# Bacterial peptidylarginine deiminase, a link between gums and joint disease

> **NIH NIH R01** · UNIVERSITY OF LOUISVILLE · 2021 · $365,750

## Abstract

Summary
Porphyromonas gingivalis, a keystone pathogen in chronic periodontitis secretes a large variety of virulence
factors, including an enzyme, peptidylarginine deiminase (PAD), unique for pathogenic species of the
Porphyromonas genus. Alike human endogenous PADs, the bacterial enzyme converts arginine residues in
proteins to citrulline but it has a strong preference for C-terminal Arg. We postulated that P. gingivalis PAD
(PPAD) activity not only contributes to pathogenesis of periodontitis but also it may be involved in the
breakdown of immunotolerance and the development of rheumatoid arthritis (RA), a diseases driven by
autoantibodies targeting citrullinated epitopes. This contention is supported by findings that PPAD, in
conjunction with Arg-specific gingipain proteases (Rgps), can generate a large spectrum of citrullinated
peptides derived from bacterial and host proteins, including fibrinogen and enolase – both accepted
autoantigens in RA. Also, citrullinated proteins of P. gingivalis stimulate human gingival fibroblasts (HGF) to
produce prostaglandin E2 (PGE2), one of the most potent mediators of bone resorption implicated in the
pathogenesis of PD and RA. Moreover, our unpublished data show that both resting and P. gingivalis
citrullinome-stimulated HGFs, derived from periodontitis patients, produce significantly more PGE2 than cells
from healthy donors. Finally, we discovered two allelic forms of the ppad gene among P. gingivalis clinical
isolates, one encoding a superactive isoform of the enzyme, which crystal structure suggests that it binds
substrates with higher affinity than the other form of PPAD. The tighter substrate binding may contribute to
proposed second important function of PPAD as the carrier protein of haptens (bacteria and/or host protein-
derived citrullinated peptides) presented to B cell, followed by T cell activation and the breakdown of
immunotolerance in a hapten/carrier mechanism. Based on these findings we postulate that PPAD is directly
responsible for the breakdown of immunotolerance and subsequent anti-citrullinated protein antibody (ACPA)
production - key pathological events preceding clinical onset of RA; and the severity of PD and its link to RA is
associated with the occurrence of a superactive variant of PPAD expressed by subset of P. gingivalis strains.
To experimentally verify these hypotheses, we propose the following specific aims: (i) investigate the functional
relevance of citrullinated bacterial proteins in pathological interactions between P. gingivalis and fibroblasts; (ii)
determine if PPAD targeting by T cells provides help for the production of ACPA through a hapten/carrier
mechanism; and (iii) analyse the prevalence of P. gingivalis strains carrying the superactive PPAD gene in the
context of the severity of PD and relation to associated RA.
Successful completion of this project will drive the field forward by providing a novel perspective to the
understanding the pathogenesis of PD-RA as...

## Key facts

- **NIH application ID:** 10114904
- **Project number:** 5R01DE022597-08
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** JAN S POTEMPA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $365,750
- **Award type:** 5
- **Project period:** 2013-02-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10114904

## Citation

> US National Institutes of Health, RePORTER application 10114904, Bacterial peptidylarginine deiminase, a link between gums and joint disease (5R01DE022597-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10114904. Licensed CC0.

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