Periphery and brain, innate and adaptive immunity in Parkinson’s disease

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder where alpha-synuclein plays a central role in the death and dysfunction of neurons, both, in central, as well as in the peripheral nervous system. Besides the neuronal events observed in patients, PD also includes a significant immune component. It is suggested that the PD-associated immune response will have consequences on neuronal health, thus opening immunomodulation as a potential therapeutic strategy in PD. The immune changes during the disease occur in the brain, involving microglia, but also in the periphery with changes in cells of the innate immune system, particularly monocytes, as well as those of adaptive immunity, such as T-cells. This realization arises from multiple patient studies, but also from data in animal models of the disease, providing strong evidence for innate and adaptive immune system crosstalk in the central nervous system and periphery in PD. Here we review the data showing that alpha-synuclein plays a crucial role in the activation of the innate and adaptive immune system. We will also describe the studies suggesting that inflammation in PD includes early changes in innate and adaptive immune cells that develop dynamically through time during disease, contributing to neuronal degeneration and symptomatology in patients. This novel finding has contributed to the definition of PD as a multisystem disease that should be approached in a more integratory manner rather than a brain-focused classical approach.

Cholinergic Modulation of the Immune System in Neuroinflammatory Diseases

“…In summary, during the course of PD the development of immune inflammation, which is characterized by glial cell activation, peripheral immune cell infiltration, immune complex deposition, and the production and release of many pro-inflammatory cytokines and chemokines, was observed [ 99 ]. These findings suggest that Parkinson’s had an important inflammatory contribution, and this inflammation could be related to the cholinergic system [ 100 ].…”

JKAP relates to disease risk, severity, and Th1 and Th17 differentiation in Parkinson's disease

“…Therefore, we performed the current study and observed that serum JKAP was greatly decreased in PD patients compared to controls, correlates with lower UPDRS‐I score, UPDRS‐II score while higher MMSE score in PD patients. The possible explanations include: (1) JKAP insufficiency decreased neuro viability and function via its hypermethylation and inflammation regulation; therefore, it was downregulated in PD patients compared to controls, and correlated with some part of UPDRS scores 6–10 ; (2) JKAP inactivated T‐cell signaling and interacted with Th1 as well as Th17, resulting in aberrant immune environment and inflammation to affect PD progression; therefore, it correlated with some part of UPDRS scores and MMSE score 8,11–13,20,21 ; (3) JKAP repressed Th17 cell differentiation, the latter was closely involved in the cognitive impairment in neurological diseases including PD; therefore, JKAP correlated with MMSE score 22 …”

Role of the Peripheral Nervous System in PD Pathology, Diagnosis, and Treatment

“…Neuroinflammation is an important pathological manifestation of PD, and reactive microglia were first found in the brains of PD autopsy cases over 30 years ago (McGeer et al, 1988). Microglia can scavenge abnormal α-synuclein produced by neurons and produce a variety of pro-inflammatory factors, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) in the brain and cerebrospinal fluid (CSF) of patients (Harms et al, 2021). The researchers also found large numbers of activated microglia in areas outside the SN, and this activation was not directly linked to the presence of LBs, suggesting that the role of microglia in PD neuroinflammation goes beyond the scavenging of abnormal proteins and dead neurons (Imamura et al, 2003).…”