B lymphocyte responses in Parkinson's disease and their possible significance in disease progression.
Inflammation contributes to Parkinson's disease pathogenesis. We hypothesized that B lymphocytes are involved in Parkinson's disease progression. We measured antibodies to alpha-synuclein and tau in serum from patients with rapid eye movement sleep behaviour disorder (n = 79), early Parkinson's disease (n = 50) and matched controls (n = 50). Rapid eye movement sleep behaviour disorder cases were stratified by risk of progression to Parkinson's disease (low risk = 30, high risk = 49). We also measured B-cell activating factor of the tumour necrosis factor receptor family, C-reactive protein and total immunoglobulin G. We found elevated levels of antibodies to alpha-synuclein fibrils in rapid eye movement sleep behaviour disorder patients at high risk of Parkinson's disease conversion (ANOVA, P < 0.001) and lower S129D peptide-specific antibodies in those at low risk (ANOVA, P < 0.001). An early humoral response to alpha-synuclein is therefore detectable prior to the development of Parkinson's disease. Peripheral B lymphocyte phenotyping using flow cytometry in early Parkinson's disease patients and matched controls (n = 41 per group) revealed reduced B cells in Parkinson's disease, particularly in those at higher risk of developing an early dementia [t(3) = 2.87, P = 0.01]. Patients with a greater proportion of regulatory B cells had better motor scores [F(4,24) = 3.612, P = 0.019], suggesting they have a protective role in Parkinson's disease. In contrast, B cells isolated from Parkinson's disease patients at higher risk of dementia had greater cytokine (interleukin 6 and interleukin 10) responses following in vitro stimulation. We assessed peripheral blood lymphocytes in alpha-synuclein transgenic mouse models of Parkinson's disease: they also had reduced B cells, suggesting this is related to alpha-synuclein pathology. In a toxin-based mouse model of Parkinson's disease, B-cell deficiency or depletion resulted in worse pathological and behavioural outcomes, supporting the conclusion that B cells play an early protective role in dopaminergic cell loss. In conclusion, we found changes in the B-cell compartment associated with risk of disease progression in rapid eye movement sleep behaviour disorder (higher alpha-synuclein antibodies) and early Parkinson's disease (lower levels of B lymphocytes that were more reactive to stimulation). Regulatory B cells play a protective role in a mouse model, potentially by attenuating inflammation and dopaminergic cell loss. B cells are therefore likely to be involved in the pathogenesis of Parkinson's disease, albeit in a complex way, and thus warrant consideration as a therapeutic target.
Acknowledgements: Thanks to Wolfgang Oertel for being co-PI on the original MJFF grant application. The samples we used in the end came from Oxford. We wish to thank Anna Petrunkina Harrison for her advice and support in flow cytometry and the NIHR BioResource centre and staff for their contribution and the National Institute for Health Research and NHS Blood and Trasplant. We acknowledge the support of the Cambridge NIHR BRC Cell Phenotyping hub and the Core Biochemical Assay Laboratory at Cambridge University Hospitals. We also carried out flow cytometry at the Laboratory for Molecular Biology (LMB) flow cytometry hub. We would also like to thank the staff in the Phenomics research facility at the University of Cambridge particularly Emma Blanchard, Kate Tansley and Martin Rice. Josef Priller (University of Edinburgh) and Ziad Mallat (University of Cambridge) for examining KMS PhD thesis and providing feedback that helped to improve this manuscript. Lindsey Wilkins and Molly O’Reilly provided administrative support and data entry for the clinical studies. Maria Spillantini and Michal Wegrinowicz provided the MI-2 mice. William Kuan in the Barker Lab prepared the alpha-synuclein fibrils used in the antibody and stimulation experiments. We are grateful to Biogen for the kind gift of the mouse anti-CD20 antibody used in the experiments.
Funder: Research Councils UK/UK Research Innovation Fellowship
Funder: Cambridge Centre for Parkinson-Plus; doi: https://doi.org/10.13039/501100019544
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Michael J. Fox Foundation (MJFF) (14811)
Wellcome Trust (106565/Z/14/Z)
National Institute for Health and Care Research (IS-BRC-1215-20014)