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¹ Center for Molecular Protein Science and ² Medical Inflammation Research, Biomedical Center I11, Lund University, 221 00 Lund, Sweden
³ Medical Inflammation Research, Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden
⁴ Nikolaus Fiebiger Centre of Molecular Medicine, Friedrich-Alexander-University of Erlangen-Nuremberg, 91054 Erlangen, Germany
⁵ Department of Medical Biochemistry and Microbiology, Biomedical Center, Uppsala University, 751 23 Uppsala, Sweden
⁶ Laboratory of Cell Biology and Cytology, Institut Fédératif de Biologie, Centre Hospitalier Universitaire de Toulouse, Institut Fédératif de Recherche 30, 31059 Toulouse Cedex 9, France
⁷ Division of Rheumatology, Johann Wolfgang Goethe-University, 60590 Frankfurt am Main, Germany

CORRESPONDENCE Rikard Holmdahl: Rikard.Holmdahl{at}ki.se OR Marjolein Thunnissen: Marjolein.Thunnissen{at}mbfys.lu.se

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 β-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.

Abbreviations used: ACPA, antibodies against citrullinated protein; CAIA, collagen antibody–induced arthritis; CDR, complementary determining region; CIA, collagen-induced arthritis; CII, collagen type II; BSA, buried accessible surface area; OA, osteoarthritis; PAD, peptidyl arginine deiminase; RA, rheumatoid arthritis; Reac A, reactive arthritis; RF, rheumatoid factor; RLU, relative luminescence unit.

© 2009 Uysal et al.
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