The immune system in Parkinson's disease: what we know so far

Abstract

Parkinson's disease is characterized neuropathologically by the degeneration of dopaminergic neurons in the ventral midbrain, the accumulation of α-synuclein (α-syn) aggregates in neurons and chronic neuroinflammation. In the past two decades, in vitro, ex vivo and in vivo studies have consistently shown the involvement of inflammatory responses mediated by microglia and astrocytes, which may be elicited by pathological α-syn or signals from affected neurons and other cell types, and are directly linked to neurodegeneration and disease development. Apart from the prominent immune alterations seen in the CNS, including the infiltration of T cells into the brain, more recent studies have demonstrated important changes in the peripheral immune profile within both the innate and adaptive compartments, particularly involving monocytes, CD4+ and CD8+ T cells. This review aims to integrate the consolidated understanding of immune-related processes underlying the pathogenesis of Parkinson's disease, focusing on both central and peripheral immune cells, neuron-glia crosstalk as well as the central-peripheral immune interaction during the development of Parkinson's disease. Our analysis seeks to provide a comprehensive view of the emerging knowledge of the mechanisms of immunity in Parkinson's disease and the implications of this for better understanding the overall pathogenesis of this disease.

Keywords: B cells; T cells; alpha-synuclein; microglia; monocytes.

Figure 1

Immune mechanisms in the CNS in Parkinson's disease. During Parkinson’s disease (PD), α-synuclein (α-syn) undergoes post-translational modification and aggregation, forming oligomeric species and finally insoluble fibrils that accumulate within dopaminergic neurons in the Lewy bodies. As a result of cell death or exocytosis, abnormal α-syn species released from neurons activate microglia acting as a damage-associated molecular pattern (DAMP) via different cell receptors including TLRs and CD36. This results in activation of the NF-κB and NLRP3 pathways, leading to the release of pro-inflammatory cytokines and reactive oxygen species (ROS), which will further promote neurodegeneration by direct action towards neurons or indirectly by supporting neurotoxic astrocyte differentiation. Such reactive astrocytes favour the damage and permeabilization of the blood–brain barrier (BBB), which enables the infiltration of peripheral immune cells, particularly CD4+ and CD8+ T lymphocytes, into the CNS. Dysfunction in key cellular processes, such as autophagy, mitochondrial respiration and the response to oxidative stress may lead to abnormal immune responses in glial cells, in an α-syn-dependent or -independent manner. The intracellular degradation of pathological α-syn leads to α-syn antigen presentation, which activates CD8⁺ T cells (CTLs) via class-I MHC, and CD4⁺ (Th and Treg) cells via class-II MHC. Th1 and Th17 T cells typically potentiate pro-inflammatory and neurotoxic events, whereas Th2 and Treg T cells support the resolution of inflammation and neuroprotection.

Figure 2

Putative mechanisms of peripheral T-lymphocyte involvement in Parkinson's disease. Autoreactive T cells might be activated in the periphery and then infiltrate into the brain, a process supported by the interaction of LFA1 expressed on the T-cell surface with ICAM1 expressed on the surface of the blood–brain barrier (BBB) endothelial cells. CD8+ T cells (cytotoxic T lymphocytes; CTLs) infiltrating into the brain might recognize their cognate antigens (α-syn-derived or mitochondrial-derived antigens) on class-I MHC molecules expressed on the surface of dopaminergic neurons, triggering the direct killing of neurons by CTLs. CD4+ T cells infiltrating the brain are exposed to low dopamine levels, which promotes poor DRD2-signalling and strong DRD3-signalling, favouring the acquisition of a strong pro-inflammatory profile (Th1 and Th17). These autoreactive Th1 and Th17 cells recognize α-syn-derived antigens presented on class-II MHC by microglia, leading to release of inflammatory cytokines directly onto microglia. In response to this, microglia produce high levels of neurotoxic factors, including TNFα, reactive oxygen species (ROS) and glutamate, thus inducing the killing of dopaminergic neurons by CTLs. TCR = T-cell receptor.