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 France 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 Terms 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 supporting 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 m 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 support 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 supportive 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
members 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 support 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
contact 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 supported 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 account 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 support 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 AgPassociated 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
members 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
contact with neutrophils can alter their
functions. For example:

 TNF- decreases neutrophil chemotaxis and

the number of chemoattractant receptors
on neutrophils. TNF- and IL-1, 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- and IL-1 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