Cytokines Alter IgA1 O-Glycosylation by Dysregulating C1GalT1 and ST6GalNAc-II Enzymes

Suzuki, Hitoshi; Raška, Milan; Yamada, Koshi; Moldoveanu, Zina; Julian, Bruce A.; Wyatt, Robert; Tomino, Yasuhiko; Gharavi, Ali G.; Novák, Jan

doi:10.1074/jbc.m113.512277

Cited by 136 publications

(161 citation statements)

References 92 publications

(128 reference statements)

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“…These in silico predictions coupled with previous in vitro data demonstrating modulation of IgA1 O-galactosylation by Th2 cytokines and IL-6 36,37 , as well as our previous observation that IgA1 O-galactosylation varies depending on the site of antigen encounter and B cell activation 38 , are consistent with an effect of the H1 haplotype on transcriptional control of C1GALT1 particularly in IgA1-committed B cells.…”

Section: Discussionsupporting

confidence: 68%

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Galactosylation of IgA1 Is Associated with Common Variation in C1GALT1

Gale

Molyneux

Wimbury

et al. 2017

JASN

112

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IgA nephropathy (IgAN), an important cause of kidney failure, is characterized by glomerular IgA deposition and is associated with changes in O-glycosylation of the IgA1 molecule. Here, we sought to identify genetic factors contributing to levels of galactose-deficient IgA1 (Gd-IgA1) in Caucasian and Chinese populations.Gd-IgA1 levels were elevated in IgAN patients compared with ethnically matched healthy subjects and correlated with evidence of disease progression. Caucasian IgAN patients exhibited significantly higher Gd-IgA1 levels than Chinese patients. Among individuals without IgAN, Gd-IgA1 levels were not correlated with kidney function. Gd-IgA1 level heritability (h ). This association was replicated in GWAS of separate cohorts comprising: 308 UK patients with membranous glomerulonephritis (p<10

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Section: Discussionsupporting

confidence: 68%

“…Cytokines, and presumably other stimuli, acting in B cells can influence IgA1 galactosylation 37 , and likely contribute to the variability in Gd-IgA1 levels. Identification of the transcriptional mechanisms influencing C1GALT1 expression may provide insights into how Gd-IgA1 levels are controlled in health and disease.…”

Section: Discussionmentioning

confidence: 99%

Galactosylation of IgA1 Is Associated with Common Variation in C1GALT1

Gale

Molyneux

Wimbury

et al. 2017

JASN

112

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“…Previous studies revealed that cytokines, including interleukin-4 and interleukin-6, increased the production of GdIgA in Epstein-Barr virusimmortalized B cells from IgAN patients; and it is intriguing that interleukin-6 also increased the GdIgA level in healthy individuals. 23 In contrast to these findings regarding cytokines, our data, based on flow cytometry, real-time quantitative PCR, and RNA sequencing, do not support the notion that TNFSF13 dose of rhTNFSF13 used was 0.2 mg/ml. The doses of the receptor blockers were 5 mg/ml.…”

Section: Discussioncontrasting

confidence: 52%

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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“…An increase of Tn antigen on the T cell surface could be related to a reduced expression of the enzyme C1GalT1 or its molecular chaperone Cosmc, which has been reported to be altered by the presence of cytokines such as IL-6 and IL-4 (Suzuki et al 2014;Yamada et al 2010 (Yamada et al 2010), which could explain the alterations of core 1 expression on CD4 + T cells from active SLE patients that we described herein.…”

Section: Discussionmentioning

confidence: 55%

Differential Expression of O-Glycans in CD4<sup>+</sup> T Lymphocytes from Patients with Systemic Lupus Erythematosus

Ramos-Martínez

Lascuraín

Tenorio

et al. 2016

Tohoku J. Exp. Med.

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T cells from patients with systemic lupus erythematosus (SLE) show a decreased activation threshold and increased apoptosis. These processes seem to be regulated by glycosylated molecules on the T cell surface. Here, we determined through flow cytometry the expression of mucin-type O-glycans on T helper cells in peripheral blood mononuclear cells (PBMC) from 23 SLE patients and its relation with disease activity. We used lectins specific for the disaccharide Gal-GalNAc, such as Amaranthus leucocarpus lectin (ALL), Artocarpus integrifolia lectin (jacalin) and Arachis hypogaea lectin (peanut agglutinin, PNA), as well as lectins for sialic acid such as Sambucus nigra agglutinin (SNA) and Maakia amurensis agglutinin (MAA). The results showed that ALL, but not jacalin or PNA, identified significant differences in O-glycan expression on T helper cells from active SLE patients (n = 10). Moreover, an inverse correlation was found between the frequency of T helper cells recognized by ALL and SLE Disease Activity Index (SLEDAI) score in SLE patients. In contrast, SNA and MAA lectins did not identify any differences between CD4 + T cells from SLE patients. There was no difference in the recognition by ALL on activated T helper cells and T regulatory (Treg) cells. Our findings point out that activation of SLE disease diminishes the expression of O-glycans in T helper cells; ALL could be considered as a marker to determine activity of the disease.

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Cytokines Alter IgA1 O-Glycosylation by Dysregulating C1GalT1 and ST6GalNAc-II Enzymes

Cited by 136 publications

References 92 publications

Galactosylation of IgA1 Is Associated with Common Variation in C1GALT1

Galactosylation of IgA1 Is Associated with Common Variation in C1GALT1

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

Differential Expression of O-Glycans in CD4<sup>+</sup> T Lymphocytes from Patients with Systemic Lupus Erythematosus

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