Session Type: Abstract Submissions (ACR)
Lupus nephritis (LN) remains the leading cause of mortality for SLE patients, and is associated with proteinuria and foot process effacement. 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. 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.
B cell model antigen model hen egg lysozyme (HEL) was biotinylated, complexed to avidin and injected into mice. Naive HEL-specific B cells were adoptively transferred and proteinuria assessed. Kidneys were processed for immunofluorescence and scanning electron microscopy (SEM). 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.
We identified IL-4 as a B cell derived cytokine capable of altering actin cytoskeletal dynamics by stimulating podocyte membrane ruffling (lamellipodia). In addition, IL-4 generated foot process retractions on ex vivo fragments of renal cortex. Using a novel model of B cell induced proteinuria, B cells polarized to secrete IL-4 upon activation induced proteinuria and focal foot process effacement without antibody or complement deposition. Intravital two-photon microscopy demonstrated that HEL-specific B cells arrested trafficking within glomeruli only in the presence of glomerular-localized HEL. Inhibition of IL-4 signaling with a JAK1/3 inhibitor markedly reduced proteinuria in IL-4 overexpressing mice. A subset of patients with steroid-sensitive nephrotic syndrome demonstrated glomerular STAT6 activation.
These findings suggest a potential explanation for the utility of immunosuppression and more targeted anti-B cell therapy with rituximab in the treatment of minimal change disease. These results supporting the role of IL-4 in human nephrotic syndromes and a novel therapeutic target.
Janssen Pharmaceutica Product, L.P.,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-novel-murine-model-of-b-cell-mediated-glomerular-injury-is-mediated-by-cytokines/