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Title: Exploring neuro-immune interactions in neurodegeneration : the role of B lymphocytes in Parkinson's disease
Author: Scott, Kirsten Maurine
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2020
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Background: Inflammation in the brain (as defined by microglial activation) and in the periphery (serum cytokines) is well described in Parkinson's disease (PD). I hypothesised that immune factors play a role in determining disease progression, focusing on the contribution of B lymphocytes. These cells play a number of roles including antibody production, maintenance of subcapsular sinus macrophages, antigen presentation and regulation of T cell activity. Methods: I phenotyped peripheral blood B lymphocytes in 3 clinical cohorts and cerebrospinal fluid (CSF) B lymphocytes in a subgroup of patients using flow cytometry (79 PD patients, 65 controls in total). The patients were risk stratified by their risk of progression to dementia. Controls were age and gender matched. I also performed a systematic review and meta-analysis of the literature on alpha-synuclein antibodies and then designed an assay to measure antibodies to alpha synuclein species and peptides. I piloted the assay in 39 patients and controls. I also used the 6-OHDA lesioned mouse model of PD and examined disease course by testing motor capacity in mice lacking B lymphocytes (MT), in mice depleted of B cells using an anti-CD20 monoclonal antibody and in wild type controls (C57bl/5). Dopaminergic cell counts and staining were compared. I examined the phenotype and distribution of B lymphocytes in alpha synuclein transgenic models of Parkinson's disease using flow cytometry. Results: B lymphocytes were decreased in PD patients at high risk of progressing to early dementia compared to matched controls. A higher proportion of IL10 producing regulatory B lymphocytes was associated with better outcomes. Alpha synuclein transgenic mice also had reduced circulating B lymphocytes. Mice with a genetically driven B lymphocyte deficiency developed a worse motor phenotype and showed more extensive loss of midbrain dopaminergic cells than wild type controls. Meningeal and skull B lymphocytes had a different phenotype to circulating B lymphocytes but were not different between controls and transgenic animals. Conclusions: My data suggest that B cells play a protective role in PD, potentially via regulation of immune responses to aberrant forms of alpha synuclein or cell death. Modulating this compartment by increasing IL10 producing B lymphocytes would be a reasonable therapeutic strategy. Exploring the function and behaviour of meningeal B lymphocytes in health and disease may reveal further therapeutic targets.
Supervisor: Clathworthy, Menna Ruth ; Barker, Roger Alistair ; Williams-Gray, Caroline Helen Sponsor: Wellcome Trust ; Michael J Fox Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Parkinson's disease ; B lymphocytes ; Alpha synuclein antibodies