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SFB 1192

Project B6

Function and regulation of systemic and local complement C3 in immune-mediated kidney diseases

Defective control and deregulation of complement pathways is a hallmark of immune-mediated kidney diseases. However, systemic C5 inhibition with Eculizumab has only proved efficacy in a limited subset of these. Upstream of C5, complement C3 is key to integrating the converging activation pathways and regulatory functions of the complement system. Deposition of systemic C3 has been associated with worse outcomes in several glomerulonephritides. In addition, we and others have shown that locally generated C3 in the kidney and other organs has crucial functions in immunity. We hypothesize that C3, generated locally or systemically, differentially regulates injury in specific glomerulonephritides. In this project, we will address the hypothesis by determining: 1) Patterns and associated effects of C3 dysregulation in human immune-mediated kidney diseases; 2) Molecular mechanism of C3-induced immune cell milieu alterations in a mouse model of local and systemic conditional C3 KO; and 3) Molecular understanding of complement C3- and complement convertase-dysregulation by Factor H-Related Protein 1. Success of these aims will enhance understanding of the functions and mechanisms of the complement system in immune-mediated kidney diseases. Thus, it will provide a precision-medicine rationale to target complement therapeutics to specific subgroups and inform the requirement for local versus systemic drug bioavailability.

Publications

  • 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 Tomas. Nat Commun. 2023 Jan

  • Bacterial infection possibly causing autoimmunity: Tropheryma whipplei and membranous nephropathy.

    Thorsten Wiech, Linda Reinhard, Sonia Wulf, Alfio Edoardo Giuffrida, Elisa Longhitano, Rosario Caruso, Hermann-Josef Gröne, Rolf A K Stahl, Peter F Zipfel, Judith Kikhney, Annette Moter, Elion Hoxha, Domenico SantoroLancet. 2022 Nov

  • Autocrine vitamin D signaling switches off pro-inflammatory programs of TH1 cells.

    Chauss D*, Freiwald T*, McGregor R*, Yan B*, Wang L*, Nova-Lamperti E, Kumar D, Zhang Z, Teague H, West EE, Vannella KM, Ramos-Benitez MJ, Bibby J, Kelly A, Malik A, Freeman AF, Schwartz DM, Portilla D, Chertow DS, John S, Lavender P, Kemper C,  Lombardi G, Mehta NN, Cooper N, Lionakis MS, Laurence A, Kazemian M, Afzali B. Nat Immunol. 2022 Jan

  • SARS-CoV-2 drives JAK1/2-dependent local complement hyperactivation.

    Yan B*, Freiwald T*, Chauss D*, Wang L*, West E*, Mirabelli C, Zhang CJ, Nichols EM, Malik N, Gregory R, Bantscheff M, Ghidelli-Disse S, Kolev M, Frum T, Spence JR, Sexton JZ, Alysandratos KD, Kotton DN, Pittaluga S, Bibby J, Niyonzima N, Olson MR, Kordasti S, Portilla D, Wobus CE, Laurence A, Lionakis MS, Kemper C, Afzali B, Kazemian M. Sci Immunol. 2021 Apr

  • In situ Visualization of C3/C5 Convertases to Differentiate Complement Activation.

    Person F, Petschull T, Wulf S, Buescheck F, Biniaminov S, Fehrle W, Oh J, Skerka C, Zipfel PF, Wiech T. Kidney Int Rep. 2020 Apr

Project-Team

Project Leaders
Prof. Dr. Thorsten Wiech
Dr. med. Tilo Freiwald