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.
- [Show abstract] [Hide abstract]
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;
- [Show abstract] [Hide abstract]
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;
- [Show abstract] [Hide abstract]
ABSTRACT: Periodontal diseases are characterized by localized infections and inflammatory conditions that directly affect teeth supporting structures which are the major cause of tooth loss. Several studies have demonstrated the involvement of autoimmune responses in periodontal disease. Evidences of involvement of immunopathology have been reported in periodontal disease. Bacteria in the dental plaque induce antibody formation. Autoreactive T cells, natural killer cells, ANCA, heat shock proteins, autoantibodies, and genetic factors are reported to have an important role in the autoimmune component of periodontal disease. The present review describes the involvement of autoimmune responses in periodontal diseases and also the mechanisms underlying these responses. This review is an attempt to throw light on the etiopathogenesis of periodontal disease highlighting the autoimmunity aspect of the etiopathogenesis involved in the initiation and progression of the disease. However, further clinical trials are required to strengthen the role of autoimmunity as a cause of periodontal disease.Autoimmune diseases. 01/2014; 2014:596824.