Porphyromonas gingivalis may play an important role in the pathogenesis of periodontitis-associated rheumatoid arthritis.
ABSTRACT 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 alpha- and beta- 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. What's more, 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.
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ABSTRACT: Objective: Peptidylarginine deiminase 4 (PAD4) is a citrullinating enzyme that has multiple associations with inflammation. In rheumatoid arthritis, PAD4 and protein citrullination are increased in inflamed joints and anti-citrullinated protein antibodies (ACPAs) form against citrullinated antigens. ACPA immune complexes can deposit in the joint and induce the production of tumor necrosis factor alpha (TNFα), a critical inflammatory cytokine in rheumatoid arthritis pathogenesis. Further, in other settings, TNFα has been shown to induce PAD4 activity and modulate antibody formation. Thus, TNFα and PAD4 may synergistically exacerbate autoantibody production and inflammatory arthritis, but this has not been directly investigated. Methods: To determine if TNFα and PAD4 augment autoantibody production and inflammatory arthritis, we first determined if mice with chronic inflammatory arthritis due to overexpression of TNFα develop autoantibodies against native and citrullinated antigens by multiplex array. We then compared autoantibody levels by array, lymphocyte activation by flow cytometry, total serum IgG levels by ELISA, arthritis by clinical and histological score, and systemic inflammation using microfluidic devices in TNF(+) PAD4(+/+) versus TNF(+) PAD4(-/-) mice. Results: TNFα overexpressing mice have increased autoantibodies reactive against native and citrullinated antigens. Mice with TNFα induced arthritis that lack PAD4, have lower levels of autoantibodies reactive against native and citrullinated antigens, decreased T cell activation and total IgG levels, and reduced inflammation and arthritis compared to TNFα overexpressing mice that have PAD4. Conclusion: PAD4 mediates autoantibody production and inflammatory arthritis downstream of TNFα. © 2014 American College of Rheumatology.Arthritis & rheumatology (Hoboken, N.J.). 02/2014;
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ABSTRACT: The aim was to assess the cytokine profile in the gingival crevicular fluid (GCF) of rheumatoid arthritis (RA) patients with chronic periodontitis (CP). Databases were searched from 1991 to August 2013 using a combination of various keywords. Eight studies were included. The GCF concentrations of interleukin (IL)-1β, IL-4, IL-10, matrix metalloproteinase (MMP)-8, MMP-13 and tumor necrosis factor-alpha (TNF-α) were reported to be higher in patients with RA than in healthy controls (HC) without CP. In one study, TNF-α levels in GCF were significantly higher in HC than in RA patients receiving anti-TNF-α therapy. One study reported no significant difference in GCF TNF-α levels among RA patients and HC regardless of anti-TNF-α therapy. One study reported no difference in IL-1β and prostaglandin E2 levels among RA patients and HC with CP. Raised levels of proinflammatory cytokines are exhibited in the GCF of RA patients with CP.Journal of investigative and clinical dentistry. 12/2013;
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ABSTRACT: Despite the progress toward understanding the molecular pathogenesis of rheumatoid arthritis (RA), its cause remains elusive. Genes are important but rather insufficient to explain the majority of RA cases. This review describes the novel data supporting the microbiome and its interactions with the human host as potential en('in')vironmental factors in RA pathogenesis. Animal models of inflammatory arthritis have shown that the presence of bacteria in mucosal surfaces is sufficient to alter local and systemic host immune responses and elicit joint inflammation. Human RA studies have focused on three mucosal sites: the gut, the gingival, and the respiratory tree. The oral microbiome, and specifically Porphyromonas gingivalis, has long been implicated. Novel sequencing technologies have allowed investigations into the role of the gut microbiome in the development of autoimmune arthritis. Most recently, the pulmonary parenchyma has also been described as yet another possible mucosal site of initiation of autoimmunity in RA. Emerging data implicate the microbiome in RA pathogenesis. Mucosal sites exposed to a high load of bacterial antigens - such as the periodontium, lung, and gut - may represent the initial site of autoimmune generation. If validated, these findings could lead to the discovery of potential biomarkers and therapeutic approaches in the preclinical and clinical phases of RA.Current opinion in rheumatology 11/2013; · 4.60 Impact Factor