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Abstract: PO1473

The Classical Pathway Triggers Pathogenic Complement Activation in Membranous Nephropathy

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Seifert, Larissa, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Zahner, Gunther, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Hickstein, Naemi Charlotte, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Köllner, Sarah, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Meyer-Schwesinger, Catherine, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Kylies, Dominik, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Borodovsky, Anna, Alnylam Pharmaceuticals Inc, Cambridge, Massachusetts, United States
  • Zipfel, Peter F., Leibniz-Institut fur Naturstoff-Forschung und Infektionsbiologie eV Hans-Knoll-Institut, Jena, Thüringen, Germany
  • Puelles, Victor G., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Panzer, Ulf, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Huber, Tobias B., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Wiech, Thorsten, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Tomas, Nicola M., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
Background

Membranous nephropathy (MN) is characterized by severe proteinuria, circulating autoantibodies against podocyte antigens such as PLA2R1 and THSD7A, and glomerular deposition of IgG and complement components (CCs). However, the pathways triggering the complement cascade (classical, alternative or lectin) and the significance of local glomerular complement action for podocyte damage and proteinuria are poorly understood.

Methods

Complement activation was investigated in 20 biopsies from patients with PLA2R1- and THSD7A-associated MN using immunofluorescence and proximity ligation assays to visualize the assembly of CCs/convertases. Experimental autoimmune MN (EAMN) was established in 12-week-old BALB/c mice by immunization with THSD7A. Anti-THSD7A antibodies, proteinuria, serum parameters, and histological signs of MN were analyzed. The role of the complement system was studied by induction of EAMN in C3-/- mice. The efficacy of complement-targeted treatment was evaluated by weekly injection of a C3-silencing siRNA after the onset of proteinuria.

Results

The assembly of the classical/lectin convertase was identified in 19/20 MN biopsies, which was accompanied by detection of IgG and C1q in the majority of cases. The alternative convertase and MBL deposits were detected in fewer cases. Upon immunization, mice developed clinical and histopathological features of MN. Proteinuria ranged from mild to severe nephrotic syndrome and histopathological features included granular glomerular deposition of IgG and CCs including C1q and C3 as well as loss of the integral podocyte proteins neph1 and nephrin. Strikingly, severe disease with ascites was prevented in C3-/- mice and overall proteinuria was reduced in comparison to WT littermates. Finally, treatment with C3-silencing siRNA after the onset of proteinuria attenuated disease.

Conclusion

The complement system is dominantly activated via the classical pathway in MN patients. Experimental data in the first autoimmune model involving an antigen that is pathogenically relevant in patients suggest complement-targeted treatment as a promising strategy for MN patients with severe disease, but also hint at a role of complement-independent mechanisms in the pathogenesis of MN.

Funding

  • Government Support – Non-U.S.