Immunology and Cell Biology
A precise understanding of immune regulation in healthy and diseased lungs is important for identifying new therapeutic targets for chronic lung diseases. Our research group investigates the regulation of proteasomal protein degradation and signal transduction at cell membranes. We study lung epithelial and immune cells. One focus is on the role of the proteasome in the epithelial immune response and in immune cells. We also analyze the function of membrane-associated tetraspanins in B cells and mast cells and their dysregulation in lung diseases.
Immunoproteasome research (Meiners lab)
One focus of research is the immunoproteasome, a specialized form of the proteasome that plays an important role in regulating immune responses. In immune cells, the immunoproteasome (i20S) is constitutively expressed, while in non-immune cells the standard proteasome (s20S) predominates, but i20S can be induced by inflammatory signals and infections (Figure 1). The immunoproteasome has a different proteolytic activity than the s20S and plays a key role in the regulation of immune and stress responses, such as the activation of CD8 T cells by MHC class I antigen presentation in viral and tumor diseases (Figure 2). However, the exact function of the immunoproteasome in immune cells, in the response to infections, and in chronic lung diseases such as COPD, pulmonary fibrosis, and lung tumors is not well understood.
Our research aims to investigate the role of the immunoproteasome in the function of immune and parenchymal cells and its dysregulation in diseases. We are currently establishing novel transgenic animal models for immunoproteasome research, which we intend to use for validation of specific immunoproteasome inhibitors as a new treatment approach for inflammatory and chronic diseases. For clinical studies, we have established methods for the systematic determination of proteasome activity in peripheral blood cells in order to examine large patient or population cohorts for altered proteasome activities.
Membranproteins (Orinska Lab)
Our focus is on regulating the function of B cells and mast cells and their role in the immune response in physiological situations and in chronic lung diseases. In particular, we want to understand how membrane proteins of the tetraspanin family are involved in regulating immune cell function and whether/how modulation of tetraspanin function could be used to treat chronic lung diseases. Using various genetic mouse models and antibody-mediated tetraspanin targeting, we characterize cell type-specific interaction partners and functions of these membrane proteins.
Leibniz-Gemeinschaft „ImmunoPROteasomes in LUNG health and disease“ – PRO-LUNG
We here explore the concept that the inducible nature of the immunoproteasome enables dynamic adaptation of proteasome function in immune and stress responses. In particular, we aim to understand whether standard, immuno- and the various types of mixed proteasomes have distinct functions e.g. by localizing to distinct cell types or subcellular sites, degrading different substrates, or by interacting with defined proteasome regulators. Solving these questions is key for a detailed understanding of the function of the immunoproteasome in health and disease. It will pave the way for validation of the immunoproteasome as a therapeutic target allowing specific inhibition of single or multiple immunoproteasome subunits in disease with novel site-specific immunoproteasome inhibitors that are currently being developed.
Leibniz Center for Infection: “Sex-specific regulation of immunoproteasome function determines response to infection“
(together with Bianca Schneider, FZB)
In this project, we investigate the (biological) sex-specific regulation of the immunoproteasome and whether this might contribute to the stronger immune responses against infections in females. We are using influenza and tuberculosis-related infection models in female and male mice to dissect the immunoproteasome related immune response as well as in vitro cellular models for sex-hormone treatment. The aim is to unravel the molecular basis of sex-related regulation of the immunoproteasome, which may enable us to develop sex-specific diagnostic tools and target the immunoproteasome therapeutically in a sex-related manner.
CRC 1713 Maternal Immune Activation: “Role of the Immunoproteasome in Feto-Maternal Immune Activation and Fetal Immune Priming”
The immunoproteasome plays an essential role in the selection and priming of CD8 T cells. It is therefore central to the establishment of self-tolerance as well as antiviral immunity and autoimmune responses. In this project, we investigate the regulation of the immunoproteasome by stress- and infection-induced maternal immune activation and how this affects antiviral immune responses in the pregnant host, immune priming in the fetal thymus, and the development of tolerance in the offspring.
Priority Program SPP2453 Mitostress: “Regulation of the human proteasome network under mitochondrial protein import stress”
CD37 is glycosylated membrane protein highly expressed in B cells. As other tetraspanins CD37 is involved in regulation of incoming receptor-derived signals, lateral membrane protein interactions and intracellular signal processing. Here we are characterizing mouse CD37-specific monoclonal antibodies and investigating the effects of epitope-specific CD37 targeting in vitro and in vivo. Generated CD37-specific monoclonal antibodies recognized two different epitopes in large extracellular loop. Added to the purified B cells in vitro, CD37 Abs induced B cell death, strongly potentiated by Ab crosslinking, Targeting of different CD37-epitopes led to depletion of different B cell subsets in vivo. Despite this, we observed induction of specific immune response to injected antibodies indicating the activation of particular B cell populations. We are going to dissect mechanisms responsible for B cell depletion potentially interesting for treatment of autoimmune diseases and induction of immune response important in development of new vaccine technologies in further experiments.
Regulation of MrgprB2-mediated mast cell activation by tetraspanin CD37
Mast cells (MCs) are long-lived sentinel cells of the immune system that control allergic and inflammatory responses. While the tetraspanin CD37 is known to be an important regulator of signal transduction in B cells, its function in mast cell activation remains poorly understood. Here, we investigate how CD37 regulates mast cell activation by comparing two genetic models of CD37 deficiency. Mast cells from conventionally CD37-deficient mice were hypersensitive to IgE-independent, MrgprB2-mediated stimulation. In contrast, mast cells from mast cell-specific CD37 knockout mice showed no altered activability and responded normally to IgE-dependent and independent stimuli. The observed IgE-independent hypersensitivity in conventionally CD37-deficient mice could be due to an off-target effect. To test this hypothesis, we are reconstituting CD37 expression in CD37-deficient mast cells using lentiviral transduction. In addition, we have identified a neighboring gene that is a potential new regulator of mast cell activation.
Modulation of B-cell function through epitope-specific CD37 targeting in mice
CD37 is a glycosylated membrane protein that is strongly expressed in B cells. Like other tetraspanins, CD37 is involved in the regulation of incoming signals, lateral membrane protein interactions, and intracellular signal processing. In this project, we characterize CD37-specific monoclonal antibodies and investigate the effects of epitope-specific CD37 targeting in vitro and in vivo. The CD37-specific monoclonal antibodies recognize two different CD37 epitopes. The binding of the antibodies to CD37 leads to the induction of B cell death in vitro. In mice, the application of CD37 AK also leads to a reduction in various B cell populations. Nevertheless, we also observed a specific immune response to injected antibodies, which indicates the activation of certain B cell populations. In further experiments, we will investigate the mechanisms responsible for B cell depletion that could be used for the treatment of chronic lung diseases. The enhanced induction of an immune response, on the other hand, is important for the development of new vaccine technologies.
Third-party funding
- Leibniz Best Minds: Programme for Women Professors: „ImmunoPROteasomes in LUNG health and disease“ (2021-2026)
- Leibniz Center for Infection (LCI): “Sex-specific regulation of immunoproteasome function determines response to infection“ (together with Bianca Schneider, FZB, 2023-2026)
- Deutsches Zentrum für Lungenforschung (DZL) (2023-2027)
- DFG: “Regulation of the human proteostasis network under mitochondrial protein import stress” within the SPP 2453 (2024 – 2027)
- Precision medicine in inflammation (PMI) excellence cluster (2025–2030)
- Dorothea Erxleben Prize from the “Precision Medicine in Inflammation” excellence cluster (2024)
- DFG: “Role of the immunoproteasome in foeto-maternal immune activation and fetal immune priming” as part of SFB 1713 (2025-2028)
- Primary culture of human and mouse lung and immune cells
- Biochemical analyses of proteasome activity (native gel, activity tests)
- Virus infections, lentiviral gene transduction, and CrispRCas9-based gene editing
- Transgenic mouse models
- Molecular biology-based methods
- Cell biology assays for growth, survival, migration, and differentiation
- CD8+ T cell reporter assays
- Analysis of MC degranulation
- Analysis of B cell differentiation and maturation
- Induction and measurement of specific immune responses in mice
- Multiparametric flow cytometry
- Measurement of IgA-mediated immune response on mucosal surfaces
- Synthesis of peptide libraries for epitope mapping of antibodies
- Solid-phase synthesis of peptides and peptide derivatives
- In silico/in vitro peptide sequence optimization
- Peptide-based array systems
- Peptide probes for live cell imaging
2025
Eibach, Y, Kreher, S, Poetsch, MS, Kho, AL, Gaertner, U, Clemen, CS, Schröder, R, Guo, K, Milting, H, Meder, B, Potente, M, Richter, M, Schneider, A, Meiners, S, Gaute, M & Braun, T 2025, 'The deubiquitinase USP5 prevents accumulation of protein aggregates in cardiomyocytes', Science advances, Jg. 11, Nr. 4, S. eado3852. https://doi.org/10.1126/sciadv.ado3852
Faner, R, Cho, MH, Koppelman, GH, Melén, E, Verleden, SE, Dharmage, SC, Meiners, S & Agusti, A 2025, 'Towards early detection and disease interception of COPD across the lifespan', European Respiratory Review, Jg. 34, Nr. 177. https://doi.org/10.1183/16000617.0243-2024
Harikumar Parvathy, G*, Hertz, D*, Bhandiwad, D, Eggers, L, von Borstel, L, Behrends, J, Hein, M, Dreyer, V, Marschner, J, Orinska, Z, Niemann, S, Kaufmann, SHE, Goldmann, T, Lotter, H, Flores-Valdez, MA & Schneider, BE 2025, 'Sex Differences in Vaccine-Induced Immunity and Protection Against Mycobacterium tuberculosis', THE JOURNAL OF INFECTIOUS DISEASES, S. jiaf277. https://doi.org/10.1093/infdis/jiaf277 *authors contributed equally
Lunding, LP, Weckmann, M, Zissler, UM, Jakwerth, C, Bodenstein-Sgró, R, Webering, S, Vock, C, Ehlers, JC, Fernandez Ceballos, RAM, Nemani, SSP, Reddy, KD, Oliver, BGG, Vermeulen, CJ, van de Berge, M, Ober, C, Künstner, A, Busch, H, König, I, Garbers, C, Schmidt-Weber, CB, Nold, MF, Yildirim, AÖ, Nold-Petry, CA, Orinska, Z, Bahmer, T, Heyckendorf, J, Hansen, G, von Mutius, E, Rabe, KF, Dittrich, A-M, Schaub, B, Brinkmann, F, Kopp, MV, Wegmann, M & ALLIANCE Study Group 2025, 'Immune Training of the Interleukin 6 Gene in Airway Epithelial Cells is Central to Asthma Exacerbations', ALLERGY. https://doi.org/10.1111/all.70070
Mendoza, N & Meiners, S 2025, 'COPD, IPF and Tobacco: What are the Common (Immune) Denominators?', Archivos de bronconeumologia. https://doi.org/10.1016/j.arbres.2025.01.006
Pepke-Żaba, J, Chorostowska-Wynimko, J, Ryan, S, Randerath, W, Meiners, S, Saglani, S, Heuvelin, E, Genton, C, Gappa, M, Powell, P, Polverino, E, Roche, N & Siddiqui, S 2025, 'ERS Clinical Research Collaboration programme: more than research networking - enriching respiratory science and impacting clinical practice in Europe and beyond', The European respiratory journal, Jg. 65, Nr. 3. https://doi.org/10.1183/13993003.02520-2024
2024
Abu Risha, M, Reddy, KD, Nemani, SSP, Jakwerth, C, Schmidt-Weber, C, Bahmer, T, Hansen, G, von Mutius, E, Rabe, KF, Dittrich, A-M, Grychtol, R, Maison, N, Schaub, B, Kopp, MV, Brinkmann, F, Meiners, S, Jappe, U, Weckmann, M & ALLIANCE Study Group 2024, 'Epigenetic training of human bronchial epithelium cells by repeated rhinovirus infections', ALLERGY, Jg. 79, Nr. 12, S. 3385-3400. https://doi.org/10.1111/all.16388
Meiners, S, Reynaert, NL, Matthaiou, AM, Rajesh, R, Ahmed, E, Guillamat-Prats, R, Heijink, IH & Cuevas-Ocaña, S 2024, 'The importance of translational science within the respiratory field', Breathe, Jg. 20, Nr. 1, S. 230183. https://doi.org/10.1183/20734735.0183-2023
Parvathy, GH, Bhandiwad, D, Eggers, L, Borstel, LV, Behrends, J, Hein, M, Hertz, D, Marschner, J, Orinska, Z & Kaufmann, SHE et al. 2024, 'Sex differences in vaccine induced immunity and protection against Mycobacterium tuberculosis', Biorxiv, S. 2024.04.20.590403. https://doi.org/10.1101/2024.04.20.590403
2023
Chen, J, Wang, X, Schmalen, A, Haines, S, Wolff, M, Ma, H, Zhang, H, Stoleriu, MG, Nowak, J, Nakayama, M, Bueno, M, Brands, J, Mora, AL, Lee, JS, Krauss-Etschmann, S, Dmitrieva, A, Frankenberger, M, Hofer, TP, Noessner, E, Moosmann, A, Behr, J, Milger, K, Deeg, CA, Staab-Weijnitz, CA, Hauck, SM, Adler, H, Goldmann, T, Gaede, KI, Behrends, J, Kammerl, IE & Meiners, S 2023, 'Antiviral CD8+ T cell immune responses are impaired by cigarette smoke and in COPD', The European respiratory journal, Jg. 62, Nr. 2, 2201374. https://doi.org/10.1183/13993003.01374-2022
Farr, A, Cuevas Ocaña, S, Gille, T, Pinnock, H, Bonsignore, MR, Roche, N, Laveneziana, P, Costello, RW, Harari, S, Meiners, S, Loukides, S & Cruz, J 2023, 'What to expect from the ERS International Congress 2023', Breathe, Jg. 19, Nr. 2, S. 230107. https://doi.org/10.1183/20734735.0107-2023
Javitt, A, Shmueli, MD, Kramer, MP, Kolodziejczyk, AA, Cohen, IJ, Radomir, L, Sheban, D, Kamer, I, Litchfield, K, Bab-Dinitz, E, Zadok, O, Neiens, V, Ulman, A, Wolf-Levy, H, Eisenberg-Lerner, A, Kacen, A, Alon, M, Rêgo, AT, Stacher-Priehse, E, Lindner, M, Koch, I, Bar, J, Swanton, C, Samuels, Y, Levin, Y, da Fonseca, PCA, Elinav, E, Friedman, N, Meiners, S & Merbl, Y 2023, 'The proteasome regulator PSME4 modulates proteasome activity and antigen diversity to abrogate antitumor immunity in NSCLC', Nature cancer, Jg. 4, Nr. 5, S. 629-647. https://doi.org/10.1038/s43018-023-00557-4
Schmalen, A, Kammerl, IE, Meiners, S, Noessner, E, Deeg, CA & Hauck, SM 2023, 'A Lysine Residue at the C-Terminus of MHC Class I Ligands Correlates with Low C-Terminal Proteasomal Cleavage Probability', Biomolecules, Jg. 13, Nr. 9, S. 1300. https://doi.org/10.3390/biom13091300
Wang, X, Zhang, H, Wang, Y, Bramasole, L, Guo, K, Mourtada, F, Meul, T, Hu, Q, Viteri, V, Kammerl, I, Konigshoff, M, Lehmann, M, Magg, T, Hauck, F, Fernandez, IE & Meiners, S 2023, 'DNA sensing via the cGAS/STING pathway activates the immunoproteasome and adaptive T-cell immunity', EMBO JOURNAL , Jg. 42, Nr. 8, S. e110597. https://doi.org/10.15252/embj.2022110597
2022
Bramasole, L & Meiners, S 2022, 'Profiling Proteasome Activities in Peripheral Blood – A Novel Biomarker Approach', Journal of cellular Immunology, Jg. 4, Nr. 5, S. 171-179. https://www.scientificarchives.com/public/assets/articles/article-pdf-1668627159-888.pdf
Kammerl, IE, Hardy, S, Flexeder, C, Urmann, A, Peierl, J, Wang, Y, Vosyka, O, Frankenberger, M, Milger, K, Behr, J, Koch, A, Merl-Pham, J, Hauck, SM, Pilette, C, Schulz, H & Meiners, S 2022, 'Activation of immune cell proteasomes in peripheral blood of smokers and COPD patients - implications for therapy', The European respiratory journal, Jg. 59, Nr. 3, 2101798. https://doi.org/10.1183/13993003.01798-2021
Meiners, S, Yazgili, A & Ebstein, F 2022, 'The proteasome activator PA200/PSME4: an emerging new player in health and disease', Biomolecules, Jg. 12, Nr. 8, S. 1150. https://doi.org/10.3390/biom12081150
Nsiah-Dosu, S, Scholz, C, Orinska, Z, Sadik, CD, Ludwig, RJ, Schmidt, E, Zillikens, D & Hartmann, K 2022, 'Mast cell-deficient mice Mcpt5Cre/Dicerfl/fl redefine the role of mast cells in experimental bullous pemphigoid', Skin Health and Disease, Jg. 2, Nr. 1, e70, S. e70. https://doi.org/10.1002/ski2.70
Schlesser, C, Meul, T, Stathopoulos, G & Meiners, S 2022, 'Metformin Induces Resistance of Cancer Cells to the Proteasome Inhibitor Bortezomib', Biomolecules, Jg. 12, Nr. 6, 756. https://doi.org/10.3390/biom12060756
Zambusi, A, Novoselc, KT, Hutten, S, Kalpazidou, S, Koupourtidou, C, Schieweck, R, Aschenbroich, S, Silva, L, Yazgili, AS, van Bebber, F, Schmid, B, Möller, G, Tritscher, C, Stigloher, C, Delbridge, C, Sirko, S, Günes, ZI, Liebscher, S, Schlegel, J, Aliee, H, Theis, F, Meiners, S, Kiebler, M, Dormann, D & Ninkovic, J 2022, 'TDP-43 condensates and lipid droplets regulate the reactivity of microglia and regeneration after traumatic brain injury', Nature neuroscience, Jg. 25, Nr. 12, S. 1608-1625. https://doi.org/10.1038/s41593-022-01199-y
2021
Kammerl IE, Flexeder C, Karrasch S, Thorand B, Heier M, Peters A, Schulz H, Meiners S. Blood Immunoproteasome Activity Is Regulated by Sex, Age and in Chronic Inflammatory Diseases: A First Population-Based Study. Cells. 2021 Nov 28;10(12):3336.
Previous publications of Silke Meiners not affiliated with the Research Center Borstel
2021
Laveneziana P, Straus C, Meiners S. How and to What Extent Immunological Responses to SARS-CoV-2 Shape Pulmonary Function in COVID-19 Patients. Front Physiol. 2021 Jun 29;12:628288.
Yazgili AS, Meul T, Welk V, Semren N, Kammerl IE, Meiners S. In-gel proteasome assay to determine the activity, amount, and composition of proteasome complexes from mammalian cells or tissues. STAR Protoc. 2021 May 4;2(2):100526.
2020
Korfei M, MacKenzie B, Meiners S. The ageing lung under stress. Eur Respir Rev. 2020 Jul 7;29(156):200126. Review
Hu C, Meiners S, Lukas C, Stathopoulos GT, Chen J. Role of exosomal microRNAs in lung cancer biology and clinical applications. Cell Prolif. 2020 May 11:e12828. Review
Coux O, Zieba BA, Meiners S. The Proteasome System in Health and Disease. Adv Exp Med Biol. 2020;1233:55-100. Book chapter
Wang X, Meul T, Meiners S. Exploring the proteasome system: A novel concept of proteasome inhibition and regulation. Pharmacol Ther. 2020 Mar 13:107526. Review
Ubags ND, Baker J, Boots A, Costa R, El-Merhie N, Fabre A, Faiz A, Heijink IH, Hiemstra PS, Lehmann M, Meiners S, Rolandsson Enes S, Bartel S. ERS International Congress, Madrid, 2019: highlights from the Basic and Translational Science Assembly. ERJ Open Res. 2020 Mar 2;6(1). pii: 00350-2019. Report
Coux O, Zieba BA, Meiners S. The Proteasome System in Health and Disease. Adv Exp Med Biol. 2020;1233:55-100. Book chapter
Wang X, Meul T, Meiners S. Exploring the proteasome system: A novel concept of proteasome inhibition and regulation. Pharmacol Ther. 2020 Mar 13:107526. Review
Ubags ND, Baker J, Boots A, Costa R, El-Merhie N, Fabre A, Faiz A, Heijink IH, Hiemstra PS, Lehmann M, Meiners S, Rolandsson Enes S, Bartel S. ERS International Congress, Madrid, 2019: highlights from the Basic and Translational Science Assembly. ERJ Open Res. 2020 Mar 2;6(1). pii: 00350-2019. Report
Meul T, Berschneider K, Schmitt S, Mayr CH, Mattner LF, Schiller H, Yazgili A, Wang W, Lukas C, Prehn C, Adamski J, Graf E, Schwarzmayr T, Perocchi F, Kukat A, Trifunovic A, Kremer L, Prokisch H, Popper B; von Toerne C, Hauck SM, Zischka H, Meiners S. Mitochondrial regulation of the 26S proteasome. Cell Reports 2020, Aug 25;32(8):108059.
Bölükbas DA, Datz S, Meyer-Schwickerath C, Morrone C, Doryab A, Gössl D, Vreka M, Yang L, Argyo C. van Rijt SH, Lindner M, Eickelberg O, Stoeger T, Schmid O, Lindstedt S, Stathopoulos GT, Bein T, Wagner DE, Meiners S. Organ-restricted vascular delivery of nanoparticles for lung cancer therapy. Advanced Therapeutics. 2020, 3: 2070016
Heitmeier T, Sydykov A, Lukas C, Vroom C, Korfei M, Petrovic A, Klingel K, Günther A, Eickelberg O, Weissmann N, Ghofrani HA, Seeger W, Grimminger F, Schermuly RT, Meiners S‡, Kosanovic D‡. Altered proteasome function in right ventricular hypertrophy. Cardiovasc Res. 2020 Feb 1;116(2):406-415. ‡ equal contribution
2019
Welk V, Meul T, Lukas C, Kammerl IE, Mulay SR, Schamberger AC, Semren N, Fernandez IE, Anders HJ, Günther A, Behr J, Eickelberg O, Korfei M, Meiners S. Proteasome activator PA200 regulates myofibroblast differentiation. Scientific Rep. 2019 Oct 23;9(1):15224.
Kesireddy VS, Chillappagari S, Ahuja S, Knudsen L, Henneke I, Graumann J, Meiners S, Ochs M, Ruppert C, Korfei M, Seeger W, Mahavadi P. Susceptibility of microtubule-associated protein 1 light chain 3β (MAP1LC3B/ LC3B) knockout mice to lung injury and fibrosis. FASEB J. 2019 Nov;33(11):12392-12408.
Kammerl IE, Caniard A, Merl-Pham J, Ben-Nissan G, Mayr CH, Mossina A, Geerlof A, Eickelberg O, Hauck SM, Sharon M, Meiners S. Dissecting the molecular effects of cigarette smoke on proteasome function. J Proteomics. 2019 Feb 20;193:1-9.
2018
Meiners S, Lloyd C, Chambers RC. Cell-matrix interactions in lung disease and regeneration: ERS Lung Science Conference 2018 report. Eur Respir Rev. 2018 Jun 27;27(148). pii: 180040. Report
Amatngalim GD, Vieira RP, Meiners S, Bartel S. Novel insights into the effects of cigarette smoke on the airway epithelial surface-lessons learned at the European Respiratory Society International Congress 2018 in Paris. J Thorac Dis. 2018 Sep;10(Suppl 25):S2977-S2982. Report
Meiners S, Evankovich J, Mallampalli RK. The ubiquitin proteasome system as a potential therapeutic target for systemic sclerosis. Transl Res. 2018 Aug;198:17-28. Review
Houssaini A, Breau M, Kebe K, Abid S, Marcos E, Lipskaia L, Rideau D, Parpaleix A, Huang J, Amsellem V, Vienney N, Validire P, Maitre B, Attwe A, Lukas C, Vindrieux D, Boczkowski J, Derumeaux G, Pende M, Bernard D, Meiners S, Adnot S. mTOR pathway activation drives lung cell senescence and emphysema. JCI Insight. 2018 Feb 8;3(3). pii: 93203.
Head
Scientific staff
Technical staff
Alumni
- Laylan Bramasole
- Fatima Mourtada
- Yuqin Wang