Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and α-enolase: Implications for autoimmunity in rheumatoid arthritis
By Natalia Wegner, R. Wait, Aneta Sroka, S. Eick, K. Nguyen, K. Lundberg, A. Kinloch, S. Culshaw, J. Potempa, P. Venables. Arthritis & Rheumatism, 2010
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Objectives To investigate protein citrullination by the periodontal pathogen Porphyromonas gingivalis (P. gingivalis) as a potential mechanism for breaking tolerance to citrullinated proteins in rheumatoid arthritis (RA). Methods Expression of endogenous citrullinated proteins was analysed by immunoblotting of cell extracts from P. gingivalis and ten other oral bacteria. P. gingivalis knockout strains lacking the bacterial PAD or gingipains were created to assess the role of these enzymes in citrullination. Citrullination of human fibrinogen and α-enolase by P. gingivalis was studied by incubating live wild-type and knockouts with the proteins and analysing the products by immunoblotting and mass spectrometry. Results Endogenous protein citrullination was abundant in P. gingivalis but lacking in the other oral bacteria. Deletion of the bacterial PAD gene resulted in complete abrogation of protein citrullination. Inactivation of arginine-gingipains, but not lysine-gingipains, led to decreased citrullination. Incubation of wild-type P. gingivalis with fibrinogen or α-enolase caused degradation of the proteins and citrullination of the resulting peptides at carboxy-terminal arginine residues, which were identified by mass spectrometry. Conclusion We demonstrate that P. gingivalis is unique amongst the tested oral bacterial pathogens in its ability to citrullinate proteins. We further show that P. gingivalis rapidly generates citrullinated host peptides by proteolytic cleavage at arginine-X peptide bonds by arginine-gingipains followed by citrullination of carboxy-terminal arginines by bacterial PAD. Our results suggest a novel model where P. gingivalis-mediated citrullination of bacterial and host proteins provides a molecular mechanism for generating antigens driving the autoimmune response in RA.
Subfields: Periodontics, Public Health, Environmental and Occupational Health, Rheumatology
View Paper: https://www.semanticscholar.org/paper/e03f9fde00e7695980c5b82b75b0c5b0142080ba
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In Rheumatology
Citations in the corpus
- Immunopathogenesis of rheumatoid arthritis (2017, neutral): “gingivalis could potentially citrullinate peptides in the oral mucosa that, in the context of inflammation, could promote ACPA generation (Wegner et al., 2010).”
- Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. (2012, neutral): “In addition, bacteria involved in periodontitis, such as Porphyromonas gingivalis , also strongly induce protein citrullination (3, 6).”
- Update on the Pathomechanism, Diagnosis, and Treatment Options for Rheumatoid Arthritis (2020, background): “gingivalis expressing PADi4 (facilitating the conversion of arginine to citrulline) promotes autoimmune responses as well as the downstream generation of anti-citrullinated protein antibodies (ACPAs) [12].”