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1. Aggressive Periodontitis
(etiology and pathogenesis)
Seminar :
Leena Parmar

2. Index
 Introduction
 Definition
 Classification
 Etiology & pathogenesis:-
a) microbiologic factor
b) immunologic factor
c) genetic factor
d) environmental factor

3. Introduction :-
 Aggressive periodontitis may be universally
distinguished from chronic periodontitis by the
age of onset, the rapid rate of disease
progression, the nature and composition of the
associated subgingival microflora, alterations
in the host's immune response, and a familial
aggregation of diseased individuals.

4. Definition
 In1971, Baer' defined it as "a disease of the
periodontium occurring in an otherwise healthy
adolescent which is characterized by a rapid
loss of alveolar bone about more than one
tooth of the permanent dentition. The amount
of destruction manifested is not commensurate
with the amount of local irritants."

5. 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.

6.  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
(Aggregatibacter actinomycetemcomitans) and, in some
Far East populations, Porphyromonas gingivalis

7. • Phagocyte abnormalities.
• Hyper-responsive macrophage phenotype,
including elevated production of prostaglandin
E2 (PGE2) and interleukin-1β (IL-1β) in
response to bacterial endotoxins
• Progression of attachment loss and bone loss
may be self-arresting.

8.  The international classification workshop identified clinical and
laboratory features deemed specific enough to allow
subclassification of AgP into localized and generalized forms
(Lang et al. 1999; Tonetti & Mombelli 1999).
 The following features were identified:
• Localized aggressive periodontitis (LAP)
• Generalized aggressive periodontitis (GAP)

9. • 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

10. • Generalized aggressive periodontitis (GAP):
 Usually affecting persons under 30 years of age, but
patients 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.

11. Etiology and Pathogenesis :-
 Microbiologic Factors
 Immunologic Factors
 Genetic Factors
 Environmental Factors

12. A) Microbiologic Factors :-
 Early studies attempting the identification
of the involved bacteria using culture
techniques were performed by Newman et
al. and by Slots (Newman et al. 1976;
Slots 1976; Newman & Socransky 1977).

13.  Dominant microorganisms in LAP included
Actinobacillus actinomycetemcomitans (A.a., now
termed Aggregatibacter actinomycetemcomitans),
Capnocytophaga sp., Eikenella corrodens,
saccharolytic Bacteroides-like organisms now
classified as Prevotella sp., and motile anaerobic
rods today labeled Campylobacter rectus.
 Gram-positive isolates were mostly streptococci,
actinomycetes, and peptostreptococci.

14.  A.a., Capnocytophaga sp., and Prevotella sp. were also
shown to be the most prominent members of the subgingival
microbiota of periodontitis lesions in the primary dentition.
One of these organisms, A. actinomycetemcomitans, a short,
facultatively anaerobic, non-motile, Gram negative rod,
received particular attention and was increasingly viewed as a
key microorganism in LAP.

15.  This view was principally based on four lines of evidence
(Socransky & Haffajee 1992):
1. Association studies, linking the organism to the disease: A.a. was
isolated in periodontal lesions from more than 90% of LAP patients
and was much less frequent in periodontally healthy individuals
(Ashley et al. 1988; Van der Velden et al. 1989; Albandar et al. 1990;
Gunsolley et al. 1990; Slots et al. 1990; Asikainen et al. 1991; Aass
et al. 1992; Ebersole et al. 1994; Listgarten et al. 1995). 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; Mandell 1984; Mandell et al. 1987).

16. 2. Demonstration of virulence factors: A.a. was shown to
produce several potentially pathogenic substances,
including a leukotoxin, was capable of translocating
across epithelial membranes, and could induce disease
in experimental animals and non-oral sites ( Zambon et
al. 1988; Slots & Schonfeld 1991).

17. 3. Findings of immune responses towards this bacterium:
Investigators repeatedly reported significantly elevated
levels of serum antibodies to A.a. in LAP patients
(Listgarten et al. 1981; Tsai et al. 1981; Altman et al.
1982; Ebersole et al. 1982, 1983; Genco et al. 1985;
Vincent et al. 1985; Mandell et al. 1987; Sandholm et al.
1987). Such patients were furthermore shown to produce
antibodies locally against this organism at diseased sites
(Schonfeld & Kagan 1982; Ebersole et al. 1985b; Tew et
al. 1985).

18. 4. Clinical studies showing a correlation between
treatment outcomes and levels of A.a. after
therapy: unsuccessful treatment outcomes
were linked to a failure in reducing the
subgingival load of A.a. (Slots & Rosling 1983;
Haffajee et al. 1984; Christersson et al. 1985;
Kornman & Robertson 1985; Mandell et al.
1986, 1987; Preus 1988).

19.  Recently six serotypes ( a,b,c,d,e and f ) of A.a have
been described based on the composition of structurally
and antigenically distinct O-polysaccharides of their
lipopolysaccharides. In addition, a novel serotype g has
recently been proposed.

20. (Zambon et al. 1983, 1996).
 In the United States, A serotype-dependent pattern
of association with LAP was found .
 Serotype b strains were more often isolated from
patients with localized juvenile periodontitis.
(Asikainen et al. 1991, 1995)
 A higher frequency of serotype b strains was also
reported from Finnish subjects with periodontitis

21. Leukotoxin production
 A major virulence factor of A.
actinomycetemcomitans and all strains.
 Which makes the bacterium capable of evading the
host response by killing leukocytes.
 A highly leukotoxic clonal type of A.
actinomycetemcomitans serotype b was first
isolated , in the early 1980s, from an 8 year old
male child with localized aggressive periodontitis.

22. Gram-negative bacteria
 It enveloped by two membranes, of which
the outer is rich in endotoxin.
 This identifying feature of Gram negative
bacteria consists of

23. Lipid + polysaccharide = lipopolysaccharide (LPS)
 LPS is set free when bacterial cells die or
multiply.

24. Mechanism of LPS
LPS of A.a Host cells
(macrophages)
Inflammatory mediators
( prostaglandins,
interleukin-1β, TNF)
Activate
secrete

25. Fives-Taylor et al. (1996)
Properties of A.a
Immunosuppressive
properties,
Collagenolytic
activity
&
Inhibition of
neutrophil
chemotaxis

26. Leukotoxin
Destroys human
polymorphonuclear
leukocytes
Macrophages

27. Lally et al. (1996).
Leukotox
in
family of RTX (Repeats in
ToXin)
Pore-
forming
toxins

28. Haraszthy et al. (2000); Tan et al.
(2001); Cortelli et al.(2005)
JP2 clone Commonly found Aggressive periodontitis patients
(North and West African)

29.  Among potential virulence factors, cytolethal distending toxin,
which seems to be characteristic for A.a, but not for other
periodontal organisms, has gained considerable research
interest.
Outer membrane vesicles of A.a
Cytolethal distending toxin
& Bacterium
Other virulence agents
Host tissue
Transfer of

30. Determinants of virulence and
pathogenic potential of A.
actinomycetemcomitans
• SignificanceFactor
• Destroys human
polymorphonuclear leukocytes
and macrophages
Leukotoxin
• Activates host cells to secrete
infammatory mediators
(prostaglandins, interleukin-1β,
tumor necrosis factor-α)
Endotoxin

31. • May inhibit growth of
beneficial species
Bacteriocin
• May inhibit IgG and IgM
production
Immunosuppressi
ve
Factors
• Cause degradation of
collagenCollagenases

32. • May inhibit neutrophil chemotaxis
Chemotactic
inhibition
factors

33. Bacterial damage to the periodontium
:-
 Disease-associated bacteria are thought to
cause destruction of the marginal
periodontium via two related mechanisms:
(Tonetti 1993).
Disease-associated bacteria
(Direct)
Action of the microorganisms or
their products on the host tissues
(Indirect)
Eliciting tissue-damaging
inflammatory responses

34.  The relative importance of these two mechanisms in AgP
remains speculative.
(Saglie et al. 1988)
Aggregatibacter
Actinomycetemcomitans
Across the junctional epithelium
Connective tissue
translocate
invade

35. Apical spread of bacteria
Controlled
through
High turnover of
junctional
epithelium
keratinocytes
Directed migration
of
polymorphonuclear
leukocytes through
the junctional
epithelium
Outward flow of
crevicular fluid

36. B) Immunologic Factors :-
 Both local and systemic host responses to
AgP associated microflora have been
described.
Local
inflammatory
responses
An intense recruitment of
polymorphonuclear
leukocytes
(PMNs)
Tissues
Periodontal
pocket

37.  Presence of PMNs underlines the importance of these
cells in the local defense against bacterial aggression
and their potential role in host-mediated tissue
destruction.
 B cells and antibody-producing plasma cells also
represent a significant component (Liljenberg & Lindhe
1980).

38.  Mackler et al. (1977, 1978); Waldrop et al.
(1981); Ogawa et al. (1989).
Plasma cells IgG-producing cells
&
IgA-producing cells

39. Taubman et al. (1988, 1991).
 Important component of the local inflammatory
infiltrate are T cells.
 Subset analysis of local T cells has indicated a
depressed T-helper to T suppressor ratio as
compared to both healthy gingival and peripheral
blood.
 These findings have been interpreted to suggest
the possibility of altered local immune regulation

40. Masada et al. (1990); Offenbacher et al. (1993).
Local inflammatory
responses
PGE2, IL-1α
IL-1β
Crevicular fluid
Tissue
Characterized by

41. Schenkein & Genco (1977); Patters et
al. (1989)
Specific
antibodies against
AgP-associated
microorganisms
Crevicular fluid
from AgP lesions.
Detected in

42. Steubing et al. (1982); Hall et al.
(1990, 1991, 1994)
Substantial amount
of antibodies
against A.a. and P.
gingivalis
serum of AgP
patients
Detected in

43. Genco et al. (1980, 1986); Van Dyke et
al. (1982, 1986, 1988).
PMNs of some LAP
and GAP
Decreased
migration
Decreased
antibacterial
functions

44.  This evidence has been interpreted as a suggestion that
the LAP-associated PMN defect may be inherited. Other
recent reports have indicated. (Shapira et al. 1994;
Agarwal et al. 1996).
PMN abnormalities in LAP
patients
serum of some AgP
Hyper-inflammatory
state
pro-inflammatory
cytokines
Result of
Presence of
In

45. C) Genetic Factors:-
 Periodontitis is a multifactorial disease for which
several risk and susceptibility factors are proposed.
 The striking familial aggregation of trait in Aggressive
Periodontitis is consistent with a significant genetic
etiology.
 A gene of major effect in Aggressive Periodontitis
appears to be etiologically complex and
heterogenous.

46.  In 1986, Boughman et al reported that a
major gene located on chromosome 4q
was responsible for autosomal dominant
transmission of Localised Aggressive
Periodontitis in an extended family that
also exhibited Dentinogenesis Imperfecta.

47.  It is now established that genetic factors
regulate the innate immune system and
that certain genetic polymorphism may
render the immune system defective.
 Genetic factors may play a more
significant role in the pathogenesis of AgP.

48.  Formyl Peptide receptors on the cell surface of
leukocytes are involved in mediating immune
cell responses to infection.
 The bacteria derived N-formly-methionyl
peptides have high affinity to the N-formly-
methionyl peptide cell receptor and after
binding to neutrophil receptor the neutrophils
get activated.
 Thus triggering them to migrate to the site of
infection.

49.  Some reports suggest that the abnormal neutrophil
chemotactic response to N-formly-methionyl peptides is
limited to some cases of AgP.
 Early studies suggested that neutrophils from the serum of
patients with AgP show impaired chemotaxis to these
antigens.
 An in-vitro experiment showed that phosphoionositide
dependent kinase-1 regulates neutrophil chemotaxis.
 This suggests that the expression & activation levels of
phosphoionositide dependent kinase-1 which are significantly
reduced in AgP may explain the impaired neutrophil
chemotaxis in such patients.

50.  Albandar et al reported that the serum levels of IgA reactive to
periodontal pathogens were significantly higher in AgP.
 Furthermore neutrophils from AgP patients show increased
levels of expression of the FcαRI receptor.
 Cross-linking of IgA with the Fcα receptor on phagocytes
triggers the following host cellular responses such as
phagocytosis, antibody-dependent cell mediated cytotoxicity
and release of inflammatory mediators.
 Hence it concluded that individuals with increased expression
levels of FcαRI receptor on phagocytes and elevated levels of
IgA reactive to periodontal pathogen, may be at higher risk for
AgP.

51.  Papillon-Lefevre syndrome there is a loss of function
mutation affecting the cathepsin C gene on chromosome
11q14.2 and this influences a key enzyme essential in
activation of certain immune cells and in regulation of
epitheial cells.
 In Chediak-Higashi syndrome, mutations have been
identified in Lysosomal trafficking regulator ( CHS1/
LYST) gene on chromosome 1q42.3.

52. D) Environmental Factors:-
 In a large study, cigarette smoking was shown to be a risk factor for patients
with generalized forms of AgP (Schenkein et al. 1995).
 Smokers with GAP had more affected teeth and greater mean levels of
attachment loss than patients with GAP who did not smoke.
 IgG2 serum levels as well as antibody levels against A.a. are significantly
depressed in subjects with GAP who smoke.

53. References:
 Clinical periodontology and implant dentistry -5th edition,
Volume-1, Jan Lindhe.
 Clinical periodontology -
10thedition,Carranza,Neuman,Takei,Klokkevold.
 Periodontology 2000,vol-65, 2014.
 Assessment of peripheral neutrophil functions in patients with
localized aggressive periodontitis in the Indian population.
Rahul S. Bhansali, R. K. Yeltiwar, K. G. Bhat, Journal of Indian
Society of Periodontology - Vol 17, Issue 6, Nov-Dec 2013.