Structure and pathogenicity of antibodies specific for citrullinated collagen type II in experimental arthritis.

TY - JOUR

T1 - Structure and pathogenicity of antibodies specific for citrullinated collagen type II in experimental arthritis.

AU - Uysal, Hüseyin

AU - Bockermann, Robert

AU - Kutty Selva, Nandakumar

AU - Sehnert, Bettina

AU - Bajtner, Estelle

AU - Engström, Ake

AU - Serre, Guy

AU - Burkhardt, Harald

AU - Thunnissen, Marjolein

AU - Holmdahl, Rikard

N1 - The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Biochemistry and Structural Biology (S) (000006142), Medical Inflammation Research (013212019)

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

U2 - 10.1084/jem.20081862

DO - 10.1084/jem.20081862

M3 - Article

C2 - 19204106

VL - 206

SP - 449

EP - 462

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 1540-9538

IS - 2

ER -