Study Finds Autoimmunity Link Within Parkinson Disease

Researchers found that signs of autoimmunity can appear in Parkinson disease (PD) years before an official diagnosis, which may allow for heightened detection before symptom onset and greater preventive measures to slow disease progression.

Published this week in Nature Communications, study authors Alessandro Sette, ScD, professor at La Jolla Institute for Immunology (LJI), and David Sulzer, PhD, professor at Columbia University Medical Center, showed that alpha-synuclein (α-synuclein) was shown to act as a beacon for certain T cells, in which it would cause them to mistakenly target brain cells and potentially promote the progression of PD. They previously indicated in a 2017 study that autoimmunity may have a role in PD.

"Once these cells are gone, they're gone. So if you are able to diagnose the disease as early as possible, it could make a huge difference," said lead study author Cecilia Lindestam Arlehamn, PhD, LJI research assistant professor.

In the current longitudinal case study, the researchers sought to gain a greater understanding of the relationship between α-synuclein T-cell reactivity and PD. They collected blood samples from a large study cohort of patients with PD and compared their T cells with a healthy, age-matched control group.

Analyses revealed that T cells that react to α-synuclein were most abundant prior to the diagnosis of motor PD, and as the disease progressed, these T cells declined. Few patients had α-synuclein T-cell reactivity 10 years after 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 Sette. "Importantly, we could dream of a scenario where early interference with T-cell responses could prevent the disease from manifesting itself or progressing."

To further examine α-synuclein T-cell reactivity, the researchers did an in-depth analysis of 1 patient with PD who had blood samples preserved before diagnosis. Aligned with the findings of the large study cohort, the patient’s T-cell response to α-synuclein was found to be most prominent 10 years before diagnosis before fading in the years after diagnosis.

"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 disease are like those that occur during seasonal flu, except that the changes take place over 10 years instead of a week," said Sulzer.

As the mechanisms behind PD progression continue to be examined, the disease’s growing association as part autoimmune disease may lead to increased preventive efforts to identify and treat α-synuclein T-cell reactivity. The researchers note that an established tool, T-cell—based assay, assists in monitoring patients already at risk for PD, which could prove vital in directing these at-risk populations to novel therapies, such as novel anti—tumor necrosis factor-alpha biologics.

The study authors additionally expressed their hope in continuing to study and follow more patients with PD over longer time periods to better understand the relationship between α-synuclein T-cell reactivity and PD progression.

Reference

Arlehamn CSL, Dhanwani R, Pham J, et al. α-Synuclein-specific T cell reactivity is associated with preclinical and early Parkinson’s disease [published online April 20, 2020]. Nat Commun. doi: 10.1038/s41467-020-15626-w.