Periodontology 2000, Vol. 35, 2004, 9±13                                      Copyright # Blackwell Munksgaard 2004Printed...
Seymour & Taylor Environmental factors                             Plaque         ties. It is therefore erroneous to compa...
Immunoregulation in periodontal disease  There is increasing evidence that the Th1/Th2 bal-        probably associated wit...
Seymour & Taylorsion of heat shock proteins in the periodontal tissues          2. Chooi JL, Borrello MA, Smith ES, Zauder...
Immunoregulation in periodontal disease20. OBrien-Simpson NM, Veith PD, Dashper SG, Reynolds EC.            ontal disease:...
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Shouts and whispers an introduction to immunoregulation in periodontal disease


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  1. 1. Periodontology 2000, Vol. 35, 2004, 9±13 Copyright # Blackwell Munksgaard 2004Printed in Denmark. All rights reserved PERIODONTOLOGY 2000Shouts and whispers: anintroduction to immunoregulationin periodontal diseaseGregory J. Seymour & John J. TaylorThere is little doubt that patient susceptibility to and control of both the innate and adaptive immunechronic periodontal disease plays a major role in responses. As pointed out by Marshall (15) Thedetermining the ultimate disease outcome. Suscept- sulcular and junctional epithelia have been thoughtibility to periodontal disease involves the interplay to represent the apparent weak link in the bodysbetween bacteria, the host and environmental factors ability to seal out the outside environment i.e. the(Fig. 1). It is well established that bacteria in the plaque bio®lm. In reality however, it acts more as adental plaque bio®lm are the cause of the in¯amma- gatekeeper, selectively allowing the passage of anti-tion. However, since the 1970s it has been clear that gens and cells as well as producing a range of defen-not all plaques result in progressive disease. In 1996 sive molecules. While the physical barrier function ofthe consensus report of the World Workshop on Clin- the epithelium cannot be understated, it is nowical Periodontics (1) concluded that three bacterial recognised that epithelia throughout the body pro-species, Porphyromonas gingivalis, Actinobacillus duce a diverse range of antimicrobial peptides. Toactinomycetemcomitans and Tannerella forsythia, date, at least four families of different antimicrobialshould be considered as the major periodontal peptides (a-defensins, b-defensins, Cathelicidins,pathogens. Subsequently, Socransky et al. (24) des- Saposins) have been found in humans. An overviewcribed a number of bacterial complexes with the of these molecules and their possible role in period-major `red complex, consisting of P. gingivalis, Tre- ontal disease is presented by Marshall (15) in thisponema denticola and T. forsythia, being associated issue. This is not an extensive review of defensins butwith advanced forms of chronic periodontitis. rather an overview to highlight the important contri-Although there is general support for this concept, bution of these molecules in disease pathogenesis andit is also well recognized that the presence of the as possible therapeutic modalities. For a more com-pathogenic bacteria per se is insuf®cient to cause prehensive review, readers are referred to Dale (7).disease. It has recently been shown that there is a Once the epithelial barrier with its antimicrobialhigh degree of volatility in terms of acquisition and peptides is breached the adaptive immune responseloss of the putative periodontal pathogens over a comes into play. Cytokines are central to this5-year period. Relatively few subjects had these response, such that the production of `appropriateorganisms on multiple occasions (4). Whether or cytokines results in development of protectivenot the bacteria were actually lost or just declined immunity and the production of `inappropriateto levels below the detection limit of the assay cytokines leads to tissue destruction and disease pro-remains to be determined. Nevertheless, this study gression (10). Just how the immune system choosesclearly showed the limitations in cross-sectional and regulates the right cytokines is unclear, althoughmicrobiological studies and periodontal disease genetic factors are most likely involved. Recently,and highlights the fact that many individuals may Cullinan et al. (3) in a 5-year longitudinal studyharbor the organisms without manifesting progres- showed that a speci®c interleukin (IL)-1 genotypesive periodontal destruction (4). was a contributing but nonessential factor in the Host factors are clearly of fundamental importance progression of periodontal disease. Equally they(21). In this context, the way in which the host showed smokers with P. gingivalis had signi®cantlyresponds to the bacteria is determined by the nature more probing depths greater than 3.5 mm compared 9
  2. 2. Seymour & Taylor Environmental factors Plaque ties. It is therefore erroneous to compare the variousSmoking cytokines quantitatively and suggest that any differ-Stress ences are of greater or lesser biological signi®cance. Within the context of this analogy it can be seen that immunoregulation or control of the immune res- Specific pathogens ponse in periodontal disease is a series of `shouts and `whispers as cells talk to one another while they combat the bacterial attack. Non-susceptible Susceptible Cytokines also have a tremendous built-in redun- dancy, many cytokines having overlapping functions. IL-1 and IL-6 are two such cytokines, as are IL-4 and Genetic factors IL-13. Hence, continuing the `shouts and `whispers Cytokine gene polymorphisms analogy, cells hear the same message from a variety of sources so that the absence of one cytokine but theFig. 1. Susceptibility to periodontal disease. presence of another may result in the same biological outcome. Equally, many cytokines are antagonisticwith smokers without P. gingivalis. At the same time, and again the overall biological effect is the result ofIL-1 genotype-positive smokers had 70% more pock- the balance between all cytokines rather than theirets >3.5 mm than IL-1 genotype-negative smokers individual levels. It should be obvious therefore that(3). This study clearly shows the interplay between cytokines function as a network and individual ele-bacteria, host and environmental factors. ments of the network cannot be studied in isolation As stated above, cytokines are central to the patho- (17). For example, Martuscelli et al. (16) have showngenesis of an ever-increasing number of diseases, that recombinant human IL-11 (an inhibitor of IL-1including periodontal disease. Cytokines are intercel- production) effectively inhibits periodontal attach-lular messengers and as such represent a key ment loss in a dog model. Therefore the study ofmechanism by which cells involved in immune IL-1 without reference to IL-11 (as well as other inhi-responses communicate. They are usually produced bitors such as IL-10 and IL-1ra) may well be mean-transiently, often in picomolar concentrations, and ingless or at best dif®cult to interpret. The wealth ofsome, such as IL-4, may have a very restricted range new information emerging from the human genomeof activity. Indeed, the majority of immune responses project and related initiatives has revealed manyoccur locally and often between two cells conjugated novel cytokines with as yet unknown functionstogether (Fig. 2). In this context, the analogy can be (19). The study of cytokines and their role in immuno-drawn that when two cells are talking together they regulation and disease pathogenesis will therefore`whisper. However, when cells talk to one another at remain a critical element of periodontal researcha distance they may `shout by producing large for some years to come.amounts of cytokine. Such cytokines such as IL-1 Since it was ®rst presented at the ICPR meeting inand IL-6 are therefore produced by a large number Osaka in 1992 (22) the T helper (Th)1/Th2 hypothesisof cells and are produced in relatively large quanti- for the immunoregulation of periodontal disease has attracted a lot of attention (for review see Seymour & Gemmell (23)). A number of studies have shown a decrease in Th1 responses in periodontitis, while others have shown increased Th2 responses. Some studies have claimed a dominance of Th1 response over Th2 responses in periodontitis, whereas others have shown a predominance of Th0 cells in period- ontitis (reviewed in 23). These studies are dif®cult to compare since they used a variety of cells and tissues, a variety of techniques and a variety of stimulants. In addition, the inability to determine disease acti- vity clinically makes interpretation dif®cult, if notFig. 2. The majority of immune responses occur locally impossible. Nevertheless, it is agreed that controlrather than systemically and often between two cells con- of the Th1/Th2 balance is central to the immuno-jugated to one another. regulation of periodontal disease.10
  3. 3. Immunoregulation in periodontal disease There is increasing evidence that the Th1/Th2 bal- probably associated with disease and hence the roleance is controlled by a range of factors, all of which of coinfection has become increasingly recognized.are possible within the periodontal tissues. An over- Recent data have suggested that combinations ofview of these factors is presented by Gemmell & organisms may result in shifts in the Th1/Th2 andSeymour (10) in this issue. These include the following: antibody pro®les (2, 10). In order to understand how combinations of organisms may in¯uence the immune response it is ®rst necessary to have aThe nature of the innate immune knowledge of the speci®c antigens of the pathogenicresponse bacteria. A comprehensive review of these antigens is presented by OBrien-Simpson et al. (20). TheseA strong innate immune response will result in large authors point out that each of the periodontal patho-amounts of IL-12 and IL-18 production by mono- gens produce an array of antigens capable of indu-cytes and neutrophils that, in turn, will promote a cing both Th1 and Th2 cytokine pro®les and theyTh1 response. Interleukin-18 was discovered in 1989 suggest that multispecies vaccines directed againstas INF-g inducing factor. IL-18 is structurally homo- key bacterial epitopes associated with the acquisitionlogous to IL-1b and, together with their receptors are of essential nutrients may restrict proliferation of themembers of the IL-1R/Toll-like receptor (TLR) super- pathogens within the bio®lm and thereby in¯uencefamily. This causes similar signalling and signal disease progression.transduction mechanisms. IL-18 is recognized as acytokine that is able to enhance the maturation ofnaive T cells to Th1 cells as a cofactor with IL-12, and The nature of the antigen-presentinghence the production of INF-g. The ability of The cellimportance of IL-18 as co-inducer of INF-g inductionin vitro by the successful reduction of INF-g produc- There is ample evidence that the nature of the anti-tion in stimulated mouse spleen cells by neutralizing gen-presenting cell can determine the nature of theantibodies to murine IL-18. The major role of IL-12 in Th1/Th2 pro®le. Cutler et al. (6) have suggested thatthis mechanism seems to be enhancing IL-18 recep- the default lesion in periodontal disease is Th1, intor expression. Interestingly, Th1 cells express IL-18 which the major antigen-presenting cell is the den-receptor whereas Th2 do not. Clearly IL-18 could be dritic cell. At the same time, Gemmell et al. (12) haveexpected to have a fundamental role in the control of shown that in periodontitis lesions CD19‡, CD83‡ Bthe Th1/Th2 response in periodontal disease. How- cells are probably the dominant antigen-presentingever, the role of IL-18 in periodontal disease and its cell, supporting the concept of shifts in the Th1/Th2interplay with IL-12 and indeed IL-15 has not yet pro®le between gingivitis and periodontitis. In theirbeen elucidated. Nevertheless the biological activity review in this issue, Cutler & Jotwani (5) look at theof IL-18 is reviewed in detail by Delaleu and Bickel (8). events leading up to antigen presentation by dendri- Equally, there is some evidence to suggest that P. tic cells and suggest that as antigen presentation isgingivalis LPS is recognized by Toll-like receptor the limiting step in the generation of an immune(TLR)-2 and TLR-6, which promote a Th2 response. response, blocking speci®c aspects of this couldNonpathogenic lipopolysaccharide (e.g. Escherichia represent a valid strategy for the control of period-coli) is recognized by TLR-4 and CD14, which pro- ontitis.mote a Th1 response. This is discussed in detail byDixon et al. (9). T-cell receptor (TCR) affinityThe nature of the antigen(s) There is emerging evidence that high T-cell receptor af®nity with short signaling time favors a Th1As discussed above, it is generally accepted that response while low T-cell receptor af®nity with awhile different people may respond differently, spe- prolonged signaling time favors a Th2 response. Asci®c bacteria are nevertheless the cause of period- yet, however, the T-cell receptor af®nity of cellsontal disease. Irrespective of the host response, from involved in periodontal disease has not been deter-a clinical perspective, if a patient has no plaque, they mined. In their review in this issue, Yamazaki &have no disease. In recent years it has also become Nakajima (26) raise the possibility of autoimmunityapparent that complexes of organisms are most contributing to the periodontal lesion. The expres- 11
  4. 4. Seymour & Taylorsion of heat shock proteins in the periodontal tissues 2. Chooi JL, Borrello MA, Smith ES, Zauderer M. Polarization of Porphyromonas gingivalis-specific helper T-cell subsetsis presented, together with the possibility that the by prior immunization with Fusobacterium nucleatum. Oralimmune response to their bacterial homolog (GroEL Microbiol Immunol 2000: 15: 181±187.antigens) cross-reacts and hence contributes to the 3. Cullinan MP, Westerman B, Hamlet SM, Palmer JE, Faddyin¯ammatory lesion. They further present evidence MJ, Lang NP, Seymour GJ. A longitudinal study of interleu-that regulatory T cells, which control autoimmunity, kin-1 gene polymorphisms and periodontal disease in aare in fact lacking in the periodontal tissues. general adult population. J Clin Periodontol 2001: 28: 1137±1144. 4. Cullinan MP, Hamlet SM, Westerman B, Palmer JE, Faddy MJ, Seymour GJ. Acquisition and loss of PorphyromonasGenetics gingivalis, Actinobacillus actinomycetemcomitans and Pre- votella intermedia over a 5-year period: the effect of a tri-Using a mouse model, Gemmell et al. (13) have closan/copolymer dentifrice. J Clin Periodontol 2003: 30: 532±541.shown that susceptibility to P. gingivalis infection 5. Cutler CW, Jotwani R. Antigen-presentation and the role ofis in part determined by the H2 haplotype and that dendritic cells in periodontitis. Periodontol 2000 2004: 35:this also re¯ects the Th1/Th2 pro®le. Also, there is 135±157.increasing evidence that the cytokines which in¯u- 6. Cutler CW, Jotwani R, Palucka KA, Davoust J, Bell D, Ban-ence Th1/Th2 function are in¯uenced by genetic chereau J. Evidence and a novel hypothesis for the role of dendritic cells and Porphyromonas gingivalis in adult per-polymorphism; this may contribute to differences iodontitis. J Periodontal Res 1999: 34: 1± individual variation in Th1/Th2 responses and 7. Dale BA. Periodontal epithelium: a newly recognised role intherefore susceptibility and progression in periodon- health and disease. Periodontol 2000 2002: 30: 70±78.tal disease. This possibility is reviewed by Taylor 8. Delaleu N, Bickel M. Interleukin-1b and interleukin-18±reg-et al. (25). These authors point out that while there ulation and activity in local inflammation. Periodontol 2000is no doubt that a genetic element is an essential 2004: 35: 42±52. 9. Dixon DR, Bainbridge BW, Darveau RP. Modulation of thecomponent of the periodontal lesion, a central role innate immune response within the periodontium. Period-for cytokine gene polymorphisms in immunoregula- ontol 2000 2004: 35: 53±74.tion remains suggestive. 10. Gemmell E, Seymour GJ. Immunoregulatory control of Th1/ All of these mechanisms are not mutually exclusive Th2 cytokine profiles in periodontal disease. Periodontoland it is likely that immunoregulation of in¯amma- 2000 2004: 35: 21±41. 11. Gemmell E, Marshall RI, Seymour GJ. Cytokines andtory diseases (such as periodontal disease) involve prostaglandins in immune homeostasis and tissue destruc-different mechanisms at different times in different tion in periodontal disease. Periodontol 2000 1997: 14:patients and probably no one mechanism is more 112±143.important than another (18). The application of 12. Gemmell E, Bird PS, Carter CL, Drysdale KE, Seymour knowledge and technologies in the ®elds of Effect of Fusobacterium nucleatum on the T and B cell responses to Porphyromonas gingivalis in a mouse model.genomics, proteomics and structural biology holds Clin Exp Immunol 2002: 128: 238±244.real promise in terms of establishing a truly holistic 13. Gemmell E, Carter CL, Bird PS, Seymour GJ. Genetic depen-picture of complex diseases as well as providing dence of the specific T-cell cytokine response to Porphy-rational targets for diagnostic and therapeutic stra- romonas gingivalis in mice. J Periodontol 2002: 73:tegies. With this in mind, the authors of the series of 591±596. 14. Gemmell E, Carter CL, Hart DNJ, Drysdale KE, Seymour GJ.articles for this issue of Periodontology 2000 have Antigen presenting cells in human periodontal disease tis-been charged to describe progress in the complex sues. Oral Microbiol Immunol 2002: 17: 388±393.®eld of immunoregulation and periodontal disease 15. Marshall RI. Gingival defensins. Linking the innate andand to include a discussion of how these novel adaptive immune responses to plaque. Periodontol 2000approaches might enlighten our research efforts in 2004: 35: 14±20.this area. This issue brings together experts from four 16. Martuscelli G, Fiorellini JP, Crohin CC, Howell TH. The effect of interleukin-11 on the progression of ligature-continents; it does not attempt to reach a consensus induced periodontal disease in the beagle dog. J Periodontolbut rather to establish our current knowledge and to 2000: 71: 573±578.set the framework for future research. 17. Mosmann TR. Cytokines: is there biological meaning? Curr Opin Immunol 1991: 3: 311±314. 18. Nathan C. Points of control of inflammation. Nature 2002:References 420: 846±852. 19. Nicklin MJ, Barton JL, Nguyen M, FitzGerald MG, Duff GW,1. Anonymous. Consensus report for periodontal diseases: Kornman K. A sequence-based map of the nine genes of pathogenesis and microbial factors. Ann Periodontol 1996: the human interleukin-1 cluster. Genomics 2002: 79: 1: 926±932. 718±725.12
  5. 5. Immunoregulation in periodontal disease20. OBrien-Simpson NM, Veith PD, Dashper SG, Reynolds EC. ontal disease: cellular and molecular mechanisms. J Period- Antigens of bacteria associated with periodontitis. Period- ontal Res 1993: 28: 478±486. ontol 2000 2004: 35: 101±134. 24. Socransky SS, Haffajee AD, Cugini MA, Smith C, Kent RL Jr.21. Seymour GJ. Importance of the host response in the period- Microbial complexes in subgingival plaque. J Clin Period- ontium. J Clin Periodontol 1991: 18: 421±426. ontol 1998: 25: 134±144.22. Seymour GJ, Gemmell E. Cytokines in periodontal disease: 25. Taylor JJ, Preshaw PM, Donaldson PT. Cytokine gene poly- where to from here? Acta Odontol Scand 2001: 59: morphism and immunoregulation in periodontal disease. 167±173. Periodontol 2000 2004: 35: 158±182.23. Seymour GJ, Gemmell E, Reinhardt RA, Eastcott J, Taubman 26. Yamazaki Y, Nakajima T. Antigen specificity and T cell clon- MA. Immunopathogenesis of chronic inflammatory period- ality in periodontal disease. Periodontol 2000 2004: 35: 75±100. 13