Structure and pathogenicity of antibodies specific for citrullinated collagen type II in experimental arthritis.
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.
Uysal
Hüseyin
H
Center for Molecular Protein Science, Biomedical Center I11, Lund University, 221 00 Lund, Sweden.
Bockermann
Robert
R
Nandakumar
Kutty S
KS
Sehnert
Bettina
B
Bajtner
Estelle
E
Engström
Ake
A
Serre
Guy
G
Burkhardt
Harald
H
Thunnissen
Marjolein M G M
MM
Holmdahl
Rikard
R
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
D000911:Antibodies, Monoclonal; D024043:Collagen Type II; D007140:Immunoglobulin Fab Fragments; D002956:Citrulline