Aggressive Periodontitis 52223

AGGRESSIVE PERIODONTITIS

INTRODUCTION • At the 1999 international classification workshop, the different forms of periodontitis were reclassified into three major forms (chronic, aggressive and necrotizing forms of periodontitis) and into periodontal manifestations of systemic diseases. • Until recently, this group of diseases was defined primarily based on the age of onset/ diagnosis and was thus named early onset periodontitis (EOP). • Features of this form of disease, however, can present themselves at any age and this form of periodontitis is not necessarily confined to individuals under the arbitrarily chosen age of 35 years.

HISTORY • Gottlieb (1923) was the first to describe the disease and he called it “the diffuse atrophy of the alveolar bone.” • Later Gottlieb (1928) changed the name to “deep cementopathia” (Cementopathia profunda) because he believed that the original defect was in the cementum.

• Ten years later, Wannenmacher (1938) stated that the bone resorption appeared mostly in the incisor and first molar areas, the developmentally oldest periodontal tissues. He called the disease “parodontitis marginalis progressiva”. • It is interesting that, while all other investigators spoke of a non-inflammatory or degenerative disease, he pointed out the domination of an inflammatory process. In fact, Wannenmacher should be considered the first to have described juvenile periodontitis.

• Thoma and Goldman (1940) later termed the disease “paradontosis”. • Miller et al. (1941) called the disease “precocious advanced alveolar bone destruction”.

• The English term “periodontosis”, which is still used by many authors, was coined by Orban & Weinmann (1942). They considered the disease more degenerative than inflammatory in origin. • They described essentially the same clinical symptoms as mentioned before: migration of the teeth and subsequent inflammation and pocket formation. • They divided the disease into three stages. The first two are clinically indistinguishable, no inflammation or pocket formation appears, but these two stages present the true periodontosis whereas the third stage, with inflammation and pocket formation (also called the periodontitis complex), is actually a periodontotis complex), complicated by periodontitis.

• Orban & Weinmann (1942) stated that females were more susceptible to this disease between the ages of 10 and 25, whereas males would not be affected under the age of 30. • The Nomenclature Committee of the American Academy of Periodontology (1950) also referred to periodontosis as a “degenerative non-inflammatory destruction of the periodontium originating in one or more of the periodontal structures, characterized by migration and loosening of the teeth in the presence or absence of secondary epithelial proliferation and pocket formation or secondary gingival disease”.

• Tenenbaum et al (1950) reported that radiographic examination revealed a loss of alveolar bone that followed a definite arch form pattern starting from the mesial surfaces of the second molars and extending to the distal surfaces of the second bicuspids. There was bone loss also in the incisor area while the alveolar bone showed the greatest resistance in the mandibular bicuspid area. • McCall (1951) commented that, because the incisors and first molars are the first teeth to erupt and thus have been exposed occlusal stress for the longest time, they should also show the first and most severe signs of alveolar weakness.

• Glickman (1952) added a few more points to the radiographic features. “1) thickening of the periodontal space, 2) destruction of the interdental septa of the alveolar bone in a vertical rather than horizontal direction; a generalized alteration in the trabecular pattern of the alveolar bone, consisting of less clearly defined trabecular markings and increase in the size of the cancellous spaces.”

• The Nomenclature and Classification Committee of American Academy of Periodontology (Lyons et al. 1959) considered that no convincing human material of sufficient quantity had been published to establish the pertinent histopathologic changes. It was at that time emphasized that it is not an entity caused by systemic factors, but that these changes are produced by occlusal trauma.

• Prichard (1965) did not believe that a degenerative process could affect only the periodontal apparatus, leaving other body structures intact. He also stressed that there is no pocket formation without inflammation, however severe the occlusal traumatism might be. • The World Workshop in Periodontics (1966) concluded that the term periodontosis should be eliminated from the periodontal nomenclature because there is not sufficient evidence to identify it as a specific disease entity.

• Kaslick & Chasens (1968) launched a new term, “periodontosis with periodontitis” and considered it to be clinical entity. • In the term “acute juvenile periodontitis” had been used since 1967 (Chaput et al. 1967). • The term “Juvenile periodontitis” was introduced into the English literature by Butler (1969).

• Baer (1971) discussed the definition of periodontosis by the Nomenclature Committee of the American Academy of periodontology (1950) and gave as his definition of the disease: "Periodontosis is a disease of periodontium occurring in an otherwise healthy adolescent, which is characterized by a rapid loss of the alveolar bone about more than one tooth of the permanent dentition”. • There are two basic forms in which it occurs.

• In one form, the teeth affected are the incisors and the first molars, in the other, more generalized form, most of the dentition can be affected. The amount or destruction manifested is not commensurate with the amounts of local irritants present". • He pointed out several distinctive features of this disease which justify its classification as a clinical entity different from chronic marginal periodontitis:

• Age of onset (early puberty, between 11 and 13 years). • Sex ratio (female/male ratio 3: 1 according to Benjamin & Baer 1967). • Familial background. • Lack of relationship between local etiologic factors and presence of deep periodontal pockets. • Distinctive radiographic pattern of alveolar bone loss. • Rate of progression. • Lack of involvement of primary teeth. However Baer (1971) said that radiographically the buccal and lingual plates were the last to resorb i.e., the bifurcation involvements were late manifestations of the disease.

• In addition, Bouyssou & Fourel (1973) discussed the terminology on the basis of their own studies and considered the term “Juvenile periodontitis” more correct than the term “Periodontosis”. • However Fourel (1974) published four cases of juvenile periodontitis and proposed to call the disease “Gottlieb syndrome”.

• Manson & Lehner (1974) emphasized the correctness of the term “Juvenile periodontitis” on the following grounds. – There was no evidence of a degenerative process; – It emphasized the principal clinical feature of the disease and its development in young individuals;

• Waerhaug (1976), who also preferred to use the term “juvenile periodontitis” in his studies on autopsy material and on extracted teeth showed that there is always a thin layer of subgingival plaque which grows apically at a maximum rate of 5  per day, i.e., 1.8 mm a year. • He also noticed that buccally and lingually, where there was no supragingival plaque, there was neither subgingival plaque nor bone loss (Comp. Baer 1971). • He concluded that rather than a degenerative process there must be some deficiency in the host defense mechanism which allows the exaggerated destructiveness and claimed that the disease should actually be called “destructive juvenile periodontitis.”

• The term “Periodontosis” should be discarded (Sugarman & Sugarman 1977) because the disease entity is a periodontitis; in all cases plaque has been found on the root-surfaces of the involved teeth. • The disease differs from the chronic marginal periodontitis in some of its characteristics and etiology but it should be treated like periodontitis and the prognosis is commensurate with the stage to which it has advanced. • The term “precocious periodontitis” instead of “Juvenile” describes the condition more exactly ((Sugarman and Sugarman 1977).

• In 1977 the Committee of Nomenclature of the American Academy of Periodontology published a Glossary of recommended for use, which quoted: “Periodontosis: A degenerative disease of the periodontium, existence of which is not accepted universally.”

CLASSIFICATION AND CLINICAL SYNDROMES • In the absence of an etiologic classification, aggressive forms of periodontal disease have been defined based on the following Primary features (Lang et al. 1999): • Non-contributory medical history • Rapid attachment loss and bone destruction. • Familial aggregation of cases

Secondary features that are considered to be generally but not universally present are: • Amounts of microbial deposits inconsistent with the severity of periodontal tissue destruction • Elevated proportions of Actinobacillus actinomycetemcomitans and, in some Far East populations, Porphyromonas gingivalis • Phagocyte abnormalities: Hyper responsive macrophage phenotype, including elevated production of PGE2 and IL-1 in response to bacterial endotoxins • Progression of attachment loss and bone loss may be self-arresting.

• The international classification workshop identified clinical and laboratory features deemed specific enough to allow sub-classification of AgP into localized and generalized forms (Tonetti & Mombelli 1999, Lang et al. 1999). The following features were identified:

Localized aggressive periodontitis (LAP) • Circumpubertal onset • Localized first molar/incisor presentation with interproximal attachment loss on at least two permanent teeth, one of which is a first molar, and Involving no more than two teeth other than first molars and incisors • Robust serum antibody response to infecting agents. • Microorganism involved is mainly A.a

Generalized aggressive Periodontitis (GAP) • Usually affecting persons under 30 years of age, butpatients may be older. • Generalized interproximal attachment loss affecting at least three permanent teeth other than first molars and incisors. • Pronounced episodic nature of the destruction of attachment and alveolar bone. • Poor serum antibody response to infecting agents. • Microorganism involved is mainly P. gingivalis.

Drawbacks • The recommendation that we should abandon the notion of age – much discredited owing to uncertainties and difficulties in setting limits – seems legitimate. • But this notion nevertheless remain valid (Heitz-Mayfield et al, 2002, Mombelli et al.2002) for the simple reason that periodontitis diagnosed in a patient aged 18 has a different significance than the same periodontitis in a patient aged 60.

• Until 2002 – some 3 years after the initial classification – this definition was used only rarely in the literature. And it is not used in nosological descriptions. • The new form of pneumonia that appeared recently in different part of world was wisely described as “atypical”. To our knowledge, no cases of hepatitis or leukemia have been described as ”aggressive”, even if severe forms do exist.

• If the definition of “aggressive periodontitis” resulted in a specific therapy, this approach would be justified. But prescribing antibiotics, for example, with or without an antibiogram, would be distressingly commonplace (Mombelli et al 2002) • No research revealed specific bacterial characteristics in aggressive periodontitis (Kinane and Attstrom 2002). • Hence the definition of “aggressive periodontitis” – no longer new – is particularly disputable. The considered opinion any dental clinician would be that this notion is merely a semantic modification of early onset periodontitis.

Mombelli et al. 2002 classified aggressive periodontitis into three types:

• Secure aggressive periodontitis is characterized by clinically documented loss of attachment of over 2mm in under a year, or by a loss of over 2mm before the age of 18, or by rapid bone destruction documented by X-rays made throughout the year, or by severe bone loss before the age of 18. • Uncertain aggressive periodontal characterized by clinical loss of attachment of over 2 mm, or by severe bone destruction before the age of 30. • Insecure aggressive periodontitis characterized by attachment loss with an unclear rate of progression of around 2 mm in over a year, or by bone destruction with an unclear rate of progression.

Drawbacks • It must be recognized, however, that an attachment loss variability of only 2 mm cannot be a realistic basis for clinical assessment. Variability this small calls in question the probing procedure itself. Moreover, in order for probing to be reliable and significant, it should be performed only after initial inflammation has been reduced, that is, after treatment has been initiated (Dridi et al 2002). • This approach would be feasible in clinical practice only if the level of activity – and progression – were correlated with the degree of inflammation, which remains a debatable notion.

• Lastly specifying a long rest period is purely speculative, as we cannot date the beginning of the pathology to develop for a year in order to assess its progress. • Diagnosis of one of these AgP forms requires the absence of systemic diseases that may severely impair host defenses and lead to premature exfoliation of teeth. In such instances the appropriate clinical diagnosis will be periodontal manifestation of systemic diseases.

• It is also important to underline that, in the present state of uncertainty regarding both the causative agents and the genetic and environmental susceptibility to AgP, it is possible that, in spite of the lines of evidence presented above, LAP and GAP may simply represent phenotypic variations of a single disease entity. • Conversely, it is possible that different AgP forms may manifest themselves with a common clinical presentation. This aspect is of great diagnostic and therapeutic importance.

LOCALIZED AGGRESSIVE PERIODONTITIS EPIDEMIOLOGY All available investigations, however, indicate that early onset (aggressive) forms of periodontal diseases are detectable in all age and ethnic groups (Papapanou 1996). Wide variation in prevalence, however, has been reported, with some studies showing up to 51.5% affected individuals. These differences are probably due to differences in the employed epidemiological methodologies and definition of EOP.

Primary dentition • Little evidence is available concerning the prevalence of AgP affecting the primary dentition. • In the few studies from industrialized countries, marginal alveolar bone loss has been found to affect the primary dentition of 5 to 11 year olds with frequencies ranging from 0.9-4.5% of subjects (Sweeney et al. 1987).

• In this respect, it should be emphasized that periodontitis affecting the primary dentition does not necessarily mean presence of an aggressive form of periodontitis, but may indicate a chronic form of disease with relative abundance of local factors (plaque and calculus). • More severe cases affecting the primary dentition, leading to tooth exfoliation early in life are usually interpreted as periodontal manifestations of systemic (hematological) diseases, such as leukocyte adhesion deficiency.

Permanent dentition ( LAP) • The risk of developing periodontitis at such an early age, however, does not seem to be shared equally in the population: • In the permanent dentition of 13 to 20year-old individuals, the majority of studies have reported a prevalence of periodontitis of less than 1% (usually 0.1- 0.2% in Caucasian populations). • In Finland and Switzerland the prevalence rate of 0.1%( Baer et al 1971); In English adolescent 0.1 %.

• Among US schoolchildren 5-17 years of age, the prevalence of periodontitis has been estimated to range from about 0.2% for whites to about 2.6% for blacks (Loe & Brown 1991). • In the US, a national survey of adolescent aged 14-17 reported that 0.53% had LAP. Blacks were at much higher risk for LAP, and black males were at 2.9 times higher risk for developing disease than black females. In contrast, white females were more likely to have Lap than white males. So the order is: • black males>black female>white female followed by white male.

Screening • The objective of screening is the detection in a population of possibly diseased subjects that would require a more comprehensive examination. In periodontology, the most sensitive diagnostic test for the detection of periodontitis is the measurement of attachment loss by probing. • Application of this diagnostic procedure in the mixed dentition and in teeth that are not fully erupted, however, may be difficult.

• In younger subjects, therefore, a currently utilized screening approach is the measurement of the distance between the alveolar crest and the cementoenamel junction on bitewing radiographs. • An advantage of this approach relates to the fact that in most industrialized countries bite-wing radiographs of children and young adolescents in mixed dentition are routinely taken for caries prevention programs; these radiographs should therefore be screened not only for carious lesions but also for the presence of marginal alveolar bone loss.

• Recent investigations have attempted to determine the "normal" distance between the cemento-enamel junction and the alveolar crest of primary and permanent molars in 7 to 9-year-old children. Mean distances at primary molars were 0.8 to 1.4 mm. The cemento-enamel junction of permanent molars was 0 to 0.5 mm apical to the alveolar crest in 7 to 9 year olds. • A distance of 2 mm between the cementoenamel junction and the alveolar crest, in the absence of the above-mentioned local factors, argues therefore for a suspected diagnosis of periodontitis. This tentative diagnosis will have to be confirmed by a complete periodontal examination.

CLINICAL FINDINGS IN LAP • The most striking feature of LAP is the lack of clinical inflammation, despite the presence of deep periodontal pockets. • Clinically, there is a small amount of plaque, which forms a thin film on the tooth and rarely mineralizes to become calculus. • The most common initial symptoms are migration and mobility of the first molars and the incisors. Classically incisors move in distolabial direction.

•

• •

•

Along with anterior tooth migration, an apparent increase in the size of clinical crown. Accumulation of plaque and calculus, and clinical inflammation appear. Denuded root surfaces become sensitive to thermal and tactile stimuli. Deep dull, radiating pain may occur with mastication, probably because of irritation of the ing structures by mobile and impacted food. Periodontal abscess may form at this stage, and regional lymph node enlargement may occur.

Distribution Of Lesion • The distribution of lesion in Localized AgP is characteristic and as yet unexplained. The classical distribution in the region of the first molars and incisors, with the least destruction in the cuspid and premolar area. • As the name suggests, LAP progresses rapidly. Evidence suggests that the rate of bone loss is about three to four times faster than in chronic periodontitis.

The following possible reasons for the limitation of periodontal destruction to certain teeth have been suggested: • After initial colonization of first permanent teeth to erupt (First molars and Incisors), A.a evades the host defenses by different mechanisms. After initial attack, adequate immune defenses are stimulated to produce opsonizing antibodies to enhance phagocytosis of invading bacteria and neutralize destructive factors. In this manner colonization of other sites may be prevented (Zambon 1983). • Bacteria antagonistic to A.a may develop, there by decreasing the destructiveness of the lesions and reducing the number of colonization sites. (Hillman 1982).

•

•

A.a may lose its leukotoxin producing ability for unknown reasons. When this happens, the progress of the disease may become arrested or retarded and new colonization sites averted. The possibility that a defect in cementum formation may be responsible for the localization of the lesion has been suggested (Page 1985). Root surfaces of teeth extracted from patients with LAP have been found to be hypoplastic or aplastic cementum (Lindskong 1983). This was true not only of root surfaces exposed to periodontal pockets, but also of root surfaces still surrounded by their periodontium. Cemental defects in these patients may appear Fibrillar result in incomplete fiber attachment to the root. Pebbly or globular-Iike areas may be the result incomplete development or mineralization resulting in incomplete fiber attachment.

Current concepts: Clinical course • LAP progresses rapidly. There is evidence that the rate of bone destruction is about three to four times faster than found in typical periodontitis (Bear 1971, 1974). In affected persons bone resorption progresses until the teeth are treated, exfoliated or extracted. There is no consistent or reliable evidence that the disease progress per se spreads to unaffected areas. • Interaction between the disease process and environmental (e.g. cigarette smoking) and genetically controlled (e.g. IgG2 response to A.a) modifying factors are thought to contribute to determining the specific clinical manifestation of disease (LAP to GAP).

Histopathology • A thin, frequently, ulcerated pocket epithelium, infiltrated by numerous leukocytes, covers large areas of inflammatory cell accumulation composed mainly of plasma cells and blast cells, with lymphocytes and macrophages present in small numbers. Collagen and other tissue components constitute only a small proportion of the diseased site, unlike the situation in adult periodontitis( Liljenberg 1980). • Electron microscopy study of LAP have revealed bacterial invasion of connective tissue that reaches the bone surface (Carranza 1983). The invading microorganism is mainly gram negative ( A.a , Capnocytophagia sputigena, Mycoplasm and Spirochetes) • Subgingival plaque in LAP remains relatively thin (20-200 µm depth) and does not tend to mineralize (Waerhaug 1976).

GENERALIZED AGGRESSIVE PERIODONTITIS Clinical characteristics • As seen in LAP, patients with GAP often-small amounts of bacterial plaque associated with affected teeth. • Quantitatively the amount of plaque seems inconsistent with amount of periodontal destruction. Qualitatively P.g, A.a, and B. Forsythus are frequently detected. • Two gingival tissue responses can be found in cases of GAP. One is a severe. Acutely inflamed tissue, often proliferating, ulcerated and fiery red. Bleeding may occur spontaneously or with slight stimulation. Suppuration may be an important feature. This tissue response is considered to occur in the destructive stage in which attachment and bone are actively lost.

•

•

• •

In other cases the gingival tissue may appear pink, free of inflammation, and occasionally with some degree of stippling, However, despite the apparently mild clinical appearances, deep pockets can be demonstrated on probing. This tissue response has been considered by Page and Schroeder to coincide with period of quiescence. The destruction appears to occur episodically with period of destruction followed by stages of quiescence of variable month (Weeks to months or years). Patients with presumptive diagnosis of GAP must have their medical histories updated and reviewed. Possible systemic involvement should be ruled out. Lesion may be arrested spontaneously or after therapy, whereas others may continue to progress inexorably to tooth loss despite intervention with convention therapy.

RADIOGRAPHIC FINDINGS • The radiographic picture in GAP can range from severe bone loss associated with number of teeth, as described previously, to advanced bone loss affecting the majority of teeth in the dentition. • Page and co workers demonstrated osseous destruction ranged from 25-60% during a range of 9-week period. Despite this extreme loss, other sites in the same patient showed no bone loss.

Prevalence and distribution by age and sex • In a study of untreated periodontal disease conducted in Sri Lanka by Loe and colleagues, 85 of the population had rapid progression of periodontal disease characterized by a yearly loss of attachment of 0.1 to 1mm. • In US national survey of adolescent aged 14-17 yrs reported 0.13% had GAP. In addition blacks were at much risk than whites for all forms of GAP and females had more prevalence than males.

ETIOLOGY AND PATHOGENESIS BACTERIAL ETIOLOGY • Acceptance of bacterial etiology of aggressive forms of periodontitis has been particularly difficult since clinical presentation of cases frequently shows little visible plaque accumulation. Of great importance, in this respect, were microscopic studies demonstrating the presence of a layer of bacterial deposits on the root surface of advanced AgP lesions (Listgarten 1976). • Newman et al and Slots performed early studies attempting the identification of the involved bacteria using culture techniques. In these studies, Gram negative organisms comprised approximately two thirds of the isolates from deep periodontal pockets. In contrast, these organisms averaged only about one third of the isolates in control sites with normal gingiva.

• The dominant microorganisms in LJP included Actinobacillus actinomycetemcomitans, Capnocytophagia, Eikenella corrodens, Prevotella intermedia and motile anaerobic rods, such as Campylobacter rectus. • Gram-positive isolates were mostly streptococci, actinomycetes and peptostreptococci. Of these organisms, A. actinomycetemcomitans (A.a.), has received particular attention in recent years and is regarded as being a key microorganism in LAP. This view is based on four lines of evidence (Socransky & Haffajee 1992):

1. Association studies, linking the organism to the disease: A.a. is generally isolated in periodontal lesions from more than 90% of LAP patients and is much less frequent in periodontally healthy individuals. In some studies it was possible to demonstrate elevated levels of A. a. in sites showing evidence of recent or ongoing periodontal tissue destruction (Haffajee et al. 1984). 2.Demonstration of virulence factors: A. a. produces several potentially pathogenic substances, including a leukotoxin, and is capable of inducing disease in experimental animals and non-oral sites. Furthermore, it can translocate across epithelial membranes.

3.Findings of immune responses towards this bacterium: investigators have repeatedly reported significantly elevated levels of serum antibodies to A.a. in LAP patients (Listgarten et al. 1981). Such patients also locally produce antibodies against this organism at diseased sites ( Ebersole et al. 1985). 4. Clinical studies showing a correlation between treatment outcomes and levels of A.a. after therapy: unsuccessful treatment outcomes have been linked to a failure in reducing the subgingival load of A.a. (Slots & Rosling 1983)

• A.a. Serotype b has been found particularly often in patients with LAP (Asikainen et al. 1991). The view of LAP as an A.a. infection is, however, not undisputed. • It has been opposed on the basis of crosssectional studies, showing a high prevalence of this organism in certain populations, particularly from developing countries (Eisenmann et al. 1983), and for the fact that there are patients with LJP who apparently neither show presence of A.a. in the oral flora nor have elevated antibody titers to the organism (Loesche et al. 1985).

Several properties of A.a. are regarded as important determinants of virulence and pathogenic potential. Among them, Leukotoxin • Leukotoxin production is considered highly significant since it may play an important role in A.a's evasion of local host defenses. The leukotoxin produced by A.a. exhibits cytotoxic specificity and destroys human polymorphonuclear leukocytes and macrophages, but neither epithelial and endothelial cells nor fibroblasts. A.a. strains exhibit a wide range of variability in leukotoxin production. High leukotoxin-producing strains have been linked to the etiology of AgP.

• A substantially higher prevalence of highly leukotoxin strains has been reported in patients with LAP than in chronic periodontitis patients or healthy subjects (Zambon et al. 1996). • Zambon et al who found that 57% of LJP subjects contained the high leukotoxin-producing variant while adult periodontitis.

• A significant association was found between the detection of variants that had a deletion in the leukotoxin promoter region, indicative of a highlevel expression leukotoxin genotype, and conversion from a healthy periodontal status to disease. • Subjects harboring A. actinomycetemcomitans of this genotype were more likely to convert to AgP than those subjects who had variants containing the full-length leukotoxin promoter region (odds ratio = 22.50, 95%). These findings the concept that highly virulent strains or clonal types of periodontal pathogens play a major role in the initiation of periodontal disease in susceptible hosts. • That the detection of leukotoxin promoter deletion by PCR may be a useful diagnostic test for the identification of disease risk subjects in specific highly homogenous patient populations.

• Leukotoxin strains of A. actinomycetemcomitans such as strain JP2 in amounts 10 to 20 times higher than is produced by minimally leukotoxic strains such as A.a strain 652. The association between JP2-like A.a and LAP is ive of the hypothesis that the leukotoxin is a major factor in the pathogenesis of this disease.

Lipopolysaccharide: • The identifying feature of Gram-negative bacteria consists of a lipid and a polysaccharide part and is therefore frequently termed lipopolysaccharide (LPS). LPS is set free when bacterial cells die or multiply. • The LPS of A.a. can activate host cells, and macrophages in particular, to secrete inflammatory mediators such as prostaglandins, interleukin-1 and tumor necrosis factor-. • It is also highly immunogenic, since high titers of antibodies against its antigenic determinant are frequently detected in infected individuals.

Bacteriocin: • A bacteriocin of A.a., capable of inhibiting the growth of some streptococci and some actinomyces, has furthermore been detected (Hammond et al. 1987). • Additional virulence factors interfering with fibroblast proliferation have been described for certain strains of A.a. Furthermore, immunosuppressive properties of A.a., as well as collagenolytic activity and inhibition of neutrophil chemotaxis, have been demonstrated.

Membrane Vesicles: • Secretion of membrane vesicles by A.a. has been observed. These vesicles may be important virulence factors since they may contain leukotoxin, endotoxin and other factors and may serve as a transport vehicle to spread pathogenic substances produced by the bacterium.

Determinants Of Virulence and Pathogenic Potential Of A . Actinomycetemcomitans Factor

Significance

Leukotoxin

Destroys human polymorphonuclear leukocytes and macrophages

Endotoxin

Activates host cells to secrete inflammatory mediators (prostaglandins, interleukin-1, tumor necrosis factor-)

Bacteriocin

May inhibit growth of beneficial species

Immunosuppressive factors

May inhibit IgG and IgM production

Collagenases

Cause degradation of collagen

Chemotactic inhibition factors

May inhibit neutrophil chemotaxis

A .a., Capnocytophaga sputigena and Prevotella intermedia have also been shown to be the most prominent of the subgingival microbiota of periodontitis lesions in the primary dentition. The microbial patterns observed in periodontal lesions of the primary dentition, however, seem to be more complex than the ones detected in LAP patients.

Role of Porphyromonas gingivalis in AgP • Generalized aggressive periodontitis (GAP), have been frequently associated with the detection of Porphyromonas gingivalis, Bacteroides forsythus and A.a. In contrast to A.a., which is facultative anaerobic. Porphyromonas gingivalis produces several potent enzymes, in particular collagenases and proteases, endotoxin, Host response to bacterial pathogens fatty acids and other possibly toxic agents (Shah 1993).

• A relationship between the clinical outcome of therapy and bacterial counts has also been documented for P. gingivalis, and non-responding lesions often contain this organism in elevated proportions. High local and systemic immune responses against this bacterium have been demonstrated in patients with GAP.

Bacterial damage to the periodontium • Human investigations have indicated that Actinobacillus actinomycetemcomitans is able to translocate across the junctional epithelium and invade the underlying connective tissue (Saglie et al. 1988). • These data the hypothesis that directs bacterial invasion may be responsible for some of the observed tissue breakdown. Data from chronic periodontitis, however, seem to indicate that two-thirds of attachment loss and alveolar bone resorption is preventable through the action of non-steroidal antiinflammatory drugs, and therefore tissue destruction seems to be driven by the inflammatory process (Williams 1989).

TRANSMISSION OF PERIODONTAL PATHOGENS IN EARLY-ONSET PERIODONTITIS

 There are several studies suggesting that infections associated with AgP are transmissible. As described above, Gunsolley et al. 1990 demonstrated a higher prevalence of A. actinomycetemcomitans in families with AgP compared to otherwise normal families pointing to A. actinomycetemcomitans transmission. Gunsolley's study, consistent with familial transmission. Husbands and wives generally had different types of A. actinomycetemcomitans, while 9 of 10 children harbored the same A. actinomycetemcomitans as one of their parents.

• Since A. actinomycetemcomitans seems to be less able to colonize, a balanced microflora (Christersson et al. 1985), the introduction of this bacterium to a recipient is based on frequent causing frequent and high inoculation doses from donor to recipient. It has been reported that transmission of A. actinomycetemcomitans between spouses seems to be an uncommon event, and that the bacterium most frequently transmits from parents to children in families (Preus et al 1994). • This is ed by the contention that A. actinomycetemcomitans is not readily established in “mature” microenvironment (Preus et al. 1988), where no established oral hygiene habits prevail, and the general standard of hygiene is very low, one may expect that bacteria are more readily transmitted than under more hygienic living conditions.

 It has been recommended that a large (29 or more) of isolates and sites per person should be sampled in order to establish with a 95% level of confidence that a person is infected by only one clonal type of an organism (Loos et al 1992). In addition, if a donor carries more than one genotype of a bacterium, the acquisition or transmission in general, of A. actinomycetemcomitans and other fastidious organisms will occur with the predominant and best environmentally adapted genotype.

•

In localized juvenile periodontitis, a notable clinical finding is "burn out'' of the disease. Patients will develop attachment loss and alveolar bone loss in molar/incisor areas during adolescence but several years later, these lesions will spontaneously arrest. There are several possible explanations for this. 1. Development of an adequate host immune response is one possibility, particularly development of antibodies against cell surface antigens.

2.

3.

Another possibility which could explain both the "burn out'' of localized juvenile periodontitis and the aggressive forms of A. actinomycetemcomitansassociated periodontitis is strain variations in virulence. Highly virulent forms of this bacterium could be associated with progressing periodontal lesions while less virulent forms could be associated with nonprogressing lesions. This hypothesis was originally proposed 10 years ago in a study of A. actinomycetemcomitans serology in which we found that the incidence of A. actinomycetemcomitans serotype b strains was approximately twice as high as serotype a or c strains in localized juvenile periodontitis patients, suggesting a particularly high pathogenic potential for this serotype.

Prevalence of periodontopathic Bacteria in Aggressive periodontitis patients in a Japanese Population. • Actinobacillus actinomycetemcomitans is considered a major etiologic agent of aggressive periodontitis. Other periodontopathic bacteria such as bacteria such as Porphyromanas gingivalis are also suspected of participating in aggressive periodontitis although the evidence is controversial.

• In Japan T. Forsythensis, C. rectus, P. gingivalis, and T. denticola were the predominant periodontopathic bacteria of aggressive periodontitis patients, Although A. actinomycetemcomitans was also detected in AgP patients, the prevalence of this bacterium was much lower than lower than that of P. gingivalis.

• The American Academy of periodontology revised the classification of periodontal diseases in 1999. In the consensus report for the new classification, A. actinomycetemcomitans was confirmed as the causative bacterium and characteristically is present in an elevated proportion in AgP, P. gingivalis was also mentioned as an etiologic agent of AgP, although its importance in the pathogenesis of this disease has been generally thought to be less than that of A. actinomycetemcomitans.

• Some researchers have reported the presence of P. gingivalis not only in the generalized form, but also in the localized form of AgP. However, the prevalence of P. gingivalis is thought to increase with subject age, and this bacterium seems to assume greater importance with increasing age. • Thus the role of P. gingivalis in periodontitis of younger people was regarded as less important as that of A. actinomycetemcomitans. In the Japanese population of AgP patients, the detection frequency of P. gingivalis was approximately four times higher than that of A. actinomycetemcomitans. • In addition, the prevalence and proportion of this bacterium correlated with severity of clinical attachment loss. However, many previous studies mainly in North America and Europe, have found A. actinomycetemcomitans to be highly prevalent as the major periodontal pathogen in adolescents / young adults with periodontitis.

• Bragd et al, who showed that more than 0.01% of A. actinomycetemcomitans in subgingival plaque posed a high risk for progression of periodontal tissue destruction. On the other hand, Hamlet et al reported that the prevalence of A. actinomycetemcomitans decreased as probing depth increased, whereas a positive relationship was observed between P. gingivalis and increasing PD. • It is also assumed that A. actinomycetemcomitans may initiate the disease, while deeper pockets and the subsequent greater anaerobiosis will favor the growth of other bacteria such as P. gingivalis.

• Zambon proposed that T. forsythensis was the main etiologic agent of periodontitis, together with A. actinomycetemcomitans and P. gingivalis. T. forsythensis has been associated with various clinical forms of periodontitis. In the Japanese, T. forsythensis was also a predominant periodontopathic, bacterium in AgP. Moreover T. forsynthensis was frequently found at sites with severe loss of attachment in LAgP groups, and it became clear that this bacterium was strongly implicated in LAP. • Tanner et al reported that the mean levels of T. forsythensis were elevated at sites showing active lesions, and this bacterium was associated with the sites converting from periodontal health to disease.

Herpes viral – Bacterial Interactions In Aggressive Periodontitis Pathogenesis of herpes virus associated periodontal disease • Available data are consistent with herpes viruses participating in the pathogenesis of various aggressive types of human periodontitis. Herpes viruses may cause periodontal pathology as a direct result of virus infection and replication, or as a result or virally mediated damage to the host defense.

•

Slots and Contreras (2000) described a novel infectious disease model for human periodontitis. The herpes viral bacterial interaction is probably bi-directional 1. One hand, suppression of periodontal immune defenses, thereby increase the risk of bacterial infection. Overgrowth of periodontal bacterial pathogens, release of proinflammatory cytokines and chemokines. 2. On the other hand, bacterial-induced gingivitis has the potential to facilitate homing or herpes virus-infected cells to gingival tissue.

• Initially, gingival inflammation induced by dental plaque bacteria causes herpesvirus-infected inflammatory cells to enter the periodontium. • HCMV resides mainly in macrophagegranulocyte progenitors and Peripheral blood mononuclear cells and EBV in Blymphocytes. Subsequent herpes virus reactivation in the gingival tissue may then aggravate the inflammatory response and accelerate existing disease. Herpesvirus reactivation may occur spontaneously or as a result of various tissue of impairment of the host immune defense, including HIV infection, pregnancy, hormonal changes, and psychosocial and physical stress.

• Factors that activate herpes viruses are recognized risk indicators of periodontitis (Salvi et al. .1997). Indeed, the reason why various Immunosuppressive events aggravate periodontal disease might be partially due to accompanying herpesvirus activation. Herpes virus active in fection would further diminish the resistance of periodontal tissues, thereby allowing subgingival upgrowth of periodontal pathogenic bacteria. • However, bacterial enzymes or other inflam mation-inducing products have probably also the potential to activate periodontal herpes viruses (the vicious circle concept).

• Herpes viral-bacterial interaction explains various diseases characteristics of destructive periodontal disease. Alteration between prolonged periods of latency interrupted by periods of activation of herpes viral infections may partly be responsible for the burst like episodes of periodontitis disease progression. • Tissue tropism of herpesviral infections may help explain the localized pattern of tissue destruction in periodontitis. Frequent reactivation of periodontal herpes viruses may for the rapid periodontal breakdown in some patients even in the presence of relatively little dental plaque. Absence of herpes viral infection or viral reactivation may clarify why some individuals carry periodontopathic bacteria while still maintaining periodontal health or minimal disease.

• HCMV, EBV-1 and HSV-1 were each detected in 72-78% of the aggressive periodontitis patients. HSV-2 occurred in 17% of the periodontitis patients. HSV-2 was not associated with any test bacteria. These results the notion that the clinical outcome of some types of severe periodontal infection depends on the presence of specific herpes viruses and bacterial pathogens.

HOST RESPONSE TO BACTERIAL PATHOGENS DEFECTIVE CHEMOTACTIC RESPONSES OF PMNs • Both local and systemic host responses to Agociated microflora have been described. Local inflammatory responses have been characterized by an intense recruitment of polymorphonuclear leukocytes both within the tissues and into the periodontal pocket. • Such a preponderance of PMNs underlines the importance of these cells in the local defense against bacterial aggression and their potential role in host-mediated tissue destruction.

• In the mid-1970s, investigators in several laboratories noted that PMNs purified from the peripheral blood of patients with AP performed poorly in chemotaxis assays when compared with PMNs from subjects without periodontitis (Clark et aI 1977). As many as 70% to 75% of these patients exhibit decreased neutrophil chemotaxis towards a number of chemoattractants in vitro. • Furthermore, a study of AP families indicated that chemotaxis defect, when present in a family member with AP, was also present in all other family with AP and absent in those without AP; conversely, if the proband with AP had no chemotaxis defect then neither did the siblings with AP. • The pattern of chemotaxis defects within the families were consistent with an inherited trait that is autosomal dominant (Van Dyke et aI., 1985). Thus it is hypothesized that both the chemotaxis defect and the disease itself may be heritable.

To date, there are two plausible explanations for the observed decreased neutrophil chemotaxis in LJP: 1. Neutrophils are intrinsically defective or 2. Extrinsic factors in the sera of LJP patients alter neutrophil functions.

OBSERVATIONS SUGGESTING THAT INTRINSIC CELLULAR DEFECTS MAY BE RESPONSIBLE FOR ALTERED NEUTROPHIL FUNCTIONS

•

The decreased neutrophil chemotaxis in LJP has been associated with a lower number of receptors for chemoattractants, such as Nformyl-methionyl-leucyl-phenylalanine (FMLP), complement fragment C5a, and leukotriene B4, GP-110, a cell surface glycoprotein involved in neutrophil locomotion and secretory function, is also present at a lower density on AgP neutrophils as compared to neutrophils from systemically and periodontally healthy individuals. Signal transduction after receptor-ligand interaction, is decreased in LJP neutrophils as compared to healthy neutrophils.

• It has been noted that consistent with decreased chemotaxis, neutrophils from LJP patients exhibit increased adherence. Additionally, in response to opsonized bacteria, superoxide anion generation and degranulation are higher in neutrophils from LAP patients. Phagocytosis of Actinobacillus actinomycetemcomitans by LAP neutrophils has been shown to be normal. However, these cells exhibit decreased intracellular killing of this organism.

• Defective calcium influx factor activity in Neutrophils. In LAP, signaling abnormalities are known to be associated with increased intracellular diacylglycerol (DAG) levels, decreased PKC activity, and abnormal Ca2+ mobilization. It is well known that PKC activity is regulated by calcium and DAG levels. Hence, calcium mobilization is critical to normal neutrophil migration. • Neutrophils from LAP patients demonstrate reduced calcium entry, and the total cytosolic calcium con centration level during cell activation is lower than that from normal subjects. Since calcium is required for phosphorylation of PKC and PKC activation is dependent on cytosolic calcium concentration, elevated DAG levels in the cytosol may not be enough to activate PKC without sufficient cytosolic calcium concentration.

– Although patients exhibit a genetic predisposition to LJP, the collective functional changes associated with LJP neutrophils have, as yet, to be linked to a common genetic element. This is further complicated by the facts that: • Not all patients with clinically diagnosed LJP exhibit decreased neutrophil chemotaxis; • LJP patients appear to be healthy and have not been documented to exhibit increased susceptibility to other infections, as would be expected in patients exhibiting impaired neutrophil functions, e.g., leukocyte adhesion deficiency syndrome; and • The manifestations of this disease, i.e., massive tissue damage and bone loss, occur in the presence of a relatively low bacterial load.

• The inability to place these collective observations into a clear unified hypothesis has compelled investigators to consider an alternate hypothesis to explain the basis of altered neutrophil functions in LJP.

OBSERVATIONS SUGGESTING THAT EXTRINSIC FACTORS IN THE SERA MAY ALTER NEUTROPHIL FUNCTIONS IN LJP

In response to a bacterial challenge, a number of cytokines derived from macrophages as well as lymphocytes are carried through blood to regulate immune response as a whole increased lymphocyte count. During an immune response, even slight elevations in serum cytokines when in with neutrophils can alter their functions. For example:

 TNF-α decreases neutrophil chemotaxis and the number of chemoattractant receptors on neutrophils. TNF-α and IL-1β, at very low concentrations, can induce increased adherence, which can reduce the migration of neutrophils to the site of infection.  Furthermore, a number of cytokines including TNF-α and IL-1β can prime neutrophils inducing higher levels of superoxide anions and degranulation in response to a bacterial challenge.

 Treatment of healthy neutrophils with LJP sera decreases the number of FMLP receptors on the neutrophil surface. Furthermore, pretreatment of LJP sera with anti-TNF and anti-IL-1 antibodies partially neutralizes the ability of LJP sera to decrease chemotaxis and the number of FMLP receptors on healthy neutrophils. The changes induced by LJP sera are specific, sustained and cannot be reversed by placing LJP serum-treated neutrophils in healthy serum. In this regard, healthy neutrophils treated with LJP sera function similarly to LJP neutrophils.

 Healthy neutrophils, when treated with sera obtained from healthy subjects, patients with adult periodontitis, or patients with clinically diagnosed LJP but normal neutrophil chemotaxis, do not exhibit a decrease in chemotaxis or number of FMLP receptors. These observations suggest that extrinsic factors in LJP sera may be responsible for altering neutrophil functions in LJP. • Neutrophil chemotaxis is facilitated by a glycoprotein called GP-110. The number of these cell surface molecules has been shown to be reduced on LJP neutrophils. The number of GP-110 molecules on healthy neutrophils is reduced following treatment with LJP sera. Similar to LJP neutrophils, the decrease in GP-110 molecules on healthy neutrophils induced by cytokines was irreversible.

• One of the major cell surface glycoproteins responsible for adherence of neutrophils to endothelium is a CD11/CD18 molecule. Expression of these molecules decreases the rate of migration of neutrophils. These molecules are present at higher numbers on neutrophils from LJP patients and may be the underlying cause for the observed increased adherence of these cells.

• These findings suggest that: • Cytokines regulate neutrophil functions; and • Quantitatively low levels of cytokines in the serum are sufficient to alter neutrophil functions.

Thank you