Porphyromonas gingivalis may play an important role in the pathogenesis of periodontitis-associated rheumatoid arthritis
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.
References (43)
The epidemiology of rheumatoid arthritis
Rheum Dis Clin North Am
(2001)- et al.
Prediction of susceptibility to rheumatoid arthritis by human leukocyte antigen genotyping
Rheum Dis Clin North Am
(1992) - et al.
The overexpression of cyclooxygenase-2 in chronic periodontitis
J Am Dent Assoc
(2003) - et al.
Nti-CCP antibodies, a specific marker for (early) rheumatoid arthritis
Clin Appl Immunol Rev
(2004) - et al.
Epidemiology and genetics of rheumatoid arthritis
Arthritis Res
(2002) - et al.
Inter-relationships between rheumatoid arthritis and periodontal disease
A rev J Clin Periodontol
(2003) - et al.
Chronic periodontal disease is associated with single – nucleotide polymorphisms of the human TLR-4 gene
Genes Immun
(2005) - et al.
Risk for periodontal disease in patients with long standing rheumatoid arthritis
Arthritis Rheum
(1997) - et al.
The role of risk factors for periodontal disease in patients with rheumatoid arthritis
Eur J Med Res
(1998) - et al.
Is there a relationship between rheumatoid arthritis and periodonta disease?
J Clin Periodontol
(2000)
A relationship between rheumatoid arthritis and periodontal disease
J Periodontol
Association among rheumatoid arthritis, oral hygiene, and periodontitis
J Periodontol
HLA heterozygosity contributes to susceptibility to rheumatoid arthritis
Am J Hum Genet
A case control study on the role of HLADR4 in severe periodontitis and rapidly progressive periodontitis
J Clin Periodontol
Advances in the pathogenesis of periodontitis: Summary of developments, clinical implications, and future directions
Periodontol
The contribution of interleukin-1 and tumor necrosis factor to periodontal tissue destruction
J Periodontol
Pathogenesis of rheumatoid arthritis
J Clin Rheumatol
The role of reactive oxygen species in homeostasis and degradation of cartilage
Osteoarthr Cartilage
Lipoxin A4 analogues inhibit leukocyte re-cruitment to Porphyromonas gingivalis: a role for cyclooxygenase-2 and lipoxins in periodontal disease
Biochemistry
Deposits of immunoglobulins, complement and immune complexes in inflamed human gingiva
ACTA Odontol Scand
Interleukin-1β regulation of adhesion molecules on human gingival and periodontal ligament fibroblasts
J Periodontol
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