Adaptive immune cell-derived biomarkers for the early diagnosis of chronic obstructive pulmonary disease

• Applicants: Professor Dr. Jürgen Behr; Professor Ali Önder Yildirim, Ph.D.
• Subject Area: Pneumology, Thoracic Surgery
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 533332905

Chronic obstructive pulmonary disease (COPD) is an irreversible condition of airflow obstruction and is currently the third leading cause of death worldwide. Current projections estimate that the average prevalence of COPD in Europe will further increase by 2060. The main risk factors for COPD are environmental insults, particularly smoking and inhalation of pollutants or biomass fuel, indicating that lifestyle plays a crucial role in its initiation. Three major pathophysiological features of smoking-induced COPD have been described; chronic inflammation, alveolar wall damage and the dysregulation of pulmonary circulation, notably the immune system is central in all three of them. Due to their clinical implications in disease pathogenesis, the most studied immune cells in COPD include lymphocytes. Nevertheless, the field has not sufficiently advanced to discover early disease lymphoid-based biomarkers and therapeutic targets. A deeper lymphocyte phenotyping which would characterize the lymphocyte populations in early and severe COPD is an unmet clinical need. In addition, the determination of lymphocyte anatomical localization can associate certain lymphocyte subsets with the disease’s clinical manifestations and provide an insight into how their functional dysregulation leads to major pathophysiological mechanisms. Finally, without the analysis of lymphocyte clonotypes we can neither fully appreciate how the clonotype repertoire expands over COPD progression nor can we identify autoimmune receptors that promote a breakdown of immune tolerance and development of autoimmunity in the lung. In this project, we will combine human clinical studies with in vivo work in an established animal model of smoke exposure and we will employ cutting-edge genomics technologies and state of the art computational approaches. We will characterize the transcriptomic and phenotypic (surface proteome) diversity of lung lymphocyte populations and we will analyze their receptor repertoire in a murine model of COPD. We will then validate the murine populations in human samples to assess their spatial distribution in early and severe-stage COPD and we will investigate their presence in the circulation. Finally, we will shortlist clinically relevant lymphocyte populations and determine changes in their functions and intercellular interactions in the bronchoalveolar space and blood of COPD patients. Our ultimate goal is to develop novel, potentially druggable biomarkers derived from lymphocyte populations in the early stages of COPD.

• DFG Programme: Research Grants