title: Structure and pathogenicity of antibodies specific for citrullinated collagen type II in experimental arthritis.
abstract: Antibodies to citrulline-modified proteins have a high diagnostic value in rheumatoid arthritis (RA). However, their biological role in disease development is still unclear. To obtain insight into this question, a panel of mouse monoclonal antibodies was generated against a major triple helical collagen type II (CII) epitope (position 359-369; ARGLTGRPGDA) with or without arginines modified by citrullination. These antibodies bind cartilage and synovial tissue, and mediate arthritis in mice. Detection of citrullinated CII from RA patients' synovial fluid demonstrates that cartilage-derived CII is indeed citrullinated in vivo. The structure determination of a Fab fragment of one of these antibodies in complex with a citrullinated peptide showed a surprising beta-turn conformation of the peptide and provided information on citrulline recognition. Based on these findings, we propose that autoimmunity to CII, leading to the production of antibodies specific for both native and citrullinated CII, is an important pathogenic factor in the development of RA.
authors.affiliation: Center for Molecular Protein Science, Biomedical Center I11, Lund University, 221 00 Lund, Sweden.
authors.forename: Hüseyin
authors.initials: H
authors.lastname: Uysal
authors.forename: Robert
authors.initials: R
authors.lastname: Bockermann
authors.forename: Kutty S
authors.initials: KS
authors.lastname: Nandakumar
authors.forename: Bettina
authors.initials: B
authors.lastname: Sehnert
authors.forename: Estelle
authors.initials: E
authors.lastname: Bajtner
authors.forename: Ake
authors.initials: A
authors.lastname: Engström
authors.forename: Guy
authors.initials: G
authors.lastname: Serre
authors.forename: Harald
authors.initials: H
authors.lastname: Burkhardt
authors.forename: Marjolein M G M
authors.initials: MM
authors.lastname: Thunnissen
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics*; D001169:Arthritis, Experimental / Q000276:immunology*; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D001483:Base Sequence; D002956:Citrulline / Q000276:immunology* / Q000378:metabolism; D024043:Collagen Type II / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D007140:Immunoglobulin Fab Fragments / Q000235:genetics; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017422:Sequence Analysis, DNA; D013582:Synovial Fluid / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D024043:Collagen Type II; D007140:Immunoglobulin Fab Fragments; D002956:Citrulline