Arumugakani, Gururaj (2015) Phenotypic and Functional Characterization of B-lineage cells Associated With Relapse and Response to B-cell Depletion Therapy for Rheumatoid Arthritis. PhD thesis, University of Leeds.
Abstract
Background:
Clinical response to therapeutic B-cell depletion by anti-CD20 antibody in rheumatoid arthritis (RA) is not associated with robust depletion of disease specific anti-citrullinated protein antibodies (ACPA). This suggests pathogenesis mediated predominantly by short-lived antibody secreting cells or an antibody independent role of B-cells or both in RA. The persistence of ACPA post B-cell depletion is consistent with secretion from long-lived plasma cells (PC) and could be linked to non-response to B-cell depletion. The aim of this thesis was to delineate populations of B-cells and plasma cells linked to RA disease activity.
Results:
Autoreactive citrullinated protein-specific B-cells were detected using ELISA from supernatants of B cell culture but not by flow cytometry or ELISpot. RA patients relapsing following B-cell depletion showed an increased proportion of a memory B-cell subset in the peripheral blood. The in vitro stage of B-cell differentiation closest to this relapse associated subset secreted multiple proinflammatory mediators. A novel mode of contact-dependent B-NK cell interaction was noted, likely to be due to EBV latency in B-cells or a novel mode of B-cell regulation by NK cells. CD19Neg PCs had a longer recovery time following depletion and had a longer life span in an in vitro PC differentiation model system but were generated early, which suggests that CD19 negativity is a marker for potential to be long-lived rather than PC age.
Conclusions:
Memory B-cell subset distribution is skewed during clinical relapse in RA which reflects on-going B-cell activity/differentiation generating inflammatory mediators or pathogenic short-lived antibody secreting cells which explains response to B-cell depletion or anti-TNF therapy. In those patients where B-cell depletion does not achieve clinical response, CD19Neg long-lived PCs may have a pathogenic role. Agents targeting certain stages of B-cell differentiation or long-lived PCs can be therapeutic options in carefully selected patients.
Metadata
Supervisors: | McGonagle, Dennis and Tooze, Reuben |
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Keywords: | B-cells, Rheumatoid arthritis, RA, autoimmunity, plasma cells, long-lived plasma cells, Memory B-cells, CD19Neg plasma cells |
Awarding institution: | University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Musculoskeletal Disease (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) |
Identification Number/EthosID: | uk.bl.ethos.669616 |
Depositing User: | Dr Gururaj Arumugakani |
Date Deposited: | 10 Nov 2015 14:44 |
Last Modified: | 25 Nov 2015 13:49 |
Open Archives Initiative ID (OAI ID): | oai:etheses.whiterose.ac.uk:10669 |
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Supplementary Material
Filename: Gene Ontology Analysis of ABC Genes.xlsx
Description: Gene Ontology Analysis
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