Investigating the role of antibody dysregulation in lung disease

• Main Author: Boustani, Karim
• Format: Dissertation
• Language: English
• Published: Imperial College London 2022
• DOI: 10.25560/100378

Antibodies play a critical role in providing long-term immunity against pathogens. They are also required for the maintenance of commensal homeostasis at mucosal surfaces. However, their dysregulation can result in the generation of autoantibody, resulting in autoimmune disease and a shift away from a protective function to a more pathogenic role. There is growing evidence to support the dysregulation of antibody responses in chronic lung diseases such as interstitial lung disease, chronic obstructive pulmonary disease and, more recently, COVID-19. The aim of this thesis was to investigate how dysregulated antibody responses contribute to the pathogenesis of ILD and to pulmonary changes in individuals with persistent respiratory symptoms following COVID-19. Total antibody and autoantibody responses were characterised in a cohort of patients with IPF, CHP, CTD-ILD and healthy controls. A broad autoantibody signature was identified in approximately half of patients that was absent in healthy controls. Additionally, this signature was specific to the airways as autoantibody was not detected systemically. Analysis of antibody coating of airway bacteria revealed a loss of binding by antibody in patients with IPF compared to healthy controls, despite local increases in antibodies against taxa whose abundances are commonly elevated in IPF airways. Patients with IPF had increases in lung B cells. Further, approximately half of patients with IPF had extensive B cell aggregates within the lung parenchyma that co-localised with CXCL13, highlighting the lungs as a potential local niche for the generation of dysregulated antibody. Dysregulated antibody responses were also a feature in post- COVID patients and were associated with worse lung function. Collectively, these findings confirm a dysregulation of antibody responses in ILD and post-COVID airways in the absence of systemic changes and highlight the importance of airway sampling, particularly in determining future therapeutic strategies for lung fibrosis.