues wrote.

Pending further study, one potential “therapeutic avenue may be to harvest and expand the patient’s own anti-inflammatory T cells,” co-lead author David Sulzer, PhD, with the Department of Psychiatry, Neurology and Pharmacology, Columbia University, New York City, told Medscape Medical News.

Sette noted that “if ALS has an autoimmune component, then apart from the harnessing antigen-specific T cells that are anti-inflammatory, we can also consider immunosuppressive treatments.”

“If T-cell responses precede the onset of disease, it could be used for early diagnosis and early treatment. Characterizing the balance of inflammatory/anti-inflammatory response could lead to a prognostic tool to chart the likely course of disease,” he added. However, he said “the development of clinical applications will take time and careful testing.”

Caution Warranted

Commenting on the research for Medscape Medical News, Kuldip Dave, PhD, senior vice president for research at the ALS Association, said the study is “interesting and adds to our understanding of the immune system in ALS, but this study alone does not justify labeling ALS as an autoimmune disease. ALS is such a heterogeneous disease that multiple mechanisms are likely involved in driving its development and progression.”

Dave noted that inflammation in ALS has “long been a ‘chicken or the egg’ debate — whether it initiates the disease or results from it. This paper shows that immune processes may be involved in the pathologic cascade, but more research is needed.”

“The study is creating a lot of questions in the community. I think we have to be measured in how we characterize something as an autoimmune disease and in how we interpret these data,” Dave added.

Jeffrey D. Rothstein, MD, PhD, director of the Robert Packard Center for ALS Research, Johns Hopkins University School of Medicine, Baltimore, who also wasn’t involved in the study, remains unconvinced.

“ALS is simply not an autoimmune disease,” he told Medscape Medical News. “There is no question that late in disease inflammatory pathways are activated. But many genes are already known to cause ALS, and none implicate autoimmunity.”

“Many autoimmune therapies over the last 30 years have targeted inflammation and immunity in ALS and unfortunately all failed to alter the disease,” Rothstein added.

This research was supported by La Jolla Institute for Immunology, Kyowa Kirin North America, the Swedish Research Council, and the Freedom Together Foundation, and in part by the National Institute of Neurological Disorders and Stroke, National Institutes of Health. Sette, Sulzer, Dave, and Rothstein had no disclosures.