Heightened immune response to autocitrullinated Porphyromonas gingivalis peptidylarginine deiminase: A potential mechanism for breaching immunologic tolerance in rheumatoid arthritis

Anne Marie Quirke, Elena Birgitta Lugli, Natalia Wegner, Bart C. Hamilton, Peter Charles, Muslima Chowdhury, A. Jimmy Ytterberg, Roman A. Zubarev, Jan Potempa, Shauna Culshaw, Yonghua Guo, Benjamin A. Fisher, Geoffrey Thiele, Ted R. Mikuls, Patrick J.W. Venables

Research output: Contribution to journalArticle

110 Scopus citations

Abstract

Background Rheumatoid arthritis (RA) is characterised by autoimmunity to citrullinated proteins, and there is increasing epidemiologic evidence linking Porphyromonas gingivalis to RA. P gingivalis is apparently unique among periodontal pathogens in possessing a citrullinating enzyme, peptidylarginine deiminase (PPAD) with the potential to generate antigens driving the autoimmune response. Objectives To examine the immune response to PPAD in patients with RA, individuals with periodontitis (PD) and controls (without arthritis), confirm PPAD autocitrullination and identify the modified arginine residues. Methods PPAD and an inactivated mutant (C351A) were cloned and expressed and autocitrullination of both examined by immunoblotting and mass spectrometry. ELISAs using PPAD, C351A and another P gingivalis protein arginine gingipain (RgpB) were developed and antibody reactivities examined in patients with RA (n=80), individuals with PD (n=44) and controls (n=82). Results Recombinant PPAD was a potent citrullinating enzyme. Antibodies to PPAD, but not to Rgp, were elevated in the RA sera (median 122 U/ml) compared with controls (median 70 U/ml; p<0.05) and PD (median 60 U/ml; p<0.01). Specificity of the anti-peptidyl citrullinated PPAD response was confirmed by the reaction of RA sera with multiple epitopes tested with synthetic citrullinated peptides spanning the PPAD molecule. The elevated antibody response to PPAD was abolished in RA sera if the C351A mutant was used on ELISA. Conclusions The peptidyl citrulline-specific immune response to PPAD supports the hypothesis that, as a bacterial protein, it might break tolerance in RA, and could be a target for therapy.

Original languageEnglish (US)
Pages (from-to)263-269
Number of pages7
JournalAnnals of the rheumatic diseases
Volume73
Issue number1
DOIs
StatePublished - Jan 1 2014

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)

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    Quirke, A. M., Lugli, E. B., Wegner, N., Hamilton, B. C., Charles, P., Chowdhury, M., Ytterberg, A. J., Zubarev, R. A., Potempa, J., Culshaw, S., Guo, Y., Fisher, B. A., Thiele, G., Mikuls, T. R., & Venables, P. J. W. (2014). Heightened immune response to autocitrullinated Porphyromonas gingivalis peptidylarginine deiminase: A potential mechanism for breaching immunologic tolerance in rheumatoid arthritis. Annals of the rheumatic diseases, 73(1), 263-269. https://doi.org/10.1136/annrheumdis-2012-202726