BAFF induces a hyper-IgA syndrome in the intestinal lamina propria concomitant with IgA deposition in the kidney independent of LIGHT

McCarthy, Douglas D.; Chiu, Sidney; Gao, Yunfei; Summers-Deluca, Leslie; Gommerman, Jennifer L.

doi:10.1016/j.cellimm.2006.08.002

Cited by 71 publications

(69 citation statements)

References 43 publications

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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%

“…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). This alternative switching of IgA could be due to the sufficient levels of BAFF produced locally in the intestine, although the levels of circulating BAFF are too low to trigger differentiation of B lymphoid cells.…”

Section: Discussionmentioning

confidence: 99%

“…The pivotal roles of BAFF in humoral immune responses have been clearly demonstrated in BAFFdeficient mice, which exhibit acute deficiencies in peripheral B cell development and maturation, as well as serious impairment of CD40-independent and T cell-dependent class-switch recombination to IgA in B cells (2,13,14). Epithelium-derived BAFF is the major trigger of Ig class switching in the subepithelial area of the intestine (15); thus, BAFF overexpression is associated with a hyper-IgA syndrome in the gut and deposition of IgA immune complexes in the glomerular mesangium (16). Overall, mounting evidence indicates that specific targeting of BAFF in association with the mucosal environment could provide a novel treatment for these disorders.…”

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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%

mentioning

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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“…Whereas IgA production is near normal in the absence of CD40, it is dramatically impaired in APRIL-or BAFF-deficient mice (27)(28)(29)(30). Moreover, the action of these molecules is independent of CD40 and TGFb (9,11,21,25).…”

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confidence: 99%

T Cell-Independent IgA Class Switch Recombination Is Restricted to the GALT and Occurs Prior to Manifest Germinal Center Formation

Bergqvist

Stensson

Lycke

et al. 2010

The Journal of Immunology

116

123

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Recently, we reported that CD40−/− mice, exhibiting exclusively T cell-independent IgA class switch recombination (CSR), demonstrated near normal levels of IgA plasma cells in the gut lamina propria (LP), despite the complete lack of germinal centers (GCs). In this study, we have extended our analysis focusing on how to reconcile these findings using flow cytometry and molecular markers for IgA CSR. In agreement with our previous results with small intestinal LP, the colon LP was found to host IgA CSR only when lymphoid follicles were present. Thus, no IgA CSR was observed in the nonorganized colon LP. By contrast, the Peyer’s patch (PP) was the dominant IgA CSR site in both CD40−/− and wild type (WT) mice, and they both hosted similar levels of mRNA expression for B cell activating factor of the TNF family, a proliferation inducing ligand, and inducible NO synthase, potential switch-factors for IgA. Unexpectedly, we found that PP B cells undergoing IgA CSR were GL7-intermediate. These cells had not undergone somatic hypermutations (SHMs), whereas GL7-high cells in WT PP, which exhibited GCs, were heavily mutated. Moreover, IgA plasma cells in the LP of CD40−/− mice demonstrated few mutations in their Ig V regions, whereas WT LP B cells from different sites showed extensive SHMs, which were also clonally related. Therefore, IgA CSR can occur in PP at a stage preceding manifest GC (GL7-intermediate), whereas SHM require GC formations (GL7-high). These findings reconcile that IgA CSR can occur in PP in the absence of GC with the fact that CD40−/− mice host near normal levels of IgA plasma cells in the LP.

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“…And these observations significantly correlate with IgA deposition in the glomerular mesangium. 22 In human, serum BAFF is elevated in patients with IgAN than controls and associated with clinical and histopathological features, including the levels of eGFR, serum creatinine, 24-h proteinuria, serum blood urea nitrogen, and serum uric acid, and the scores for mesangial hypercellularity, segmental glomerulosclerosis, and tubular atrophy/interstitial fibrosis. 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.…”

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

confidence: 99%

New insights into the pathogenesis of IgA nephropathy: do toll like receptor 9-B cell activation factor-IgA class switching recombination signaling axis induce IgA hyper-production?

Liu

Peng

et al. 2014

Renal Failure

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BAFF induces a hyper-IgA syndrome in the intestinal lamina propria concomitant with IgA deposition in the kidney independent of LIGHT

Cited by 71 publications

References 43 publications

SOCS3 Regulates BAFF in Human Enterocytes under Ribosomal Stress

SOCS3 Regulates BAFF in Human Enterocytes under Ribosomal Stress

T Cell-Independent IgA Class Switch Recombination Is Restricted to the GALT and Occurs Prior to Manifest Germinal Center Formation

New insights into the pathogenesis of IgA nephropathy: do toll like receptor 9-B cell activation factor-IgA class switching recombination signaling axis induce IgA hyper-production?

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