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Kapellos Lab

Immunoregulation in obstructive airway diseases

The Kapellos Lab investigates the heterogeneity in structure and functions of human lung immune cells, primarily myeloid cells, to better understand the inflammatory mechanisms that drive the initiation and development of obstructive airway diseases.

The Kapellos Lab investigates the heterogeneity and functions of human immune cells, particularly myeloid cells, in order to better understand the inflammatory mechanisms that drive the initiation and progression of obstructive lung diseases.

The immune system plays a pivotal role in obstructive airway diseases, which are characterized by chronic inflammation and structural changes in the airways, including chronic obstructive pulmonary disease (COPD), non-cystic fibrosis bronchiectasis and allergic asthma. Immune cells mediate and modulate pathophysiological mechanisms by responding to various environmental triggers, such as inhaled pollutants and allergens, ultimately promoting irreversible inflammation and lung tissue damage. Understanding the interactions between immune cells and the respiratory system is essential for uncovering the mechanisms driving disease progression, from the initial stages to more advanced manifestations. Insights into immune responses are crucial for identifying therapeutic targets and developing novel drugs.

Our laboratory is dedicated to exploring obstructive airway diseases, with the primary objective of unraveling the immune system's contributions to disease progression. We aim to identify cellular pathways that can be targeted to mitigate disease manifestations and improve clinical outcomes and patient quality of life. By meticulously assessing the molecular heterogeneity of clinical cohorts affected by obstructive airway diseases, we strive to accelerate the development of personalized therapeutics.

We employ a dual-pronged strategy in our research. First, we leverage cutting-edge omics technologies and computational analyses to define immune molecular phenotypes relevant to disease. To gain deeper insights into host-pathogen interactions, we integrate the genomic profiling of clinical samples with microbiome analysis through 16S rRNA sequencing and metagenomics. Second, to validate our findings, we utilize ex vivo lung models, including in vitro functional assays from human lung fluids, fresh explanted lung tissue and blood specimens from patients with COPD, bronchiectasis and allergic asthma. Precision-cut lung slices strengthen our mechanistic investigations, while highly multiplexed imaging technologies allow us to determine the spatial distribution and cell-cell interactions of innate and adaptive immune cells. Lastly, through established local and international collaborations with experts in animal models of disease, we assess the translatability of proposed mechanisms and candidate drugs from our human models in vivo.

We currently focus on three major scientific avenues:

  • Molecular heterogeneity of the immune system in obstructive airway diseases: We are actively working on immunophenotyping COPD and bronchiectasis patients in collaboration with the Ludwig-Maximilian-University clinics. We hypothesize that immune composition in the lung and circulation undergoes significant alterations over the course of obstructive airway diseases. Our goal is to identify clinical biomarkers for early detection that distinguish severity stages and endotypes. Additionally, we investigate how immune responses are shaped by microbiome changes and how immune cells respond to microbial dysbiosis.
  • Immune cell metabolism in obstructive airway diseases: We aim to understand how immune cell metabolism drives disease progression.Specifically, we investigate the role of macromolecules, particularly secreted proteins and lipid mediators, in shaping immune cell trajectories from early to advanced disease stages. By identifying key cellular players undergoing metabolic reprogramming, we explore how these changes influence immune function and assess the potential to repurpose therapeutics to reverse disease-associated gene expression profiles.
  • Deep imaging analysis in obstructive airway diseases: We employ advanced iterative immunofluorescence to investigate immune cell localization and spatial interactions in COPD and bronchiectasis. Through in silico analysis, we examine sex-related immune responses, focusing on the interplay between immune and non-immune alveolar populations. We integrate these imaging approaches with in-house transcriptomics and proteomics datasets to provide crucial mechanistic insights into disease progression.

If you are interested in joining our interdisciplinary team, feel free to reach out to Dr. Kapellos to discuss your scientific interests and project ideas.

Scientists at Kapellos Lab

Börner_Lisa_Portrait

Lisa Börner

Bachelor Student
Dorn_Sina_Portrait

Sina Dorn

PhD Student
Melo_Letícia_Portrait

Letícya Melo

Postdoc
Primerano_Elias_Portrait

Elias Primerano

PhD Student
Toman_Eli_Portrait

Eli Toman

MSc student
Wadkar_Shrutika_Portrait

Shrutika Wadkar

MSc student

Publications

2024, Wissenschaftlicher Artikel in JCI insight

Interpretable machine learning uncovers epithelial transcriptional rewiring and a role for Gelsolin in COPD.

Transcriptomic analyses have advanced the understanding of complex disease pathophysiology including chronic obstructive pulmonary disease (COPD). However, identifying relevant biologic causative factors has been limited by the integration of high dimensionality data. COPD is characterized by lung destruction and inflammation with smoke exposure being a major risk factor. To define novel biological mechanisms in COPD, we utilized unsupervised and supervised interpretable machine learning analyses of single cell-RNA sequencing data from the gold standard mouse smoke exposure model to identify significant latent factors (context-specific co-expression modules) impacting pathophysiology. The machine learning transcriptomic signatures coupled to protein networks uncovered a reduction in network complexity and novel biological alterations in actin-associated gelsolin (GSN), which was transcriptionally linked to disease state. GSN was altered in airway epithelial cells in the mouse model and in human COPD. GSN was increased in plasma from COPD patients, and smoke exposure resulted in enhanced GSN release from airway cells from COPD patients. This method provides insights into rewiring of transcriptional networks that are associated with COPD pathogenesis and provide a novel analytical platform for other diseases.

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2023, Wissenschaftlicher Artikel in European Respiratory Journal

The impact of the immune system on lung injury and regeneration in COPD.

COPD is a devastating respiratory condition that manifests via persistent inflammation, emphysema development and small airway remodelling. Lung regeneration is defined as the ability of the lung to repair itself after injury by the proliferation and differentiation of progenitor cell populations, and becomes impaired in the COPD lung as a consequence of cell intrinsic epithelial stem cell defects and signals from the micro-environment. Although the loss of structural integrity and lung regenerative capacity are critical for disease progression, our understanding of the cellular players and molecular pathways that hamper regeneration in COPD remains limited. Intriguingly, despite being a key driver of COPD pathogenesis, the role of the immune system in regulating lung regenerative mechanisms is understudied. In this review, we summarise recent evidence on the contribution of immune cells to lung injury and regeneration. We focus on four main axes: 1) the mechanisms via which myeloid cells cause alveolar degradation; 2) the formation of tertiary lymphoid structures and the production of autoreactive antibodies; 3) the consequences of inefficient apoptotic cell removal; and 4) the effects of innate and adaptive immune cell signalling on alveolar epithelial proliferation and differentiation. We finally provide insight on how recent technological advances in omics technologies and human ex vivo lung models can delineate immune cell-epithelium cross-talk and expedite precision pro-regenerative approaches toward reprogramming the alveolar immune niche to treat COPD.

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2023, Wissenschaftlicher Artikel in iScience

Mass spectrometry-based autoimmune profiling reveals predictive autoantigens in idiopathic pulmonary fibrosis.

Autoimmunity plays a role in certain types of lung fibrosis, notably connective tissue disease-associated interstitial lung disease (CTD-ILD). In idiopathic pulmonary fibrosis (IPF), an incurable and fatal lung disease, diagnosis typically requires clinical exclusion of autoimmunity. However, autoantibodies of unknown significance have been detected in IPF patients. We conducted computational analysis of B cell transcriptomes in published transcriptomics datasets and developed a proteomic Differential Antigen Capture (DAC) assay that captures plasma antibodies followed by affinity purification of lung proteins coupled to mass spectrometry. We analyzed antibody capture in two independent cohorts of IPF and CTL-ILD patients over two disease progression time points. Our findings revealed significant upregulation of specific immunoglobulins with V-segment bias in IPF across multiple cohorts. We identified a predictive autoimmune signature linked to reduced transplant-free survival in IPF, persisting over time. Notably, autoantibodies against thrombospondin-1 were associated with decreased survival, suggesting their potential as predictive biomarkers.

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2023, Wissenschaftlicher Artikel in Nature medicine

An integrated cell atlas of the lung in health and disease.

Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP1+ profibrotic monocyte-derived macrophages in COVID-19, pulmonary fibrosis and lung carcinoma. Overall, the HLCA serves as an example for the development and use of large-scale, cross-dataset organ atlases within the Human Cell Atlas.

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Contact

Theodoros Kapellos LHI

Dr. Theodoros Kapellos

Team Leader