Abstract: There is a significant association between rheumatoid arthritis (RA) and periodontal disease (PD). Patients with longstanding active RA have been found to have a substantially increased frequency of PD compared with healthy subjects. Further, patients with PD have been shown to have a higher prevalence of RA than patients without periodontitis. Antibodies to Gram-negative, anaerobic periodontal pathogens such asPorphyromonas gingivalis, Prevotella intermedia, Prevotella melaninogenica, and Tannerella forsythia have been detected in the serum and synovial fluid of RA patients. These pathogens have also been identified in the synovial fluid of RA patients, with higher levels of bacterial DNA in RA patients than in controls. This review examines the association between periodontopathic bacteria and the etiology of RA.
Introduction
Rheumatoid arthritis (RA) is the most common systemic inflammatory autoimmune disease in which the joint synovium is primarily affected by a dysregulated immune system (Song and Kang, 2010).
The diseases collectively termed periodontitis are bacterial infections that begin with inflammation of the periodontium and can progress to loss of teeth. Untreated infections lead to destruction of the periodontal ligament and alveolar bone. It is estimated that over 49 million people in the United States have some form of periodontitis (Cutler et al., 1995).
Clinical studies of RA and periodontal disease (PD) have provided evidence for a significant association between the two disorders (Ogrendik, 2009a). Patients with longstanding active RA have a substantially increased frequency of PD compared with that among healthy subjects. Further, patients with PD have a higher prevalence of RA than patients without periodontitis (Ogrendik, 2009a). About 20 bacteria species have been identified as periodontal pathogens and are linked to several forms of PD. The best analyzed of these bacteria are Porphyromonas gingivalis, Prevotella intermedia, Tannerella forsythia, and Aggregatibacter actinomycetemcomitans — theperiodontopathic bacteria (Ogrendik et al., 2005).
We have shown that clarithromycin and roxithromycin are effective against early or late, and disease-modifying antirheumatic drug (DMARD) resistant RA (Ogrendik, 2007; 2009b; 2011). Roxithromycin and clarithromycin are used in the treatment of infections caused by anaerobic bacteria. The effectiveness of these antibiotics is independent of the stage or severity of RA. Alterations in the bowel flora have been proposed as a mechanism of action of sulfasalazine, and it has been shown that patients with inflammatory bowel disease treated with sulfasalazine have a decreased number of nonsporing anaerobes (Das, 1989). Doxycycline and minocycline are members of the tetracycline family of broad-spectrum antibiotics (Amin et al., 1996). Double-blind, randomized controlled trials have shown that minocycline is an effective DMARD in RA, compared with placebo (Tilley et al., 1995; Kloppenburg et al., 1994).
Periodontopathic Bacteria
P. gingivalis belongs to the phylum Bacteroidetes and is a non-motile, Gram-negative, rod-shaped, anaerobic pathogenic bacterium. It forms black colonies on blood agar. It is found in the oral cavity, where it is implicated in certain forms of PD (Naito et al., 2008), as well as in the upper gastrointestinal tract, respiratory tract, and colon. P. gingivalis has been shown to have the greatest proteolytic activity of all Gram-negative bacteria isolated in high numbers from sites affected by PD, and is the most virulent species when inoculated into animals in a simple pathogenicity test (Marsh and Martin, 2001). P. gingivalis produces arginine-specific (gingipain R) and lysine-specific (gingipain K) cysteine endopeptidase (Ogrendik et al., 2005). Several virulence factors including the polysaccharide capsule, fimbriae, proteases for opsonin C3, proteases for IgG, gingipains, bacterial lipopolysaccharides (LPS), toxins, and hemagglutinins enable P. gingivalis to persist in the oral mucosa and help facilitate some of the physiopathology of chronic periodontitis (Marsh and Martin, 2001). Other periodontal pathogens, including T. forsythia and Treponema denticola, also produce proteases with arginine-x specificity (Marsh and Martin, 2001).
Periodontal Disease
PD is one of the most common chronic disorders of infectious origin known in humans with a prevalence of 10-60% in adults depending on the diagnostic criteria used (Modi et al., 2009). PD includes gingivitis (an inflammatory condition of soft tissues surrounding the tooth) and periodontitis (a bacterial infection of the periodontium). Periodontitis is the most common type of PD. Most patients with periodontitis respond to bacterial invaders by mobilizing their defensive cells and releasing cytokines such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6, which ultimately causes tissue destruction by stimulating the production of collagenolytic enzymes such as matrix metalloproteinases (MMPs) (Modi et al., 2009). Recently, growing evidence has suggested an association between periodontitis and an increased risk of systemic diseases such asatherosclerosis, diabetes mellitus, adverse pregnancy outcomes, and RA. Periodontitis and RA share many pathologic aspects and immunologic findings (Modi et al., 2009).
Etiology of Rheumatoid Arthritis
Antibodies to Gram-negative, anaerobic periodontal pathogens such as P. gingivalis, P. intermedia, P. melaninogenica, and T. forsythia have been detected in the serum and synovial fluid of RA patients (Ogrendik et al., 2005; Moen et al., 2003; Mikuls et al., 2009). These pathogens also have been identified in the synovial fluid of RA patients, with higher levels of bacterial DNA in RA patients than in controls (Moen et al., 2006; Martinez-Martinez et al., 2009).
Periodontal pathogens have a direct systemic access to the blood circulation (Moen et al., 2006; Martinez-Martinez et al., 2009). The transport of periodontal bacterial DNA from periodontal sites to the synovium is as free DNA (Martinez-Martinez et al., 2009). P. gingivalis is able to invade primary human chondrocytes isolated from knee joints and to induce cellular effects (Pischon et al., 2008). As a consequence of this invasion, P. gingivalis delays cell cycle progression and increases cellapoptosis in these chondrocytes (Pischon et al., 2008).
Some studies have investigated the association between P. gingivalis and RA in animal models. One recent study, in which heat-killed P. gingivalis was injected into the backs of RA rats, showed that P. gingivalis promotes the development of arthritis as measured by paw swelling (Bartold et al., 2010). This study clearly showed that a pre-existing, extra-synovial chronic inflammatory lesion induced byP. gingivalis promotes the development of arthritis in an animal model (Bartold et al., 2010).
The impact of controlling periodontal infection, by reducing the concentration of pathogens, with thorough initial phase debridement of periodontal pockets in reducing the severity of active RA has been reported (Al-Katma et al., 2007).
Pathogenesis of Rheumatoid Arthritis
In RA, the strongest genetic association has been demonstrated with the major histocompatibility complex class II, HLA-DRβ1 gene. This highly polymorphic gene encodes for a cell surface molecule expressed prominently on antigen presenting cells, such as dendritic cells, macrophages, and B cells. This molecule mediates peptide antigen presentation to T cells, thus activating the cells to respond to these antigens (Smolik et al., 2009). Several variants of HLA-DRβ1 have been shown to be associated with RA (Smolik et al., 2009). Intriguingly, the same variants are also associated with periodontitis (Ogrendik et al., 2005). The association resides in a key segment of 5 key amino acids situated in the side wall of the HLA-DRβ1 molecule (QK[R]RAA). This sequence has been named the shared epitope, and disease susceptibility requires the presence of the positively charged amino acids arginine or lysine in position 71 of the HLA-DRβ1 molecule. This positively charged motif appears to facilitate the presentation of peptides containing the amino acid citrulline to T cells (Smolik et al., 2009).
In 2005, we hypothesized that one such environmental factor that could potentially play a role in breaking tolerance to citrullinated autoantigens, in a genetically susceptible host, is P. gingivalis, a gram-negative anaerobic rod, one of the major pathogens associated with PD (Ogrendik et al., 2005). The "red complex," composed of T. forsythia, P. gingivalis, and T. denticola, is implicated in severe forms of PD (Rôças et al., 2001). These bacteria express the peptidylarginine deiminase (PAD) enzyme (Marsh and Martin, 2001) and are capable of citrullinating terminal arginine residues on peptides (Smolik et al., 2009). Thus, it is possible that the presence of these bacteria in chronically inflamed periodontal tissue may lead to the local generation of citrullinated peptides. In such a chronic inflammatory oral lesion, the presentation of citrullinated antigens to T cells by local antigen presenting cells would be facilitated by a microenvironment rich in proinflammatory cytokines, such as TNF-α and IL-1β, which serve to stimulate and accelerate this process. In turn, through a process of molecular mimicry, the immune response would be directed toward other homologous citrullinated human autoantigens and become progressively amplified and evolved. A study showed one such candidate antigen is the ubiquitous enzyme enolase, the citrullinated form of which has been identified as an autoantigen in RA (Kinloch et al., 2005). Moreover, the incubation of wild-typeP. gingivalis with fibrinogen or α-enolase has been shown to cause degradation of these proteins and citrullination of the resulting peptides at carboxy-terminal arginine residues (Wegner et al., 2010).
Autoimmunity
Rheumatoid factors
Rheumatoid factors (RFs) have been identified as autoantibodies that react with the IgG molecule at the Fc region, and these antibodies may be of IgM, A, G, or E epitopes (Firestein, 2005). RF has been found in patients with RA and in other chronic inflammatory diseases, including PD (Rosensteinet al., 2004). RF has been observed in the gingiva, in the subgingival plaque, and in the serum of patients with PD (Rosenstein et al., 2004). RF in seropositive patients shows a cross-reaction with oral bacterial epitopes (Thé and Ebersole, 1996). Bonagura and colleagues identified the lysine and arginine amino acid sequences of the Fc region of the IgG molecule (Bonagura et al., 1993). Because P. gingivalis specifically decomposes lysine and arginine, the IgG3 CH2 and CH3 domains cleaved off by P. gingivalis proteinase become binding targets for the RF produced by rheumatoid cells (Ogrendik et al., 2005).
Autoimmunity to cartilage-specific antigens
Type II collagens
The presence of autoantibodies against collagen II (CII) — the main component of hyaline cartilage — has previously been demonstrated in RA patients (Clague et al., 1983; Ronnelid et al., 1994). P. gingivalis shows collagenase activity and degrades all collagen molecules except for CII (Bedi and Williams, 1994). Also, P. gingivalis expresses a lysine-specific proteinase (Ogrendik et al., 2005). Lysine in position 270 of CII 263-370 can be hydroxylized and further glycolized to monosaccharides or disaccharides (for example, with a beta-D-galactopyranosyl or an alpha-glycopyranosyl-[1,2]-beta-galactopyranosyl residue). It has been shown that lysine is a crucial amino acid for the antigenicity of CII in transgenic mice expressing HLA DR4 (DRB1*0401) and human CD4 (Bäcklund et al., 2002).
Other cartilage-specific antigens
The cartilage proteoglycan aggrecan can induce an erosive polyarthritis and spondylitis in BALB/c mice and the G1 globular domain of the aggrecan constitutes the arthritogenic region (Li et al., 2000). T cell clones derived from the peripheral blood of RA patients can proliferate in response to aggrecan, and these cells recognize the arginine in the arthritogenic region (Li et al., 2000). In addition, these T cells have a T helper type 1 (Th1) cytokine profile, suggesting that they contribute to the Th1 bias in the synovial tissue (Firestein, 2005; Li et al., 2000).
Autoimmunity to nonarticular antigens
Citrullinated peptides
The amino acid citrulline is generated by an enzymatic modification of the amino acid arginine by enzymes PADs (Smolik et al., 2009). Citrullination plays a physiologic role in the regulation of protein folding and degradation and is prominently involved in processes such as cornification of the skin. Thus, the generation of citrullinated peptides is certainly not unique to RA, but the development of antibody responses to citrullinated peptides is quite specific to RA (Smolik et al., 2009). Arginine is the most important of the amino acids associated with autoantigenicity in proteins (Ogrendik et al., 2005). T. forsythia, T. denticola, and P. gingivalis contain an arginine-specific proteinase. The P. gingivalis antibody titer in patients with RA has been shown to correlate significantly with the concentration of anti-citrullinated protein/peptide antibody (Detert et al., 2010).
Heat shock proteins
Heat shock proteins (HSPs) protect the cell from stress by reversibly interacting with abnormal proteins and peptides and by participating in their backfolding and decomposition. Furthermore, HSPs fulfill a function in innate and acquired immunity and are associated with the pathogenesis of RA (Ragno et al., 1997). Antibodies against hsp40 of A. actinomycetemcomitans have been found in serum samples of patients with RA possibly triggering an immune response (Yoshida et al., 2001).
Agalactosyl IgG
RA patients have significantly fewer galactose residues on their IgG Fc region compared with age-matched healthy control subjects. A lack of terminal galactose residues early in the course of the disease is associated with a worse prognosis (Firestein, 2005). P. melaninogenica, as a saccharolytic bacterium, disintegrates galactose. Consequently, this saccharolytic bacterium is able to bind at the Fc region of the IgG molecule and metabolize galactose with its enzyme (Ogrendik et al., 2005).
Synovial T Lymphocytes
In chronic RA, the synovium contains a collection of T cells that can lead to an organizational structure that resembles a lymph node. The distribution of lymphocytes in the tissues varies from discrete lymphoid aggregates to diffuse sheets of mononuclear cells, with the most prominent location for T cells being the perivascular region. These collections consist of small, CD4+ memory T cells (CD45RO+) with scant cytoplasm (Firestein, 2005). An increased number of CD45RO+ memory T cells in diseased tissues has been reported in individuals with various forms of PD (Mathur and Michalowicz, 1997). Further, periodontopathic bacteria stimulate the production of CD45RO+ memory T cells (Mathur and Michalowicz, 1997).
One unusual phenotype of synovial T cells in RA is a population that expresses CD4 but lacks CD28. Oligoclonal expansion of CD4+CD28- T cells has been described in the peripheral blood and joint samples of patients with RA (Warrington et al., 2001). These cells may be cytotoxic and can respond to autoantigens but are inefficient B cell stimulators (Firestein, 2005). This population of T cells also occurs more frequently in patients with extra-articular manifestations of RA (Firestein, 2005). It has been shown that P. gingivalis outer membrane (OM) antigens enhance Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) expression on T cells from periodontitis patients (Aoyagi et al., 2000). The P. gingivalis OM induces significantly higher IL-10 mRNA expression in periodontitis patients than in healthy controls (Aoyagi et al., 2000). Therefore, T cell responses to P. gingivalis OM may be regulated by CTLA-4, which is expressed during the late phase of T cell activation, and, in part, by immunosuppressive cytokines (Aoyagi et al., 2000).
Superantigens
Some T cell receptor Vbeta genes (Vbeta-6, 8, 14, and 17) are present more frequently in patients with RA than in control subjects (Cuesta et al., 1997; Hall et al., 1998). Similarly, P. intermediaspecifically stimulates the expression of Vbeta-8 and Vbeta-17 genes in CD4+ T cells (Leung and Torres, 2000). P. gingivalis and P. intermedia increase the expression of Vbeta-6 and Vbeta-8 (superantigens in RA) (Mathur et al., 1995).
Synovial B Cells
Anti-glucose-6-phosphate isomerase (GPI) antibody (Ab) can be detected in some RA patients, with the reported prevalence varying from 5% to 64% of RA patients (Hayashi et al., 2007). This Ab is associated with extra-articular manifestations, and its titer correlates with the disease activity (Hayashi et al., 2007). Moreover, anti-GPI Ab is also detected in the inflamed synovium of RA patients (Hayashi et al., 2007). Thus, B cells and autoantibodies appear to play an important role in the pathogenesis of RA in anti-GPI Ab-positive patients, especially in the inflamed joint synovium. The antigen binding site is made up of variable regions and rearranged complementarity determining regions (CDR) that determine the individual immune properties of any given B cell. The immunoglobulin heavy chain CDR3 (IgH-CDR3) is the most crucial site for antigen binding. One study found that the IgH-CDR3 region in anti-GPI Ab (+) RA patients was rich in basic-ionized amino acids (arginine and lysine) in their near central position, compared to the composition in anti-GPI Ab (-) individuals (Hayashi et al., 2007). The ionized side-chains of arginine in CDRs contribute to the higher binding affinity for some antigens such as DNA, cardiolipin (Rahman, 2004; Giles et al., 2005), and TAG72 (Xiang et al., 1993). A previous study found that arginine in IgH-CDR3 of human and murine anti-dsDNA was most likely to be generated during V-D-J rearrangement in B cells, and the higher frequency of arginine in the IgH-CDR may similarly be due to the clonal expansion of B cells (Xiang et al., 1993). In addition, the precise location of arginine is important for binding (Giles et al., 2005).
Cytokines
A number of cytokines including TNF-α, IL-1, and IL-6 are involved in the pathogenesis of RA (Firestein, 2005). Periodontopathic bacteria also are powerful stimulators of TNF-α and other proinflammatory cytokines in humans (Seymour and Gemmell, 2001; Yoshimura et al., 1997; Kjeldsen et al., 1995; Rossano et al., 1993). The liver plays a major role in clearing systemic bacterial infections and IL-6 is a major factor in the regulation of acute-phase response proteins by the liver. A striking correlation exists between serum IL-6 activity and serum levels of acute-phase reactants such as C-reactive protein, alpha1-antitrypsin, fibrinogen, and haptoglobin in patients with RA (Firestein, 2005). Further, it has been shown that P. gingivalis extract induces TNF-α and IL-6 production in an in vitro liver model and that macrophage-derived TNF-α mediates the induction of TNF-α in hepatocytes (Takano et al., 2012).
IL-1 receptor antagonist (Ra) levels are high in rheumatoid synovial effusions; IL-1Ra is largely produced by neutrophils and macrophages (Malyak et al., 1993). Similarly, LPS from periodontopathic bacteria is capable of stimulating polymorphonuclear leukocytes to release not only proinflammatory cytokines but also their inhibitors such as IL-1Ra (Yoshimura et al., 1997). Substantial amounts of transforming growth factor beta (TGF-β) are present in the synovial fluid (although it is mainly present in an inactive, latent form), and TGF-β mRNA can be detected in RA synovial tissue (Fava et al., 1989). P. gingivalis LPS increases the production of TGF-β in gingival tissue (Morandini et al., 2011). IL-10 protein is present in RA synovial fluid, and the IL-10 gene is expressed by synovial tissue macrophages (Firestein, 2005). The P. gingivalis OM induces significantly higher IL-10 mRNA expression in periodontitis patients than in healthy controls (Aoyagiet al., 2000).
IL-17
IL-17 is a proinflammatory cytokine secreted by the newly described CD4+ Th17 subset, which is distinct from classic Th1 and Th2 subsets (Miossec et al., 2009). Th17 cells and IL-17 play an important role in the pathogenesis of RA (Tesmer et al., 2008). Th17 cells are present in the sites ofchronic inflammation in human periodontal disease (Cardoso et al., 2009). IL-17 is produced in periodontal lesions and has a potential role in the etiopathogenesis of PD (Kramer and Gaffen, 2007). P. gingivalis antigen preferentially stimulates T cells to express IL-17 (Oda et al., 2003).
Finally, P. gingivalis induces robust expression of cytokines, including TNF-α, IL-6, and IL-10. It stimulates production of chemokines, neutrophil chemoattractant protein, macrophage colony stimulating factor-1, and macrophage inflammatory protein-1α. It enhances expression of nitric oxide(measured as nitrite) and prostaglandin E2 from macrophages (Shaik-Dasthagirisaheb et al., 2010).
Matrix Metalloproteinases
The primary mechanism by which RA synovial fibroblasts (SF) erode cartilage appears to be via the synthesis and secretion of MMPs (Abeles and Pillinger, 2006). MMPs are a family of more than 20 enzymes, each of which has the potential to digest a non-identical but overlapping group ofconnective tissue components. MMPs produced by RA SF include MMP-1, 3, 9, 10, and 13 (Abeles and Pillinger, 2006). P. gingivalis proteinase leads to full activation of MMP-1, MMP-3, and MMP-9 (DeCarlo et al., 1997).
Conclusion
Above findings indicate that periodontopathic bacteria are a contributing factor in the etiopathogenesis of RA. These findings help guide more comprehensive and efficacious treatment strategies for RA.
Disclosure
The author reports no conflicts of interest.
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[Discovery Medicine; ISSN: 1539-6509; Discov Med 13(72):349-355, May 2012. Copyright © Discovery Medicine. All rights reserved.]
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