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
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CFHR Gene Variations Provide Insights in the Pathogenesis of the Kidney Diseases Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy.
Zipfel PF, Wiech T, Stea ED, Skerka C.J Am Soc Nephrol. 2020 Feb
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Serum FHR1 binding to necrotic-type cells activates monocytic inflammasome and marks necrotic sites in vasculopathies
Sarah Irmscher, Silke R. Brix, Svante L. H. Zipfel, Luke D. Halder, Sibel Mutlutürk, Sonia Wulf, Evaldas Girdauskas, Hermann Reichenspurner, Rolf A. K. Stahl, Berit Jungnickel, Thorsten Wiech, Peter F. Zipfel & Christine SkerkaNat Commun. 2019 Jul
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C3-Glomerulopathy Autoantibodies Mediate Distinct Effects on Complement C3- and C5-Convertases.
Zhao F, Afonso S, Lindner S, Hartmann A, Löschmann I, Nilsson B, Ekdahl KN, Weber LT, Habbig S, Schalk G, Kirschfink M, Zipfel PF, Skerka C.Front Immunol. 2019 May
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C3 Glomerulopathy-Understanding a Rare Complement-Driven Renal Disease.
Smith RJH, Appel G, Blom AM, Cook HT, D’Agati V, Fakhouri F, Véronique Fremeaux-Bacchi V, Józsi M, Kavanagh D, Lambris J, Noris M, Pickering MC, Remuzzi G, Santiago Rodriguez de Córdoba S, Sethi S, Van der Vlag J, Zipfel PF, Nester CMNat Rev Nephrol. 2019 Mar
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Development and validation of a renal risk score in ANCA-associated glomerulonephritis
Brix S, Noriega M, Tennstedt P, Vettorazzi E, Busch M, Nitschke M, Jabs W, Özcan F, Wendt R, Hausberg M, Sellin L, Panzer U, Huber T, Waldherr R, Hopfer H, Stahl R, Wiech TKidney Int. 2018 Dec
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Potential role for urine PCR in the diagnosis of Whipple's disease.
Moter A, Janneck M, Wolters M, Iking-Konert C, Wiessner A, Loddenkemper C, Hartleben B, Lütgehetmann M, Schmidt J, Langbehn U, Janssen S, Geelhaar-Karsch A, Schneider T, Moos V, Rohde H, Kikhney J, Wiech T.Clin Infect Dis. 2018 Oct
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Organisation of lymphocytic infiltrates in ANCA-associated glomerulonephritis
Brix S, Noriega M, Herden E, Goldmann B, Langbehn U, Busch M, Jabs W, Steinmetz O, Panzer U, Huber T, Stahl R, Wiech THistopathology. 2018 Jun
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FHR5 Binds to Laminins, Uses Separate C3b and Surface-Binding Sites, and Activates Complement on Malondialdehyde-Acetaldehyde Surfaces.
Rudnick RB, Chen Q, Stea ED, Hartmann A, Papac-Milicevic N, Person F, Wiesener M, Binder CJ, Wiech T, Skerka C, Zipfel PFJ Immunol. 2018 Apr
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FHR3 Blocks C3d-Mediated Coactivation of Human B Cells.
Buhlmann D, Eberhardt HU, Medyukhina A, Prodinger WM, Figge MT, Zipfel PF, Skerka CJ Immunol. 2016 Jul
Project-Team
Project Leaders
Prof. Dr. Thorsten Wiech
Dr. med. Tilo Freiwald