Parkinson disease and the immune system — associations, mechanisms and therapeutics

Abstract

Multiple lines of evidence indicate that immune system dysfunction has a role in Parkinson disease (PD); this evidence includes clinical and genetic associations between autoimmune disease and PD, impaired cellular and humoral immune responses in PD, imaging evidence of inflammatory cell activation and evidence of immune dysregulation in experimental models of PD. However, the mechanisms that link the immune system with PD remain unclear, and the temporal relationships of innate and adaptive immune responses with neurodegeneration are unknown. Despite these challenges, our current knowledge provides opportunities to develop immune-targeted therapeutic strategies for testing in PD, and clinical studies of some approaches are under way. In this Review, we provide an overview of the clinical observations, preclinical experiments and clinical studies that provide evidence for involvement of the immune system in PD and that help to define the nature of this association. We consider autoimmune mechanisms, central and peripheral inflammatory mechanisms and immunogenetic factors. We also discuss the use of this knowledge to develop immune-based therapeutic approaches, including immunotherapy that targets α-synuclein and the targeting of immune mediators such as inflammasomes. We also consider future research and clinical trials necessary to maximize the potential of targeting the immune system.

Key points

  • The relationship between neuroinflammation and Parkinson disease (PD) is unclear because the exact mechanisms involved remain to be elucidated.

  • Clinical and laboratory findings have linked autoimmune diseases, impaired cellular and humoral immune responses, inflammatory cell activation and immune dysregulation with PD pathogenesis.

  • Establishing the temporal relationships of innate and adaptive immune responses with the initiation and progression of neurodegeneration will provide insights into the underlying pathophysiology.

  • Most clinical studies of immune-targeted therapies in PD have been limited by cross-sectional methodology and relatively small sample sizes.

  • Clinical trials of therapies that target α-synuclein and other immune targets have been conducted, but the safety and efficacy of such immunotherapies in PD remain to be established.

  • Longitudinal studies are needed to identify groups of patients with PD who are most suitable for immunotherapy and to determine the long-term efficacy, outcome and viability of such treatments.

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Fig. 1: Evidence for involvement of the immune system in PD.
Fig. 2: Mechanisms of microglial involvement in dopaminergic neuron damage.
Fig. 3: Mechanisms of autoimmunity in Parkinson disease.

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Acknowledgements

E.K.-T. and Y.X.-C. are supported by grants from the Singapore Ministry of Health’s National Medical Research Council STaR (E.K.-T.), PD Clinical translational research, SPARK II, OF LCG 0002 (E.K.-T. and Y.X.-C.), TA Award (Y.X.-C.) and CSA 0021/2017 Award (L.L.-C). The authors thank S. Chan, C. Chan and W. T. Saw from the National Neuroscience Institute, Singapore, for their assistance with editing parts of the manuscript.

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E.K.-T., Y.X.-C., L.-L.C. and J.J. contributed to writing of the manuscript. All authors researched data for the article, made substantial contributions to discussion of the content and reviewed and/or edited the manuscript before submission.

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Correspondence to Eng-King Tan.

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Glossary

Expression quantitative trait locus

A genomic locus that explains a fraction of the variation in phenotype.

False discovery rate

A statistical approach used in multiple hypothesis testing to correct for multiple comparisons.

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Tan, E., Chao, Y., West, A. et al. Parkinson disease and the immune system — associations, mechanisms and therapeutics. Nat Rev Neurol 16, 303–318 (2020). https://doi.org/10.1038/s41582-020-0344-4

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