Periodontitis is the most prevalent infectious inflammatory disease of the mankind. It is estimated that up 30% of adult population suffers from periodontitis and in about 8% of population a severe form of the disease ultimately leads to teeth lost (1). If morbidity caused by tooth loss due to advanced periodontitis is not enough, mounting evidence suggests a causative links between periodontal disease and rheumatoid arthritis (2), as well as between periodontitis and cardiovascular diseases (3). Furthermore, periodontal pathogens are also recognized as the major cause of aspiration pneumonia (4).
It is now generally accepted that a relatively small consortium of bacteria (P. gingivalis, T. denticola and T. forsythia) described as the "red complex" is strongly associated with the pathological changes in the periodontium (5). These anaerobic, Gram-negative bacteria are uninvited and unwelcome guests in the very diverse community of microbial biofilm on the tooth surface and their proliferation can significantly change the composition of the community (microbiota shift) with all pathological consequences then following.
Proliferation of "red complex" species in on the sub-gingival tooth surface initiates the chronic inflammation of periodontium, which, if untreated, can last for years causing erosion of tooth supporting structures. It is now clearly understood that periodontal tissue damage is a consequence of a futile attempt of the innate immune system to eradicate microbial invaders protected by the broad array of virulence factors. The signs of ongoing "battle" are visible not only locally in the periodontal pockets but also systematically as in blood of periodontitis patients the increased level of inflammatory molecules are present. This apparently may have a direct bearing on development of atherosclerotic plaque (6).
Periodontitis and atherosclerosis
In recent years epidemiological studies have ascertained an association between cardiovascular disease (CVD) and periodontal diseases (3). In several laboratory studies using rabbits and mice it was shown that oral infection with P. gingivalis causing periodontal disease manifested by bone loss caused significant enhancement of atheroma formation in comparison to control animals (6). Results of these investigations provide direct longitudinal evidence that suggests that periodontal inflammation can impact upon the progression of CVD. Importantly, several studies revealed the presence of P. gingivalis in the atherosclerotic plaque in human subjects and experimental animals orally infected with the bacterium. Taken together, it is getting broadly accepted that periodontopathogens, especially P. gingivalis, have either direct or indirect impact on development and/or progression of CVD. It the context of this application is important to underline that gingipains activity via platelet (7,8) and coagulation cascade activation (9), effect on endothelium (10) and some protein degradation (11,12) is a likely P. gingivalis-derived factor providing a direct mechanistic link between both diseases.
Periodontitis and rheumatoid arthritis
Rheumatoid arthritis (RA) is a severe and debilitating chronic autoimmune disease affecting 0.5-1% of the adult population worldwide. RA is fueled by disease-specific autoantibodies to citrullinated proteins, products of physiological post-translational modification of proteins by endogenous peptidylarginine deiminases (PADs) (13). Factors which trigger the breakdown of tolerance to citrullinated proteins are unknown. Interestingly, clinical studies of RA and periodontitis have provided strong evidence for a significant association between the two diseases. Patients with long-standing active RA have a substantially increased frequency of periodontitis compared with that among healthy subjects. Vice versa, patients with periodontal disease have higher prevalence of RA than patients without periodontitis (1). The expression of PAD by P. gingivalis (unique for this bacterium!) may constitute a mechanistic link explaining the clinical correlation between RA and periodontitis (14). Protein citrullination by P. gingivalis may expose new protein epitopes. In the infectious context of bacteria-driven inflammation providing endogenous and exogenous danger signals this may trigger a latent antibody response to citrullinated bacterial and self-proteins and initiate autoimmune destructive reaction.
Periodontitis and aspiration pneumonia
The normal oropharyngeal flora contains anaerobic periodontal bacteria that, once aspired, may cause severe respiratory infections, including pneumonia (4,15). Transfer of anaerobic bacteria to the lower respiratory tract is carried with aspiration of saliva, other secretion fluids contaminated with bacteria or food/ingested fluids/vomits. Decreased function of the host immune system, e.g. in children, elderly and immunocompromised patients, predisposes to anaerobic respiratory tract infection and may lead to incomplete bacteria clearance. Colonization of the respiratory tract may lead not only to acute illness, but also to chronic infection and accompanying development of conditions appropriate for anaerobic growth, which include the reduction in oxygen tension and acidification of the environment. If active or passive clearance of the aspirate is not achieved, there is a latent period of several hours before the onset of pneumonia. The initial lesion following aspiration is pneumonitis that has a relatively dangerous onset and involves dependent segments of the lung. If left untreated, tissue necrosis may, in some cases that fail to resolve, lead to abscess formation or empyema after 7 - 14 days and eventually to necrotizing pneumonia (16,17). To the date, mechanisms involved in development and persistence of aspiration pneumonia are not clear, though it is anticipated that proteases may be one of the major virulence factors. Indeed, gingipains show spectrum of activity that targets vital components maintaining lung homeostasis, including elafin (18) and surfactant proteins.
Cobb et al. (2009) Is the prevalence of periodontitis in the USA in decline? Periodontol. 2000, 50: 13-24.
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Papapanagiotou et al. (2009) Periodontitis is associated with platelet activation. Atherosclerosis 202: 605-611.
Lourbakos et al. (2001) Activation of protease-activated receptors by gingipains from Porphyromonas gingivalis leads to platelet aggregation: a new trait in microbial pathogenicity. Blood 97: 3790-3797.
Imamu ra et al. (2002) The biphasic virulence activities of gingipains: activation and inactivation of host proteins. Curr Protein Pept. Sci. 4: 443-450.
Sheets et al. (2006) Gingipains from Porphyromonas gingivalis W83 synergistically disrupt endothelial cell adhesion and can induce caspase-independent apoptosis. Infect Immun. 74: 5667-5678.
Inomata et al. (2009) Degradation of vascular endothelial thrombomodulin by arginine- and lysine-specific cysteine proteases from Porphyromonas gingivalis. J. Periodontol. 80: 1511-1517.
Oörni K, Kovanen PT (2008) Proteolysis of low density lipoprotein particles by Porphyromonas gingivalis microorganisms: a novel biochemical link between periodontitis and cardiovascular diseases? J. Intern. Med. 263: 553-557.
Suzuki et al. (2007) Citrullination by peptidylarginine deiminase in rheumatoid arthritis. Ann. N. Y. Acad. Sci. 1108: 323-339.
Rosenstein et al. (2004) Hypothesis: the humoral immune response to oral bacteria provides a stimulus for the development of rheumatoid arthritis. Inflammation 28: 311-318.
Bartlett et al. (1974) The bacteriology of aspiration pneumonia. Am. J. Med. 56: 202-207.