Monoclonal IgG antibodies generated from joint-derived B cells of RA patients have a strong bias toward citrullinated autoantigen recognition

Amara, Khaled; Steen, Johanna; Murray, Fiona; Morbach, Henner; Fernandez-Rodriguez, Blanca M.; Joshua, Vijay; Engström, Marianne; Snir, Omri; Israelsson, Lena; Catrina, Anca I.; Wardemann, Hedda; Corti, Davide; Meffre, Eric; Klareskog, Lars; Malmström, Vivianne

doi:10.1084/jem.20121486

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Journal article

Monoclonal IgG antibodies generated from joint-derived B cells of RA patients have a strong bias toward citrullinated autoantigen recognition

Amara, Khaled Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, SE-171 76 Solna, Stockholm, Sweden
Steen, Johanna Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, SE-171 76 Solna, Stockholm, Sweden
Murray, Fiona Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, SE-171 76 Solna, Stockholm, Sweden
Morbach, Henner Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520
Fernandez-Rodriguez, Blanca M. Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Joshua, Vijay Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, SE-171 76 Solna, Stockholm, Sweden
Engström, Marianne Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, SE-171 76 Solna, Stockholm, Sweden
Snir, Omri Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, SE-171 76 Solna, Stockholm, Sweden
Israelsson, Lena Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, SE-171 76 Solna, Stockholm, Sweden
Catrina, Anca I. Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, SE-171 76 Solna, Stockholm, Sweden
Wardemann, Hedda Max Planck Research Group Molecular Immunology, Max Planck Institute for Infection Biology, D-10117 Berlin, Germany
Corti, Davide Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Meffre, Eric Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520
Klareskog, Lars Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, SE-171 76 Solna, Stockholm, Sweden
Malmström, Vivianne Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, SE-171 76 Solna, Stockholm, Sweden

25.02.2013

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The journal of experimental medicine. - 2013, vol. 210, no. 3, p. 445-455

English Antibodies targeting citrullinated proteins (ACPAs [anticitrullinated protein antibodies]) are commonly found in patients with rheumatoid arthritis (RA), strongly associate with distinct HLA-DR alleles, and predict a more aggressive disease course as compared with seronegative patients. Still, many features of these antibodies, including their site of production and the extent of MHC class II–driven T cell help, remain unclarified. To address these questions, we have used a single B cell–based cloning technology to isolate and express immunoglobulin (Ig) genes from joint-derived B cells of active RA patients. We found ∼25% of synovial IgG-expressing B cells to be specific for citrullinated autoantigens in the investigated ACPA+ RA patients, whereas such antibodies were not found in ACPA− patients. The citrulline-reactive monoclonal antibodies did not react with the unmodified arginine peptides, yet several reacted with more than one citrullinated antigen. A role for active antigen selection of the citrulline-reactive synovial B cells was supported by the strong bias toward amino acid replacement mutations in ACPA+ antibodies and by their loss of reactivity to citrullinated autoantigens when somatic mutations were reverted to the corresponding germline sequences.

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