Infection or Inflammation

7/25/2019 Infection or Inflammation

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Infection or Inflammation:The Link Between PeriodontalDisease and Systemic DiseaseGregory J. Seymour, BDS, MDSc, PhD, FRCPath, FFOP(RCPA), FRACDS(Perio)Pauline J. Ford, BDentSt, BDScErica Gemmell, BSc, PhDKazuhisa Yamazaki, DDS, PhD

1

T here is increasing evidence thatchronic infections are associated withcardiovascular diseases (CVDs). Theseinfections include Helicobacter pylori,Chlamydia pneumoniae , cytomegalovirus,and, more recently, periodontopathic

bacteria such as Porphyromonas gingivalis.Although a large number of potentialmechanisms have been postulated, themechanism by which these infectionsassociate with CVDs is still unclear. Anumber of hypotheses nevertheless exist,

ABSTRACT

There is increasing evidence that chronic infections are associated with cardiovascular diseases. A num-ber of hypotheses have been put forward to explain these associations, including common susceptibility, systemic inflammation, direct infection of the blood vessels, and cross-reactivity or molecular mimicry between bacterial and self-antigens. In terms of common susceptibility, a person who is susceptible to progressive periodontal disease isalso susceptible to atherosclerosis, but the periodontal disease does not cause the atherosclerosis. In recent yearsmuch research has been focused on the role of systemic inflammation and the increase in circulating cytokines and inflammatory mediators. These cytokines and mediators can lead to direct endothelial damage and ultimately to atherosclerosis. A number of studies have shown that periodontal bacteria can directly invade the endothelium and thereby lead to inflammation in the blood vessel wall resulting in atherosclerosis. In terms of molecular mimicry, it is proposed that because of the homology between bacterial GroEL antigens and human heat shock protein (HSP), thelocal immune response to the periodontopathic bacteria cross-reacts with self-HSP expressed on the endotheliumleading to vascular inflammation and hence atherosclerosis.There is increasing evidence in support of this hypothesis;however, none of these possible mechanisms are mutually exclusive, and it is likely that in different people different mechanisms may explain the link between periodontal infection and cardiovascular disease.

Gregory J. Seymour, BDS, MDSc, PhD, FRCPath, FFOP(RCPA), FRACDS(Perio)Dean, Faculty of Dentistry University of Otago Dunedin, New Zealand Pauline J. Ford, BDentSt, BDScOral Biology and Pathology School of Dentistry The University of Queensland Queensland, AustraliaErica Gemmell, BSc, PhDOral Biology and Pathology School of Dentistry The University of Queensland Queensland, AustraliaKazuhisa Yamazaki, DDS, PhDFaculty of Dentistry Niigata University Niigata, Japan INSIDE DENTISTRY VOL. 2 (SPECIAL ISSUE 1)


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2 INSIDE DENTISTRY VOL. 2 (SPECIAL ISSUE 1) INTERNATIONAL CONSENSUS STATEMENT GREGORY J. SEYMOUR

including common susceptibility, sys-temic inflammation with increased cir-culating cytokines and inflammatory mediators, direct infection of the bloodvessels, and, finally, cross-reactivity ormolecular mimicry between bacterialand self-antigens. This final hypothesis

is gaining support and will be discussedin this review.

COMMON SUSCEPTIBILITYCommon susceptibility involves a genet-ically determined phenotype,which leadsto a greater risk of both atherosclerosis

and infection. In this hypothesis, in thepresence of periodontal pathogens, asusceptible person develops periodontaldisease. This same person would also besusceptible to atherosclerosis, but, inthis model, the periodontal disease doesnot cause the atherosclerosis (Figure 1).

SYSTEMIC INFLAMMATIONThe second hypothesis is that of systemicinflammation and increased circulatingcytokines and inflammatory mediators.In this hypothesis, inflammation leadsto an increase in the levels of circulatingcytokines, which in turn damage thevascular endothelium and ultimately result in atherosclerosis (Figure 2). Thecirculating cytokines of interest include

C-reactive protein (CRP), Interleukin-1,Interleukin-6 (IL-6), tumor necrosis fac-tor alpha (TNF- ), and prostaglandin.

The highest relative risk for myocar-dial infarction was found to be the levelsof CRP together with the ratio of totalcholesterol to high-density lipid. 1 CRPis a powerful marker of vascular risk andthere is some evidence for a direct role invascular dysfunction and atherogenesis.It is produced by the liver and is stimu-lated by TNF- and IL-6, leading to a

decrease in nitric oxide availability andan increase in angiotensin 1 receptors. Itbinds to low density lipids, increasingtheir uptake by macrophages and hencean increase in foam cell formation. Forthese reasons,CRP has been postulated asa major mechanism for atherosclerosis.

MEASURES OF ENDOTHELIAL DYSFUNCTIONEndothelium dysfunction can be meas-ured by a number of available techniques.

The most common is flow-mediateddilatation. Pulse-wave analysis and pulsepressure have also been used to look atendothelial dysfunction.

Flow-Mediated DilatationFlow-mediated dilatation measures thecapacity of the arteries to dilate inresponse to altered flow.Basically, a bloodpressure cuff with 300 mm of mercury isapplied for 5 minutes. It is then releasedand the diameter of the artery is meas-ured by ultrasound. The percent increasein diameter after release is a measure of the elasticity of the artery. In healthy subjects, a 7% to 10% increase in the

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Figure 1 Model of the common susceptibility hypothesis, in which a person would be susceptible toatherosclerosis, but the periodontal disease does not cause the atherosclerosis.

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Figure 2 Model of the systemic inflammation hypothesis. Inflammation leads to an increase inthe levels of circulating cytokines, which in turn damage the vascular endothelium and ultimatelyresult in atherosclerosis.


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INSIDE DENTISTRY VOL. 2 (SPECIAL ISSUE 1) INTERNATIONAL CONSENSUS STATEMENT GREGORY J. SEYMOUR 3

diameter of the artery is expected. Indiabetics, in whom there is a vasculardefect, there would only be a 4% to 6%increase. Unfortunately, flow-mediateddilatation is technically demanding, cost-ly, and painful. Nonetheless, it has beenshown that flow-mediated dilatation isdecreased in severe periodontal diseaseand that this is associated with highlevels of CRP.2

Pulse-Wave AnalysisPulse-wave analysis measures heart rate,blood pressure (systolic, diastolic, pulse),large artery elasticity, small artery elas-ticity, and systemic vascular resistance.This technique is clinically feasible, andabnormal results are predictive of CVD. The results are abnormal in hyper-tension, diabetes, early renal disease,and rheumatoid arthritis. The defectsare reversible with angiotensin-convert-ing enzyme inhibitors and statins.Wilson and Jenkins showed that pulse-wave analysis correlates with flow-mediated dilatation. 3 Preliminary dataindicate that with treatment of perio-dontal disease, there is not only a decreasein the CRP but also an increase in small

artery elasticity.

INFECTIONThe third hypothesis is direct infectionof the blood vessels by bacteria. In thishypothesis, the bacterial pathogens getinto the bloodstream, and subsequently invade the endothelium leading toendothelial dysfunction, inflammation,and atherosclerosis.

A number of studies have shownbacteria in the arteries, but a study by Ford and colleagues 4 used real-time poly-merase chain reaction to show P gingi-valis in 100% of the arteries. Fusobac-terium nucleatum was found in approxi-mately 80% of the arteries, Tannerella forsythia was found in just under 50%,and C pneumoniae was found in justunder 30%. H pylori and Haemophilusinfluenzae were both found in approxi-mately 4% of the arteries (Figure 3).These results clearly show that oralorganisms can and do invade blood ves-sel walls, but it is unclear as to whetherthey cause atherosclerosis or simply invade an already damaged artery.

CROSS-REACTIVITY/MOLECULAR MIMICRYThe fourth hypothesis is that of cross-reactivity or molecular mimicry. In thishypothesis, the periodontal bacteriainduce a local immune response, whichsubsequently cross-reacts with self-anti-gens expressed on the vascular epithelium.This in turn leads to vascular inflam-mation and atherosclerosis (Figure 4).

Recently, there has been increasing aware-ness that immune responses are centralto atherogenesis,5 and a mechanism by which infection may initiate and facilitatethe progression of atherosclerosis canbe explained in terms of the immuneresponse to bacterial heat shock genesand heat shock proteins (HSPs).All cellsexpress HSPs on exposure to variousforms of stress, including temperature,

Figure 3 Real-time polymerase chain reaction was used to show that oral organisms can invadeblood vessel walls (from Ford et al 4).

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Figure 4 Model of the cross-reactivity hypothesis, in which the periodontal bacteria induce a localimmune response and cross-react with self-antigens expressed on the vascular epithelium. This leadsto vascular inflammation and atherosclerosis (based on the hypothesis of Wick et al 11 ).


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oxidative injury, and infection. 6,7 Thereis a remarkable conservation in the struc-ture of HSPs across species, and many pathogens bear antigens that are homol-ogous to human HSPs. During infection,bacterial HSPs constitute major antigenicdeterminants, 8 which have been studiedextensively to determine their role in theinduction of protective or nonprotective

immune responses. The immune systemmay not be able to differentiate betweenself-HSP and bacterial-HSP. Cross-reactive epitopes of T cells with specificity for self-HSP can be activated duringinfection 9 and antibodies generated by the host directed at pathogenic HSPcould result in an autoimmune responseto similar sequences in the host. 6 In this

context, human heat shock protein 60(hHSP60) shows a remarkable similari-ty with a very large number of auto-antigens. In terms of atherosclerosis,factors such as bacterial lipopolysaccha-ride, cytokines, and mechanical stressmay induce the expression of host pro-tective hHSP60 on endothelial cells.Because of the homologous nature of HSPs among species, 10 cross-reactivity of antibodies to bacterial HSP (termedGroEL) with hHSP60 on endothelial cellsmay subsequently result in endothelialdysfunction and the development of atherosclerosis. 11 The presence of risk factors such as high blood cholesterolwould enhance the expression of hHSP60and adhesion molecules by endothelial

cells and result in progression from early fatty streak lesions to severe and irre-versible atherosclerotic alterations. Acorrelation between high anti-HSP60/65antibody titers and high morbidity andmortality because of atherosclerosis hasbeen demonstrated. 12 These antibodieswere shown to be cross-reactive withthose of other bacteria and were able tolyse stressed but not unstressedendothelial cells. 13 The demonstrationof elevated hHSP60 levels in patients

with borderline hypertension and anassociation between early atherosclero-sis and HSP60 levels offers furthersupport for this hypothesis. 14

GroEL proteins, belonging to theHSP60 family, have been reported to bemajor antigens in several pathogenicbacteria. 15 An Escherichia coli GroELhomologue has been identified in theperiodontopathic bacteria P gingivalis,F nucleatum, and Actinobacillus actino-mycetemcomitans,16,17 which was im-

munogenic and was recognized by serumantibodies in patients with periodontaldisease.17 GroEL antigens share a highdegree of homology with hHSP60 pro-teins and antibody to hHSP60 cross-reactswith this periodontopathic bacterialGroEL.18 Patients with periodontal dis-ease were shown to have a higher posi-tive response to P gingivalis GroEL thanhealthy controls and cross-reactivity between anti- P gingivalis GroEL anti-bodies in the serum of these periodontitispatients with hHSP60 and between anti-bodies to hHSP60 with P gingivalisGroELhas been demonstrated. 19

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Figure 5 Higher levels of antibodies HSP60, P gingivalis, and GroEL were found in patients withatherosclerosis compared with periodontitis and controls (from Tabeta et al 19 ).

Figure 6 A high correlation was found between the anti-GroEL and anti-HSP60 antibodies(from Tabeta et al 19 ).


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Studies conducted in our laboratory 4

have confirmed the expression of hHSP60on endothelial cells and also on fibroblast/smooth muscle cells in atheroscleroticlesions in humans.Tabeta and colleagues 19

were able to show that there are higherlevels of antibodies HSP60, P gingivalis,and GroEL in patients with artheroscle-rosis compared with periodontitis andcontrols (Figure 5). They were also ableto show that there was a high correlationbetween the anti-GroEL and anti-HSP60antibodies (Figure 6). Ford and col-leagues4 were able to show the same intheir CVD patients. In this case, again,the highest levels of antibody to HSP60and GroEL were in those subjects withadvanced periodontitis (Figure 7). They

were also able to show that if those anti-bodies were absorbed with HSP60, thereactivity could be absorbed out, indicat-ing a high degree of cross-reactivity between the antibody to the HSP60 andGroEL (Figure 8).

We have established GroEL-,hHSP60-and P gingivalis-specific T-cell linesfrom peripheral blood and from humanatherosclerotic plaques. 20 Of particularnote was the cross-reactivity observedby a number of GroEL-specific T-cell

lines to hHSP60 and hHSP60-specificlines to GroEL, again suggesting molec-ular mimicry of GroEL and hHSP60.These results demonstrate the presenceof T cells specific for GroEL in theperipheral blood as well as in lesions of atherosclerosis and their cross-reactivi-ty with hHSP60. The artery T-cell linesspecific for GroEL, hHSP60, and P gingivalis demonstrate a predominant Th2phenotype in the CD4 subset and a Tc0predominance in the CD8 subset with a

high proportion of CD8 cells expressingthe chemokines IP-10,RANTES,MCP-1,and MIP- . Finally, there was an over-expression of the T-cell receptor V 5.2family in all lines suggesting clonality within the cell lines. The cytokine,chemokine, and V results are similar tothose demonstrated previously for P gingivalis-specific lines from patientswith periodontal disease. 21 Yamazaki andcolleagues22 demonstrated that HSP60-stimulated peripheral blood mononu-clear cells (PBMC) and P gingivalisGroEL-stimulated PBMC had identicalnucleotide sequences in the CDR3 of

the T-cell receptor chain and that T cellswith the same nucleotide sequences werepresent in the gingival tissues as well asin atherosclerotic aneurysmal tissues(Figure 9). Taken together, these resultsshow that HSPs are expressed in athero-sclerotic plaques and that cross-reactiveT cells exist in periodontal disease tissue,

in peripheral blood,and in atherosclero-sis lesions. This provides strong supportto the hypothesis that cross-reactivity of the immune response to bacterial HSPswith arterial endothelial cells expressinghHSP60 may be a mechanism involvedin the disease process of atherosclerosisat least in some patients. 23

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Figure 7 In CVD patients, the highest levels of antibody to HSP60 and GroEL were in those subjectswith advanced periodontitis (from Ford et al 27 ).

Figure 8 The percent levels of anti-GroEL and anti- P gingivalis antibodies in plasma of atheroscle-rosis patients after absorption with hHSP60 (from Ford et al 27 ).


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Ang and colleagues24

put forwardfour criteria for diseases mediated by molecular mimicry:

1. Establishment of an epidemiologicalassociation between the infectiousagent and the immune-mediateddisease.

2. Identification of T cells or antibodiesdirected against host target antigens.

3. Identification of the microbial mimicof the target antigen.

4. Reproduction of the disease in an

animal model.There is clear evidence of an epidemi-

ological association between periodon-tal disease and CVD. The results of ourstudies in Brisbane and Niigata (refer-ences 4, 19, 20, 21, 22, and 27 reviewedin this article) provide evidence forcriteria two and three. Together wehave identified the microbial target; wehave shown that there are antibodiesand T cells that react with this target; wehave identified the human antigens withwhich these cells and antibodies cross-react; we have shown that these cells arein the arteries as well as in the gingival

tissues; and we have shown that these cellsare in the peripheral blood.

Li and colleagues25 showed thatrepeated intravenous injection with P

gingivalis accelerates the progression of atherosclerosis in apoE-deficient mice.Lalla and coworkers 26 showed that oralinfection with P gingivalis also acceler-ates the progression of atherosclerosisin apoE-deficient mice. We have alsoshown that in the apoE mouse model,weekly injections of either P gingivalisorC pneumoniae intraperitoneally resultedin marked atherosclerotic lesions in theproximal aorta, while control miceshowed no lesions compared with con-

trols (Figures 10A through 10C). Wehave further shown that, althoughlesions developed later with P gingivaliscompared with C pneumoniae , increas-ing the pathogen burden of P gingivalisbut not C pneumoniae enhanced athero-sclerosis.27 Increased pathogen loadresulted in increased titers of specificantibody in the case of P gingivalis butnot C pneumoniae , suggesting that thepeak atherosclerotic response to P gingi-valis coincided with the peak immune(antibody) response. This further sug-gests that immunological cross-reactivi-ty could be involved.

CONCLUSIONThe results from these studies add to theweight of evidence implicating infection,including periodontal infection, with ath-

erosclerosis.Taken together, these resultsprovide evidence for all four molecularmimicry criteria and, therefore, sup-port for the concept that cross-reactivity between GroEL and HSP60 represents, atleast in part, the link between infection,including periodontal disease, and CVD.None of the hypotheses is mutually exclusive and it is clear that in some peo-ple one or either of the proposed mech-anism may be more important. In thiscontext, it is clear that infection can con-

tribute to atherosclerosis via molecularmimicry. This infection could be respira-tory (eg, C pneumoniae ), gastrointestinal(eg, H pylori), or oral (eg, P gingivalis).Together these all contribute to the totalburden of infection; and in some peopleoral infection may make a significantcontribution to the total burden of infec-tion while in others it may be only aminor contributor. Nevertheless, it is theresponsibility of dental professionals toensure that all oral infection is kept to aminimum. In addition, all of these infec-tions lead to inflammation in the respec-tive tissue and in this context contribute

A A BB CC DD

Figure 9 (A) HSP60-stimulated PBMC.(B) P gingivalis-stimulated PBMC. (C) Athero-sclerotic aneurismal-derived T-cell clones.(D) Gingival tissue-derived T-cell clones.Arrow indicates identical TCR sequence inall four clones (from Yamazaki et al 22 ).

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C.

Figures 10A through 10C In the apoE mouse model, weekly injections of either P gingivalisor C pneumoniae intraperitoneally resulted in marked atherosclerotic lesions in the proximal aorta.Control mice showed no lesions. (A) P gingivalis. (B) C pneumoniae . (C) Control. (From Ford et al,unpublished data.)


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to the total burden of inflammation,which in turn can contribute to athero-sclerosis. Obesity, diabetes, and otherauto-immune diseases can also con-tribute to this total burden of inflam-mation and atherosclerosis. Athero-sclerosis itself is an inflammatory con-

dition which contributes to the totalburden of inflammation. All of theseinteractions can be seen in Figure 11,which begins to explain the observed asso-ciations between periodontal disease,atherosclerosis, diabetes, rheumatoidarthritis, smoking, mental stress, etc.Overall, it is an extremely complex inter-action and no one mechanism is likely to provide the complete explanation.

ACKNOWLEDGMENTThe authors would like to acknowledge anumber of collaborators from theUniversity of Queensland, includingMalcolm West, Mary Cullinan, BillWesterman, Steve Hamlet, Jan Palmer,and Phil Walker. Chlamydia studies weredone with Peter Timms and David Goodfrom Queensland University of Tech-nology. In Niigata, we would like toacknowledge Takako Nakajima, YutakaOhsawa, Harue Itoh, Koichi Tabeta, andKaoru Ueki-Maruyama. In Australia,these studies were supported by theNational Health and Medical ResearchCouncil of Australia, the Australian

Dental Research Fund, Colgate Oral CareAustralia, and Colgate Palmolive LimitedUSA. In Japan, they were supported by grants from the Ministry of Education,Science, Sports, and Culture (13470462,14657553, 14771219),grants for the pro-motion of Niigata University Research

Projects, and the Fund for ScientificPromotion of Tanaka Industries Co.,Ltd,Niigata, Japan.

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3. Ryan MC, Wilson, AM, Slavin J , e t al .Comparison of arterial assessments in

low and high vascular disease risk groups. Am J Hypertens. 2004:17(4):285-91.4. Ford PJ, Gemmell E, Hamlet SM, et al.

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7. Ellis RJ. Stress proteins as molecularchaperones. In: van Eden W, Young DB,eds. Stress Proteins in Medicine . New York,NY: Marcel Dekker; 1996:1-26.

8. Kaufmann S. Heat shock proteins and theimmune response. Immunol Today. 1990;11:129-136.

9. Young RA, Elliott TJ. Stress proteins, infection,and immune surveillance. Cell. 1989;59:5-8

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11. Wick G, Perschinka H, Xu Q. Autoimmunity and atherosclerosis. Am Hear t J . 1999;138:S444-S449.

12. Metzler B, Schett G, Kleindienst R, et al.Epitope specificity of anti-heat shock protein65/60 serum antibodies in atherosclero-sis. Arterioscler Thromb Vasc Biol . 1997;17:536-541.

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Cloning and sequencing of the groESL homo-logue from Porphyromonas gingivalis .Biochim Biophys Acta . 1994;1219:175-178.

17. Maeda H, Miyamoto M, Hongyo H, et al.Heat shock protein 60 (GroEL) fromPorphyromonas gingivalis : molecularcloning and sequence analysis of its geneand purification of the recombinant protein.FEMS Microbiol Lett . 1994;119:129-135.

18. Ando T, Kato T, Ishihara K, et al. Heatshock proteins in the human periodontaldisease process. Microbiol Immunol . 1995;39:321-327.

19. Tabeta K, Yamazaki K, Hotokezaka H, etal. Elevated humoral immune response toheat shock protein 60 (hsp60) family inperiodontitis patients. Clin Exp Immunol .2000;120:285-293.

20. Ford PJ, Gemmell E, Walker PJ, et al.Characterization of heat shock protein-specific T cells in atherosclerosis. ClinDiagn Lab Immunol . 2005;12:259-267.

21. Gemmell E, Grieco DA, Cullinan MP, et al.Antigen-specific T-cell receptor Vb expres-sion in Porphyromonas gingivalis -specificT-cell lines. Oral Microbiol Immunol . 1998;13:355-361.

22. Yamazaki K, Ohsawa Y, Tabeta K, et al.Accumulation of human heat shock protein60-reactive cells in the gingival tissues of periodontitis patients. Infect Immun . 2002;70:2492-2501.

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ease due to an immune reaction against heat-shock protein 60. Herz . 2000;25:87-90.24. Ang CW, Jacobs BC, Laman JD. The Guillain-

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25. Li L, Messas E, Bati sta EL, et al .Porphyromonas gingivalis infection acceler-ates the progression of atherosclerosis in aheterozygous apolipoprotein E-deficientmurine model. Circulation 2002;105:861-867.

26. Lalla E, Lamster IB,Hofmann MA, et al. Oralinfection with a periodontal pathogen accel-erates early atherosclerosis in apolipopro-tein E-null mice. Arterioscler Thromb VascBiol . 2003;23:1405-1411.

27. Ford PJ , Gemmell E, Chan A, et a l.Inflammation, heat shock proteins andperiodontal pathogens in atherosclerosis:an immunological study. Oral MicrobiolImmunol . In press.

Figure 11 Model of the complex interactions of the observed associations between periodontaldisease, atherosclerosis, diabetes, rheumatoid arthritis, smoking, mental stress, etc.

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