Innate and adaptive immune-mediated neuroinflammation and neurodegeneration in parkinson's disease

Abstract

Innate and adaptive immunity affect the pathogenesis of Parkinson's disease (PD). In particular, the activation of microglia that feed neuroinflammation and oxidative stress influences the degeneration of dopaminergic neurons along the nigrostriatal axis during disease. Activated microglia that proximate degenerating neurons within the substantia nigra are a hallmark of PD. Other PD hallmarks include neuronal Lewy body inclusions composed primarily of aggregated ubiquitin and neuronal proteins. Under inflammatory conditions, oxidative or nitrative modifications of neuronal proteins, such as ?-synuclein, lead to misfolding and formation of neurotoxic species that accumulate within the neuron. Release of misfolded proteins from injured or dead neurons intensifies neuroinflammation and neuronal injury within the surrounding area. Moreover, once in the peripheral immune compartments, processing and presentation of modified proteins, such as nitrated ?-synuclein by dendritic cells, induce effector T cells to those nitrated epitopes that act as neoantigens. Robust effector T cell immune responses against nitrated or modified self-proteins and migration of those effector T cells to inflammatory sites exacerbate neuroinflammation and dopaminergic neurodegeneration, which lead to accelerated disease progression. The links between T cell immunity and nigrostriatal neurodegeneration are supported by laboratory and animal models as well as human investigations of immune-associated biomarkers in the spinal fluid, peripheral blood, and brain tissue of patients with idiopathic or familial forms of PD. Regulatory T cells modulate both innate and effector T cell-mediated immunity to attenuate neuroinflammation and alleviate neurodegeneration along the nigrostriatal axis. Thus, harnessing proinflammatory and neurotoxic effector immune responses with drugs, vaccination, or immunomodulation affords promising therapeutic strategies either alone as an interdictory therapy or in combination as adjunctive therapy in the context of neuronal replacement. Herein immune-mediated inflammation, oxidative stress, and neurodegeneration as linked to PD pathogenesis are examined as well as the potential benefits of efficacious immune regulatory control over those neurotoxic processes.