Please use this identifier to cite or link to this item: http://theses.ncl.ac.uk/jspui/handle/10443/4935
Title: Characterisation of age-associated B cells in rheumatoid arthritis patients
Authors: Vidal-Pedrola, Gemma
Issue Date: 2020
Publisher: Newcastle University
Abstract: Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterised by joint inflammation and bone destruction. The presence of autoantibodies, years before the clinical onset of disease, and the efficacy of rituximab, a B-cell depleting therapy, highlight a pathogenic role for B cells in the initiation and development of RA. Different groups have recently identified a novel subset of B cells named age-associated B cells (ABCs). Studies in murine autoimmune models and patients suffering from autoimmune diseases described these cells as CD19high CD21- CD11c+. Moreover, a subset of synovial fluid B cells with a similar phenotype, also expressing FcRL4, has been demonstrated to contribute to RA pathogenesis. I aimed to fully characterise, phenotypically, transcriptionally and functionally, peripheral blood ABCs in patients suffering from early RA. I have shown that although my study did not show significant differences in the frequency of peripheral blood ABCs between RA patients and other disease and healthy controls, the percentage of cells with an ABC phenotype in the synovial fluid is very high in patients suffering from inflammatory arthritides. I characterised these cells phenotypically and confirmed that they have high expression of activation and co-stimulatory molecules, in addition to expressing high levels of T-bet and the members of the FcRL family (i.e. FcRL2-5). Moreover, these cells are actively proliferating and a high proportion of them have a class-switched memory B cells phenotype expressing IgG. Interestingly, the transcriptome analysis showed that the ABCs are a subset of B cells, distinct from naïve, CD5+ and memory B cell subsets, with a unique transcriptome profile. ABCs had a high expression of chemokine receptors, such as CXCR3, as well as adhesion molecules, such as integrins and CD97, supporting a role for the migration of these cells into inflammatory sites. In addition, ABCs also had high expression of apoptotic markers, such as caspases and Fas. Finally, the functional characterisation of ABCs showed that these cells are capable of secreting IgM and IgG after stimulation. However, due to low cell numbers and high cell death, very low quantities of secreted cytokines were detected; making it very difficult to determine if these cells could contribute to inflammation. Overall, I confirmed that the ABC subset is an activated memory-like B cell subset which could potentially migrate into inflammatory sites and promote disease pathogenesis. However, exactly how these cells contribute to RA pathogenesis is still unknown and further functional work will help elucidate their role in autoimmunity.
Description: Ph. D. Thesis
URI: http://theses.ncl.ac.uk/jspui/handle/10443/4935
Appears in Collections:Translational and Clinical Research Institute

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