Porphyromonas gingivalis Facilitates the Development and Progression of Destructive Arthritis through Its Unique Bacterial Peptidylarginine Deiminase (PAD)

Katarzyna J Maresz,Malgorzata Benedyk,Karina Adamowicz,Ewa Bielecka,Danuta Mizgalska,Aneta Sroka,Joanna Koziel,Jan Potempa,Anne-Marie Quirke,Patrick J Venables,Katarzyna A Marcinska,Roland Jonsson,Katarzyna Gawron,Annelie Hellvard,Ky-Anh Nguyen,Krzysztof Pyrc,Saba Alzabin,Piotr Mydel

doi:10.1371/journal.ppat.1003627

Abstract

Rheumatoid arthritis and periodontitis are two prevalent chronic inflammatory diseases in humans and are associated with each other both clinically and epidemiologically. Recent findings suggest a causative link between periodontal infection and rheumatoid arthritis via bacteria-dependent induction of a pathogenic autoimmune response to citrullinated epitopes. Here we showed that infection with viable periodontal pathogen Porphyromonas gingivalis strain W83 exacerbated collagen-induced arthritis (CIA) in a mouse model, as manifested by earlier onset, accelerated progression and enhanced severity of the disease, including significantly increased bone and cartilage destruction. The ability of P. gingivalis to augment CIA was dependent on the expression of a unique P. gingivalis peptidylarginine deiminase (PPAD), which converts arginine residues in proteins to citrulline. Infection with wild type P. gingivalis was responsible for significantly increased levels of autoantibodies to collagen type II and citrullinated epitopes as a PPAD-null mutant did not elicit similar host response. High level of citrullinated proteins was also detected at the site of infection with wild-type P. gingivalis. Together, these results suggest bacterial PAD as the mechanistic link between P. gingivalis periodontal infection and rheumatoid arthritis.

Highlights

Rheumatoid arthritis (RA) and periodontal disease (PD) are two common chronic inflammatory diseases affecting humans with considerable consequences for public health and for the quality of life of affected individuals [1]
To document that P. gingivalis can impact on the initiation, rate of progression, and severity of arthritis we have adopted the collageninduced arthritis (CIA) model to quantify the contribution of infection with P. gingivalis in the disease process
Chamber contents were sampled via needle aspiration to assay for myeloperoxidase activity, level of protein citrullination and to confirm the presence of live bacteria. 29 days after subsequent collagen type II (CII) immunization, all animals inoculated with P. gingivalis wild-type strain W83 showed clinical signs of arthritis compared to only 28% of the control animals (p = 0.001, Fig. 1A)

Summary

Introduction

Rheumatoid arthritis (RA) and periodontal disease (PD) are two common chronic inflammatory diseases affecting humans with considerable consequences for public health and for the quality of life of affected individuals [1]. The resulting chronic inflammatory response by the host cause eventual destruction of the supporting structures of the teeth, leading to loss of the dentition in severe PD. Rheumatoid arthritis is an autoimmune disease with subsequent chronic inflammation responsible for bone and cartilage destruction within the joints [2,3]. Protein citrullination is carried out by endogenous peptidyl-arginine deiminases (PADs). These enzymes catalyze the conversion of peptidyl-arginine to peptidyl-citrulline, which is essential for many physiological processes [4]. PADcatalyzed protein citrullination occurs under pathological inflammatory conditions like necrosis and has been linked to the breakdown of immune tolerance to citrullinated proteins leading to induction of RA in susceptible individuals [5,6]

Methods

Results

Conclusion