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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.

Selected Publications:

  • Anti-nephrin autoantibodies in steroid-resistant nephrotic syndrome may inform treatment strategy.

    Hengel FE, Dehde S, Yilmaz A, Bayasit AK, Ozaltin F, Paripovic D, Emma F, Ronco P, Vivarelli M, Hogan J, Schaefer F, Tomas NM, Huber TB. Kidney Int. 2025 Jun

  • Non-invasive diagnosis of anti-nephrin–associated podocytopathy.

    Hengel FE, Chong MCZ, Leung WY, Dehde S, Mühlig A, Janneck M, Wu HHL, Huber TB, Ponnusamy A, Tomas NM. Kidney Int Rep. 2025 May

  • Potential and pitfalls of measuring circulating anti-nephrin autoantibodies in glomerular diseases.

    Hengel FE, Huber TB, Tomas NM. Clin Kidney J. 2025 Apr

  • Passive transfer of patient-derived anti-nephrin autoantibodies causes a podocytopathy with minimal change lesions.

    Hengel FE, Dehde S, Kretz O, Engesser J, Zimmermann T, Huber TB*, Tomas NM.  J Clin Invest. 2025 Jan

  • Autoantibodies Targeting Nephrin in Podocytopathies.

    Hengel FE, Dehde S, Lassé M, Zahner G, Seifert L, Schnarre A, Kretz O, Demir F, Pinnschmidt HO, Grahammer F, Lucas R, Mehner LM, Zimmermann T, Billing AM, Oh J, Mitrotti A, Pontrelli P, Debiec H, Dossier C, Colucci M, Emma F, Smoyer WE, Weins A, Schaefer F, Alachkar N, Diemert A, Hogan J, Hoxha E, Wiech T, Rinschen MM, Ronco P, Vivarelli M, Gesualdo L, Tomas NM, Huber TB.  N Engl J Med. 2024 Aug