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.

Keywords: Alpha-synuclein; Microglia; Monocyte; Neuroinflammation; Parkinson; T-Cell.

Fig. 1

Immune response to alpha-synuclein induced neurodegeneration. During Parkinson’s disease, α-Synuclein (α-syn) undergoes post-translational modifications (phosphorylation, nitration, truncation…), forms oligomeric species and finally insoluble fibrils that aggregate in neurons in the Lewy Bodies. This process leads to neuronal dysfunction and ultimately cell death. Neurons can release monomeric or modified α-syn to the extracellular space. There, they should be cleared by microglia and/or infiltrating macrophages (CD163 + /CCR2 +), but also by astrocytes. If this process fails, the modified α-syn can be taken up by neighboring healthy neurons, where it will seed the aggregation of the endogenous α-syn. The modified α-syn will in parallel act as a damage-associated molecular pattern (DAMP) and via diverse immune receptors found in microglia and macrophages, induce a pro-inflammatory response. The pro-inflammatory cytokines will further promote neurodegeneration by direct action in neurons or indirectly by promoting A1 astrocyte differentiation. This innate immune response will also be accompanied by the adaptive immune response. The intracellular degradation of pathological α-syn will direct peptides of the protein to the MHC system that will in turn activate CD8 (T-cytotoxic cells, Tc), via MHCI, and CD4 (T-helper cells, Th), via MHCII. Such processes might occur both in the brain, but also in the periphery. Depending on the cytokines produced, the CD4-Th cells will undergo differentiation/maturation to Th1 or Th17 T-cells, which typically potentiate pro-inflammatory events; or into Th2 or Treg T-cells that will resolve the inflammation. In addition, B-cell activation will result in production of antibodies that will aid the clearance of α-syn and to NK activation, that can also help clearing α-syn. Additionally, this process will be influenced by parallel immune related events such as bacterial infections, intestinal inflammation, and changes of microbiota in the gut, which can increase gut permeability and result in a leaky gut-wall. This will change the immune milieu, possibly facilitating α-syn pathology and further promote inflammation. (Figure created using BioRender.com)