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

Hüseyin Uysal; Robert Bockermann; Kutty S Nandakumar; Bettina Sehnert; Estelle Bajtner; Ake Engström; Guy Serre; Harald Burkhardt; Marjolein M G M Thunnissen; Rikard Holmdahl

doi:10.1084/jem.20081862

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

Hüseyin Uysal, Robert Bockermann, Kutty S Nandakumar, Bettina Sehnert, Estelle Bajtner, Ake Engström, Guy Serre, Harald Burkhardt, Marjolein M G M Thunnissen, Rikard Holmdahl

168 Citations (Scopus)

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.

Original language	English
Journal	Journal of Experimental Medicine
ISSN	0022-1007
DOIs	https://doi.org/10.1084/jem.20081862
Publication status	Published - 2009

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10.1084/jem.20081862

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@article{1361a5e0f9e011ddb219000ea68e967b,

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.",

author = "H{\"u}seyin Uysal and Robert Bockermann and Nandakumar, {Kutty S} and Bettina Sehnert and Estelle Bajtner and Ake Engstr{\"o}m and Guy Serre and Harald Burkhardt and Thunnissen, {Marjolein M G M} and Rikard Holmdahl",

year = "2009",

doi = "10.1084/jem.20081862",

language = "English",

journal = "The Journal of Experimental Medicine",

issn = "0022-1007",

publisher = "Rockefeller University Press",

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TY - JOUR

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

AU - Uysal, Hüseyin

AU - Bockermann, Robert

AU - Nandakumar, Kutty S

AU - Sehnert, Bettina

AU - Bajtner, Estelle

AU - Engström, Ake

AU - Serre, Guy

AU - Burkhardt, Harald

AU - Thunnissen, Marjolein M G M

AU - Holmdahl, Rikard

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 - Journal article

C2 - 19204106

SN - 0022-1007

JO - The Journal of Experimental Medicine

JF - The Journal of Experimental Medicine

ER -

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

Abstract

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