SFB 1192

Projekt B1

Membranous nephropathy: Pathogenetic mechanisms and clinical implications

The identification of the phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type 1 domain containing 7A (THSD7A) as major target antigens in membranous nephropathy (MN) has fundamentally changed the scientific and clinical approach to this disease. The diagnosis of MN is now made based on the molecular pathogenesis of the disease. Treatment decisions and prediction of prognosis are based on the immune pathomechanisms of disease, allowing a more precise and individualized therapy. Currently, the basic treatment options for MN remain immunosuppressive and not specific for the disease itself. The development of novel treatment approaches, which are not based on a general immunosuppression, require a more profound understanding of the specific pathomechanisms leading to disease development and progression. To achieve this goal, we have the following aims in this project: 1) Identification of additional antigens in patients with MN, who are negative for PLA2R1 and THSD7A antibodies. For this purpose, we have developed new screening and antigen retrieval and detection strategies, which will allow us to detect susceptible antigens evading detection by conventional methods. 2) Characterization of B cell subsets and their role in the pathogenesis of human MN. This will allow a better prognosis of treatment success and potentially help to develop more specific treatment strategies. 3) A better understanding of the pathogenesis of PLA2R1 and THSD7A antibody mediated MN. To this end, we aim to implement an animal model for PLA2R1- associated MN in minipigs. This model will not only prove the pathogenicity of PLA2R1 antibodies, but will also be crucial for the implementation of novel treatment strategies in MN. These studies will be essential to further improve our understanding of the pathophysiology of MN, which is a prerequisite for the development of pathogenesis-based and personalized treatments.

Publikationen

  • Role of phospholipase A2 receptor 1 antibody level at diagnosis for long-term renal outcome in membranous nephropathy.

    Mahmud M, Pinnschmidt HO, Reinhard L, Harendza S, Wiech T, Stahl RAK, Hoxha E PLoS One. 2019 Sep

  • Diagnostic role of renal biopsy in PLA2R1-antibody-positive patients with nephrotic syndrome.

    Wiech T, Stahl RAK, Hoxha E Mod Pathol. 2019 Sep

  • Bevacizumab-associated glomerular microangiopathy.

    Person F, Rinschen M, Brix S, Wulf S, Noriega M, Fehrle W, Schmitz J, Schwarz A, Ivanyi P, Steinmetz O, Reinhard L, Hoxha E, Zipfel P, Bräsen J, Wiech TMod Pathol. 2018 Dec

  • Antigen-Specific IgG Subclasses in Primary and Malignancy-Associated Membranous Nephropathy.

    von Haxthausen F, Reinhard L, Pinnschmidt HO, Rink M, Soave A, Hoxha E, Stahl RAKFront Immunol. 2018 Dec

  • Characterization of Autoantibodies in Primary Membranous Nephropathy and their clinical Significance.

    Stahl RAK, Reinhard L, Hoxha E.Expert Rev Clin Immunol. 2018 Nov

  • Genetics of membranous nephropathy.

    Gupta S, Köttgen A, Hoxha E, Brenchley P, Bockenhauer D, Stanescu HC, Kleta R.Nephrol Dial Transplant. 2018 Sep

  • The Most N-Terminal Region of THSD7A Is the Predominant Target for Autoimmunity in THSD7A-Associated Membranous Nephropathy.

    Seifert L, Hoxha E, Eichhoff AM, Zahner G, Dehde S, Reinhard L, Koch-Nolte F, Stahl RAK, Tomas NMJ Am Soc Nephrol. 2018 May

  • Immunohistochemical and serological characterization of membranous nephropathy in children and adolescents

    Dettmar A, Wiech T, Kemper M, Soave A, Rink M, Oh J, Stahl R, Hoxha E Pediatr Nephrol. 2018 Mar

  • A Heterologous Model of Thrombospondin Type 1 Domain-Containing 7A-Associated Membranous Nephropathy

    Tomas N, Meyer-Schwesinger C, von Spiegel H, Kotb A, Zahner G, Hoxha E, Helmchen U, Endlich N, Koch-Nolte F, Stahl R J Am Soc Nephrol. 2017 Nov

  • Translational Aspects of Primary Membranous Nephropathy.

    Hoxha E, Stahl RAK.Semin Nephrol. 2017 Sep

  • Membranous nephropathy-one morphologic pattern with different diseases

    Hoxha E, von Haxthausen F, Wiech T, Stahl RPflugers Arch. 2017 Aug

  • THSD7A expression in human cancer

    Stahl P, Hoxha E, Wiech T, Schröder C, Simon R, Stahl R Genes Chromosomes Cancer. 2017 Apr

  • An Indirect Immunofluorescence Method Facilitates Detection of Thrombospondin Type 1 Domain-Containing 7A-Specific Antibodies in Membranous Nephropathy

    Hoxha E, Beck L, Wiech T, Tomas N, Probst C, Mindorf S, Meyer-Schwesinger C, Zahner G, Stahl P, Schöpper R, Panzer U, Harendza S, Helmchen U, Salant D, Stahl R J Am Soc Nephrol. 2017 Feb

  • Autoantibodies against thrombospondin type 1 domain-containing 7A induce membranous nephropathy. 

    Tomas NM, Hoxha E, Reinicke AT, Fester L, Helmchen U, Gerth J, Bachmann F, Budde K, Koch-Nolte F, Zahner G, Rune G, Lambeau G, Meyer-Schwesinger C, Stahl RA.J Clin Invest. 2016 Jul

  • A Mechanism for Cancer-Associated Membranous Nephropathy. 

    Hoxha E, Wiech T, Stahl PR, Zahner G, Tomas NM, Meyer-Schwesinger C, Wenzel U, Janneck M, Steinmetz OM, Panzer U, Harendza S, Stahl RAN Engl J Med. 2016 May

III. Medizinische Klinik und Poliklinik
Universitätsklinikum Hamburg-Eppendorf

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