title: Monoclonal IgG antibodies generated from joint-derived B cells of RA patients have a strong bias toward citrullinated autoantigen recognition.
abstract: 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.
authors: Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, SE-171 76 Solna, Stockholm, Sweden. Khaled.amara@ki.se
authors: Khaled
authors: K
authors: Amara
authors: Johanna
authors: J
authors: Steen
authors: Fiona
authors: F
authors: Murray
authors: Henner
authors: H
authors: Morbach
authors: Blanca M
authors: BM
authors: Fernandez-Rodriguez
authors: Vijay
authors: V
authors: Joshua
authors: Marianne
authors: M
authors: Engström
authors: Omri
authors: O
authors: Snir
authors: Lena
authors: L
authors: Israelsson
authors: Anca I
authors: AI
authors: Catrina
authors: Hedda
authors: H
authors: Wardemann
authors: Davide
authors: D
authors: Corti
authors: Eric
authors: E
authors: Meffre
authors: Lars
authors: L
authors: Klareskog
authors: Vivianne
authors: V
authors: Malmström
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D002956:Citrulline / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005340:Fibrinogen / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010751:Phosphopyruvate Hydratase / Q000276:immunology; D027041:Somatic Hypermutation, Immunoglobulin; D014746:Vimentin / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D001324:Autoantigens; D007074:Immunoglobulin G; D014746:Vimentin; D002956:Citrulline; D005340:Fibrinogen; D010751:Phosphopyruvate Hydratase