Mice overexpressing BAFF develop a commensal flora–dependent, IgA-associated nephropathy

McCarthy, Douglas D.; Kujawa, Julie; Wilson, Cheryl A.; Papandile, Adrian; Poreci, Urjana; Porfilio, Elisa A.; Ward, Lesley A.; Lawson, Melissa A.; McCoy, Kathy D.; Pei, York; Novak, Lea; Lee, Jeannette; Julian, Bruce A.; Novák, Jan; Ranger, Ann; Gommerman, Jennifer L.; Browning, Jeffrey L.

doi:10.1172/jci62188

Cited by 41 publications

(77 citation statements)

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“…One potent lymphocyte modulator can be IFN-g2aug-mented BAFF in mucosal epithelial cells, which may account for diverse pathologic events linked to intestinal inflammation (15,25). Locally elevated IFN-g triggers a cascade of JAK/STAT1 signals via the cytokine receptor; this contributes to epithelial BAFF upregulation, which is associated with the features of autoimmune disease, such as B cell hyperplasia, circulating immune complexes, and IgA deposition in renal mesangium (16,66,67). In particular, BAFF overexpression leads to mucosal IgA class switching in a T cell-independent manner (16).…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, more profound factors in the mucosal niche must also be responsible for mucosa-associated renal pathogenesis. Commensal bacteria in mucosa are one such potent factor (e.g., BAFF overproduction causes commensal microflora-dependent IgA nephritis in animal models) (67). Moreover, the frontline epithelial production of BAFF is quite dependent on the epithelial recognition of luminal commensal microorganisms through TLRs, such as TLR3, for viral dsRNA (74).…”

Section: Discussionmentioning

confidence: 99%

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SOCS3 Regulates BAFF in Human Enterocytes under Ribosomal Stress

Hun

Choi

Kim

et al. 2013

The Journal of Immunology

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Although the activation of B cells in the gastrointestinal tract is of great importance in the context of immunity to pathogens and mucosal inflammatory diseases, little is known about the mechanisms responsible for the local activation of B cells in the subepithelial area of the intestine. Epithelium-derived BAFF is the major modulator of B cell development and Ig class switching. The present study was performed to address the molecular mechanism of BAFF expression in gut epithelial cells in the presence of proinflammatory stimuli. Inflammation-induced BAFF expression in mucosal epithelial cells might be responsible for diverse mucosa-associated diseases linked to intestinal inflammation and autoimmunity. Although BAFF was marginally expressed in unstimulated epithelial cells, BAFF mRNA was significantly upregulated by proinflammatory IFN-γ. Furthermore, IFN-γ triggered JAK/STAT1 signals via the cytokine receptor, which contributed to epithelial BAFF upregulation. In terms of signaling intervention, ribosomal insult attenuated IFN-γ–activated JAK/STAT signal transduction and subsequent BAFF induction in gut epithelial cells. Ribosomal insults led to the superinduction of SOCS3 by enhancing its mRNA stability via HuR RNA-binding protein. Upregulated SOCS3 then contributed to the blocking of the JAK/STAT-linked signal, which mediated BAFF suppression by ribosomal stress. All of these findings show that ribosomal stress–induced SOCS3 plays a novel regulatory role in epithelial BAFF production, suggesting that epithelial ribosomal dysfunction in association with SOCS3 may be a promising therapeutic point in BAFF-associated human mucosal diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

SOCS3 Regulates BAFF in Human Enterocytes under Ribosomal Stress

Hun

Choi

Kim

et al. 2013

The Journal of Immunology

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“…The level of TNFSF13 in patients with IgAN was significantly higher than in healthy subjects (median, 0 ng/ml [interquartile range, 0-0.448 ng/ml]; mean, 0.3760.79 ng/ml) ( Figure 1). The discrepancy in TNFSF13 16 When comparing the TNFSF13 levels with those of disease controls who had comparable eGFRs (except diabetic nephropathy), the plasma levels of patients with IgAN (median, 0.32 ng/ml; IQR, 0-1.202 ng/ml) were higher than those of patients with membranous nephropathy (median, 0 ng/ml; IQR, 0-0.673 ng/ml) but were not different from those of lupus nephritis patients (median, 0.1 ng/ml; IQR, 0-0.823 ng/ml) and patients with diabetic nephropathy (median, 0.74 ng/ml; IQR, 0.016-1.892 ng/ml). Their TNFSF13 levels were inversely related with baseline eGFR values except for the cases of membranous nephropathy (Supplemental Table 5).…”

Section: Plasma Tnfsf13 Levels and Clinical Outcomesmentioning

confidence: 99%

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

Han¹,

Yang

Choi

et al. 2016

JASN

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TNF superfamily member 13 (TNFSF13) has been identified as a susceptibility gene for IgA nephropathy in recent genetic studies. However, the role of TNFSF13 in the progression of IgA nephropathy remains unresolved. We evaluated two genetic polymorphisms (rs11552708 and rs3803800) and plasma levels of TNFSF13 in 637 patients with IgA nephropathy, and determined the risk of ESRD according to theses variable. Neither of the examined genetic polymorphisms associated with a clinical outcome of IgA nephropathy. However, high plasma levels of TNFSF13 increased the risk of ESRD. To explore the causal relationship and underlying mechanism, we treated B cells from patients (n=21) with or without recombinant human TNFSF13 (rhTNFSF13) and measured the expression of IgA and galactose-deficient IgA (GdIgA) using ELISA and flow cytometry. Treatment with rhTNFSF13 significantly increased the total IgA level among B cells, and TNFSF13 receptor blockade abrogated this increase. Furthermore, the absolute levels of GdIgA increased with rhTNFSF13 treatment, but the total IgA-normalized levels did not change. Both RNA sequencing and quantitative PCR results showed that rhTNFSF13 did not alter the expression of glycosyltransferase enzymes. These results suggest that high plasma TNFSF13 levels associate with a worse prognosis of IgA nephropathy through the relative increase in GdIgA levels.

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“…8 Furthermore, a study reported that in BAFF-Tg mice only with the participation of bacterial signals or antigens can induce increased IgA production and IgA deposition in the kidney. 23 Therefore, we may conclude that after MALT particularly tonsils infected by pathogenic bacterium which containing CpG-DNA, TLR9 recognize CpG-DNA and induce production of cytokines, for IFN-g instance, which up-regulate BAFF production, finally lead hyper-production of IgA.…”

Section: Baff: the Medium Of Tlr9 And Iga Hyper-production In Iganmentioning

confidence: 95%