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Front. Immunol. | doi: 10.3389/fimmu.2018.03035

Antigen-specific IgG Subclasses in Primary and Malignancy-Associated Membranous Nephropathy

 Franziska von Haxthausen1,  Linda Reinhard1,  Hans O. Pinnschmidt2, Michael Rink3, Armin Soave3, Elion Hoxha1 and  Rolf A. Stahl1*
  • 1III. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Germany
  • 2Institut für Medizinische Biometrie und Epidemiologie, Universitätsklinikum Hamburg-Eppendorf, Germany
  • 3Klinik und Poliklinik für Urologie, Universitätsklinikum Hamburg-Eppendorf, Germany

Membranous nephropathy (MN) is an autoimmune disease caused by binding of circulating antibodies to podocyte antigens in the kidney. For decades and still today primary MN has been considered to have an unspecified IgG4-driven autoimmune genesis, while secondary MN has been associated with other diseases, most notably cancer, and not linked to IgG4. Immunologic mechanisms of primary and malignancy-associated MN are assumed to be different, however, this has never been systematically evaluated. The identification of Phospholipase A2 Receptor 1 (PLA2R1) and Thrombospondin Type-1 Domain-Containing 7A (THSD7A) as target antigens in MN allows a pathogenesis-driven differential diagnosis. Recent data showing a molecular link between increased THSD7A-expression in tumors and THSD7A-antibody positive MN suggest a similar pathogenesis of malignancy-associated and primary MN. In order to better define the underlying immunologic processes, we systematically analyzed circulating antigen-specific IgG subclasses in the serum of 76 patients with PLA2R1-associated MN and 41 patients with THSD7A-associated MN in relationship to concurrent malignancy and disease outcome. Twenty-three patients in the study had malignancy-associated MN. We analyzed antigen-specific IgG subclasses in the serum of all patients at baseline and in 55 patients during follow-up by Western blot applying antigens derived from human kidney and lung. At baseline all 117 patients were positive for IgG4-antibodies against either PLA2R1 or THSD7A, while IgG3, IgG1 and IgG2-antibodies were found in 87%, 72% and 26% of patients, respectively. There were no differences in the IgG subclass distribution between patients with primary versus cancer-associated MN and no association with disease outcome. Moreover, levels of antigen-specific IgG4-antibodies were not different between primary and malignancy-associated MN and levels of all IgG subclasses did not differ between these groups. Both podocytes and lung bronchioles showed expression of both PLA2R1 and THSD7A when analyzed by immunofluorescence and Western blot. Every antigen-specific IgG subclass showed identical binding in both organs and autoantibodies bound the respective antigen only under non-reducing conditions. We conclude that antigen-specific IgG subclasses do not differentiate primary from malignancy-associated MN or predict disease prognosis. These data support the view that one common pathway may lead to primary and cancer-associated MN induced by PLA2R1- or THSD7A-antibodies.

Keywords: Membranous nephropathy, IgG subclasses, malignancy, PLA2R1, Thsd7a, prognosis

Received: 20 Aug 2018; Accepted: 07 Dec 2018.

Edited by:

Hideki Ueno, Icahn School of Medicine at Mount Sinai, United States

Reviewed by:

Eirik Bratland, University of Bergen, Norway
Kazuhiko Tsuruya, Kyushu University, Japan  

Copyright: © 2018 von Haxthausen, Reinhard, Pinnschmidt, Rink, Soave, Hoxha and Stahl. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Rolf A. Stahl, III. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany, rstahl@uke.de