Medicine & Health

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  • (2022) Ho, Jacqueline
    Eosinophilic chronic rhinosinusitis (eCRS) or type 2 dominant chronic rhinosinusitis (CRS) is a complex inflammatory disease mediated by type-2 cytokines, including interleukin (IL)-5. Management of this condition is often difficult, requiring multimodal approaches with local and systemic medications as well as surgical therapy. Biologic therapies, including mepolizumab (a monoclonal antibody targeting IL-5), have been successfully used in eosinophilic asthma and are emerging as a new treatment in CRS and eCRS, however there is limited data in this field. This thesis focuses on biomarkers and biologics in CRS. Firstly, identifying and assessing clinical biomarkers that are available to the guide management in patients with CRS and eCRS. Secondly, a prospective open-label single-arm single-centre study of the effectiveness of mepolizumab in patients with eCRS was performed. In this study, biomarkers as well as clinical, functional, and patient reported outcomes are assessed to determine the utility of mepolizumab as biologic treatment for eCRS.

  • (2022) Kelly, Shane
    Autoimmune diseases represent a significant cause of morbidity and mortality, for which there is no cure. The pathogenesis of autoimmunity is unknown. Identifying and profiling antigen-specific lymphocytes has the potential to advance our knowledge of disease pathogenesis, and potentially offer more targeted therapy. The overall aim of this thesis was to identify antigen-specific cells in a range of autoimmune diseases and characterise them proteomically, transcriptomically and genomically using novel sequencing technologies. The experimental design comprised identifying pathogenic B cells from peripheral blood by flow cytometry, followed by single cell sorting and sequencing by G&T seq. Those cells confirmed as antigen-specific then underwent in depth genomic, transcriptomic and proteomic analysis. For the cryoglobulinaemia project I succesfully charcaterised antigen-specific B cells in a pateint who had a rare IgA RF-producing clone. It harboured nonsense mutations in TNFAIP3 and in BCL-10, both of which it is anticipated lead to increased NFKB signalling. For the MAG neuropathy project I successfully characterised antigen-specific B cells in all three patients. All had multiple IgM kappa clonal populations, although for two I was able to show that they arose from a common progenitor, despite being heavily mutated. Essentially all clones, irrespective of MAG specificity, harboured a MYD88p.L265P mutation. I also identified a number of other somatic mutations, including in CXCR4 in one patient, and in SIGLEC11 which was present in only one clonal branch of another patient. For the polyclonal models of autoimmunity project (ie PR3-AAV, MPO-AAV and Ro60+SjS) I was successful for two of the three diseases, although the cell frequency was exceedingly rare. In the one patient (who had PR3-AAV) where I isolated enough antigen-specific B cells to perform a meaningful analysis it was notable that they were enriched for IgG4, lambda, J6 gene usage, IGHE expression, and demonstrated low levels of somatic hypermutation. In summary in this thesis I was successful in most of my aims in identifying and multiomic profiling of antigen-specific B cells in a range of autoimmune diseases including cryoglobulinaemic vasculitis, MAG neuropathy and PR3-AAV. However given the significant challenges in isolating such cells in polyclonal models of autoimmunity, consideration needs to be given in sourcing alternative samples to peripheral blood and/or modifying the current experimental strategy.