Background Podocyte foot process effacement is a feature of proteinuria, thought to be a stereotyped response of the podocyte to injury. The stimulus for podocyte injury and foot process effacement is unknown, although changes in the actin cytoskeleton has been implicated. B cell depletion therapies have demonstrated efficacy in some patients with proteinuria including those with minimal change disease. Since pathogenic antibodies are not causative, we hypothesized that a B cell derived cytokine might be capable of directly inducing podocyte injury and foot process effacement.
Objectives Develop a B cell model of proteinuria in mice, and identify glomerulopathic cytokines derived from B cells.
Methods B cell model antigen model hen egg lysozyme (HEL) was biotinylated, complexed to avidin and injected into mice. HEL-specific B cells were adoptively transferred and proteinuria assessed. Two-photon microscopy was performed in vibrotomed kidneys following transfer of CFSE-labeled HEL-specific B cells with or without HEL antigen injection. Cultured podocyte membrane ruffling was assessed with DIC videomicroscopy. IL-4 expression in mice was achieved by hydrodynamically injecting murine IL-4 in the piggyBac vector system. Human kidney biopsies were assessed for phospho-STAT6 by immunohistochemistry.
Results We identified IL-4 as a B cell derived cytokine capable of stimulating podocyte actin rearrangement. Using a novel model of B cell induced proteinuria, B cells polarized to secrete IL-4 upon activation with HEL induced proteinuria without antibody or complement deposition. Using two-photon microscopy, we observed an accumulation of HEL-specific B cells within glomeruli containing HEL antigen.
To confirm the glomerulopathic properties of IL-4, we overexpressed IL-4 in mice and found this was sufficient to induce foot process effacement and proteinuria. Inhibition of IL-4 signaling with a JAK1/3 inhibitor markedly reduced proteinuria in these IL-4 overexpressing mice. Finally, a subset of patients (31%) with steroid-sensitive nephrotic syndrome possessed glomerular STAT6 activation.
Conclusions These findings suggest a potential explanation for the utility of immunosuppression and more targeted anti-B cell therapy with rituximab in the treatment of steroid-sensitive nephrotic syndromes. These results support the role of IL-4 in human nephrotic syndromes and represents a novel therapeutic target.
Disclosure of Interest A. Kim Grant/research support from: Rheumatology Research Foundation, Kypha Inc., S. Akilesh: None declared, A. Koziell: None declared, B. Saunders: None declared, S. Jain Grant/research support from: NIDDK/NIH, J. Hodgin Grant/research support from: NephCure/American Society of Nephrology, B. Zinselmeyer: None declared, T. Stappenback: None declared, J. Miner Grant/research support from: NIDDK/NIH, A. Shaw Employee of: Genentech, Inc.
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