B cell–derived IL-4 acts on podocytes to induce proteinuria and foot process effacement
Alfred H.J. Kim, Jun-Jae Chung, Shreeram Akilesh, Ania Koziell, Sanjay Jain, Jeffrey B. Hodgin, Mark J. Miller, Thaddeus S. Stappenbeck, Jeffrey H. Miner, Andrey S. Shaw
Alfred H.J. Kim, Jun-Jae Chung, Shreeram Akilesh, Ania Koziell, Sanjay Jain, Jeffrey B. Hodgin, Mark J. Miller, Thaddeus S. Stappenbeck, Jeffrey H. Miner, Andrey S. Shaw
View: Text | PDF
Research Article Immunology Nephrology

B cell–derived IL-4 acts on podocytes to induce proteinuria and foot process effacement

Abstract

The efficacy of B cell depletion therapies in diseases such as nephrotic syndrome and rheumatoid arthritis suggests a broader role in B cells in human disease than previously recognized. In some of these diseases, such as the minimal change disease subtype of nephrotic syndrome, pathogenic antibodies and immune complexes are not involved. We hypothesized that B cells, activated in the kidney, might produce cytokines capable of directly inducing cell injury and proteinuria. To directly test our hypothesis, we targeted a model antigen to the kidney glomerulus and showed that transfer of antigen-specific B cells could induce glomerular injury and proteinuria. This effect was mediated by IL-4, as transfer of IL-4–deficient B cells did not induce proteinuria. Overexpression of IL-4 in mice was sufficient to induce kidney injury and proteinuria and could be attenuated by JAK kinase inhibitors. Since IL-4 is a specific activator of STAT6, we analyzed kidney biopsies and demonstrated STAT6 activation in up to 1 of 3 of minimal change disease patients, suggesting IL-4 or IL-13 exposure in these patients. These data suggest that the role of B cells in nephrotic syndrome could be mediated by cytokines.

Authors

Alfred H.J. Kim, Jun-Jae Chung, Shreeram Akilesh, Ania Koziell, Sanjay Jain, Jeffrey B. Hodgin, Mark J. Miller, Thaddeus S. Stappenbeck, Jeffrey H. Miner, Andrey S. Shaw

×

Figure 6

HEL-specific IL-4–secreting B cells generated proteinuria in mice treated with multimerized HEL.

Options: View larger image (or click on image) Download as PowerPoint
HEL-specific IL-4–secreting B cells generated proteinuria in mice treate...
(A) HEL-specific B cells were either polarized in vitro into B effector 2 (Be2) cells to produce IL-4, or left unpolarized, and then stimulated through the B cell receptor with anti-μ antibody overnight. Only Be2-polarized B cells secreted IL-4 into the supernatant, as measured by ELISA. (B) Coomassie blue–stained SDS-PAGE and (C) spot albumin/creatinine ratios of urine from mice treated with multimerized HEL, followed by transfer of either Be2-polarized HEL-specific B cells or IL-4–deficient, Be2-polarized HEL-specific B cells. Proteinuria was observed only when B cells were capable of producing IL-4. Urine was collected 24 hours after B cell transfer. Symbols represent individual mice, and bars represent the mean. (D) Representative still images obtained from intravital 2-photon microscopy movies (Supplemental Videos 3 and 4) of mice injected with PBS (top) or multimerized HEL (bottom), followed by the transfer of fluorescently labeled HEL-specific B cells. When glomerular HEL was present, HEL-specific B cells arrested within glomeruli. In the absence of HEL, B cell trafficking through glomeruli was not changed. Quantum dots were injected i.v. to identify glomeruli and vessels. Glomeruli are outlined in circles. Red: glomeruli and vessels; blue: renal tubules; yellow: HEL-specific B cells. Original magnification, ×20. Mean ± SD of 2 experiments, with a total of 5 mice/group. *P < 0.001, **P < 0.008 by 2-tailed Mann-Whitney.