Steen J, Forsström B, Sahlström P, Odowd V, Israelsson L, Krishnamurthy A, Badreh S, Mathsson Alm L, Compson J, Ramsköld D, Ndlovu W, Rapecki S, Hansson M, Titcombe PJ, Bang H, Mueller DL, Catrina AI, Grönwall C, Skriner K, Nilsson P, Lightwood D, Klareskog L, Malmström V
Arthritis & rheumatology (Hoboken, N.J.) - (-) - [2018-08-27; online 2018-08-27]
Antibodies against post-translationally modified (PTM) proteins are a hallmark of rheumatoid arthritis (RA), but the emergence and pathogenicity of these autoantibodies are still incompletely understood. We aimed to analyze the antigen specificities and mutation patterns of monoclonal antibodies derived from RA synovial plasma cells and address the question of antigen cross reactivity. 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 antibodies (n=93) and also as germline reverted versions. The reactivity pattern to 53019 citrullinated and 49211 carbamylated peptides were investigated, as was the potential of the antibodies to promote osteoclastogenesis. Four unrelated anti-citrullinated protein autoantibodies, of which one was clonally expanded, were identified and found to be highly somatically mutated. The autoantibodies recognized >3000 unique peptides modified by either citrullination or carbamylation. This highly multireactive autoantibody feature was replicated for Ig sequences derived from B cells from blood of other RA patients. The plasma cell-derived monoclonal antibodies were found to target distinct amino acid motifs and partially overlapping protein targets. They also conveyed different effector functions in an osteoclast activation assay. Our findings suggest that the high level of cross reactivity amongst the RA autoreactive B cells is the result of different antigen encounters, possibly at different sites and at different time points. This is in line with the notion that RA is initiated in one context, such as in mucosal organs, and thereafter target other sites, such as joints. This article is protected by copyright. All rights reserved.
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