Elsevier

Medical Hypotheses

Volume 72, Issue 6, June 2009, Pages 732-735
Medical Hypotheses

Porphyromonas gingivalis may play an important role in the pathogenesis of periodontitis-associated rheumatoid arthritis

https://doi.org/10.1016/j.mehy.2008.12.040Get rights and content

Summary

Rheumatoid arthritis (RA) is a common, systemic autoimmune disease which leads to destruction of the joint architecture and consequent disability. Although the aetiology of RA remains unknown, accumulating studies have established a strong association between RA and periodontitis (PD).

Recently, anti-cyclic citrullinated peptide (anti-CCP) autoantibody and citrullinated peptide have been realized to be involved in the breaking of self-tolerance and development of autoimmune in RA. The citrullinated peptide is generated by post-translational modification (citrullination) of protein-bound arginine by peptidylarginine deiminase (PAD). Porphyromonas gingivalis (P. gingivalis), the major aetiological agent of PD and the only bacterium known to express a PAD enzyme, has been reported to be significantly associated with RA. The antibody titers to P. gingivalis are significantly increased in patients with RA and P. gingivalis antibody titers are significantly correlated with anti-CCP antibody isotypes that are specific to RA. Recent study indicates that the major synovial targets of the RA-specific anti-CCP autoantibodies are deiminated forms of the α- and β- chains of fibrin. Meanwhile, it is also confirmed that bacterial PAD produced by P. gingivalis has the capacity of deiminating arginine in fibrin found in the periodontal lesion. Whatsmore, it has been demonstrated that citrullination of HLA binding peptide causes a 100-fold increase in peptide-MHC affinity and leads to the activation CD4+T cells in HLA DRB1 0401 transgenic mice. Therefore, we postulate that P. gingivalis may play a crucial role in the pathogenesis of periodontitis-associated RA. P. gingivalis, which colonizes in the oral cavity, produces PAD enzyme continuously that leads to the citrullination of RA autoantigen such as fibrin in synovium joint. These PAD engendered antigens, presented in association with major histocompatibility complex (MHC) molecules by antigen-presenting cells (APC), ultimately lead to production of the anti-CCP antibody. The anti-CCP antibodies form immune complexes with citrullinated proteins, which can be bound by inflammatory cells via their Fc receptors. The roles of these immune complexes and inflammatory cells are mediated by a complex cascade involving complement activation. These mechanisms result in a release of mediators of inflammation and joint destruction ultimately leading to the onset of RA. This hypothesis reveals that oral bacterial infection may play a role in peptide citrullination which might be involved in loss of self-tolerance and development of autoimmune in RA.

Introduction

Rheumatoid arthritis(RA) is a common,systemic autoimmune disease affecting 0.5–1% of the population [1], [2]. It is characterized by synovial hyperplasia, inflammatory cell recruitment and intraarticular fibrin deposition that leads to the destruction of the joint architecture and consequent disability. Until now, the cause of RA remains unclear. Continuous low-grade infection, autoimmune and genetic traits are considered to be involved in the pathogenesis of RA.Over the last two decades, the interrelationship between RA and periodontitis (PD) has become increasingly appreciated [3]. PD is a chronic inflammatory disease, initiated by bacteria, invading gingival, periodontal ligament, cementum and alveolar bone, which could severely affect approximately 10% of the adult population and lead to bone resorption and ultimately tooth loss [4]. Recent studies have reported a significant association between RA and PD [5], [6], [7], [8]. Whatsmore, measures of RA disease severity (e.g. a higher number of swollen joints, increased C-reactive protein concentration and erythrocyte sedimentation rate) are associated with increased periodontal bone loss [3]. One report indicates that the incidence of RA in patients with periodontitis is 3.95% compared to 1% prevalence in the general population [7]. The association of PD with RA appears to be independent of other risk factors including cigarette smoking, socioeconomic status, body mass index, alcohol consumption, and poor oral hygiene [9].

To date, several common features shared by RA and PD have been proposed. First, both RA and PD are characterized by self-sustaining inflammation in a fluid filled compartment adjacent to bone, in which inflammatory cells and other phlogistic factors lead to common clinical symptoms (pain, swelling, tenderness) and, ultimately, to destruction of the adjacent bone. Second, RA and PD may share similar immunogenetics features. Immunogenetic studies of patients with RA have established an association with specific HLA antigens, in particular at the HLA DR4 locus [1]. The strongest association is with a conserved amino-acid sequence corresponding with positions 70–74 of the third hypervariable region of the HLA-DRB1 gene (termed the “shared epitope”), primarily subtypes 0401, 0404, and 0408 in the white population and 0405 in Asians [10], [11]. The same genetic locus (HLA DR4) has been associated with development of severe and rapidly progressive PD, mainly subtypes 0401, 0404, 0405, and 0408 [12]. Finally, the cells, enzymes and cytokines which determine the degree of tissue destruction all share a common pathologic process in both RA and PD. In both periodontal lesions and rheumatoid synovium, local immune responses are amplified with recruitment of inflammatory cells from the systemic circulation into the target tissue (gingival mucosa or synovial membrane). Both cellular and humoral immune reactions have been shown to contribute to the pathogenesis of the two diseases. Activation of monocytes by stimulated T-lymphocytes is a major initiator of the production of large amounts of tumor necrosis factor (TNF)-α and interleukin (IL)-1β [13], [14], [15]. These cytokines further stimulate the expression of adhesion molecules and other inflammatory mediators that amplify the local inflammatory reaction, leading to the generation of proinflammatory mediators, including cytokines, eicosanoids, including induction of COX-2, proteolytic enzymes, in particular the production of matrix metalloproteinases, activated oxygen, and nitrogen species [13], [14], [15], [16], [17], [18]. Immune complexes and complement are the final common mediators of inflammation in both diseases [15], [19], with the ultimate result being destruction of adjacent bone [15], [20], [21].

Section snippets

Porphyromonas gingivalis, peptidyl arginine deiminase (PAD), citrullination and RA

Porphyromonas gingivalis (P. gingivalis), a gram-negative, nonmotile, facultative anaerobe, is correlated with the prevalence of adult-onset periodontitis [22].In primate models of periodontitis, the implantation of P. gingivalis in the oral cavity has been shown to be sufficient for the development of the disease [23]. The linkage between P.gingivalis and RA comes to be realized in the studies of anti-cyclic citrullinated peptide (anti-CCP) antibody which is a highly specific marker for RA.

Hypothesis

The significant correlation between RA and PD, the potential role of citrullination in pathogenesis of RA and the significant association between P. gingivalis antibody concentrations and anti-CCP antibody isotypes that are specific to RA remind us the hypothesis that P. gingivalis, the major aetiological agent of PD and the only bacterium known to express a PAD enzyme, may play a crucial role in the pathogenesis of periodontitis-associated RA. Thus, the following hypothetical scenarios are

Implications of the hypothesis

A growing number of epidemiologic, serologic, and animal model studies provided evidence that P. gingivalis, the major aetiological agent of PD, might be involved in the onset and progression of RA. Although the aetiology of RA remains unclear, the hypothesis suggests a new direction in the study of aetiology of RA.It reveals that bacterial infection may play a role in peptide citrullination which might be involved in loss of self-tolerance and development of autoimmune in RA. It is meaningful

Acknowledgement

This study was supported by Grant No.30772445 from the Natural Science Foundation of China.

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