1. Pathogenicity of Human Anti-PLA2R1 Antibodies in Minipigs: A Pilot Study
- Author
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Linda Reinhard, Thorsten Wiech, Aline Reitmeier, Moritz Lassé, Maya Machalitza, Asmus Heumann, Nicoletta Ferru, Desiree Loreth, Marie-Luise Schröder, Arvid Hutzfeldt, Felix R. Stahl, Sven Peine, Hermann-Josef Gröne, Catherine Meyer-Schwesinger, Markus M. Rinschen, Rolf A.K. Stahl, and Elion Hoxha
- Subjects
Proteomics ,Virulence ,Swine ,Receptors, Phospholipase A2 ,Pilot Projects ,General Medicine ,Glomerulonephritis, Membranous ,Autoimmune Diseases ,Swine, Miniature/metabolism ,Proteinuria ,Nephrology ,Animals ,Humans ,Autoantibodies - Abstract
BACKGROUND: Primary membranous nephropathy (MN) is an autoimmune kidney disease in which immune complexes are deposited beneath the epithelium in the glomeruli. The condition introduces a high risk for end-stage kidney disease. Seventy to 80 percent of patients with MN have circulating antibodies against phospholipase A2 receptor 1 (PLA2R1), and levels correlate with treatment response and prognosis. However, experimental evidence that human anti-PLA2R1 antibodies induce MN has been elusive.METHODS: In passive transfer experiments, minipigs received plasma or purified IgG from patients with PLA2R1-associated MN or from healthy controls. Anti-PLA2R1 antibodies and proteinuria were monitored using Western blot, ELISA, and Coomassie staining. Kidney tissues were analyzed using immunohistochemistry, immunofluorescence, electron microscopy, and proteomic analyses.RESULTS: Minipigs, like humans, express PLA2R1 on podocytes. Human anti-PLA2R1 antibodies bound to minipig PLA2R1 in vitro and in vivo. Passive transfer of human anti-PLA2R1 antibodies from patients with PLA2R1-associated MN to minipigs led to histological characteristics of human early-stage MN, activation of components of the complement cascade, and low levels of proteinuria. We observed development of an autologous, later phase of disease.CONCLUSIONS: A translational approach from humans to minipigs showed that human anti-PLA2R1 antibodies are pathogenic in MN, although in the heterologous phase of disease only low-level proteinuria developed.
- Published
- 2023