Periodontal manifestations of systemic disease

Periodontitis is a chronic bacterial infection of the supporting structures of the teeth. The host response to infection is an important factor in determining the extent and severity of periodontal disease. Systemic factors modify periodontitis principally through their effects on the normal immune and inflammatory mechanisms. Several conditions may give rise to an increased prevalence, incidence or severity of gingivitis and periodontitis. The effects of a significant number of systemic diseases upon periodontitis are unclear and often it is difficult to causally link such diseases to periodontitis. In many cases the literature is insufficient to make definite statements on links between certain systemic factors and periodontitis and for several conditions only case reports exist whereas in other areas an extensive literature is present. A reduction in number or function of polymorphonuclear leukocytes (PMNs) can result in an increased rate and severity of periodontal destruction. Medications such as phenytoin, nifedipine, and cyclosporin predispose to gingival overgrowth in response to plaque and changes in hormone levels may increase severity of plaque-induced gingival inflammation. Immuno-suppressive drug therapy and any disease resulting in suppression of the normal inflammatory and immune mechanisms (such as HIV infection) may predispose the individual to periodontal destruction. There is convincing evidence that smoking has a detrimental effect on periodontal health. The histiocytoses diseases may present as necrotizing ulcerative periodontitis and numerous genetic polymorphisms relevant to inflammatory and immune processes are being evaluated as modifying factors in periodontal disease. Periodontitis severity and prevalence are increased in diabetics and worse in poorly controlled diabetics. Periodontitis may exacerbate diabetes by decreasing glycaemic control. This indicates a degree of synergism between the two diseases. The relative risk of cardiovascular disease is doubled in subjects with periodontal disease. Periodontal and cardiovascular disease share many common risk and socio-economic factors, particularly smoking, which is a powerful risk factor for both diseases. The actual underlying aetiology of both diseases is complex as are the potential mechanisms whereby the diseases may be causally linked. It is thought that the chronic inflammatory and microbial burden in periodontal disease may predispose to cardiovascular disease in ways proposed for other infections such as with Chlamydia pneumoniae. To move from the current association status of both diseases to causality requires much additional evidence. Determining the role a systemic disease plays in the pathogenesis of periodontal disease is very difficult as several obstacles affect the design of the necessary studies. Control groups need to be carefully matched in respect of age, gender, oral hygiene and socio-economic status. Many studies, particularly before the aetiological importance of dental plaque was recognised, failed to include such controls. Longitudinal studies spanning several years are preferable in individuals both with and without systemic disease, due to the time period in which periodontitis will develop.     

The contribution of interleukin-1 and tumor necrosis factor to periodontal tissue destruction

Interleukin (IL)-1 and tumor necrosis factor (TNF) represent proinflammatory cytokines that stimulate a number of events which occur during periodontal disease. These include the induction of adhesion molecules and other mediators that facilitate and amplify the inflammatory response, the stimulation of matrix metalloproteinase, and bone resorption. The activity of these cytokines coincides with the critical events that occur during periodontal disease, namely, loss of attachment and bone resorption. The use of antagonists to IL-1 and TNF in experimental periodontitis have demonstrated a cause-and-effect relationship between the activity of these cytokines and the spread of an inflammatory front to deeper areas in the connective tissue, loss of connective tissue attachment, osteoclast formation, and loss of alveolar bone. In addition, the loss of fibroblasts that occurs during infection with periodontal pathogens is, in part, mediated by TNF. Thus, much of the damage that occurs during periodontal tissue destruction can be attributed to IL-1 and TNF activity. This destruction may very well represent an overreaction of the host response to periodontal pathogens caused by excessive production of IL-1 and TNF.     

Smoking and inflammation: evidence for a synergistic role in chronic disease

Tobacco smoking is the most important preventable risk factor for periodontitis; however, the underlying biological mechanisms responsible for the detrimental effects of smoking on periodontal health remain largely unclear. It is also well established that smoking has a negative impact on several inflammatory diseases, including rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. The aim of this paper was to review smoking‐related changes in local and systemic host responses with a focus on cellular and molecular effects that could explain a hyperinflammatory response leading to periodontal destruction. Biological mechanisms that may be common to periodontal disease and other chronic inflammatory diseases were also explored, together with gene–smoking interactions. An epidemiologic perspective on the burden of smoking on periodontal health and the potential for smoking cessation is also presented. Tobacco smoking seems to induce changes ranging from decreased leukocyte chemotaxis to decreased production of immunoglobulins. Smoking also seems to cause a stronger inflammatory reaction with an increased release of potentially tissue‐destructive substances (e.g. reactive oxygen species, collagenase, serine proteases and proinflammatory cytokines). These findings support a hypothesis that periodontitis is a hyperinflammatory condition rather than a hypo‐inflammatory condition.     

TNF-α/ NF-κB信号通路对牙周炎发展和牙周再生的影响及其干预

牙周病是以菌斑微生物为始动因子的感染性疾病,菌斑微生物可刺激宿主细胞产生炎性和免疫因子,其中肿瘤坏死因子-α（tumor necrosis factor alpha,TNF-α）作为一个多向性的先导感染细胞因子,在牙周炎的发生、发展过程中起重要作用,同时也是牙周再生的重要影响因素。龈沟液中TNF-α水平的变化已经被用来作为牙周炎治疗的效果以及判断预后的重要指标,越来越多的研究开始关注以TNF-α作用过程为靶点探讨牙周炎发展控制和牙周再生促进的有效方法。本文就TNF-α/NF-κB信号通路对牙周病发展和牙周再生的影响及其干预治疗现状作一综述,以期为牙周病治疗提供新思路。     

The complement system and its role in the pathogenesis of periodontitis: current concepts

Periodontitis is a highly prevalent inflammatory disease in tooth supporting tissues, induced by bacteria growing in a biofilm on tooth surfaces. Components of the complement system are present in the periodontal tissue and the system is activated in periodontitis. Continuous complement activation and modulation by bacteria within the biofilm in periodontal pockets, however, may enhance local tissue destruction, providing the biofilm with both essential nutrients and space to grow. A more profound understanding of the mechanisms involved in complement‐derived tissue degradation may facilitate the development of new treatment concepts for periodontitis. Further studies on the role of complement in periodontitis pathogenesis may also contribute to the understanding of why some individuals fail to resolve periodontitis. Here, we review evidence that links complement to the pathogenesis of periodontitis with an emphasis on interaction of complement with bacteria from periodontitis‐associated biofilm.     

Tissue destruction in periodontitis: bacteria or cytokines fault?

The pathogenesis of periodontal disease involves the sequential activation of a great variety of components of the host immune response, primarily acting to defend periodontal tissues against bacterial aggression, but also functioning as mediators of tissue destruction. The expression of the disease results from the interaction of host, microbiological agents, and environmental factors. Leukocytes play a critical role in the pathogenesis of the disease, producing different cytokines, chemokines, and other mediators, thus generating a host defense response, as well as inducing tissue inflammation and bone destruction. The aim of this review is to address the role of some inflammatory mediators in response to bacterial aggression in periodontitis.     

The role of natural killer cells in periodontitis

Periodontitis is the most common chronic inflammatory disease of humans. The microbial etiology of the disease is well documented, as is the major role of the host response in disease pathogenesis. As natural killer cells are one of the most important components of innate immunity against bacteria and viruses, they can be expected to act as major players in the development of the disease. Through direct interaction with periodontal pathogens, natural killer cells produce pro‐inflammatory cytokines that subsequently may lead to tissue destruction. Indeed, using a murine periodontitis model, such mechanisms have been shown to be involved in bacterial‐induced alveolar bone loss. In the present review we document the available literature and evidence base regarding the origin, biology and characteristics of natural killer cells, and their interactions with periodontal pathogens. The potential role of natural killer cells in periodontal pathogenesis and the mechanisms involved are discussed.     

Pathogenesis of periodontitis

Periodontitis is an inflammatory disease of the periodontium which is characterized by a progressive destruction of the tissues supporting the tooth. Its primary etiology is an ill-defined series of microbial infections which may be composed of only some of the more than 300 species of bacteria currently recognized in the oral cavity. The disease is currently considered to progress as periodic, relatively short episodes of rapid tissue destruction followed by some repair, and prolonged intervening periods of disease remission. Despite the apparent random distribution of episodes of disease activity, the resulting tissue breakdown exhibits a symmetrical pattern of alveolar bone loss and pocket formation which is common to several forms of periodontitis, although the distribution of the most affected teeth and surfaces may vary among diseases (e.g., juvenile periodontitis versus adult periodontitis or rapidly progressive periodontitis). Several reports have indicated that bacterial cells can be found in the pocket wall of periodontitis lesions. The translocation of bacteria into the tissues from the pocket environment is quite common, as evidenced by the common occurrence of bacteremias in patients with periodontitis following relatively minor events such as chewing and oral hygiene procedures. However, it is important to distinguish between the passive introduction of bacteria into periodontal tissues and frank invasion as might occur in an acute infection, since the pathological implications may be quite different.     

Diabetes mellitus--a modifier of periodontal disease expression

The understanding of causes and progression of periodontal disease has increased considerably in recent years making it all the more important to gain knowledge about diabetes and its interrelationship with periodontal disease so as to be able to assess their impact on one another more accurately. Strong evidence exists to support the fact that diabetic patients are at an increased risk for periodontitis. A number of underlying factors are known to contribute to enhanced periodontal destruction in diabetics. There has been intensive research to characterise the mechanisms responsible for the pathogenesis of both microvascular and macrovascular complications. It is also known that there is variability in the rate of development and severity of these complications with some diabetics experiencing none of them. Many of the host response traits that confer susceptibility to periodontitis in otherwise healthy individuals are exaggerated in diabetics. These diabetes associated susceptibility traits include neutrophil dysfunction, abnormal cross-linking and glycosylation of collagen, defective secretion of growth factors and subsequent impaired healing. However it is uncertain which of the hypothesised mechanisms or combinations of mechanisms is directly responsible for the pathogenesis of the complications or whether different mechanisms are operative in different tissues.     

Periodontal disease: modulation of the inflammatory cascade by dietary n‐3 polyunsaturated fatty acids

Periodontal disease, including gingivitis and periodontitis, is caused by the interaction between pathogenic bacteria and the host immune system. The ensuing oxidative stress and inflammatory cascade result in the destruction of gingival tissue, alveolar bone and periodontal ligament. This article reviews the underlying mechanisms and host–bacteria interactions responsible for periodontal disease and evidence that nutritional supplementation with fish oil may provide a protective effect. Historical investigations of diet and disease have highlighted an inverse relationship between ingestion of fish oil, which is high in n‐3 polyunsaturated fatty acids, and the incidence of typical inflammatory diseases such as arthritis and coronary heart disease. Ingestion of n‐3 polyunsaturated fatty acids, such as docosahexaenoic acid and eicosapentaenoic acid, results in their incorporation into membrane phospholipids, which can alter eicosanoid production after stimulation during the immune response. These eicosanoids promote a reduction in chronic inflammation, which has led to the proposal that fish oil is a possible modulator of inflammation and may reduce the severity of periodontal diseases. Tentative animal and human studies have provided an indication of this effect. Further human investigation is needed to establish the protective effects of fish oil in relation to periodontal disease.     

牙周炎与抗心磷脂抗体相关性研究进展

抗心磷脂抗体(anti-cardiolipin antibody,ACA)是与血栓形成、血小板减少有关的自身免疫抗体,受细菌感染因素影响.牙周炎是一种慢性感染性疾病,通过菌斑微生物引发宿主免疫反应产生炎症介质导致牙周组织破坏.目前研究发现,牙周炎患者的牙周致病菌可通过"分子模拟"机制导致血清ACA水平升高,牙周基础治疗...     

Personalized medicine: an update of salivary biomarkers for periodontal diseases

This article provides an up‐to‐date review of the more robust salivary biomarkers, as well as of panels of combinatorial markers and periodontal pathogens, that reveal high sensitivity and specificity for enhancing clinical decision‐making in periodontal disease progression, risk and diagnosis. Periodontal diseases are complex and require an inflammatory response to bacterial pathogens in a susceptible host to stimulate tissue destruction. When used alone, traditional clinical assessments provide a diagnosis of periodontitis only after the biologic onset of the disease process, and are unable to substantiate disease activity or future risk. New technologies are becoming available that are capable of measuring combinations of inflammatory cytokines and proteinases for rapid chair‐side testing. Utilizing saliva to identify and measure specific phenotypes and host‐derived mediators will allow highly individualized diagnosis, prognosis and treatments for periodontal diseases. This personalized medicine approach will strengthen the power of the clinical oral examination and medical history assessments, providing patients with evidence‐based, targeted risk care.     

The immunopathogenic and immunomodulatory effects of interleukin‐12 in periodontal disease

Interleukin 12 (IL‐12) is an inflammatory cytokine that promotes the response of the immune system. This cytokine has been implicated as a potent stimulator of several diseases characterized by inflammatory‐induced bone destruction, such as rheumatoid arthritis and periodontitis. Yet, the exact role of IL‐12 in the development and progress of periodontitis has not been clarified. Several studies have demonstrated a positive correlation between the level of IL‐12 and the severity of periodontal destruction. Deletion of IL‐12 in mice with periodontitis significantly suppressed the level of bone destruction. Interestingly, next to a role in modulating the pathogenesis, IL‐12 also has immunological‐regulatory properties. This cytokine induces expression of immunosuppressive molecules, such as indoleamine‐pyrrole 2,3‐dioxygenase (IDO). Thus, these findings suggest both negative and positive influences of IL‐12 in periodontal disease. It is currently proposed that the diversity of action of cytokines is a molecular key which regulates biological development and homeostasis. Accordingly, the actions of IL‐12 might be one of the mechanisms that regulate homeostasis of periodontal tissue during and following inflammation. Therefore, this article aims to review both destructive and protective functionalities of IL‐12 with an emphasis on periodontal disease.     

Obesity, inflammation, and periodontal disease

The prevalence of obesity has increased substantially over the past decades in most industrialized countries. Obesity is a systemic disease that predisposes to a variety of co-morbidities and complications that affect overall health. Cross-sectional studies suggest that obesity is also associated with oral diseases, particularly periodontal disease, and prospective studies suggest that periodontitis may be related to cardiovascular disease. The possible causal relationship between obesity and periodontitis and potential underlying biological mechanisms remain to be established; however, the adipose tissue actively secretes a variety of cytokines and hormones that are involved in inflammatory processes, pointing toward similar pathways involved in the pathophysiology of obesity, periodontitis, and related inflammatory diseases. We provide an overview of the definition and assessment of obesity and of related chronic diseases and complications that may be important in the periodontist's office. Studies that have examined the association between obesity and periodontitis are reviewed, and adipose-tissue-derived hormones and cytokines that are involved in inflammatory processes and their relationship to periodontitis are discussed. Our aim is to raise the periodontist's awareness when treating obese individuals.     

The impact of new technologies to diagnose and treat periodontal disease

Abstract The last 25 years have brought unprecedented advances to our understanding of periodontal disease. Consider that the 1970 periodontitis was believed to effect most individuals over the age of 35 years, to progress steadily in an individual once initiated until teeth were lost, to be the primary cause of tooth loss in adults, to be caused by the bacterial mass accumulating on the tooth surface and subgingivally, and to involve the host in some fashion or another. In the 25 years since then, impressive research advances in the epidemiology of periodontal disease, the specific bacterial etiology of periodontal disease and the immunoinflammatory mediators of periodontal tissue destruction have greatly altered our view of periodontal disease. Thus, given these research advances in the understanding of periodontitis, what may the future hold for improved diagnosis and treatment of periodontal disease1 Impressive research into new ways to diagnose the periodontal diseases is well underway. Investigators are seeking new ways to diagnose an individual's degree of risk for periodontal disease initiation, susceptibility to disease progression, level of disease “activity” and the likely response to treatment and recurrence of active disease. New diagnostic tests should greatly advance our ability to more accurately and specifically diagnose periodontal disease. The future also looks promising for new treatment strategies to slow or arrest periodontal disease progression. The bacterial specificity of periodontal disease etiology revealed since 1970 has logically led to the use of antibiotics in periodontitis treatment. In the late 1980s the concept of locally delivering antibiotics to the periodontal pocket was introduced, and subsequent clinical trials have indicated that it is possible to reduce pocket depth and inflammation with tetracycline locally delivered to the periodontal pocket. Likely, we have barely scratched the surface in studying the efficacy of locally delivery antimicrobial agents to alter the progression of periodontal disease. As new agents are developed and better delivery systems to the periodontal pocket are developed, the future should see a variety of antimicrobial agents available which can slow periodontal disease progression. The future also holds promise for slowing periodontal disease progression by blocking inflammatory pathways important in periodontal tissue destruction. Clinical trials of flubiprofen, naproxen and ketoprofen indicate that it is possible to slow periodontal disease progression with non-steroidal anti-inflammatory drugs which inhibit one destructive pathway. In addition, data from animal models indicate that chemically modified tetracycline as an inhibitor of couagenase can slow disease progression in animals. Again, we have likely only just begun to explore the wide range of molecular mediators of tissue destruction which may be targeted for blocking and thereby slow or arrest periodontal disease progression. Last, research into regenerating periodontal structures lost as a result of disease has had a noteworthy record of progress m the past 25 years. Techniques that utilize bone grafts, root treatments, tissue guiding membranes or polypeptide growth factors have ably indicated that it is possible to regenerate new attachement structures in humans. As investigators continue to unravel the mysteries of the embryonic development of the periodontium. the ability to predictably regenerate lost periodontal attachment structures holds great promise for the future.     

Periodontitis and diabetes interrelationships: role of inflammation

Diabetes mellitus is a systemic disease with several major complications affecting both the quality and length of life. One of these complications is periodontal disease (periodontitis). Periodontitis is much more than a localized oral infection. Recent data indicate that periodontitis may cause changes in systemic physiology. The interrelationships between periodontitis and diabetes provide an example of systemic disease predisposing to oral infection, and once that infection is established, the oral infection exacerbates systemic disease. In this case, it may also be possible for the oral infection to predispose to systemic disease. In order to understand the cellular/molecular mechanisms responsible for such a cyclical association, one must identify common physiological changes associated with diabetes and periodontitis that produce a synergy when the conditions coexist. A potential mechanistic link involves the broad axis of inflammation, specifically immune cell phenotype, serum lipid levels, and tissue homeostasis. Diabetes-induced changes in immune cell function produce an inflammatory immune cell phenotype (upregulation of proinflammatory cytokines from monocytes/polymorphonuclear leukocytes and downregulation of growth factors from macrophages). This predisposes to chronic inflammation, progressive tissue breakdown, and diminished tissue repair capacity. Periodontal tissues frequently manifest these changes because they are constantly wounded by substances emanating from bacterial biofilms. Diabetic patients are prone to elevated low density lipoprotein cholesterol and triglycerides (LDL/TRG) even when blood glucose levels are well controlled. This is significant, as recent studies demonstrate that hyperlipidemia may be one of the factors associated with diabetes-induced immune cell alterations. Recent human studies have established a relationship between high serum lipid levels and periodontitis. Some evidence now suggests that periodontitis itself may lead to elevated LDL/TRG. Periodontitis-induced bacteremia/endotoxemia has been shown to cause elevations of serum proinflammatory cytokines such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha), which have been demonstrated to produce alterations in lipid metabolism leading to hyperlipidemia. Within this context, periodontitis may contribute to elevated proinflammatory cytokines/serum lipids and potentially to systemic disease arising from chronic hyperlipidemia and/or increased inflammatory mediators. These cytokines can produce an insulin resistance syndrome similar to that observed in diabetes and initiate destruction of pancreatic beta cells leading to development of diabetes. Thus, there is potential for periodontitis to exacerbate diabetes-induced hyperlipidemia, immune cell alterations, and diminished tissue repair capacity. It may also be possible for chronic periodontitis to induce diabetes.     

Expression of VLA-integrins and their related basement membrane ligands in gingiva from patients of various periodontitis categories

Periodontitis is characterized by destruction of dento-gingival fibers and apical migration of the junctional epithelium. Tissue destruction may be associated with altered interactions between epithelium and connective tissue mediated by integrins localized in the basement membrane zone. We examined the expression of alpha2beta1, alpha3beta1, alpha4/alpha5/beta1, alpha6beta4 and their related extracellular matrix (ECM) ligands: laminin-1, laminin-5, and collagen type IV in untreated periodontitis sites of various categories. The expression and location of ECM proteins along the basement membrane were found to be similar between clinically healthy and periodontitis affected tissues. However, ECM proteins were more diffusely distributed in connective tissue (CT) of periodontitis tissues as streak-like/ fibrillar/granular stainings, particularly beneath the pocket epithelium (PE) and around the blood vessels. This may reflect an increase in inflammatory cell migration. The more widespread distribution of integrins alpha2beta1, alpha3beta1 in PE of periodontitis specimens may be related to disease activity and increased rate of keratinocyte proliferation and migration. Moreover, the weaker expression of alpha6beta4 in junctional epithelium (JE) of periodontitis affected tissues may be related to the epithelial detachment from the tooth surface. Clarification of expressions of integrins and their ligands in relation to known clinical disease susceptibility factors may provide information on the onset and progression mechanisms of periodontal disease destruction.     

Crevicular fluid prostaglandin E levels as a measure of the periodontal disease status of adult and juvenile periodontitis patients

The measurement of crevicular fluid PGE (CF-PGE) as an indicator of periodontal disease status was investigated. The association between CF-PGE levels and the PGE content of the adjacent periodontal tissues was found to be highly significant (P=5.3 × 10⁻⁶). The high correlation (r=0.925) between the log CF-PGE level and the tissue PGE concentration indicates that CF levels can be used to reliably predict tissue levels. The CF-PGE measurements at each periodontal site were found to be highly reproducible. Samples from adult and juvenile periodontitis patients demonstrated that the mean CF-PGE levels were correlated with disease severity, as determined by mean attachment loss. The mean CF-PGE level in juvenile periodontitis patients was almost three-fold higher than that present in adult periodontitis (144.0 ± 28.0 ng/ml vs 57.5 ± 8.7 ng/ml, mean ± S.E., significant at P = 0.002). The use of CF-PGE concentrations as an indicator of disease activity (i.e. longitudinal attachment loss) cannot be demonstrated by this cross-sectional study. However, the CF-PGE measurement has been demonstrated to be a non-invasive, sensitive, reproducible, and reliable reflection of tissue levels of PGE₂. The association of increasing levels of CF-PGE with increased severity and aggressiveness of disease is consistent with PGE as an inflammatory mediator of tissue destruction.     

Resolution of inflammation: a new paradigm for the pathogenesis of periodontal diseases

The periodontal diseases are infectious diseases caused by predominantly Gram-negative bacteria. However, as our understanding of the pathogenesis of the periodontal diseases grows, it is becoming clear that most of the tissue damage that characterizes periodontal disease is caused by the host response to infection, not by the infectious agent directly. Investigation into the mechanism of action of host-mediated tissue injury has revealed that the neutrophil plays an important role in destruction of host tissues. In this paper, we review the biochemical pathways and molecular mediators that are responsible for regulation of the inflammatory response in diseases such as periodontitis, with a focus on lipid mediators of inflammation. Pro-inflammatory mediators, such as prostaglandins and leukotrienes, are balanced by counter-regulatory signals provided by a class of molecules called lipoxins. The role of lipoxins in the control and resolution of inflammation is discussed, as is the possibility of the development of new therapeutic strategies for the control and prevention of neutrophil-mediated tissue injury in inflammatory diseases like periodontitis.     

Th17细胞在牙周炎中的研究进展

牙周炎是以牙周组织炎症和牙槽骨破坏为主要特征的慢性炎症性破坏性疾病。近来研究发现Th17细胞存在于牙周炎的病变牙周组织中,提示Th17细胞参与牙周炎的发病过程。本文就Th17细胞在牙周炎发病中的作用进行综述。