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

Date Published: September 12, 2013

Publisher: Public Library of Science

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

http://doi.org/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.

Partial Text

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]. In the case of PD, inflammation is initiated and perpetuated by a subset of bacteria, including Porphyromonas gingivalis, which colonize the gingival sulcus and proliferate in the subgingival plaque. 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. In contrast, rheumatoid arthritis is an autoimmune disease with subsequent chronic inflammation responsible for bone and cartilage destruction within the joints [2], [3]. Antibodies against citrullinated proteins are known to be a specific marker that can be detected years before the onset of the disease and their presence and serum levels correlate strongly with disease severity. 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]. However, PAD-catalyzed protein citrullination also 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].

Across millennia, oral health status, as evaluated by tooth decay, has been a prognostic indicator of general health in humans. As early as 400 BC, Hippocrates noted the association with ‘rheumatism’ by describing a case of joint pain that was successfully treated by tooth extraction [12]. Within the last 20 years, this correlation has been strengthened clinically and epidemiologically but the mechanistic link between periodontitis and RA has remained elusive. Now, there is an increasing body of evidence that severity of periodontitis is not only related to progression of RA, but also that the profile of oral microbiota in patients with new onset RA is extremely similar to that in patients suffering from chronic RA [28], [29]. Here, for the first time, we demonstrate that infection with P. gingivalis not only exacerbates CIA but also appears to play a role in sensitizing animals to early disease development. The arthritis that occurred in mice infected with P. gingivalis was characterized by significantly greater bone and cartilage destruction in the affected joints. These clinical signs of arthritis manifested significantly earlier and were accompanied by a more severe disease course than in non-infected animals. Moreover, aggravation of these RA-associated pathologies was shown to be dependent on PPAD activity which either directly or indirectly via enhancement of inflammatory reaction and release of host PADs leads to generation of citrullinated neo-epitopes. Regardless of the mechanism the presented data implicates that PPAD, which among prokaryotes is unique to P. gingivalis, is a possible trigger of a pathogenic autoimmune response leading to RA development or at least may aggravate the course of the disease.

 

Source:

http://doi.org/10.1371/journal.ppat.1003627

 

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