Immune responses may explain Parkinson’s sex-specific differences
Research findings offer clues for why disease is more common in men
Men with Parkinson’s disease mount stronger and more frequent immune responses than do women against PINK1, a protein that protects nerve cells from death, a new U.S. study found.
These findings offer new clues for how the immune system shapes the course of disease in men and women, the researchers noted, and may help to explain why Parkinson’s is more common among males.
“This research allows us to better understand the role of the immune system in Parkinson’s disease,” Alessandro Sette, PhD, one of the study’s senior authors and a professor at the La Jolla Institute for Immunology in California, where he heads the Sette lab, said in an institute news story.
According to Sette, also the director of the institute’s Center for Autoimmunity and Inflammation, “this [stronger] immune response may be a component of why we see a sex difference in Parkinson’s disease.”
The study, “PINK1 is a target of T cell responses in Parkinson’s disease,” was published in The Journal of Clinical Investigation.
Investigating T-cell responses for 6 Parkinson’s-linked proteins
In Parkinson’s, a protein known as alpha-synuclein becomes prone to misfolding, and forming toxic clumps that cause the death of nerve cells that produce dopamine, a chemical involved in motor control. Loss of dopamine results in Parkinson’s hallmark motor symptoms, as well as its nonmotor symptoms.
The disease can manifest in different ways in men and women, and is about twice as common in males as in females, the team noted. Some research suggests that differences in immune responses, including against toxic alpha-synuclein clumps, may underly these sex-specific differences.
Some patients have self-reactive immune T-cells that mistakenly recognize the alpha-synuclein protein as foreign and enter the brain, where they mount immune responses against the protein and contribute to neurodegeneration.
According to the researchers, because not all Parkinson’s patients have these abnormal T cells, “we hypothesize that additional autoantigens may exist.” Autoantigens are parts of healthy molecules in the body that abnormally trigger an immune response against them.
To find out whether this was true, the researchers analyzed T-cell responses against six Parkinson’s-associated proteins — GBA, SOD1, PINK1, Parkin, OGDH, and LRRK2 — in 60 adults with Parkinson’s and 49 healthy people, who served as controls.
T-cells were collected from participants’ blood and grown in the lab in the presence of each of the six proteins. Cells were re-exposed to the initial protein to measure the production of immune proteins specific to the potential autoantigen.
Immune responses to PINK1 2 times stronger among male patients
PINK1 is a protein that helps maintain healthy mitochondria, which serve as a cell’s powerhouses, and protects nerve cells from death. The team found that PINK1 triggered an immune response that was nearly twofold stronger in T-cells from the Parkinson’s patients versus the healthy controls.
While this difference failed to reach statistical significance, the proportion of samples in which a PINK1-specific T-cell response was observed was significantly higher among the patients than the controls (70% vs. 51%).
This stronger immune response against PINK1 “appeared predominantly driven by differences in males,” the researchers wrote.
In particular, PINK1-specific T-cell responses in men with Parkinson’s were six times higher than in healthy men. Meanwhile, there were no significant differences in the magnitude of the immune response between women with or without the disease.
Sette noted that “the sex-based differences in T cell responses were very, very striking.” Further, they may contribute to the sex-specific differences seen in Parkinson’s, Sette said.
These results reinforce the need for studying [Parkinson’s disease] in the context of the immune system, with the goal of developing personalized immune-based therapies.
To Cecilia Lindstam Arlehamn, PhD, who co-led the study at the La Jolla Institute, these PINK1-targeting T-cells have the potential to be a Parkinson’s biomarker. As such, they could allow an earlier diagnosis in people at a higher risk of developing the disease.
Understanding these differences between men and women could also lead to better, more personalized treatments for Parkinson’s, Lindstam Arlehamn noted.
“We could potentially develop therapies to block these T cells, now that we know why the cells are targeting in the brain,” the researcher said.
Still, according to Sette, researchers “need to expand to perform more global analysis of the disease progression and sex differences — considering all the different [autoantigens], disease severities, and time since disease onset.”
Overall, the team noted, “these results reinforce the need for studying [Parkinson’s disease] in the context of the immune system, with the goal of developing personalized immune-based therapies.”
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