Das Prodekanat für Forschung würdigt jeden Monat UKE Autorinnen und Autoren einer herausragenden Publikation, die in den vorangegangenen 2 Monaten hochrangig publiziert wurde. Ziel ist es, die am UKE enstandenen Forschungsergebnisse mit ihrer Bedeutung in der Wissenschaft einer größeren Öffentlichkeit am UKE vorzustellen. Der Aufruf zur Teilnahme richtet sich an Wissenschaftlerinnen und Wissenschaftler aller Fachgebiete. Einreichungsfrist für eine Bewerbung um die Auszeichnung des "Paper of the Month" ist jeweils Ende eines Monats (siehe Bewerbungsformular).
UKE Papier des Monats Februar 2023
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*, and Nicola M. Tomas*
ABSTRACT:
Membranous nephropathy (MN) is an antibody-mediated autoimmune disease characterized by glomerular immune complexes containing complement components. However, both the initiation pathways and the pathogenic significance of complement activation in MN are poorly understood. Here, we show that components from all three complement pathways (alternative, classical and lectin) are found in renal biopsies from patients with MN. Proximity ligation assays to directly visualize complement assembly in the tissue reveal dominant activation via the classical pathway, with a close correlation to the degree of glomerular C1q-binding IgG subclasses. In an antigen-specific autoimmune mouse model of MN, glomerular damage and proteinuria are reduced in complement-deficient mice compared with wild-type littermates. Severe disease with progressive ascites, accompanied by extensive loss of the integral podocyte slit diaphragm proteins, nephrin and neph1, only occur in wild-type animals. Finally, targeted silencing of C3 using RNA interference after the onset of proteinuria significantly attenuates disease. Our study shows that, in MN, complement is primarily activated via the classical pathway and targeting complement components such as C3 may represent a promising therapeutic strategy.
STATEMENT:
This translational study for the first time demonstrates that the classical pathway of complement is the main driver of complement activation in membranous nephropathy and a pathogenic disease driver.
BACKGROUND:
This work was performed at the UKE and is the result of a long-standing collaboration between the groups of Nicola Tomas, III. Department of Medicine, and Thorsten Wiech, Institute of Pathology, Section Nephropathology. The project was funded by the DFG as part of the Emmy Noether Research Group “Molecular mechanisms of membranous nephropathy” and the Collaborative Research Center 1192 “Immune-mediated kidney diseases”.
Nat Commun. 2023 Jan 28;14(1):473
- Gratulation allen Autoren!
Nächstes PoM: Die Publikation muss im März 2023 erschienen sein. Bewerbungen stehen für 2 Runden (Monate) zur Auswahl. Bitte senden Sie Ihre komplett ausgefüllte PoM-Bewerbung bis zum 31. März 2023 an Dr. Anne Wulf