Aggressive Periodontitis (etiology and pathogenesis)

Seminar :

Leena Parmar

Index Introduction

Definition

Classification

Etiology & pathogenesis:-

a) microbiologic factor

b) immunologic factor

c) genetic factor

d) environmental factor

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.

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."

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

(Aggregatibacter actinomycetemcomitans) and, in some

Far East populations, Porphyromonas gingivalis

• 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.

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)

• 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

• 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.

Etiology and Pathogenesis :-

Microbiologic Factors Immunologic Factors Genetic Factors Environmental Factors

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).

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.

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.

 

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).

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).

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). 

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).

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.

(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

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.

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

Lipid + polysaccharide = lipopolysaccharide (LPS)

LPS is set free when bacterial cells die or

multiply.

Mechanism of LPS

LPS of A.a

Host cells (macrophages)

Inflammatory mediators ( prostaglandins, interleukin-1β, TNF)

Activate

secrete

Fives-Taylor et al. (1996)

Properties of A.a

Immunosuppressive properties,

Collagenolytic activity

&

Inhibition of neutrophil

chemotaxis

Leukotoxin

Destroys human polymorphonuclear

leukocytes

Macrophages

Lally et al. (1996).

Leukotoxin

Belongs to

family of RTX (Repeats in ToXin)

Pore-forming

toxins

Haraszthy et al. (2000); Tan et al. (2001); Cortelli et al.(2005)

JP2 clone Commonly found Aggressive periodontitis patients

(North and West African)

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

Determinants of virulence and pathogenic potential of A. actinomycetemcomitans

• Significance

Factor

• Destroys human polymorphonuclear leukocytes and macrophages

Leukotoxin

• Activates host cells to secrete infammatory mediators (prostaglandins, interleukin-1β, tumor necrosis factor-α)

Endotoxin

• May inhibit growth of beneficial species

Bacteriocin

• May inhibit IgG and IgM production

Immunosuppressive

Factors

• Cause degradation of collagen

Collagenases

• May inhibit neutrophil chemotaxis

Chemotactic inhibition

factors

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-damaginginflammatory responses

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

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

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

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).

Mackler et al. (1977, 1978); Waldrop et al. (1981); Ogawa et al. (1989).

Plasma cells IgG-producing cells

&

IgA-producing cells

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

Masada et al. (1990); Offenbacher et al. (1993).

Local inflammatory responses

PGE2, IL-1α

IL-1β

Crevicular fluid

Tissue

Characterized by

Schenkein & Genco (1977); Patters et al. (1989)

Specific antibodies against AgP-associated microorganisms

Crevicular fluid from AgP lesions.

Detected in

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

Genco et al. (1980, 1986); Van Dyke et al. (1982, 1986, 1988).

PMNs of some LAP and GAP

Decreased migration

Decreased antibacterial

functions

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

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.

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.

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.

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.

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.

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.

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.

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.

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.