Periodontology 2000, Vol. 6, 1994, 7-25 Printed in Denmark.
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Copvrinht 0 Munksnaard 1994
Early-onset periodontitis: systemic aspects of etiology and pathogenesis
HARVEY A. SCHENKEIN & THOMAS E. VANDYKE
Early-onset periodontal diseases comprise a group of clinical entities with the common attributes of an age of onset approximating puberty and relatively rapid destruction of the supporting tissues in apparently healthy individuals (26). These diseases are manifested clinically in several forms, including a localized form called localized juvenile periodontitis, involving only first molar and incisor teeth (and perhaps a very limited number of additional teeth), and a generalized form or forms in which many or all teeth are affected (6). The generalized form may further comprise a clinically heterogeneous group of diseases, including generalized juvenile periodontitis, rapidly progressive periodontitis and perhaps other forms. It remains unclear, however, whether the localized form and the generalized forms are distinct diseases. Although juvenile periodontitis was first formally defined by Baer in 1971 (6), the clinical syndrome has been recognized since the 1920s (59) and Orban & Weinman (117) used the term periodontosis to emphasize the prevailing belief that the etiology of the syndrome was degenerative and perhaps systemic. Modern concepts of the etiology and pathogenesis of this group of diseases are based on observations during the past 20 years demonstrating that systemic, local, and extraoral environmental factors contribute to its expression. Data from various subject populations further indicate that the etiological factors and pathogenic processes associated with disease are not consistent in all subjects. These observations, which will be discussed in more detail below, are the following:
The distribution of early-onset periodontal diseases in the population is familial, indicating that there are likely to be heritable risk factors for these
diseases. Risk factors related to bacterial floras, immunological responses, and leukocyte function are frequently different between affected individuals within the same family. The subgingival bacterial microflora associated with disease lesions contains bacterial species with some specificity. These bacteria are particularly associated with disease presence and progression; some, especially Actinobacillus actinomycetemcomitans, may invade the periodontal tissues and be resistant to conservative mechanical therapy. It is widely held, however, that specific types of bacterial plaque are necessary but not sufficient for disease expression. There is a remarkable systemic antibody response to A. actinomycetemcomitans in patients with early-onset periodontal disease, particularly the localized form. A large percentage of early-onset periodontal disease patients, up to 80% of localized juvenile periodontitis subjects in some populations, demonstrate a relative depression of systemic and local polyrnorphonuclear leukocyte (neutrophil) function related to defective numbers or function of relevant membrane receptors. Since other systemic syndromes in which neutrophil function is defective are usually associated with early and rapid periodontal attachment loss, it is thought that the defective neutrophil function in early-onset periodontal disease contributes to its pathogenesis. Many of the established attributes and correlates of early-onset periodontal disease, including its epidemiology, the antibody response to A. actinomyceterncomitans, neutrophil chemotactic function and serum immunoglobulin subclass concentrations, differ according to the racial characteristics of population groups.
etiology and pathogenesis. distinct diseases. 135) and suggest that the localized form progresses to involve additional teeth to become generalized. This review described rapidly progressive periodontitis (118) and juvenile periodontitis as distinct entities. 91. a variable that is ill defined at best for all forms of early-onset periodontal disease). has been clinically observed to progress and become generalized in some patients. Although localized juvenile periodontitis is classically defined as affecting only first molars and incisors. in fact. A number of investigators have published data
. and thus it is difficult to determine the initial manifestation of the periodontitis. Juvenile periodontitis is subdivided into a localized (localized juvenile periodontitis) and generalized (generalized juvenile periodontitis) form based on the number of affected teeth. the etiology of disease within one family may differ from that within another family. The chapter emphasizes the observations in the literature that point to various aspects of heterogeneity in earlyonset periodontal disease and assesses the significance of findings common to most investigations of these diseases.
A hallmark of early-onset periodontal disease is the variability of its expression in affected individuals. it is prudent to apply restrictive or demanding definitions of disease status on the pro-
The definitions and characteristics of rapidly progressive periodontitis and generalized juvenile periodontitis are nearly identical. published by the American Academy of Periodontology. severe periodontal destruction. attempts to categorize subforms in the absence of well-defined clinical and laboratory criteria or knowledge of the underlying genetic or environmental etiologies may be inappropriate. 92. Aspects of the systemic immune response.Schenkein & Van Dyke
The observations of bacterial. The generalized form(s) appears to display even greater heterogeneity of clinical expression. defective function of leukocytes and the genetic and environmental aspects of disease are emphasized. with both diseases subdivided into clinical subforms. However. there is information that would argue against the fidelity and exclusivity of these classifications.
It is apparent that the differential diagnosis of the various clinical forms of early-onset periodontal disease is fraught with potential inaccuracy and that the clinical manifestations of early-onset periodontal disease are quite heterogeneous. both occur in young adults (albeit with slightly differing ages of onset. Despite this attempt to split early-onset periodontal disease into a variety of distinct entities. Given the low prevalence of early-onset periodontal disease. Some cross-sectional studies of early-onset periodontal disease populations have indicated that the distinction between the localized and generalized forms is age-dependent (75. 113.
that indicate that localized juvenile periodontitis. with multiple affected teeth in no welldefined pattern. The localized form of early-onset periodontal disease. For example. 170). other tooth types are frequently observed to also be affected although the disease is clinically localized (21). are characterized by rapid.
Clinical aspects of early-onset periodontal disease
A recent review of the diagnostic characteristics of the periodontal diseases. and rapidly progressive periodontitis is divided into type A and type B subforms based on slightly differing age ranges and plaque and calculus accumulation. This frequently occurs during the putative age of onset of rapidly progressive periodontitis. in studies of families with early-onset periodontal disease. it is unlikely that this would be observed if these clinical types had different underlying etiologies and were. with the purpose of critically assessing current concepts of diagnosis.
This review examines recent information on the systemic aspects of early-onset periodontal disease. has attempted to define and delineate the various forms of early-onset periodontal disease (26). when followed longitudinally. However. have characteristic neutrophil defects in a subpopulation of subjects and have similar types of bacterial flora. generalized juvenile periodontitis and rapidly progressive periodontitis (as well as prepubertal periodontitis) coexist in the same nuclear families (15. The threshold for attachment loss measurement at affected sites that is used to determine whether a tooth site is affected with early-onset periodontal disease is likewise uncertain. immune and inflammatory phenomena outlined above may not be observed in all populations demonstrating the clinical characteristics of early-onset periodontal disease.
Initial descriptions of localized juvenile periodontitis emphasized that there was little apparent
. thus complicating the diagnosis of individual cases and possibly confounding the diagnosis of cases that are not longitudinally assessed. the definitive diagnosis of family members who appear to
be periodontally healthy 10-15 years beyond the age of puberty may not be entirely correct. 105. it is difficult to assign definitive diagnoses to family members who could be at risk for early-onset periodontal disease. Since epidemiological data and clinical observation indicate that onset of early-onset periodontal disease may occur at least until age 17 years (90) and possibly into the twenties. Studies have examined race as a variable in the assessment of pathogenic and etiological correlates of periodontal diseases and have indicated that differences between black and white subjects may be detected in assays of bacterial factors (139). and thus the diagnostic categories into which relatives are placed may be based on less restrictive criteria. The striking difference in the prevalence of early-onset periodontal disease between black and white populations raises interesting issues relating to the relative impact of cultural. The uncertain age of onset of early-onset periodontal disease is problematic in studies of its genetic and environmental etiologies. 66). It is likewise difficult to assign periodontal diagnoses to individuals in early-onset periodontal disease families with attachment loss who are beyond the age of 30 years due to uncertainties regarding their dental history and the possible onset of adult periodontitis. 85. It is widely held that localized juvenile periodontitis displays onset at or around puberty. there are numerous examples of onset of this disease at various ages after the expected time of puberty. Epidemiology Several authors have examined the distribution of early-onset periodontal disease in various populations by a number of methods. relatives of the proband may then display much less attachment loss. environmental and genetic factors on the risk for early-onset periodontal disease.to 17-year-old children in the United States has indicated that black Americans are at far higher risk for early-onset periodontal disease than are white Americans (90). Various laboratory assays that determine bacterial and host defense characteristics in individual subjects may be of only limited utility due to the variability of findings in different populations (see below). may be enhanced in certain racial populations. 12. 173). Although the diagnostic variables discussed above would affect the comparative results of such studies. however. and some recent data indicate that bone loss can be detected in the primary dentition of young children who eventually develop early-onset periodontal disease (141). It is thus likely that risk factors or protective responses for early-onset periodontal disease.
Bacterial etiology of early-onset periodontal disease
Although a thorough review of the bacteriological aspects of early-onset periodontal disease is beyond the scope of this chapter.Earlv-onset periodontitis
band (that is. 93. some trends are obvious in the prevalence rates in different parts of the world. and thus the categorization of subjects in studies of the etiology and pathogenesis of early-onset periodontal disease is not precise. 133. 127. Since the risk factors and pathogenic processes that lead to early-onset periodontal disease have not been completely elucidated it is difficult to assign an age at which the onset of early-onset periodontal disease is no longer possible. it is crucial to summarize some of this information since many of the systemic phenomena observed in early-onset periodontal disease relate to direct responses to oral bacteria. The clinical definitions of these diseases vary somewhat from author to author. leukocyte function (138) and immune responses (64. and the differentiation of adult-onset periodontitis from earlyonset periodontal disease may be unclear. However. with regard to the pattern of affected teeth and the amount of attachment loss required). The study of families with early-onset periodontal disease usually requires assignment of the presence or absence of a trait to family members who are at or beyond puberty. Age as a factor in determining diagnosis
A factor that contributes to both heterogeneity and difficulty in assigning diagnosis is the age of onset of early-onset periodontal disease. Thus. These prevalence estimates are consistent with those documented in other studies of different populations (10. whether genetic or environmental. 111. A recent survey of 14. An additional complication already cited is the observation that the generalized form of early-onset periodontal disease is often preceded by what appears to be a localized disease.
studies from several groups using a number of methods have indicated that fewer than 10 species are common in the flora of affected sites from early-onset periodontal disease subjects. actinomycetemcomitans in localized juvenile periodontitis plaque (13. In fact.Schenkein & Van Dyke
association between the severity of disease and the amount of plaque surrounding affected teeth. and the results differ from reports in which alternative methods were applied to bacteriological analysis. sample dispersion methods. Cultural analyses of the flora have frequently been inconsistent. 181). actinomycetemcomitans may account for a large percentage of localized juvenile periodontitis lesions. (143. the disease was thought to be dystrophic rather than infectious in origin. actinomycetemcomitans and localized juvenile periodontitis. However. 180. 145. Several methodological and biological factors could account for these differences:
The nonselective cultural method is relatively insensitive and can only detect organisms present at greater than 2-3% of the total plaque concentration in a given sample. Statistical evaluation of cultural bacterial data indicates that.1% of the cultivable microflora. In a few studies of localized juvenile periodontitis. depending on sampling methods. The “rapid” methods (immunofluorescence and DNA probes) may be excessively sensitive and potentially cross-reactive and detect effete and dead cells as well as viable bacteria. For example.
Species other than A. (112) and Slots et al. and that these bacteria have some commonality among the various forms of early-onset periodontal disease as well as adult periodontitis (67. Moore et al. about one-third of localized juvenile periodontitis lesions could be accounted for by A. However. 131. the bacteriology of localized and generalized early-onset periodontal disease lesions do not differ.
In addition to problematic methodological differences. Some of these may be accounted for as follows:
Species other than A. DNA probes and immunofluorescent determination of cell counts. microscopic methods. (108) have indicated that more than 50 bacterial species are present in subgingival plaque from localized juvenile periodontitis subjects that each comprise. The flora of generalized early-onset periodontal disease lesions is likewise complex (109). have reported much higher incidence rates and concentrations of A. it is possible that real differences exist in the bacterial etiology of early-onset periodontal disease lesions. Differences in diagnostic criteria. actinomycetemcoinitans in China. cultural bacteriology by a number of investigators using a variety of selective and nonselective media indicate that this organism is detectable in about one-third of affected localized juvenile periodontitis sites at greater than 1% of the flora. 96-99. 145) demonstrated that the microflora of early-onset periodontal disease contained some unusual and unique bacterial species. those that propagate attachment loss in existing lesions and those that fortuitously inhabit the niches provided by such lesions. Some of these issues are discussed by Moore (107) in his review of microbiological findings in periodontal diseases.
The most notorious relationship between specific bacterial infection and any periodontal disease is that between A. studies by Newman et al. using alternatives such as selective cultural methods. (69) reported no association of localized juvenile periodontitis with A. culture media. Some of these bacteria have become widely examined candidate pathogens because of supplementary data from studies of their virulence characteristics (144) and their ability to induce systemic and local immune responses in humans with periodontitis. Han et al. 182). This work led to a series of studies in several laboratories that defined the predominant microflora of early-onset periodontal disease. Most reports fail to account for disease activity as
. Cultural bacteriological studies have demonstrated that the subgingival flora in early-onset periodontal disease sites is complex. may give spurious results for the incidence of occurrence. study design and lack of statistical power in analyzing resulting data contribute to differences in results. greater than 0. actinomyce-
temcomitans. based on reported results in the literature. As reviewed in detail by Moore (1071. on the average. Other investigators. Some sites may harbor the organisms within the tissues and thus. little or no A. actinomycetemcomitans was detected (69). In the mid-1970s. studies of human early-onset periodontal disease have not yet definitively differentiated the organism or groups of organisms that initiate the lesions of early-onset periodontal disease. sampling techniques. actinomycetemcomitans may account for cases of localized juvenile periodontitis in some parts of the world. Moore (107) estimated that. 180. overall.
A limited number of studies of treatment of patients with localized juvenile periodontitis have shown that elimination of detectable levels of A.Earlv-onset Deriodontitis
a variable in assessing bacterial etiology of localized juvenile periodontitis. despite the complexity of the periodontal microflora in localized juvenile periodontitis lesions and some reports to the contrary. induction of immune responses in humans and virulence characteristics. However. actinomycetemcomitans. the invasive properties of A. Eubacterium species. we wish to review some current work that brings together immunological.A. actinomycetemcomitans (and Porphyromonas gingivalis) have less severe and extensive disease than do those who lack such antibody (62. this may be due to the likelihood that the populations studied are more heterogeneous and thus could represent subpopulations with different etiologies. 84. Campylobacter rectus and a number of spirochetes. actinomycetemcomitans found in most localized juvenile periodontitis patients as well as in some generalized juvenile periodontitis and rapidly progressive periodontitis patients. fibroblast and keratinocyte inhibitor.
Thus. actinomycetemcomitans did not appear to present in all active sites. bacteriological and genetic observations. early-onset periodontal disease subjects with such antibody responses against A. Serological data indicate that patients with earlyonset periodontal disease can have very high antibody titers against A. 63. actinomycetemcomitans has been detected within diseased periodontal tissues in affected sites in localized juvenile periodontitis patients (28). In a case reported by Haffajee et al. Despite the anomalies associated with A. 126. supplementary lines of evidence indict this organism as playing a role in many cases of early-onset periodontal disease. A. These include a leukotoxin. actinomycetemcomitans in early-onset periodontal disease. Each is emphasized here because of its documented presence in disease. A. indicating that they have been infected with the bacteria (50. 182). Ebersole (45) comprehensively reviewed current knowledge relating to antibody responses in early-onset periodontal disease as well as other forms of periodontal disease. Fusobacterium nucleatum.
indicate that A. actinomycetemcomitans displays a number of virulence characteristics that would support its capacity to induce or propagate early-onset periodontal disease. Furthermore. epidemiological. The bacteriology of generalized early-onset periodontal disease appears to be somewhat more complex than that of localized juvenile periodontitis (44. The bacteria that are apparently most representative of this diverse group of patients include P gingivalis and A. 109. actinomycetemcomitans as well as Prevotella intermedia. collagenase and lipopolysaccharides. 57. 47). compelling data
. 89. actinomycetemcomitans can be demonstrated in high prevalence and relatively high concentration in relatives of individuals with early-onset periodontal disease in the absence of periodontal attachment loss (63). 156.As a group. and we will thus not review them here. actinomycetemcomitans can be demonstrated in vitro (148). These include:
A. Bacteroides forsythus. actinomycetemcomitans through modalities including scaling.
Immunological aspects of earlyonset periodontal disease
Studies relating to immune responses in early-onset periodontal disease have emphasized humoral antibody responses to periodontal bacteria. (67). actinomycetemcomitans is an important pathogen in this disease and likely to be responsible for a large percentage of associated lesions. since we are attempting to emphasize new directions in the study of early-onset periodontal disease and in developing concepts that better integrate current knowledge of its etiology and pathogenesis. root planing. This is due to the remarkable systemic antibody response to A. Ebersole thoroughly treated most aspects of the antibody response to periodontal microorganisms. 65). surgery and antibiotic treatment resulted in cessation of attachment loss as well as diminution of the antibody response (29. 172). lymphocyte suppression factor. raising questions as to the relative role of this organism as a pathogen as opposed to a marker of disease. Current work relating to immune responses in early-onset periodontal disease have focused upon the following: the nature and function of specific antigens reacting with antibodies in early-onset periodontal disease patients.
actinomycetemcomitans is an important pathogen in early-onset periodontal disease and data demonstrating the virulence characteristics of this organism. actinomycetemcomitans have been reported. Generalized early-onset periodontal disease could result from infection with any of a number of organisms or could require infection with multiple species. This relative lack of specificity could be explained in a number of ways.
The most clear-cut relationship between specific immune responsiveness and any periodontal disease is that between the antibody response to A. a great deal of effort has been exerted in defining this response and understanding its significance. its dependence on persisting antigen and the alterations of both the disease process and the microflora by such environmental factors as therapy. The subject populations in studies of. elevated responses are absent (66). The generalized early-onset periodontal disease group. actinomycetemcomitans. 171. There is clearly some heterogeneity in the response of early-onset periodontal disease patients to A. could at best be diagnosed with 60% accuracy. actinomycetemcomitans. in localized juvenile periodontitis patients in Korea (30). actinomycetemcomitans and E nucleatum. for example.Schenkein & Van Dyke
the nature and function of antibodies in early-onset periodontal disease subjects. Examination of the immunoglobulin G (IgG) response in generalized early-onset periodontal disease indicates that about 40-50% of such patients demonstrate positive responses to this organism (65. actinomycetemcomitans among family members with clinically similar forms of early-onset periodontal disease and. Antibody responses in patients with generalized early-onset periodontal disease may be characterized by hyperresponsiveness to the elements of subgingival plaque. Since that time. generalized earlyonset periodontal disease and adult periodontitis subjects. some Eubacterium species. in some families. (65) examined the antibody responses of 242 individuals to over 20 bacterial strains most commonly cultured from the subgingival microbiota of localized juvenile periodontitis. and C. 110. which contained individuals with elevated antibody responses to a large number of organisms. When generalized earlyonset periodontal disease subjects were misclassified as periodontally healthy due to their weak or
. This phenomenon has been reproduced in countries with different racial demographics than the United States. and antibody responses in specific patient groups. for example. 49. (56) first described the presence of precipitating antibody to A. demonstrate elevated antibody levels to the tested antigens (65. 153. Gunsolley et al. 172). 153). I? intermedia. Genco et al. Williams et al. In an effort to determine the diagnostic utility of such antibody responses as well as the heterogeneity of antibody responses within patient groups. antibiotic treatment and patients’ general health status. elevations in antiA. indicating that this response is fundamental to localized juvenile periodontitis. for example. actinomycetemcomitans and localized juvenile periodontitis. This may in part be explained by the dependence of this response on race (dealt with in more detail later)
or on other environmental factors that influence familial immune responses. Not all subjects with localized juvenile periodontitis. Increases in antibody in all serum isotypes have been reported (153). The most common components of the flora to which elevated levels of antibody are detected are A. The response to l? gingivalis demonstrates the heterogeneity of the generalized early-onset periodontal disease group with respect to antibody response. A large percentage of localized juvenile periodontitis patients demonstrate remarkably high antibody titers to A. This may not be surprising in view of the dynamic nature of the antibody response. The limited number of organisms for which localized juvenile periodontitis sera are elevated permitted accurate diagnosis in nearly 80% of cases based on the antibody response to A. l? gingivalis. 157. 156. rectus (46. The antibody responses detected in generalized early-onset periodontal disease groups are typically more nonspecific than those seen in localized juvenile periodontitis. actinomycetemcomitans in localized juvenile periodontitis sera. 110). 102. 103. leading to reactivity to multiple bacterial types. In view of the prevailing dogma that A. understanding the role of this host response may be essential in controlling this disease. actinomycetemcomitans. Other studies of early-onset periodontal disease families have demonstrated inconsistencies in the response to anti-A. rapidly progressive periodontitis may include patients with differing underlying etiologies and susceptibility to different bacterial pathogens. 151. China (158) and Chile (92). (177) found that the occurrence of a positive antibody response did not necessarily correlate with disease presence or even the presence of the bacterium in a family.
indirect associations.In view of the racial
. These data plus the observation that the presence of antibody to A. These are reviewed below. actinomycetemcomitans apparently have a milder extent and severity of disease. actinomycetemcomitans responses was in reality a racially determined pattern (66). This implies that anti-A. actinomycetemcomitans could not account for these differences. There appears to be an interesting interplay between the epidemiological and immunological aspects of the antibody response to A. high titer sera from localized juvenile periodontitis patients frequently contain antibody reactive to the leukotoxin of A. (142) have observed that sera from rapidly progressive periodontitis patients with antibody titers equivalent to those in periodontally healthy individuals induce lower chemiluminescence responses. Correlative data would indicate that early-onset periodontal disease patients with positive antibody responses to P gingivalis have less severe disease than those who do not (62). particularly in the generalized early-onset periodontal disease subpopulation. however. actinomycetemcomitans antibodies. An interpretation of these data is that earlyonset periodontal disease subjects with antibody responses against antigens of P gingivalis and A. actinomycetemcomitans and functionally inhibit leukotoxic activity in vitro (48). Thus. gender and the presence of A.Early-onset periodontitis
absent antibody responses. The literature relating to antibody responses in early-onset periodontal disease focuses on the heterogeneity of responsiveness. actinomycetemcomitans as well as higher levels of anti-A. For example. Further examination of antibody titers to organisms that predominate in the cultivable flora of the generalized early-onset periodontal disease group indicated that the racial dependence of this response was evident almost exclusively for A. (160) have further demonstrated the function of such antibodies as determined by chemiluminescence responses. the function of such antibody may be inferior. A. that is. (176) have examined the nature of such antibody and found that the antibody avidities in both seropositive and seronegative rapidly progressive periodontitis subjects are equivalent and significantly lower than those in periodontally healthy controls. For this reason. (27) have found that treatment of rapidly progressive periodontitis patients resulted in significant increases in antibody avidity against both protein and carbohydrate antigens. the correlation of this activity with improved clinical signs or prognosis has not been demonstrated. We (66) examined the demographic and clinical variables related to such responses in earlyonset periodontal disease patients. actinomycetemcomitans. Whitney
et al. investigators have been examining the functional role of such antibodies. However. actinomycetemcomitans correlates with the extent and severity of disease in early-onset periodontal disease patients may argue for a protective role within the localized juvenile periodontitis population but a qualitatively inferior antibody response in rapidly progressive periodontitis subjects. the IgG fraction of such sera promote ingestion of the organism by neutrophils. Furthermore. they had significantly more severe clinical disease than subjects who were misclassified as localized juvenile periodontitis subjects (due to their more robust antibody responses). Chen et al. despite high antibody titers to P gingiualis in about half of rapidly progressive periodontitis patients. This relationship held whether or not the periodontally healthy subjects were members of early-onset periodontal disease families or were independently ascertained. we have found that some aspects of the epidemiology. Sjostrom et al. The function of antibody reactive with P gingivalis is likewise uncertain. whether with early-onset periodontal disease or periodontally healthy. A possible functional role of antibodies in protection against early-onset periodontal disease is also apparent from the results of the study described above. actinomycetemcomitans antibodies in rapidly progressive periodontitis subjects may be less protective than those in healthy individuals. gingival inflammation. in particular. However. their relatives and periodontally healthy age-matched controls and found that what initially appeared to be a familial pattern in anti-A. immune response and genetic risk for early-onset periodontal disease appear to have some remarkably interesting interrelationships that explain part of the apparent heterogeneity in such responses. Black subjects. actinomycetemcomitans. In pursuing the significance of the antibody response to. This finding emphasizes that the heterogeneity of the immune response reflects the clinical and etiological heterogeneity within the population diagnosed as having generalized early-onset periodontal disease. These data are. Baker &Wilson (8) have observed that localized juvenile periodontitis sera contain opsonic anti-A. demonstrated a higher prevalence of positive antibody responses to A. actinomycetemcomitans serotype b than white subjects. age. Other variables such as plaque scores. actinomycetemcomitans serotypes b and c (64). Underwood et al.
This observation is intriguing in view of the prevalent notion that antibodies of the IgG2 subclass are poor opsonins and poor activators of the complement system. and that the IgG2 and IgAl subclasses produce the major response. Lu et al. generalized early-onset periodontal disease (comprising both generalized juvenile periodontitis and rapidly progressive periodontitis subjects) and adult periodontitis and in periodontally healthy individuals. The high-responder patients had about 80 Fglml of IgG reactive with the immunodominant antigen. the vast
majority of which was IgG2. (119. These data are reminiscent of the results of earlier studies (81. who found no differences in IgG subclass levels in localized juvenile periodontitis patients compared with healthy controls. 140) as a polysaccharide side chain of lipopolysaccharide. Lu et al. (23) identified the immunodominant antigen of A. One approach taken by several investigators has been to attempt to identify the antigen or antigens responsible for induction of high antibody concentrations against A. however. Furthermore. actinomycetemcomituns. The studies by Wilson & Hamilton (1781. (18) reported on the IgA subclass response to A.6 pglml for IgG3 and 0. (95) measured total IgG subclass serum concentrations in patients with localized juvenile periodontitis. (176) further illustrated this point by examining serum IgG responses and IgG subclass distributions to P gingivalis in subjects with rapidly progressive periodontitis. performed using a small number of subjects. actinomycetemcomitans was in the IgG2 subclass. we felt that examination of IgG subclass concentrations as a function of both race and periodontal diagnosis was indicated. This finding contrasts. Wilson & Hamilton (178) determined that the dominant response of localized juvenile periodontitis patients to lipopolysaccharides from A. these data implied that there could be a more global difference in the control of IgG2 levels in localized juvenile periodontitis patients than in the rest of the population. 125) in which elevated levels of IgG were found in early-onset periodontal disease patients. in all diagnostic categories.Schenkein & Van Dyke
dependence evident in epidemiological studies of early-onset periodontal disease and the observation that white subjects rarely have localized juvenile periodontitis. since localized juvenile periodontitis subjects are predominantly black and we have noted significant differences between black and white subjects in antibody titers. thus casting some doubt on the protective quality of the majority of the antibody reactive with this organism. Brown et al. Furthermore. 88. 0. Califano et al. a comparison of the immunodominant antigen in black and white subjects with elevated anti-A.and race-matched controls. actinomycetemcomituns antibody titers also have higher total serum IgG2 concentrations than do age. the response to several of these antigens. are under genetic control and are racially influenced (GO. (175). actinomycetemcomitans. localized juvenile periodontitis subjects have 30-40% more IgG2 than race-matched controls. comparing levels in black and white racial subgroups. actinomycetemcomitans is quantitative rather than qualitative. It has been established with other carbohydrate antigens and with lipopolysaccharide antigens of other bacterial species that there is subclass specificity in the antibody response to such compounds. uctinomycetemcomitans titers demonstrated that the immunodominant antigen was identical in both racial groups (24). which was subsequently defined by Wilson & Schifferle (179) and Sims et al. (94) have also demonstrated that titers to this antigen are highest in the IgG2 subclass. They reported that the IgG2 levels of localized juvenile periodontitis patients reactive with lipopolysaccharides averages 136 pg/ml versus only 7. the interaction of race and antibody responses to clinical forms of early-onset periodontal disease was pursued further.01 pglml for IgG4. actinomycetemcomituns. In addition. however. Since only a small percentage of the increase in total IgG2 in these sera can be accounted for by the increase in antibody titer against this single organism.8 pg/ml for IgG1. implied that individuals with localized juvenile periodontitis who have high anti-A. notably the capsular polysaccharide antigens of Huemophilus infuenzae. We hypothesized that this antigen may only induce high antibody levels in black early-onset periodontal disease subjects. The results indicated that both race and periodontal diagnosis affect serum IgG2 levels. actinonzycetemcomitans to determine the class and subclass specificity of the antibody response to A. Black subjects in general. have higher IgG2 levels than do ageand diagnosis-matched white subjects. Several groups have therefore analysed the IgG subclass response to A. This indicates that the effect of race on the response to A. indicating that the IgAl response dominated. Whitney et al. actinomycetemcomituns serotype b as the serotype specific carbohydrate antigen. with earlier studies by Waldrop et al.
. They observed that the predominant response to P gingivalis was also in the IgG2 subclass and that the relative avidity of the response in high-titer individuals was low. 61).
This genetic model is significant even after correcting for localized juvenile periodontitis status and thus follows a genetic model independent of the segregation of early-onset periodontal disease in these families.Earlv-onset Deriodontitis
whereas generalized early-onset periodontal disease subjects had IgG2 levels that were virtually identical with their age-matched healthy controls. However. plus 511 unrelated individuals and performed genetic analysis. a relative defect in 15-lipoxygenase activity in neutrophils from both localized juvenile periodontitis and rapidly progressive periodontitis patients has been observed (114). signal transduction abnormalities have been identified (1. 122. 86. DeNardin et al. 39. 2. consistently fail to manifest this defect in all studies. 120. it was observed that a substantial percentage of individuals with localized juvenile periodontitis demonstrate a relative defect in the ability of their peripheral blood neutrophils to respond to chemotactic agents in a bioassay of chemotaxis (31. there is an interesting relationship between the race of the study population and chemotactic function. Variance component analysis indicated that about 25% of the total variance in IgG2 levels was estimated to be due to genetic factors and about 75% due to environmental factors. localized juvenile periodontitis neutrophils have been shown to exhibit a specific defect of bacterial activity towards A. Since the bioassay assay requires testing of a healthy control subject at the same time as an early-onset periodontal disease subject. has been observed (168). The results of most early studies in this area were interpreted to indicate that an intrinsic cellular defect was likely to account for the observed dysfunction. (138) demonstrated that neutrophils from periodontally healthy black subjects are intrinsically less responsive in the chemotaxis assay than those from white subjects. 165) as well as of a chemotaxis-related surface glycoprotein designated GP 150 (167). and that the best-fitting model is the autosomal codominant major locus model. 159) including abnormal cell mem-
brane calcium channels. Finally. although some investigators have been unable to demonstrate this phenomenon (83. In addition. have confirmed and extended this observation. We have begun to explore genetic factors that could explain the ability of some groups to produce high levels of IgG2. actinomycetemcomitans that comprises defective phagosome-lysosome fusion following phagocytosis (78). 162). leading to chronic elevation of protein kinase C activity. enhanced production of superoxide. 36. a recent series of experiments imply that
. In addition. Several groups (3. Since the subjects tested are clinically homogeneous. Genetic segregation analysis indicated that transmission of IgG2 concentration is consistent with a Mendelian major locus. There is further controversy as to whether this dysfunction is intrinsic to the cell itself (and thus likely to be genetically determined) or is an altered state of cellular activation that results from the disease process of early-onset periodontal disease. the prevalence of the defect may have been somewhat overestimated in studies in which racial matching was not carried out. This phenomenon is seen only with localized juvenile periodontitis neutrophils and only with A. Marazita et al. This indicates that a portion of the variation of IgG2 levels in the population can be accounted for by inheritance. Nevertheless. Schenkein et al. The response of localized juvenile periodontitis patients in the assay of chemotaxis is heterogeneous. Some controversy exists regarding the nature of these defects and the relationship of the apparent dysfunction to expression of disease in early-onset periodontal disease. Second. 32. The resultant elevation of diacylglycerol. In addition. 87). probably about 20-30% of subjects with localized juvenile periodontitis. (101) determined IgG2 levels in 122 families. 121. 129). 51. 150. this defective function could be an important etiological factor in many cases of early-onset periodontal disease or at least could serve as an important marker for presumptive inflammatory dysfunction. this raises the question of the relationship of the dysfunction to early-onset periodontal disease. Examination of neutrophils from patients with the chemotactic defect indicates that such cells have a relative deficiency of surface receptors for chemotactic agents such as formyl peptides and the complement-derived chemotactic factor C5a (164. (41) have further demonstrated altered reactivity of antibodies directed at the formyl peptide receptor with localized juvenile periodontitis neutrophils. actinomycetemcomitans. increased intracellular diacylglycerol and decreased diglyceride kinase activity.
Neutrophil dysfunction in earlyonset periodontal disease
In the late 1970s. is hypothesized to account for the functional abnormalities in localized juvenile periodontitis neutrophils. a significant percentage of subjects. including nuclear and extended early-onset periodontal disease families and twin pairs. an oxygen metabolite important in antibacterial activity.
25. only indirect evidence exists far this possibility. These observations provide strong arguments for the likelihood that the neutrophil chemotactic defects in early-onset periodontal disease are intrinsic. 40. Although this is certainly not direct evidence of a genetic defect in localized juvenile periodontitis. Such cytokines could be produced as a consequence of the response of leukocytes to infection and secondarily down-regulate the activity of neutrophils. an individual genetically susceptible to early-onset periodontal disease) and secondarily induce defective neutrophil activity. implying that the disease process is unnecessary for demonstration of the neutrophil defect (163). it is also possible that the pattern of both disease expression and neutrophil dysfunction could result from the passage of an infectious agent within the family unit. many have been found to display this leukocyte dysfunction. (161) have demonstrated that many periodontal bacteria can induce such defects in vitro. 5. the chemotactic defect could be detected prior to disease onset in some family members (166). These include the following: In most of the initial studies in this area it was observed that the dysfunction cannot typically be induced in normal cells by sera from localized juvenile periodontitis subjects (8 7. 154) chronic granulomatous disease (38). There are several disorders in which there are genetically determined defects in phagocyte function with an associated presence of severe periodontitis (4. may be an important pathogenic mechanism worthy of further study. in families in which the defect of neutrophil function correlates strongly with the expression of early-onset periodontal disease and when such functional defects are detected prior to disease onset. actinomycetemcomitans may be found in nearly all members of early-onset periodontal disease families. including cyclic neutropenia (35). 163). and especially within a subset of localized juvenile periodontitis subjects. implying a possible defect in the structural gene for such receptors in this individual. Studies by Van Dyke et al. In the same study. 152). It is also noteworthy that a report of one family with a high prevalence of localized juvenile periodontitis failed to demonstrate a perfect correlation between localized juvenile periodontitis and neutrophil chemotactic dysfunction. it is clear that a number of possible genetic abnormalities could account for the dysfunction of neutrophils in localized juvenile periodontitis. 20. The data indicate that the phagocyte defect seen in early-onset periodontal disease. 55. Although it has been reported that inhibitory bacteria such as A. Nevertheless. the bacterial load is somewhat less in unaffected family members and could account for the absence of an effect on neutrophils (63). 52. A number of observations indicate that the defect is likely to be intrinsic. 1741. direct demonstration of the presence and activity of such cytokines in early-onset periodontal disease sera would be necessary to begin to substantiate this hypothesis.
Perez et al. Such an agent might infect a susceptible family member (that is. 19. Inspection of the pedigrees demonstrated consistency of the neutrophil dysfunction with a dominant mode of inheritance of the trait (166). Thus insufficient functional levels of cytokines are likely to be present in localized juvenile periodontitis sera. and diabetes mellitus. A study of members of a limited number of families with localized juvenile periodontitis probands demonstrated that the defect was demonstrable only in affected family members. (123) demonstrated a diminution of high affinity receptors for formyl peptides and decreased amounts of formyl peptide receptor isaforms in a patient with localized juvenile periodontitis. as do experiments in which patients’ sera are used to
. Data obtained so far on the molecular mechanisms leading to expression of this defect are phenomenological to the extent that the laboratory observations of decreased receptor expression and alterations in signal transduction phenomena can be explained by either a genetic or environmental hypothesis.lazy leukocyte syndrome (106) hyperimmunoglobulinemia E syndrome (73).Schenkein & Van Dvke
the defect may be acquired by the cells following in vivo exposure to various desensitizing cytokines (2). However. indicating that the putative absence of active periodontal infections does not reverse the dysfunction. 7. For example. However. Periodontal therapy does not appear to affect the expression of the defect (87. some of these observations could be interpreted as being consistent with intrinsic or acquired neutrophil dysfunction. 76. 33. Chediak-Higashi syndrome (68. In adults who have verifiable histories of previously active localized juvenile periodontitis. although other infectious diseases were observed in such family members (170). the clinical observations relating to the persistence of the defect in post-localized juvenile periodontitis subjects and in treated patients imply an intrinsic defect.
which play an important role in regulating and mediating immune processes. 53. and HLA-Bw15 in localized juvenile periodontitis subjects and a somewhat decreased frequency of HLA-A2. (155) and Kaslick et
. In a study of rapidly progressive periodontitis subjects. have been the subject of most of the association studies reported to date.Earlv-onset periodontitis attempt to induce the response in healthy cells. 170. early-onset periodontal disease probands are identified and family members are then studied to determine the presence or absence of disease. 169. and studies have failed to associate different haplotypes with localized juvenile periodontitis in different families. These studies have been limited in scope and difficult to interpret because of the small numbers of subjects. Katz et al. Subsequently. It is crucial to test both hypotheses. Failure to consistently demonstrate such associations may relate to the different populations studied. Sofaer concluded that the combined data from these studies failed to substantiate that human leukocyte antigen markers were associated with risk for or protection from early-onset periodontal disease. if rendered ineffective or hyperactive due to defective or inactive genes. 58. A number of other studies failed to conclusively demonstrate an association with human leukocyte antigens. The human leukocyte antigens (HLA). only small numbers of subjects were studied. However. 120. using segregation analysis. HLA-A28. 130. The first such reports by Terasaki et al. heritable factors may be related to inflammatory or immune mechanisms that. Both Cullinan (37) and Sax& & Koskimies (134) failed to detect significant association or linkage with human leukocyte antigens. 147. study of the families of probands with early-onset periodontal disease has verified this. Furthermore. As in most studies of early-onset periodontal disease. 121. Hypotheses that accommodate both explanations may be most correct. the accessibility to examining genetic loci that logically could relate to early-onset periodontal disease has been limited. 92. The complications of performing such studies parallel the difficulties outlined previously relating to disease diagnosis and the heterogeneous response of apparently clinically homogeneous populations in assays of biological
Genetics of early-onset periodontal disease
A number of studies and case reports have demonstrated that early-onset periodontal disease is found to aggregate within families (22. Reinholdt et al. 149. 124). The aggregation of cases of early-onset periodontal disease in families implies that there may be heritable risk factors for this disease. the explosive progress in mapping the human genome in recent years is creating opportunities to explore the relationship of early-onset periodontal disease to genetic markers. (128) reported increased frequencies of HLA-AS. 77. 34. 74. Such studies have likewise failed to demonstrate an association of early-onset periodontal disease with such markers. and analyses could be confounded by such factors as the racial composition of the subject groups or geographic location. since strategies to control the expression of disease would differ substantially depending on the disease mechanism.
Association of early-onset periodontal disease with genetic markers One approach used by several authors to examine the genetic risk for early-onset periodontal disease is to investigate its association with genetic markers known to be related to other diseases. A small number of studies have likewise examined the association of early-onset periodontal disease with blood group markers (79. 116. 177). (80) indicated that HLA-A2 and localized juvenile periodontitis are negatively correlated. al. Furthermore. Genetic analysis of early-onset periodontal disease: segregation and linkage analysis Pedigree data from early-onset periodontal disease families have been used to attempt to determine the likely mode(s) of inheritance of this disease. (82) reported a higher frequency of HLA-DR4 in affected subjects compared with controls. Typically. 113. Sofaer (146) recently compiled and analyzed data from a number of these studies and concluded that the strongest negative associations with early-onset periodontal disease are with HLA-A2 and that subjects with HLA-A9 or HLA-B15 may have an increased risk for localized juvenile periodontitis. 115. although the fact that early-onset periodontal disease has a bacterial etiology could implicate the transmission of infectious agents as the explanation for familial patterns. 104. Studies have examined some of the possible genetic factors that could account for such susceptibility. if any. could enhance the pathogenic potential of plaque bacteria in susceptible individuals. 137.
as cases were infrequent in the parents of affected children (77. the ratio of female-tomale probands is 2:l. (100) recently performed segregation analysis of early-onset periodontal disease in 100 families ascertained through 104 probands and containing 149 nuclear families with 631 individuals. equal prevalence rates for males and females were found. transmission through the mother appeared to be the most likely explanation of inheritance. 16) have outlined many of the factors relating to the reliable diagnosis of family members that complicate genetic studies: Heterogeneity in the trait with regard to the relative extent and severity of disease leads to problems in defining the periodontal status of family members who may not demonstrate the classical signs of early-onset periodontal disease. the allele fre-
. Segregation analysis has been performed that would support the autosomal recessive model. Marazita et al. 58) found families with multiple affected siblings. however. in some families. 132. Long et al. Hart et al. implying genetic heterogeneity in their group of families. The segregation analysis results were most consistent with an autosomal major locus being sufficient to explain the familial pattern of early-onset periodontal disease. (91) compared the relative likelihood of autosoma1 recessive and X-linked models in a study of 33 early-onset periodontal disease families and observed that the autosomal recessive model was most
likely. an autosomal dominant model was not considered. 136). that transmission of early-onset periodontal disease in some families appeared to follow a dominant model. The definitions of the various forms of early-onset periodontal disease overlap and are based on clinical history and presentation rather than on etiology and pathogenesis. Early published studies (11. Boughman et al. that the observed female preponderance of early-onset periodontal disease may be due to ascertainment bias. The clinical impression that early-onset periodontal disease is familial was developed many years ago. However. with the extremes being tooth loss or resolution of disease with the regeneration of periodontal attachment. Recent data from a number of groups indicate. 22. (9) examined 28 families and found that the data favored the autosomal recessive model. with a penetrance of about 70%. However. The most commonly proposed mode of inheritance for early-onset periodontal disease has been autosomal recessive. Systemic diseases that modulate the expression of periodontitis may be present in family members. in many of these families a large percentage of the parents were not examined or could not be diagnosed with any degree of reliability. Beaty et al. A dominant mode of transmission was most likely. (71) have recently outlined arguments against X-linked transmission of early-onset periodontal disease. The genetic etiology appeared to be the same for black and non-black families. The expression of early-onset periodontal disease may be clinically modified in family members via clinical therapeutic intervention. 1301. 104. in high-density families (those with multiple affected individuals). The uncertain age of onset of early-onset periodontal disease and the complicating presence of adult forms of periodontitis limit the ability to diagnose individuals who are older than age 30-35 years.Schenkein & Van Dvke
risk factors and host responsiveness. thus complicating diagnosis. Probands and family members were considered affected if they fit the diagnoses of localized juvenile periodontitis or generalized juvenile periodontitis (including rapidly progressive periodontitis). A number of genetic hypotheses for the risk for early-onset periodontal disease have subsequently been proposed and tested. These reports had insufficient numbers of families to perform segregation analysis. but familial aggregation of the trait was repeatedly detected. They observed. based on the observation that the prevalence of early-onset periodontal disease in females appeared to be greater than in males and that. The recent epidemiological survey by Loe & Brown (90) also indicates equal prevalence rates for males and females with early-onset periodontal disease. for affected family members other than probands. This study demonstrated the following:
The female preponderance of early-onset periodontal disease appears to be an ascertainment bias. (72) demonstrated that. Hart et al. although some unequal rates may be detected within the localized and generalized subforms. however. (14. Transmission of early-onset periodontal disease via X-linked mode of inheritance has been proposed (54. There was significant heterogeneity in the parameter estimates: in particular. 34. complicate the diagnosis of healthy family members who are within the putative age range for disease onset and entirely exclude prepubertal family members from analysis.
Considerations for future studies
The difficulties in studying such complex diseases as early-onset periodontal disease arise from several sources. Genetic probes are available or being developed that could specifically examine the genes coding for these cellular proteins in localized juvenile periodontitis families to determine whether mutations exist that both correlate with the occurrence of disease and alter the function of these molecules. Although there are clues to possible candidate loci for performance of linkage studies. including decreased activity of the enzyme diglyceride kinase. Two fundamental approaches are feasible. given these problems. Van Dyke et al. then linkage studies could be carried out in these relatively homogeneous groups. These groups could in turn be further subdivided into more homogeneous groups based on their immune responsiveness to bacterial groups. an alternative approach would be to collect large numbers of families with early-onset forms of periodontitis and to examine not only spe-
. it has been asserted that further studies of early-onset periodontal disease should target the biological risk factors or associated characteristics of disease. These families had generalized or localized early-onset periodontal disease or both. Until the various pathological processes that can cause early-onset periodontal disease are defined.
First.016 versus 0. one might place all the families with exclusively localized juvenile periodontitis subjects who demonstrate neutrophil chemotactic defects into one group and those without such defects into another group. The most basic difficulty is that early-onset periodontal disease may very well demonstrate a great deal of heterogeneity. Recent interest in the genetic aspects of early-onset periodontal disease has led to questions regarding the most efficient manner to study a disease (or diseases) that has features that combine genetic and environmental risk factors that are modulated by host responsiveness. For example. Thus. There has been some controversy regarding the appropriate way to proceed. Subsequently. The results of this analysis failed to confirm the finding of linkage of early-onset periodontal disease to chromosome 4. there are sufficient data to justify the further examination of genes known to be associated with neutrophil function and their association with the risk for early-onset periodontal disease. (70) attempted to reproduce this study in a more heterogeneous population of early-onset periodontal disease families in which dentinogenesis imperfecta was not found. Second. and from these should establish criteria for assigning cases or families to homogeneous groupings.001 in nonblacks. For example. it is just as likely that the results further confirm the heterogeneity of earlyonset periodontal disease. these are few in number and there are obvious inconsistencies in their relationship to disease. and such large numbers of families may not be available. They reported a large family with both localized juvenile periodontitis and dentinogenesis imperfecta that demonstrated genetic linkage of localized juvenile periodontitis (as well as of dentinogenesis imperfecta) to a site on chromosome 4. Although differences in clinical or genetic methods could explain the conflicting results of these studies.Early-onset periodontitis
quency in blacks was 0. Hart et al. If these chosen disease markers then segregate in families and if genetic loci related to the associated trait@) are available for study at the molecular level. with consensus regarding clinical definitions based tenuously on clinical rather than etiologic definitions. Linkage studies The most convincing demonstration of autosomal dominant transmission of early-onset periodontal disease was a study by Boughman et al. analyses of large numbers of families that are more homogeneous for such traits may be required. since we lack fundamental understanding about the specific genetic or environmental etiologies of early-onset periodontal disease in its many manifestations. The Boughman family may have a form of early-onset periodontal disease different from the majority of the families in the Hart study or even a genetically unique form of localized juvenile periodontitis. logical categorization and appropriate preventive and therapeutic measures may not become available. (164) have reported the abnormal expression of chemotactic peptide receptors on localized juvenile periodontitis neutrophils as well as abnormal signal transduction. Despite the inconsistencies observed both between and within populations with regard to this defect and alternative hypotheses concerning its biochemical foundation. (17). the information about neutrophil dysfunction and its relationship to early-onset periodontal disease can potentially identify genetic markers that could be associated with risk for disease in some populations.
DE 10703 and DE06436 from the National Institutes of Health.
5. Astemborski JA. Boughman JA. Goodman SB.Schenkein & Van Dyke
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