Pulmonary Immune Diseases
Our mission is the investigation of autoimmune mechanisms as pathogenic principles in chronic lung diseases.
According to the central hypothesis of our group, functional autoantibodies against specific GPCRs are involved in the pathogenesis of systemic autoimmune diseases as well as asthma and COPD. We investigate Systemic Sclerosis (SSc), an autoimmune disease which is characterized by severe complications in the lung like pulmonary hypertension, lung fibrosis, and lung inflammation as a model disorder. As a Liaison Group with the Department of Rheumatology at the University of Lübeck we are committed to the close translational interchange between basic research and clinical application.
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
2025
Emtenani, S, Baines, JF, Bieber, K, Gaffal, E, Goletz, S, Hernández, G, Hirose, M, Hoffmann, M, Joly, P, Kirchner, H, Köhl, J, Murthy, S, Patzelt, S, Petersen, F, Pigors, M, Riemekasten, G, Schmidt-Jiménez, LF, Sezin, T, Spielmann, M, Thaçi, D, van Beek, N, Waschke, J, Ludwig, RJ & Schmidt, E 2025, 'Meeting Report on "10th Anniversary Symposium on Inflammatory Skin Disease"', JID innovations : skin science from molecules to population health, Jg. 5, Nr. 3, S. 100344. https://doi.org/10.1016/j.xjidi.2024.100344
Guo, J, Huang, H, Lin, S, Wang, G, Cen, F, Huang, S, Liu, D, Lin, Y, Yu, X, Shi, S & Ma, A 2025, 'Serum carbohydrate antigen 153 as a predictor of interstitial lung disease associated with rheumatoid arthritis is positively correlated with serum Krebs von den Lungen-6', BMC PULMONARY MEDICINE, Jg. 25, Nr. 1, S. 102. https://doi.org/10.1186/s12890-025-03558-4
Hu, X, Li, S, Huang, R, Fu, Z, Ma, C, Cheng, Z, Hu, H, Zhou, Q, Petersen, F, Yu, X & Zheng, J 2025, 'The autoimmune disease risk variant NCF1-His90 is associated with a reduced risk of tuberculosis in women', FRONTIERS IN IMMUNOLOGY, Jg. 16, S. 1514296. https://doi.org/10.3389/fimmu.2025.1514296
Huang, R, Li, X, Lu, Z, Xu, J, Lin, D, Fu, Y, Liang, Y, Petersen, F, Li, X, Zhou, Q & Yu, X 2025, 'Thalassemia carriers exhibit reduced expression of CD234 on erythrocytes and levels of malaria-associated chemokines', Blood advances. https://doi.org/10.1182/bloodadvances.2024014792
Huang, R, Lu, Z, Li, X, Zhou, D, Xu, J, Lin, D, Fu, Y, Liang, Y, Li, X, Petersen, F, Zhou, Q & Yu, X 2025, 'Positive association between chronic hepatitis B virus infection and anemia in pregnancy in Southern China', Scientific Reports, Jg. 15, Nr. 1, S. 1980. https://doi.org/10.1038/s41598-024-84927-7
Ma, A, Huang, R, Guo, J, Wang, G, Huang, H, Li, X, Zhong, S, Huang, Y, Lin, S, Lin, Y, Zhou, Q, Krauss-Etschmann, S, Petersen, F, Wang, Z & Yu, X 2025, 'Association of combined pulmonary fibrosis and emphysema in rheumatoid arthritis with high titer of rheumatoid factor and autoimmunity to the lung', FRONTIERS IN IMMUNOLOGY, Jg. 16, S. 1514552. https://doi.org/10.3389/fimmu.2025.1514552
Ohmes, J, Mehrpouyan, A, Wimmer-Groß, J, Ahmed, AR, Amber, KT, Biswas, S, Christiano, A, Emtenani, S, Goletz, S, Hundt, JE, Kirchhoff, L, Kridin, K, Lasselin, J, Laudes, M, Lee, WY, Ludwig, RJ, Murthy, S, Mousavi, S, Nemeth, T, Neumann, M, Popken, I, Saurabh, R, Sbaraglia, AM, Schanzenbacher, J, Schmidt, C, Schmidt-Jimènez, LF, Scheiner, CW, Schlotfeldt, M, Schoell, N, Bahreini, F & Stenger, S 2025, 'Meeting Report on "The International Congress on Autoimmune Pre-disease (2024)"', JID innovations : skin science from molecules to population health, Jg. 5, Nr. 3, S. 100342. https://doi.org/10.1016/j.xjidi.2024.100342
Yu, X, Yue, X, Tchudjin Magatsin, JD, Marwitz, S, Behrends, J, Goldmann, T, Opferman, JT, Kasper, B & Petersen, F 2025, 'Neutrophils negatively control IL-17A-producing γδ T cell frequencies in a contact-dependent manner under physiological conditions', FRONTIERS IN IMMUNOLOGY, Jg. 16, S. 1542191. https://doi.org/10.3389/fimmu.2025.1542191
2024
Li, X, Zhou, Q, Lu, Z, Huang, R, Lin, D, Xu, J, Yu, X & Li, X 2024, 'Association of HLA-DRB1 alleles with status of antibodies to hepatitis B surface and e antigen', Journal of medical virology, Jg. 96, Nr. 8, S. e29867. https://doi.org/10.1002/jmv.29867
Riemekasten, G & Müller-Ladner, U 2024, 'Update zur systemischen Sklerose', Zeitschrift fur Rheumatologie, Jg. 83, Nr. 6, S. 460-470. https://doi.org/10.1007/s00393-024-01552-5
Shu, Y, Huang, R, Li, Q, Lu, Y, Yin, J, Li, H, Lan, Z, Zheng, X, Ye, J & Long, Y et al. 2024, 'Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy Is Associated with HLA-A*3303 and HLA-DPB1*0501', Annals of neurology, Jg. 95, Nr. 5, S. 901-906. https://doi.org/10.1002/ana.26899
Yin, J, Verschoor, A, Yue, X, Goldmann, T, Heidecke, H, Riemekasten, G, Petersen, F & Yu, X 2024, 'C3 deficiency promotes pulmonary inflammation in AT1R-induced mouse model for systemic sclerosis', FRONTIERS IN IMMUNOLOGY, Jg. 15, S. 1491324. https://doi.org/10.3389/fimmu.2024.1491324
Zhang, L, Zhao, L, Du, K, Chen, J, Ding, H, Petersen, F, Ye, S, Lin, Z & Yu, X 2024, 'Serum levels of CXCL5 are decreased and correlate with circulating platelet counts in systemic lupus erythematosus', International journal of rheumatic diseases, Jg. 27, Nr. 3, S. e15089. https://doi.org/10.1111/1756-185X.15089
Zheng, J, Guo, J, Wang, G, Zhang, L, Yu, X, Liu, D, Lin, Y, Zhang, R, Ma, A & Yu, X 2024, 'Interstitial lung abnormality in COPD is inversely associated with the comorbidity of lung cancer', BMC PULMONARY MEDICINE, Jg. 24, Nr. 1, S. 506. https://doi.org/10.1186/s12890-024-03311-3
2023
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Cabral-Marques, O, Moll, G, Catar, R, Preuß, B, Bankamp, L, Pecher, A-C, Henes, J, Klein, R, Kamalanathan, AS, Akbarzadeh, R, van Oostveen, W, Hohberger, B, Endres, M, Koolmoes, B, Levarht, N, Postma, R, van Duinen, V, van Zonneveld, AJ, de Vries-Bouwstra, J, Fehres, C, Tran, F, do Vale, FYN, da Silva Souza, KB, Filgueiras, IS, Schimke, LF, Baiocchi, GC, de Miranda, GC, da Fonseca, DLM, Freire, PP, Hackel, AM, Grasshoff, H, Stähle, A, Müller, A, Dechend, R, Yu, X, Petersen, F, Sotzny, F, Sakmar, TP, Ochs, HD, Schulze-Forster, K, Heidecke, H, Scheibenbogen, C, Shoenfeld, Y & Riemekasten, G 2023, 'Autoantibodies targeting G protein-coupled receptors: An evolving history in autoimmunity. Report of the 4th international symposium', AUTOIMMUNITY REVIEWS , Jg. 22, Nr. 5, S. 103310. https://doi.org/10.1016/j.autrev.2023.103310
Yu, X, Wax, J, Riemekasten, G & Petersen, F 2023, 'Functional autoantibodies: Definition, mechanisms, origin and contributions to autoimmune and non-autoimmune disorders', AUTOIMMUNITY REVIEWS , Jg. 22, Nr. 9, S. 103386. https://doi.org/10.1016/j.autrev.2023.103386
2022
Kasper, B, Yue, X, Goldmann, T, Gülsen, A, Kugler, C, Yu, X & Petersen, F 2022, 'Air exposure and cell differentiation are essential for investigation of SARS-CoV-2 entry genes in human primary airway epithelial cells in vitro', Frontiers in Medicine, Jg. 9, S. 897695. https://doi.org/10.3389/fmed.2022.897695
Philippe, A, Kleinau, G, Gruner, JJ, Wu, S, Postpieszala, D, Speck, D, Heidecke, H, Dowell, SJ, Riemekasten, G, Hildebrand, PW, Kamhieh-Milz, J, Catar, R, Szczepek, M, Dragun, D & Scheerer, P 2022, 'Molecular Effects of Auto-Antibodies on Angiotensin II Type 1 Receptor Signaling and Cell Proliferation', INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES , Jg. 23, Nr. 7. https://doi.org/10.3390/ijms23073984
Shan, L, Zhang, L, Zhu, X, Wang, Z, Fang, S, Lin, J, Wang, J, Li, N, Liu, H, Zhang, X, Feng, Y, Liu, J, Pan, J, Ye, G, Yu, X, Tufman, A, Katalinic, A, Goldmann, T, Petersen, F, Jiang, J, Geng, G & Yu, X 2022, 'Chinese never smokers with adenocarcinoma of the lung are younger and have fewer lymph node metastases than smokers', RESPIRATORY RESEARCH , Jg. 23, Nr. 1, S. 293. https://doi.org/10.1186/s12931-022-02199-z
Shu, Y, Ma, X, Chen, C, Wang, Y, Sun, X, Zhang, L, Lu, Z, Petersen, F, Qiu, W & Yu, X 2022, 'Myelin oligodendrocyte glycoprotein-associated disease is associated with BANK1, RNASET2 and TNIP1 polymorphisms', Journal of neuroimmunology, Jg. 372, S. 577937. https://doi.org/10.1016/j.jneuroim.2022.577937
Shu, Y, Yue, X, Wax, J, Kasper, B, Yin, J, Wang, X, Zhang, L, Ahmadi, M, Heidecke, H, Müller, A, Lamprecht, P, Yu, X, Riemekasten, G & Petersen, F 2022, 'Both T and B cells are indispensable for the development of a PBMC transfer-induced humanized mouse model for SSc', ARTHRITIS RESEARCH & THERAPY , Jg. 24, Nr. 1, S. 209. https://doi.org/10.1186/s13075-022-02896-6
Tran, F, Harris, DMM, Scharmacher, A, Graßhoff, H, Sterner, K, Schinke, S, Käding, N, Humrich, JY, Cabral-Marques, O, Bernardes, JP, Mishra, N, Bahmer, T, Franzenburg, J, Hoyer, BF, Glück, A, Guggeis, M, Ossysek, A, Küller, A, Frank, D, Lange, C, Rupp, J, Heyckendorf, J, Gaede, KI, Amital, H, Rosenstiel, P, Shoenfeld, Y, Halpert, G, Rosenberg, AZ, Schulze-Forster, K, Heidecke, H, Riemekasten, G & Schreiber, S 2022, 'Increased protease-activated receptor 1 autoantibodies are associated with severe COVID-19', ERJ Open Research, Jg. 8, Nr. 4. https://doi.org/10.1183/23120541.00379-2022
Wang, G, Ma, A, Zhang, L, Guo, J, Liu, Q, Petersen, F, Wang, Z & Yu, X 2022, 'Acute exacerbations of chronic obstructive pulmonary disease in a cohort of Chinese never smokers goes along with decreased risks of recurrent acute exacerbation, emphysema and comorbidity of lung cancer as well as decreased levels of circulating eosinophils and basophils', Frontiers in Medicine, Jg. 9, S. 907893. https://doi.org/10.3389/fmed.2022.907893
Yue, X, Yin, J, Wang, X, Heidecke, H, Hackel, AM, Dong, X, Kasper, B, Wen, L, Zhang, L, Schulze-Forster, K, Junker, J, Grasshoff, H, Müller, A, Wallukat, G, Schimke, I, Zeiner, J, Deckstein, LM, Mertens, N, Kerstein-Staehle, A, Hundt, JE, Kostenis, E, Yu, X, Riemekasten, G & Petersen, F 2022, 'Induced antibodies directed to the angiotensin receptor type 1 provoke skin and lung inflammation, dermal fibrosis and act species overarching', ANNALS OF THE RHEUMATIC DISEASES , Jg. 81, Nr. 9, annrheumdis-2021-222088, S. 1281-9. https://doi.org/10.1136/annrheumdis-2021-222088
Zhang, L, Wax, J, Huang, R, Petersen, F & Yu, X 2022, 'Meta-Analysis and Systematic Review of the Association between a Hypoactive NCF1 Variant and Various Autoimmune Diseases', Antioxidants (Basel, Switzerland), Jg. 11, Nr. 8, 1589. https://doi.org/10.3390/antiox11081589
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