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: Hüseyin Uysal, Robert Bockermann, Kutty S Nandakumar, Bettina Sehnert, Estelle Bajtner, Ake Engström, Guy Serre, Harald Burkhardt, Marjolein M G M Thunnissen, Rikard Holmdahl
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 206 Issue 2 Pg. 449-62 (Feb 16 2009) ISSN: 1540-9538 [Electronic] United States
• PMID: 19204106 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Collagen Type II
• Immunoglobulin Fab Fragments
• Citrulline

Topics

• Animals
• Antibodies, Monoclonal (genetics)
• Arthritis, Experimental (immunology)
• Autoimmunity (genetics, immunology)
• Base Sequence
• Citrulline (immunology, metabolism)
• Collagen Type II (immunology, metabolism)
• Enzyme-Linked Immunosorbent Assay
• Immunoglobulin Fab Fragments (genetics)
• Immunohistochemistry
• Immunoprecipitation
• Mice
• Models, Molecular
• Molecular Sequence Data
• Protein Conformation
• Sequence Analysis, DNA
• Synovial Fluid (immunology)