Hidden face of Parkinson's disease: Is it a new autoimmune disease?

Abstract

Parkinson's disease is a neurodegenerative disorder marked by the degeneration of dopaminergic neurons and clinical symptoms such as tremors, rigidity, and slowed movements. A key feature of Parkinson's disease is the accumulation of misfolded α-synuclein, forming insoluble Lewy bodies in the substantia nigra pars compacta, which contributes to neurodegeneration. These α-synuclein aggregates may act as autoantigens, leading to T-cell-mediated neuroinflammation and contributing to dopaminergic cell death. Our perspective explores the hypothesis that Parkinson's disease may have an autoimmune component, highlighting research that connects peripheral immune responses with neurodegeneration. T cells derived from Parkinson's disease patients appear to have the potential to initiate an autoimmune response against α-synuclein and its modified peptides, possibly leading to the formation of neo-epitopes. Recent evidence associates Parkinson's disease with abnormal immune responses, as indicated by increased levels of immune cells, such as CD4 + and CD8 + T cells, observed in both patients and mouse models. The convergence of T cells filtration increasing major histocompatibility complex molecules, and the susceptibility of dopaminergic neurons supports the hypothesis that Parkinson's disease may exhibit autoimmune characteristics. Understanding the immune mechanisms involved in Parkinson's disease will be crucial for developing therapeutic strategies that target the autoimmune aspects of the disease. Novel approaches, including precision medicine based on major histocompatibility complex/human leukocyte antigen typing and early biomarker identification, could pave the way for immune-based treatments aimed at slowing or halting disease progression. This perspective explores the relationship between autoimmunity and Parkinson's disease, suggesting that further research could deepen understanding and offer new therapeutic avenues. In this paper, it is organized to provide a comprehensive perspective on the autoimmune aspects of Parkinson's disease. It investigates critical areas such as the autoimmune response observed in Parkinson's disease patients and the role of autoimmune mechanisms targeting α-synuclein in Parkinson's disease. The paper also examines the impact of CD4 + T cells, specifically Th1 and Th17, on neurons through in vitro and ex vivo studies. Additionally, it explores how α-synuclein influences glia-induced neuroinflammation in Parkinson's disease. The discussion extends to the clinical implications and therapeutic landscape, offering insights into potential treatments. Consequently, we aim to provide a comprehensive perspective on the autoimmune aspects of Parkinson's disease, incorporating both supportive and opposing views on its classification as an autoimmune disorder and exploring implications for clinical applications.

Keywords: Parkinson’s disease; T cells; astrocyte; autoimmune response; biomarkers; clinical implication; major histocompatibility complex/human leukocyte antigen; microglia; neurodegenerative disease; neuroinflammation; α-synuclein.

Figure 1

Dopaminergic neuronal cell death induced by glial cell activation via α-syn, and the relationship between α-syn and T cell-mediated autoimmune response. A schematic diagram illustrates the relationship between autoimmune response and Parkinson’s disease pathology. (1) Peripheral inflammation, shifts in lymphocyte subtypes, and disruption of the BBB may facilitate T cell and APC infiltration into affected brain regions in PD. (2) These epitopes are displayed to T cells, allowing them to recognize the complex formed between MHC molecules and α-syn peptide epitopes. This may lead the immune system to identify as an autoantigen. (3) CD4⁺ and CD8⁺ T cells can directly or indirectly release several cytokines that promote neuronal cell death. (4) Changes in T cell populations can affect circulating pro-inflammatory cytokine levels. These cytokines may have a detrimental effect on neurons. (5) α-Syn can be transmitted from neuron to neuron or from neuron to glia. Glia cells and APCs can present α-syn to T cells. α-Syn can be presented by microglia or APCs via MHC to stimulate T cell-mediated responses. (6) Activated microglia led to increased levels of cytokines such as TNFα, IL-6, IL-1α, and IFNγ. It can induce an upregulation of reactive astrocyte and neurotoxic A1-specific transcripts. (7) The accumulation of α-syn released from neurons can induce a pro-inflammatory cascade. Pro-inflammatory cytokines released from glia can contribute to neuronal cell death. Created with BioRender.com. APC: Antigen-presenting cell; BBB: blood–brain barrier; IFN: interferon; IL: interleukin; MHC: major histocompatibility complex; PD: Parkinson’s disease; TCR: T-cell receptor; Th cell: T-helper cell; TNF: tumor necrosis factor; α-syn: α-synuclein.