De Gruijter, Nina Maria;
(2023)
Contribution of GPR183-expressing B cells to the pathogenesis of
juvenile-onset rheumatic disease.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Extrafollicularly derived B cells are an important reservoir for autoantibody-producing cells in multiple autoimmune rheumatic diseases (ARDs), in particular in systemic lupus erythematosus (SLE). The exact mechanisms controlling the differentiation of extrafollicular B cells in ARDs is unclear. Previous studies have shown that oxidised cholesterol or ‘oxysterol’ receptor GPR183 is critical in positioning B cells within the extrafollicular regions of secondary lymphoid tissue, and for early differentiation of plasmablasts. The contribution of this pathway to SLE pathogenesis is unclear. In this thesis, I show that GPR183-expressing B cells in human peripheral blood (PB) have a memory phenotype, co-expressing CD27, and that patients with juvenile-onset SLE – who have a more severe phenotype than adult- onset SLE – have a reduction in GPR183+CD27+ B cells compared to healthy controls (HCs). In-depth analysis demonstrated that JSLE GPR183+CD27+ B cells have an atypical, activated phenotype, with reduced chemokine receptor expression, and that there is a concomitant increase in extrafollicularly derived CD11c+CD27-IgD- DN2 B cells compared to HC. Using the parent into F1 model of experimental lupus, I also show that induction of disease leads to an increase in Cyp7B1, the enzyme responsible for producing GPR183’s main ligand 7α,25-dihydroxycholesterol, and that inhibiting GPR183- oxysterol interactions using a GPR183 antagonist suppressed the severity of experimental lupus and reduced the frequency of plasmablasts. Mimicking the sex bias in human lupus, these effects were only seen in female but not male mice. Immunophenotyping of GPR183+CD27+ B cells in the PB of two other ARDs, JIA and JDM, further showed that my results were specific to JSLE as the phenotypic and transcriptional profile of these cells were distinct in each juvenile- onset ARD. Blocking aberrant GPR183-oxysterol interactions, for example with medication or dietary changes, may provide a novel targeted treatment for certain ARDs by reducing autoreactive B cell development.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Contribution of GPR183-expressing B cells to the pathogenesis of juvenile-onset rheumatic disease |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2023. 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/10182793 |
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