Unravelling mechanisms of B cell reactivity in COVID-19, ANCA-associated vasculitis and psoriatic arthritis

Thesis

B cells are central components of the adaptive immune system, contributing to host defence through antigen presentation, cytokine secretion and antibody production. Because of these diverse functions, B cell responses require precise regulation: insufficient activation predisposes to infection and oncogenesis, whereas excessive activity can promote autoimmunity. Central and peripheral tolerance mechanisms normally restrain autoreactive B cells, with central tolerance removing or altering self-reactive clones through receptor editing or deletion, and peripheral tolerance maintaining autoreactive mature B cells in an unresponsive state termed anergy. However, these checkpoints are not infallible. Enriched autoreactive B cell populations or autoantibody responses have been observed in contexts such as SARS-CoV-2 infection, ANCA-associated vasculitis (AAV), whereas in psoriatic arthritis (PsA) the contribution of B cells has remained comparatively unclear. A more detailed understanding of B cell tolerance, activation and differentiation, together with how these pathways are perturbed in human disease, is essential for guiding the development of targeted B cell–directed therapies.

This thesis investigates three facets of B cell biology across three disease contexts. First, it characterises markers associated with naïve B cell anergy in healthy individuals and COVID-19 patients, identifying a reproducible relationship between surface IgM expression and functional responsiveness, supporting the concept of naïve B cell anergy as a continuum rather than a binary state. Second, it examines B cell receptor (BCR) repertoire reconstitution following treatment with belimumab (anti-BAFF) combined with rituximab (anti-CD20) compared with rituximab plus placebo in AAV, analysing samples collected within the COMBIVAS clinical trial. Recovery of specific B cell subsets, including IGHA2 and IGHG2-expressing populations, was delayed under BAFF inhibition, indicating altered selection dynamics that align with the numerically lower relapse rates reported for combination therapy. Third, this thesis investigates the contribution of B cells to PsA pathogenesis, demonstrating pronounced clonal B cell expansions within PsA synovium, comparable to those observed in rheumatoid arthritis, and showing that BCRs from expanded clones can recognise fibroblast-derived antigens. Finally, it identifies fibroblast activation protein (FAP) as a candidate extracellular autoantigen in PsA, suggesting a previously underappreciated B cell–fibroblast axis in disease.

Together, these findings refine our understanding of human B cell tolerance and reveal mechanisms by which B cells may contribute to inflammatory and autoimmune pathology, offering potential avenues for therapeutic intervention.

Authors: Rones, IP

• DOI: 10.5287/ora-nzodx0pmv
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: COVID-19; autoimmunity; psoriatic arthritis; ANCA-associated vasculitis; peripheral tolerance; B cell receptor repertoire
• Subjects: Rheumatology; Immunology; Autoimmunity; Infection