Autoantibody-triggered podocyte membrane budding drives autoimmune kidney disease
Karen Lahme, Wiebke Sachs, Sarah Froembling, Desirée Loreth, Vincent Böttcher-Dierks, Katrin Neumann, Frederik-Michael Hann, Nick Arkan, Michael Brehler, Julia Reichelt, Antonia Sgries, Kristin Surmann, Simone Gaffling, Marie R. Adler, Pablo J. Sáez, Uta Wedekind, Alina Lampert, Elena Tasika, Paul Säftig, Christian Conze, Roland Thünauer, Sinah Skuza, Karen L. Neitzel, Stephanie Zielinski, Johannes Brand, Stefan Bonn, Stephan Michalik, Uwe Völker, Marina Zimmermann, Thorsten Wiech, Tobias Meyer, Lars Fester, Catherine Meyer‐Schwesinger
Abstract
Chronic kidney disease affects 1 in 10 people worldwide, with damage to specialized blood filter cells of the kidney, called podocytes, playing a critical role. In membranous nephropathy (MN), a major cause of nephrotic syndrome, circulating autoantibodies attack proteins on podocyte foot processes (FPs), damaging the kidney's filtration barrier. Our study shows that these autoantibodies trigger the formation of antigen-autoantibody aggregates on the podocyte FP plasma membrane. These aggregates bud off as stalked vesicles, termed autoimmunoglobulin-triggered extracellular vesicles (AIT-EVs), which are released into the urine. AIT-EVs carry disease-causing autoantibodies, their target antigens, essential FP proteins, and disease-associated stressors representing a mechanism for removing immune complexes (ICs) and waste. However, their excessive release leads to FP effacement and podocyte dysfunction. In MN patients, urinary AIT-EVs correspond to glomerular urinary-space aggregates. Enriching AIT-EVs enables detection and monitoring of pathogenic autoantibodies, suggesting a non-invasive approach for autoimmune kidney disease diagnosis and therapy.