Parkinson’s: Autoimmune attack may start years before diagnosis

Around 10 million people in the world are affected by Parkinson’s disease. It is a chronic, progressive disorder, with symptoms including tremor, slowness of movement, rigidity, and impaired balance.

The disease is due to a loss of nerve cells in an area of the brain known as the substantia nigra. The cells that are lost produce dopamine, which is involved in controlling movement.

Generally, people with Parkinson’s receive the diagnosis over the age of 50, but some people develop motor symptoms at an earlier age. Other symptoms of the disease can be detected years before the physical symptoms appear – these can include a reduced sense of smell, constipation, mood changes, and REM sleep behaviour disorder.

The existence of these prediagnostic symptoms suggests that damage to the previously mentioned nerve cells may begin long before the motor control symptoms begin to appear.

Autoimmune damage

A study from the La Jolla Institute for Immunology in the US (LJI) adds to existing evidence that the immune system may be responsible for the damage to the nerve cells.

The research, which appears in Nature Communications, indicates that the autoimmune attack may start more than a decade before the person receives a Parkinson’s diagnosis.

It is hoped that from these findings, a method could be developed for doctors to diagnose the disease earlier, and prescribe immunosuppressant treatment in order to slow or prevent the loss of dopamine cells.

“Once these cells are gone, they’re gone,” says Cecilia Lindestam Arlehamn, PhD, the first author of the study and an assistant professor at LJI. “So, if you are able to diagnose the disease as early as possible, it could make a huge difference”(1).

A 2017 study by some of the same team was the first to suggest that autoimmunity could play a role in the development of Parkinson’s. The team discovered that a protein called alpha-synuclein acts like a beacon for the immune system’s T-cells, and therefore causes them to attack brain cells, leading to the progression of Parkinson’s (2).

Alpha-synuclein misfolds and forms toxic clumps in the nerve cells of people with the disease. The clumps can also accumulate to form Lewy bodies.

Early signs of autoimmunity

The authors of the study examined a case of a man whose blood contained T-cells that reacted to alpha-synuclein at least a decade before he was diagnosed with Parkinson’s disease.

“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,” says LJI professor Alessandro Sette, a corresponding author of the study.

“Importantly, we could dream of a scenario where early interference with T-cell responses could prevent the disease from manifesting itself or progressing.”

The man then started experiencing motor symptoms in 2008, and went on to receive a Parkinson’s diagnosis in 2009, at the age of 47.

He contacted the team after reading about their 2017 study, and donated samples of his blood that had been taken between 1998 and 2018. The samples showed that as far back as 1988, T-cells in his blood were targeting alpha-synuclein.

This means that there was autoimmune activity at least 10 years before the man began to develop motor symptoms.

Changes after diagnosis

In order to further investigate this, the researchers recruited 97 people who had received a Parkinson’s diagnosis less than a decade ago.

Blood samples were taken, and the team compared the samples’ immune reactivity to alpha-synuclein to that of blood samples from 67 healthy control participants of the same age.

This revealed that T-cells targeting alpha-synuclein are most abundant around the time of diagnosis. Their numbers continue to decline as the disease progresses, with few of the cells remaining 10 years after diagnosis.

The researchers conceded that the autoimmune response that they highlighted may not be specific to Parkinson’s disease, and say that further studies are required to further investigate whether T-cells target alpha-synuclein in other neurodegenerative diseases.

However, if the reactivity is specific to Parkinson’s, it contributes to evidence that most of the damage to the cells occurs early in the illness.

Previous research has suggested that the number of nerve cells in a key region of the substantia nigra decreases by up to 90% in the first 4 years after a Parkinson’s diagnosis.

This may help to explain why attempts to develop the slow of the disease have been unsuccessful – the condition may already be irreversible after the majority of dopamine-producing neurons have been lost.

However, if people received immunosuppressant therapy before they developed motor symptoms, this may help to protect the cells.

Future plans

The team are keen to monitor people at high genetic risk of developing Parkinson’s disease, as well as people who have early symptoms, such as REM sleep disorder.

If tests are able to show that the T-cells are reacting to alpha-synuclein, patients could benefit from receiving experimental treatments to dampen their immune response.

There is some evidence that a type of immunotherapy called anti-tumour necrosis factor (TNF) therapy may work.

In one study, participants who received anti-TNF therapy for inflammatory bowel disease were found to be 78% less likely to develop Parkinson’s disease when compared with people who did not receive the treatment (3). The authors of the present study note:

“Attempts to develop treatment to slow the progression of [Parkinson’s disease] have so far been unsuccessful. One of the important factors in the lack of success is that it may be difficult to modify the disease when treatment is initiated after the majority of [nerve cells in the substantia nigra] have already been lost. Thus, identifying effective early predictors of [Parkinson’s] is of fundamental importance to developing future therapies.”

(See our articles on The Chemical Driving The Increase In Parkinson’s Disease and Parkinson’s Disease: Sniff Test Could Predict Risk Up To A Decade Earlier)

References

1. Lindestam Arlehamn CS, Dhanwani R, Pham J, et al. α-Synuclein-specific T cell reactivity is associated with preclinical and early Parkinson’s disease. Nat Commun 11, 1875 (2020). https://doi.org/10.1038/s41467-020-15626-w.

2. Sulzer D, Alcalay RN, Garretti F, Cote L, Kanter E, Agin-Liebes J, Liong C, McMurtrey C, Hildebrand WH, Mao X, Dawson VL, Dawson TM, Oseroff C, Pham J, Sidney J, Dillon MB, Carpenter C, Weiskopf D, Phillips E, Mallal S, Peters B, Frazier A, Lindestam Arlehamn CS, Sette A. T cells from patients with Parkinson’s disease recognize α-synuclein peptides. Nature. 2017 Jun 29;546(7660):656-661. doi: 10.1038/nature22815. Epub 2017 Jun 21. Erratum in: Nature. 2017 Sep 13;549(7671):292. PMID: 28636593; PMCID: PMC5626019.

3. Peter I, Dubinsky M, Bressman S, et al. Anti–Tumor Necrosis Factor Therapy and Incidence of Parkinson Disease Among Patients With Inflammatory Bowel Disease. JAMA Neurol. 2018;75(8):939–946. doi:10.1001/jamaneurol.2018.0605.