Beesley, Claire Frances;
(2025)
Investigating Transitional B Cells in Health and Systemic Sclerosis.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Transitional B cells are a distinct population of B cells that have recently migrated from the bone marrow to the periphery. In the fibrotic and severe autoimmune disease systemic sclerosis (SSc), there are elevated numbers of autoreactive transitional B cells compared with healthy controls (HC). This suggests that B cell tolerance is compromised in disease, although mechanisms that underpin autoantibody production in SSc remain incompletely understood. Hence, this thesis aims to characterise transitional B cells in health and disease with the hope of improving treatment strategies for SSc in the future. Much of this work focuses on a 5’ single-cell RNA-sequencing dataset derived from sorted transitional B cells from four healthy controls (HC) and four treatment-naive anti-topoisomerase I (ATA) seropositive SSc patients. Analysis revealed four distinct transitional subsets: T1, T2, CD27+ and marginal zone precursors (MZP). Notably, T1 B cells were increased two-fold in the SSc patients. Additionally, pro-survival genes such as TCL1A and S100A4 were increased in SSc. This was corroborated through analysis of a second single-cell dataset, including anti-RNA polymerase III (ARA) seropositive patients. Furthermore, the transitional B cell repertoire is distinct in SSc with differences in CDR3 properties, such as a trend towards longer CDR3 regions, as well as overrepresentation of immunoglobulin genes, such as IGKV3-20 and IGHV4-39. IgD+ B cells are also elevated, possibly reflecting increased transitional B cell activation in disease. Finally, this study demonstrated that the kappa/lambda ratio was elevated in SSc with increased kappa+ transitional B cells. This may indicate that receptor editing is not occurring sufficiently within the bone marrow. Overall, this thesis has examined transitional B cell subsets in SSc and identified an AKT-driven gene signature which may be important for allowing autoreactive B cell survival and proliferation. This work has also highlighted B cell repertoire features which may be associated with autoimmunity in SSc and could be targeted in the future.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Investigating Transitional B Cells in Health and Systemic Sclerosis |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2025. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10204432 |
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