Intrarenal production of B-cell survival factors in human lupus nephritis

Neusser, Matthias A.; Lindenmeyer, Maja T.; Edenhofer, Ilka; Gaiser, Stefanie; Kretzler, Matthias; Regele, Heinz; Segerer, Stephan; Cohen, Clemens D.

doi:10.1038/modpathol.2010.184

Cited by 62 publications

(42 citation statements)

References 47 publications

(65 reference statements)

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“…Therefore, it can be speculated that IFN-g2modulated BAFF expression in mucosal epithelial cells is responsible for diverse mucosa-associated diseases linked to intestinal inflammation and autoimmunity. Available evidence indicates that locally concentrated BAFF plays critical roles in a number of autoinflamed tissue types in which lymphoid neogenesis occurs (62)(63)(64)(65). Furthermore, increases in BAFF levels are positively correlated with the intensities of local inflammatory responses (10,66).…”

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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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%

SOCS3 Regulates BAFF in Human Enterocytes under Ribosomal Stress

Hun

Choi

Kim

et al. 2013

The Journal of Immunology

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“…71 Such B cells undergo intrarenal proliferation and activation, which contributes to local inflammation and tissue pathology in addition to their role for systemic and intrarenal autoantibody production. 26,72,73 These data provide a rationale for B celltargeted therapies in LN. 74,75 T cell infiltrates also contribute to immunopathology in LN, particularly IL-17 producing CD3 + /CD4 + or CD3 + CD4/8 2/2 T cells.…”

Section: Intrarenal Pathogenic Mechanisms Of Lnmentioning

confidence: 99%

The Pathogenesis of Lupus Nephritis

Lech¹,

Anders

2013

Journal of the American Society of Nephrology

366

282

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Lupus nephritis is an immune complex GN that develops as a frequent complication of SLE. The pathogenesis of lupus nephritis involves a variety of pathogenic mechanisms. The extrarenal etiology of systemic lupus is based on multiple combinations of genetic variants that compromise those mechanisms normally assuring immune tolerance to nuclear autoantigens. This loss of tolerance becomes clinically detectable by the presence of antinuclear antibodies. In addition, nucleic acids released from netting or apoptotic neutrophils activate innate and adaptive immunity via viral nucleic acid-specific Toll-like receptors. Therefore, many clinical manifestations of systemic lupus resemble those of viral infection. In lupus, endogenous nuclear particles trigger IFN-a signaling just like viral particles during viral infection. As such, dendritic cells, T helper cells, B cells, and plasma cells all contribute to the aberrant polyclonal autoimmunity. The intrarenal etiology of lupus nephritis involves antibody binding to multiple intrarenal autoantigens rather than the deposition of circulating immune complexes. Tertiary lymphoid tissue formation and local antibody production add to intrarenal complement activation as renal immunopathology progresses. Here we provide an update on the pathogenic mechanisms that lead to lupus nephritis and provide the rationale for the latest and novel treatment strategies.

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“…We selected these loci on the basis of previous studies and minor allele frequencies in Asians. 8,9,14,15 The major and minor alleles and genotype frequencies are described in Supplemental Table 2. Neither of the SNPs violated HardyWeinberg equilibrium (P.0.05).…”

Section: Baseline Characteristicsmentioning

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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Intrarenal production of B-cell survival factors in human lupus nephritis

Cited by 62 publications

References 47 publications

SOCS3 Regulates BAFF in Human Enterocytes under Ribosomal Stress

SOCS3 Regulates BAFF in Human Enterocytes under Ribosomal Stress

The Pathogenesis of Lupus Nephritis

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

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