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Objective  Antibodies against posttranslationally modified proteins are a hallmark of rheumatoid arthritis ( RA ), but the emergence and pathogenicity of these autoantibodies are still incompletely understood. The aim of this study was to analyze the antigen specificities and mutation patterns of monoclonal antibodies ( mA b) derived from  RA  synovial plasma cells and address the question of antigen cross‐reactivity.    Methods  IgG‐secreting cells were isolated from  RA  synovial fluid, and the variable regions of the immunoglobulins were sequenced (n = 182) and expressed in full‐length  mA b (n = 93) and also as germline‐reverted versions. The patterns of reactivity with 53,019 citrullinated peptides and 49,211 carbamylated peptides and the potential of the  mA b to promote osteoclastogenesis were investigated.    Results  Four unrelated anti–citrullinated protein autoantibodies ( ACPA s), of which one was clonally expanded, were identified and found to be highly somatically mutated in the synovial fluid of a patient with  RA . The  ACPA s recognized >3,000 unique peptides modified by either citrullination or carbamylation. This highly multireactive autoantibody feature was replicated for Ig sequences derived from B cells from the peripheral blood of other  RA  patients. The plasma cell–derived  mA b were found to target distinct amino acid motifs and partially overlapping protein targets. They also conveyed different effector functions as revealed in an osteoclast activation assay.    Conclusion  These findings suggest that the high level of cross‐reactivity among  RA  autoreactive B cells is the result of different antigen encounters, possibly at different sites and at different time points. This is consistent with the notion that  RA  is initiated in one context, such as in the mucosal organs, and thereafter targets other sites, such as the joints.

arthritis and rheumatology

Recognition of Amino Acid Motifs, Rather Than Specific Proteins, by Human Plasma Cell–Derived Monoclonal Antibodies to Posttranslationally Modified Proteins in Rheumatoid Arthritis