Immune Mechanisms in Parkinson's Disease

Parkinson’s disease is characterised not only by the progressive loss of dopaminergic neurons but also by a multifaceted immune response that spans both the central nervous system and the periphery. Misfolded α-synuclein aggregates trigger microglial activation, leading to the release of pro-inflammatory cytokines and chemokines that exacerbate neuronal injury. Alongside microglia, specialised border-associated macrophages near the meninges and choroid plexus present antigen and orchestrate the recruitment of peripheral T cells into the brain. CD4+ T-cell subsets display a complex balance between pro-inflammatory phenotypes (Th1/Th17) and anti-inflammatory regulatory T cells (Tregs), influencing both neurodegeneration and repair. Peripheral monocytes and macrophages exhibit hyperreactivity and altered chemokine profiles, further fuelling inflammation. Emerging data also implicate gut-brain axis interactions, where intestinal immune activation contributes to prodromal non-motor features and may prime systemic immunity. Together, these innate and adaptive pathways form a dynamic network that both drives neuronal loss and offers targets for immunomodulatory therapies.

Research from Nature Portfolio

Recent studies have identified a critical role for border-associated macrophages in α-synuclein-induced neuroinflammation. These cells expand in number upon α-synuclein accumulation, adopt a damage-associated activation state and present antigen via MHC II, thereby initiating CD4+ T-cell responses that promote further immune cell recruitment and neuronal damage. In human post-mortem Parkinson’s brains, these macrophages localise in close proximity to infiltrating T cells, underscoring their contribution to disease progression. In parallel, investigations into α-synuclein-specific T-cell reactivity have revealed that adaptive immune responses to α-synuclein epitopes emerge years before motor symptoms. T-cell responses peak shortly after clinical diagnosis and then wane, indicating their potential as early biomarkers and suggesting a window for immunointervention before overt neurodegeneration occurs.

Immune Mechanisms in Parkinson's Disease publication trend

The graph below shows the total number of articles in immune mechanisms in parkinson's disease across all publications each year (not limited to Nature Index journals).

Technical terms

α-synuclein: A neuronal protein prone to misfolding and aggregation in Parkinson’s disease.

Neuroinflammation: The inflammatory response within the central nervous system involving glial cells and infiltrating leukocytes.

Microglia: Resident immune cells of the brain that respond to injury and pathogens.

Border-associated macrophages (BAMs): CNS macrophages located at brain borders that present antigen and regulate immune cell entry.

Regulatory T cells (Tregs): A subset of CD4+ T cells that suppress excessive immune activation and maintain tolerance.

Major histocompatibility complex class II (MHC II): Cell-surface molecules on antigen-presenting cells essential for CD4+ T-cell activation.

References

1. Repetitive transcranial magnetic stimulation alleviates motor impairment in Parkinson’s disease: association with peripheral inflammatory regulatory T-cells and SYT6. Molecular Neurodegeneration (2024).
2. Border-associated macrophages mediate the neuroinflammatory response in an alpha-synuclein model of Parkinson disease. Nature Communications (2023).
3. An open-label multiyear study of sargramostim-treated Parkinson’s disease patients examining drug safety, tolerability, and immune biomarkers from limited case numbers. Translational Neurodegeneration (2023).
4. Interaction of an α-synuclein epitope with HLA-DRB1∗15:01 triggers enteric features in mice reminiscent of prodromal Parkinson’s disease. Neuron (2023).
5. α-Synuclein-specific T cell reactivity is associated with preclinical and early Parkinson’s disease. Nature Communications (2020).
6. Periphery and brain, innate and adaptive immunity in Parkinson’s disease. Acta Neuropathologica (2021).
7. Inflammatory dysregulation of blood monocytes in Parkinson’s disease patients. Acta Neuropathologica (2014).
8. Parkinson’s disease patients have a complex phenotypic and functional Th1 bias: cross-sectional studies of CD4+ Th1/Th2/T17 and Treg in drug-naïve and drug-treated patients. Journal of Neuroinflammation (2018).
9. Microglial inflammation in the parkinsonian substantia nigra: relationship to alpha-synuclein deposition. Journal of Neuroinflammation (2005).