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Abstract: SA-PO336

The Conformational Anti-Phospholipase A2 Receptor Autoantibodies in Primary Membranous Nephropathy

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation


  • Zhu, Quansheng, ImmunoWork, Monrovia, California, United States
  • Waldman, Meryl A., NIH, Bethesda, Maryland, United States
  • Kao, Liyo, Division of Nephrology, UCLA, Los Angeles, California, United States
  • Tang, Hong, ImmunoWork, Monrovia, California, United States

Primary membranous nephropathy (PMN) is a leading cause of nephrotic syndrome in adults. The dominant antigen, phospholipase A2 receptor (PLA2R) is detected in the subepithelial immune deposits in over 80% of the PMN patients. Anti-PLA2R autoantibodies (PLA2R-Ab) bind to PLA2Rs on the basal surface of the podocytes triggering immune complex formation in situ that impairs the glomerular filtration barrier function causing massive leakage of the plasma proteins into the urine. We and others determined that the dominant epitope for autoantibody binding is located at the N-terminus of PLA2R. Additional studies also reported that 3 independent epitopes are present in PLA2R and that epitope spreading occurs in the patients and is associated with disease progression. Here we further characterized the autoantibody-PLA2R epitope interaction using 48 patient samples.


48 PLA2R-Ab positive sera from patients with biopsy-proven MN were collected and assessed for their reactivities to PLA2R using Western-blot, immunoprecipitation under the native condition and immunodiffusion assays.


6 serum samples were identified to react strongly to the region of CysR-FnII-CTLD1-3, but weakly to the region of CysR-FnII-CTLD1 when diluted at 1:5000 on the Western-blot. 42 samples collected from patients who had relapsed disease all reacted strongly to the CysR-FnII-CTLD1 region at the same dilution. Follow-up studies in 3 patients who did not receive immunosuppressive treatment demonstrated that the autoantibodies initially reacted to the large CysR-FnII-CTLD1-3 region but later switched to the small CysR-FnII-CTLD1 region, coinciding with the worsening of proteinuria. Further analysis of autoantibody interaction with the purified PLA2R extracellular region in the immunodiffusion assay indicated that no insoluble lattice could be formed with any of the collected sera, suggesting that PLA2R is unlikely to have independent, separated epitopes in the extracellular region.


Our results indicated that two overlapping PLA2R epitope regions are present in the PMN patients with the autoantibody reaction to CysR-FnII-CTLD1-3 is likely to occur before the reaction to CysR-FnII-CTLD1. This data suggest that the overall conformation of PLA2R plays an important role in autoantibody formation and that autoantibody maturation is associated with PMN progression.