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Mapping the Pathogenesis of Periodontitis: A New Look

Kenneth S. Kornman*
Chronic adult periodontitis is a bacterially induced chronic inammatory disease that destroys the connective tissue and bone that support teeth. Concepts of the specic mechanisms involved in the disease have evolved with new technologies and knowledge. Histopathologic observations of diseased human tissues were used previously to speculate on the causes of periodontitis and to describe models of pathogenesis. Experimental evidence later emerged to implicate bacterial plaque deposits as the primary factor initiating periodontitis. At the same time, specic bacteria and immunoinammatory mechanisms were differentially implicated in the disease. In the mid-1990s, early insights about complex diseases, such as periodontitis, led to new conceptual models of the pathogenesis of periodontitis. Those models included the bacterial activation of immunoinammatory mechanisms, some of which targeted control of the bacterial challenge and others that had adverse effects on bone and connective tissue remodeling. Such models also acknowledged that different environmental and genetic factors modied the clinical phenotype of periodontal disease. However, the models did not capture the dynamic nature of the biochemical processes, i.e., that innate differences among individuals and changes in environmental factors may accelerate biochemical changes or dampen that shift. With emerging genomic, proteomic, and metabolomic data and systems biology tools for interpreting data, it is now possible to begin describing the basic elements of a new model of pathogenesis. Such a model incorporates gene, protein, and metabolite data into dynamic biologic networks that include disease-initiating and -resolving mechanisms. This type of model has a multilevel framework in which the biochemical networks that are regulated by innate and environmental factors can be described and the interrelatedness of networks can be captured. New models in the next few years will be merely frameworks for integrating key knowledge as it becomes available from the -omics technologies. However, it is possible to describe some of the key elements of the new models and discuss distinctions between the new and older models. It is hoped that improved conceptual models of pathogenesis will assist in focusing new research and speed the translation of new data into practical applications. J Periodontol 2008;79:1560-1568. KEY WORDS Pathogenesis; periodontal disease; periodontitis; systems biology.

* Interleukin Genetics, Waltham, MA.

esearch into the pathogenesis of disease has traditionally involved a reductionist approach in which discrete inammatory pathways and processes are investigated to elucidate underlying mechanisms. With advances in genomic, epigenetic, proteomic, and metabolomic capabilities, an increased interest has emerged in a biologic systems approach to dene the complex regulatory networks that result in health or disease.1 The biologic networks may be implemented in executable models that respond to perturbations in the system, or they may be captured as conceptual models to provide a structural framework for better communications of relationships among data as they relate to pathogenesis. Periodontitis is a complex disease in which disease expression involves intricate interactions of the biolm with the host immunoinammatory response and subsequent alterations in bone and connective tissue homeostasis.2-4 As such, conceptual models of the pathogenesis of periodontitis may benet from a systems approach, in which biologic mechanisms are studied and interpreted in a hierarchical set of functional modules, such as the microbial ecosystem or the immunoinammatory response, which may be modied by factors (e.g., smoking) that operate at the patient level. A model of the pathogenesis of periodontitis based on systems biology approaches should allow investigators to better communicate the interrelatedness of various
doi: 10.1902/jop.2008.080213

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biologic components involved in the initiation and resolution of disease. This article attempts to highlight selected key steps in the evolution of our concepts of periodontal pathogenesis and to dene how future models are likely to evolve based on the new technologies. EARLY CONCEPTS OF THE PATHOGENESIS OF PERIODONTAL DISEASE The modern era of the pathogenesis, prevention, and treatment of periodontal diseases began in the mid1960s with human and animal experimental evidence demonstrating the critical role of bacteria in the initiaFigure 1. tion of gingivitis and periThe evolution of conceptual models of periodontal disease. A) An early linear model depicting the odontitis.5,6 This led to a clear principal etiologic role for bacteria in the initiation and progression of periodontal disease. B) Circa 1980s model emphasizing a central role for the host immunoinammatory response in the clinical concept of pathogenesis, development and progression of periodontal disease. C) A 1997 model demonstrating various factors i.e., bacteria cause periodoncontributing to the pathogenesis of human periodontitis based on pathways and processes known at tal disease (Fig. 1A). This the time. Figure 1C reprinted with permission from Blackwell Publishing.44 model implicated bacterial plaque deposits as the primary, direct factor in the development of periodontitis ized juvenile periodontitis and contrasted with chronic and resulted in the abandonment of former concepts adult periodontitis.10,20-23 Finally, during this period, that involved non-bacterial factors, such as trauma the initiation and progression of periodontitis was defrom occlusion, systemic conditions, and diet. This tescribed in terms of distinctive histopathologic characnet of the critical role of bacteria dramatically changed teristics that provided insights into the pathogenesis the prevention and treatment of periodontitis. However, processes.12,15,24 several implicit statements were hidden within the simThe extensive research through the mid-1980s led to ple concept, including, for example, the assumption critical renements in the pathogenesis concept, many that bacterial plaque mass was the causative factor of which were not broadly appreciated outside of the reand that bacterial products, such as collagenases, disearch community (Fig. 1B). In most of the models of rectly destroyed tissue. the late 1980s, specic bacteria initiated the disease Research and scientic discussions based on the process by activating host responses, which were prosimple concept of bacterial causation led to great adtective and destructive. The actual destruction of convances in knowledge during the 1970s and early nective tissue and bone resulted primarily from 1980s. Specic Gram-negative, anaerobic, or microactivated tissue mechanisms, such as matrix metalloaerophilic bacteria were implicated in the causation proteinases, interleukin-1, and prostaglandins. Perof periodontitis,7-11 and the protective and destructive haps the most important aspect of the 1980s model is that a distinction was now apparent between the role roles of the immunoinammatory responses were deof the microbial challenge and immunoinammatory scribed in health and disease.12-18 The critical role of mechanisms in the pathogenesis of periodontal dispolymorphonuclear neutrophils (PMNs) in contributease. ing to periodontal damage in humans became more From 1985 to 1995, there was increased recognition widely recognized, as well as the underlying PMN that the concepts presented in the models describing a mechanisms of action.16,19 Furthermore, there was simple relationship between the microbial challenge an increased understanding that some clinical disease and the immunologic responses may have held true patterns, or phenotypes, had characteristic bacteria when mean data were considered, but remarkable varand host responses. For example, microbiologic and iations were observed in host responses and in the immunologic characteristics were described for local1561

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clinical expression of disease. Despite a strong and reproducible association between plaque accumulation and the development of gingivitis, these associations were less clear on a patient-to-patient analysis and were confusing on an individual site analysis within the same patient. In addition, although epidemiologic data suggested that exposure to plaque accumulations over long periods of time led to periodontitis, the longitudinal animal and human data were surprising. In a classic study25 in beagle dogs, plaque accumulation was associated with a progression to periodontitis, but two of eight dogs failed to develop periodontitis, despite substantial plaque and calculus accumulations and extensive gingivitis. Perhaps most striking were the published reports from longitudinal studies26,27 of tea plantation workers in Sri Lanka. As rst reported, a failure to clean teeth regularly resulted in the development of extensive gingivitis and in early and severe periodontitis.27,28 However, further analysis determined that there were three distinct subsets of the population relative to the development of periodontitis in response to bacterial accumulations, including one group that had poor oral hygiene and gingivitis but developed minimal to no periodontitis.26 To add further complexity to the earlier conceptual models, there was a growing appreciation during this period of the importance of genetic variations in determining the development and severity of periodontal disease, with genetic inuences accounting for as much as 30% to 60% of the variability in the clinical severity of periodontitis.29,30 The profound inuence of genotype on susceptibility to periodontitis was apparent from studies in twins,29,31,32 in which a greater variability in the risk for periodontal disease was found in dizygotic twins compared to monozygotic twins, assuming a similar home environment within families. As such, genetic differences among individuals seemed to be a signicant determinant of risk for periodontal disease and, most importantly, there were gene variations that altered host responses and modied the clinical severity of disease.33 ORIGINS OF A NON-LINEAR MODEL With new knowledge of the various factors contributing to periodontal disease came recognition that clinical phenotype is not simply the microbial challenge translated by a standard host response. Strong data emerged showing that smoking34-37 and diabetes38-43 were powerful determinants of disease severity. Laboratory and clinical research demonstrated that these risk factors were most likely inuencing disease expression by altering host protective and destructive mechanisms. In periodontal disease, although the microbial challenge is a primary initiating factor, a number of other factors seemed to be modifying disease expression, but they were not, by themselves, causa1562

tive factors. The contrast between modifying and causative factors was a subtle, but important, distinction. Earlier attempts to evaluate the role of various risk factors, such as smoking and diabetes, in periodontal disease had assumed an independent causation model. Investigators were correct to conclude that these factors did not cause disease, but prior to the 1980s, we incorrectly concluded that these factors were not involved in pathogenesis. In the absence of disease-modifying risk factors, it seems that the host responds appropriately to the bacterial accumulations by attempting to protect against bacterial invasion. In such situations, the host seems capable of limiting periodontal tissue destruction. Evidence began to accumulate that disease modiers, such as smoking, in the presence of bacterial accumulations on the teeth, shifted the immunoinammatory responses outside of the normal boundaries of host response and repair processes. In the presence of modifying factors, such as smoking, an exuberant host response and/or impaired repair mechanisms seem to lead to more destructive periodontitis. Of course, this raised many questions, including what controls the resolution of disease after the inammatory cascades are activated. The basic conceptual model of periodontitis was revised in 1997 (Fig. 1C),44 in great part to acknowledge that various risk factors operated by modifying host responses led to changes in disease expression. In this model, host immunoinammatory mechanisms are activated by bacterial products. Such activation of the host response induces the expression of antibodies as well as activating PMNs in an attempt to control the microbial challenge in the gingival sulcus. In addition, cytokines and prostanoids, as well as matrix metalloproteinases activated through the host response, may stimulate damage to connective tissue and bone and shape the clinical presentation of disease. The primary conceptual change in the 1997 model was that it explicitly acknowledged the role of a number of environmental and acquired risk factors, including genetics, as modiers of the immunoinammatory response and in resulting connective tissue and bone metabolism. Thus, the clinical presentation and expected progression and responses to therapy are a net integration of how the host response, as modied by patient genetics and acquired factors, expressed protective and destructive biologic mediators. Simply put, modifying factors such as exposure to cigarette smoke and/or inherent genetic risk factors may alter the nature of the immunoinammatory response to shift the balance to more severe periodontal destruction. The 1997 model was non-linear. The presence of pathogenic bacteria did not automatically lead to a single host-response pattern and severe destruction. The model implied that there were a range of

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host responses and a range of clinical expressions of disease that were primarily determined by genetic and environmental factors that modied the host response. Each combination of genetic variations and environmental factors may dene a specic geneexpression pattern. It has been postulated, but not yet proven, that some of the different gene-expression patterns, as measured by various biomarkers, dene periodontal diseases with different clinical implications.3 ADVANCES IN KNOWLEDGE OF THE PATHOGENESIS OF PERIODONTITIS Although many of the concepts presented in the 1997 non-linear model of periodontal disease remain relevant today, there have been advances in knowledge about periodontal disease that may alter our models of pathogenesis. First, it was demonstrated that microbial periodontal pathogens are found in ecologic complexes, and an ecologic shift can lead to emergence of a specic set of microbial pathogens.45,46 Second, a number of studies33-41 conrmed that a small group of disease modiers, including diabetes, genotype, and smoking, contribute strongly to individual patient differences in the susceptibility to periodontitis. For example, in a recent prospective study47 of young adults aged 26 to 32 years, as many as two-thirds of new cases of periodontitis were attributed to smoking. Third, many studies48-59 described associations between periodontitis and other diseases, such as cardiovascular disease, and potentially explained such associations through bacterial seeding, common inammatory mechanisms, and/or common modifying factors. Fourth, there was an extension of knowledge about specic bacterial mechanisms and immunoinammatory mechanisms in periodontitis.60-64 ADVANCES IN KNOWLEDGE OF COMPLEX DISEASES During the same period of time, there were substantial advances in knowledge about chronic diseases in general that have inuenced our thinking about the pathogenesis of periodontitis. First, inammatory mechanisms were recognized as being common to many chronic diseases of aging, such as cardiovascular disease.65-67 Second, periodontitis and other chronic diseases were acknowledged as complex in character. This means that the overall biologic system has a distinct behavior that is more than the sum of its parts, i.e., it exhibits emergent properties. A recent study68 emphasized that complex biologic traits, such as obesity, have molecular networks that display emergent properties as a result of contributions from genetic and environmental factors. Third, although the biology is complex, the integrated behavior of the entire system can be studied using new simulation tools.69-71 For example, molec-

ular networks of specic biologic components, e.g., the immunoinammatory response, can be studied as a functional module. Combinations of modules can be integrated to study the overall system behavior that translates into clinical outcomes. Each module is dened in terms of cellular and molecular inputs and outputs. For example, the bacterial components that activate the immunoinammatory systems are inputs to the module. In addition, the genetic and environmental factors that modify that modules responses are inputs. The antibodies, cytokines, growth factors, prostanoids, reactive oxygen species, and other mediators that are produced by the cells of the immunoinammatory responses are the modules internal feedback mechanisms and outputs that provide inputs to other modules. Although there are many different combinations of inputs to a module, there are limited ranges of responses and outputs because biologic processes are well regulated within boundaries that are consistent with life. The behavior of the entire system has emergent properties because of the interaction of the factors within each module and interactions among modules. An example of such a modular, yet complex, biologic system is the leptin-dependent sympathetic regulation of bone mass.72,73 Adipose tissue has a number of different inputs and outputs, including the release of leptin that acts directly or indirectly on the hypothalamic neurons of the brain to modify sympathetic activity. As such, adipose tissue may represent a distinct module, whereas the brain tissue is a separate module that has its own inputs and outputs. Stimulation of hypothalamic neurons by leptin leads to activation of other modules through a neural mechanism involving b2-adrenergic receptors in osteoblasts, which indirectly drives osteoclastogenesis and alters bone metabolism. These observations may be directly relevant to periodontal diseases because leptin levels have been associated with periodontal disease.74 The fourth learning about complex diseases that may be applicable to models of periodontal pathogenesis involves the roles of environmental factors. Additional complexity in chronic disease biology seems to result from the fact that environmental factors may regulate gene expression in multiple ways. Environmental factors, including smoking and diabetes, which are associated with periodontal disease severity, may inuence the biology through multiple mechanisms, and we may speculate that the multiple hits on the biology contribute to the magnitude of their inuence on the disease. For example, certain dietary factors may produce epigenetic alterations in DNA that result in long-lasting changes in the expression of selected genes. At different stages in life, the same dietary factors may act directly as transcription factors to regulate specic genes and alter their expression
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at that immediate point in time. To add further complexity to a conceptual model for periodontal disease, we must recognize that the modifying factors, such as a particular gene variant, may interact in a specic environmental context. Recently, Shen et al.75 reported that interleukin-1 gene variations were signicantly associated with parameters of metabolic syndrome, but only in individuals with low levels of polyunsaturated fatty acids. Although nutritional factors do not cause periodontitis, their role in periodontal disease may be reexamined in light of more current knowledge about how nutrients regulate gene expression. For example, a dietary inuence on the severity of periodontitis was demonstrated in a primate model of periodontal disease in which calorie restriction (30% of normal caloric intake) was associated with decreased gingival bleeding, reduced clinical attachment loss, and a slower rate of disease progression compared to an ad libitum diet.76 Other advances in the general knowledge of chronic diseases included the use of genomic, proteomic, and metabolomic technologies to better explain the molecular networks that are involved in specic geneenvironment interactions in selected tissues. The massive amounts of information emerging from the new -omics technologies are being integrated into systems biology models of complex diseases.1,71 ELEMENTS OF A NEW MODEL OF PATHOGENESIS OF PERIODONTAL DISEASE Many of the same factors considered in the 1997 conceptual model of the pathogenesis of periodontal disease are still relevant today; however, the framework would now be based on a multilevel hierarchical organization, and the interactions are reected in gene, protein, and metabolite expression patterns (Fig. 2). In such models, the top layer includes clinically observable parameters, such as smoking, whereas the levels below include tissue, cellular, and subcellular layers, each divided into biologic networks. We can start to dene the elements of periodontal pathogenesis in terms of hierarchical models (Fig. 3). At the lower levels, the biologic expression of the immunoinammatory network and bone and connective tissue network are determined by the microbial factors and the specic combination of environmental factors and gene variations for that individual. Building a systems biology model of periodontitis presents substantial requirements and challenges, but investigators3,77-82 have started to provide data on the entities and gene and protein expressions associated with certain components of the periodontal model. As shown in the lower level of Figure 3, the expression patterns of an individual may be shaped by smoking >20 cigarettes per day and by a specic pattern of gene variations. Data to incorporate into this frame1564

Figure 2.
A key organizing principle of systems biology is the use of multiple levels to provide a framework for dening the interactions between the cellular and molecular processes occurring at the lowest levels to the clinical presentation of disease at the uppermost level. For example, level 1 may capture the factors that are inputs (*) to cell X and that regulate signaling mechanisms to control gene expression. The inputs to level 1 may come from other cells, from cell X proteins that are produced on activation (Level 4, **), or from the individuals environment (e.g., dietary polyunsaturated fatty acids). The genes expressed at level 1 may contribute proteins involved in cell energy metabolism (Level 2), cell differentiation (Level 3), or phenotypic expression (Level 4) that are characteristic of the differentiated cell type (Cell Xa), e.g., monocytes activated by lipopolysaccharide produce a characteristic cytokine prole. The tissue (Level 5) has a mixture of cell types and differentiation states (e.g., Cell Xa, Cell Yd, and Cell Za). At the clinical level (Level 6), tissue interactions are observable as clinical outcomes.

work are emerging, e.g., array proles, including gene expression patterns from macrophages or macrophage-like human cell lines following exposure to Porphyromonas gingivalis,83 lipopolysaccharide,84 and nicotine.79 This individual response, including cytokines and lipid mediators, produced by the host, as well as alterations in bone and connective tissue, can be clearly characterized by a specic pattern of gene, protein, and metabolite expression. The expressed proteins and metabolites provide feedback on the system to regulate the host response and bone and connective tissue, while helping to control the bacterial challenge. Although there has been progress in beginning to dene the expression of these biologic system maps, further detail is required in a number of areas. A more complete identication of expression proles from the bacterial challenge is needed, including identifying the proteome and metabolome associated with various microbial complexes. In addition, it would be valuable to dene the factors that regulate microbial

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are iterative and should inform researchers about key missing data, while they guide new concepts of disease management. CONCLUSIONS Over the past 50 years, a number of conceptual models describing the pathogenesis of periodontal disease have been presented based on existing knowledge at the time. The more recently explored biologic systems approach to modeling holds promise for revolutionizing conceptual models of the past by providing a comprehensive view of the disease process as a complex regulatory network. Within this framework, disFigure 3. crete modules of genetic, A biologic systems model representing the pathogenesis of periodontitis may be dened by the bacterial components, environmental factors, and hostgenetic variations associated with disease. Level A depicts environmental, and other the biologic mechanisms involved in immunoinammatory responses and in bone and connective tissue modifying factors would demetabolism, and level B depicts the observable clinical parameters and biomarkers. In level B, the ne a specic expression products produced by different microbial complexes are represented by arrays (*). These products activate pattern that represents the the immunoinammatory mechanisms, which subsequently inuence the behavior of bone and connective shift from health to disease. tissue metabolism. For each individual there are combinations of genetic variations and environmental factors (e.g., host genetic variation: pattern 1 and smoking >20 cigarettes/day). These genetic and Genomic, proteomic, and environmental factors act on mechanisms in level A to modify the expression of genes activated by the metabolomic data related to bacterial products. The gene expression and proteins and metabolites produced in level A can be assayed periodontal diseases are bein tissue samples (**), and the action of those biologic components produce tissue changes that can be ing collected. When these measured as clinical signs (***). data are combined with knowledge of even a limited set ecology under different genetic and environmental of environmental and genetic factors contributing to periodontitis, we should be able to build more roconditions. Finally, a more complete understanding bust models of the pathogenesis of periodontal disis needed of the biologic effects of known disease eases. modiers, such as smoking, diet, co-occurrence of other diseases, and specic genetic variations that inuence the expression of periodontitis. ACKNOWLEDGMENTS Ultimately, the goal will be to dene expression patDr. Kornman is the chief scientic ofcer, member of terns in the tissues with respect to each set of environthe Board of Directors, and a shareholder of Interleumental and genetic conditions and to understand the kin Genetics. Interleukin Genetics has patents issued corresponding clinical parameters and proles. Such and pending on the use of various genetic variations to information will allow construction of a systems biology assess the risk for diseases with inammatory compomodel that includes the state of key parameters at the nents, including periodontal disease. The initial draft basic biology level, which is critical to dening the regof this manuscript was developed by a medical writer ulatory status of the tissue at any point in time. Although (Axon Medical Communications Group, Toronto, Oneven partial information should improve the ability to tario) based on content provided solely by the author. identify an individuals susceptibility to disease and a The nal manuscript submitted was under the sole likely response to treatment, the complete expression control of the author. of these networks should be a valuable tool for determining new preventive and therapeutic approaches. REFERENCES Most importantly, research groups must commit to in1. Hood L, Heath JR, Phelps ME, Lin B. Systems biology tegrate their own data, as well as the data of others, into and new technologies enable predictive and preventacomprehensive systems-based models. These models tive medicine. Science 2004;306:640-643.
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43. Tervonen T, Knuuttila M. Relation of diabetes control to periodontal pocketing and alveolar bone level. Oral Surg Oral Med Oral Pathol 1986;61:346-349. 44. Page RC, Kornman KS. The pathogenesis of human periodontitis: An introduction. Periodontol 2000 1997; 14:9-11. 45. Socransky SS, Haffajee AD, Cugini MA, Smith C, Kent RL Jr. Microbial complexes in subgingival plaque. J Clin Periodontol 1998;25:134-144. 46. Ximenez-Fyvie LA, Haffajee AD, Socransky SS. Comparison of the microbiota of supra- and subgingival plaque in health and periodontitis. J Clin Periodontol 2000;27:648-657. 47. Thomson WM, Broadbent JM, Welch D, Beck JD, Poulton R. Cigarette smoking and periodontal disease among 32-year-olds: A prospective study of a representative birth cohort. J Clin Periodontol 2007;34:828834. 48. Beck JD, Slade G, Offenbacher S. Oral disease, cardiovascular disease and systemic inammation. Periodontol 2000 2000;23:110-120. 49. Offenbacher S, Beck JD, Lieff S, Slade G. Role of periodontitis in systemic health: Spontaneous preterm birth. J Dent Educ 1998;62:852-858. 50. Taylor GW, Loesche WJ, Terpenning MS. Impact of oral diseases on systemic health in the elderly: Diabetes mellitus and aspiration pneumonia. J Public Health Dent 2000;60:313-320. 51. Tezal M, Wactawski-Wende J, Grossi SG, Ho AW, Dunford R, Genco RJ. The relationship between bone mineral density and periodontitis in postmenopausal women. J Periodontol 2000;71:1492-1498. 52. Beck JD, Offenbacher S. The association between periodontal diseases and cardiovascular diseases: A stateof-the-science review. Ann Periodontol 2001;6:9-15. 53. Offenbacher S, Lieff S, Boggess KA, et al. Maternal periodontitis and prematurity. Part I: Obstetric outcome of prematurity and growth restriction. Ann Periodontol 2001;6:164-174. 54. Elter JR, Champagne CM, Offenbacher S, Beck JD. Relationship of periodontal disease and tooth loss to prevalence of coronary heart disease. J Periodontol 2004;75:782-790. 55. Scannapieco FA, Bush RB, Paju S. Associations between periodontal disease and risk for atherosclerosis, cardiovascular disease, and stroke. A systematic review. Ann Periodontol 2003;8:38-53. 56. DAiuto F, Tonetti MS. Contribution of periodontal therapy on individual cardiovascular risk assessment. Arch Intern Med 2005;165:1920-1921. 57. Craig RG, Kotanko P, Kamer AR, Levin NW. Periodontal diseases A modiable source of systemic inammation for the end-stage renal disease patient on haemodialysis therapy? Nephrol Dial Transplant 2007;22:312-315. 58. Michaud DS, Joshipura K, Giovannucci E, Fuchs CS. A prospective study of periodontal disease and pancreatic cancer in US male health professionals. J Natl Cancer Inst 2007;99:171-175. 59. Southerland JH, Taylor GW, Moss K, Beck JD, Offenbacher S. Commonality in chronic inammatory diseases: Periodontitis, diabetes, and coronary artery disease. Periodontol 2000 2006;40:130-143. 60. Yamazaki K, Ohsawa Y, Yoshie H. Elevated proportion of natural killer T cells in periodontitis lesions: A common feature of chronic inammatory diseases. Am J Pathol 2001;158:1391-1398.

61. Van Dyke TE, Serhan CN. Resolution of inammation: A new paradigm for the pathogenesis of periodontal diseases. J Dent Res 2003;82:82-90. 62. Tsuda K, Amano A, Umebayashi K, et al. Molecular dissection of internalization of Porphyromonas gingivalis by cells using uorescent beads coated with bacterial membrane vesicle. Cell Struct Funct 2005; 30:81-91. 63. Inagaki S, Onishi S, Kuramitsu HK, Sharma A. Porphyromonas gingivalis vesicles enhance attachment, and the leucine-rich repeat BspA protein is required for invasion of epithelial cells by Tannerella forsythia. Infect Immun 2006;74:5023-5028. 64. Popadiak K, Potempa J, Riesbeck K, Blom AM. Biphasic effect of gingipains from Porphyromonas gingivalis on the human complement system. J Immunol 2007;178:7242-7250. 65. Libby P, Ridker PM. Inammation and atherosclerosis: Role of C-reactive protein in risk assessment. Am J Med 2004;116(Suppl. 6A):9S-16S. 66. Ridker PM. Inammatory biomarkers and risks of myocardial infarction, stroke, diabetes, and total mortality: Implications for longevity. Nutr Rev 2007;65: S253-S259. 67. Ridker PM, Morrow DA. C-reactive protein, inammation, and coronary risk. Cardiol Clin 2003;21:315-325. 68. Chen Y, Zhu J, Lum PY, et al. Variations in DNA elucidate molecular networks that cause disease. Nature 2008;452:429-435. 69. Kitano H. Biological robustness in complex host-pathogen systems. Prog Drug Res 2007;64:239, 241-263. 70. Loscalzo J, Kohane I, Barabasi AL. Human disease classication in the postgenomic era: A complex systems approach to human pathobiology. Mol Syst Biol 2007;3:124. 71. Zheng Y, Kreuwel HT, Young DL, et al. The virtual NOD mouse: Applying predictive biosimulation to research in type 1 diabetes. Ann N Y Acad Sci 2007; 1103:45-62. 72. Sato S, Hanada R, Kimura A, et al. Central control of bone remodeling by neuromedin U. Nat Med 2007;13: 1234-1240. 73. Takeda S, Karsenty G. Molecular bases of the sympathetic regulation of bone mass. Bone 2008;42:837840. 74. Karthikeyan BV, Pradeep AR. Leptin levels in gingival crevicular uid in periodontal health and disease. J Periodontal Res 2007;42:300-304. 75. Shen J, Arnett DK, Peacock JM, et al. Interleukin1beta genetic polymorphisms interact with polyunsaturated fatty acids to modulate risk of the metabolic syndrome. J Nutr 2007;137:1846-1851. 76. Branch-Mays GL, Dawson D, Gunsolley JC, et al. The effects of a calorie-reduced diet on periodontal inammation and disease in a non-human primate model. J Periodontol 2008;79:1184-1191. 77. Duarte PM, Neto JB, Casati MZ, Sallum EA, Nociti FH Jr. Diabetes modulates gene expression in the gingival tissues of patients with chronic periodontitis. Oral Dis 2007;13:594-599. 78. Papapanou PN, Abron A, Verbitsky M, et al. Gene expression signatures in chronic and aggressive periodontitis: A pilot study. Eur J Oral Sci 2004;112:216-223. 79. Koshi R, Sugano N, Orii H, Fukuda T, Ito K. Microarray analysis of nicotine-induced changes in gene expression in a macrophage-like human cell line. J Periodontal Res 2007;42:518-526. 1567

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80. Kubota T, Itagaki M, Hoshino C, et al. Altered gene expression levels of matrix metalloproteinases and their inhibitors in periodontitis-affected gingival tissue. J Periodontol 2008;79:166-173. 81. Papapanou PN, Sedaghatfar MH, Demmer RT, et al. Periodontal therapy alters gene expression of peripheral blood monocytes. J Clin Periodontol 2007;34: 736-747. 82. Peruzzo DC, Benatti BB, Antunes IB, et al. Chronic stress may modulate periodontal disease: A study in rats. J Periodontol 2008;79:697-704. 83. Zhou Q, Amar S. Identication of signaling pathways in macrophage exposed to Porphyromonas gingivalis

or to its puried cell wall components. J Immunol 2007;179:7777-7790. 84. Roach JC, Smith KD, Strobe KL, et al. Transcription factor expression in lipopolysaccharide-activated peripheral-blood-derived mononuclear cells. Proc Natl Acad Sci USA 2007;104:16245-16250. Correspondence: Dr. Kenneth Kornman, Interleukin Genetics, 135 Beaver St., Waltham, MA 02452. Fax: 781/ 398-0720; e-mail: kkornman@ilgenetics.com. Submitted April 22, 2008; accepted for publication May 30, 2008.

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