Early Onset Periodontitis

7/28/2019 Early Onset Periodontitis

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Periodontology 2000, Vol. 6, 1994, 7-25Pr in te d i n D e nma rk . All rights reserved C o p v r i n h t 0 M u n k s n a a r d 1 9 9 4~PERIODONTOLOGY2000ISSN 0906-6713

Early-onsetperiodontitis:systemic aspects of etiology andpathogenesisHARVEY. SCHENKEINTHOMAS. VANDYKE

Early-onset periodontal diseases comprise a groupof clinical entities with the common attributes of anage of onset approximating puberty and relativelyrapid destruction of the supporting tissues in appar-ently healthy individuals (26). These diseases aremanifested clinically in several forms, including a lo-calized form called localized juvenile periodontitis,involving only first molar and incisor teeth (and per-haps a very limited number of additional teeth), anda generalized form or forms in which many or allteeth are affected ( 6 ) . The generalized form mayfurther comprise a clinically heterogeneous group ofdiseases, including generalized juvenile peri-odontitis, rapidly progressive periodontitis and per-haps other forms. It remains unclear, however,whether the localized form and the generalizedforms are distinct diseases.

Although juvenile periodontitis was first formallydefined by Baer in 1971 ( 6 ) , the clinical syndromehas been recognized since the 1920s (59) and Orban& Weinman (117) used the term periodontosis toemphasize the prevailing belief that the etiology ofthe syndrome was degenerative and perhaps sys-temic.

Modern concepts of the etiology and pathogenesisof this group of diseases are based on observationsduring the past 20 years demonstrating that sys-temic, local, and extraoral environmental factorscontribute to its expression. Data from various sub-ject populations further indicate that the etiologicalfactors and pathogenic processes associated withdisease are not consistent in all subjects. These ob-servations, which will be discussed in more detailbelow, are the following:0 The distribution of early-onset periodontal dis-

eases in the population is familial, indicating thatthere are likely to be heritable risk factors for these

diseases. Risk factors related to bacterial floras,immunological responses, and leukocyte functionare frequently different between affected individ-uals within the same family.

0 The subgingival bacterial microflora associatedwith disease lesions contains bacterial specieswith some specificity. These bacteria are particu-larly associated with disease presence and pro-gression; some, especially Actinobacillus actino-mycetemcomitans, may invade the periodontaltissues and be resistant to conservative mechan-ical therapy. It is widely held, however, that speci-fic types of bacterial plaque are necessary but notsufficient for disease expression.

0 There is a remarkable systemic antibody responseto A . actinomycetemcomitans in patients withearly-onset periodontal disease, particularly thelocalized form.

0 A large percentage of early-onset periodontal dis-ease patients, up to 80% of localized juvenile peri-odontitis subjects in some populations, demon-strate a relative depression of systemic and localpolyrnorphonuclear leukocyte (neutrophil) func-tion related to defective numbers or function ofrelevant membrane receptors. Since other sys-temic syndromes in which neutrophil function isdefective are usually associated with early andrapid periodontal attachment loss, it is thoughtthat the defective neutrophil function in early-on-set periodontal disease contributes to its patho-genesis.

0 Many of the established attributes and correlatesof early-onset periodontal disease, including itsepidemiology, the antibody response to A. actino-myceterncomitans, neutrophil chemotactic func-tion and serum immunoglobulin subclass concen-trations, differ according to the racial character-istics of population groups.

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Schenkein& Van Dyke0 The observations of bacterial, immune and in-

flammatory phenomena outlined above may notbe observed in all populations demonstrating theclinical characteristics of early-onset periodontaldisease.

This review examines recent information on the sys-temic aspects of early-onset periodontal disease. As-pects of the systemic immune response, defectivefunction of leukocytes and the genetic and environ-mental aspects of disease are emphasized, with thepurpose of critically assessing current concepts ofdiagnosis, etiology and pathogenesis. The chapteremphasizes the observations in the literature thatpoint to various aspects of heterogeneity in early-onset periodontal disease and assesses the signifi-cance of findings common to most investigations ofthese diseases.

Clinical aspects of early-onsetperiodontal diseaseA recent review of the diagnostic characteristics ofthe periodontal diseases, published by the AmericanAcademy of Periodontology, has attempted to defineand delineate the various forms of early-onset peri-odontal disease (26). This review described rapidlyprogressive periodontitis (118) and juvenile peri-odontitis as distinct entities, with both diseases sub-divided into clinical subforms. Juvenile periodontitisis subdivided into a localized (localized juvenileperiodontitis) and generalized (generalized juvenileperiodontitis) form based on the number of affectedteeth, and rapidly progressive periodontitis is di-vided into type A and type B subforms based onslightly differing age ranges and plaque and calculusaccumulation. Despite this attempt to split early-on-set periodontal disease into a variety of distinct enti-ties, there is information that would argue againstthe fidelity and exclusivity of these classifications.0 The definitions and characteristics of rapidly pro-gressive periodontitis and generalized juvenile

periodontitis are nearly identical; both occur inyoung adults (albeit with slightly differing ages ofonset, a variable that is ill defined at best for allforms of early-onset periodontal disease), arecharacterized by rapid, severe periodontal de-struction, have characteristic neutrophil defects ina subpopulation of subjects an d have similar typesof bacterial flora.A number of investigators have published data

that indicate that localized juvenile periodontitis,generalized juvenile periodontitis and rapidly pro-gressive periodontitis (as well as prepubertal peri-odontitis) coexist in the same nuclear families (15,91, 92, 113, 170). Given the low prevalence ofearly-onset periodontal disease, it is unlikely thatthis would be observed if these clinical types haddifferent underlying etiologies and were, in fact,distinct diseases. However, the etiology of diseasewithin one family may differ from that within an-other family.

0 The localized form of early-onset periodontal dis-ease, when followed longitudinally, has been clin-ically observed to progress and become general-ized in some patients. This frequently occurs dur-ing the putative age of onset of rapidly progressiveperiodontitis, and thus it is difficult to determinethe initial manifestation of the periodontitis.

0 Some cross-sectional studies of early-onset peri-odontal disease populations have indicated thatthe distinction between the localized and general-ized forms is age-dependent (75, 135) and suggestthat the localized form progresses to involve ad-ditional teeth to become generalized.

It is apparent that the differential diagnosis of thevarious clinical forms of early-onset periodontal dis-ease is fraught with potential inaccuracy and thatthe clinical manifestations of early-onset periodontaldisease are quite heterogeneous. However, attemptsto categorize subforms in the absence of well-de-fined clinical and laboratory criteria or knowledge ofthe underlying genetic or environmental etiologiesmay be inappropriate.

Clinical variabilityA hallmark of early-onset periodontal disease is thevariability of its expression in affected individuals.Although localized juvenile periodontitis is classi-cally defined as affecting only first molars and inci-sors, other tooth types are frequently observed toalso be affected although the disease is clinically lo-calized (21). The generalized form(s) appears to dis-play even greater heterogeneity of clinical ex-pression, with multiple affected teeth in no well-defined pattern. The threshold for attachment lossmeasurement at affected sites that is used to deter-mine whether a tooth site is affected with early-on-set periodontal disease is likewise uncertain. For ex-ample, in studies of families with early-onset peri-odontal disease, it is prudent to apply restrictive ordemanding definitions of disease status on the pro-


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band (that is, with regard to the pattern of affectedteeth and the amount of attachment loss required);however, relatives of the proband may then displaymuch less attachment loss, and thus the diagnosticcategories into which relatives are placed may bebased on less restrictive criteria. An additional com-plication already cited is the observation that thegeneralized form of early-onset periodontal diseaseis often preceded by what appears to be a localizeddisease, thus complicating the diagnosis of individ-ual cases and possibly confounding the diagnosis ofcases that are not longitudinally assessed. The clin-ical definitions of these diseases vary somewhatfrom author to author, and thus the categorizationof subjects in studies of the etiology and patho-genesis of early-onset periodontal disease is not pre-cise.

Age as a factor in determining diagnosisA factor that contributes to both heterogeneity anddifficulty in assigning diagnosis is the age of onset ofearly-onset periodontal disease. It is widely held thatlocalized juvenile periodontitis displays onset at oraround puberty. However, there are numerousexamples of onset of this disease at various agesafter the expected time of puberty, and some recentdata indicate that bone loss can be detected in theprimary dentition of young children who eventuallydevelop early-onset periodontal disease (141).

The uncertain age of onset of early-onset peri-odontal disease is problematic in studies of its gen-etic and environmental etiologies. The study of fam-ilies with early-onset periodontal disease usually re-quires assignment of the presence or absence of atrait to family members who are at or beyond pu-berty. Since epidemiological data and clinical obser-vation indicate that onset of early-onset periodontaldisease may occur at least until age 17 years (90) andpossibly into the twenties, it is difficult to assign de-finitive diagnoses to family members who could beat risk for early-onset periodontal disease.

It is likewise difficult to assign periodontal diag-noses to individuals in early-onset periodontal dis-ease families with attachment loss who are beyondthe age of 30years due to uncertainties regarding theirdental history and the possible onset of adult peri-odontitis. Since the risk factors and pathogenic pro-cesses that lead to early-onset periodontal diseasehave not been completely elucidated it is difficult toassign an age at which the onset of early-onset peri-odontal disease is no longer possible. Thus, the de-finitive diagnosis of family members who appear to

be periodontally healthy 10-15 years beyond the ageof puberty may not be entirely correct, and the dif-ferentiation of adult-onset periodontitis from early-onset periodontal disease may be unclear. Variouslaboratory assays that determine bacterial and hostdefense characteristics in individual subjects may beof only limited utility due to the variability of find-ings in different populations (see below).

EpidemiologySeveral authors have examined the distribution ofearly-onset periodontal disease in various popula-tions by a number of methods. Although the diag-nostic variables discussed above would affect thecomparative results of such studies, some trends areobvious in the prevalence rates in different parts ofthe world.

A recent survey of 14- to 17-year-old children inthe United States has indicated that black Americansare at far higher risk for early-onset periodontal dis-ease than are white Americans (90). These preva-lence estimates are consistent with those docu-mented in other studies of different populations (10,12, 85, 93, 105, 111, 127, 133, 173). The striking dif-ference in the prevalence of early-onset periodontaldisease between black and white populations raisesinteresting issues relating to the relative impact ofcultural, environmental and genetic factors on therisk for early-onset periodontal disease. Studies haveexamined race as a variable in the assessment ofpathogenic and etiological correlates of periodontaldiseases and have indicated that differences be-tween black and white subjects may be detected inassays of bacterial factors (139), leukocyte function(138) and immune responses (64,66). It is thus likelythat risk factors or protective responses for early-on-set periodontal disease, whether genetic or environ-mental, may be enhanced in certain racial popula-tions.

Bacterial etiology of early-onsetperiodontal diseaseAlthough a thorough review of the bacteriological as-pects of early-onset periodontal disease is beyondthe scope of this chapter, it is crucial to summarizesome of this information since many of the systemicphenomena observed in early-onset periodontal dis-ease relate to direct responses to oral bacteria.

Initial descriptions of localized juvenile peri-odontitis emphasized that there was little apparent

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Schenkein& Van Dykeassociation between the severity of disease and theamount of plaque surrounding affected teeth. Infact, the disease was thought to be dystrophic ratherthan infectious in origin. In the mid-1970s, studiesby Newman et al. (112) and Slots et al. (143, 145)demonstrated that the microflora of early-onsetperiodontal disease contained some unusual andunique bacterial species. This work led to a series ofstudies in several laboratories that defined the pre-dominant microflora of early-onset periodontal dis-ease.

Cultural bacteriological studies have demon-strated that the subgingival flora in early-onset peri-odontal disease sites is complex. Cultural analyses ofthe flora have frequently been inconsistent, and theresults differ from reports in which alternativemethods were applied to bacteriological analysis.Some of these issues are discussed by Moore (107) inhis review of microbiological findings in periodontaldiseases. Differences in diagnostic criteria, culturemedia, microscopic methods, sampling techniques,sample dispersion methods, study design and lackof statistical power in analyzing resulting data con-tribute to differences in results.

Moore et al. (108) have indicated that more than50 bacterial species are present in subgingivalplaque from localized juvenile periodontitis subjectsthat each comprise, on the average, greater than0.1% of the cultivable microflora. The flora of gener-alized early-onset periodontal disease lesions is like-wise complex (109). Statistical evaluation of culturalbacterial data indicates that, overall, the bacteriologyof localized and generalized early-onset periodontaldisease lesions do not differ. However, studies fromseveral groups using a number of methods have in-dicated that fewer than 10 species are common inthe flora of affected sites from early-onset peri-odontal disease subjects, and that these bacteriahave some commonality among the various formsof early-onset periodontal disease as well as adultperiodontit is (67, 145, 180, 182). Some of these bac-teria have become widely examined candidatepathogens because of supplementary data fromstudies of their virulence characteristics (144) andtheir ability to induce systemic and local immuneresponses in humans with periodontitis. However,studies of human early-onset periodontal diseasehave not yet definitively differentiated the organismor groups of organisms that initiate the lesions ofearly-onset periodontal disease, those that propa-gate attachment loss in existing lesions and thosethat fortuitously inhabit the niches provided by suchlesions.

The most notorious relationship between specificbacterial infection and any periodontal disease isthat between A. actinomycetemcomitans and local-ized juvenile periodontitis. As reviewed in detail byMoore (1071, cultural bacteriology by a number ofinvestigators using a variety of selective and non-selective media indicate that this organism is detect-able in about one-third of affected localized juvenileperiodontitis sites at greater than 1% of the flora.Other investigators, using alternatives such as selec-tive cultural methods, DNA probes and immuno-fluorescent determination of cell counts, have re-ported much higher incidence rates and concen-trations of A. actinomycetemcomitans in localizedjuvenile periodontitis plaque (13, 96-99, 131, 180,181). In a few studies of localized juvenile peri-odontitis, little or no A. actinomycetemcomitans wasdetected (69). Several methodological and biologicalfactors could account for these differences:0 The nonselective cultural method is relatively in-

sensitive and can only detect organisms present atgreater than 2-3% of the total plaque concen-tration in a given sample.

0 The rapid methods (immunofluorescence andDNA probes) may be excessively sensitive and po-tentially cross-reactive and detect effete and deadcells as well as viable bacteria.

0 Some sites may harbor the organisms within thetissues and thus, depending on samplingmethods, may give spurious results for the inci-dence of occurrence.

In addition to problematic methodological differ-ences, it is possible that real differences exist in thebacterial etiology of early-onset periodontal diseaselesions. Some of these may be accounted for as fol-lows:0 Species other than A. actinomycetemcomitans may

account for a large percentage of localized juvenileperiodontitis lesions; Moore (107) estimated that,based on reported results in the literature, aboutone- hird of localized juvenile periodontitislesions could be accounted for by A. actinomyce-temcomitans,

0 Species other than A. actinomycetemcomitans mayaccount for cases of localized juvenile peri-odontitis in some parts of the world. For example,Han et al. (69) reported no association of localizedjuvenile periodontitis with A. actinomycetem-coinitans in China.Most reports fail to account for disease activity as

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a variable in assessing bacterial etiology of local-ized juvenile periodontitis. In a case reported byHaffajee et al. (67),A. actinomycetemcomitans didnot appear to present in all active sites, raisingquestions as to the relative role of this organismas a pathogen as opposed to a marker of disease.A. actinomycetemcomitans can be demonstratedin high prevalence and relatively high concen-tration in relatives of individuals with early-onsetperiodontal disease in the absence of periodontalattachment loss (63).

Despite the anomalies associated with A. actino-mycetemcomitans in early-onset periodontal disease,supplementary lines of evidence indict this organ-ism as playing a role in many cases of early-onsetperiodontal disease. These include:

A. actinomycetemcomitans displays a number ofvirulence characteristics that would support itscapacity to induce or propagate early-onset peri-odontal disease. These include a leukotoxin,lymphocyte suppression factor, fibroblast andkeratinocyte inhibitor, collagenase and lipopoly-saccharides.Serological data indicate that patients with early-onset periodontal disease can have very high anti-body titers against A. actinomycetemcomitans, in-dicating that they have been infected with thebacteria (50, 57, 63, 89, 126, 156, 172).As a group,early-onset periodontal disease subjects with suchantibody responses against A. actinomycetem-comitans (and Porphyromonas gingivalis) haveless severe and extensive disease than do thosewho lack such antibody (62, 65).A limited number of studies of treatment of pa-tients with localized juvenile periodontitis haveshown that elimination of detectable levels of A.actinomycetemcomitans through modalities in-cluding scaling, root planing, surgery and anti-biotic treatment resulted in cessation of attach-ment loss as well as diminution of the antibodyresponse (29, 47).A. actinomycetemcomitans has been detectedwithin diseased periodontal tissues in affectedsites in localized juvenile periodontitis patients(28). Furthermore, the invasive properties of A.actinomycetemcomitans can be demonstrated invitro (148).

Thus, despite the complexity of the periodontal mi-croflora in localized juvenile periodontitis lesionsand some reports to the contrary, compelling data

indicate that A. actinomycetemcomitans is an im-portant pathogen in this disease and likely to be re-sponsible for a large percentage of associatedlesions.

The bacteriology of generalized early-onset peri-odontal disease appears to be somewhat more com-plex than that of localized juvenile periodontitis (44,84, 109, 182); this may be due to the likelihood thatthe populations studied are more heterogeneousand thus could represent subpopulations with differ-ent etiologies. The bacteria that are apparently mostrepresentative of this diverse group of patients in-clude P gingivalis and A. actinomycetemcomitans aswell as Prevotella interm edia, Bacteroides forsythus,Eubacterium species, Fusobacterium nucleatum,Campylobacter rectus and a number of spirochetes.Each is emphasized here because of its documentedpresence in disease, induction of immune responsesin humans and virulence characteristics.

Immunological aspects of early-onset periodontal diseaseStudies relating to immune responses in early-onsetperiodontal disease have emphasized humoral anti-body responses to periodontal bacteria. This is dueto the remarkable systemic antibody response to A.actinomycetemcomitans found in most localized juv-enile periodontitis patients as well as in some gener-alized juvenile periodontitis and rapidly progressiveperiodontitis patients. Ebersole (45) comprehen-sively reviewed current knowledge relating to anti-body responses in early-onset periodontal disease aswell as other forms of periodontal disease. Ebersolethoroughly treated most aspects of the antibody re-sponse to periodontal microorganisms, and we willthus not review them here. However, since we areattempting to emphasize new directions in the studyof early-onset periodontal disease and in developingconcepts that better integrate current knowledge ofits etiology and pathogenesis, we wish to reviewsome current work that brings together immunolog-ical, epidemiological, bacteriological and genetic ob-servations.

Current work relating to immune responses inearly-onset periodontal disease have focused uponthe following:

the nature and function of specific antigens re-acting with antibodies in early-onset periodontaldisease patients;

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Schenkein& Van Dyke0 the nature and function of antibodies in early-on-0 antibody responses in specific patient groups.

set periodontal disease subjects; and

The most clear-cut relationship between specificimmune responsiveness and any periodontal dis-ease is that between the antibody response to A.actinomycetemcomitans and localized juvenile peri-odontitis. Genco et al. (56) first described the pres-ence of precipitating antibody to A. actinomyce-temcomitans in localized juvenile periodontitissera. Since that time, a great deal of effort hasbeen exerted in defining this response and under-standing its significance. A large percentage of lo-calized juvenile periodontitis patients demonstrateremarkably high antibody titers to A. actinomyce-temcomitans. This phenomenon has been repro-duced in countries with different racial demo-graphics than the United States; elevations in anti-A. actinomycetemcomitans have been reported, forexample, in localized juvenile periodontitis patientsin Korea (30), China (158) and Chile (92), indi-cating that this response is fundamental to local-ized juvenile periodontitis. Increases in antibody inall serum isotypes have been reported (153). Inview of the prevailing dogma that A. actinomyce-temcomitans is an important pathogen in early-on-set periodontal disease and data demonstrating thevirulence characteristics of this organism, under-standing the role of this host response may be es-sential in controlling this disease.There is clearly some heterogeneity in the re-sponse of early-onset periodontal disease patients toA. actinomycetemcomitans. Not all subjects with lo-calized juvenile periodontitis, for example, demon-strate elevated antibody levels to the tested antigens(65, 153). Williams et al. (177) found that the occur-rence of a positive antibody response did not necess-arily correlate with disease presence or even thepresence of the bacterium in a family. This may notbe surprising in view of the dynamic nature of theantibody response, its dependence on persistingantigen and the alterations of both the disease pro-cess and the microflora by such environmental fac-tors as therapy, antibiotic treatment and patientsgeneral health status. Other studies of early-onsetperiodontal disease families have demonstrated in-consistencies in the response to anti-A. actinomyce-temcomitans among family members with clinicallysimilar forms of early-onset periodontal disease and,in some families, elevated responses are absent (66).This may in part be explained by the dependence ofthis response on race (dealt with in more detail later)

or on other environmental factors that influencefamilial immune responses.

The antibody responses detected in generalizedearly-onset periodontal disease groups are typicallymore nonspecific than those seen in localized juven-ile periodontitis. The most common components ofthe flora to which elevated levels of antibody are de-tected are A . actinomycetemcomitans, l? gingivalis,some Eubacterium species, I? intermedia, and C. rec-tu s (46, 49, 102, 103, 110, 151, 153, 156, 157, 171,172). The response to l? gingivalis demonstrates theheterogeneity of the generalized early-onset peri-odontal disease group with respect to antibody re-sponse. Examination of the immunoglobulin G (IgG)response in generalized early-onset periodontal dis-ease indicates that about 40-50% of such patientsdemonstrate positive responses to this organism (65,110). This relative lack of specificity could be ex-plained in a number of ways.

Generalized early-onset periodontal disease couldresult from infection with any of a number of or-ganisms or could require infection with multiplespecies.Antibody responses in patients with generalizedearly-onset periodontal disease may be character-ized by hyperresponsiveness to the elements ofsubgingival plaque, leading to reactivity tomultiple bacterial types.The subject populations in studies of, for example,rapidly progressive periodontitis may include pa-tients with differing underlying etiologies and sus-ceptibility to different bacterial pathogens.

In an effort to determine the diagnostic utility ofsuch antibody responses as well as the heterogeneityof antibody responses within patient groups, Gun-solley et al. (65) examined the antibody responsesof 242 individuals to over 20 bacterial strains mostcommonly cultured from the subgingival microbiotaof localized juvenile periodontitis, generalized early-onset periodontal disease and adult periodontitissubjects. The limited number of organisms for whichlocalized juvenile periodontitis sera are elevated per-mitted accurate diagnosis in nearly 80% of casesbased on the antibody response to A. actinomyce-temcomitans and E nucleatum. The generalizedearly-onset periodontal disease group, which con-tained individuals with elevated antibody responsesto a large number of organisms, could at best be di-agnosed with 60% accuracy. When generalized early-onset periodontal disease subjects were misclassi-fied as periodontally healthy due to their weak or

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absent antibody responses, they had significantlymore severe clinical disease than subjects who weremisclassified as localized juvenile periodontitis sub-jects (due to their more robust antibody responses).This finding emphasizes that the heterogeneity ofthe immune response reflects the clinical and etio-logical heterogeneity within the population diag-nosed as having generalized early-onset periodontaldisease.

A possible functional role of antibodies in protec-tion against early-onset periodontal disease is alsoapparent from the results of the study describedabove. An interpretation of these data is that early-onset periodontal disease subjects with antibody re-sponses against antigens of P gingivalis and A. acti-nomycetemcomitans apparently have a milder extentand severity of disease. These data are, however, in-direct associations. For this reason, investigatorshave been examining the functional role of suchantibodies. For example, high titer sera from local-ized juvenile periodontitis patients frequently con-tain antibody reactive to the leukotoxin of A. actino-mycetemcomitans and functionally inhibit leukotoxicactivity in vitro (48). However, the correlation of thisactivity with improved clinical signs or prognosis hasnot been demonstrated. Baker &Wilson (8) have ob-served that localized juvenile periodontitis sera con-tain opsonic anti-A. actinomycetemcomitans anti-bodies; that is, the IgG fraction of such sera promoteingestion of the organism by neutrophils. Under-wood et al. (160) have further demonstrated thefunction of such antibodies as determined by chemi-luminescence responses. However, Sjostrom et al.(142) have observed that sera from rapidly progress-ive periodontitis patients with antibody titers equiv-alent to those in periodontally healthy individualsinduce lower chemiluminescence responses. Thisimplies that anti-A. actinomycetemcomitans anti-bodies in rapidly progressive periodontitis subjectsmay be less protective than those in healthy individ-uals. These data plus the observation that the pres-ence of antibody to A. actinomycetemcomitans cor-relates with the extent and severity of disease inearly-onset periodontal disease patients may arguefor a protective role within the localized juvenileperiodontitis population but a qualitatively inferiorantibody response in rapidly progressive peri-odontitis subjects.

The function of antibody reactive with P gingivalisis likewise uncertain. Correlative data would indicatethat early-onset periodontal disease patients withpositive antibody responses to P gingivalis have lesssevere disease than those who do not (62). Whitney

et al. (176) have examined the nature of such anti-body and found that the antibody avidities in bothseropositive and seronegative rapidly progressiveperiodontitis subjects are equivalent and signifi-cantly lower than those in periodontally healthycontrols. Furthermore, Chen et al. (27) have foundthat treatment of rapidly progressive periodontitispatients resulted in significant increases in antibodyavidity against both protein and carbohydrate anti-gens. Thus, despite high antibody titers to P gingi-ualis in about half of rapidly progressive peri-odontitis patients, the function of such antibodymay be inferior.

The literature relating to antibody responses inearly-onset periodontal disease focuses on theheterogeneity of responsiveness, particularly in thegeneralized early-onset periodontal disease sub-population. In pursuing the significance of the anti-body response to, in particular, A. actinomycetem-comitans, we have found that some aspects of theepidemiology, immune response and genetic risk forearly-onset periodontal disease appear to have someremarkably interesting interrelationships that ex-plain part of the apparent heterogeneity in such re-sponses. These are reviewed below.

There appears to be an interesting interplay be-tween the epidemiological and immunological as-pects of the antibody response to A. actinomycetem-comitans. We (66) examined the demographic andclinical variables related to such responses in early-onset periodontal disease patients, their relativesand periodontally healthy age-matched controls andfound that what initially appeared to be a familialpattern in anti-A. actinomycetemcomitans responseswas in reality a racially determined pattern (66).Black subjects, whether with early-onset periodontaldisease or periodontally healthy, demonstrated ahigher prevalence of positive antibody responses toA. actinomycetemcomitans as well as higher levels ofanti-A. actinomycetemcomitans serotype b thanwhite subjects. Other variables such as plaquescores, gingival inflammation, age, gender and thepresence of A. actinomycetemcomitans could not ac-count for these differences. This relationship heldwhether or not the periodontally healthy subjectswere members of early-onset periodontal diseasefamilies or were independently ascertained.

Further examination of antibody titers to organ-isms that predominate in the cultivable flora of thegeneralized early-onset periodontal disease groupindicated that the racial dependence of this responsewas evident almost exclusively for A. actinomycetem-comitans serotypes b and c (64). In view of the racial

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Schenkein&Van Dykedependence evident in epidemiological studies ofearly-onset periodontal disease and the observationthat white subjects rarely have localized juvenileperiodontitis, the interaction of race and antibodyresponses to clinical forms of early-onset peri-odontal disease was pursued further.

One approach taken by several investigators hasbeen to attempt to identify the antigen or antigensresponsible for induction of high antibody concen-trations against A. actinomycetemcomituns. Califanoet al. (23) identified the immunodominant antigenof A. actinomycetemcomituns serotype b as the sero-type specific carbohydrate antigen, which was sub-sequently defined by Wilson & Schifferle (179) andSims et al. (119, 140) as a polysaccharide side chainof lipopolysaccharide. We hypothesized that thisantigen may only induce high antibody levels inblack early-onset periodontal disease subjects; how-ever, a comparison of the immunodominant antigenin black and white subjects with elevated anti-A.uctinomycetemcomitans titers demonstrated that theimmunodominant antigen was identical in bothracial groups (24). This indicates that the effect ofrace on the response to A. actinomycetemcomitans isquantitative rather than qualitative.

It has been established with other carbohydrateantigens and with lipopolysaccharide antigens ofother bacterial species that there is subclass speci-ficity in the antibody response to such compounds,and that the IgG2 and IgAl subclasses produce themajor response. In addition, the response to severalof these antigens, notably the capsular polysac-charide antigens of Huemophilus infuenzae, areunder genetic control and are racially influenced (GO,61). Brown et al. (18) reported on the IgA subclassresponse to A. actinomycetemcomitans, indicatingthat the IgAl response dominated. Several groupshave therefore analysed the Ig G subclass response toA . actinonzycetemcomitans to determine the classand subclass specificity of the antibody response toA. actinomycetemcomituns.

Wilson & Hamilton (178) determined that thedominant response of localized juvenile peri-odontitis patients to lipopolysaccharides from A.actinomycetemcomitans was in the IgG2 subclass.They reported that the IgG2 levels of localized juven-ile periodontitis patients reactive with lipopolysac-charides averages 136 pg/ml versus only 7.8 pg/mlfor IgG1, 0.6 pglml for IgG3 and 0.01 pglml for IgG4.Lu et al. (94) have also demonstrated that titers tothis antigen are highest in the IgG2 subclass. Thehigh-responder patients had about 8 0 Fglml of IgGreactive with the immunodominant antigen, the vast

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majority of which was IgG2. This observation is in-triguing in view of the prevalent notion that anti-bodies of the IgG2 subclass are poor opsonins andpoor activators of the complement system, thuscasting some doubt on the protective quality of themajority of the antibody reactive with this organism.Whitney et al. (176) further illustrated this point byexamining serum IgG responses and IgG subclassdistributions to P gingivalis in subjects with rapidlyprogressive periodontitis. They observed that thepredominant response to P gingivalis was also in theIgG2 subclass and that the relative avidity of the re-sponse in high-titer individuals was low.

The studies by Wilson & Hamilton (1781, per-formed using a small number of subjects, impliedthat individuals with localized juvenile periodontitiswho have high anti-A. actinomycetemcomituns anti-body titers also have higher total serum IgG2 con-centrations than do age- and race-matched controls.These data are reminiscent of the results of earlierstudies (81, 88, 125) in which elevated levels of IgGwere found in early-onset periodontal disease pa-tients. This finding contrasts, however, with earlierstudies by Waldrop et al. (175), who found no differ-ences in IgG subclass levels in localized juvenileperiodontitis patients compared with healthy con-trols. Since only a small percentage of the increasein total IgG2 in these sera can be accounted for bythe increase in antibody titer against this single or-ganism, these data implied that there could be amore global difference in the control of IgG2 levelsin localized juvenile periodontitis patients than inthe rest of the population. Furthermore, since local-ized juvenile periodontitis subjects are predom-inantly black and we have noted significant differ-ences between black and white subjects in antibodytiters, we felt that examination of IgG subclass con-centrations as a function of both race and peri-odontal diagnosis was indicated.Lu et al. (95) measured total IgG subclass serumconcentrations in patients with localized juvenileperiodontitis, generalized early-onset periodontaldisease (comprising both generalized juvenile peri-odontitis and rapidly progressive periodontitis sub-jects) and adult periodontitis and in periodontallyhealthy individuals, comparing levels in black andwhite racial subgroups. The results indicated thatboth race and periodontal diagnosis affect serumIgG2 levels. Black subjects in general, in all diagnos-tic categories, have higher IgG2 levels than do age-and diagnosis-matched white subjects. Furthermore,localized juvenile periodontitis subjects have30-40% more IgG2 than race-matched controls,

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whereas generalized early-onset periodontal diseasesubjects had IgG2 levels that were virtually identicalwith their age-matched healthy controls.

We have begun to explore genetic factors thatcould explain the ability of some groups to producehigh levels of IgG2. Marazita et al. (101) determinedIgG2 levels in 122 families, including nuclear a nd ex-tended early-onset periodontal disease families andtwin pairs, plus 511 unrelated individuals and per-formed genetic analysis. Variance component analy-sis indicated that about 25% of the total variance inIgG2 levels was estimated to be due to genetic fac-tors and about 75% due to environmental factors.Genetic segregation analysis indicated that trans-mission of IgG2 concentration is consistent with aMendelian major locus, and that the best-fittingmodel is the autosomal codominant major locusmodel. This genetic model is significant even aftercorrecting for localized juvenile periodontitis statusand thus follows a genetic model independent of thesegregation of early-onset periodontal disease inthese families. This indicates that a portion of thevariation of IgG2 levels in the population can be ac-counted for by inheritance.

Neutrophil dysfunction in early-onset periodontal diseaseIn the late 1970s, it was observed that a substantialpercentage of individuals with localized juvenileperiodontitis demonstrate a relative defect in theability of their peripheral blood neutrophils to re-spond to chemotactic agents in a bioassay ofchemotaxis (31, 32, 87). Several groups (3, 36, 51,120, 121, 150, 162), have confirmed and extendedthis observation, although some investigators havebeen unable to demonstrate this phenomenon (83,86, 122, 129). In addition, enhanced production ofsuperoxide, an oxygen metabolite important in anti-bacterial activity, has been observed (168). Examin-ation of neutrophils from patients with the chemo-tactic defect indicates that such cells have a relativedeficiency of surface receptors for chemotacticagents such as formyl peptides and the comple-ment-derived chemotactic factor C5a (164, 165) aswell as of a chemotaxis-related surface glycoproteindesignated GP 150 (167). DeNardin et al. (41) havefurther demonstrated altered reactivity of antibodiesdirected at the formyl peptide receptor with local-ized juvenile periodontitis neutrophils. In addition,signal transduction abnormalities have been iden-tified (1, 2, 39, 159) including abnormal cell mem-

brane calcium channels, increased intracellular di-acylglycerol and decreased diglyceride kinase activ-ity. The resultant elevation of diacylglycerol, leadingto chronic elevation of protein kinase C activity, ishypothesized to account for the functional abnor-malities in localized juvenile periodontitis neutro-phils. In addition, a relative defect in 15-lipoxy-genase activity in neutrophils from both localizedjuvenile periodontitis and rapidly progressive peri-odontitis patients has been observed (114). Finally,localized juvenile periodontitis neutrophils havebeen shown to exhibit a specific defect of bacterialactivity towards A. actinomycetemcomitans thatcomprises defective phagosome-lysosome fusionfollowing phagocytosis (78). This phenomenon isseen only with localized juvenile periodontitis neu-trophils and only with A. actinomycetemcomitans.

Some controversy exists regarding the nature ofthese defects and the relationship of the apparentdysfunction to expression of disease in early-onsetperiodontal disease. The response of localized juven-ile periodontitis patients in the assay of chemotaxisis heterogeneous; a significant percentage of sub-jects, probably about 20-30% of subjects with local-ized juvenile periodontitis, consistently fail to mani-fest this defect in all studies. Since the subjectstested are clinically homogeneous, this raises thequestion of the relationship of the dysfunction toearly-onset periodontal disease. Second, there is aninteresting relationship between the race of thestudy population and chemotactic function. Schen-kein et al. (138) demonstrated that neutrophils fromperiodontally healthy black subjects are intrinsicallyless responsive in the chemotaxis assay than thosefrom white subjects. Since the bioassay assay re-quires testing of a healthy control subject at thesame time as an early-onset periodontal diseasesubject, the prevalence of the defect may have beensomewhat overestimated in studies in which racialmatching was not carried out. Nevertheless, this de-fective function could be an important etiologicalfactor in many cases of early-onset periodontal dis-ease or at least could serve as an important markerfor presumptive inflammatory dysfunction.

There is further controversy as to whether thisdysfunction is intrinsic to the cell itself (and thuslikely to be genetically determined) or is an alteredstate of cellular activation that results from the dis-ease process of early-onset periodontal disease. Theresults of most early studies in this area were inter-preted to indicate that an intrinsic cellular defectwas likely to account for the observed dysfunction.However, a recent series of experiments imply that

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Schenkein&Van Dvkethe defect may be acquired by the cells following invivo exposure to various desensitizing cytokines (2).Such cytokines could be produced as a consequenceof the response of leukocytes to infection an d sec-ondarily down-regulate the activity of neutrophils.However, only indirect evidence exists far this possi-bility; direct demonstration of the presence and ac-tivity of such cytokines in early-onset periodontaldisease sera would be necessary to begin to substan-tiate this hypothesis.

A number of observations indicate that the defectis likely to be intrinsic. These include the following:

In most of the initial studies in this area it wasobserved that the dysfunction cannot typically beinduced in normal cells by sera from localized juv-enile periodontitis subjects (8 7, 163). Thus insuf-ficient functional levels of cytokines are likely tobe present in localized juvenile periodontitis sera.Periodontal therapy does not appear to affect theexpression of the defect (87, 152), indicating thatthe putative absence of active periodontal infec-tions does not reverse the dysfunction.In adults who have verifiable histories of pre-viously active localized juvenile periodontitis,many have been found to display this leukocytedysfunction, implying that the disease process isunnecessary for demonstration of the neutrophildefect (163).There are several disorders in which there are gen-etically determined defects in phagocyte functionwith an associated presence of severe peri-odontitis (4 ,5, 7, 19, 20, 25, 33, 40, 52, 55, 76, 1741,including cyclic neutropenia (35), Chediak-Higa-shi syndrome (68, 154) chronic granulomatousdisease (38), azy leukocyte syndrome (106) hyper-immunoglobulinemia E syndrome (73), and dia-betes mellitus. Although this is certainly not directevidence of a genetic defect in localized juvenileperiodontitis, it is clear that a number of possiblegenetic abnormalities could account for the dys-function of neutrophils in localized juvenile peri-odontitis.A study of members of a limited number of fam-ilies with localized juvenile periodontitis probandsdemonstrated that the defect was demonstrableonly in affected family members. Inspection of thepedigrees demonstrated consistency of the neu-trophil dysfunction with a dominant mode of in-heritance of the trait (166).In the same study, the chemotactic defect couldbe detected prior to disease onset in some familymembers (166).

Perez et al. (123) demonstrated a diminution ofhigh affinity receptors for formyl peptides and de-creased amounts of formyl peptide receptor isa-forms in a patient with localized juvenile peri-odontitis, implying a possible defect in the struc-tural gene for such receptors in this individual.

These observations provide strong arguments for thelikelihood that the neutrophil chemotactic defects inearly-onset periodontal disease are intrinsic. Never-theless, some of these observations could be inter-preted as being consistent with intrinsic or acquiredneutrophil dysfunction. For example, in families inwhich the defect of neutrophil function correlatesstrongly with the expression of early-onset peri-odontal disease and when such functional defectsare detected prior to disease onset, it is also possiblethat the pattern of both disease expression and neu-trophil dysfunction could result from the passage ofan infectious agent within the family unit. Such anagent might infect a susceptible family member (thatis, an individual genetically susceptible to early-on-set periodontal disease) and secondarily induce de-fective neutrophil activity. Studies by Van Dyke et al.(161) have demonstrated that many periodontal bac-teria can induce such defects in vitro. Although ithas been reported that inhibitory bacteria such as A.actinomycetemcomitans may be found in nearly allmembers of early-onset periodontal disease families,the bacterial load is somewhat less in unaffectedfamily members and could account for the absenceof an effect on neutrophils (63). It is also noteworthythat a report of one family with a high prevalence oflocalized juvenile periodontitis failed to demonstratea perfect correlation between localized juvenile peri-odontitis and neutrophil chemotactic dysfunction,although other infectious diseases were observed insuch family members (170).

The data indicate that the phagocyte defect seenin early-onset periodontal disease, and especiallywithin a subset of localized juvenile periodontitissubjects, may be an important pathogenic mechan-ism worthy of further study. Data obtained so far onthe molecular mechanisms leading to expression ofthis defect are phenomenological to the extent thatthe laboratory observations of decreased receptorexpression and alterations in signal transductionphenomena can be explained by either a genetic orenvironmental hypothesis. However, the clinical ob-servations relating to the persistence of the defect inpost-localized juvenile periodontitis subjects and intreated patients imply an intrinsic defect, as do ex-periments in which patients sera are used to

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Earlv-onset periodontitisattempt to induce the response in healthy cells. It iscrucial to test both hypotheses, since strategies tocontrol the expression of disease would differ sub-stantially depending on the disease mechanism.

Genetics of early-onsetperiodontal diseaseA number of studies and case reports have demon-strated that early-onset periodontal disease is foundto aggregate within families (22, 34, 53 , 58, 74, 77,92, 104, 113, 115, 116, 120, 121, 130, 137, 147, 149,169, 170, 177). Furthermore, study of the families ofprobands with early-onset periodontal disease hasverified this. The aggregation of cases of early-onsetperiodontal disease in families implies that theremay be heritable risk factors for this disease, al-though the fact that early-onset periodontal diseasehas a bacterial etiology could implicate the trans-mission of infectious agents as the explanation forfamilial patterns. Hypotheses that accommodateboth explanations may be most correct; heritablefactors may be related to inflammatory or immunemechanisms that, if rendered ineffective or hyperac-tive due to defective or inactive genes, could en-hance the pathogenic potential of plaque bacteria insusceptible individuals. Studies have examined someof the possible genetic factors that could account forsuch susceptibility.Association of early-onset periodontal diseasewith genetic markersOne approach used by several authors to examinethe genetic risk for early-onset periodontal diseaseis to investigate its association with genetic markersknown to be related to other diseases. These studieshave been limited in scope and difficult to interpretbecause of the small numbers of subjects. Further-more, the accessibility to examining genetic loci thatlogically could relate to early-onset periodontal dis-ease has been limited. However, the explosive pro-gress in mapping the human genome in recent yearsis creating opportunities to explore the relationshipof early-onset periodontal disease to geneticmarkers.

The human leukocyte antigens (HLA), which playan important role in regulating and mediating im-mune processes, have been the subject of most ofthe association studies reported to date. The firstsuch reports by Terasaki et al. (155) and Kaslick et

al. (80) indicated that HLA-A2 and localized juvenileperiodontitis are negatively correlated. Subsequent-ly, Reinholdt et al. (128) reported increased frequen-cies of HLA-AS, HLA-A28, and HLA-Bw15 in local-ized juvenile periodontitis subjects and a somewhatdecreased frequency of HLA-A2. Both Cullinan (37)and Sax& &Koskimies (134) failed to detect signifi-cant association or linkage with human leukocyteantigens. In a study of rapidly progressive peri-odontitis subjects, Katz et al. (82) reported a higherfrequency of HLA-DR4 in affected subjects com-pared with controls. A number of other studies failedto conclusively demonstrate an association with hu-man leukocyte antigens.

Sofaer (146) recently compiled and analyzed datafrom a number of these studies and concluded thatthe strongest negative associations with early-onsetperiodontal disease are with HLA-A2 and that sub-jects with HLA-A9 or HLA-B15 may have an in-creased risk for localized juvenile periodontitis. Sofa-er concluded that the combined data from thesestudies failed to substantiate that human leukocyteantigen markers were associated with risk for or pro-tection from early-onset periodontal disease. As inmost studies of early-onset periodontal disease, onlysmall numbers of subjects were studied, and studieshave failed to associate different haplotypes with lo-calized juvenile periodontitis in different families.Failure to consistently demonstrate such associ-ations may relate to the different populationsstudied, and analyses could be confounded by suchfactors as the racial composition of the subjectgroups or geographic location.

A small number of studies have likewise examinedthe association of early-onset periodontal diseasewith blood group markers (79, 124). Such studieshave likewise failed to demonstrate an association ofearly-onset periodontal disease with such markers.

Genetic analysis of early-onset periodontaldisease: segregation and linkage analysisPedigree data from early-onset periodontal diseasefamilies have been used to attempt to determine thelikely mode(s) of inheritance of this disease, if any,using segregation analysis. Typically, early-onsetperiodontal disease probands are identified andfamily members are then studied to determine thepresence or absence of disease. The complicationsof performing such studies parallel the difficultiesoutlined previously relating to disease diagnosis andthe heterogeneous response of apparently clinicallyhomogeneous populations in assays of biological

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Schenkein& Van Dvkerisk factors and host responsiveness. Boughman etal. (14, 16) have outlined many of the factors relatingto the reliable diagnosis of family members thatcomplicate genetic studies:

Heterogeneity in the trait with regard to the rela-tive extent and severity of disease leads to prob-lems in defining the periodontal status of familymembers who may not demonstrate the classicalsigns of early-onset periodontal disease.The definitions of the various forms of early-onsetperiodontal disease overlap and are based on clin-ical history and presentation rather than on etiol-ogy and pathogenesis.The uncertain age of onset of early-onset peri-odontal disease and the complicating presence ofadult forms of periodontitis limit the ability to di-agnose individuals who are older than age 30-35years, complicate the diagnosis of healthy familymembers who are within the putative age rangefor disease onset and entirely exclude prepubertalfamily members from analysis.The expression of early-onset periodontal diseasemay be clinically modified in family members viaclinical therapeutic intervention, with the ex-tremes being tooth loss or resolution of diseasewith the regeneration of periodontal attachment.Systemic diseases that modulate the expression ofperiodontitis may be present in family members,thus complicating diagnosis.

The clinical impression that early-onset periodontaldisease is familial was developed many years ago.Early published studies (11 , 22, 34, 58) found fam-ilies with multiple affected siblings. These reportshad insufficient numbers of families to perform seg-regation analysis, but familial aggregation of the traitwas repeatedly detected. A number of genetic hypo-theses for the risk for early-onset periodontal diseasehave subsequently been proposed and tested. Themost commonly proposed mode of inheritance forearly-onset periodontal disease has been autosomalrecessive, as cases were infrequent in the parents ofaffected children (77, 132, 136). However, in many ofthese families a large percentage of the parents werenot examined or could not be diagnosed with anydegree of reliability.

Segregation analysis has been performed thatwould support the autosomal recessive model. Longet al. (91) compared the relative likelihood of auto-soma1 recessive and X-linked models in a study of 33early-onset periodontal disease families and ob-served that the autosomal recessive model was most

likely; an autosomal dominant model was not con-sidered. Beaty et al. (9) examined 28 families andfound that the data favored the autosomal recessivemodel. They observed, however, that transmission ofearly-onset periodontal disease in some families ap-peared to follow a dominant model, implying gen-etic heterogeneity in their group of families.

Transmission of early-onset periodontal diseasevia X-linked mode of inheritance has been proposed(54, 104, 1301, based on the observation that theprevalence of early-onset periodontal disease in fe-males appeared to be greater than in males and that,in some families, transmission through the motherappeared to be the most likely explanation of in-heritance. Recent data from a number of groups in-dicate, however, that the observed female prepon-derance of early-onset periodontal disease may bedue to ascertainment bias. Hart et al. (72) demon-strated that, in high-density families (those withmultiple affected individuals), the ratio of female-to-male probands is 2:l. However, for affected familymembers other than probands, equal prevalencerates for males and females were found. The recentepidemiological survey by Loe &Brown (90) also in-dicates equal prevalence rates for males and femaleswith early-onset periodontal disease, although someunequal rates may be detected within the localizedand generalized subforms. Hart et al. (71) have re-cently outlined arguments against X-linked trans-mission of early-onset periodontal disease.

Marazita et al. (100) recently performed segre-gation analysis of early-onset periodontal disease in100 families ascertained through 104 probands andcontaining 149 nuclear families with 631 individuals.Probands and family members were consideredaffected if they fit the diagnoses of localized juvenileperiodontitis or generalized juvenile periodontitis(including rapidly progressive periodontitis). Thisstudy demonstrated the following:0 The female preponderance of early-onset peri-

odontal disease appears to be an ascertainmentbias.The segregation analysis results were most con-sistent with an autosomal major locus being suf-ficient to explain the familial pattern of early-on-set periodontal disease.

0 A dominant mode of transmission was most likely,with a penetrance of about 70%.

0 The genetic etiology appeared to be the same forblack and non-black families.

0 There was significant heterogeneity in the par-ameter estimates: in particular, the allele fre-

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Early-onset periodontitisquency in blacks was 0.016 versus 0.001 in non-blacks.

Linkage studiesThe most convincing demonstration of autosomaldominant transmission of early-onset periodontaldisease was a study by Boughman et al. (17).Theyreported a large family with both localized juvenileperiodontitis and dentinogenesis imperfecta thatdemonstrated genetic linkage of localized juvenileperiodontitis (as well as of dentinogenesis imper-fecta) to a site on chromosome 4. Subsequently, Hartet al. (70) attempted to reproduce this study in amore heterogeneous population of early-onset peri-odontal disease families in which dentinogenesisimperfecta was not found. These families had gener-alized or localized early-onset periodontal disease orboth. The results of this analysis failed to confirmthe finding of linkage of early-onset periodontal dis-ease to chromosome 4. Although differences in clin-ical or genetic methods could explain the conflictingresults of these studies, it is just as likely that theresults further confirm the heterogeneity of early-onset periodontal disease. The Boughman familymay have a form of early-onset periodontal diseasedifferent from the majority of the families in the Hartstudy or even a genetically unique form of localizedjuvenile periodontitis.

Considerations for future studiesThe difficulties in studying such complex diseases asearly-onset periodontal disease arise from severalsources. The most basic difficulty is that early-onsetperiodontal disease may very well demonstrate agreat deal of heterogeneity, with consensus regard-ing clinical definitions based tenuously on clinicalrather than etiologic definitions. Until the variouspathological processes that can cause early-onsetperiodontal disease are defined, logical categoriz-ation and appropriate preventive and therapeuticmeasures may not become available.

There has been some controversy regarding theappropriate way to proceed, given these problems.Recent interest in the genetic aspects of early-onsetperiodontal disease has led to questions regardingthe most efficient manner to study a disease (or dis-eases) that has features that combine genetic andenvironmental risk factors that are modulated byhost responsiveness. Two fundamental approachesare feasible.

First, it has been asserted that further studies ofearly-onset periodontal disease should target thebiological risk factors or associated characteristics ofdisease, and from these should establish criteria forassigning cases or families to homogeneous group-ings. For example, one might place all the familieswith exclusively localized juvenile periodontitis sub-jects who demonstrate neutrophil chemotactic de-fects into one group and those without such defectsinto another group. These groups could in turn befurther subdivided into more homogeneous groupsbased on their immune responsiveness to bacterialgroups. If these chosen disease markers then segre-gate in families and if genetic loci related to the as-sociated trait@) are available for study at the mol-ecular level, then linkage studies could be carriedout in these relatively homogeneous groups. Al-though there are clues to possible candidate loci forperformance of linkage studies, these are few innumber and there are obvious inconsistencies intheir relationship to disease. Thus, analyses of largenumbers of families that are more homogeneous forsuch traits may be required, and such large numbersof families may not be available.

For example, the information about neutrophildysfunction and its relationship to early-onset peri-odontal disease can potentially identify geneticmarkers that could be associated with risk for dis-ease in some populations. Van Dyke et al. (164)havereported the abnormal expression of chemotacticpeptide receptors on localized juvenile periodontitisneutrophils as well as abnormal signal transduction,including decreased activity of the enzyme diglycer-ide kinase. Genetic probes are available or being de-veloped that could specifically examine the genescoding for these cellular proteins in localized juven-ile periodontitis families to determine whethermutations exist that both correlate with the occur-rence of disease and alter the function of these mol-ecules. Despite the inconsistencies observed bothbetween and within populations with regard to thisdefect and alternative hypotheses concerning itsbiochemical foundation, there are sufficient data tojustify the further examination of genes known to beassociated with neutrophil function and their associ-ation with the risk for early-onset periodontal dis-ease.

Second, since we lack fundamental understandingabout the specific genetic or environmental etiol-ogies of early-onset periodontal disease in its manymanifestations, an alternative approach would be tocollect large numbers of families with early-onsetforms of periodontitis and to examine not only spe-

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Schenkein& Van Dykecific candidate regions for genetic linkage or associ-ations but to also perform genome-wide searches forlinkage to loci without prior information on the re-lationship to etiology. This method could excludelarge regions of the genome and, given enough fam-ilies with common genetic etiologies, could identifygenetic risk factors in some families. The clear disad-vantage of this approach is the possibility that nopositive findings may occur due to the lack of stat-istical power to detect linkage should early-onsetperiodontal disease actually exist in many forms (forexample, each family may have a different gene orgenes conferring risk). However, new technology ingenetics as well as new statistical methods to dealwith heterogeneity problems are making it evermore feasible to conduct such searches in shortperiods of time.

The biological basis for these diseases must beunderstood better. For example, molecular genetictools may now be applied to answer questions relat-ing to how pathogenic bacteria are obtained andpassed on within family groupings (42, 43) and therelative pathogenicity of bacterial strains and theirrelationship to human disease. In addition, the abil-it y of extraoral environmental factors to modify riskfor early-onset periodontal disease should be ex-plored.

AcknowledgementsThis work was supported in part by grants DE08972,DE 10703and DE06436 from the National Institutesof Health.

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