Pulmonary Immune Diseases

The ULG Pulmonary Immune Disease is a cooperation group between the Research Center Borstel and the Department of Rheumatology at the University of Lübeck. We consist of a clinical arm located in Lübeck and a basic research arm located at the FZB. This structure allows us a close translational interaction between 'Bench' and 'Bedside'. 

G-protein coupled receptors (GPCRs) form the largest family of transmembrane receptors and are involved in the regulation of almost all physiological and pathophysiological processes. In recent years, it has been shown that the activity of various GPCRs is regulated not only by their cognate ligand(s), but also by autoantibodies that bind to a single GPCR and act specifically on that receptor as an agonist or antagonist (functional autoantibodies). According to our central hypothesis, functional autoantibodies against specific GPCRs are involved in the pathogenesis of systemic autoimmune diseases as well as asthma and COPD. We are studying systemic Sclerosis (SSc), an autoimmune disease characterized by severe pulmonary complications such as pulmonary arterial hypertension, pulmonary fibrosis, and pneumonia, as a model disease.

Functional autoantibodies to angiotensin II receptor type 1 (AT1R) as drivers of pathogenicity in systemic sclerosis

Based on our studies in SSc patient cohorts, we identified functional autoantibodies against AT1R as biomarkers for SSc whose levels correlate with disease severity and prognosis. Based on this observation, we are establishing novel animal models for SSc in which the disease is induced by immunization with human AT1R.  Furthermore, we were able to generate a humanized mouse model of SSc by adoptive transfer of lymphocytes from SSc patients into immunodeficient mice. Furthermore, we succeeded for the first time in generating functional monoclonal antibodies against AT1R. By demonstrating their pathogenic effect in the lung, we could provide direct evidence of their impact on the pathophysiology of SSc. Using our models, we identify immune cells and cytokines relevant for the disease in order to understand disease mechanisms and develop new therapeutic strategies.

De-regulated cytokines as triggers of autoimmune-mediated disease manifestations in the lung

Systemic sclerosis presents in highly individualized clinical phenotypes in patients with vasculopathy-mediated pulmonary arterial hypertension (PAH) and pulmonary fibrosis as major causes of SSc-related deaths. This suggests that, in addition to autoimmunity and functional autoantibodies, other mechanisms exist that determine the individual pathology of the disease. This view is supported by our recently developed mouse model, in which autoimmunity to AT1R predominantly causes lung and skin inflammation but neither PAH nor pulmonary fibrosis is observed. In our conception, SSc and probably other chronic lung diseases develop in two sequential steps ("two-hit" hypothesis) As "first hit", autoantibodies mediate chronic local inflammation, which decides at which site the later manifestations occur.  As a "second hit", specific de-regulated cytokines (provides by de-regulated cytokine producers; De-reg CP) are required to establish a specific symptom at the site of inflammation. This idea is strengthened by results from our ongoing study in IL-13-overexpressing mice, in which AT1R immunization leads to severe occlusive vasculopathy and most likely also PAH in the lung. Furthermore, evidence from a collaborative project with C. Hölscher suggests that the "first hit" may not necessarily be autoimmune in origin but may result from chronic infections of the lung and possibly also from chronic exposure to cigarette smoke. Our concept not only provides a new understanding of a modular structure of chronic lung diseases, but may represent an approach for new therapies in which deregulated cytokines are controlled in a symptom- and patient-dependent manner by appropriate biologicals.

Two-hit hypothesis for the disease manifestations in the lung

Identification of novel biomarkers and pathogenic drivers of tissue damage and remodeling in COPD

Neutrophil-epithelial interactions: Although the prominent role of neutrophils in the pathogenesis of COPD has long been recognized, the precise manner in which neutrophils carry out their function is not clear. We hypothesize that uncontrolled activation of neutrophils leads to chronic transition of airway epithelia to an inflammatory state, which conditions chronic inflammation, tissue damage, and peribronchiolar fibrosis. In this project, we are studying more than 50 isolated primary epithelial cell lines from clinically characterized patients with or without COPD at the functional and molecular levels.

Autoimmunity in COPD: Autoimmunity is a well-known but only partially understood process in the pathogenesis of COPD. Our previous results show that autoantibodies against extracellular antigens and neutrophil granular proteins are increased in patients with COPD compared to healthy controls. In this project, we are investigating autoantibodies against extracellular antigens to elucidate their role in COPD.

Ministry of Education and Science (BMBF)

• Member of Deutsches Zentrum für Lungenforschung (DZL), Airway Research Center North (ARCN): 1. Disease Area Asthma/Allergy; 2. Disease Area Pulmonary Hypertension2022

German Research Foundation (DFG)

• Generation and characterization of an antibody-based mouse model of systemic sclerosis, (2019-2022)
• Exzellenz Cluster: Precision Medicine in Chronic Inflammation (PMI), (2019 - 2025)
• RI 056/11 “Generierung und Charakterisierung eines Antikörper-basierten Mausmodells für die systemische Sklerose”
• Research Training Group RTG 1727 “Modulation of Autoimmunity”; Project B6: Pathomechanisms in experimental systemic sclerosis
• International Research Training Group IRTG 1911 “Immunoregulation of Inflammation in Allergy and Infection” Project A5: The role of small GTPases Cdc42 and Rap1b in neutrophil transmigration, adhesion, and proteolytic tissue damage in chronic obstructive lung disease
• Research Training Group RTG 2633 “Autoimmune Pre-Disease”; Project B3: Controlling autoimmune-mediated disease manifestations in the lung by targeting Th2 cytokines in a novel mouse model of systemic sclerosis

• Animal models for
  • Systemic sclerosis
  • Autoimmune bullous dermatoses
  • Allergic asthma
• Lung function analyses
• Ex vivo model for autoimmune bullous dermatoses
• Protein biochemical methods
• Cultivation of hybridomas, production and purification of monoclonal antibodies
• Primary cell culture from human and animal tissues
• Functional analyses of neutrophil granulocytes
• In vitro differentiation and analysis of bone marrow-derived neutrophils, macrophages and dendritic cells
• Isolation of organs from experimental mice, preparation of single cell suspensions
• Magnetic cell sortingFlow cytometry and immunofluorescence
• In-Cell Western Assay
• Histological and immunohistochemical techniques
• Quantitative RT-PCR, real time PCR
• Detection of antibodies, cytokines and chemokines in tissue homogenates, supernatants and serum/plasma
• Cytometric bead arrays
• Determination of reactive oxygen metabolites (ROS)
• Signal transduction

Head

Prof. Dr. Xinhua Yu

+49 4537 / 188-2520

+49 4537 / 188-2091

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Prof. Dr. Frank Petersen

+49 4537 / 188-4510

+49 4537 / 188-2091

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Prof. Dr. Gabriela Riemekasten

Klinik für Rheumatologie, UKSH, Campus Lübeck

+49 451 / 500 45200

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