Is Parkinson's an autoimmune disease?

US scientists have discovered further evidence that Parkinson’s disease is partly an autoimmune disease, reporting that signs of autoimmunity can appear in Parkinson’s patients years before their official diagnosis.

Published in the journal Nature Communications, the research could make it possible to someday detect Parkinson’s disease before the onset of debilitating motor symptoms — and potentially intervene with therapies to slow the disease progression.

Scientists have long known that clumps of a damaged protein called alpha-synuclein build up in the dopamine-producing brain cells of patients with Parkinson’s disease. These clumps eventually lead to cell death, causing motor symptoms and cognitive decline.

“Once these cells are gone, they’re gone,” said Professor Cecilia Lindestam Arlehamn, first author of the study from the La Jolla Institute for Immunology (LJI). “So if you are able to diagnose the disease as early as possible, it could make a huge difference.”

In 2017, LJI’s Professor Alessandro Sette and Professor David Sulzer from Columbia University Irving Medical Center showed that alpha-synuclein can act as a beacon for certain T cells, causing them to mistakenly attack brain cells and potentially contribute to the progression of Parkinson’s — the first direct evidence that autoimmunity could play a role in Parkinson’s disease. The new study, also led by Profs Sette and Sulzer, sheds light on the timeline of T cell reactivity and disease progression.

The researchers looked at blood samples from a large group of Parkinson’s patients and compared their T cells to a healthy, age-matched control group. They found that the T cells that react to alpha-synuclein are most abundant when patients are first diagnosed with the disease. These T cells tend to disappear as the disease progresses, and few patients still have them 10 years after diagnosis.

The researchers also did an in-depth analysis of one Parkinson’s patient who happened to have blood samples preserved going back long before his diagnosis. This case study showed that the patient had a strong T cell response to alpha-synuclein 10 years before he was diagnosed. Again, these T cells faded away in the years following diagnosis.

“This tells us that detection of T cell responses could help in the diagnosis of people at risk or in early stages of disease development, when many of the symptoms have not been detected yet,” said Prof Sette. “Importantly, we could dream of a scenario where early interference with T cell responses could prevent the disease from manifesting itself or progressing.”

Prof Sulzer added, “One of the most important findings is that the flavor of the T cells changes during the course of the disease, starting with more aggressive cells, moving to less aggressive cells that may inhibit the immune response, and after about 10 years disappearing altogether. It is almost as if immune responses in Parkinson’s disease are like those that occur during seasonal flu, except that the changes take place over 10 years instead of a week.”

So-called TNF therapies already exist to treat inflammation from autoreactive T cells, and these therapies are associated with lower incidence of Parkinson’s disease. Going forward, the researchers are interested in using a tool called a T cell-based assay to monitor patients already at risk for Parkinson’s to see if they could benefit from TNF therapies, including people with REM sleep disorders and certain genetic mutations. The researchers also hope to study more Parkinson’s patients and follow them over longer time periods to better understand how T cell reactivity changes as the disease progresses.

Image caption: Clumps of a damaged protein called alpha-synuclein build up in the dopamine-producing brain cells of patients with Parkinson’s disease. T cells that react to alpha-synuclein are most abundant when patients are first diagnosed with the disease.

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