Infection and inflammatorymechanismsVan Dyke TE, van Winkelhoff AJ. Infection and inflammatory mechanisms.J Clin Periodontol 2013; 40 (Suppl. 14): S1–S7. doi: 10.1111/jcpe.12088.

AbstractThis introductory article examines the potential mechanisms that may play a rolein the associations between periodontitis and the systemic conditions being con-sidered in the EFP/AAP Workshop in Segovia, Spain. Three basic mechanismshave been postulated to play a role in these interactions; metastatic infections,inflammation and inflammatory injury, and adaptive immunity. The potential roleof each alone and together is considered in in vitro and animal studies and inhuman studies when available. This is not a systematic or critical review, butrather an overview of the field to set the stage for the critical reviews in each ofthe working groups.

Thomas E. Van Dyke1

and Arie Jan van Winkelhoff2

1The Forsyth Institute, Cambridge, MA,

USA; 2Department of Dentistry and Oral

Hygiene, University of Groningen, Groningen,

The Netherlands

Key words: cardiovascular disease; infection;

inflammation; pathogenesis; periodontitis;

systemic diseases

Accepted for publication 14 November 2012

The proceedings of the workshop were jointly

and simultaneously published in the Journal

of Clinical Periodontology and Journal of

Periodontology.

Two disorders/diseases can simulta-neously occur or may developsequentially where progression orexacerbation of one disease may affectthe second disease. In parallel withKoch’s postulates, which are used toidentify the aetiological agents of aninfectious disease, the criteria for acausal association between two dis-eases have been defined and areknown as the Bradford Hill criteria.These include epidemiological associ-ation, biological plausibility and theimpact of intervention of one on thesecond disease.

A large body of evidence exists rel-evant to the association of periodonti-tis with diabetes mellitus,cardiovascular disease and dentalfocal infections. Three mechanisms

have been postulated to play a role innon-oral manifestations of oral dis-eases (Thoden van Velzen et al. 1984):metastatic infections, dissemination ofbacterial toxins and immunologicalinjury. The word metastasis comesfrom the Greek “displacement”; leτά,meta, “next”, and rτάrις, stasis,“placement”. Metastasis, or meta-static disease, has been defined as thespread of a disease from one organ orpart of the body to another non-adja-cent organ or body part. The defini-tion is not limited by the commonusage involving malignant tumourcells; infection and inflammation havethe capacity to metastasize (Chiang &Massague 2008).

In the context of the relationshipbetween periodontal disease and sys-temic diseases, the underlyingassumption is that periodontitis is aninfection that causes an inflammatorydisease that metastasizes. This can bemetastasis of the infection (bactera-emia and infection at non-oral sitescaused by oral bacteria or other directbacterial actions), inflammation andinflammatory mediators having animpact on systemic inflammation

mediated by innate immune cells andmediators, activation of adaptiveimmunity and the systemic conse-quences, or an undefined combina-tion of any or all of these potentialmechanisms. However, it is plausible,if unlikely based on available data,that the associations are the result ofcommon risk factors and not causallyrelated. From our understanding ofthe biology of the relationshipbetween periodontitis and systemicdisease, it remains clear that the rela-tionship is not linear, but complex.

The purpose of this introductorySupplement article is to discuss thepotential mechanisms underpinningthe associations between periodontaldisease and systemic conditions. Thisnot intended to be a systematic orcritical review, but than an overviewof the possibilities based upon ourunderstanding of the systemic conse-quences of periodontal infection andinflammation. The classification ofGonzalez-Periz et al. (2009), Kinaneet al. (2005) has been modified forthe purposes of this Supplement arti-cle, where metastatic infections andbacterial toxins will be considered

Conflict of interest and source offunding statement

The authors declare no conflict ofinterest. The workshop was funded byan unrestricted educational grant fromColgate-Palmolive to the EuropeanFederation of Periodontology and theAmerican Academy of Periodontology.

© 2013 European Federation of Periodontology and American Academy of Periodontology S1

J Clin Periodontol 2013; 40 (Suppl. 14): S1–S7 doi: 10.1111/jcpe.12088

under the heading of ‘Infection”followed by “Inflammation” and itsconsequences, and finally “AdaptiveImmunity”.

Infection

Periodontal disease (gingivitis andperiodontitis) is a destructive diseaseof the gingiva and of the supportingstructures of the teeth, which devel-ops through inflammatory processesinduced by a microbial biofilm. Thisfundamental periodontal principlewas first established by a landmarkstudy by Loe et al. (1965). Periodon-tal bacteria possess a plethora of vir-ulence factors that induce cells toproduce inflammatory mediators atthe gingival level. It is also impor-tant to note that inflammation isusually not confined only to peri-odontal tissues. Bacteria and inflam-matory mediators may enter theblood and disseminate systemicallyhaving a measurable impact on sys-temic inflammation. The epidemio-logical evidence linking periodontitisto the progression of systemic dis-eases, such as cardiovascular disease,adverse pregnancy outcomes anddiabetes mellitus, is associated withboth bacteraemia and elevated levelsof various markers of systemicinflammation. Periodontal disease isnot universally expressed in peoplewith poor oral hygiene that harbourperiodontal pathogens; diseaseexpression also requires a susceptiblehost (Offenbacher 1996). The deter-minants of susceptibility for destruc-tive periodontal disease are not welldefined.

In addition, virulence factors suchas cytotoxins, proteases and haemag-glutinins, structural molecules of thebacteria, including lipopolysaccharide(LPS) and peptidoglycan (PGN),interact with the host immune system.Most of these molecules have con-served motifs known as pathogen-associated molecular patterns(PAMPs), which are recognized byhost cell receptors called pattern rec-ognition receptors (PRRs). PRRsdetect PAMPs in the environment andactivate specific signalling pathways inhost cells that initiate inflammatoryresponses. Bacterial virulence factorsincluding PAMPs are LPS, PGN, li-poteichoic acid (LTA), fimbriae, pro-teases, heat-shock proteins (HSPs),formyl-methionyl-leucyl-phenylalanine

(fMLP) and toxins. PRRs includethe Toll-like receptors (TLRs) and avariety of G-protein coupled recep-tors (GPCRs) (Madianos et al.2005). However, it is important tonote that most of these proposedinteractions have only been observedin vitro or in animal models.

Metastatic infection

Metastatic or focal infection by bac-terial translocation connotes aninfectious disease mediated by micro-organisms that have originated froma distant body site. In periodontitis,the infection is not limited to thegingiva or oral cavity. The resultantbacteraemia comes from perturba-tion of ulcerated periodontal tissuesby simple acts of tooth brushing andeating disseminating whole bacteriaand their products and toxins suchas LPS (Kinane et al. 2005). Non-oral infections caused by oral patho-gens were first described decades agoand include among others endocardi-tis, lung infections, and liver andbrain abscesses (van Winkelhoff &Slots 1999). Oral bacteria, dissemi-nated from periodontal, endodonticor mucosal lesions can survive in theblood stream and may adhere atnon-oral body sites. A locus minorisresistentiae (such as scar tissue,or microangiopathology, prostheticdevices) may be a prerequisite foradherence of oral bacteria.

Using PCR, DNA of periodontalbacteria has been detected in carotidatheromas and other sites of pathol-ogy distal to the source (Haraszthyet al. 2000), but the role of theseobservations in the pathogenesis ofvascular disease remains unclear. Itis possible that these bacteria causetissue damage or initiate inflamma-tion. In certain instances, they growin tissues causing disease as in thelung (Raghavendran et al. 2007), butbacteria identified in atheromas, forinstance, do not form colonies. In aseries of experiments using APO-Eknockout mice, Genco and co-work-ers (Deshpande et al. 1998a,b)induced cardiovascular lesions withoral administration of Porphyromon-as gingivalis and subsequently recov-ered the bacterium from fattystreaks in the aorta. These findingswere not supported in rabbit experi-ments (Jain et al. 2003). The role ofdisseminating infection in each sys-

temic condition will be evaluated inthe subsequent systematic and criti-cal reviews.

Inflammation

Despite the localized nature of peri-odontal disease, infection of the sul-cus/periodontal pocket can lead toinflammatory responses beyond theperiodontium. Several biologicalpathways have been identified link-ing periodontal disease to inductionof systemic inflammation. In health,the sulcular epithelium and localinnate immunity act as a naturalbarrier that prevents bacterial pene-tration. In gingival health, only asmall number of bacteria, mostlyfacultative anaerobes, are found inthe gingival crevice and bloodstream.However, in periodontal disease,inflamed and ulcerated subgingivalpocket epithelium is vulnerable tobacteria and provides a port ofentry. Recently, Nesse et al. (2008)described a technique to calculatethe amount of inflamed periodontaltissue (Periodontal Inflamed SurfaceArea, PISA) to assess the inflamma-tory burden posed by periodontitis.They found a dose–response rela-tionship between PISA and HbA1cin type 2 diabetics.

Bacteraemia is further aggravatedby mechanical means during toothbrushing, chewing, oral examination,endodontic treatment (Debelian et al.1995) and scaling and root planing(Kinane et al. 2005). Microorganismsthat gain access to the blood are usu-ally eliminated by the reticuloendothe-lial system within minutes (transientbacteraemia) with no clinical symp-toms (Li et al. 2000). However, it isplausible that bacteria persist at distalsites disseminating virulence factorsthat act as soluble antigens. Bacteriaand bacterial antigens that are system-ically dispersed trigger significantsystemic inflammation. Leucocytes,endothelial cells and hepatocytesrespond to bacteria/virulence factorswith secretion of pro-inflammatoryimmune mediators [cytokines, chemo-kines, C-reactive protein (CRP)]. Withcontinued exposure, soluble antigensreact with circulating specific antibodyto form immune complexes thatfurther amplify inflammation at sitesof deposition (Thoden van Velzenet al. 1984, Li et al. 2000). Likewise,pro-inflammatory mediators, such as

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S2 Van Dyke and van Winkelhoff

IL-1b, IL-6, TNF-a and PGE2, pro-duced locally in the inflamed gingivaltissues may “spill” into the circulationand have systemic impact, such asinduction of endothelial dysfunction(Amar et al. 2003, Elter et al. 2006).Pro-inflammatory cytokines in circu-lation induce leucocytosis and acute-phase proteins. In addition to CRP,acute-phase reactants include serumamyloid A protein, fibrinogen, plas-minogen activator inhibitor 1, com-plement proteins, LBP and solubleCD14; all are implicated in thesystemic conditions linked to peri-odontitis.

Innate immunity – The inflammatory

response

Cytokines are low molecular weightproteins that initiate and perpetuateinflammation, as well as regulate theamplitude and duration of theresponse. The genetic regulationleading to secretion of pro-inflamma-tory cytokines from a variety of cellsis generally dependent on the activa-tion of NFjB nuclear protein activa-tion of transcription (Baldwin 1996,Hanada & Yoshimura 2002). TheNKjB regulated pathways are acti-vated by PAMPs such as LPSthrough the TLR pathway (Hanada& Yoshimura 2002).

Cytokines are produced by resi-dent cells, such as epithelial cells andfibroblasts, and phagocytes (neu-trophils and macrophages) in theacute phase and early chronic phaseof inflammation, and by immunecells (lymphocytes) in adaptiveimmunity (Ara et al. 2009). Aftermicrobial recognition, cytokines ofthe innate response, including TNF-a, IL-1b and IL-6, are the firstsecreted in periodontal disease path-ogenesis (Garlet 2010). IL-1b andIL-6 are signature innate cytokinesand have been characteristicallyassociated with inflammatory cellmigration and osteoclastogenesis(Graves et al. 2008 Fonseca et al.2009). TNF-a is a pleotropic cyto-kine that has many functions fromcell migration to tissue destruction(Peschon et al. 1998, Dinarello 2000,Wajant et al. 2003, Kindle et al.2006). TNF-a up-regulates the pro-duction IL-1b and IL-6 (Okadaet al. 1997, Dinarello 2000, Wajantet al. 2003, Kwan Tat et al. 2004,Garlet et al. 2007, Graves et al.

2008, Musacchio et al. 2009). TNF-ais also correlated with extracellularmatrix degradation and bone resorp-tion through actions promotingsecretion of MMPs and RANKL(Graves & Cochran 2003, Garletet al. 2004, Graves et al. 2008) andcoupled bone formation (Behl et al.2008). Accordingly, TNFa in circula-tion significantly impacts systemicinflammation and associated sys-temic conditions (CRP and CVD,obesity, Type 2 diabetes).

Chemokines are chemotacticcytokines that play a very importantrole in phagocytic cell migration tothe site of infection. Once bloodleucocytes exit a blood vessel, theyare attracted by functional gradientsof chemotactic factors to the site ofinfection (Rossi & Zlotnik 2000Zlotnik & Yoshie 2000). Chemokin-es are synthesized by a variety ofcells including endothelial, epithelialand stromal cells, as well as leuco-cytes. Functionally, chemokines canbe grouped as homeostatic orinflammatory (Moser et al. 2004).In addition to their cell traffickingrole, chemokines provide messagesleading to other biological pro-cesses, such as angiogenesis, cellproliferation, apoptosis, tumourmetastasis and host defence (Rossi& Zlotnik 2000, Zlotnik & Yoshie2000, Moser et al. 2004, Rot & vonAndrian 2004, Esche et al. 2005).Bacterial peptides are also chemo-tactic for inflammatory cells.Chemokines target leucocytes of theinnate immune system, as well aslymphocytes of the adaptiveimmune system (Terricabras et al.2004).

Lipid mediators of inflammation

Prostaglandins (PGs) are derivedfrom hydrolysis of membrane phos-pholipids. Phospholipase A2 cleavesthe sn-2 position of membrane phos-pholipids to free arachidonic acid, aprecursor of a group of small lipidsknown as eicosanoids (Lewis 1990).Arachidonic acid is metabolized bytwo major enzyme pathways. Lipox-ygenases (LO) catalyse the forma-tion of hydroxyeicosatetraenoicacids (HETEs) leading to the forma-tion of leucotrienes (LT). Cyclooxy-genases (COX-1 and COX-2)catalyse the conversion of arachi-donic acid into prostaglandins,

prostacyclins and thromboxanes.Prostaglandins have 10 sub-classes,of which D, E, F G, H and I arethe most important in inflammation(Gemmell et al. 1997). Inflamed gin-giva synthesizes significantly largeramounts of prostaglandins whenincubated with arachidonic acidthan does healthy gingiva (Mendietaet al. 1985). Prostaglandin E2

(PGE2) is a potent stimulator ofalveolar bone resorption (Goodsonet al. 1974, Dietrich et al. 1975).Periodontal ligament cells also pro-duce PGE2 even when unstimulated.This secretion is enhanced by IL-1b,TNF-a and parathyroid hormone(Richards & Rutherford 1988, Saitoet al. 1990a,b). LO and COX prod-ucts (LTB4, Thromboxanes andPGE2, respectively) play importantroles in systemic inflammation,endothelial cell activation and vascu-lar endothelial growth factor(VEGF) expression and plateletaggregation.

Natural regulation of innate inflammation

Periodontal inflammation begins as aprotective response to bacterial bio-film. In susceptible individuals, peri-odontal inflammation fails to resolveand chronic inflammation becomesperiodontal pathology with systemicimpact. The acute inflammatoryresponse is protective, but a failureto remove inflammatory cells, espe-cially neutrophils, characterizes thechronic, pathological lesion. Therapid and complete elimination ofleucocytes from a lesion is the idealoutcome following an inflammatoryevent (Van Dyke 2007). Accordingly,inadequate resolution and failure toreturn tissue to homeostasis results inneutrophil-mediated destruction andchronic inflammation (Van Dyke &Serhan 2003), with destruction ofextracellular matrix, and bone, scar-ring and fibrosis (Van Dyke 2008).

Efforts to control inflammation todate have been focused on the use ofpharmacological agents that inhibitpro-inflammatory mediator pathways,for example, non-steroidal anti-inflammatory drugs (NSAIDs) (Ser-han et al. 2007). NSAIDs targetCOX-1 and COX -2–dependent path-ways inhibiting generation of prosta-noids. Newer classes of inhibitorstarget lipoxygenase pathways andleucotriene (LT) production or TNFa.

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Infection and inflammatory mechanisms S3

The side-effect profiles of these agentsprohibit their extended use in peri-odontal therapy and have been shownto have negative impact on the pro-gression of systemic inflammatoryconditions including CVD, diabetesand rheumatoid arthritis (RA).

More recent discoveries haveuncovered eicosanoid pathways thatsignal the physiological end of theacute inflammatory phase (Levy et al.2001, Van Dyke 2007). The eicosa-noid product, lipoxins, are receptoragonists that stimulate the resolutionof inflammation and promote the res-toration of tissue homeostasis by lim-iting PMN migration into sites ofinflammation, modulating the pheno-type of macrophages, stimulating theuptake of apoptotic PMN withoutsecretion of pro-inflammatory cyto-kines (Serhan et al. 1993, Maddox &Serhan 1996, Maddox et al. 1997).

Lipoxins are the natural pro-resolving molecules derived fromendogenous fatty acids. Dietary fattyacids of the omega-3 class are alsometabolized by similar pathways andthe products (resolvins) have similarbiological activity to lipoxins (VanDyke 2007, Serhan & Chiang 2008).Resolvins stimulate the resolution ofinflammation through multiplemechanisms, including preventingneutrophil penetration, phagocytosisof apoptotic neutrophils to clear thelesion, and enhancing clearance ofinflammation within the lesion topromote tissue regeneration (Ban-nenberg et al. 2005, Hasturk et al.2007, Schwab et al. 2007).

In the context of inflammation,several animal studies with agonistsof resolution of inflammationemphasize the importance of inflam-mation in the pathogenesis of sys-temic diseases. In type 2 diabetesmodels in mice, resolvins have beendemonstrated to reverse insulin resis-tance and prevent complications ofdiabetes (Claria et al., 1998; Spiteet al., 2009). Lipoxin levels in circu-lation have been directly linked tosusceptibility to periodontitis andCVD in rabbits (Jain et al. 2003,Serhan et al. 2003) providing apotential link between the pathogen-sis of these diseases.

Adaptive immunity

If the acute periodontal lesion per-sists without resolution, bacterial

antigens are processed and presentedto the adaptive immune system bymacrophages, and dendritic cells.Broadly, two subsets of lymphocytesrecognize immune cell presentedantigens of extracellular and intracel-lular pathogens; T lymphocytes andB lymphocytes. B lymphocytes bearimmunoglobulin (Ig) molecules ontheir surface, which function as anti-gen receptors. Antibody (Ab), whichis a soluble form of immunoglobulin,is secreted following activation of Bcells to bind pathogens and foreignmaterial in the extracellular spaces(humoral immunity). T cells are theeffectors of cell-mediated immunity(delayed hypersensitivity). The T-cellantigen receptor is a membrane-bound molecule similar to immu-noglobulin that recognizes peptidefragments of pathogens. Activationof the T-cell receptor requires themajor histocompatibility complex(MHC), which is also a member ofthe immunoglobulin superfamily.Two classes of MHC molecules arerequired for activation distinct sub-sets of T cells. Various T-cell subsetskill infected target cells, and activatemacrophages, B cells and other Tcells.

Classically, T lymphocytes havebeen classified into subsets based onthe cell surface expression of CD4or CD8 molecules. CD4+ T-cells(T-helper cells) were initially subdi-vided into two subsets, designatedTh1 and Th2, on the basis of theirpattern of cytokine production. Th1cells secrete interleukin-2 and inter-feron-c (IFN-c), whereas Th2 cellsproduce IL-5, IL-6, IL-4, IL- 10and IL-13. Both cell types produceIL-3, TNFa and granulocyte-macro-phage colony-stimulating factor(GM-CSF) (Kelso 1995, Zadehet al. 1999). The major role of theTh1 cytokines IL-2 and IFN-c is toenhance cell-mediated responses,whereas the Th2 signature cytokineIL-4 suppresses cell-mediatedresponses (Modlin & Nutman1993). T-cell subsets are also impor-tant in the behaviour of B cells.For example, Th1 cells direct B cellsecretion of immunoglobulin G2(IgG2), whereas Th2 cells up-regu-late IgG1 secretion. CD8 T cells(cytotoxic T-cells) are immune effec-tor cells that also secrete cytokinesthat are characteristic of either Th1or Th2 cells (Zadeh et al. 1999).

Two other well-defined CD4 T-cell subsets, Th17 and T-regulatory(Tregs) T-cells, play antagonisticroles as effector and suppressor cellsrespectively (Appay et al. 2008,Sallusto & Lanzavecchia 2009, Wea-ver & Hatton 2009). Th17 are namedfor their unique IL-17 production.Th17 cells also produce IL-22. Th17lymphocytes, like Th1 cells, are alsonoted for their stimulatory role inosteoclastogenesis (Yago et al. 2009).Th17 cells are observed in chronicperiodontitis sites, and Th17 relatedcytokines are produced in periodon-tal lesions (Takahashi et al. 2005,Vernal et al. 2005, Ohyama et al.2009).

Tregs have a protective role inperiodontal tissue damage. NaturalTregs are CD4 and CD25 expressingT cells that specifically regulate theactivation, proliferation, and effectorfunction of activated conventionalT-cells (Appay et al. 2008, Belkaid &Tarbell 2009, Sallusto & Lanzavec-chia 2009). Tregs are found in theperiodontal disease sites (Nakajimaet al. 2005, Cardoso et al. 2008).The cytokines produced by Tregs areTGF-b and T-lymphocyte-associatedmolecule 4 (CTLA-4), which down-regulate inflammation. IL-10, TGF-band CTLA-4 are reported todecrease periodontal disease progres-sion (Cardoso et al. 2008).

Macrophages, phagocytic cellsfrom the myeloid lineage, efficientlyingest particulate antigen andexpress MHC class II moleculesinducing T cells. Macrophages arewidely distributed cells that play anindispensible role in homeostasis anddefence. Dendritic cells also expressMHC class II molecules and haveco-stimulatory activity. It is evidentthat innate and adaptive systems areco-ordinately involved in the inflam-matory response and tissue destruc-tion, although we lack a completeunderstanding of the mechanism inmany inflammatory conditions,including periodontitis, obesity, dia-betes, RA and CVD.

The link to systemic conditions

Severe periodontal disease affects 10–15% of the general population andhas been linked to cardiovasculardisease in cross-sectional and cohortstudies (Janket et al. 2003, Khaderet al. 2003, Pussinen et al. 2005).

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S4 Van Dyke and van Winkelhoff

Studies reported that elevated celland cytokine-mediated markers ofinflammation, including C-reactiveprotein (CRP), fibrinogen and vari-ous cytokines are associated withperiodontal disease (Black 2004).The same pro-inflammatory markersin periodontal disease have also beenlinked with atherothrombogenesis(Danesh et al. 2000). By reducingthe progression of periodontal dis-ease, levels of inflammatory markerscommon to both diseases (i.e. IL-6,TNF a and CRP) are decreased,which might in turn decrease vascu-lar disease (Mustapha et al. 2007). Itis still unknown whether inhibiting/reducing inflammation in general orCRP in particular will decrease therate of vascular effects.

In several atherosclerosis studiesusing animal models, periodontaldisease was shown to be a contribut-ing factor (Jain et al. 2003, Gibsonet al. 2004). Activated immune cellsin the atherogenic plaque produceinflammatory cytokines (interferon,interleukin-1 and TNF a), whichinduce the production of substantialamounts of IL-6. These cytokinesare also produced in various tissuesin response to infection and in theadipose tissue of patients with themetabolic syndrome (Hansson 2005).IL-6, in turn, stimulates the produc-tion of large amounts of acute-phasereactants, including CRP, serumamyloid A, and fibrinogen, especiallyin the liver. Although cytokines atall steps have important biologicaleffects, their amplification at eachstep of the cascade makes the mea-surement of downstream mediatorssuch as CRP particularly useful forclinical diagnosis (Hansson 2005).Increased hsCRP plasma levels inpatients with pre-hypertension andpatients with established hyperten-sion (Sesso et al. 2003) may linkthese two conditions. Major depres-sion, physical inactivity, family his-tories of CVD and periodontaldisease, advancing age and male gen-der are other risk factors for athero-sclerotic CVD that are commonlyfound in patients with periodontitisand also may serve as confounders(Friedewald et al. 2009a,b, Genco &Van Dyke 2010).

Systemic inflammation, definedby increased circulating TNF-a, isassociated with obesity and peri-odontitis and has been proposed as

a mechanism for the connectionbetween these conditions (Al-Zahra-ni et al. 2003, Genco et al. 2005). Acase-controlled study demonstratedthat periodontitis is associated withelevated plasma triglycerides andtotal cholesterol (Loesche et al.2005).

Summary and Recommendations

The critical and systematic reviewsthat have been performed to date,and those that will follow in thispublication, suggest that periodontaldisease is an independent predictorof several systemic conditions,including CVD, diabetes, PT- LBWinfants, RA and cancer. Epidemio-logical studies, most retrospective,demonstrate the association. Animalstudies of potential mechanism sug-gest biological plausibility; a verycomplex array of biological pro-cesses. Clinical proof of causality iselusive. Nonetheless, it remains clearfrom the data, that the three aspectsof the pathogenesis of periodontaldisease; infection, inflammation andadaptive immunity, all have apotential role and impact on thesystemic inflammatory/immuneresponse that either initiates ormediates a wide range of systemicdiseases.

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Address:Thomas E. Van DykeVice President for Clinical and TranslationalResearchChair, Department of Applied Oral SciencesSenior Member of the StaffThe Forsyth Institute245 First StreetCambridge, MA 02142 USAE-mail: tvandyke@forsyth.org

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