Jan Lindhe. Clinical Periodontology

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AGGRESSIVE PERIODONTITIS • 223

Fig. 9-4. Radiographs obtained from a Caucasian female with generalized pre-pubertal periodontitis. Radiographic

situation in (A) April 1978 when she was 4-5 years old, (B) December 1978; and (C) August 1979. The

radiographs illustrate the extent of alveolar bone loss that occurred over the 15-month period. Note the

widespread bone loss. During infancy, this patient had severe, recurrent skin and ear infections sustained by

Staphylococcus aureus and

Pseudomonas aeruginosa,

respectively. Delayed healing was also observed following

minor injuries. White cell counts revealed a persistent leukocytosis, with absolute neutrophil counts always above

8000/mm

. Gingival biopsy indicated that the inflammatory infiltrate consisted almost completely of plasma cells

and lymphocytes. No neutrophils were present, in spite of the abundance of these cells in the circulation. This

history and clinical manifestation appears to be consistent with the diagnosis of periodontal manifestations of

systemic disease in a subject with leukocyte adhesion deficiency (LAD). From Page et al. 1983.

dontitis. A distance of 2 mm between the cemento- and 9-7) (Sjodin & Mattson 1992). This tentative diagenamel

junction and the alveolar crest, in the absence nosis will have to be confirmed by a complete peri-

of the above-mentioned local factors, argues therefore odontal examination. In utilizing bite-wing radio-

for a suspected diagnosis of periodontitis (Figs. 9-6 graphs for the screening of patients, clinicians should

224 • CHAPTER 9

Fig. 9-5. Radiographs illustrating bone loss at the distal aspect of the mandibular first molar in a 15-year-old girl (a)

and progression of disease 1 year later (b).

Fig. 9-6. Diagrammatic representation of the use of bite-wing radiographs to screen for prepubertal periodontitis in

mixed dentition. The distance from the cemento-enamel junction (CEJ) and the marginal bone level (MBL) is meas-

ured from a line connecting the CEJ of the two adjacent teeth. Measurements are taken for each mesial and distal

surface. Normal CEJ-MBL distances for 7-9 year olds are less than 2.0 mm. If the measurement exceeds this

value, prepubertal periodontitis should be suspected, and a comprehensive periodontal examination should be

per-

formed.

be aware that radiographic marginal bone loss (in the

presence of probing attachment loss) is a highly spe-

cific diagnostic sign of periodontitis. Its sensitivity,

however, is lower than that of periodontal probing

because initial intrabony lesions may not appear on

radiographs as a result of the masking effects of intact

cortical plates (Suomi et al. 1968, Lang & Hill 1977).

Some initial cases of periodontitis may therefore re-

main undetected.

In older adolescents and adults, periodontal probing

is a more appropriate screening examination than the

use of radiographs. It is in this respect important to

differentiate between clinical use of periodontal

probing to perform a complete periodontal examina-

tion, and its use as a screening tool. Using probing to

detect attachment loss during a screening examination

requires circumferential probing to evaluate all sites

around the tooth. In a screening examination,

AGGRESSIVE PERIODONTITIS • 225

Fig. 9-7. Bite-wing radiographs illustrating advanced bone loss at primary molars, and initial involvement of

the mesial aspect of the first molar in a child with early onset periodontitis. Note the marginal pattern of bone

loss, which is significantly different from the pattern expected in association with the normal exfoliation of

deciduous teeth. Subgingival calculus can also be observed.

however, attachment loss values for all sites are usu-

ally not recorded. Furthermore, the screening exami-

nation can be stopped once evidence of attachment

loss has been detected, and therefore the need for a

comprehensive examination has been established.

The American Academy of Periodontology has re-

cently endorsed a simplified screening examination

for this purpose. This examination is based on a modi-

fication of the Community Periodontal Index of Treat-

ment Needs (CPITN) (Ainamo et al. 1982, American

Academy of Periodontology & American Dental As-

sociation 1992).

Once a case has been detected by a screening exami

nation, a comprehensive periodontal examination will

be necessary to establish a proper diagnosis. At this

stage, once a case of periodontitis has been con-

firmed, a differential diagnosis between aggressive (

type 1) periodontitis and chronic (type 2) periodonti-

tis needs to be made in accordance with the criteria

mentioned above and keeping in mind that cases

which do not fit the AgP criteria should be diagnosed

as chronic periodontitis.

Conclusion

Screening periodontal examinations should be per-

formed as part of every dental visit. Marginal bone

loss assessed on bite-wing radiographs, though less

sensitive than periodontal probing, may be used as a

screening tool in subjects with primary and mixed

dentitions. Attachment loss evaluated by periodontal

probing is the most sensitive screening approach cur-

rently available; it should be used in older adolescents

and adults. Differential diagnosis between AgP and

chronic periodontitis is made based on exclusion of

AgP.

ETIOLOGY AND PATHOGENESIS

As a group, aggressive forms of periodontitis are char-

acterized by severe destruction of the periodontal at-

tachment apparatus at an early age. This short time of

manifestation of clinically detectable lesions is gener-

ally interpreted as being the expression of highly viru-

lent causative agents or high levels of susceptibility of

the individual patient, or a combination of the two.

Bacterial etiology

The evidence implicating bacterial etiology in perio-

dontitis has been described in Chapter 4. The most

abundant evidence regarding the bacterial etiology of

AgP comes from studies of LAP. Evidence relating to

other forms of AgP (GAP) will be discussed only when

specifically different from LAP.

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 impor-

tance, in this respect, were microscopic studies dem-

onstrating the presence of a layer of bacterial deposits

on the root surface of advanced AgP lesions (List-

garten 1976, Westergaard et al. 1978). 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). 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 LIP in-

cluded Actinobacillus actinomycetemcomitans, Capnocy-

tophaga

sp.,

Eikenella corrodens, Prevotella intermedia

226 • CHAPTER 9

Table 9-1. Classical studies on the distribution of A. a. in LAP, gingivitis, adult periodontitis and in normal

non-diseased subjects

See text for a selection of more recent investigations.

and motile anaerobic rods, such as

Campylobacter rec-

tus. Gram-positive isolates were mostly streptococci,

actinomycetes and peptostreptococci.

One 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 (Socran-

sky & Haffajee 1992):

1. Association studies, linking the organism to the dis-

ease: A.a. is generally isolated in periodontal le-

sions from more than 90% of LAP patients and is

much less frequent in periodontally healthy indi-

viduals (Table 9-1) (for more recent investigations,

see also 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 ele-

vated 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. produces

several potentially pathogenic substances, includ-

ing a leukotoxin, and is capable of inducing disease

in experimental animals and non-oral sites (for

review see Zambon et al. 1988, Slots & Schonfeld

1991). Furthermore, it can translocate across epi-

thelial membranes.

3. Findings of immune responses towards this bacte-

rium: investigators have repeatedly reported sig-

nificantly 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 also

locally produce antibodies 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 have been linked

to a failure in reducing the subgingival load of A.a. (

Slots & Rosling 1983, Haffajee et al. 1984, Chris-

tersson et al. 1985, Kornman & Robertson 1985,

Mandell et al. 1986, 1987, Preus 1988).

A.a. is one of the few oral microorganisms regarded as

true infectious agents in periodontal disease. The ac-

ceptance of this concept has far-reaching conse-

quences with regards to strategies for prevention and

therapy of LAP or AgP. If A.a. is a real exogenous

pathogen, (1) avoidance of exposure to the organism

becomes a relevant issue in prevention, and (2) elimi-

nation of A.a. becomes a valid treatment goal. Thus,

the mere presence of A.a. would have to be regarded

as an indication for intervention. Consequently,

highly sensitive tests to detect the bacterium would be

useful diagnostic tools. Several studies have, in fact,

provided evidence for transmission of A.a. between

humans, e.g. from parent to child or between spouses

AGGRESSIVE PERIODONTITIS • 227

Table 9-2. Determinants of virulence and pathogenic potential of

A. actinomycetemcomitans

Factor

Significance

Leukotoxin

Destroys human polymorphonuclear leukocytes and macrophages

Endotoxin

Activates host cells to secrete nflammatory mediators (prostaglandins, interleukin-1 [3, tumor necrosis factor-a)

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

(DiRienzo et al. 1990, 1994, Preus et al. 1992, Petit et al.

1993a,b, Poulsen et al. 1994, Von Troil-Linden et al.

1995). Other studies have indicated that

A.a.

can be

eliminated with appropriate mechanical treatment

and adjunctive antibiotic therapy (Rams et al. 1992,

Pavicic et al. 1994).

The view of LAP as an

A.a.

infection is, however,

not undisputed. It has been opposed on the basis of

cross-sectional studies, showing a high prevalence of

this organism in certain populations, particularly

from developing countries (Eisenmann et al. 1983,

Dahlen et al. 1989, McNabb et al. 1992, Al-Yahfoufi et

al. 1994, Gmur & Guggenheim 1994), and for the fact

that there are patients with LJP who apparently nei-

ther show presence of

A.a.

in the oral flora nor have

elevated antibody titers to the organism (Loesche et

al. 1985, Moore 1987).

A.a. is

a short, facultatively anaerobic, non-motile,

Gram-negative rod. Using monoclonal antibody tech-

nology five serotypes (a, b, c, d, e) of

A.a.

can be

distinguished. Serotype-dependent variance in viru-

lence has been suggested. Differences in serotype dis-

tribution have been noted between patients with peri-

odontal disease and apparently non-affected carriers

A.a.

Serotype b has been found particularly often in

patients with LAP (Asikainen et al. 1991, Zambon et

al. 1996).

Several properties of

A.a.

are regarded as important

determinants of virulence and pathogenic potential (

Table 9-2). Among them, leukotoxin production is

considered highly significant since it may play an

important role in A.a.'s evasion of local host defences.

The leukotoxin produced by A.a. exhibits cytotoxic

specificity and destroys human polymorphonuclear

leukocytes and macrophages, but neither epithelial

and endothelial cells nor fibroblasts. It belongs to the

family of the RTX (Repeats in ToXin) toxins, which are

pore-forming lytic toxins (for details the reader is

referred to Lally et al. 1996).

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 leukotoxic strains has been reported in patients

with LAP than in chronic periodontitis patients or

healthy subjects (Zambon et al. 1996).

All Gram-negative bacteria are enveloped by two

membranes, of which the outer is rich in endotoxin.

This 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-113 and tumor necrosis

factor-a. It is also highly immunogenic, since high

titers of antibodies against its antigenic determinant

are frequently detected in infected individuals.

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 fi-

broblast 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 dem-

onstrated (for review see Fives-Taylor et al. 1996).

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 bac-

terium.

A.a.,

Capnocytophaga sputigena

and

Prevotella inter-

media have also been shown to be the most prominent

members of the subgingival microbiota of periodonti-

tis lesions in the primary dentition. The microbial

patterns observed in periodontal lesions of the pri-

mary dentition, however, seem to be more complex

than the ones detected in LAP patients.

Generalized aggressive periodontitis (GAP), for-

merly named generalized early onset periodontitis (

G-EOP) and rapidly progressive periodontitis (RPP),

have been frequently associated with the detection of

Porphyromonas gingivalis, Bacteroides forsythus and

A.a.

In contrast to A.a., which is facultatively anaerobic, P.

gingivalis and

B. forsythus

are fastidious strict anaer-

obes. P. gingivalis produces several potent enzymes, in

228 • CHAPTER 9

Table 9-3. Host defense mechanisms in the gingival sulcus

Intact epithelial barrier and epithelial attachment

Salivary flushing action, agglutinins, antibodies

Sulcular fluid flushing action, opsonins, antibodies, complement and other plasma components

Local

antibody production

High levels of tissue turnover

Presence of normal flora or beneficial species

Emigrating PMNs and other leukocytes

Modified from Page (1990).

particular collagenases and proteases, endotoxin,

fatty acids and other possibly toxic agents (Shah 1993).

A relationship between the clinical outcome of ther-

apy and bacterial counts has also been documented

for P.

girigivalis,

and non-responding lesions often con-

tain this organism in elevated proportions. High local

and systemic immune responses against this bacte-

rium have been demonstrated in patients with GAP (

Tolo & Schenck 1985, Vincent et al. 1985, Ebersole et

al. 1986, Murray et al. 1989).

Bacterial damage to the periodontium

Disease-associated bacteria are thought to cause de-

struction of the marginal periodontium via two re-

lated mechanisms: (1) the direct action of the microor-

ganisms or their products on the host tissues, and/or (

2) as a result of their eliciting tissue-damaging inflam-

matory responses (see Chapter 5 and Tonetti 1993).

The relative importance of these two mechanisms in

AgP remains speculative. Human investigations have

indicated that Actinobacillus actinonnfcetemcomitans is

able to translocate across the junctional epithelium

and invade the underlying connective tissue (Saglie et

al. 1988). These data support the hypothesis that direct

bacterial invasion may be responsible for some of the

observed tissue breakdown. Data from chronic perio-

dontitis, however, seem to indicate that two-thirds of

attachment loss and alveolar bone resorption is pre-

ventable through the action of non-steroidal anti-in-

flammatory drugs, and therefore tissue destruction

seems to be driven by the inflammatory process (Wil-

liams et al. 1985, 1989). Apical spread of bacteria

loosely adhering to the hard, non-shedding surface of

the tooth is thought to be controlled through a first line

of defense consisting of mechanisms such as the high

turnover of junctional epithelium keratinocytes, the

outward flow of crevicular fluid and the directed mi-

gration of polymorphonuclear leukocytes through the

junctional epithelium; the efficiency of these innate

immune mechanisms is highly enhanced by the pres-

ence in the gingival fluid of specific antibodies and

complement fragments (Page 1990) (Table 9-3).

Host response to bacterial pathogens

Both local and systemic host responses to AgP-associ-

ated microflora have been described. Local inflamma-

tory 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 impor-

tance of these cells in the local defense against bacte-

rial aggression and their potential role in host-medi-

ated tissue destruction. B cells and antibody-produc-

ing plasma cells represent a significant component of

the mononuclear cell-dominated connective tissue le-

sion (Liljenberg & Lindhe 1980). Plasma cells have

been shown to be predominantly IgG-producing cells,

with a lower proportion of IgA-producing cells (

Mackler et al. 1977, 1978, Waldrop et al. 1981, Ogawa

et al. 1989). Local IgG

-producing cells, in particular,

seem to be elevated. Another 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 gingiva and peripheral blood. These findings

have been interpreted to suggest the possibility of

altered local immune regulation (Taubman et al. 1988,

1991). Peripheral blood mononuclear cells from AgP

patients have been reported to exhibit a reduced

autologous mixed lymphocyte reaction, as well as a

higher than normal response to B cell mitogens (for

review see Engel 1996). Local inflammatory responses

are characterized by high levels of prostaglandin E

interleukin-1c and interleukin-113 in both crevicular

fluid and tissue (Masada et al. 1990, Offenbacher et al.

1993). Prostaglandin E

production, in particular, has

been shown to be highly elevated in AgP subjects

when compared to periodontally healthy individuals

and chronic periodontitis patients.

Specific antibodies against AgP-associated micro-

organisms (Lally et al. 1980, Steubing et al. 1982, Eber

sole et al. 1984, 1985a,b) and cleaved complement

fragments (Schenkein & Genco 1977, Patters et al.

1989) have also been detected in crevicular fluid from

AgP lesions. Of interest is the evidence indicating that

crevicular fluid titers of antibodies against AgP-asso-

ciated microorganisms are frequently higher than in

the serum of the same patient (Ebersole et al. 1984,

AGGRESSIVE PERIODONTITIS • 229

(Fig. a)

Localized aggressive periodontitis in siblings of 22 families

Fig. 9-8. (a) Patients suffering

from LAP in 22 families are repre

sented by solid black figures. In

each family the proband is on the

left. (h) Diagrammatic repre-

sentation of sibships involved in

study group. Numbers are the

same as in (a). Solid black figures

represent patients exhibiting de-

pressed neutrophil chemotaxis. In

this group, after correcting for

sampling bias, 40% of subjects pre

-sent with abnormal chemotaxis.

Subjects in sibship 8 are identical

twins. From Van Dyke et al. (1985).

Prevalence of LAP

67% of siblings (> 12 yrs), uncorrected

34% of siblings (> 12 yrs)corrected for proband bias

1985a,b). This observation, together with substantial

in vitro and

ex vivo

data, strongly suggests that sub-

stantial fractions of these antibodies are locally pro-

duced in the inflammatory infiltrate (Steubing et al.

7982, Hall et al. 1990, 1991, 1994). Substantial titers of

antibodies against A.a. and

P. gingivalis

have also been

detected in the serum of AgP patients. Furthermore,

in some patients, titers of antibodies reactive with A.a.

have been shown to be as high as the ones against

Treponema pallidum present in tertiary syphilis (0.1-1

g/ml); this clearly indicates the extent of host response

that can be mounted against these periodontal patho-

gens (for a review see Ebersole 1990, 1996).

Recent investigations have identified the immuno-

dominant A. actinomycetcmcomitans antigen to be the

serotype specific carbohydrate; furthermore, it has

been shown that the vast majority of antibodies reac-

tive with this carbohydrate in AgP patients consist of

IgG

(Califano et al. 1992). High titers and high avidity

A.a.

specific IgG

have been demonstrated in LAP

patients, where high antibody titers are thought to be

associated with the host's ability to localize attach-

ment loss to few teeth; conversely, GAP patients are

frequently seronegative for A.a. or display low titers

and avidity. Anti A.a. serotype polysaccharide IgG

therefore, are considered to be protective against

widespread AgP (Tew et al. 1996).

Of importance are findings reporting antibody re-

sponse to

P. gingivalis

in GAP forms. Patients suffering

from these forms of disease frequently show both low

levels of serum antibodies against P. gingivalis and low

levels of antibody avidity, indicating a specific inabil-

ity of some GAP patients to effectively cope with these

bacteria. Importantly, however, both titers and avidity

of antibodies reacting with

P. gingivalis

can be im-

proved as a result of therapy.

Another important aspect of host response towards

AgP microorganisms has been the recognition that

polymorphonuclear leukocytes (PMN) of some LAP

and GAP patients present decreased migration and

antibacterial functions (Genco et al. 1980, 1986, Van

Dyke et al. 1982, 1986, 1988). These abnormalities are

frequently minor in the sense that they are usually not

associated with infections other than periodontitis. A

(Fig. b)

Neutrophil chemotaxis in LAP families

230 • CHAPTER 9

Major gene locus: AgP susceptibility gene

(Fig. a)

H = high IgG

titer, I = intermediate IgG

titer, L = low IgG

titer

--------------------------------------------------------

Clinical disease expression

(Fig. c)

Fig. 9-9. (a) Genetic predisposition

to AgP is determined by a single

gene of major effect, inherited as

an autosomal dominant trait. (b)

Modifying genes may control im-

mune responses that determine the

clinical extent and severity of

periodontal destruction in AgP.

Here an allele controlling IgG

lev-

els is inherited as a codominant

trait. (c) Independent inheritance of

major locus and modifying locus

illustrating how LAP and GAP may

segregate within the same family.

The propensity to develop AgP is

dependent upon inheritance of a

major susceptibility gene. The

clinical phenotype is de-pendent

upon host ability to pro-duce IgG

in response to periodontopathic

bacteria. High IgG

titers limit

disease extension. Intermediate

and low IgG

titers are less ef-

fective in limiting intermediate

disease progression. From

Schenkein (1994), as modified by

Hart (1996).

key report has indicated that PMN abnormalities in LAP

patients seem to cluster in families much in the same

way as AgP does (Van Dyke et al. 1985) (Fig. 9-8). This

evidence has been interpreted as a suggestion that the

LAP-associated PMN defect may be inherited. Other

recent reports have indicated that PMN abnor-

malities in LAP patients may be, at least in part, the

result of a hyper-inflammatory state resulting in the

presence of pro-inflammatory cytokines in the serum of

some AgP patients (Shapira et al. 1994, Agarwal et al.

1996).

AGGRESSIVE PERIODONTITIS • 231

Genetic aspects of host susceptibility

Several family studies have indicated that the preva-

lence of AgP is disproportionately high among certain

families, where the percentage of affected siblings

may reach 40-50% (Saxen & Nevanlinna 1984, Beaty

et al. 1987, Long et al. 1987, Boughman et al. 1992,

Marazita et al. 1994). Such a dramatic familial aggre-

gation of cases indicates that genetic factors may be

important in susceptibility to AgP. Genetic studies in

these families suggest that the pattern of disease trans-

mission is consistent with mendelian inheritance of a

gene of major effect (Saxen & Nevanlinna 1984, Beaty

et al. 1987, Boughman et al. 1992, Hart et al. 1992,

Marazita et al. 1994). This means that the observed

familial pattern can be partly accounted for by one or

more genes that could predispose individuals to de-

velop AgP. Segregation analyses have indicated that

the likely mode of inheritance is autosomal dominant (

Saxen & Nevanlinna 1984, Beaty et al. 1987, Hart et

al. 1992, Marazita et al. 1994; Fig. 9-9a). Most of these

investigations, however, were carried out in African-

American populations; it is therefore possible that

other modes of inheritance may exist in different

populations. Segregation analysis can provide infor-

mation about the mode of inheritance of a genetic trait

but does not provide information about the specific

gene(s) involved. The chromosomal location of a gene

of major effect for a trait such as AgP susceptibility can

be determined by linkage analysis. An investigation

utilizing this methodology reported linkage of LAP to

the vitamin D binding locus on region q of chromo-

some 4 in a large family of the Brandywine population

(Boughman et al. 1986). These results, however, were

Table 9-4. Genes known to affect human PMN function or host response to LPS load and/or thought to be

among the candidate genes of major effect in EOP susceptibility

Condition

OMIM*

Trans-

mission

Chromo-

some

location

Comments

Bactericidal

permeability

increasing

protein (BPIP)

109195

20q11-12

BPIP is associated with PMN granules and is bactericidal to Gram

organisms. It binds to LPS with high affinity. BPIP is 45% homologous

to LPS binding protein.

Lipopolysaccharide

binding protein (LBP)

151990

20q11-12 Produced during acute phase of infection: binds to LPS and functions

as a carrier for LPS; functions in monocyte response.

Monocyte

differentiation antigen

(CD 14)

158126

5q31

Receptor for LBP-LPS complex.

Prostaglandin synthase

2 (PTGS2)

600262

1q25.2-3

Major role in regulation of prostaglandin synthesis. Dramatic induction

of PTGS2 mRNA occurs in normal peripheral blood leukocytes in

response to LPS.

PMN actin

dysfunction (NAD)

257150

Carriers (heterozygotes) have a 50% decrease in actin filament

assembly; affected individuals (homozygotes) have recurrent bacterial

infections. PMN severely defective in migration and particle ingestion;

basic defect due to failure of PMN actin polymerization.

Myeloperoxidase

deficiency (MPO)

254600

17q12-21

Absence of MPO. MPO is a dimeric protein that catalyzes the

production of oxidating agents with microbicidal activity against a

wide range of microbes. Several variants have been described.

IgE elevation

with PMN

chemotaxis defect

147060

Impaired lymphocyte response to Candida antigen; recurrent bacterial

infections.

Fc receptor

gamma IIA

polymorphism

(FCGR2A)

146790

1 q21-q23

Allelic variants of the Fc-gamma receptor 2A confer distinct phagocytic

capacities providing a possible mechanism for hereditary susceptibility

to infection. The H131 allele is the only FGR2A that recognizes IgG

efficiently, and optimal IgG

handling occurs only in the homozygous

state for H131. The allelic variant R131 has low binding of IgG

Immunoglobulin G2m

allotypes

N/A N/A

Specific allotypes associated with IgG

response to specific bacterial

antigens. Subjects lacking specific allotypes may be selectively unable

to mount efficient antibody response against specific antigens.

* Online Mendelian Inheritance in Man (OMIM). Modified from Hart (1996).

232 • CHAPTER 9

Table 9-5. Effect of smoking on extent and severity of GAP

Smoking status

Mean % of sites with PAL 5

mm *

Mean PAL (mm) *

GAP

Smokers

49.0 ± 3.9 2.78 ± 0.2

Non-smokers

36.8 ± 3.8 2.14 ± 0.2

* Values adjusted for age and mean plaque index, subject as unit of analysis. Smokers showed significantly greater extent and Rverity of

periodontal disease than non-smokers after correcting for age and oral hygiene level.

Modified from Schenkein et al. (1995).

not confirmed in a subsequent study utilizing a differ-

ent population (Hart et al. 1993). Such data are cur-

rently considered to support the existence of genetic

heterogeneity in LAP forms, and of distinct forms of

AgP. Therefore, it is currently maintained that al-

though formal genetic studies of AgP support the

existence of a gene of major effect, it is unlikely that all

forms of AgP are due to the same genetic defect (Hart

1996). This notion is consistent with the fact that nu-

merous diseases and syndromes with similar clinical

appearance are known to result from different genetic

polymorphisms. Based on current knowledge that

AgP subjects present high prevalence of PMN func-

tion defects, and that they have been shown to pro-

duce high levels of inflammatory mediators in re-

sponse to LPS stimulation, several loci have been

proposed as genes conferring increased susceptibility

to AgP. These genes are associated with neutrophil

function and with the host ability to effectively deal

with LPS exposure, and are listed in Table 9-4 (for

review see Hart 1996).

Besides genes of major effect that may determine

susceptibility to AgP, other genes may act as modify-

ing genes and influence clinical expression of the dis-

ease. In this respect, particular interest has been fo-

cused on the impact of genetic control on antibody

responses against specific AgP associated bacteria and

against A.a. in particular. These studies have indicated

that the ability to mount high titers of specific antibod

ies is race-dependent and probably protective (Gun-

solley et al. 1987, 1988). This has been shown to be

under genetic control as a co-dominant trait, inde-

pendent of the risk for AgP. In individuals susceptible

to AgP, therefore, the ability to mount high titers of

antibodies (IgG

in particular) may be protective and

prevent extension of disease to a generalized form (

Schenkein 1994, Fig. 9-9b,c). Allelic variations in the

Fc receptor for IgG

immunoglobulins have also been

suggested to play a role in suboptimal handling of A.a.

infections. PMN expressing the R131 allotype of

FcyRIIa (i.e. an Fc receptor containing an arginine

instead of a histidine at aminoacid 131) show de-

creased phagocytosis of

A.a.

(Wilson & Kalmar 1996).

Environmental aspects of host susceptibility

Recent evidence has indicated that, besides genetic

influences, environmental factors may affect the clini-

cal expression of AgP. In a large study, cigarette smok

ing 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 (Table 9-5). Environ-

mental exposure to cigarette smoking, therefore,

seems to add significant risk of more severe and preva

lent disease to this group of already highly

susceptible subjects. The mechanism(s) for this

observation are not completely understood, but

findings from the same group indicate that IgG

serum

levels as well as antibody levels against A.a. are

significantly de-pressed in subjects with GAP who

smoked. Since these antibodies are considered to

represent a protective response against A.a., it is

possible that depression of IgG

in smokers may be

associated with the observed increase in disease

extent and severity in these subjects.

Current concepts

Aggressive forms of periodontitis are currently con-

sidered to be multifactorial diseases developing as a

result of complex interactions between specific host

genes and the environment. Inheritance of AgP sus-

ceptibility is probably insufficient for the develop-

ment of disease: environmental exposure to potential

pathogens endowed with specific virulence factors is

also a necessary step. Host inability to effectively deal

with the bacterial aggression and to avoid inflamma-

tory tissue damage results in the initiation of the dis-

ease process. Interactions between the disease process

and environmental (e.g. cigarette smoking) and ge-

netically controlled (e.g. IgG

response to A.a.) modi-

fying factors are thought to contribute to determining

the specific clinical manifestation of disease (Figs. 9-

9a-c and 9-10).