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Abstract: FR-OR082

PLA2R1 as the Major Autoantigen in Membranous Nephropathy: From New Epitope Identification to Personalized Medicine

Session Information

Category: Glomerular Diseases

  • 1203 Glomerular Diseases: Clinical, Outcomes, and Trials

Authors

  • Justino, Joana, Institute of Molecular and Cellular Pharmacology, CNRS and University Cote d'Azur, Valbonne, France
  • Brglez, Vesna, Institute of Molecular and Cellular Pharmacology, CNRS and University Cote d'Azur, Valbonne, France
  • Dolla, Guillaume, Institute of Molecular and Cellular Pharmacology, CNRS and University Cote d'Azur, Valbonne, France
  • Zaghrini, Christelle, Institute of Molecular and Cellular Pharmacology, CNRS and University Cote d'Azur, Valbonne, France
  • Payre, Christine, Institute of Molecular and Cellular Pharmacology, CNRS and University Cote d'Azur, Valbonne, France
  • Seitz-Polski, Barbara, Pasteur University Hospital, Nice, France
  • Debiec, Hanna, Hospital Tenon, Sorbonne University, Paris, France
  • Ronco, Pierre M., Hospital Tenon, Sorbonne University, Paris, France
  • Lambeau, Gerard J., Institute of Molecular and Cellular Pharmacology, CNRS and University Cote d'Azur, Valbonne, France
Background

Membranous nephropathy (MN) is a rare autoimmune kidney disease yet the most common cause of nephrotic syndrome. Clinical evolution is complex and treatment controversial. There is a need for better biomarkers to identify patients at risk of severe disease and orient therapy. In 2009, PLA2R1 was identified as the major autoantigen, with circulating autoantibodies in 70% of patients. The severity of MN and clinical outcome is associated with anti-PLA2R1 titer and the presence of multiple antibodies. PLA2R1 epitopes have been identified in the CysR (CR), C1 and C7 domains and may be linked by a mechanism of epitope spreading. However, their exact number and location including controversial findings concerning their presence in the CR and C1 domains require further studies. The aim of this work was to clarify the number of PLA2R1 domains containing epitopes.

Methods

To clarify the conundrum between CR and C1 N-terminal domains, we expressed in HEK293 cells a series of CR-FnII-C1 triple domains with insertion of protease cleavage sites between each domain. Reactivities were tested with different patients’ sera before and after protease cleavage. To further investigate the number of epitope domains in the distal region of PLA2R1, we expressed a series of individual PLA2R1 domains and tested their reactivity for a cohort of >150 MN patients by ELISA.

Results

The triple domain CR-FnII-C1 was recognized by all patients’ sera when tested before cleavage. After cleavage releasing isolated domains, some sera had reactivities limited to CR or C1 while others reacted with both CR and C1, demonstrating the presence of independent epitopes targeted by different antibodies. The ELISA screening of a cohort of 150 patients towards individual PLA2R1 domains led us to identify C5 and C8 as two new epitope-containing domains.

Conclusion

Our results show that patient's autoantibodies can target up to 5 PLA2R1 domains: CR, C1, C5, C7 and C8 with different prevalence’s. The clinical association between reactivity towards these 5 PLA2R1 domains and disease activity is currently being analyzed and may help to design new diagnosis and prognosis tools towards better personalized medicine.

JJ and VB contributed equally as first authors.

Funding

  • Government Support - Non-U.S.