Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.724923
Title: Porphyromonas gingivalis peptidylarginine deiminase in the aetiology of rheumatoid arthritis
Author: Montgomery, Anna Barbara Kay
ISNI:       0000 0004 6421 4999
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2016
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Abstract:
Anti-citrullinated protein antibodies (ACPA) are the main autoantibodies in rheumatoid arthritis (RA). Citrullination is the conversion of arginine to citrulline by peptidylarginine deiminase (PAD) enzymes. Periodontitis (PD) is a risk factor for RA, and there is evidence this may be due to citrullination by the unique prokaryotic PAD enzyme expressed by PD pathogen Porphyromonas gingivalis (PPAD). The aim of this work was to characterise PPAD, and investigate its potential role in the aetiology of RA. The 3D crystal structure of PPAD was solved, and functional residues identified. The catalytic domain comprises five ββαβ motif repeats, which create a canonical binding groove into the active site, and the immunoglobulin-like domain is an anti-parallel β-sandwich. PPAD lacks significant homology to human PADs, and forms distinct citrullinated peptides from those formed by human PAD isoforms PAD2 and PAD4 due to unique C-terminal substrate specificity. In vivo, immunisation with P. gingivalis proteins: PPAD, arginine gingipain (Rgp), and enolase (PgEnolase), induced ACPA responses in mice. In human cohorts, antibodies to PPAD, Rgp, and PgEnolase were increased in RA patients compared to osteoarthritis or healthy controls, and in RA patients with PD compared to those without. Six months of PD treatment saw a significant reduction in antibodies to P. gingivalis in RA patients with PD, but no change in ACPA. These results demonstrate P. gingivalis induces ACPA responses comparable to those observed in RA, potentially through formation of novel citrullinated peptides by PPAD. Structural and mechanistic information obtained here can be used in future studies targeting PPAD as a potential therapeutic strategy in RA.
Supervisor: Venables, Patrick J. ; Yue, Wyatt Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.724923  DOI: Not available
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