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

慢性肺病的细胞动力学：被忽视的 B 细胞轴

• 批准号: MR/X03383X/1
• 负责人: Madhvi Menon
• 金额: $ 183.67万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX03383X%2F1
• 关键词: Cellular; dynamics; chronic; lung; disease

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.

健康的肺只含有稀疏的免疫细胞，以允许有效的气体交换所需的物理特性并维持其关键功能。在慢性肺病（例如慢性阻塞性肺病（COPD））中，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。COPD是全球第三大死亡原因，没有可用的治疗方法来延缓疾病进展。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免疫细胞的概况及其对COPD的贡献。值得注意的是，尽管B细胞在COPD肺中积累并持续存在，但对它们的了解远远落后于对其他免疫细胞的了解。该UKRI FLF旨在揭示B细胞如何促进COPD发病机制。肺浸润性B细胞促进组织炎症和气道重塑吗？这些异常的B细胞反应与疾病的严重程度有关吗？我们能否利用新的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细胞及其周围细胞和基质之间的相互作用，以了解这些通信是如何加剧或限制疾病的。使用新鲜分离的免疫细胞和组织切片，以及小鼠模型的COPD，我的目标是问以下关键研究问题：-哪些方面的B细胞反应在COPD患者与疾病的严重程度？- 我们能否在COPD患者的肺和外周中识别出COPD相关B细胞的分子特征？B细胞和周围肺微环境之间的相互作用如何影响疾病结果？- 我们能通过靶向驱动B细胞功能障碍的新途径来改善疾病吗？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完成。对COPD中B细胞的进一步了解可以为更好的疾病管理开辟新的治疗途径。这些发现也可能有益于患有其他慢性肺部疾病的患者，如哮喘。