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

Johanna Steen, Björn Forsström, Peter Sahlström, Victoria Odowd, Lena Israelsson, Akilan Krishnamurthy, Sara Badreh, Linda Mathsson Alm, Joanne Compson, Daniel Ramsköld, Welcome Ndlovu, Stephen Rapecki, Monika Hansson, Philip J. Titcombe, Holger Bang, Daniel L Mueller, Anca I. Catrina, Caroline Grönwall, Karl Skriner, Peter NilssonDaniel Lightwood, Lars Klareskog, Vivianne Malmström

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26 Scopus citations

Abstract

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 (mAb) 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 mAb (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 mAb to promote osteoclastogenesis were investigated. Results: Four unrelated anti–citrullinated protein autoantibodies (ACPAs), 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 ACPAs 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 mAb 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.

Original languageEnglish (US)
Pages (from-to)196-209
Number of pages14
JournalArthritis and Rheumatology
Volume71
Issue number2
DOIs
StatePublished - Feb 1 2019

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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    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, P. J., Bang, H., Mueller, D. L., Catrina, A. I., Grönwall, C., Skriner, K., ... Malmström, V. (2019). Recognition of Amino Acid Motifs, Rather Than Specific Proteins, by Human Plasma Cell–Derived Monoclonal Antibodies to Posttranslationally Modified Proteins in Rheumatoid Arthritis. Arthritis and Rheumatology, 71(2), 196-209. https://doi.org/10.1002/art.40699