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Home , Gingival disease, Gingival sulcus, Gingivitis, Periodontal disease, Periodontium

PEDIATRIC /Copyright ° 1981 by The American Academy of Pedodontics Vol. 3, Special Issue

Pathogenesis of and in children and young adults Dr. Ranney Richard R. Ranney, DOS, MS Bernard F. Debski, DMD, MS John G. Tew, PhD

Abstract Introduction In adults and animal models, gingivitis consistently The most common forms of human periodontal dis- develops when bacterial plaque accumulates, and progresses ease are gingivitis and periodontitis. Gingivitis is sequentially through , T-lymphocyte and B- defined as an of the gingiva. The gingiva lymphocyte/plasma cell dominated stages in a reproducible is all soft tissue surrounding the coronal to the time frame. Periodontitis, also plasma cell dominated, crest of alveolar bone and to a varying extent lateral develops at a later time on the same regime, but with time- variability and less than 100% consistency. Gingivitis rarely to the bone, extending to the . progresses to periodontitis in pre-pubertal children and On the other hand, the definition of in- seems to remain lymphocyte- rather than plasma cell- cludes , periodontal ligament, alveolar bone, dominated. Bacteria are the accepted etiologic agents, with and the gingiva; and periodontitis includes loss of some particular species being associated with specific attachment of periodontal tissues from the tooth and clinical features; however, definitive correlations have not net loss of alveolar bone height.1 Gingivitis is reversi- been shown and a number of different species may be of ble, while regeneration after the destruction during etiologic significance in given cases. The signs of disease are periodontitis is not predictably achievable. Periodon- more easily explained on the basis of activities of host titis in healthy children is not an extremely frequent response rather than solely to effects of bacterial enzymes or occurrence. The most frequent periodontal disease in cytotoxins. Immunological responses have been implicated children, by far, is gingivitis. in this regard. Polyclonal, as well as -specific, stimulation may be important. In studies of severe Until quite recently, there was no information dis- periodontal destruction in adolescents and young adults, tinguishing gingivitis in children from gingivitis in dysfunctional PMN- has been associated with adults, either clinically or histopathologically. It was many cases, and B-cell hyperresponsiveness to polyclonal perceived as a confined to the marginal gingiva activation (which may be attributed to a T-cell regulatory that might slow progress with age, although virtually defect), with some cases. Three working hypotheses are no detailed study of the "juvenile marginal lesion" suggested: 1) periodontal disease presents as a well had been done.2 Consequently, hypotheses of patho- contained and regulated inflammation in children until genesis have arisen almost exclusively from study of around puberty, after which the usual, relative slow- adult humans and animals. Therefore, concepts of progression of a B-cell mediated adult lesion is the rule; pathogenesis related to these studies will be reviewed 2) exceptions to the self-containment in pre-puberty would be found in systemic disease states; and 3) exceptions briefly while considering emerging information related beginning in young adulthood (rapid progression) would be to children and young adults. Hypotheses of patho- found additionally in rather subtle functional aberrations of genesis in children and young adults will be devel- host defense. oped; however, definitive proof of disease mechan- ism^) is lacking.

Acknowledgments Clinical Studies of Disease Progression Work at Virginia Commonwealth University, referred to The foundation for current concepts of pathogen- in this review has been supported by grants DE-05139, DE esis of gingivitis lies in the now classic experimental 05054 and DE 04397 from the National Institute for Dental 34 Research. gingivitis studies of Loe and coworkers. The central observations that cessation of results in

PEDIATRIC DENTISTRY 89 Volume 3, Special Issue gingivitis, and that resumption of oral hygiene reverts in contrast to rapid development in the young adults gingivitis to health, are critical indictments of the was documented by the relatively objective measures causative relationship of to gingivitis. of gingival exudate and bleeding units. In a cross- These observations have been confirmed repeatedly. sectional investigation, young children exhibited a The production of gingivitis in this model is universal higher proportion of non-inflamed gingival units and among adult subjects, the only significant variable less gingival= fluid than did adolescents. being the time necessary to reach a predetermined Thus, there is definite suggestion at the clinical endpoint of gingivitis severity for each individual sub- level for differences in pathogenesis between pre- ject. This significant relationship of plaque bacteria to pubertal children and older individuals. Differences in gingivitis has been buttressed further by demonstra- histopathology also exist, and will be discussed later in tions that prevention of plaque formation5 or repeti- this review. If we accept dental plaque bacteria as the tive removal6 also prevents gingivitis. Since the latter causative agents, variances in rates of progression and study involved children, the causative relationship of exceptions to progression could be explained either by plaque to gingivitis is affirmed for children as well differences in bacteria present or by differences in host as adults. responsiveness~ to the bacteria. Although the perceived irreversibility prevents ethical extension of this model to periodontitis in Bacteriology 7,8 humans, analogous efforts in animals indicate that In contrast to earlier concepts, there is good continuance of the model for longer times results in evidence that all dental bacterial plaques are not the periodontitis. This tends to reinforce the earlier pre- same. There are qualitative differences between sumptions based on epidemiological surveys which plaques adjacent to healthy sites and those adjacent showed the amount of debris on the teeth to be the to diseased sites, and between supragingival and only significant correlate, other than age, of the sever- subgingival floras; 6 Healthy sites are associated with a ity of periodontal disease.*" More recent longitudinal predominantly gram-positive flora, with major repre- observations in human populations indicate much sentation of Streptococcus and Actinom~vces species.~~ greater severity and rate of progression of periodon- The flora adjacent to diseased sites has a higher repre- titis in human populations with poor oral hygiene, sentation of gram-negative rods and motile forms in- than in populations of the same age with good oral hy- cluding spirochetes, with Fusobactedum nucleatum giene; 2 Clinical studies relating mechanical control of and Bacteroides species being among the most promi- bacteria to successful periodontal therapy and preven- nent representatives; ~-~ There are also suggestions of tion of recurrence~*’5 also support the concept of etiolo- rather specific associations between certain microor- gic significance for oral bacteria in periodontitis as ganisms and specific periodontal conditions; e.g., a rel- well as gingivitis. It is generally conceded that bac- ative dominance of Bacteroides assacharolyticus (pre- teria’*~8 are the etiologic agents. sumably now recognized as B. gingiyalis) in highly inflamed destructive sites, ~ B. melaninogenicus ss. in- There are very important differences, however, termedius and in destructive sites between the results of experimental gingivitis studies with minimal inflammation, ~ and and efforts at natural induction of periodontitis. species, Actinobacillus actinomycetemcomitans and Whereas the former are uniformly effective in induc- other unidentified saccharolytic gram-negative rods in ing gingivitis amongadult individuals, only 8070 of the areas of severe destruction in young people. ~ - dogs9 studied for four years developed periodontitis; Recent reviews~-~ have favored this concept of bac- There are other confirmations that gingivitis does not terial specificity in periodontal diseases. However,as invariably progress to periodontitis, and that it can concluded by others, ~ correlation of specific groups of persist for considerable time in some instances with- organisms with certain clinical syndromes is not de- out~ such progression in adults. finitively established. Results of research in this In children, progression to periodontitis is the ex- emerging area of knowledge are highly method-de- ception rather than the rule; There are also notable pendent. Ongoing work in our clinics and laboratories contrasts with respect to clinical development of gin- in association with W. E. C. Moore and L. V. givitis between children and adults documented in Holdeman attempts complete enumeration of the per- recent years. Mackler and Crawford~’ reported that six iodontal flora. ~,~ Results have been in general agree- of eight children 3-5½ years of age failed to develop ment with the previous findings of different flora in gingivitis during 26 days of an experimental gingivitis healthy and diseased states, and gram-negative organ- protocol. Another study of six children, 4-5 years old, isms being more numerous than gram-positives in sub- compared with six male dental students, 23-29 years of gingival samples. However, more than 170 species age, confirmed a marked difference. = Further, the low have been differentiated from 73 samples. While 60% tendency for development of gingivitis in the children of the isolates belong to 54 previously described spe-

PATHOGENESISOF PERIODONTALDISEASE 90 Ranney, Debski, and Tew cies, the other 40%were members of 116 species which mononuclear cells has formed, and content in have not been described. Some of these, notably three the infiltrated area has markedly decreased. species of the genus EubacteHum, occur frequently In approximately four to seven days of plaque accu- and in high numbersY mulation, gingivitis in humansevolves into the early Our data are consistent with the usual findings lesion. The differentiating sign is the accumulation of from mixed infections in various sites of the body, large numbers of lymphocytes as an enlarged infiltrate namely that each instance is an individual occurrence in the gingival . Associations between that may, or may not, be similar to others, and that lymphocytes and cytopathically altered fibro-blasts there are probably common, less common, and quite are present. Earlier changes are quantitatively in- unusual mixtures of bacteria that may be associated creased. By two to three weeks, the established lesion with any given periodontally diseased site2 Thus it is is present, characterized by the preponderance of not yet possible to conclude that there are single, or a plasma cells in an expanded inflammatory lesion with few bacteria, that are the specific etiologic agents for continuance of earlier features. The time frame of pro- given periodontal diseases in adults. There are also gression to the established lesion in adult humans problems in knowing whether particular bacteria asso- seems quite predictable and reproducible. However, ciated with a diseased site contributed to the cause the established lesion may persist for variably long or are there because the disease created a favorable periods of time before becoming "aggressive" and environment. progressing to the advanced lesion (periodontitis). The bacteriology of periodontal disease in children The infiltrate in the advanced lesion continues to has received very little study. There are reports that the incidence of B. melaninogenicus was found rela- be dominated by plasma cells. Collagen destruction tively rarely in children compared to adults or has continued and loss of alveolar bone and apical re- adolescents. ~ However, another paper reported B. location of the JE with "pocket" formation are now melaninogenicus in all age groups studied, including apparent. Throughout the sequence, viable bacteria ages 4-10.~1 Observations based on gram stain and mor- apparently remain outside the gingiva, on the surface phology in smears of plaque during experimental gin- of the tooth and in the periodontal "pocket" against, 21 but not invading, the soft tissue. givitis in children were not very different from those ~,~ previously reported for adults/and B. melaninogeni- A notable finding by Longhurst and coworkers is cus was recovered at least once from each child in the that the histopathology of chronic gingivitis in chil- study. All of these reports were made prior to subspe- dren does not correspond to the plasma cell-domi- ciation of B. melaninogenicus, so their relevance to nated, established lesion of the adult, but has an current reports from adult studies is difficult to assess. inflammatory infiltrate with a great majority of the The question of whether differences in bacteria cells being lymphocytes. This is most analogous to the present account for the differences in clinical perio- early lesion as described by Page and Schroeder for dontal disease status between pre- and post-pubertal the adult. Other reports on the nature of cellular infil- individuals remains open. It has barely been trates in various stages of periodontal disease had in- investigated. dicated that in mild gingivitis (early lesion?), the pre- dominant lymphocyte was the T-cell, based on lack of Histopathology cytoplasmic or membrane-associated immunoglobu- The histopathological changes in gingivitis and per- lin, ~,~ while in more severe gingivitis ~ and periodonti- iodontitis in adults and animal models have been tis ~,~,~ the B-cell line (of which the plasma cell is the studied intensively; ~.42~7 Anextensive review of this in- mature end-cell) predominated. The implication may formation through early 1977 was published, u Page be that gingivitis in children is T-cell dominated, and Schroeder2° divided the sequences of changes dur- although this degree of delineation is not yet ing the development of gingivitis and periodontitis established. into four stages, according to prominent histo- Further argument may be made that conversion pathological signs. They termed these the Initial, from a T-cell lesion to a B-cell lesion is the outstand- Early, Established, and Advanced . In health, ing correlate of conversion from a stable to a progres- the hallmark features in the gingival connective tissue sive lesion. ~ Alternatively, since the major interpreta- are an even collagen density throughout the gingiva tion holds that there are plasma cell-dominated estab- and an absence of clusters of inflammatory cells. In lished lesions that do not progress for long periods of the initial lesion, present within two to four days after time,~ there may be B-cell lesions that are progressive allowing plaque to accumulate, an increased volume of and those that are not. In either event, lesions that are the junctional (JE) is occupied by poly- progressive or have progressed are preponderantly B- morphonuclear leukocytes (PMN), blood vessels sub- cell; the only T-cell dominated lesion demonstrated jacent to the JE becomedilated and exhibit increased thus far is within gingivitis, probably including the permeability, a small cellular infiltrate of PMNand most prevalent lesion in children. PEDIATRICDENTISTRY Volume3, SpecialIssue 91 PathogeneticMechanisms explanation of this finding may cause a re-evaluation Because of the external location of bacteria, of the role of in periodontal disease. While concepts of pathogenetic mechanisms have involved immunoglobulins have been shown to be present in bacterial products or constituents rather than multi- gingival plasma cells, ~,~.8~.~ antibody specificity has plication of bacteria within the tissue. In this context, been difficult to prove. ~ from ,dental plaque although plaque bacteria can demonstrably produce have been demonstrated in gingiva affected by perio- potentially tissue-destructive enzymes and cytotox- dontitis, ~ as have complement deposits, ~ but coinci- ins 17.~ which may be involved in pathogenesis, the dent localization of complement, antigen and anti- nature of the infiltrate, rapidity of collagen destruc- body has not. Further, a recent mo~phologic and tion, and resorption of alveolar bone are more easily biochemical attempt failed to detect sig~ificant quan- explainable by mechanisms of host response. The tities~ of immune complexes in periodontal tissue; immune response has received much attention in this Thus, a pathogenetic mechanism invol.ving immune regard. The many effector systems evoked by an complexes, while theoretically attractive, has not been immune response provide attractive explanations for proven. Local anaphylaxis, mediated by IgE antibody, the inflammatory and tissue-destructive features of seems unlikely as a major mechanism because of the periodontal disease. ~ These features can be produced relative~.~°1 paucity of IgE in gingiva. experimentally in animals on an immunebasis. ~ Spe- cific immunereactions, both T-cell and B-cell medi- Analysis of complement conversion products in ated, have been the usual explanation. Early reports gingival fluid did indicate that activation has occurred, of correlation between lymphocyte blastogenesis in re- possibly by antigen-antibody reactions as well as al- sponse to oral bacterial preparations and the severity ternative pathway.m~ Overall, there is considerable of peridontal disease, ~ followed by demonstrations of circumstantial evidence that specific immunologic similarly stimulated release of bone resorbing fac- phenomena may mediate tissue damage in gingivitis tor(s), ~ , 69 and other mediators6.71 provided and periodontitis, but there are also significant items supportn for classical T-cell mediated mechanisms, of substantiation which are cloudy or missing. The protective functions of the Many other studies have demonstrated lympho- should not be overlooked in these considerations; in cyte blastogenic responsiveness to oral bacteria in gingi- fact, this feature plus other defensive capacities, such vitis and/or periodontitis. 7.~ However,striking correla- as provided by PMNactivity, probably account tions with disease severity are not consistently found, for the fact that disease progression is generally except perhaps, in response to prepara- quite slow in the face of a rather massive bacterial tions in gingivitis and Bacteroides in periodontitis, population. and interpretations are clouded by the manyinconsis- It is apparent that antigen-specific immune re- tent experimental variables among different studies. sponses are not the only means by which the efforts of Although not all reports would agree, it would appear the immunesystem can be induced. In contrast to the that periodontally "normal" individuals do respond to monoclonal activation in antigen-specific immunity, a most stimulants used in these assays, and the condi- role for polyclonal activation in the etiology of perio- tions of the experiment may dictate whether quantita- dontal disease has been postulated. Clagett and Engel tive differences are found between "normals" and have reviewed polyclonal B-cell activation and specu- other groups. Evidence from these studies does not re- lated on its potential role in pathogenesis of inflam- ~ late strictly to T-cell mediated immunity, as both T- matory disease. and B-lymphocytes have been shown to proliferate Reports have indicated that lymphocytes from per- and produce lymphokines TM including ac- iodontally diseased subjects were more responsive tivating factor. 81 The morphologic evidence discussed than those from persons with a healthy periodontium above suggests that destructive lesions are B-cell when stimulated with levans, branched dextrans, and dominated. ;~,1~ Similar to classical T-cell mediation, circumstantial evidence is available for classical B-cell mechanisms In a publication of work from our laboratories, (antibody and activated effectors), but convincing strains of B. melaninogenicus, A. naeslundii, and A. proof has been elusive. Many studies have demon- ~iscosus were shown to have polyclonal B-cell activa- strated circulating antibody reactive with oral tors (PBA) for human cells, and a hypothesis for the ,~-u but correlation with disease is not participation~ of PBAin periodontitis was developed; regularly found or convincingly remarkable. Engel et al. had previously shown PBAactivity for A. A recent report, however, did indicate strikingly ~iscosus in murine systems. ~ We have studied to date, elevated antibody reactive with A. actinomycetem- nine strains of gram-negative (five species) and gram comitans in juvenile periodontitis. ~ Extension and positive (two species) bacteria commonly isolated

PATHOGENESISOF PERIODONTAL DISEASE 92 Ranney,Debski, and Tew from periodontal microflora. Only one of these strains age range with a healthy periodontium (HP). failed to function as a PBA. Potency, compared to a 1. Lymphocyte function positive reference control (pokeweed mitogen), varied In investigations of the SP group, we have been un- among strains tested, but some appeared as potent or able to detect significant differences from HP in medi- more potent than the positive control. The magnitude cal laboratory testing, immunoglobulin and comple- of the response to a given PBAappeared to differ ment levels, percent circulating B- and T-cells, serum among individuals. antibody, lymphocyte blastogenesis, and lymphokine In addition to the features of the cellular infiltrate synthesis stimulated by a panel of bacteria, or phago- of gingivitis and periodontitis with which PBA-stimu- cytic and microbicidal capacity of PMN.However, the lated inflammation would be consistent/u bone re- SP group was significantly more responsive than the sporption can be induced in in vitro systems by mito- HP group to the polyclonal B-cell activator, staphylo- genic (polyclonal) as well as antigenic stimulation2 coccal protein A (SPA);~ This hyperresponsiveness to preliminary experiments, we have observed produc- PBAmay be the reason these patients have had severe tion of bone-resorbing factor{s) under the conditions periodontal destruction at an early age, and gives of polyclonal activation by extracts of oral bacteria. additional reason to suspect that PBAs may be im- Claggett and EngeP~ speculate that it may not be portant factors in periodontal disease in general. SPA possible to implicate single etiologic agents where nu- ism a T-cell dependent B-cell polyclonal activator; merous species are present in close association with thus, the hyperresponsiveness could be due to aberra- soft tissue, since manybacterial species possess PBAs. tions in either T-cell or B-cell function. Also, the role This would be consistent with the impressions gained of macrophages in polyclonal response needs to be from our bacteriological studies." Combinedeffects of clarified. several PBAare also possible. Subsets of B-cells vary- Preliminary data indicates a further characteristic ing in their maturity are selectively affected by PBAs, of the SP group thus far in our results, that distin- and stimulation of immature B-cells can drive them to guishes them not only from the HP but also the JP a maturational state in which they are susceptible to population. Unstimulated peripheral blood leukocytes activation~1" by a different PBA; (PBL) from the SP subjects appear to incorporate sig- nificantly less 3H-thymidine with time in culture than Studiesof SeverePeriodontal Destruction in Adolescents do PBL from either the HP or JP groups (Table 1). and YoungAdults The increased uptake at days five and seven of culture We have been studying individuals ranging in age by PBLfrom the HP and JP groups is consistent with from adolescence to 30 years, arbitrarily divided by a normal autologous mixed lymphocyte culture reac- clinical criteria into two populations. In one of these tion (AMLR).u3,11. Thus, the significantly lower uptake we have termed severe periodontitis (SP), further de- by PBL from the SP group may indicate a suppressed fined as the presence of 5 mmor more loss of attach- or reduced AMLR.The normal AMLRis due to stim- ment on eight or more teeth, not limited to first ulation of T-cells by autologous non-T cells, "3-"~ im- molars and/or incisors, in the presence of 6 mmor plying that failure to exhibit a normal AMLRcan re- more of pocket depth and generalized gingival inflam- flect abnormal T-cell responsiveness and regulatory mation. The other group, termed juvenile periodon- function. This seems to be the case in systemic lupus titis (JP), differs in that the severe periodontal de- erythematosus"~,u7 (SLE), wherein an impaired AMLR struction is limited to first molars and incisors, allow- and~"~ defects in induced suppressor T-cell function ing for up to two additional teeth, and may involve have been found. fewer than eight total teeth. Both groups are free of Our findings in the SP group are tenative as yet, in systemic disease by history and signs. Studies are rou- that we have not definitively identified our observa- tinely performed in comparison to persons of the same tions as AMLR,and the findings expressed in mean Table1. Thymidineuptake by unstimulatedperipheral blood leukocytes after 3, 5 and7 daysof culture(CPM, Mean + SE).

Subject* Group N 3 Days 5 Days 7 Days

HP 16 4,319+ 1,059 7,032 + 1,475 17,577 + 3,732 JP 8 3,215+ 598 15,303+-- 3,467 26,647 + 6,024 SP 13 3,222 + 426 4,413+ 540 9,285 + 2,308

*HP- HealthyPeriodontium, JP - JuvenilePeriodontitis, SP- SeverePeriodontitis.

PEDIATRICDENTISTRY 93 Volume3, SpecialIssue data do not accurately describe every individual in the capabilities of the PMNwould seem to be more im- group. Nonetheless, these mean differences in the portant considerations in pathogenesis of periodontal kinetics of 3H-thymidine uptake in unstimulated PBL disease in young people. cultures, of the subjects studied so far, provide the Quantitative PMNdeficiencies, such as cyclic clearest separation between clinical groups of any lab- 1~,~ and1~ chronic benign neutropenia oratory assay we have utilized. These findings, to- have been associated with severe periodontal destruc- gether with the hyperresponsiveness to SPA, provide tion. Qualitative capabilities of the PMNrelative to a working hypothesis that there are individuals who phagocytic function, including chemotaxis, pathogen suffer severe periodontal destruction at an early age recognition and ingestion, lysosome degranulation, because of a regulatory T-cell defect resulting in B-cell and killing and digestion of microbes, may also have hyperresponsiveness. implications for the expression of periodontal disease if functional impairment exists. For example, Chediak- A recent report indicates that the abnormalities Higashi syndrome in both animals and man has been in SLE are marked during active phases of disease and associated with abnormalities of PMNfunction, in- return1~ to normal when disease activity decreases. cluding depressed PMNchemotaxis, with severe per- That suggests that the loss of regulatory immune iodontitis;3~-~. function in SLE expressed by suppressed AMLCis not Recently, PMNchemotactic responsiveness has a simple genetically determined trait, although an un- been investigated in cases of juvenile periodontitis. derlying genetic abnormality which requires a trigger- The term "juvenile periodontitis" has been associated ing, environmental event is not excluded. Should our with the term ".". Periodontosis was investigations of the SP group confirm a defective used to describe a non-inflammatory, degenerative AMLR,we will then want to know whether the appar- lesion, generally occurring in relative absence of de- ent defect is reversible. posits on the teeth and leading to migration, loosening Regulation of B-cell response is quite complex. For and exfoliation of the teeth; ~ This concept has been example, the B-cell response to SPA in humans was largely discarded for lack of supportive evidence. found to be dependent on the activity of helper T-cell As referred to earlier in this review, somehave asso- and1~ regulated by the activity of suppressor T-cells, ciated a rather specific microflora to juvenile perio- and the magnitude of response may depend on the dontitis2 ~-~ Our own studies to date are not conclusive balance between helper and suppressor influences. with regard to whether there is a flora distinct from Also, relative reponsiveness of helper and suppressor other peridontal diseases, but we do not routinely find T-cells varies with concentration of the stimulant. the same organisms suggested by others to be promi- In addition to T-cell dependent polyclonal activa- nent so far.~ For example, our studies would indicate tors, there are T-cell independent, bacterially derived Capnocytoph~g~ species to be almost exclusively PBAs.~1 Soluble suppressors can be released on ap- supragingival in location. propriate stimulation, which are suppressive for both T-cell dependent and T-cell independent mitogenic Rather consistent findings have been reported by stimulation; = Further, T-cell helper activity for poly- several laboratories, however, indicating depressed clonal B-cell responsiveness can be generated in re- chemotactic responsiveness by PMNfrom individuals sponse= to antigen-specific activation of T-helpers; with juvenile peridontitis compared to PMNfrom These regulatory systems provide reasons for vari- periodontally healthy persons; ~ We also have con- able responsiveness, under given conditions, in addi- ducted studies to observe the association between tion to the variable responsiveness of B-cell subsets PMNchemotaxis (PMN-CTX)and severe periodontal and differences in relative potency of various bacter- disease in adolescents and young adults. Individuals ially derived PBAspreviously mentioned. from both the JP and SP populations defined above The fact that gingivitis in pre-pubertal children have served as subjects. We have routinely compared normally does not seem to progress to B-cell domi- one or two such subjects with two HP subjects in an nance as it does in adults raises intriguing questions. experiment conducted in a single day. Experimental Is this due to the type of stimulation received, or to conditions are similar to those previously described by regulatory influences? The answer(s) might aid Van Dyke et al; ~ In comparing 20 diseased subjects providing answers to why inflammatory lesions in (12 JP, 8 SP), 16 experiments were performed. Data adults progress to a destructive phase. generated from a typical experiment are represented 2. Polymorpl~onuclear leukocyte (PMN) t~unction. in Figure 1. The HP response to increasing concentra- Although deleterious effects of PMN,through re- tions of fMLP{5 x 10~ to 5 x 10~ M) is described by lease of lysosomal hydrolytic enzymes, have received bell-shaped-~ curve with a maximumresponse at 5 x 10 attention as potential contributors to pathogenesis of M. On this day the diseased subject’s response curve periodontal disease/m~ impairments of the defensive was lower than, and dissimilar to, those of the HP

PATHOGENESISOF PERIODONTALDISEASE 94 Ranney, Debski, and Tew Table2. Analysisof variance*chemotaxis results for 20diseased PMN CHEMOTAXIS subjects. 15-

H P # I .... Sourceof HP # 2 ...... Variance P value DP -- ~ 1.." ~

Datea 0.0001 I0 Subjectb Class 0.0001 Date-Subject Class NS s :" ;.~ Dose¢ 0.0001 Dose-Date 0.0001 o~ Subject Class-Dose 0.0250 I : I ..’~ ~ ! ..." *Dependentvariable : squareroot of the sumof the meansof the I ~*" / \ "._~ filters. Eachfilter meanrepresents the numberof PMN/fieldin 9 fields calculatedto representthe entire filter. aDayexperiment performed bHealthy or diseased ¢Concentration of chemoattractant

of PMN-CTXdata was used to analyze the heteroge- neity within the population (Table 3). This analysis associated diseased subjects according to their PMN- CTXdifferences from HP subjects. The selection of MOL~ CONCENTRATIONOF F~LP {-LOG} three clusters most clearly separated the diseased pop- ulation into distinct groups. Although cluster 1 ap- Figure1. Neutrophilchemotactic response to variousconcentra- tionsof formylmethionylleucylphenylalanineof threesubjects - HP pears to be elevated, or indistinct from HP’s, clusters 2 # 1 = oneperiodontally healthy subiect; HP # 2 -- secondhealthy and 3 are relatively chemotactically deficient, and subject;DP = youngadult subject with sites of markeddestructive cluster 3 was the least responsive group. periodontaldisease. The responses represent the mean of threefil- The majority of the tested diseased subjects fell ters.The variance for eachpoint was less than 10% of themean. into the "depressed" clusters, but the JP’s were evenly distributed amongthe three clusters. With respect to subjects. Statistical analysis (analysis of variance) dose relationships in this analysis, the dose at which all such experiments is presented in Table 2. the greatest difference from HP appeared was 107 M This analysis indicated that direct comparisons for 75%of the subjects in clusters 2 and 3 (10.7 M is among daily studies were not possible because of the generally one-half log greater concentration than that great variability among observations from experi- which results in peak chemotactic responsiveness). ments performed on different days (see DATE). The Among the other 25%, maximum difference from readily perceived fact of a relationship between con- HP appeared at various tested doses. Differences in centration of fMLP and chemotactic response was apparent magnitude of the depression are present if confirmed (see DOSE), although the exact dose- data are analyzed according to the dose exhibiting response relationship did vary among experiments maximumdifference, compared to the mean of all performed on different days (DOSE-DATE). How- doses, as shown in the table; a further difference in ever, the significant variable, SUBJECT-CATE- impressions of magnitude would occur if the peak GORY,(HP vs. JP & SP) and lack of significant varia- chemotactic dose were chosen for analysis. bility due to Date-Subject Category interaction, con- Thus, the variability associated with in vitro firmed that the diseased population did differ from human PMN-CTX presents the most noteworthy the healthy population independent of the variability challenge to interpretation of findings. The use of two associated with experiments performed on different "healthy" controls with each experiment in our study days. The moderately significant interaction of SUB- helped to reduce the impact of day-to-day variability JECT-CATEGORY-DOSEas a variable indicates and facilitated the observation that the diseased pop- that the subject comparisons are different at different ulation was chemotactically deficient. concentrations of chemoattractant. Alternative approaches include repetitive testing of To permit between-diseased subject comparisons, subjects’~ on different days, although Van Dyke et al. given the above limits of variability, a cluster analysis reported that 9/54 comparisons among 18 pairs of

PEDIATRICDENTISTRY 95 Volume3, SpecialIssue Tablea 3. Clusteranalysis of PMNchemotaxis,

Standardized Unstandardized Clinical Group Clusterb No. N. Subjects Chemotaxis Difference %c Response (N Subjects) 1 4 4 + 2 167+33 JP SP 12 + 3 123 + 52 3 1

2 12 14 + 1 66 + 3 23 + 2 43 + 5 4 8

3 4 26 + 2 47 +_ 4 37 + 4 28 + 5 4 0

aRaw data from chemotaxis assays of PMN from diseased subjects was subtracted from that of healthy subjects performed on the same day for each concentration of chemoattractant. ~Theupper number in eachcluster is the meandifference for all concentrationsof chemoattractant andall subjectsin that cluster; the lowernumber is the meanof the greatestdifference for eachsub- ject. CTheupper numberin each cluster is the meanproduct (diseased/healthy) for all concentrations chemoattractantand all subjects in that cluster; the lowernumber is the meanpercent {diseased/ healthy)using the data fromconcentrations resulting in the greatestdifference for eachdiseased sub- ject. healthy individuals were significantly different (i.e., young persons must include acknowledgment of "false positives"), and only 8/32 diseased subjects other systemic disease states having prominent mani- always tested as deficient in repeat assays (26/32 festations in the periodontium (in addition to the were judged deficient). Because of the variability, ex- neutropenias already mentioned). The particular rele- pressions of data as percent deficiency should be vance is that notable periodontitis in pre-pubertal viewed with caution with respect to in viyo biological children seems not to occur except in the presence of relevance. systemic disease. Among these are hypophosphata- Nonetheless, similar observations from different sia ’4’’4~ and syndromes associated with dermatologic laboratories, using different methods, lend strength disorders1.~ such as Papillon-Lefevre syndrome. to the conclusion that there is a deficiency in PMN In hypophosphatasia a deficiency of alkaline phos- chemotaxis among the population of young individu- phatase exists associated with a failure of cementum als with severe periodontal destruction. Based on the formation and resultant premature exfoliation of pri- distribution of JP and SP amongclusters according to mary teeth. Papillon-Lefevre syndrome includes chemotaxis’~ in our work, and on the reports of others, severe periodontal inflammation and bone destruction demonstration of a PMNchemotactic defect will not associated with hyperkeratosis of the palms of the serve to clearly separate groups correlated with differ- hands and soles of the feet and occasionally other skin ent clinical distributions of periodontal destruction. areas. Pathogenetic mechanisms are unknown. Reticu- Neither does the fact of an association of chemotactic loendothelioses 1~ and the leukemias~47 may have perio- defect and periodontal destruction prove that the de- dontal manifestations through infiltration of perio- fect is a factor in pathogenesis. It is reasonable, dontal tissues by affected cells and concomitant al- though, to hypothesize that this does represent a tered defensive capacities. weakened defensive capacity and might facilitate per- iodontal pathology. Conclusion Our findings with respect to lymphocyte function would suggest that the PMNdefect is not the only The probable etiologic agents of gingivitis and per- aberration in defensive capacity or systems which may iodontitis in children are bacteria, as in adults. Al- underlie some similar clinical syndromes in young though specific bacteria have been implicated in some adults. Other identified variables that may influence clinical syndromes in adolescents, this has not been disease expression include serum factors ’~.’39 and anti- shown beyond question. Very little information on the body.~ Defects in other cell types, such as monocytes, bacteriology related to periodontal disease of pre- may also be found in young individuals with severe pubertal children is available. In adults the pathologic periodontal’~ destruction. features of established gingivitis and periodontitis are PeriodontalDisease in Childrenwith SystemicDisease domianted by B-lymphocytes and plasma cells, while A review of periodontal disease pathogenesis in earlier features of gingivitis have a greater percentage

PATHOGENESISOF PERIODONTAL DISEASE 96 Ranney,Debski, and Tew of T-lymphocytes. Most of the pathologic features of 2. Baer, P. N. and Benjamin, S. D.: Periodontal Disease in Ctu’l- the destructive B-cell dominated lesion can be account- dren and AdoIexcents, Philadelphia: J. B. Lippincott Com- ed for theoretically by immunological phenomena, pany, 1974, Ch. 3. both antigen-specific and polyclonal, and by consider- 3. L~e, H., Theilade, E. and Jensen, S. B.: Experimental gingivi- tis in man, J Periodontol, 36:177-187, 1965. ation of functional attributes of other host response 4. Theilade, E., Wright, W. H., Jensen, S. B. and L~e, H.: Experi- mechanisms. Many bacteria have polyclonal activa- mental gingivitis in man. II. A longitudinal, clinical and bac- tion capacity, and polyclonal activation would be con- teriological investigation, d Periodont Rex, 1:1-13, 1966. sistent with the possibility that manydifferent bac- 5. 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E. and I~e, H.: Experimental perlodon- genesis of periodontal disease in general. titis in the beagle dog, JPeriodont Rex, 8:1-10, 1973. Those relatively rare instances of pre-pubertal 9. Greene, J. C.: Oral hygiene and periodontal disease, AmJPub Hlth, 53:913-922, 1963. severe periodontal destruction that do occur seem al- 10. Russell, A. L.: Epidemiology of Periodontal Disease, Int Dent most exclusively found when there is a concomitant J, 17:282-296, 1967. systemic disease; e.g., Papillion-Lefevre syndrome, 11. Ramfjord, S. P., Emslie, R. D., Greene, J. C., Held, A. F. and neutropenias. Waerhaug, J.: Epidemiological studies of periodontal disease, Instances of severe periodontal destruction in Am j PubjHlth, 58~:1713-1722, 1968. 12. 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PATHOGENESISOF PERIODONTALDISEASE 98 Ranney, Debski, and Tew 70. Budtz-J~rgensen, E., Kelstrup, J., Funder-Nielsen, T. D., humanperiodontal disease, Arch Oral Biol, 19:959-968, 1974. Knudsen, A. M.: Leukocyte migration inhibition by bacterial 89. Genco, R. J., Mashimo,P. A., Kxygier, G. A. and Ellison, S. A.: antigens in patients with periodontal disease, J Pedodont Res, Antibody mediated effects on the periodontium, J Pe~odontol, 12:21-29, 1977. 45:330-337, 1974. 71. Ivanyi, L., Wilton, J. M. A. and Lehner, T.: Cell-mediated im- 90. Lehner, T., Wilton, J. M. A., Ivanyi, S. and Manson, J. D.: Im- munity in periodontal disease: Cytotoxicity, migration inhibi- munological aspects of juvenile periedontitis (Periodontosis), tion, and lymphocyte transformation studies, Immunology, 22: Pedodont Res, 9:261-272, 1974. 141-145, 1972. 91. Hawley, C. E. and Falkler, W. A., Jr.: Antigens of Leptotdcl~a 72. Horton, J. E., Oppenheim,J. J., Mergenhagen, S. E. and Raisz, buccah’s. II. 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PEDIATRICDENTISTRY 99 Volume3, Special Issue 111.Rynnel-Dragoo,B., Ringden, O., Alfredeson, H. andMSller, E.: festations in chronic benign neutropenia, J Clin Pe~odontol, The use of bacteriafor the functionalcharacterization of 5:74-80, 1978. human lymphocytesubpopulations in variouslymphoid or- 129. Lampert, F. and Fesseler, A.: Periodontal changes in chronic gans,Scand J Immuno],8:369-375, 1978. benign granylocytopenia in childhood, J Clin Pe~odontol, 112.Lipski,P. E.: Staphylococcalprotein A, A T-cell-regulated 2:105-110, 1975. polyclonalactivator of humanB cells,J Immano],125:155-162, 130. Deasy, M. J., Vogel, R. I., Macedo-Sobrinho, B., Gertzman, G. 1980. and Simon, B.: Familial benign chronic neutropenia associated 113.Opelz,G., Kinchi,M., Takasugi,M. and Terasaki,T.: Autol- with periodontal disease, JPeHodontol, 51:206-210, 1980. ogousstimulation of humanlymphocyte subpopulation, J Exp 131. Lavine, W. S., Page, R. C. and Padgett, G. 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PATHOGENESISOF PERIODONTALDISEASE 100 Ranney, Debski, and Tew