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Abstract Number: 1940

A Novel Murine Model of B Cell-Mediated Glomerular Injury Is Mediated By Cytokines

Alfred Kim1, Shreeram Akilesh2, Ania Koziell3, Sanjay Jain4, Jeffrey Hodgin5, Mark Miller6, Jeffrey Miner4 and Andrey Shaw7, 1IM/Div of Rheumatology, Washington Univ School of Med, St. Louis, MO, 2Pathology & Immunolog, Washington University School of Medicine, Saint Louis, MO, 3Experimental Immunobiology, King's College, London, United Kingdom, 4Renal Division, Washington University School of Medicine, Saint Louis, MO, 5Nephrology, University of Michigan, Ann Arbor, MI, 6Infectious Diseases, Washington University School of Medicine, Saint Louis, MO, 7Pathology & Immunology/HHMI, Washington University School of Medicine, Saint Louis, MO

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: B cells, cytokines and proteinuria

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Session Information

Session Title: B cell Biology and Targets in Autoimmune Disease: Systemic Lupus Erythematosus and Related Diseases

Session Type: Abstract Submissions (ACR)

Background/Purpose

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.

Methods

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.

Results

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.

Conclusion

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.


Disclosure:

A. Kim,

Pfizer Inc,

5,

Amgen,

5,

Janssen Pharmaceutica Product, L.P.,

5,

Kypha, Inc.,

2;

S. Akilesh,
None;

A. Koziell,
None;

S. Jain,
None;

J. Hodgin,
None;

M. Miller,
None;

J. Miner,
None;

A. Shaw,
None.

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