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

健康的肺只包含稀疏的免疫细胞，以允许有效的气体交换和维持其关键功能所必需的物理特性。在慢性肺部疾病中，如慢性阻塞性肺疾病（COPD），免疫细胞浸润扩大，持续存在并导致肺功能缺陷。因此，肺不能恢复到原来的状态，这可能会对患者产生长期影响。慢性阻塞性肺病是全球第三大死亡原因，目前尚无可延缓疾病进展的治疗方法。因此，开发新的治疗策略以改善疾病管理是全球的优先事项。最近的研究集中在了解肺浸润性免疫细胞的概况及其对慢性阻塞性肺病的贡献。值得注意的是，对B细胞的了解远远落后于对其他免疫细胞的了解，尽管它们在COPD肺中积累和持续存在。这项UKRI FLF旨在揭示B细胞如何促进COPD发病机制。肺浸润性B细胞是否促进组织炎症和气道重塑？这些异常的B细胞反应与疾病严重程度有关吗？我们能否利用新途径为患者开发更好的治疗方法？为了解决这些核心问题，我将详细研究B细胞与其周围细胞和基质之间的相互作用，以了解这些通信如何加剧或限制疾病。使用新分离的免疫细胞和组织切片，以及COPD小鼠模型，我的目标是提出以下关键研究问题：- COPD患者B细胞反应的哪些方面与疾病严重程度相关？-我们能否在COPD患者的肺和外周中识别COPD相关B细胞的分子特征？- B细胞与周围肺微环境的相互作用如何影响疾病结局？-我们能否通过靶向驱动B细胞功能障碍的新途径来改善疾病？这项工作将在曼彻斯特大学世界领先的Lydia Becker免疫学和炎症研究所完成，与曼彻斯特大学NHS基金会信托的临床医生和病理学家以及我在英国和海外的研究伙伴合作。提高对B细胞在COPD中的认识可以为更好的疾病管理开辟新的治疗途径。这些发现也可能对其他慢性肺部疾病（如哮喘）患者有益。

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.