Abstract: TH-PO0662
Immunodominant Epitope Patch on the CysR Domain of Phospholipase A2 Receptor 1 Is Targeted by Autoreactive PLA2R1 High-Affinity Memory B Cells Generated Through Somatic Mutations in Membranous Nephropathy
Session Information
- Glomerular Diseases: Immunopathogenesis and Targeted Therapeutics
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Montagner, Sara, Novartis AG, Basel, BS, Switzerland
- Reinhard, Linda, University Hospital of Hamburg - Eppendorf, Hamburg, HH, Germany
- Lavoisier, Alexandra, Novartis AG, Basel, BS, Switzerland
- Marchant, Martine, Novartis AG, Basel, BS, Switzerland
- Zhou, Zheng, Novartis AG, Basel, BS, Switzerland
- Iazeolla, Mariavittoria, Novartis AG, Basel, BS, Switzerland
- Welker, Nathalie, Novartis AG, Basel, BS, Switzerland
- Hoxha, Elion, University Hospital Würzburg Department of Nephrology, Würzburg, Bavaria, Germany
- Traggiai, Elisabetta, Novartis AG, Basel, BS, Switzerland
Background
Membranous Nephropathy (MN) is an autoantibody-mediated disease primarily targeting Phospholipase A2 Receptor1 (PLA2R1) on podocytes. The formation of immune complexes alters the structure and function of podocytes, disrupting the glomerular barrier. This study aims at characterizing the serological and memory cellular components in MN patients, with identification of dominant PLA2R1 epitopes recognized by circulating autoantibodies and autoreactive memory B cells, which could be potentially used to guide depletion of PLA2R1-specific B cells.
Methods
Anti-PLA2R1 serum response was evaluated with either Euroimmun kit or optimized ELISA for IgG subclasses or FLISA-based approach for affinity determination. Lymphocyte phenotype has been performed via flow cytometry. Patients’-derived anti-PLA2R1 antibodies have been isolated ex-vivo from IgG memory B cells and produced recombinantly.
Results
MN patients showed a high prevalence of anti-PLA2R1 antibodies in the serum, mostly high affine IgG4, with a broad concentration range (1-20ug/ml). IgG1 response versus the N-terminal region of PLA2R1 has been also detected in the serum in different proportion with IgG4. Consistently, a significant expansion of IgG4 memory B cells and plasma blast compartment and CX3CR1+ CD4+ T peripheral helper cells have been observed in MN-derived lymphocytes. Moreover, we isolated and cloned five very specific, highly affine, and somatically hypermutated patient’s derived anti-PLA2R1 antibodies. Interestingly, reversion of somatic mutations abolishes binding to PLA2R1. Competition experiments between patients’-derived monoclonal antibodies and independent MN sera showed inhibition of the binding capability to PLA2R1.
Conclusion
We showed that differences in the isotype composition of the immune response against the N-terminal immunodominant region of PLA2R1 at diagnosis can be associated with different disease progression (monitored as proteinuria remission). Inhibition of binding of sera autoantibodies by competing for an individual epitope suggests the presence of a shared epitope recognized on the surface of the CysR domain of PLA2R1 within the patients’ population.
Funding
- Commercial Support – Novartis