The Role of TNF Superfamily Member 13 in the Progression of IgA Nephropathy

Han, Seung Seok; Yang, Seung Hee; Choi, Murim; Kim, Hang Rae; Kim, Kwangsoo; Lee, Sang Moon; Moon, Kyung Chul; Kim, Joo Young; Lee, Hajeong; Jung, Ji Yong; Kim, Sejoong; Joo, Kwon Wook; Lim, Chun Soo; Kang, Shin Wook; Kim, Yon Su

doi:10.1681/asn.2015060677

Cited by 43 publications

(44 citation statements)

References 35 publications

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“…Among them, McCarthy et aldemonstrated higher serum APRIL levels measured by ELISA in a subset of patients with IgAN, these being higher levels related to creatinine and proteinuria. Similar findings were reported in 166 IgAN patients by Zhai et al, who also identified that plasma APRIL level was positively correlated with Gd‐IgA1 levels, and by Han et al who discovered that APRIL levels increased the risk of ESRD in 637 patients with IgAN. Moreover, aberrant APRIL overexpression in tonsillar germinal centers of IgAN patients relate to a greater proteinuria .…”

Section: Discussionsupporting

confidence: 85%

“…In a murine model of IgAN, treatment with an anti‐APRIL monoclonal antibody decreased albuminuria, histological damage, and IgA glomerular deposition . Lastly, some studies in humans have demonstrated that serum APRIL levels were higher in patients with IgAN and were also associated with a Gd‐IgA1 levels, a more severe histology, and worse renal function and proteinuria . Among them, McCarthy et aldemonstrated higher serum APRIL levels measured by ELISA in a subset of patients with IgAN, these being higher levels related to creatinine and proteinuria.…”

Section: Discussionmentioning

confidence: 97%

“…Genomewide association studies support the important role of APRIL in IgAN pathogenesis. Some TNFSF13 polymorphisms relate to a higher IgAN risk, higher proteinuria and lower renal function, and a higher risk for ESRD . Recent advances help recognize how APRIL contributes to IgAN appearance and progression.…”

Section: Discussionmentioning

confidence: 99%

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A proliferation‐inducing ligand increase precedes IgA nephropathy recurrence in kidney transplant recipients

Martín-Penagos

Benito-Hernández

Segundo

et al. 2019

Clinical Transplantation

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Background IgA nephropathy (IgAN) may recur in kidney transplant recipients. B‐cell‐activating factor (BAFF), a proliferation‐inducing ligand (APRIL), and α‐defensins are involved in the pathogenesis of native IgAN; however, their role on IgAN recurrence has not been previously analyzed. Methods Thirty‐five patients with IgAN who received a kidney transplant in our center between January 1, 1993, and December 31, 2015, were included. Recurrence was diagnosed and ruled out in 14 and 11 patients, respectively, by indication biopsies. Pre‐transplant, 6‐month, 1‐, 3‐, and 5‐year sera selected to measure BAFF, APRIL, and defensin by ELISA. Results Six months post‐transplantation, APRIL levels (300.1 vs 1203.8 pg/mL, P = 0.033) and the mean APRIL values from 6 months to 3 years (409.8 vs 1258.0 pg/mL, P = 0.003) were higher in recurrent patients. Both 6‐month APRIL levels (AUC‐ROC 0.753, P = 0.033) and mean APRIL values (AUC‐ROC 0.844, P = 0.004) discriminated patients with recurrence risk. By logistic regression, APRIL at 6 months (P = 0.044) and mean APRIL (P = 0.021) related to the risk of IgAN recurrence independently. Neither BAFF nor defensin related to recurrence. Conclusions Serum APRIL increased at 6 months and mean APRIL remained higher the first 3 years in patients in whom IgAN was going to recur.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 97%

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A proliferation‐inducing ligand increase precedes IgA nephropathy recurrence in kidney transplant recipients

Martín-Penagos

Benito-Hernández

Segundo

et al. 2019

Clinical Transplantation

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“…11,12,[14][15][16][17] Recently, high serum level of APRIL in patients with IgAN correlating with urinary proteins was reported. 18,19 In addition, a genomewide association study of patients with IgAN suggested APRIL (TNFSF13) to be a susceptibility gene. 20 However, the cellular source of APRIL production and the pathway by which this molecule is upregulated in IgAN remain ill defined.…”

mentioning

confidence: 99%

Toll-Like Receptor 9 Stimulation Induces Aberrant Expression of a Proliferation-Inducing Ligand by Tonsillar Germinal Center B Cells in IgA Nephropathy

Muto

Manfroi

Suzuki

et al. 2016

JASN

106

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The TNF family member a proliferation-inducing ligand (APRIL; also known as TNFSF13), produced by myeloid cells, participates in the generation and survival of antibody-producing plasma cells. We studied the potential role of APRIL in the pathogenesis of IgA nephropathy (IgAN). We found that a significant proportion of germinal centers (GCs) in tonsils of patients with IgAN contained cells aberrantly producing APRIL, contributing to an overall upregulation of tonsillar APRIL expression compared with that in tonsils of control patients with tonsillitis. In IgAN GC, antigen-experienced IgD+ B cells expressing a switched IgG/IgA B cell receptor produced APRIL. Notably, these GC B cells expressed mRNA encoding the common cleavable APRIL-a but also, the less frequent APRIL-d/z mRNA, which encodes a protein that lacks a furin cleavage site and is, thus, the uncleavable membrane-bound form. Significant correlation between TLR9 and APRIL expression levels existed in tonsils from patients with IgAN. In vitro, repeated TLR9 stimulation induced APRIL expression in tonsillar B cells from control patients with tonsillitis. Clinically, aberrant APRIL expression in tonsillar GC correlated with greater proteinuria, and patients with IgAN and aberrant APRIL overexpression in tonsillar GC responded well to tonsillectomy, with parallel decreases in serum levels of galactose-deficient IgA1. Taken together, our data indicate that antibody disorders in IgAN associate with TLR9-induced aberrant expression of APRIL in tonsillar GC B cells.

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“…MCP-1 induced mesangial cell proliferation and matrix deposition, and further aggravated renal damage [45][46][47][48][49]. TNF-α may be involved in IgAN crescent formation and is associated with the severity of renal interstitial fibrosis [30,[50][51][52][53], and GWAS indicated that TNF-α-related genes were associated with IgAN [54][55][56]. To further investigate the relationship between cytokine production and TLR4, we used TLR4 shRNA lentiviral transfection to silence TLR4 expression in HRMCs.…”

Section: Discussionmentioning

confidence: 99%

The TLR4-MyD88-NF-κB pathway is involved in sIgA-mediated IgA nephropathy

Zhou

Liu

et al. 2020

J Nephrol

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Previous studies have shown that secretory IgA (sIgA) was critically involved in IgA nephropathy (IgAN) immune responses. Toll-like receptors (TLRs), especially TLR4 which participates in mucosal immunity, may be involved in the pathogenesis of IgAN. The purpose of this study was to investigate whether sIgA and TLR4 interact to mediate kidney damage in IgAN patients. IgAN patients with positive sIgA deposition in renal tissues were screened by immunofluorescence assay. Patient salivary sIgA (P-sIgA) was collected and purified by jacalin affinity chromatography. Salivary sIgA from healthy volunteers was used as a control (N-sIgA). Expression of TLR4, MyD88, NF-κB, TNF-α, IL-6, and MCP-1 were detected in the mesangial area of IgAN patients by immunohistochemistry, the expression levels in patients with positive sIgA deposition were higher than that with negative sIgA deposition. Human renal mesangial cells (HRMCs) were cultured in vitro, flow cytometry showed that P-sIgA bound HRMCs significantly better than N-sIgA. HRMCs were cultured in the presence of sIgA (400 μg/ mL) for 24 h, compared with cells cultured with N-sIgA, HRMCs cultured in vitro with P-sIgA showed enhanced expression of TLR4, increased secretion of TNF-α, IL-6, and MCP-1, and increased expression of MyD88/NF-κB. TLR4 shRNA silencing and NF-κB inhibition both reduced the ability of HRMCs to synthesize TNF-α, IL-6, and MCP-1. Our results indicate that sIgA may induce high expression of TLR4 in HRMCs and further activate downstream signalling pathways, prompting HRMCs to secrete multiple cytokines and thereby mediating kidney damage in IgAN patients.

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The Role of TNF Superfamily Member 13 in the Progression of IgA Nephropathy

Cited by 43 publications

References 35 publications

A proliferation‐inducing ligand increase precedes IgA nephropathy recurrence in kidney transplant recipients

A proliferation‐inducing ligand increase precedes IgA nephropathy recurrence in kidney transplant recipients

Toll-Like Receptor 9 Stimulation Induces Aberrant Expression of a Proliferation-Inducing Ligand by Tonsillar Germinal Center B Cells in IgA Nephropathy

The TLR4-MyD88-NF-κB pathway is involved in sIgA-mediated IgA nephropathy

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