Adaptive immunity in the pathogenesis and treatments of Parkinson's disease

Abstract

Neuroimmunity drives the pathophysiology of Parkinson's disease (PD). This disease affects both the central and peripheral nervous systems. The immune system is engaged through the progressive accumulation of alpha-synuclein (α-syn), a driver of immunity and a pathological hallmark of PD. Consequent α-syn-induced immune activation leads to neuronal damage. This leads not only to the activation of microglia within the central nervous system, but also to the recruitment and activation of peripheral immune cells that infiltrate the brain and contribute to a widespread immune response. Moreover, PD-associated genes and risk factors have been increasingly recognized as essential regulators of immune functions. This review summarizes the current understanding of adaptive immunity in PD and explores emerging immunomodulatory strategies that may inform future therapeutic development.

Keywords: Parkinson’s disease; adaptive immunity; alpha-synuclein.

Figure 1:

Neuroinflammation and adaptive immune response in PD. Exposure of modified and aggregated α-synuclein (α-syn) in the brain activates microglia that secrete neurotoxic proinflammatory cytokines such as TNF-α, IL-6 and IL-1β. Modified α-syn and inflammatory mediators drain to peripheral immune tissues to activate antigen presenting cells that lead to induction of α-syn-specific CD4+ and CD8+ T cells that differentiate to specific effector T cells (Teffs), such as Th1, Th17, and Tc, extravasate to foci of brain inflammation, and release proinflammatory cytokines such as IFN-γ, IL-17, and TNF-α that exacerbate microglial activation, inflammation, and neurodegeneration. These responses also induce astrocyte activation, resulting in the production of additional inflammatory mediators including TNF-α, IL-6, and IL-1β, thereby contributing to neuronal degeneration. Regulatory T cells (Tregs) infiltrating the brain counteract neuroinflammation by suppressing activated astrocytes through the secretion of IL-10 and TGF-β. According to the “gut-first” hypothesis, dysbiosis of the intestinal microbiota disrupts gut metabolic activity and barrier integrity, leading to increased levels of microbial products such as lipopolysaccharide (LPS). Elevated levels of LPS can translocate into systemic circulation, promoting peripheral immune activation. Microbial dysbiosis and breech of the gut barrier along the gut-brain axis may contribute to α-syn misfolding and aggregation, central inflammation via immune cell trafficking, and spreading and transmission via vagus nerve.