title: Glycosylation changes of IgG associated with rheumatoid arthritis can activate complement via the mannose-binding protein.
abstract: The glycosylation of the circulating immunoglobulin-gamma (IgG) antibody molecules changes in rheumatoid arthritis. The extent of the changes correlates with the disease severity and reverses in remission. We demonstrate here that the alteration in glycosylation associated with rheumatoid arthritis can create a new mode for the interaction of IgG with complement through binding to the collagenous lectin mannose-binding protein (MBP). Rheumatoid arthritis is associated with a marked increases in IgG glycoforms that lack galactose (referred to as G0 glycoforms) in the Fc region of the molecule and that terminate in N-acetyl glucosamine (GlcNAc). We show, using nuclear magnetic resonance (NMR) and X-ray data, that these terminal GlcNAc residues become accessible for MBP binding. We further demonstrate that multiple presentation of IgG-G0 glycoforms to MBP results in activation of the complement. This suggests that a contribution to the chronic inflammation of the synovial membrane could arise from the localization of the IgG-G0 glycoforms in the affected joint and from resulting activation of complement.
authors.affiliation: Department of Biochemistry, University of Oxford, UK.
authors.forename: R
authors.initials: R
authors.lastname: Malhotra
authors.forename: M R
authors.initials: MR
authors.lastname: Wormald
authors.forename: P M
authors.initials: PM
authors.lastname: Rudd
authors.forename: P B
authors.initials: PB
authors.lastname: Fischer
authors.forename: R A
authors.initials: RA
authors.lastname: Dwek
authors.forename: R B
authors.initials: RB
authors.lastname: Sim
mesh_terms: D001172:Arthritis, Rheumatoid / Q000276:immunology*; D002240:Carbohydrate Sequence; D002352:Carrier Proteins / Q000378:metabolism*; D003167:Complement Activation; D003198:Computer Simulation; D006031:Glycosylation; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry / Q000276:immunology; D007074:Immunoglobulin G / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D037241:Mannose-Binding Lectins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D013582:Synovial Fluid / Q000276:immunology
chemical_list: D002352:Carrier Proteins; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D037241:Mannose-Binding Lectins