Parkinson’s mutations can alter inflammatory immune responses

Immune cell profiles analyzed in study into inflammation thought to drive disease

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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An image showing white blood cells, part of the immune system, with red blood cells and plasma.

People with sporadic Parkinson’s disease and those with Parkinson’s-associated mutations in the GBA gene show a distinct immune cell profile in the blood relative to healthy people, a study showed.

In turn, Parkinson’s patients carrying disease-causing LRRK2 mutations had an immune cell profile comparable to people without any disease.

“Peripheral inflammatory immune responses are thought to play a major role in the pathogenesis [development] of Parkinson’s disease,” the researchers wrote. And this “inflammatory immune response seems to differ between sporadic [unknown cause] and some genetic forms of the disease, particularly in LRRK2-PD,” or LRRK2-associated Parkinson’s disease.

The peripheral immune system affects everything outside the brain and spinal cord, known as the central nervous system.

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Inflammatory profiles of LRRK2- or GBA-linked disease, and sporadic Parkinson’s

The study, “Peripheral inflammatory immune response differs among sporadic and familial Parkinson’s disease,” was published in npj Parkinson’s Disease.

Parkinson’s is characterized by the progressive death and dysfunction of specific nerve cells in the brain, but exactly what causes the disease to develop remains obscure. Mutations in certain genes, such as LRRK2 and GBA, have been linked to Parkinson’s, though most people have sporadic disease, meaning there’s no clear genetic component. This form is also called idiopathic Parkinson’s.

Excessive inflammation has been implicated in Parkinson’s and other neurological disorders, thought to damage brain tissue and so help drive the disease. How inflammatory status differs among people with genetic or sporadic forms of Parkinson’s, however, is not fully understood.

Scientists in Spain analyzed the immune cell profiles of 222 Parkinson’s patients, including 132 with sporadic disease, 44 with LRRK2 mutations (LRRK2-PD group), and 46 with GBA mutations (GBA-PD group). A group of 299 healthy people were used as controls.

“Few studies have considered the genetic background of the individuals when studying the peripheral inflammatory immune response,” the researchers wrote.

Patients with GBA mutations were significantly younger and had a younger age at onset than those with sporadic Parkinson’s and those carrying LRRK2 mutations. Most patients in the sporadic and GBA-PD groups were men, while women comprised most of those with LRRK2-PD.

Notably, “there were no differences between groups either in the duration or severity of the disease,” the researchers wrote. Patients’ mean age at onset was 54.6 and their mean disease duration was 8.25 years.

Immune cell counts differ based on known Parkinson’s disease mutations

Results showed that the number of lymphocytes — a group of immune cells that includes B-cells and T-cells — was significantly lower in sporadic Parkinson’s patients and those with GBA mutations compared with controls.

Counts of neutrophils, another type of immune cell involved in early inflammatory responses, tended to be higher in sporadic and GBA-associated Parkinson’s patients than in controls, though results did not reach statistical significance.

The neutrophil-to-lymphocyte ratio, or NLR, was significantly higher in sporadic and GBA-associated Parkinson’s patients than controls.

However, no significant differences in lymphocyte and neutrophil counts or in NLR were detected between patients with LRRK2 mutations and healthy controls, not even when dividing the results based on sex.

To validate these findings, the scientists analyzed data from a separate group of patients participating in the Parkinson’s Progression Markers Initiative (PPMI), a large international study following patients over time.

This group included 281 sporadic Parkinson’s patients, 66 LRRK2-PD patients, 54 GBA-PD patients, and 174 healthy controls. Their mean age at onset was 58.67, and their mean disease duration was 2.57 years.

Results were generally consistent with findings from the first group of patients, showing that lymphocyte counts were lower while neutrophil counts and NLR were higher in people with sporadic and GBA-associated Parkinson’s relative to controls.

“Again, no differences in either the lymphocyte, or neutrophil counts or the NLR were found between the LRRK2-PD group and the [healthy controls],” the team wrote.

Further statistical analyses generally showed no significant associations between immune cell counts and disease duration or measures of Parkinson’s severity. However, in the overall PPMI group a higher NLR showed a moderate association with more severe motor symptoms.

These findings “support the involvement of a peripheral inflammatory immune response in sPD [sporadic Parkinson’s] and GBA-PD patients,” the researchers wrote, adding that they also suggest the disease-associated inflammatory mechanisms “underlying LRRK2-PD may be different from those underlying sPD.”

Among the study’s limitations, the team noted its cross-sectional nature — data were collected from patients at a single point in time, making it impossible to draw conclusions about how immune profiles change over time. In addition, other markers of inflammation, apart from immune cells, weren’t available for analysis.

“Further prospective and longitudinal studies are required to confirm our results,” the scientists wrote, adding that “a better understanding of the different peripheral inflammatory immune response in sporadic and familial [Parkinson’s] is likely to have clinical and therapeutic implications.”