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SFB 1192

Project B2

Structural and functional characterization of podocyte antigens in autoantibody-mediated glomerulonephritis

Antigenic podocyte proteins play a critical role in autoantibody-mediated glomerular diseases and provide an extraordinary possibility to deepen our molecular pathophysiologic understanding as well as to improve diagnosis and monitoring of the underlying podocytopathy. In the last funding period, we extensively characterized the key roles of phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type-1 domain-containing 7A (THSD7A) and the corresponding autoantibodies causing membranous nephropathy (MN) in vivo, in vitro and in silico. More recently, the description of autoantibodies targeting the slit diaphragm (SD) protein nephrin in patients with minimal change disease (MCD) broadened the spectrum of autoantibody-mediated nephrotic kidney diseases. These findings prompt us to extend our studies and develop a more generalizable understanding of antibody-mediated podocyte disease. Additionally, the involved autoantigenic proteins, THSD7A and nephrin, both localize to the SD and thereby enable us to synergistically gain further insights into the complex architecture of the SD. Therefore, we will pursue the following aims: 1) Characterization of the newly discovered anti-nephrin autoantibodies in MCD including clinical correlations, analysis of immunodominant epitope-containing regions and epitope-specific antigen-antibody interaction. 2) Investigation of the structure-function relationship between epitope-dependent antibody binding, antibody-mediated disturbances in nephrin signaling, and therapeutic blocking of antibody binding. 3) High-resolution structural analysis of podocyte antigens including antibody-binding regions of THSD7A and nephrin by means of x-ray crystallography and cryo-electron microscopy. Taken together, the analysis of high-resolution antigen structure, antigen-antibody interaction, and epitope-dependent signaling programs will lead to a deeper molecular understanding of autoantibody-mediated glomerular diseases and the role of the SD as a target of autoimmunity.

Publications:

  • Targeting T cell plasticity in kidney and gut inflammation by pooled single-cell CRISPR screening.

    Leon U.B. Enk, Malte Hellmig, Kristoffer Riecken, Christoph Kilian, Paul Datlinger, Saskia L. Jauch-Speer, Tobias Neben, Zeba Sultana, Varshi Sivayoganathan, Alina Borchers, Hans-Joachim Paust, Yu Zhao, Nariaki Asada, Shuya Liu, Theodora Agalioti, Penelope Pelczar, Thorsten Wiech, Christoph Bock, Tobias B. Huber, Samuel Huber, Stefan Bonn, Nicola Gagliani, Boris Fehse, Ulf Panzer, Christian F. KrebsSci Immunol. 2024 Jun

  • Podocyte expression of human phospholipase A2 receptor 1 causes immune-mediated membranous nephropathy in mice.

    Nicola M Tomas, Silke Dehde, Catherine Meyer-Schwesinger, Ming Huang, Irm Hermans-Borgmeyer, Johanna Maybaum, Renke Lucas, Jennie L von der Heide, Oliver Kretz, Sarah M S Köllner, Larissa Seifert, Tobias B Huber, Gunther Zahner Kidney int. 2023 Feb

  • The classical pathway triggers pathogenic complement activation in membranous nephropathy.

    Larissa Seifert, Gunther Zahner, Catherine Meyer-Schwesinger, Naemi Hickstein, Silke Dehde, Sonia Wulf, Sarah M S Köllner, Renke Lucas, Dominik Kylies, Sarah Froembling, Stephanie Zielinski, Oliver Kretz, Anna Borodovsky, Sergey Biniaminov, Yanyan Wang, Hong Cheng, Friedrich Koch-Nolte, Peter F Zipfel, Helmut Hopfer, Victor G Puelles, Ulf Panzer, Tobias B Huber, Thorsten Wiech, Nicola M TomasNat Commun. 2023 Jan

  • A slit-diaphragm-associated protein network for dynamic control of renal filtration.

    Maciej K Kocylowski, Hande Aypek, Wolfgang Bildl, Martin Helmstädter, Philipp Trachte, Bernhard Dumoulin, Sina Wittösch, Lukas Kühne, Ute Aukschun, Carolin Teetzen, Oliver Kretz, Botond Gaal, Akos Kulik, Corinne Antignac, Geraldine Mollet, Anna Köttgen, Burulca Göcmen, Jochen Schwenk, Uwe Schulte, Tobias B Huber, Bernd Fakler, Florian Grahammer Nat Commun. 2022 Oct

  • Podocyte expression of human phospholipase A2 receptor 1 causes immune-mediated membranous nephropathy in mice

    Tomas NM, Dehde S, Meyer-Schwesinger C, Huang M, Hermans-Borgmeyer I, Maybaum J, Lucas R, von der Heide JL, Kretz O, Köllner SMS, Seifert L, Huber TB, Zahner G.Kidney Int. 2022 Sep

  • Across scales: novel insights into kidney health and disease by structural biology.

    Nicola M Tomas, Simon A Mortensen, Matthias Wilmanns, Tobias B Huber Kidney Int. 2021 Apr

  • Perspectives in membranous nephropathy

    Tomas NM, Huber TB, Hoxha E.  Cell Tissue Res. 2021 Apr

  • Podocytes maintain high basal levels of autophagy independent of mtor signaling.

    Tillmann Bork, Wei Liang, Kosuke Yamahara, Philipp Lee, Zhejia Tian, Shuya Liu, Christoph Schell, Kathrin Thedieck, Bjoern Hartleben, Ketan Patel , Pierre-Louis Tharaux, Olivia Lenoir, Tobias B HuberAutophagy. 2020 Nov

  • A novel mouse model of phospholipase A2 receptor 1-associated membranous nephropathy mimics podocyte injury in patients

    Meyer-Schwesinger C*, Tomas NM*, Dehde S, Seifert L, Hermans-Borgmeyer I, Wiech T, Koch-Nolte F, Huber TB, Zahner G.Kidney Int. 2020 May* contributed equally

  • A novel mouse model of phospholipase A2 receptor 1-associated membranous nephropathy mimics podocyte injury in patients.

    Catherine Meyer-Schwesinger, Nicola M Tomas, Silke Dehde, Larissa Seifert, Irm Hermans-Borgmeyer, Thorsten Wiech, Friedrich Koch-Nolte, Tobias B Huber, Gunther ZahnerKidney Int. 2020 May

Project-Team

Project Leaders
Dr. Felicitas E. Hengel
Prof. Dr. Dr. Matthias Wilmanns
Prof. Dr. Tobias B. Huber

Co-Workers
Dr. Ming Huang
Dr. Alice Bochel