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

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

doi:10.1172/jci.insight.81836

Cited by 58 publications

(44 citation statements)

References 91 publications

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“…Nevertheless, the researchers found that it was the delayed repopulation by classswitched memory B cells that was protective against disease relapse (as in SLE), again suggesting that depletion of memory B cells is therapeutic. A pathogenic role of B cells is consistent with data from a B cell-dependent in vivo mouse model of proteinuria in which podocyte damage was dependent on B cell-derived IL-4 (148). This cytokine is expressed at high levels by lymphocytes from paediatric patients with minimal change nephrotic syndrome when stimulated ex vivo (149).…”

Section: [H2] Kidney Transplantationsupporting

confidence: 81%

Effector and regulatory B cells in immune-mediated kidney disease

2018

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B cells have a central role in many autoimmune diseases, including in those with renal involvement, as well as in the immunological response to kidney transplantation. The majority of studies of B cells have focused on their pathological role as antibody producers. However, these cells have broad functions in immune responses beyond immunoglobulin secretion, including antigen presentation to T cells and cytokine production. Importantly, not all B cell subsets enhance immune responses. Regulatory B (Breg) cells attenuate inflammation and contribute to the maintenance of immune tolerance. Breg cells are numerically deficient and/or dysfunctional in several autoimmune diseases that can affect the kidney, including systemic lupus erythematosus and anti-neutrophil cytoplasmic antibody-associated vasculitis, as well as in some groups of renal transplant recipients with alloimmune graft damage. B cell-targeting biologics have been trialled with promising results in diverse immune-mediated renal conditions. These therapies can affect both pro-inflammatory B cells and Breg cells potentially limiting their long-term efficacy. Future strategies might involve the modulation of inflammatory B cells in combination with the stimulation of regulatory subsets. Additionally, the monitoring of individual B cell subsets in patients may lead to the discovery of novel biomarkers that could help to predict disease relapse or progression.

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Section: [H2] Kidney Transplantationsupporting

confidence: 81%

Effector and regulatory B cells in immune-mediated kidney disease

2018

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“…Kim et al 32 recently highlighted the importance of B cells and their cytokines in mediating proteinuria. Through in vitro experiments, they confirm that rituximab does not show binding to sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) receptor on the human embryonic kidney, 293T cells.…”

Section: Discussionmentioning

confidence: 99%

Rituximab modulates T- and B-lymphocyte subsets and urinary CD80 excretion in patients with steroid-dependent nephrotic syndrome

et al. 2018

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“…In human epithelial cells from airway, esophagus and intestine, the regulation of eotaxin-3 expression by IL-13 has been shown to require STAT6 activation [36]. IL-13 exposure causes STAT6 activation in up to one third of minimal change disease patients [37]. The above studies suggest that IL-13/STAT6 signaling pathway may play a key role in NS.…”

mentioning

confidence: 99%

Effects of Tristetraprolin on Doxorubicin (Adriamycin)-induced experimental nephrotic syndrome though inhibiting IL-13 /STAT6 signal pathway

Zhang¹,

Ge²,

Guo³

et al. 2019

Preprint

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Background: To study the effects of Tristetraprolin (TTP) on Doxorubicin (DOX)-induced experimental kidney injury (KI). Methods: DOX was used to induce kidney injury in Balb/c male mice (in vivo) and in human kidney proximal tubular epithelial cell line (HK-2) and normal rat kidney epithelial cell line (NRK-52E) (in vitro). Body weight of the animal groups under investigation were recorded daily throughout the experimental period. Histological changes were observed using Hematoxylin-eosin (HE) staining, and levels of blood urea nitrogen, serum creatinine and serum cystatin C in KI mice, and ROS, MDA, LDH and SOD in cells were detected using the corresponding kits. Meanwhile, intracellular levels of oxidative stress were assessed using 2, 7-dichlorodihydrofluorescein diacetate (DCF-DA) fluorescent staining. TTP and Kim-1 expression levels were measured by immunohistochemistry and western blot. The TNF-α, IL-1β and IL-6 levels were evaluated by ELISA. Expressions of IL-13, STAT6, p-STAT6, Bcl-2, Bax, cleaved-caspase3 were detected via western blot, respectively. CCK-8 was conducted for analyzing cell viability, and cells apoptosis were assessed by DAPI staining and flow cytometry. Results: DOX treatment decreased body weight and aggravated renal injury without changes in water and food intake. DOX significantly reduced TTP expression, stimulated IL-13/STAT6 pathway and elevated the levels of several factors related to renal injury, including inflammatory response, oxidative stress and cell apoptosis, which were significantly restored by the treatment of overexpression TTP in vitro. Conclusion: Overexpression of TTP significantly reduces DOX-induced adverse outcomes so as to prevent renal injury. Inhibition of IL-13/STAT6 pathway may be the functional mechanism under TTP in experimental KI.

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

Cited by 58 publications

References 91 publications

Effector and regulatory B cells in immune-mediated kidney disease

Effector and regulatory B cells in immune-mediated kidney disease

Rituximab modulates T- and B-lymphocyte subsets and urinary CD80 excretion in patients with steroid-dependent nephrotic syndrome

Effects of Tristetraprolin on Doxorubicin (Adriamycin)-induced experimental nephrotic syndrome though inhibiting IL-13 /STAT6 signal pathway

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