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

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, peptidylargini...

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Autores principales: Quirke, Anne-Marie, Lugli, Elena Birgitta, Wegner, Natalia, Hamilton, Bart C, Charles, Peter, Chowdhury, Muslima, Ytterberg, A Jimmy, Zubarev, Roman A, Potempa, Jan, Culshaw, Shauna, Guo, Yonghua, Fisher, Benjamin A, Thiele, Geoffrey, Mikuls, Ted R, Venables, Patrick JW
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3888615/
https://www.ncbi.nlm.nih.gov/pubmed/23463691
http://dx.doi.org/10.1136/annrheumdis-2012-202726
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author Quirke, Anne-Marie
Lugli, Elena Birgitta
Wegner, Natalia
Hamilton, Bart C
Charles, Peter
Chowdhury, Muslima
Ytterberg, A Jimmy
Zubarev, Roman A
Potempa, Jan
Culshaw, Shauna
Guo, Yonghua
Fisher, Benjamin A
Thiele, Geoffrey
Mikuls, Ted R
Venables, Patrick JW
author_facet Quirke, Anne-Marie
Lugli, Elena Birgitta
Wegner, Natalia
Hamilton, Bart C
Charles, Peter
Chowdhury, Muslima
Ytterberg, A Jimmy
Zubarev, Roman A
Potempa, Jan
Culshaw, Shauna
Guo, Yonghua
Fisher, Benjamin A
Thiele, Geoffrey
Mikuls, Ted R
Venables, Patrick JW
author_sort Quirke, Anne-Marie
collection PubMed
description 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.
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spelling pubmed-38886152014-01-14 Heightened immune response to autocitrullinated Porphyromonas gingivalis peptidylarginine deiminase: a potential mechanism for breaching immunologic tolerance in rheumatoid arthritis Quirke, Anne-Marie Lugli, Elena Birgitta Wegner, Natalia Hamilton, Bart C Charles, Peter Chowdhury, Muslima Ytterberg, A Jimmy Zubarev, Roman A Potempa, Jan Culshaw, Shauna Guo, Yonghua Fisher, Benjamin A Thiele, Geoffrey Mikuls, Ted R Venables, Patrick JW Ann Rheum Dis Basic and Translational Research 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. BMJ Publishing Group 2014-01 2013-03-05 /pmc/articles/PMC3888615/ /pubmed/23463691 http://dx.doi.org/10.1136/annrheumdis-2012-202726 Text en Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/
spellingShingle Basic and Translational Research
Quirke, Anne-Marie
Lugli, Elena Birgitta
Wegner, Natalia
Hamilton, Bart C
Charles, Peter
Chowdhury, Muslima
Ytterberg, A Jimmy
Zubarev, Roman A
Potempa, Jan
Culshaw, Shauna
Guo, Yonghua
Fisher, Benjamin A
Thiele, Geoffrey
Mikuls, Ted R
Venables, Patrick JW
Heightened immune response to autocitrullinated Porphyromonas gingivalis peptidylarginine deiminase: a potential mechanism for breaching immunologic tolerance in rheumatoid arthritis
title Heightened immune response to autocitrullinated Porphyromonas gingivalis peptidylarginine deiminase: a potential mechanism for breaching immunologic tolerance in rheumatoid arthritis
title_full Heightened immune response to autocitrullinated Porphyromonas gingivalis peptidylarginine deiminase: a potential mechanism for breaching immunologic tolerance in rheumatoid arthritis
title_fullStr Heightened immune response to autocitrullinated Porphyromonas gingivalis peptidylarginine deiminase: a potential mechanism for breaching immunologic tolerance in rheumatoid arthritis
title_full_unstemmed Heightened immune response to autocitrullinated Porphyromonas gingivalis peptidylarginine deiminase: a potential mechanism for breaching immunologic tolerance in rheumatoid arthritis
title_short Heightened immune response to autocitrullinated Porphyromonas gingivalis peptidylarginine deiminase: a potential mechanism for breaching immunologic tolerance in rheumatoid arthritis
title_sort heightened immune response to autocitrullinated porphyromonas gingivalis peptidylarginine deiminase: a potential mechanism for breaching immunologic tolerance in rheumatoid arthritis
topic Basic and Translational Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3888615/
https://www.ncbi.nlm.nih.gov/pubmed/23463691
http://dx.doi.org/10.1136/annrheumdis-2012-202726
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