title: O-linked glycosylation determines the nephritogenic potential of IgA rheumatoid factor.
abstract: Deficient glycosylation of O-linked glycans in the IgA1 hinge region is associated with IgA nephropathy in humans, but the pathogenic contribution of the underlying structural aberrations remains incompletely understood. We previously showed that mice implanted with cells secreting the class-switch variant 6-19 IgA anti-IgG2a rheumatoid factor, but not 46-42 IgA anti-IgG2a rheumatoid factor, develop glomerular lesions resembling IgA nephropathy. Because the levels of O-linked glycosylation in the hinge region and the structures of N-linked glycans in the CH1 domain differ in 6-19 IgA and 46-42 IgA, we determined the respective contributions of O- and N-linked glycans to the nephritogenic potential of the 6-19 IgA rheumatoid factor in mice. Wild-type 6-19 IgA secreted by implanted cells induced significant formation of glomerular lesions, whereas poorly O-glycosylated 6-19 IgA glycovariants or a 6-19 IgA hinge mutant lacking O-linked glycans did not. However, we observed no apparent heterogeneity in the structure of N-linked glycans attached to three different sites of the Fc regions of nephritogenic and non-nephritogenic 6-19 IgAs. Collectively, our data suggest a critical role of O-linked glycans attached to the hinge region in the development of IgA nephropathy-like GN induced by 6-19 IgA rheumatoid factor in mice.
authors: Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland; Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan;
authors: Masao
authors: M
authors: Kihara
authors: Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland;
authors: Kiyoaki
authors: K
authors: Ito
authors: Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland; Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan;
authors: Junichiro
authors: J
authors: Nakata
authors: Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland;
authors: Masako
authors: M
authors: Otani
authors: Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland;
authors: Ngoc Lan
authors: NL
authors: Tran
authors: Department of Nephrology, and.
authors: Naoki
authors: N
authors: Morito
authors: Department of Anatomy and Embryology, Life System Medical Sciences, Faculty of Medicine, and International Institute for Integrative Sleep Medicine, University of Tsukuba, Ibaraki, Japan; and.
authors: Satoru
authors: S
authors: Takahashi
authors: Department of Molecular Medicine, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.
authors: Yoshinao
authors: Y
authors: Wada
authors: Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland; Shozo.Izui@unige.ch.
authors: Shozo
authors: S
authors: Izui
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005920:Glomerular Mesangium / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005922:Glomerulonephritis, IGA / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D006020:Glycopeptides / Q000032:analysis / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D006825:Hybridomas; D007070:Immunoglobulin A / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D016296:Mutagenesis; D009844:Oligosaccharides / Q000032:analysis / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012217:Rheumatoid Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D000911:Antibodies, Monoclonal; D006020:Glycopeptides; D007070:Immunoglobulin A; D009844:Oligosaccharides; D012217:Rheumatoid Factor