title: 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.
authors.affiliation: Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0524, USA.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Gomes
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Monica T
authors.initials: MT
authors.lastname: Brooks
authors.forename: Milan
authors.initials: M
authors.lastname: Tomana
authors.forename: Zina
authors.initials: Z
authors.lastname: Moldoveanu
authors.forename: Jiri
authors.initials: J
authors.lastname: Mestecky
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Julian
authors.forename: Jan
authors.initials: J
authors.lastname: Novak
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Herr
mesh_terms: D000116:Acetylgalactosamine / Q000276:immunology* / Q000378:metabolism; D000373:Agglutinins / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000888:Antibodies, Anti-Idiotypic; D000936:Antigen-Antibody Complex / Q000276:immunology / Q000378:metabolism; D001665:Binding Sites / Q000276:immunology; D000939:Epitopes / Q000276:immunology / Q000378:metabolism; D005690:Galactose / Q000276:immunology* / Q000378:metabolism; D005920:Glomerular Mesangium / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005922:Glomerulonephritis, IGA / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006031:Glycosylation; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood / Q000276:immunology / Q000378:metabolism; D007668:Kidney / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D037102:Lectins / Q000276:immunology / Q000378:metabolism*; D009194:Myeloma Proteins / Q000276:immunology / Q000378:metabolism; D011134:Polysaccharides / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D012908:Snails / Q000276:immunology / Q000378:metabolism
chemical_list: D000373:Agglutinins; D000888:Antibodies, Anti-Idiotypic; D000936:Antigen-Antibody Complex; D000939:Epitopes; C038095:Helix lectin; D007070:Immunoglobulin A; D037102:Lectins; D009194:Myeloma Proteins; D011134:Polysaccharides; C048844:anti-IgG; D000116:Acetylgalactosamine; D005690:Galactose