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  • Review Article
  • Published:

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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References

  1. Obeso, J. A., Stamelou, M., Goetz, C. G., Poewe, W. & Lang, A. E. Past, present, and future of Parkinson’s disease: a special essay on the 200th anniversary of the shaking palsy. Mov. Disord. 32, 1264–1310 (2017). This review provides a history of and insights into the clinical features and pathogenesis of PD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. GBD 2016 Parkinson’s Disease Collaborators. Global, regional, and national burden of Parkinson’s disease, 1990–2016: a systematic analysis for the global burden of disease study 2016. Lancet Neurol. 17, 939–953 (2018).

    Article  Google Scholar 

  3. Kalia, L. V. & Lang, A. E. Parkinson’s disease. Lancet 386, 896–912 (2015).

    Article  CAS  PubMed  Google Scholar 

  4. Johnson, M. E., Stecher, B., Labrie, V., Brundin, L. & Brundin, P. Triggers, facilitators, and aggravators: redefining Parkinson’s disease pathogenesis. Trends Neurosci. 42, 4–13 (2019).

    Article  CAS  PubMed  Google Scholar 

  5. Chao, Y., Wong, S. C. & Tan, E. K. Evidence of inflammatory system involvement in Parkinson’s disease. Biomed. Res. Int. 2014, 308654 (2014).

    PubMed  PubMed Central  Google Scholar 

  6. Moehle, M. S. & West, A. B. M1 and M2 immune activation in Parkinson’s disease: foe and ally? Neuroscience 302, 59–73 (2015).

    Article  CAS  PubMed  Google Scholar 

  7. Jankovic, J. Pathogenesis-targeted therapeutic strategies in Parkinson’s disease. Mov. Disord. 34, 41–44 (2019).

    Article  PubMed  Google Scholar 

  8. Rugbjerg, K., Friis, S., Ritz, B., Schernhammer, E. S. & Korbo, L. Autoimmune disease and risk for Parkinson disease: a population-based case-control study. Neurology 73, 1462–1468 (2009). This is a population study on the association between autoimmune diseases and the risk of PD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Li, X., Sundquist, J. & Sundquist, K. Subsequent risks of Parkinson disease in patients with autoimmune and related disorders: a nationwide epidemiological study from Sweden. Neurodegener. Dis. 10, 277–284 (2012).

    Article  CAS  PubMed  Google Scholar 

  10. Sheu, J. J., Wang, K. H., Lin, H. C. & Huang, C. C. Psoriasis is associated with an increased risk of parkinsonism: a population-based 5-year follow-up study. J. Am. Acad. Dermatol. 68, 992–999 (2013).

    Article  PubMed  Google Scholar 

  11. Chung, J., Takeshita, J., Shin, D. B., Haynes, K. & Arnold, S. E. The risk of Parkinson’s disease in patients with psoriasis: a population-based cohort study. J. Invest. Dermatol. 135, 53–55 (2015).

    Article  CAS  Google Scholar 

  12. Wu, M. C., Xu, X., Chen, S. M., Tyan, Y. S. & Chiou, J. Y. Impact of Sjogren’s syndrome on Parkinson’s disease: a nationwide case-control study. PLoS One 12, e0175836 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Amanat, M., Salehi, M. & Rezaei, N. Neurological and psychiatric disorders in psoriasis. Rev. Neurosci. 29, 805–813 (2018).

    Article  PubMed  Google Scholar 

  14. Chang, C. C., Lin, T. M., Chang, Y. S., Chen, W. S. & Sheu, J. J. Autoimmune rheumatic diseases and the risk of Parkinson disease: a nationwide population-based cohort study in Taiwan. Ann. Med. 50, 83–90 (2018).

    Article  CAS  PubMed  Google Scholar 

  15. Ju, U. H. et al. Risk of Parkinson disease in Sjogren syndrome administered ineffective immunosuppressant therapies: a nationwide population-based study. Medicine 98, e14984 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Liu, F. C. et al. Inverse association of Parkinson disease with systemic Lupus Erythematosus: a nationwide population-based study. Medicine 94, e2097 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Baizabal-Carvallo, J. F. & Jankovic, J. Stiff-person syndrome: insights into a complex autoimmune disorder. J. Neurol. Neurosurg. Psychiatry 86, 840–848 (2015).

    Article  PubMed  Google Scholar 

  18. Baizabal-Carvallo, J. F. & Jankovic, J. Autoimmune and paraneoplastic movement disorders: an update. J. Neurol. Sci. 385, 175–184 (2018).

    Article  CAS  PubMed  Google Scholar 

  19. Raj, T., Rothamel, K., Mostafavi, S., Ye, C. & Lee, M. N. Polarization of the effects of autoimmune and neurodegenerative risk alleles in leukocytes. Science 344, 519–523 (2014). This study shows overlap between autoimmune and neurodegenerative diseases in the overexpression of some risk alleles.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Rivas, M. A., Avila, B. E., Koskela, J., Huang, H. & Stevens, C. Insights into the genetic epidemiology of Crohn’s and rare diseases in the Ashkenazi Jewish population. PLoS Genet. 14, e1007329 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Holmans, P., Moskvina, V., Jones, L., Sharma, M. & Vedernikov, A. A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson’s disease. Hum. Mol. Genet. 22, 1039–1049 (2013).

    Article  CAS  PubMed  Google Scholar 

  22. Lai, S. et al. Herpes zoster correlates with increased risk of Parkinson’s disease in older people. Medicine 96, 6075 (2017).

    Article  Google Scholar 

  23. Limphaibool, N., Iwanowski, P., Holstad, M. J. V., Kobylarek, D. & Kozubski, W. Infectious etiologies of Parkinsonism: pathomechanisms and clinical implications. Front. Neurol. 10, 652 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Akhtar, R. S., Licata, J. P., Luk, K. C., Shaw, L. M. & Trojanowski, J. Q. Measurements of auto-antibodies to α-synuclein in the serum and cerebral spinal fluids of patients with Parkinson’s disease. J. Neurochem. 145, 489–503 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bach, J. P. & Falkenburger, B. H. What autoantibodies tell us about the pathogenesis of Parkinson’s disease: an editorial for ‘Measurements of auto-antibodies to α-synuclein in the serum and cerebral spinal fluids of patients with Parkinson’s disease’ on page 489. J. Neurochem. 145, 433–435 (2018).

    Article  CAS  PubMed  Google Scholar 

  26. Yanamandra, K., Gruden, M. A., Casaite, V., Meskys, R. & Forsgren, L. Alpha-synuclein reactive antibodies as diagnostic biomarkers in blood sera of Parkinson’s disease patients. PLoS One 6, e18513 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gruden, M. A., Sewell, R. D., Yanamandra, K., Davidova, T. V. & Kucheryanu, V. G. Immunoprotection against toxic biomarkers is retained during Parkinson’s disease progression. J. Neuroimmunol. 233, 221–227 (2011).

    Article  CAS  PubMed  Google Scholar 

  28. Gruden, M. A., Yanamandra, K., Kucheryanu, V. G., Bocharova, O. R. & Sherstnev, V. V. Correlation between protective immunity to α-synuclein aggregates, oxidative stress and inflammation. Neuroimmunomodulation 19, 334–342 (2012).

    Article  CAS  PubMed  Google Scholar 

  29. Besong-Agbo, D., Wolf, E., Jessen, F., Oechsner, M. & Hametner, E. Naturally occurring alpha-synuclein autoantibody levels are lower in patients with Parkinson disease. Neurology 80, 169–175 (2013).

    Article  CAS  PubMed  Google Scholar 

  30. Brudek, T., Winge, K., Folke, J., Christensen, S. & Fog, K. Autoimmune antibody decline in Parkinson’s disease and multiple system atrophy; a step towards immunotherapeutic strategies. Mol. Neurodegener. 12, 44 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Horvath, I., Iashchishyn, I. A., Forsgren, L. & Morozova-Roche, L. A. Immunochemical detection of alpha-synuclein autoantibodies in Parkinson’s disease: correlation between plasma and cerebrospinal fluid levels. ACS Chem. Neurosci. 8, 1170–1176 (2017).

    Article  CAS  PubMed  Google Scholar 

  32. Scott, K. M., Kouli, A., Yeoh, S. L., Clatworthy, M. R. & Williams-Gray, C. H. A systemic review and meta-analysis of alpha synuclein auto-antibodies in Parkinson’s disease. Front. Neurol. 1, 815 (2018). This is a review of the mechanistic basis of the development and function of autoantibodies to α-synuclein in PD.

    Article  Google Scholar 

  33. Papachroni, K. K., Ninkina, N., Papapanagiotou, A., Hadjigeorgiou, G. M. & Xiromerisiou, G. Autoantibodies to alpha-synuclein in inherited Parkinson’s disease. J. Neurochem. 101, 749–756 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Akhtar, R. S., Licata, J. P., Luk, K. C., Shaw, L. M. & Trojanowski, J. Q. Measurements of auto-antibodies to alpha-synuclein in the serum and cerebral spinal fluids of patients with Parkinson’s disease. J. Neurochem. 145, 489–503 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sulzer, D., Alcalay, R. N., Garretti, F., Cote, L. & Kanter, E. T cells from patients with Parkinson’s disease recognize α-synuclein peptides. Nature 546, 656–661 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Louveau, A. et al. CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphaticvasculature. Nat. Neurosci. 21, 1380–1391 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Brioschi, S. & Colonna, M. The CNS immune-privilege goes down the drain(age). Trends Pharmacol. Sci. 40, 1–3 (2019).

    Article  CAS  PubMed  Google Scholar 

  38. Turkheimer, F. E. et al. The methodology of TSPO imaging with positron emission tomography. Biochem. Soc. Trans. 43, 586–592 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Roussakis, A. A. & Piccini, P. Molecular imaging of neuroinflammation in idiopathic Parkinson’s disease. Int. Rev. Neurobiol. 141, 347–363 (2018). This is a review of PET studies with tracers specific for microglia and the development of astrocyte-specific PET tracers.

    Article  PubMed  Google Scholar 

  40. Gerhard, A., Pavese, N., Hotton, G., Turkheimer, F. & Es, M. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol. Dis. 21, 404–412 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Hirsch, E. C. & Hunot, S. Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol. 8, 382–397 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Terada, T., Yokokura, M., Yoshikawa, E., Futatsubashi, M. & Kono, S. Extrastriatal spreading of microglial activation in Parkinson’s disease: a positron emission tomography study. Ann. Nucl. Med. 30, 579–587 (2016).

    Article  CAS  PubMed  Google Scholar 

  43. Varnäs, K., Cselényi, Z., Jucaite, A., Halldin, C. & Svenningsson. PET imaging of [11C]PBR28 in Parkinson’s disease patients does not indicate increased binding to TSPO despite reduced dopamine transporter binding. Eur. J. Nucl. Med. Mol. Imaging 46, 367–375 (2019).

    Article  PubMed  CAS  Google Scholar 

  44. Horti, A. G., Naik, R., Foss, C. A., Minn, I. & Misheneva, V. PET imaging of microglia by targeting macrophage colony-stimulating factor 1 receptor (CSF1R). Proc. Natl Acad. Sci. USA 116, 1686–1691 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Van Weehaeghe, D., Koole, M., Schmidt, M. E., Deman, S. & Jacobs, A. H. [11C]JNJ54173717, a novel P2X7 receptor radioligand as marker for neuroinflammation: human biodistribution, dosimetry, brain kinetic modelling and quantification of brain P2X7 receptors in patients with Parkinson’s disease and healthy volunteers. Eur. J. Nucl. Med. Mol. Imaging 46, 1–14 (2019).

    Google Scholar 

  46. Misra, A., Chakrabarti, S. S. & Gambhir, I. S. New genetic players in late-onset Alzheimer’s disease: findings of genome-wide association studies. Indian. J. Med. Res. 148, 135–144 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Pluvinage, J. V. et al. CD22 blockade restores homeostatic microglial phagocytosis in ageing brains. Nature 568, 187–192 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Streit, W. J., Braak, H., Xue, Q. S. & Bechmann, I. Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease. Acta Neuropathol. 118, 475–485 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Bae, E. J., Lee, H. J., Rockenstein, E., Ho, D. H. & Park, E. B. Antibody-aided clearance of extracellular α-synuclein prevents cell-to-cell aggregate transmission. J. Neurosci. 32, 13454–13469 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Duffy, M. F., Collier, T. J., Patterson, J. R., Kemp, C. J. & Luk, K. C. Correction to: Lewy body-like alpha-synuclein inclusions trigger reactive microgliosis prior to nigral degeneration. J. Neuroinflammation 15, 169 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Doorn, K. J., Moors, T., Drukarch, B., Van de Berg., W. D. J. & Lucassen, P. J. Microglial phenotypes and toll-like receptor 2 in the substantia nigra and hippocampus of incidental Lewy disease cases and Parkinson’s disease patients. Acta Neuropathol. Commun. 7, 90 (2014).

    Google Scholar 

  52. Fellner, L., Irschick, R. & Schanda, K. Toll-like receptor 4 is required for α-synuclein dependent activation of microglia and astroglia. Glia 61, 349–360 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Harms, A. S., Delic, V., Thome, A. D., Bryant, N. & Liu, Z. α-Synuclein fibrils recruit peripheral immune cells in the rat brain prior to neurodegeneration. Acta Neuropathol. Commun. 5, 85 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Guo, H., Callaway, J. B. & Ting, J. P. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat. Med. 21, 677–687 (2015). This is a review of the role of inflammasomes and potential therapeutics to target inflammasome activity in medical conditions.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Panicker, N., Sarkar, S., Harischandra, D. S., Neal, M. & Kam, T. I. Fyn kinase regulates misfolded α-synuclein uptake and NLRP3 inflammasome activation in microglia. J. Exp. Med. 216, 1411–1430 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Yun, S. P., Kam, T. I., Panicker, N., Kim, S. & Oh, Y. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease. Nat. Med. 24, 931–938 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hinkle, J. T., Dawson, V. L. & Dawson, T. M. The A1 astrocyte paradigm: new avenues for pharmacological intervention in neurodegeneration. Mov. Disord. 34, 959–969 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C. & Bohlen, C. J. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Harms, A. S., Cao, S., Rowse, A. L., Thome, A. D. & Li, X. MHCII is required for alpha-synuclein-induced activation of microglia, CD4 T cell proliferation, and dopaminergic neurodegeneration. J. Neurosci. 33, 9592–9600 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Waisman, A. & Johann, L. Antigen-presenting cell diversity for T cell reactivation in central nervous system autoimmunity. J. Mol. Med. 96, 1279–1292 (2018).

    Article  CAS  PubMed  Google Scholar 

  61. Williams, G. P., Schonhoff, A. M., Jurkuvenaite, A., Thome, A. D. & Standaert, D. G. Targeting of the class II transactivator attenuates inflammation and neurodegeneration in an alpha-synuclein model of Parkinson’s disease. J. Neuroinflammation 15, 244 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Duffy, M. F., Collier, T. J. & Patterson, J. R. Lewy body-like alpha-synuclein inclusions trigger reactive microgliosis prior to nigral degeneration. J. Neuroinflammation 15, 129 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Lin, C. H., Chen, C. C., Chiang, H. L., Liou, J. M. & Chang, C. M. Altered gut microbiota and inflammatory cytokine responses in patients with Parkinson’s disease. J. Neuroinflammation 16, 129 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Mogi, M., Harada, M., Narabayashi, H., Inagaki, H. & Minami, M. Interleukin (IL)-1β, IL-2, IL-4, IL-6 and transforming growth factor-α levels are elevated in ventricular cerebrospinal fluid in juvenile parkinsonism and Parkinson’s disease. Neurosci. Lett. 211, 13–16 (1996).

    Article  CAS  PubMed  Google Scholar 

  65. Brodacki, B., Staszewski, J., Toczylowska, B., Kozlowska, E. & Drela, N. Serum interleukin (IL-2, IL-10, IL-6, IL-4), TNFα, and INFγ concentrations are elevated in patients with atypical and idiopathic parkinsonism. Neurosci. Lett. 441, 158–162 (2008).

    Article  CAS  PubMed  Google Scholar 

  66. Bauernfeind, F. G. et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J. Immunol. 183, 787–791 (2009).

    Article  CAS  PubMed  Google Scholar 

  67. Lee, P. P. et al. Wiskott-Aldrich syndrome protein regulates autophagy and inflammasome activity in innate immune cells. Nat. Commun. 8, 1576 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Wang, W. et al. Caspase-1 causes truncation and aggregation of the Parkinson’s disease-associated protein α-synuclein. Proc. Natl Acad. Sci. USA 113, 9587–9592 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Codolo, G., Plotegher, N., Pozzobon, T., Brucale, M. & Tessari, I. Triggering of inflammasome by aggregated alpha-synuclein, an inflammatory response in synucleinopathies. PLoS One 8, e55375 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Gordon, R., Albornoz, E. A., Christie, D. C., Langley, M. R. & Kumar, V. Inflammasome inhibition prevents alpha-synuclein pathology and dopaminergic neurodegeneration in mice. Sci. Transl. Med. 10, 465 (2018). This is a proof-of-concept study showing that the inflammasome inhibitor MCC950 abolished fibrillar α-synuclein-mediated inflammasome activation in mouse microglial cells.

    Article  CAS  Google Scholar 

  71. Lee, S. J. Origins and effects of extracellular alpha-synuclein: implications in Parkinson’s disease. J. Mol. Neurosci. 34, 17–22 (2008).

    Article  CAS  PubMed  Google Scholar 

  72. Wang, W. et al. Caspase-1 causes truncation and aggregation of the Parkinson’s disease-associated protein alpha-synuclein. Proc. Natl Acad. Sci. USA 113, 9587–9592 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Bylicky, M. A., Mueller, G. P. & Day, R. M. Mechanisms of endogenous neuroprotective effects of astrocytes in brain injury. Oxid. Med. Cell. Longev. https://doi.org/10.1155/2018/6501031 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Shao, W. et al. Suppression of neuroinflammation by astrocytic dopamine D2 receptors via alphaB-crystallin. Nature 494, 90–94 (2013).

    Article  CAS  PubMed  Google Scholar 

  75. Kempuraj, D., Selvakumar, G. P., Zaheer, S., Thangavel, R. & Ahmed, M. E. Cross-talk between glia, neurons and mast cells in neuroinflammation associated with Parkinson’s disease. J. Neuroimmune Pharmacol. 13, 100–112 (2018).

    Article  PubMed  Google Scholar 

  76. Jones, M. K., Nair, A. & Gupta, M. Mast cells in neurodegenerative disease. Front. Cell. Neurosci. 13, 171 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wijeyekoon, R. S., Kronenberg-Versteeg, D., Scott, K. M., Hayat, S. & Jones, J. L. Monocyte function in Parkinson’s disease and the impact of autologous serum on phagocytosis. Front. Neurol. 9, 870 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Harms, A. S., Thome, A. D., Yan, Z., Schonhoff, A. M. & Williams, G. P. Peripheral monocyte entry is required for alpha-synuclein induced inflammation and neurodegeneration in a model of Parkinson disease. Exp. Neurol. 300, 179–187 (2019).

    Article  CAS  Google Scholar 

  79. Cook, D. A., Kannarkat, G. T., Cintron, A. F., Butkovich, L. M. & Fraser, K. B. LRRK2 levels in immune cells are increased in Parkinson’s disease. NPJ Parkinsons Dis. 3, 11 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Stefanis, L. et al. How is alpha-synuclein cleared from the cell? J. Neurochem. 150, 577–590 (2019).

    Article  CAS  PubMed  Google Scholar 

  81. Alcalay, R. N., Levy, O. A., Waters, C. C., Fahn, S. & Ford, B. Glucocerebrosidase activity in Parkinson’s disease with and without GBA mutations. Brain 138, 2648–2658 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Atashrazm, F., Hammond, D., Perera, G., Dobson-Stone, C. & Mueller, N. Reduced glucocerebrosidase activity in monocytes from patients with Parkinson’s disease. Sci. Rep. 8, 15446 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Witoelar, A., Jansen, I. E., Wang, Y., Desikan, R. S. & Gibbs, J. R. Genome-wide pleiotropy between Parkinson disease and autoimmune diseases. JAMA Neurol. 74, 780–792 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Ahmed, I., Tamouza, R., Delord, M., Krishnamoorthy, R. & Tzourio, C. Association between Parkinson’s disease and the HLA-DRB1 locus. Mov. Disord. 27, 1104–1110 (2012).

    Article  CAS  PubMed  Google Scholar 

  85. Kustrimovic, N. et al. Parkinson’s disease patients have a complex phenotypic and functional Th1 bias: cross-sectional studies of CD4+ Th1/Th2/T17 and Treg in drug-naive and drug-treated patients. J. Neuroinflammation 15, 205 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Sommer, A., Marxreiter, F., Krach, F., Fadler, T. & Grosch, J. Th17 lymphocytes induce neuronal cell death in a human iPSC-based model of Parkinson’s disease. Cell Stem Cell 24, 1006 (2019).

    Article  CAS  PubMed  Google Scholar 

  87. Bas, J., Calopa, M., Mestre, M., Mollevi, D. G. & Cutillas, B. Lymphocyte populations in Parkinson’s disease and in rat models of parkinsonism. J. Neuroimmunol. 113, 145–152 (2001).

    Article  Google Scholar 

  88. Saunders, J. A., Estes, K. A., Kosloski, L. M., Allen, H. E. & Dempsey, K. M. CD4+ regulatory and effector/memory T cell subsets profile motor dysfunction in Parkinson’s disease. J. Neuroimmune Pharmacol. 7, 927–938 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  89. McGeer, P. L., Itagaki, S. & McGeer, E. G. Expression of the histocompatibility glycoprotein HLA-DR in neurological disease. Acta Neuropathol. 76, 550–557 (1988).

    Article  CAS  PubMed  Google Scholar 

  90. Fiszer, U., Mix, E., Fredrikson, S., Kostulas, V. & Link, H. Parkinson’s disease and immunological abnormalities: increase of HLA-DR expression on monocytes in cerebrospinal fluid and of CD45RO+ T cells in peripheral blood. Acta Neurol. Scand. 90, 160–166 (1994).

    Article  CAS  PubMed  Google Scholar 

  91. Schroder, J. B., Pawlowski, M., Meyer Zu Horste, G., Gross, C. C. & Wiendl, H. Immune cell activation in the cerebrospinal fluid of patients with Parkinson’s disease. Front. Neurol. 9, 1081 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Kortekaas, R., Leenders, K. L., van Oostrom, J. C., Vaalburg, W. & Bart, J. Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Ann. Neurol. 57, 176–179 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Ham, J. H., Yi, H., Sunwoo, M. K., Hong, J. Y. & Sohn, Y. H. Cerebral microbleeds in patients with Parkinson’s disease. J. Neurol. 261, 1628–1635 (2014).

    Article  PubMed  Google Scholar 

  94. Janelidze, S., Lindqvist, D., Francardo, V., Hall, S. & Zetterberg, H. Increased CSF biomarkers of angiogenesis in Parkinson disease. Neurology 85, 1834–1842 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Louveau, A., Smirnov, I., Keyes, T. J., Eccles, J. D. & Rouhani, S. J. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Brochard, V., Combadiere, B., Prigent, A., Laouar, Y. & Perrin, A. Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J. Clin. Invest. 119, 182–192 (2009).

    CAS  PubMed  Google Scholar 

  97. Liu, Z., Huang, Y., Cao, B. B., Qiu, Y. H. & Peng, Y. P. Th17 cells induce dopaminergic neuronal death via LFA-1/ICAM-1 interaction in a mouse model of Parkinson’s disease. Mol. Neurobiol. 54, 7762–7776 (2017).

    Article  CAS  PubMed  Google Scholar 

  98. Cebrián, C. et al. MHC-I expression renders catecholaminergic neurons susceptible to T-cell-mediated degeneration. Nat. Commun. 5, 3633 (2014).

    Article  PubMed  CAS  Google Scholar 

  99. Mogi, M. et al. Tumor necrosis factor-alpha (TNF-alpha) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients. Neurosci. Lett. 165, 208–210 (1994).

    Article  CAS  PubMed  Google Scholar 

  100. Mogi, M., Harada, M., Narabayashi, H., Inagaki, H. & Minami, M. Interleukin (IL)-1 beta, IL-2, IL-4, IL-6 and transforming growth factor-alpha levels are elevated in ventricular cerebrospinal fluid in juvenile parkinsonism and Parkinson’s disease. Neurosci. Lett. 221, 13–16 (1996).

    Article  Google Scholar 

  101. Nagatsu, T., Mogi, M., Ichinose, H. & Togari, A. Cytokines in Parkinson’s disease. J. Neural. Transm. Suppl. 58, 143–151 (2000).

    Google Scholar 

  102. Karpenko, M. N., Vasilishina, A. A., Gromova, E. A., Muruzheva, Z. M. & Bernadotte, A. Interleukin-1beta, interleukin-1 receptor antagonist, interleukin-6, interleukin-10, and tumor necrosis factor-alpha levels in CSF and serum in relation to the clinical diversity of Parkinson’s disease. Cell. Immunol. 327, 77–82 (2018).

    Article  CAS  PubMed  Google Scholar 

  103. Brodacki, B., Staszewski, J., Toczylowska, B., Kozlowska, E. & Drela, N. Serum interleukin (IL-2, IL-10, IL-6, IL-4), TNFalpha, and INFgamma concentrations are elevated in patients with atypical and idiopathic parkinsonism. Neurosci. Lett. 441, 158–162 (2008).

    Article  CAS  PubMed  Google Scholar 

  104. Reale, M. et al. Peripheral cytokines profile in Parkinson’s disease. Brain Behav. Immun. 23, 55–63 (2009).

    Article  CAS  PubMed  Google Scholar 

  105. Chen, H., O’Reilly, E. J., Schwarzschild, M. A. & Ascherio, A. Peripheral inflammatory biomarkers and risk of Parkinson’s disease. Am. J. Epidemiol. 167, 90–95 (2008).

    Article  PubMed  Google Scholar 

  106. Lian, T. H., Guo, P., Zuo, L. J., Hu, Y. & Yu, S. Y. Tremor-dominant in Parkinson disease: the relevance to iron metabolism and inflammation. Front. Neurosci. 13, 255 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Dufek, M., Rektorova, I., Thon, V., Lokaj, J. & Rektor, I. Interleukin-6 may contribute to mortality in Parkinsons disease patients: a 4-year prospective study. Parkinsons Dis. 2015, 898192 (2015).

    PubMed  PubMed Central  Google Scholar 

  108. Sathe, K., Maetzler, W., Lang, J. D., Mounsey, R. B. & Fleckenstein, C. S100B is increased in Parkinson’s disease and ablation protects against MPTP-induced toxicity through the RAGE and TNF-alpha pathway. Brain 135, 3336–3347 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Rydbirk, R., Elfving, B., Andersen, M. D., Langbol, M. A. & Folke, J. Cytokine profiling in the prefrontal cortex of Parkinson’s disease and multiple system atrophy patients. Neurobiol. Dis. 106, 269–278 (2017).

    Article  CAS  PubMed  Google Scholar 

  110. Cardona, A. E., Li, M., Liu, L., Savarin, C. & Ransohoff, R. M. Chemokines in and out of the central nervous system: much more than chemotaxis and inflammation. J. Leukoc. Biol. 84, 587–594 (2008).

    Article  CAS  PubMed  Google Scholar 

  111. Shimoji, M., Pagan, F., Healton, E. B. & Mocchetti, I. CXCR4 and CXCL12 expression is increased in the nigro-striatal system of Parkinson’s disease. Neurotox. Res. 16, 318–328 (2009).

    Article  CAS  PubMed  Google Scholar 

  112. Bagheri, V., Khorramdelazad, H., Hassanshahi, G., Moghadam-Ahmadi, A. & Vakilian, A. CXCL12 and CXCR4 in the peripheral blood of patients with Parkinson’s disease. Neuroimmunomodulation 25, 201–205 (2018).

    Article  CAS  PubMed  Google Scholar 

  113. Ross, O. A., O’Neill, C., Rea, I. M., Lynch, T. & Gosal, D. Functional promoter region polymorphism of the proinflammatory chemokine IL-8 gene associates with Parkinson’s disease in the Irish. Hum. Immunol. 65, 340–346 (2004).

    Article  CAS  PubMed  Google Scholar 

  114. Qiu, X., Xiao, Y., Wu, J., Gan, L. & Huang, Y. C-reactive protein and risk of Parkinson’s disease: a systematic review and meta-analysis. Front. Neurol. 10, 384 (2019). This is a meta-analysis of data on the association between CRP and risk of PD.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Lindqvist, D., Hall, S., Surova, Y., Nielsen, H. M. & Janelidze, S. Cerebrospinal fluid inflammatory markers in Parkinson’s disease-associations with depression, fatigue, and cognitive impairment. Brain Behav. Immun. 33, 183–189 (2013).

    Article  CAS  PubMed  Google Scholar 

  116. Hall, S., Janelidze, S., Surova, Y., Widner, H. & Zetterberg, H. Cerebrospinal fluid concentrations of inflammatory markers in Parkinson’s disease and atypical parkinsonian disorders. Sci. Rep. 8, 13276 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Sanjari Moghaddam, H., Valitabar, Z., Ashraf-Ganjouei, A., Mojtahed Zadeh, M. & Ghazi Sherbaf, F. Cerebrospinal fluid C-reactive protein in Parkinson’s disease: associations with motor and non-motor symptoms. Neuromolecular Med. 20, 376–385 (2018).

    Article  CAS  PubMed  Google Scholar 

  118. Yamada, T., McGeer, P. L. & McGeer, E. G. Lewy bodies in Parkinson’s disease are recognized by antibodies to complement proteins. Acta Neuropathol. 84, 100–104 (1992).

    Article  CAS  PubMed  Google Scholar 

  119. Double, K. L., Rowe, D. B., Carew-Jones, F. M., Hayes, M. & Chan, D. K. Anti-melanin antibodies are increased in sera in Parkinson’s disease. Exp. Neurol. 217, 297–301 (2009).

    Article  CAS  PubMed  Google Scholar 

  120. Gelders, G., Baekelandt, V. & Van der Perren, A. Linking neuroinflammation and neurodegeneration in Parkinson’s disease. J. Immunol. Res. 2018, 4784628 (2018).

    Article  CAS  Google Scholar 

  121. Klingelhoefer, L. & Reichmann, H. Pathogenesis of Parkinson disease–the gut-brain axis and environmental factors. Nat. Rev. Neurol. 11, 625–636 (2015).

    Article  CAS  PubMed  Google Scholar 

  122. Chapelet, G., Leclair-Visonneau, L., Clairembault, T., Neunlist, M. & Derkinderen, P. Can the gut be the missing piece in uncovering PD pathogenesis? Parkinsonism Relat. Disord. 59, 26–31 (2019).

    Article  PubMed  Google Scholar 

  123. Braak, H., Rüb, U., Gai, W. P. & Del Tredici, K. Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J. Neural. Transm. 110, 517–536 (2003).

    Article  CAS  PubMed  Google Scholar 

  124. Hawkes, C. H., Del Tredici, K. & Braak, H. Parkinson’s disease: a dual-hit hypothesis. Neuropathol. Appl. Neurobiol. 33, 599–614 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Kim, S., Kwon, S. H., Kam, T. I., Panicker, N. & Karuppagounder, S. S. Transneuronal propagation of pathologic α-synuclein from the gut to the brain models Parkinson’s disease. Neuron 103, 1–15 (2019).

    Article  CAS  Google Scholar 

  126. Svensson, E., Horvath-Puho, E., Thomsen, R. W., Djurhuus, J. C. & Pedersen, L. Vagotomy and subsequent risk of Parkinson’s disease. Ann. Neurol. 78, 522–529 (2015).

    Article  PubMed  Google Scholar 

  127. Parashar, A. & Udayabanu, M. Gut microbiota: implications in Parkinson’s disease. Parkinsonism Relat. Disord. 38, 1–7 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Rietdijk, C. D., Perez-Pardo, P., Garssen, J., van Wezel, R. J. & Kraneveld, A. D. Exploring Braak’s hypothesis of Parkinson’s disease. Front. Neurol. 8, 37 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Su, A., Gandhy, R., Barlow, C. & Triadafilopoulos, G. A practical review of gastrointestinal manifestations in Parkinson’s disease. Parkinsonism Relat. Disord. 39, 17–26 (2017).

    Article  PubMed  Google Scholar 

  130. Devos, D., Lebouvier, T., Lardeux, B., Biraud, M. & Rouaud, T. Colonic inflammation in Parkinson’s disease. Neurobiol. Dis. 50, 42–48 (2013).

    Article  CAS  PubMed  Google Scholar 

  131. Lin, J. C., Lin, C. S., Hsu, C. W., Lin, C. L. & Kao, C. H. Association between Parkinson’s disease and inflammatory bowel disease: a nationwide Taiwanese retrospective cohort study. Inflamm. Bowel Dis. 22, 1049–1055 (2016).

    Article  PubMed  Google Scholar 

  132. Peter, I., Dubinsky, M., Bressman, S., Park, A. & Lu, C. Anti-tumor necrosis factor therapy and incidence of Parkinson disease among patients with inflammatory bowel disease. JAMA Neurol. 75, 939–946 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Nerius, M., Doblhammer, G. & Tamguney, G. GI infections are associated with an increased risk of Parkinson’s disease. Gut https://doi.org/10.1136/gutjnl-2019-318822 (2019).

    Article  PubMed  Google Scholar 

  134. Dardiotis, E., Tsouris, Z., Mentis, A. A., Siokas, V. & Michalopoulou, A. H. pylori and Parkinson’s disease: meta-analyses including clinical severity. Clin. Neurol. Neurosurg. 175, 16–24 (2018).

    Article  PubMed  Google Scholar 

  135. McGee, D. J., Lu, X. H. & Disbrow, E. A. Stomaching the possibility of a pathogenic role for Helicobacter pylori in Parkinson’s disease. J. Parkinsons Dis. 8, 367–374 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Sampson, T. R., Debelius, J. W., Thron, T., Janssen, S. & Shastri, G. G. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 167, 1469–1480 (2016). This study shows that colonization of mice that overexpress α-synuclein with microorganisms from patients with PD affected motor function.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Choi, J. G., Kim, N., Ju, I. G., Eo, H. & Lim, S. M. Oral administration of Proteus mirabilis damages dopaminergic neurons and motor functions in mice. Sci. Rep. 8, 1275 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Perez-Pardo, P., Dodiya, H. B., Engen, P. A., Forsyth, C. B. & Huschens, A. M. Role of TLR4 in the gut-brain axis in Parkinson’s disease: a translational study from men to mice. Gut 68, 829–843 (2019).

    Article  CAS  PubMed  Google Scholar 

  139. Barichella, M., Pacchetti, C., Bolliri, C., Cassani, E. & Iorio, L. Probiotics and prebiotic fiber for constipation associated with Parkinson disease: an RCT. Neurology 87, 1274–1280 (2016).

    Article  CAS  PubMed  Google Scholar 

  140. Magistrelli, L., Amoruso, A., Mogna, L., Graziano, T. & Cantello, R. Probiotics may have beneficial effects in Parkinson’s disease: in vitro evidence. Front. Immunol. 10, 969 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Buhat, D. M. & Tan, E. K. Genetic testing of LRRK2 in Parkinson’s disease: is there a clinical role? Parkinsonism Relat. Disord. 20, 54–56 (2014).

    Article  Google Scholar 

  142. Foo, J. N., Chung, S. J., Tan, L. C., Liany, H. & Ryu, H. S. Linking a genome-wide association study signal to a LRRK2 coding variant in Parkinson’s disease. Mov. Disord. 31, 484–487 (2016).

    Article  CAS  PubMed  Google Scholar 

  143. Hui, K. Y., Fernandez-Hernandez, H., Hu, J., Schaffner, A. & Pankratz, N. Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease. Sci. Transl. Med. 10, eaai7795 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Polymeropoulos, M. H., Lavedan, C., Leroy, E., Ide, S. E. & Dehejia, A. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276, 2045–2047 (1997).

    Article  CAS  PubMed  Google Scholar 

  145. Tan, E. K. & Skipper, L. M. Pathogenic mutations in Parkinson disease. Hum. Mutat. 28, 641–653 (2007).

    Article  CAS  PubMed  Google Scholar 

  146. Deng, H., Wang, P. & Jankovic, J. The genetics of Parkinson disease. Ageing Res. Rev. 42, 72–85 (2018).

    Article  CAS  PubMed  Google Scholar 

  147. Prigent, A., Lionnet, A., Durieu, E., Chapelet, G. & Bourreille, A. Enteric alpha-synuclein expression is increased in Crohn’s disease. Acta Neuropathol. 137, 359–361 (2019).

    Article  PubMed  Google Scholar 

  148. Liu, Z. et al. LRRK2 phosphorylates membrane-bound Rabs and is activated by GTP-bound Rab7L1 to promote recruitment to the trans-Golgi network. Hum. Mol. Genet. 27, 385–395 (2018).

    Article  CAS  PubMed  Google Scholar 

  149. Mir, R., Tonelli, F., Lis, P., Macartney, T. & Polinski, N. K. The Parkinson’s disease VPS35[D620N] mutation enhances LRRK2-mediated Rab protein phosphorylation in mouse and human. Biochemical J. 475, 1861–1883 (2018).

    Article  CAS  Google Scholar 

  150. Purlyte, E., Dhekne, H. S., Sarhan, A. R., Gomez, R. & Lis, P. Rab29 activation of the Parkinson’s disease-associated LRRK2 kinase. EMBO J. 37, 1–18 (2018).

    Article  CAS  PubMed  Google Scholar 

  151. Prashar, A., Schnettger, L., Bernard, E. M. & Gutierrez, M. G. Rab GTPases in Immunity and Inflammation. Front. Cell. Infect. Microbiol. 7, 435 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Matheoud, D., Sugiura, A., Bellemare-Pelletier, A., Laplante, A. & Rondeau, C. Parkinson’s disease-related proteins PINK1 and Parkin repress mitochondrial antigen presentation. Cell 166, 314–327 (2016).

    Article  CAS  PubMed  Google Scholar 

  153. International Parkinson’s Disease Genomics Consortium (IPDGC) & Wellcome Trust Case Control Consortium 2 (WTCCC2). A two-stage meta-analysis identifies several new loci for Parkinson’s disease. PLoS Genet. 7, e1002142 (2011).

    Article  CAS  Google Scholar 

  154. Foo, J. N., Liu, J. J. & Tan, E. K. Whole-genome and whole exome sequencing in neurological diseases. Nat. Rev. Neurol. 8, 508–517 (2012).

    Article  CAS  PubMed  Google Scholar 

  155. Foo, J. N., Tan, L. C., Irwan, I. D., Au, W. L. & Low, H. Q. Genome-wide association study of Parkinson’s disease in East Asians. Hum. Mol. Genet. 26, 226–232 (2017).

    CAS  PubMed  Google Scholar 

  156. Blauwendraat, C., Heilbron, K., Vallerga, C. L., Bandres-Ciga, S. & von Coelln, R. Parkinson’s disease age at onset genome-wide association study: defining heritability, genetic loci, and alpha-synuclein mechanisms. Mov. Disord. 34, 866–874 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Aliseychik, M. P., Andreevam, T. V. & Rogaev, E. I. Immunogenetic factors of neurodegenerative diseases: the role of HLA class II. Biochemistry (Mosc) 83, 1104–1116 (2018).

    Article  CAS  Google Scholar 

  158. Hamza, T. H., Zabetian, C. P., Tenesa, A., Laederach, A. & Montimurro, J. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat. Genet. 42, 781–785 (2010). This is the first genome-wide association study to identify the association between the HLA locus and the risk of PD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Nalls, M. A., Pankratz, N., Lill, C. M., Do, C. B. & Hernandez, D. G. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat. Genet. 46, 989–993 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Zhao, Y., Gopalai, A. A., Ahmad-Annuar, A., Teng, E. W. & Prakash, K. M. Association of HLA locus variant in Parkinson’s disease. Clin. Genet. 84, 501–504 (2013).

    Article  CAS  PubMed  Google Scholar 

  161. Wissemann, W. T., Hill-Burns, E. M., Zabetian, C. P., Factor, S. A. & Patsopoulos, N. Association of Parkinson disease with structural and regulatory variants in the HLA region. Am. J. Hum. Genet. 93, 984–993 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Hollenbach, J. A., Norman, P. J., Creary, L. E., Damotte, V. & Montero-Martin, G. A specific amino acid motif of HLA-DRB1 mediates risk and interacts with smoking history in Parkinson’s disease. Proc. Natl Acad. Sci. USA 116, 7419–7424 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Pierce, S. & Coetzee, G. A. Parkinson’s disease-associated genetic variation is linked to quantitative expression of inflammatory genes. PLoS One 12, e0175882 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  164. Savitt, D. & Jankovic, J. Targeting α-Synuclein in Parkinson’s disease: progress towards the development of disease-modifying therapeutics. Drugs 79, 797–810 (2019). This is an up-to-date review of clinical immunotherapy studies targeting α-synuclein and other targets in PD.

    Article  CAS  PubMed  Google Scholar 

  165. Liu, Y., Xie, X., Xia, L. P., Lv, H. & Lou, F. Peripheral immune tolerance alleviates the intracranial lipopolysaccharide injection-induced neuroinflammation and protects the dopaminergic neurons from neuroinflammation-related neurotoxicity. J. Neuroinflammation 14, 223 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  166. Huang, Y., Liu, Z., Cao, B. B., Qiu, Y. H. & Peng, Y. P. Treg cells protect dopaminergic neurons against MPP+ neurotoxicity via CD47-SIRPA interaction. Cell. Physiol. Biochem. 41, 1240–1254 (2017).

    Article  CAS  PubMed  Google Scholar 

  167. Herrero, M. T., Estrada, C., Maatouk, L. & Vyas, S. Inflammation in Parkinson’s disease: role of glucocorticoids. Front. Neuroanatomy 9, 32 (2015).

    Article  CAS  Google Scholar 

  168. Ren, L., Yi, J., Yang, J., Li, P. & Cheng, X. Nonsteroidal anti-inflammatory drugs use and risk of Parkinson disease: a dose-response meta-analysis. Medicine 97, e12172 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Poly, T. N., Islam, M. M. R., Yang, H. C. & Li, Y. J. Non-steroidal anti-inflammatory drugs and risk of Parkinson’s disease in the elderly population: a meta-analysis. Eur. J. Clin. Pharmacol. 75, 99–108 (2019). This is an up-to-date meta-analysis of the use of NSAIDs and the risk of PD.

    Article  PubMed  Google Scholar 

  170. Racette, B. A., Gross, A., Vouri, S. M., Camacho-Soto, A. & Willis, A. W. Immunosuppressants and risk of Parkinson disease. Ann. Clin. Transl. Neurol. 5, 870–875 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Olesen, M. N., Christiansen, J. R., Petersen, S. V., Jensen, P. H. & Paslawski, W. CD4 T cells react to local increase of alpha-synuclein in a pathology-associated variant-dependent manner and modify brain microglia in absence of brain pathology. Heliyon 4, e00513 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  172. Huang, Y. R., Xie, X. X., Ji, M., Yu, X. L. & Zhu, J. Naturally occurring autoantibodies against alpha-synuclein rescues memory and motor deficits and attenuates alpha-synuclein pathology in mouse model of Parkinson’s disease. Neurobiol. Dis. 124, 202–217 (2019).

    Article  CAS  PubMed  Google Scholar 

  173. Carta, A. R. & Pisanu, A. Modulating microglia activity with PPAR-γ agonists: a promising therapy for Parkinson’s disease? Neurotox. Res. 23, 112–123 (2012).

    Article  PubMed  CAS  Google Scholar 

  174. Simuni, T., Kieburtz, K., Tilley, B., Elm, J. J. & Ravina, B. Pioglitazone in early Parkinson’s disease: a phase 2, multicentre, double-blind, randomised trial. Lancet Neurol. 14, 795–803 (2015).

    Article  CAS  Google Scholar 

  175. Machado, M. M. F., Bassani, T. B., Cóppola-Segovia, V., Moura, E. L. R. & Zanata, S. M. PPAR-y agonist pioglitazone reduces microglial proliferation and NF-kB activation in the substantia nigra in the 6-hydroxydopamine model of Parkinson’s disease. Pharmacol. Rep. 71, 556–564 (2018).

    Article  PubMed  CAS  Google Scholar 

  176. Tamburrino, A., Churchill, M. J., Wan, O., Colino-Sanguino, Y. & Ippolito, R. Cyclosporin promotes neurorestoration and cell replacement therapy in pre-clinical models of Parkinson’s disease. Acta Neuropathol. Commun. 14, 84 (2015).

    Article  CAS  Google Scholar 

  177. Van der Perren, A., Macchi, F., Toelen, J., Carlon, M. S. & Maris, M. FK506 reduces neuroinflammation and dopaminergic neurodegeration in an a-synuclein-based rat model for Parkinson’s disease. Neurobiol. Aging 36, 1559–1568 (2015).

    Article  PubMed  CAS  Google Scholar 

  178. McGinnis, G. J. et al. Neuroinflammatory and cognitive consequences of combined radiation and immunotherapy in a novel preclinical model. Oncotarget 8, 9155–9173 (2017).

    Article  PubMed  Google Scholar 

  179. Prots, I. & Winner, B. Th17 cells: a promising therapeutic target for Parkinson’s disease? Expert. Opin. Ther. Targets 23, 309–314 (2019).

    Article  CAS  PubMed  Google Scholar 

  180. Elgueta, D. et al. Dopamine receptor D3 expression is altered in CD4+ T-cells from Parkinson’s disease patients and its pharmacologic inhibition attenuates the motor impairment in a mouse model. Front. Immunol. 10, 981 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Czaja, A. J. Immune inhibitory proteins and their pathogenic and therapeutic implications in autoimmunity and autoimmune hepatitis. Autoimmunity 52, 144–160 (2019).

    Article  CAS  PubMed  Google Scholar 

  182. Sun, C., Wei, L., Luo, F., Li, Y. & Li, J. HLA-DRB1 alleles are associated with the susceptibility to sporadic Parkinson’s disease in Chinese Han population. PLoS One 7, e48594 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Saiki, M., Baker, A., Williams-Gray, C. H., Foltynie, T. & Goodman, R. S. Association of the human leucocyte antigen region with susceptibility to Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 81, 890–891 (2010).

    Article  PubMed  Google Scholar 

  184. Badres-Ciga, S., Price, T. R., Barrero, F. J., Escamilla-Sevilla, F. & Pelegrina, J. Genome-wide assessment of Parkinson’s disease in a southern Spanish population. Neurobiol. Aging 45, 213.e3–213.e9 (2016).

    Article  Google Scholar 

  185. Chang, K. H., Wu, Y. R., Chen, Y. C., Fung, H. C. & Lee-Chen, G. J. STK39, but not BST1, HLA-DQB1, and SPPL2B polymorphism, is associated with Han-Chinese Parkinson’s disease in Taiwan. Medicine 94, e1690 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Jamshidi, J., Movafagh, A., Emamalizadeh, B., Zare Bidoki, A. & Manafi, A. HLA-DRA is associated with Parkinson’s disease in Iranian population. Int. J. Immunogenet. 41, 508–511 (2014).

    Article  CAS  PubMed  Google Scholar 

  187. Zhu, R. L., Lu, X. C., Tang, L. J., Huang, B. S. & Yu, W. Association between HLA rs3129882 polymorphism and Parkinson’s disease: a meta-analysis. Eur. Rev. Med. Pharmacol. Sci. 19, 423–432 (2015).

    PubMed  Google Scholar 

  188. Mo, M. S., Xiao, Y. S., Wu, Z. H., Sun, C. C. & Zhang, L. M. Association analysis of HLA-DRA in Chinese patients with sporadic Parkinson’s disease. Int. J. Physiol. Pahtophysiol. Pharmacol. 7, 185–194 (2015).

    CAS  Google Scholar 

  189. Ma, Z. G., Liu, T. W. & Bo, Y. L. HLA-DRA rs3129882A/G poplymorphism was not a risk factor for Parkinson’s disease in Chinese-based populations: a meta-analysis. Int. J. Neurosci. 125, 241–246 (2015).

    Article  CAS  PubMed  Google Scholar 

  190. Schneeberger, A., Mandler, M., Mattner, F. & Schmidt, W. Vaccination for Parkinson’s disease. Parkinsonism Relat. Disord. https://doi.org/10.1016/S1353-8020(11)70006-2 (2012).

    Article  PubMed  Google Scholar 

  191. Braczynski, A. K., Schulz, J. B. & Bach, J. P. Vaccination strategies in tauopathies and synucleinopathies. J. Neurochem. 143, 467–488 (2017).

    Article  CAS  PubMed  Google Scholar 

  192. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02216188 (2015).

  193. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01885494 (2015).

  194. Sardi, S. P., Cedarbaum, J. M. & Brudin, P. Targeted therapies for Parkinson’s disease: from genetics to the clinic. Mov. Disord. 33, 684–696 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  195. Zella, S. M. A., Metzdorf, J., Ciftci, E., Ostendorf, F. & Muhlack, S. Emerging immunotherapies for Parkinson disease. Neurol. Ther. 8, 29–44 (2019).

    Article  PubMed  Google Scholar 

  196. No authors listed. ABBV-0805 — Parkinson’s disease. Bioarctic https://www.bioarctic.se/en/ban0805-parkinsons-disease-2498/ (2019).

  197. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02095171 (2015).

  198. Jankovic, J., Goodman, I., Safirstein, B., Marmon, T. K. & Schenk, D. B. Safety and tolerability of multiple ascending doses of PRX002/RG7935, an anti-α-Synuclein monoclonal antibody, in patients with Parkinson disease: a randomized clinical trial. JAMA Neurol. 75, 1206–1214 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  199. Schenk, D. B., Koller, M., Ness, D. K., Griffith, S. G. & Grundman, M. First-in-human assessment of PRX002, an anti-alpha-synuclein monoclonal antibody, in healthy volunteers. Mov. Disord. 32, 211–218 (2017).

    Article  CAS  PubMed  Google Scholar 

  200. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03100149 (2019).

  201. Brys, M., Fanning, L., Hung, S., Ellenbogen, A. & Penner, N. Randomized phase I clinical trial of anti-alpha-synuclein antibody BIIB054. Mov. Disord. 34, 1154–1163 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03318523 (2020).

  203. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01882010 (2016).

  204. Roser, A. E., Tonges, L. & Lingor, P. Modulation of microglial activity by Rho-kinase (ROCK) inhibition as therapeutic strategy in Parkinson’s disease and amyotrophic lateral sclerosis. Front. Aging Neurosci. 4, 94 (2017).

    Google Scholar 

  205. Martinez, B. & Peplow, P. V. Neuroprotection by immunomodulatory agents in animal models of Parkinson’s disease. Neural Regen. Res. 13, 1493–1506 (2018). This is a detailed review of the studies on immunomodulatory agents in experimental models of PD.

    Article  PubMed  PubMed Central  Google Scholar 

  206. Chandra, G., Rangasamy, S. B., Roy, A., Kordower, J. H. & Pahan, K. Neutralization of RANTES and eotaxin prevents the loss of dopaminergic neurons in a mouse model of Parkinson disease. J. Biol. Chem. 291, 15267–15281 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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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, EK., Chao, YX., 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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