Cellular dynamics in chronic lung disease: the neglected B cell axis

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The healthy lung contains only sparse immune cells to allow the physical properties necessary for efficient gas exchange and maintain its critical functions. In chronic lung diseases, such as chronic obstructive lung disease (COPD), immune cell infiltrates expand, persist and contribute to defective lung function. As a result, the lung does not return to its original state, and this can have long-term consequences for the patient. COPD is the third leading cause of death worldwide, with no available treatments to delay disease progression. Therefore, developing novel therapeutic strategies for improved disease management is a global priority. Recent studies have focussed on understanding the profile of lung-infiltrating immune cells and their contribution to COPD. Remarkably, knowledge of B cells has lagged far behind that of other immune cells, despite their accumulation and persistence in the COPD lung. This UKRI FLF aims to uncover how B cells promote COPD pathogenesis. Do lung-infiltrating B cells promote tissue inflammation and airway remodelling? Do these aberrant B cell responses associate with disease severity? Can we harness novel pathways involved to develop improved treatment approaches for patients? To address these central questions, I will study in detail the interactions between B cells and their surrounding cells and matrix, to understand how these communications either exacerbate or limit disease.Using freshly isolated immune cells and tissue sections, as well as mouse models of COPD, I aim to ask the following key research questions:- Which aspects of B cell responses in COPD patients associate with disease severity? - Can we identify a molecular signature of COPD-associated B cells in the lung and periphery of COPD patients?- How do interactions between B cells and the surrounding lung microenvironment influence disease outcomes? - Can we ameliorate disease by targeting novel pathways driving B cell dysfunction?This work will be done at The University of Manchester within the world-leading Lydia Becker Institute of Immunology and Inflammation in collaboration with clinicians and pathologists at Manchester University NHS Foundation Trust, as well as my research partners in the UK and overseas. Improved understanding of B cells in COPD could open novel therapeutic avenues for better disease management. These findings may also benefit patients with other chronic lung diseases, such as asthma.