Liao F, Li Z, Wang Y, et al. Porphyromonas gingivalis may play an important role in the pathogenesis of periodontitis-associated rheumatoid arthritis

Key Laboratory for Oral Biomedical Engineering of Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237# Luo Yu Road, Wuhan, Hubei, PR China.
Medical Hypotheses (Impact Factor: 1.07). 03/2009; 72(6):732-5. DOI: 10.1016/j.mehy.2008.12.040
Source: PubMed


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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    • "2.7. Role of Anti-CCP in Periodontal Disease and RA [22, 23] "
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    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.
    05/2014; 2014:596824. DOI:10.1155/2014/596824
    • "In 2004, citrullinated antigens were proposed to play an important role in the pathogenesis of RA (Nijenhuis et al. 2004 ; Vossenaar and van Venrooij 2004 ; Zendman et al. 2006 ). It was hypothesized that the infl ammatory cycle starts with a certain initial trigger (Fig. 3.1 ), which is likely to have an environmental origin, such as an infection (e.g., Porphyromonas gingivalis or viral infection) or exposure to toxic compounds (e.g., smoking) (Mikuls et al. 2004 ; Liao et al. 2009 ; Makrygiannakis et al. 2008 ). As a result of this event, peptidylarginine deiminase (PAD) enzymes can become activated, leading to citrullinated proteins, which in turn can elicit an immune response, resulting in ACPA production. "
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    ABSTRACT: Autoantibodies targeting citrullinated proteins are generated in the majority of rheumatoid arthritis (RA) patients and generally detectable prior to disease onset. Increasing evidence indicates that these autoantibodies play a role in the pathophysiology of RA and this is most likely related to the interaction with their target proteins, which are indeed present in the inflamed joints of RA patients. Although protein citrullination is not a unique feature of joint inflammation in RA, the disease-specific production of anti-citrullinated protein antibodies will lead to the formation of immune complexes that may contribute to disease progression. This chapter starts with the processes that are believed to mediate protein citrullination and anti-citrullinated protein antibody production in RA patients, as well as the main factors involved. Subsequently, several citrullinated proteins identified in the inflamed joint, fibrinogen, vimentin, alpha-enolase, fibronectin, apolipoprotein E, myeloid nuclear differentiation antigen and beta-actin, and their (possible) function in RA are described in more detail. Besides pathophysiological aspects, the diagnostic and prognostic value of antibodies to these citrullinated autoantigens is discussed. In addition to citrullination, another, though chemically related, post-translational modification called carbamylation and antibodies to carbamylated proteins have recently been suggested to play a role in the pathophysiology of rheumatoid arthritis as well. Finally, this chapter summarizes our current knowledge on the role of citrullination in animal models for arthritis, which are used to obtain more detailed information on pathophysiological mechanisms.
    Protein Deimination in Human Health and Disease, Edited by Nicholas, Anthony; Bhattacharya, Sanjoy (Eds, 01/2014: chapter Chapter 3: pages p.41-69; Springer., ISBN: ISBN 978-1-4614-8316-8
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    • "The effects of SDD on TREM-1 identified in this study could be well in line with the clinically proven beneficial effects of SDD on local inflammatory host responses (Caton & Ryan, 2011). This may have implications not only in the treatment of inflammatory periodontal disease but also in reducing the contribution of P. gingivalis in the development of systemic inflammatory responses (Salvi et al., 1997; Lin et al., 2003; Brodala et al., 2005; Liao et al., 2009; Maekawa et al., 2011a, b "
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    ABSTRACT: The triggering receptor expressed on myeloid cells 1 (TREM-1) is a cell surface receptor of the immunoglobulin superfamily, with the capacity to amplify pro-inflammatory cytokine production. Porphyromonas gingivalis is a Gram-negative anaerobic species highly implicated in inflammatory periodontal disease, with potential involvement in systemic inflammation. Porphyromonas gingivalis positively regulates TREM-1 expression and production in monocytic cells. Subantimicrobial doses of doxycycline (SDD) are used as an adjunct treatment in periodontal therapy, because of their anti-inflammatory properties. The aim of this study was to investigate the effect of SDD on P. gingivalis-induced TREM-1 expression and secretion by the myelomonocytic cell line MonoMac-6. After 24 h of challenge, P. gingivalis enhanced TREM-1 gene expression by the cells, with a concomitant increase in soluble TREM-1 release. Nevertheless, SDD concentrations between 2 and 10 μg mL(-1) abolished TREM-1 expression and release, already after 4 h of administration. Moreover, SDD reduced P. gingivalis-induced interleukin-8 secretion, confirming its anti-inflammatory effects. In conclusion, SDD inhibits bacterially induced TREM-1, and this effect may partly account for its generalized anti-inflammatory properties. This could partly explain the clinical efficacy of SDD as an adjunctive treatment for periodontal disease, but may also indicate that SDD could serve as a suitable modulator of systemic inflammatory responses.
    FEMS Immunology & Medical Microbiology 04/2012; 66(1):37-44. DOI:10.1111/j.1574-695X.2012.00982.x · 3.08 Impact Factor
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