Parkinson’s disease (PD) profoundly affects the immune system, creating a complex interplay between the brain’s immune environment and the body’s peripheral immune responses. This interaction contributes significantly to the progression and symptoms of the disease.
At the core of Parkinson’s disease is chronic neuroinflammation, a state where the brain’s immune cells, particularly microglia, become persistently activated. Microglia are the resident immune cells of the central nervous system (CNS) and normally help maintain brain health by clearing debris and protecting neurons. However, in PD, these cells shift into a pro-inflammatory state known as the M1 phenotype. This activated state leads microglia to release inflammatory molecules such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which can damage the dopamine-producing neurons in the brain’s substantia nigra, the area most affected in Parkinson’s. This neuronal damage is a hallmark of PD and underlies many of its motor symptoms.
The immune dysfunction in Parkinson’s is not limited to the brain. Peripheral immune cells, including neutrophils, monocytes, and lymphocytes, also show altered behavior. For example, neutrophils, which are a type of white blood cell involved in fighting infections, become overactive. They release enzymes and reactive oxygen species that can cause tissue damage and amplify inflammation. Meanwhile, lymphocyte counts, especially T cells (CD3+ and CD4+ subsets), are often reduced in the bloodstream. This reduction is thought to be due to these lymphocytes migrating into the brain, where they contribute to neuroinflammation by releasing their own pro-inflammatory cytokines. This creates a vicious cycle where peripheral immune activation fuels brain inflammation, and vice versa.
One consequence of this ongoing inflammation is the disruption of the blood-brain barrier (BBB), a protective layer that normally prevents harmful substances and immune cells from entering the brain. In Parkinson’s, inflammatory molecules and enzymes degrade the BBB, making it more permeable. This increased permeability allows more peripheral immune cells, like neutrophils, to infiltrate the CNS, further exacerbating inflammation and neuronal damage. The presence of these immune cells in the brain also promotes the aggregation of alpha-synuclein, a protein that forms toxic clumps in PD and contributes to neurodegeneration.
Interestingly, recent research has identified a virus called Human Pegivirus (HPgV) in the brains and spinal fluid of some Parkinson’s patients. This virus, previously thought to be harmless, may play a role in triggering or worsening immune responses in the brain. Patients with HPgV showed more advanced Parkinson’s-related brain changes, including protein buildup and altered brain chemistry, suggesting that viral infections might influence immune system behavior in PD.
Exercise emerges as a powerful modulator of the immune system in Parkinson’s disease. Physical activity can reduce chronic inflammation by influencing immune signaling pathways and promoting the release of neuroprotective factors like brain-derived neurotrophic factor (BDNF) and irisin. Irisin, a hormone released during exercise, helps suppress harmful alpha-synuclein aggregation, reduces oxidative stress, and dampens microglia-mediated neuroinflammation. By improving mitochondrial function and enhancing the brain’s resilience, exercise helps counteract the immune dysregulation seen in PD and may slow disease progression.
Another important aspect is the dysregulation of iron metabolism in Parkinson’s disease, which affects both the brain and peripheral immune system. Iron mishandling can lead to oxidative stress and inflammation, further activating immune cells and contributing to neuronal injury. This iron-related immune activation adds another layer of complexity to how the immune system is involved in PD.
Overall, Parkinson’s disease involves a chronic, dysregulated immune response that spans both the central nervous system and the peripheral immune system. The persistent activation of immune cells, the breakdown of protective barriers, and the infiltration of peripheral immune cells into the brain create a feedback loop of inflammation and neurodegeneratio