Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 210, Issue 3, Pages 445-455Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20121486
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Funding
- European Research Council [250167]
- Innovative Medicines Initiative Be The Cure Joint Undertaking program [115142-2]
- Swedish Combine program
- Swedish Association Against Rheumatism
- King Gustaf the V's 80-Year Foundation
- Swedish Research Council
- National Institutes of Health National Institute of Allergy and Infectious Diseases [AI071087]
- Deutsche Forschungsgemeinschaft (DFG) [MO 2160/2-1]
- European Research Council (ERC) [250167] Funding Source: European Research Council (ERC)
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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 similar to 25% of synovial IgG-expressing B cells to be specific for citrullinated auto-antigens 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 anti-gen. 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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