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SFB 1192

Project B6

Role of Role of factor H related proteins in glomerular diseases

Complement is associated with several human kidney dieases and complement therapy is approved for atypical Hemolytic Uremic Syndrome. Sequence- and copy number variations in the human Factor H-CFHR (Complement Factor H Related) gene cluster are linked to the kidney diseases, atypical Hemolytic Uremic Syndrome, C3 Glomerulopathy, Membranous Nephropathy, IgA Nephropathy and lupus nephritis. Mutant CFHR-genes, FHR::FHR- and FHR::Factor H-hybrid-proteins and an altered FHR-plasma repertoire show that variant FHR proteins are associated with kidney pathology. FHRs are emerging immune and complement modulators: We have shown in the first funding period that FHR1 is an inflammatory mediator, FHR2 blocks C3 convertase action and inhibits FHR1 mediated inflammation. FHR5 is a complement activator binding to actin in damaged glomeruli. FHRs together with Factor H, the central C3 convertase regulator, adjust complement activity in glomeruli. In this project we aim to define how altered FHR variants cause pathology in the kidney, and evaluate whether FHR deposition in renal biopsies serve as diagnostic and predictive markers. To this end we plan to: 1) Define the physiological roles of FHR2 and FHR5 and evaluate how new FHR2 mutants (not listed in the exome aggregation consortium database) influence complement action, affect surface binding and complement regulation, 2) correlate FHR1-, FHR2- and FHR5 deposition with morphological changes, immunohistological staining or cellular modifications in glomeruli to define unique patterns for the various glomerular diseases, and 3) develop FHRs as diagnostic markers and coordinate with clinicians to extrapolate the altered FHR profiles for personalized, complement targeting therapies.


  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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