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Type II collagen antibody response is enriched in the synovial fluid of rheumatoid joints and directed to the same major epitopes as in collagen induced arthritis in primates and mice

Ingrid Lindh1, Omri Snir24, Erik Lönnblom1, Hüseyin Uysal15, Ida Andersson1, Kutty Selva Nandakumar1, Michel Vierboom3, Bert 't Hart3, Vivianne Malmström2 and Rikard Holmdahl1*

Author Affiliations

1 Department of Medical Biochemistry and Biophysics, Section for Medical Inflammation Research, Karolinska Institutet, SE-171 77 Stockholm, Sweden

2 Department of Medicine, Rheumatology Unit, Karolinska University Hospital, SE-171 76 Stockholm, Sweden

3 Department of Immunobiology, Biomedical Primate Research Centre, 2280 GH Rijswijk, The Netherlands

4 Present address; Department of Immunology, Centre for Immune Regulation, Oslo University Hospital-Rikshospitalet, University of Oslo, 0424 Oslo, Norway

5 Present address; Department of Molecular Biology and Genetics, Çanakkale Onsekiz Mart Üniversity, 17020 Çanakkale, Turkey

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Arthritis Research & Therapy 2014, 16:R143  doi:10.1186/ar4605

Published: 8 July 2014



Antibodies towards type II collagen (CII) are detected in patients with rheumatoid arthritis (RA) and in non-human primates and rodents with collagen induced arthritis (CIA). We have previously shown that antibodies specific for several CII-epitopes are pathogenic using monoclonal antibodies from arthritic mice, although the role of different anti-CII epitopes has not been investigated in detail in other species. We therefore performed an inter-species comparative study of the autoantibody response to CII in patients with RA versus monkeys and mice with CIA.


Analysis of the full epitope repertoire along the disease course of CIA was performed using a library of CII triple-helical peptides. The antibody responses to the major CII epitopes were analyzed in sera and synovial fluid from RA patients, and in sera from rhesus monkeys (Macaca mulatta), common marmosets (Callithrix jacchus) and mice.


Many CII epitopes including the major C1, U1, and J1 were associated with established CIA and arginine residues played an important role in the anti-CII antibody interactions. The major epitopes were also recognized in RA patients, both in sera and even more pronounced in synovial fluid: 77% of the patients had antibodies to the U1 epitope. The anti-CII immune response was not restricted to the anti-citrulline protein antibodies (ACPA) positive RA group.


CII conformational dependent antibody responses are common in RA and are likely to originate from rheumatoid joints but did not show a correlation with ACPA response. Importantly, the fine specificity of the anti-CII response is similar with CIA in monkeys and rodents where the recognized epitopes are conserved and have a major pathogenic role. Thus, anti-CII antibodies may both contribute to, as well as be the consequence of, local joint inflammation.