title: Structure of human IgM rheumatoid factor Fab bound to its autoantigen IgG Fc reveals a novel topology of antibody-antigen interaction.
abstract: Rheumatoid factors are the characteristic autoantibodies of rheumatoid arthritis, which bind to the Fc regions of IgG molecules. Here we report the crystal structure of the Fab fragment of a patient-derived IgM rheumatoid factor (RF-AN) complexed with human IgG4 Fc, at 3.2 A resolution. This is the first structure of an autoantibody-autoantigen complex. The epitope recognised in IgG Fc includes the C gamma 2/C gamma 3 cleft region, and overlaps the binding sites of bacterial Fc-binding proteins. The antibody residues involved in autorecognition are all located at the edge of the conventional combining site surface, leaving much of the latter available, potentially, for recognition of a different antigen. Since an important contact residue is somatic mutation, the structure implicates antigen-driven selection, following somatic mutation of germline genes, in the production of pathogenic rheumatoid factors.
authors.affiliation: Randall Institute, King's College London, UK.
authors.forename: A L
authors.initials: AL
authors.lastname: Corper
authors.forename: M K
authors.initials: MK
authors.lastname: Sohi
authors.forename: V R
authors.initials: VR
authors.lastname: Bonagura
authors.forename: M
authors.initials: M
authors.lastname: Steinitz
authors.forename: R
authors.initials: R
authors.lastname: Jefferis
authors.forename: A
authors.initials: A
authors.lastname: Feinstein
authors.forename: D
authors.initials: D
authors.lastname: Beale
authors.forename: M J
authors.initials: MJ
authors.lastname: Taussig
authors.forename: B J
authors.initials: BJ
authors.lastname: Sutton
mesh_terms: D000937:Antigen-Antibody Reactions; D001324:Autoantigens / Q000737:chemistry*; D001426:Bacterial Proteins / Q000737:chemistry; D018360:Crystallography, X-Ray; D000939:Epitopes / Q000737:chemistry; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry*; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry; D007074:Immunoglobulin G / Q000737:chemistry; D007075:Immunoglobulin M / Q000737:chemistry*; D008958:Models, Molecular; D009844:Oligosaccharides / Q000737:chemistry; D012217:Rheumatoid Factor / Q000737:chemistry*; D013205:Staphylococcal Protein A / Q000737:chemistry
chemical_list: D001324:Autoantigens; D001426:Bacterial Proteins; D000939:Epitopes; C034284:IgG Fc-binding protein, Streptococcus; D007140:Immunoglobulin Fab Fragments; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D009844:Oligosaccharides; D013205:Staphylococcal Protein A; D012217:Rheumatoid Factor