Glycosylation of Immunoglobulin A Influences Its Receptor Binding

Basset, Christelle; Devauchelle, Valérie; Durand, Véronique; Jamin, C; Pennec, Y.L.; Youinou, Pierre; Dueymes, Maryvonne

doi:10.1046/j.1365-3083.1999.00628.x

Cited by 50 publications

(32 citation statements)

References 24 publications

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“…Another study (49) that took both Fab and Fc glycosylation patterns in pSS patients into consideration reported that the proportion of sialylated IgA1 and IgA2 was increased in pSS patients compared with normal controls. This was postulated to decrease binding of IgA by immune receptors and result in altered clearance (50). We are currently evaluating as to whether our observations in pSS could be relevant in the context of other autoimmune diseases as well.…”

Section: Acquisition Of N-glycosylation Motifs On Frs Of Igg-producinmentioning

confidence: 95%

Ig Gene Analysis Reveals Altered Selective Pressures on Ig-Producing Cells in Parotid Glands of Primary Sjögren’s Syndrome Patients

Hamza

Hershberg

Kallenberg

et al. 2015

The Journal of Immunology

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In this study, we sought to understand the selective pressures shaping the Ig-producing cell repertoire in the parotid glands of primary Sjögren’s syndrome (pSS) patients before and after rituximab treatment (RTX). In particular, we evaluated the role of potential N-glycosylation motifs acquired by somatic hypermutation (ac-Nglycs) within Ig H chain V region (IGHV) genes as alternative selective pressures for B cells in pSS. Five pSS patients received RTX. Sequential parotid salivary gland biopsies were taken before RTX, at 12 wk and at 36–52 wk after treatment. Parotid biopsies from four non-pSS patients served as controls. Sequence analysis was carried out on the IgA and IgG RNA transcripts expressing IGHV3 genes in all parotid biopsies. Both IgG and IgA sequences from pSS patients exhibited no evidence for positive Ag-driven selection pressure in their CDRs in contrast to non-pSS controls. The prevalence of IgG sequences with ac-Nglycs was significantly higher in pSS patients than in non-pSS controls. Selection pressures shaping the IgG and IgA repertoire within pSS patients’ parotid glands are distinct from those in non-pSS controls, with very little evidence for positive (auto)antigen selection. The higher prevalence of ac-Nglycs on pSS-IgG compared with non-pSS IgG indicates that ac-Nglycs could be an alternative form of selection pressure. We speculate that B cell hyperproliferation within parotid glands of pSS patients may result from Ag-independent interactions such as that between glycosylated B cell receptors and lectins within the microenvironment rather than (auto)antigen-specific stimulation. Our study brings a new perspective into research on pSS.

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Section: Acquisition Of N-glycosylation Motifs On Frs Of Igg-producinmentioning

confidence: 95%

Ig Gene Analysis Reveals Altered Selective Pressures on Ig-Producing Cells in Parotid Glands of Primary Sjögren’s Syndrome Patients

Hamza

Hershberg

Kallenberg

et al. 2015

The Journal of Immunology

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“…Oversialylated IgA1 has a reduced affinity for ASPGR, which would reduce clearance by the liver and therefore lead to higher serum IgA1 levels [75]. Undersialylation and undergalactosylation lead to the aggregation of IgA1 in a hinge-specific manner [76], and undergalactosylation of IgA1 leads to increased adhesion to extracellular matrix proteins [77].…”

Section: Iga1 and Fcαri Aberrations Implicated In Iga Nephropathymentioning

confidence: 99%

IgA and IgA-specific receptors in human disease: structural and functional insights into pathogenesis and therapeutic potential

Gomes

Herr

2006

Springer Semin Immun

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IgA antibodies play an important role in humoral immunity. IgA is the predominant antibody in mucosal secretions and the second most prevalent in the serum. It occupies a unique position among human antibodies in that it can both trigger and suppress inflammatory responses, depending on the situation. Recent structural and functional studies have revealed details of the structure of IgA and its interaction with key cell-surface receptors. We look at the role IgA and IgA receptors (particularly FcalphaRI) play in the pathogenesis of diseases such as IgA nephropathy and other autoimmune conditions. Finally, we address the potential of IgA as a therapeutic tool to either trigger specific inflammatory responses to destroy target cells or suppress inflammatory responses in the case of autoimmune diseases, and the promise of mucosal vaccines for eliciting specific IgA responses to pathogens in mucosal environments.

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“…This aberrant glycosylation of serum IgA1 could favor self-aggregation and formation of macromolecular complexes including the anti-IgA1 hinge peptide antibody [Coppo and Amore, 2004;Iwase et al, 1999;Kokubo et al, 2000]. Abnormally glycosylated IgA1 may also escape clearance by hepatic receptors for asialoglycoproteins [Basset et al, 1999]. Previous studies by us and others demonstrated that IgA1 with aberrant O-glycosylation had a higher binding capacity and stronger biologic effect on cultured human mesangial cells, leading to accumulation and/or persistence of IgA deposits within the mesangium Wang et al, 2004].…”

Section: Introductionmentioning

confidence: 99%

Variants of theST6GALNAC2promoter influence transcriptional activity and contribute to genetic susceptibility to IgA nephropathy

Zhu

Zhang

et al. 2007

Hum. Mutat.

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IgA nephropathy (IgAN) is a polygenic disorder. Increasing evidence has implicated that aberrant glycosylation of IgA1 molecules, including alpha2,6 sialic acid defects, are involved in the pathogenesis of IgAN. In the present study, we designed an association study to investigate polymorphisms of two important genes, ST6GALNAC2 and NEU1, which are involved in the sialylation of the IgA1 molecule, in the susceptibility to IgAN. A total of 670 patients with histologically proven IgAN and 494 healthy controls were enrolled. Screening of SNPs in the coding and promoter regions of the ST6GALNAC2 and NEU1 genes was performed by sequencing. ST6-SNP1 (c.-988A>G), ST6-SNP2 [rs3840858:D>I(CGGC), c.-450_-449insCGGC], ST6-SNP3 (rs1867561:C>G, c.-135C>G), and ST6-SNP7 (rs2304921:G>A, c.186+12G>A) in the ST6GALNAC2 gene were selected as tagging SNPs. Functional evaluations of targets were assayed by luciferase activity. The alpha2,6 sialic acid contents of serum IgA1 in 497 patients were analyzed. Our results demonstrated that the frequency of haplotype ADG in the promoter region of ST6GALNAC2 was significantly higher in IgAN patients than that in controls (p=0.0069; odds ratio [OR]=1.36; 95% confidence interval [CI], 1.08-1.72). Furthermore, the ADG haplotype was associated with the deficient degrees of alpha2,6 sialic acid of IgA1 molecules in IgAN patients (r=0.408, p=0.0035). The ADG haplotype conferred significantly reduced promoter activity compared with the most common haplotype GDG in vitro (196.43+/-21.55 vs. 258.41+/-46.25; p=0.002). In the present study, we identified for the first time the ADG haplotype in the ST6GALNAC2 gene as a functional regulatory variant that may contribute to the genetic susceptibility in a subset of patients in whom the desialylation of IgA1 molecules was the main causative pathogenesis of IgAN.

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Glycosylation of Immunoglobulin A Influences Its Receptor Binding

Cited by 50 publications

References 24 publications

Ig Gene Analysis Reveals Altered Selective Pressures on Ig-Producing Cells in Parotid Glands of Primary Sjögren’s Syndrome Patients

Ig Gene Analysis Reveals Altered Selective Pressures on Ig-Producing Cells in Parotid Glands of Primary Sjögren’s Syndrome Patients

IgA and IgA-specific receptors in human disease: structural and functional insights into pathogenesis and therapeutic potential

Variants of theST6GALNAC2promoter influence transcriptional activity and contribute to genetic susceptibility to IgA nephropathy

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