The immunology of Parkinson's disease

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disorder which affects 6.1 million people worldwide. The neuropathological hallmarks include the loss of dopaminergic neurons in the substantia nigra, the presence of Lewy bodies and Lewy neurites caused by α-synuclein aggregation, and neuroinflammation in the brain. The prodromal phase happens years before the onset of PD during which time many patients show gastro-intestinal symptoms. These symptoms are in support of Braak's theory and model where pathological α-synuclein propagates from the gut to the brain. Importantly, immune responses play a determinant role in the pathogenesis of Parkinson's disease. The innate immune responses triggered by microglia can cause neuronal death and disease progression. In addition, T cells infiltrate into the brains of PD patients and become involved in the adaptive immune responses. Interestingly, α-synuclein is associated with both innate and adaptive immune responses by directly interacting with microglia and T cells. Here, we give a detailed review of the immunobiology of Parkinson's disease, focusing on the role α-synuclein in the gut-brain axis hypothesis, the innate and adaptive immune responses involved in the disease, and current treatments.

Fig. 1

Diagrammed representation of the gut-brain axis hypothesis for the development and progression of PD. An infection or exposure of the gut to toxins can cause preliminary intestinal inflammation and dysbiosis of the gut microbiome. As a result, there is an upregulation of α-synuclein expression and transport through the vagus nerve and into the brain. Increased permeability of the blood–brain barrier (BBB) facilitates the accumulation of α-synuclein within various brain regions, including the dorsal motor nucleus of the vagus nerve (DMV), leading to pro-inflammatory glial responses and the pathogenesis of neuroinflammation during PD

Fig. 2

Microglia-mediated neuroinflammation and neuroprotective mechanisms in PD pathogenesis. Microglia become an activated M1 phenotype when exposed to PD pathological conditions like misfolded proteins and pro-inflammatory factors. M1 microglia secrete pro-inflammatory factors that further induces neuroinflammatory and neurotoxic mechanisms in the human brain through process such as enhanced phagocytotic activity and increased ROS production. On the other hand, the presence and stimulation by anti-inflammatory factors can lead to an activated M2 phenotype. Neuroprotective mechanisms in PD from M2 microglia include the release of anti-inflammatory cytokines into the brain which inhibits continued neuroinflammation

Fig. 3

Inflammatory factors that regulate T cell–mediated immunity in PD progression. Primarily originating from the gut, various mechanisms such as α-synuclein, gut microbiota, dopamine, and short-chain fatty acids (SCFAs) can result in the activation of T cells that can then bypass a leaky blood–brain barrier (BBB) and travel into the brain. Infiltrated T cells induce neuroinflammation through the secretion of pro-inflammatory cytokines and activation of microglia, leading to the pathogenesis of neurodegenerative diseases like PD