New Research Reveals an Autoimmune Aspect of ALS

• Scientists from the La Jolla Institute for Immunology (LJI) and Columbia University Irving Medical Center report findings suggesting ALS may be an autoimmune disease
• The shows that ALS appears to be an autoimmune disease; in ALS patients, CD4+ T cells of the immune system attack a protein called C9orf72, which is normally part of the nervous system.

ALS, a neurodegenerative disease, affects approximately 2-3 people per 100,000 worldwide. The average life expectancy is about four years after diagnosis. It should be noted that more than 25 genetic mutations are associated with ALS. “The most common mutation affects the gene encoding the protein C9orf72. Mutations in C9orf72 are present in 40% of familial ALS cases and around 10% of sporadic ALS cases,” as noted in a new study.

The study “Autoimmune response to C9orf72 protein in amyotrophic lateral sclerosis,” was published in October this year.

According to the study, they analyzed peripheral blood mononuclear cells from whole-blood donations from 40 individuals with ALS and 28 age- and sex-matched healthy controls. Study participants were recruited from four collaborating clinic sites across the USA: Emory University; the National Institute for Neurological Disorders and Stroke at the National Institutes of Health; the University of California, Irvine; and Harvard Medical School/Massachusetts General Hospital. Additionally, nine of the study participants with ALS were recruited through Sanguine Biosciences, a contract research organization.

We spoke with Professor Alessandro Sette, Dr. Biol. Sci., who co-led the study. It should be noted that Dr. Alessandro Sette has dedicated more than 35 years to researching the immune response, measuring immune activity, and developing intervention strategies against cancer, as well as autoimmunity, allergies, and infectious diseases.

The results: the first study showing an autoimmune reaction targeting specific proteins in people with ALS

The study found that in ALS patients, inflammatory immune cells called CD4+ T cells mistakenly attack neuronal proteins, specifically C9orf72, which is normally part of the nervous system. The overall CD4+ T cell response to C9orf72 was approximately 4.15 times higher in ALS patients compared with healthy controls. The researchers also identified two distinct groups of patients with different survival times. The first group had aggressive, inflammatory CD4+ T cells that strongly targeted C9orf72, associated with shorter predicted survival. The second group had both inflammatory and anti-inflammatory CD4+ T cells, which help regulate immune responses and protect healthy tissue, and this group had significantly longer predicted survival. These findings suggest that protective T cells may slow disease progression in ALS.

Future Research Directions

How can other research in this area help in understanding CD4+ T cells in this context?

Professor Sette: Much remains to be addressed regarding whether these T cell responses are a cause of the disease or whether the immune response is an effect of the inflammation associated with the disease. Some of this can be addressed by studies in animal models, but ultimately, clinical studies will be needed to answer this question.

A large number of CD4+ T cells target a specific protein, called C9orf72, which is expressed in neurons. Why do they target that protein?

Professor Sette: This protein may be targeted because, in the process of the disease, it becomes misfolded and is thereby flagged for recognition by the immune system. Mutations in this protein might also cause it to aggregate more readily and impact how much of the protein is made, ultimately impacting whether the immune system will target it.

On the question of what further investigations are needed to obtain a more complete picture, Dr. Sette concludes, “It would be important to study how T cells evolve over the course of disease progression, what specific genes are turned on or off in the inflammatory or anti-inflammatory T cells, and how mutations associated with the disease affect T cell responses.“

Image: Professor Alessandro Sette/La Jolla Institute for Immunology