Parkinson’s disease progression may be influenced by immune B-cells
Elevated levels of antibodies by regular B-cells linked to move from RBD to disease
Greater proportions of immune regulatory B-cells were associated with better motor performance in people with early Parkinson’s disease, a study revealed.
Regulatory B-cell subsets may be protective by limiting pro-inflammatory responses that contribute to disease progression, data showed. Meanwhile, elevated levels of antibodies produced by regular B-cells against the alpha-synuclein protein, a molecular hallmark of Parkinson’s, were linked with transitioning from prodromal (early) sleep behavior disorder (RBD) to the disease. This disorder commonly appears in the years before a Parkinson’s diagnosis.
These data support therapeutic strategies that modulate B-cell activity to treat early Parkinson’s disease or RBD, the researchers noted in “B lymphocyte responses in Parkinson’s disease and their possible significance in disease progression,” which was published in Brain Communications.
Parkinson’s is a neurodegenerative disease primarily marked by motor symptoms. It’s driven by the progressive loss of the brain’s dopaminergic neurons, nerve cells that help control body movements by releasing the signaling molecule dopamine.
Years before motor signs appear, there’s a well-described prodromal phase marked by nonmotor features. These include constipation, loss of smell, and RBD, wherein dreams are physically acted out. What influences the conversion of the prodromal phase to Parkinson’s disease remains unclear, however. Emerging evidence indicates inflammation may be an early driver of Parkinson’s instead of just a response to neuronal damage.
Immune T-cells and antibodies against toxic aggregates (clumps) of alpha-synuclein, thought to contribute to dopaminergic neuron death in Parkinson’s, have been found in patients. T-cell responses were highest soon after motor symptoms appear, suggesting immune activation at the onset of disease.
Beyond their role as antibody-producing immune cells, B-cells have various other functions, including regulating T-cell responses.
Given the potential role of the immune system in developing Parkinson’s and its progression, researchers in the U.K. conducted a comprehensive characterization of patients’ B-cells. They also examined antibody responses to alpha-synuclein with RBD and early Parkinson’s.
Role of regulatory B-cells in motor function
Blood samples were collected from 79 patients with RBD, classified as idiopathic, or without a known cause. RBD was divided into high- and low-risk of prodromal-to-Parkinson’s conversion based on Movement Disorder Society (MDS) criteria.
Fifty early-stage Parkinson’s patients, ages 55-80, were recruited and stratified into a high, intermediate, and low risk of developing early dementia using MAPT, a genetic risk factor associated with faster disease progression and cognitive decline. Fifty people, matched in age, gender, and MAPT, were included as controls.
Blood tests revealed RBD patients at high risk of converting to Parkinson’s had significantly elevated levels of antibodies against alpha-synuclein aggregates compared with those at low risk, early Parkinson’s, and controls. Low- and high-risk prodromal groups also had elevated antibody levels, in general.
The higher likelihood of converting to Parkinson’s significantly correlated with elevated antibodies against alpha-synuclein aggregates.
“This suggests [an immune] response to an aggregated form of the protein is present prior to the development of overt Parkinson’s disease,” the researchers wrote.
B-cells counts were significantly lower in early Parkinson’s patients, particularly those at high risk of early dementia. Proportions of B-cell subtypes were similar between patients and controls except for B-cells with regulatory function, which were reduced in all Parkinson’s patients.
Higher proportions of regulatory B-cells in Parkinson’s patients correlated with better motor function, as assessed with MDS-Unified Parkinson’s Disease Rating Scale (UPDRS) part 3, suggesting “they have a protective role in Parkinson’s disease,” the researchers wrote. Levels of these B-cell subtypes were also significant predictors of motor severity.
Those at a higher risk of dementia secreted more inflammatory immune signaling molecules (cytokines) than lower risk groups.
To support these findings, researchers showed that B-cell counts were significantly lower in two Parkinson’s mouse models modified to produce alpha-synuclein aggregates. This suggests a link between B-cell function and the presence of toxic aggregates, the researchers noted.
Lastly, mice bred to be B-cell deficient were injected with the chemical 6-OHDA directly into the striatum, the location of dopaminergic neurons, to mimic neuronal loss in patients. Compared with controls, these mice had significantly worse motor outcomes and more extensive dopamine loss.
“Our results highlight that changes in the B-cell compartment are associated with disease progression,” the researchers wrote, adding that raises the possibility that “therapeutic strategies augmenting regulatory B cells may have utility in very early Parkinson’s disease or RBD.”