title: O-glycosylated IgA rheumatoid factor induces IgA deposits and glomerulonephritis.
abstract: Structural aberrations of O-linked glycans present in the IgA1 hinge region are associated with IgA nephropathy, but their contribution to its pathogenesis remains incompletely understood. In this study, mice implanted with hybridoma secreting 6-19 IgA anti-IgG2a rheumatoid factor, but not 46-42 IgA rheumatoid factor bearing the same IgA allotype, developed mesangial deposits consisting of IgA, IgG2a, and C3. Studies in immunoglobulin- and C3-deficient mice revealed that the development of these glomerular lesions required the formation of IgA-IgG2a immune complexes and subsequent activation of complement. The proportion of polymeric and monomeric forms, the IgG2a-binding affinity, and the serum levels of IgA-IgG2a immune complexes were similar between 6-19 IgA- and 46-42 IgA-injected mice. In contrast, the analysis of oligosaccharide structures revealed highly galactosylated O-linked glycans in the hinge region of 6-19 IgA and poorly O-glycosylated in the hinge region of 46-42 IgA. Furthermore, the structure of N-linked glycans in the CH1 domain was the complex type in 6-19 IgA and the hybrid type in 46-42 IgA. In summary, this study demonstrates the presence of O-linked glycans in the hinge region of mouse IgA and suggests that 6-19 IgA rheumatoid factor-induced GN could serve as an experimental model for IgA nephropathy.
authors.affiliation: Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
authors.forename: Masako
authors.initials: M
authors.lastname: Otani
authors.forename: Junichiro
authors.initials: J
authors.lastname: Nakata
authors.forename: Masao
authors.initials: M
authors.lastname: Kihara
authors.forename: Valérie
authors.initials: V
authors.lastname: Leroy
authors.forename: Solange
authors.initials: S
authors.lastname: Moll
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Wada
authors.forename: Shozo
authors.initials: S
authors.lastname: Izui
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000032:analysis; D003176:Complement C3 / Q000378:metabolism; D004195:Disease Models, Animal; D005921:Glomerulonephritis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D005922:Glomerulonephritis, IGA / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D006825:Hybridomas / Q000378:metabolism; D007070:Immunoglobulin A / Q000276:immunology / Q000378:metabolism*; D007126:Immunoglobulin Allotypes / Q000378:metabolism; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D012217:Rheumatoid Factor / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D003176:Complement C3; D007070:Immunoglobulin A; D007126:Immunoglobulin Allotypes; D007074:Immunoglobulin G; C042441:glycosylated IgA; D012217:Rheumatoid Factor