Kidney Int. 2025 Sep 29. pii: S0085-2538(25)00757-4. [Epub ahead of print]
INTRODUCTION: The discovery of anti-phospholipase A2 receptor 1 (PLA2R1) autoantibodies in patients with membranous nephropathy (MN) has led to a paradigm change in diagnosis, monitoring, risk prediction, and therapy of this autoimmune disease. However, there is only limited data on the pathogenicity of these autoantibodies.
METHODS: We purified the IgG from sera of patients with PLA2R1-associated MN and injected it into Rag2-deficient mice (mice lacking functional adaptive immunity) expressing human PLA2R1 in their podocytes. The IgG-depleted serum from the same patients and IgG purified from healthy individuals served as controls.
RESULTS: Two weeks after transfer, mice receiving anti-PLA2R1 IgG (largely IgG4), but not IgG-depleted serum or control IgG, developed proteinuria and showed granular deposition of human IgG and complement components of both the classical and alternative pathways in glomeruli by immunofluorescence and podocyte foot process effacement and subepithelial electron dense deposits in electron microscopy. There was no mouse IgG deposited. The IgG eluted from glomeruli of anti-PLA2R1 IgG-injected mice exclusively recognized PLA2R1.
CONCLUSIONS: Our findings provide evidence for a direct pathogenic role of anti-PLA2R1 autoantibodies, supporting the development of treatments aiming at the reduction of anti-PLA2R1 autoantibody levels.
Keywords: glomerular disease; glomerulonephritis; membranous nephropathy; podocyte