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Recognition of galactose-deficient O-glycans in the hinge region of IgA1 by N-acetylgalactosamine-specific snail lectins: a comparative binding study.

ABSTRACT: Aberrancies in IgA1 glycosylation have been linked to the pathogenesis of IgA nephropathy (IgAN), a kidney disease characterized by deposits of IgA1-containing immune complexes in the glomerular mesangium. IgA1 from IgAN patients is characterized by the presence of galactose (Gal)-deficient O-glycans in the hinge region that can act as epitopes for anti-glycan IgG or IgA1 antibodies. The resulting circulating immune complexes are trapped in the glomerular mesangium of the kidney where they trigger localized inflammatory responses by activating mesangial cells. Certain lectins recognize the terminal N-acetylgalactosamine (GalNAc)-containing O-glycans on Gal-deficient IgA1 and can be potentially used as diagnostic tools. To improve our understanding of GalNAc recognition by these lectins, we have conducted binding studies to assess the interaction of Helix aspersa agglutinin (HAA) and Helix pomatia agglutinin (HPA) with Gal-deficient IgA1. Surface plasmon resonance spectroscopy revealed that both HAA and HPA bind to a Gal-deficient synthetic hinge region glycopeptide (HR-GalNAc) as well as various aberrantly glycosylated IgA1 myeloma proteins. Despite having six binding sites, both HAA and HPA bind IgA1 in a functionally bivalent manner, with the apparent affinity for IgA1 related to the number of exposed GalNAc groups in the IgA1 hinge. Finally, HAA and HPA were shown to discriminate very effectively between the IgA1 secreted by cell lines derived from peripheral blood cells of patients with IgAN and that from cells of healthy controls. These studies provide insight into lectin recognition of the Gal-deficient IgA1 hinge region and lay the groundwork for the development of reliable diagnostic tools for IgAN.

SUBMITTER: Gomes MM

PROVIDER: S-EPMC3721678 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Recognition of galactose-deficient O-glycans in the hinge region of IgA1 by N-acetylgalactosamine-specific snail lectins: a comparative binding study.

Gomes Michelle M MM Suzuki Hitoshi H Brooks Monica T MT Tomana Milan M Moldoveanu Zina Z Mestecky Jiri J Julian Bruce A BA Novak Jan J Herr Andrew B AB

Biochemistry 20100701 27

Aberrancies in IgA1 glycosylation have been linked to the pathogenesis of IgA nephropathy (IgAN), a kidney disease characterized by deposits of IgA1-containing immune complexes in the glomerular mesangium. IgA1 from IgAN patients is characterized by the presence of galactose (Gal)-deficient O-glycans in the hinge region that can act as epitopes for anti-glycan IgG or IgA1 antibodies. The resulting circulating immune complexes are trapped in the glomerular mesangium of the kidney where they trigg ...[more]

PMID: 20507092

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Project description:IntroductionPatients with IgA nephropathy (IgAN) have elevated serum levels of galactose-deficient IgA1 (Gd-IgA1) that are bound by Gd-IgA1-specific autoantibodies in pathogenic immune complexes. Renal biopsy histopathologic features of IgA vasculitis (IgAV) with nephritis (IgAV-N) are similar to those of IgAN. Mucosal infections often are associated with clinical onset and exacerbation in both diseases. We investigated whether patients with IgAV-N share pathogenic characteristics of IgAN.MethodsWe generated IgA1- and IgG-secreting cell lines from Epstein-Barr virus (EBV)-immortalized cells of patients with IgAV without nephritis (IgAV-woN), IgAV-N, and IgAN and from healthy individuals. Sera and cell-culture supernatants were used for analysis of Gd-IgA1 and Gd-IgA1-specific IgG autoantibodies.ResultsIgA1-producing cells from patients with IgAV-N, like cells from patients with IgAN, secreted more Gd-IgA1 than did cells from patients with IgAV-woN or healthy control subjects, in agreement with elevated serum Gd-IgA1 levels in patients with IgAV-N and IgAN. IgA1-producing cells from patients with IgAV-N had altered expression of genes involved in O-glycan biosynthesis: decreased for core 1 synthase (glycoprotein-N-acetylgalactosamine 3-β-galactosyltransferase 1; C1GALT1) and C1GALT1 Specific Chaperone 1 (C1GALTC1; COSMC) and elevated for N-acetylgalactosaminide α-2,6-sialyltransferase 2 (ST6GALNAC2). Levels of Gd-IgA1-specific IgG in sera and supernatants of IgG-producing cells were similar for patients with IgAV-N and IgAN and higher than those for IgAV-woN patients or healthy control subjects. Moreover, patients with IgAV-N who had active disease, manifested by hematuria and substantial proteinuria, had higher serum levels of Gd-IgA1-specific IgG autoantibodies than did patients with IgAV-N who had inactive disease.ConclusionSerum levels and cellular production of Gd-IgA1 and Gd-IgA1-specific IgG autoantibodies were elevated in patients with IgAV-N, supporting the hypothesis that IgAV-N and IgAN share pathogenic features.

Dataset Information

Recognition of galactose-deficient O-glycans in the hinge region of IgA1 by N-acetylgalactosamine-specific snail lectins: a comparative binding study.

Publications

Recognition of galactose-deficient O-glycans in the hinge region of IgA1 by N-acetylgalactosamine-specific snail lectins: a comparative binding study.

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