Antibodies to a Citrullinated Porphyromonas gingivalis Epitope Are Increased in Early Rheumatoid Arthritis, and Can Be Produced by Gingival Tissue B Cells: Implications for a Bacterial Origin in RA Etiology

Natalia Sherina, Charlotte de Vries, Nastya Kharlamova, Natalie Sippl, Xia Jiang, Boel Brynedal, Elin Kindstedt, Monika Hansson, Linda Mathsson-Alm, Lena Israelsson, Ragnhild Stålesen, Saedis Saevarsdottir, Rikard Holmdahl, Aase Hensvold, Gunnar Johannsen, Kaja Eriksson, Federica Sallusto, Anca I. Catrina, Johan Rönnelid, Caroline GrönwallTülay Yucel-Lindberg, Lars Alfredsson, Lars Klareskog, Luca Piccoli, Vivianne Malmström, Khaled Amara, Karin Lundberg*

*Corresponding author for this work

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Based on the epidemiological link between periodontitis and rheumatoid arthritis (RA), and the unique feature of the periodontal bacterium Porphyromonas gingivalis to citrullinate proteins, it has been suggested that production of anti-citrullinated protein antibodies (ACPA), which are present in a majority of RA patients, may be triggered in the gum mucosa. To address this hypothesis, we investigated the antibody response to a citrullinated P. gingivalis peptide in relation to the autoimmune ACPA response in early RA, and examined citrulline-reactivity in monoclonal antibodies derived from human gingival B cells. Antibodies to a citrullinated peptide derived from P. gingivalis (denoted CPP3) and human citrullinated peptides were analyzed by multiplex array in 2,807 RA patients and 372 controls; associations with RA risk factors and clinical features were examined. B cells from inflamed gingival tissue were single-cell sorted, and immunoglobulin (Ig) genes were amplified, sequenced, cloned and expressed (n=63) as recombinant monoclonal antibodies, and assayed for citrulline-reactivities by enzyme-linked immunosorbent assay. Additionally, affinity-purified polyclonal anti-cyclic-citrullinated peptide (CCP2) IgG, and monoclonal antibodies derived from RA blood and synovial fluid B cells (n=175), were screened for CPP3-reactivity. Elevated anti-CPP3 antibody levels were detected in RA (11%), mainly CCP2+ RA, compared to controls (2%), p<0.0001, with a significant association to HLA-DRB1 shared epitope alleles, smoking and baseline pain, but with low correlation to autoimmune ACPA fine-specificities. Monoclonal antibodies derived from gingival B cells showed cross-reactivity between P. gingivalis CPP3 and human citrullinated peptides, and a CPP3+/CCP2+ clone, derived from an RA blood memory B cell, was identified. Our data support the possibility that immunity to P. gingivalis derived citrullinated antigens, triggered in the inflamed gum mucosa, may contribute to the presence of ACPA in RA patients, through mechanisms of molecular mimicry.

Original languageEnglish
Article number804822
Pages (from-to)804822
JournalFrontiers in Immunology
Publication statusPublished - 20 Apr 2022

Bibliographical note

Funding Information:
This work was supported by grants from the Swedish Research Council (2017-01696), King Gustav V:s 80-year foundation (FAI-2016-0273), the Swedish Rheumatism foundation (R-931647), Professor Nanna Svartz’s foundation (2019-00292), and the EU/EFPIA Innovative Medicines Initiative Joint Undertaking RTCure (777357). FS and the Institute for Research in Biomedicine are supported by the Helmut Horten Foundation.

Funding Information:
We thank EIRA study participants, the EIRA study group, and patients donating tissue biopsies to the project, for their contributions. We would also like to thank Gloria Rostvall, Susana Hernandez Machado and Julia Norkko at Karolinska Institutet for managing the EIRA blood samples and biobank, as well as scientists involved in the generation of EIRA data: Dr Leonid Padyukov, Dr Patrick Stolt, and Dr Camilla Bengtsson. Also, Per Matsson, Mats Nystrand and Thomas Schlederer at Thermo Fisher Scientific for scientific support regarding the multiplex platform, and Michael Kramer, Institute for Research in Biomedicine, for work on BVCA1.

Publisher Copyright:
Copyright © 2022 Sherina, de Vries, Kharlamova, Sippl, Jiang, Brynedal, Kindstedt, Hansson, Mathsson-Alm, Israelsson, Stålesen, Saevarsdottir, Holmdahl, Hensvold, Johannsen, Eriksson, Sallusto, Catrina, Rönnelid, Grönwall, Yucel-Lindberg, Alfredsson, Klareskog, Piccoli, Malmström, Amara and Lundberg.

Other keywords

  • anti-citrullinated protein antibodies (ACPA)
  • B cells
  • monoclonal antibodies (mAbs)
  • periodontitis (PD)
  • Porphyromonas gingivalis (Pg)
  • rheumatoid arthritis (RA)


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