Immune T cell response may detect Parkinson’s before symptom onset
Study findings point to potential window for earlier diagnosis, intervention
People in the prodromal, or presymptomatic, stage of Parkinson’s disease show increased immune activity, with T cells targeting the proteins PINK1 and alpha-synuclein at levels similar to those seen in patients already diagnosed with the neurodegenerative condition, a new study reports.
These two proteins — PINK1 and alpha-synuclein — are key components of Lewy bodies, the abnormal protein clumps, or aggregates, implicated in the progressive loss of dopamine-producing neurons that underlies Parkinson’s and leads to its symptoms.
The study’s findings thus suggest that T cell-driven immune responses may begin years before motor symptoms appear, pointing to a potential window for earlier diagnosis and intervention.
“This T cell immunity could be a marker for early Parkinson’s treatment, even before people show symptoms. … And there’s reason to think that treating Parkinson’s in the very early stages can lead to a better outcome,” Alessandro Sette, professor at the La Jolla Institute for Immunology and senior author of the study, said in an institute news story.
The study, “T cell responses towards PINK1 and α-synuclein are elevated in prodromal Parkinson’s disease,” was published in npj Parkinson’s disease.
Parkinson’s is caused by the loss of dopaminergic neurons — the nerve cells that produce dopamine, a signaling molecule involved in motor control. A disease hallmark is the formation of Lewy bodies, which are abnormal clumps of alpha-synuclein that are toxic to neurons (nerve cells) and able to spread throughout the brain. These protein clumps are believed to drive nerve cell dysfunction and death.
In previous research, the same team of scientists discovered that T cells, which are immune cells typically involved in fighting infections, may also play a role in the development of Parkinson’s.
The scientists found that individuals with Parkinson’s frequently exhibited T cell responses against two key proteins: alpha-synuclein, a hallmark of Lewy body pathology, and PINK1, a protein crucial for cellular quality control that has been genetically linked to early-onset forms of the disease.
Here, the team investigated whether T-cell reactivity toward PINK1 and alpha-synuclein was present during the prodromal phase and contributed to disease development in a group of individuals at a high risk of developing Parkinson’s disease. Prodromal refers to the early stage of a disease, when initial, often nonspecific symptoms appear, and before a full clinical diagnosis can be made.
Scientists looked at immune T cell response in patients, at-risk volunteers
A total of 82 volunteers were enrolled. All either carried genetic risk factors — mutations in the GBA or LRRK2 genes, both linked to an increased risk of developing Parkinson’s — or exhibited early symptoms such as REM sleep behavior disorder or a loss of sense of smell. Such symptoms are considered prodromal indicators of the disease. Also enrolled were 70 people with Parkinson’s and 70 age- and sex-matched individuals, who served as controls.
A technique called Fluorospot was used to determine which volunteers had elevated levels of T cells that responded to the Parkinson’s-related proteins alpha-synuclein and PINK1. This assay detects immune activity by measuring the secretion of immune molecules known as cytokines, specifically interferon-gamma (IFN-gamma) and interleukin-5 (IL-5). These cytokines are produced by T cells upon exposure to these proteins, helping to identify the disease phase when T cell reactivity was most pronounced.
Compared with healthy controls, both Parkinson’s patients and prodromal volunteers had significantly higher combined IFN-gamma and IL-5 mediated T-cell responses toward PINK1 and alpha-synuclein, the data showed.
According to the researchers, “these results demonstrate that prodromal [Parkinson’s] donors have increased T cell responses to two previously described targets of autoreactive T cells in [Parkinson’s disease], indicating that autoimmune responses are present during the prodromal [Parkinson’s] disease stage.”
Parkinson’s disease is associated with the destruction of nervous system cells. Does that destruction cause autoimmunity, or is the autoimmunity the cause of the disease? That’s the chicken-and-the-egg of inflammation in Parkinson’s.
Sette noted that while these findings provide further evidence that T cell reactivity has a role in Parkinson’s, researchers still don’t know exactly how the process works.
“Parkinson’s disease is associated with the destruction of nervous system cells. Does that destruction cause autoimmunity, or is the autoimmunity the cause of the disease? That’s the chicken-and-the-egg of inflammation in Parkinson’s,” Sette said. “The fact that this T cell reactivity is highest when patients are closest to a diagnosis is intriguing,” and “suggests T cells could have something to do with it.”
Consistent with the higher incidence of Parkinson’s in males, elevated T cell reactivity was observed in male patients but not in females when compared with healthy controls. In contrast, among individuals in the prodromal phase of the disease, both males and females showed increased T cell responses.
The researchers said “these differing trends in reactivity [highlight] the need for further studies of the impact of biological sex on neuroinflammation and [Parkinson’s] progression.”
Overall, these new data may prove helpful in guiding the development of early diagnostic tools, according to the team.
“We want to see if there are specific T cells that are protective,” said Emil Johansson, PhD, a researcher in the Sette Lab and coauthor of the study. A key question, Johansson said, is “Could they interfere in inflammation and maybe reduce the number of autoimmune T cells?”
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