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Host response in aggressiveperiodontitis

CY E L E E KU L K A R N I & DE N I S F. KI N A N E

As a preliminary to discussing the host response in

aggressive periodontitis it is worthwhile considering

briey the classication and presentation of this dis-

ease entity. There are numerous periodontal diseases

that affect children and adolescents. Previous classi-

cation systems dened the common forms of chronic

periodontal diseases by age of onset and named this

group early-onset periodontitis. Classication sys-

tems for periodontal diseases changed in recognition

of the signicant overlap between these categories.

Newer classication systems have reclassied

periodontitis into three major forms: chronic perio-

dontitis; aggressive periodontitis; and necrotizing

periodontitis (38). We now refer to early-onset peri-

odontitis as aggressive periodontitis.

The prevalence of chronic periodontal disease

increases with age, with periodontitis being quite rare

in the

rst three decades of life. Aggressive periodon-titis manifesting in children and adolescents is again

quite uncommon, affecting typically

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deciencies in host defenses.

genetic predisposition.

This volume of Periodontology 2000 includes articles

dealing in depth with microbial aspects and genetic

predisposition, and this article will focus on host

defenses and deciencies whilst discussing the

microbial etiology as it initiates disease and the

genetic background to the host-defense deciencies

in general.The term periodontal diseases encompasses the

full spectrum of inammatory periodontal diseases,

from gingivitis to all forms of periodontitis, including

chronic, aggressive and necrotizing forms. The Euro-

pean Workshop in Periodontology (32) declared gin-

givitis and periodontitis as a continuum of the same

chronic inammatory condition that affects the

supporting structures of the teeth (32). It was previ-

ously believed that gingivitis was an inevitable conse-

quence of microbial plaque accumulation on the

teeth; however, it is now recognized that inherent

patient susceptibility plays a large role in the expres-

sion of gingivitis and its progression to periodontitis.

Gingivitis occurs in a signicant percentage of the

population, whereas advanced chronic periodontitis,

leading to multiple tooth loss, develops in only a frac-

tion of the population (1015%) (30). The progression

of gingivitis to periodontitis is thought to be inu-

enced by the individuals immune and inamma-

tory responses. Chronic periodontitis and aggressive

periodontitis are among the more signicant of the

periodontal diseases as they result in tooth loss but,

given the progression from gingivitis to periodontitis,prevention of gingivitis may be more important than

previously thought.

Concept of susceptibility

Differences among individuals in the response to

bacterial plaque may be a result of variation in host

susceptibility, with some individuals being very

susceptible and developing aggressive forms of peri-

odontitis at a relatively young age, whilst others might

be resistant and will never develop periodontitis (36).The majority of the population falls within this range

and will develop a degree of gingival inammation

and possibly some periodontal disease over time

when exposed to bacterial plaque. The rate at which

this develops can vary between individuals, with

some experiencing a slow progressing disease over

the course of a lifetime and others developing more

rapid and severe periodontal tissue destruction

resulting in tooth loss. It has been suggested that an

excessive host immune response to the periodontal

microora may also be partly responsible for varia-

tion in the disease response but so far this has not

been well supported by scientic research. An exces-

sive monocyte/macrophage response can be found in

patients with periodontitis compared with subjects

with no periodontitis (22, 61). Engebretson et al. (18)

have shown that periodontal indices are strongly cor-

related with the levels of inammatory cytokines ingingival crevicular uid. However, thus far these

inammatory markers have not shown diagnostic

utility, and a better understanding of the host-

response processes is needed to furnish better diag-

nostic aids for clinical application.

Numerous etiological factors are responsible for

the ultimate expression of periodontal disease.

Clearly, bacterial plaque accounts for only a portion

of the risk of an individual and therefore other

factors must also be considered, including host

factors, environmental factors and genetic factors.

Each component modies the individuals manifesta-

tion of the severity and progression of periodontal

diseases.

Susceptibility to gingivalinammation

Susceptibility to gingivitis is supported by literature

showing that subjects have a highly variable rate of

development of gingivitis. Weidmann et al. (75)

reported a group of 62 subjects in whom a wide rangeof host responses occurred after withdrawal of oral

hygiene measures for 21 days; a susceptible group

who exhibited signicant gingival inammation

within 14 days; and an intermediate group (the

majority) who developed gingival inammation by

day 21. This separation of resistant and susceptible

individuals has been observed in several studies (1,

41, 42) with an across-studies estimate indicating

that this resistant group makes up 13% of subjects.

Trombelli et al. (73) and Engebreton et al. (18) have

shown that there are interindividual differences in

the response to dental plaque in gingivitis studies. Allsubjects expressed some gingivitis, but some devel-

oped much more severe and rapid inammation.

These interindividual differences may be explained

by genetics or environmental factors but preliminary

genetic evidence supports the possibility that there

are interindividual differences in the ability to

develop gingival inammation and showed that spe-

cic genetic characteristics (for example interleukin-

1 polymorphisms) may contribute to exacerbated

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gingival inammation in response to plaque accu-

mulation. The relationship between an individuals

susceptibility to gingivitis and their susceptibility to

the development of periodontitis is currently

unclear. Those who develop excessive gingivitis may

also be expected to be prone to developing aggres-

sive periodontitis. However, clinically, subjects with

aggressive periodontitis appear to have dispropor-

tionately low levels of bacterial plaque and inam-mation relative to the degree of periodontal

destruction. In the case of smokers, there are simi-

larly low levels of gingival inammation, presumably

owing to the restriction of blood ow, and yet a high

level of periodontal disease. In smokers, environ-

mental factors play a role in masking the presence of

gingivitis and in the aggravation of periodontal dis-

ease. This begs the question: is there a link between

gingivitis susceptibility and periodontitis in which

environmental or other risk factors play a role in

modifying the connection or are the two completely

independent entities with distinct etiologies?

Numerous studies have shown genetic modulation

in the susceptibility of an individual to develop

gingivitis but how this relates to periodontitis is yet

to be determined. For the clinician, the ability to

determine a patients susceptibility, either through

genetic markers or otherwise, may play a major role

in determining a course of treatment. For example,

in a susceptible child or adolescent undergoing

orthodontic treatment it can be expected that gingi-

vitis will occur much more rapidly or severely than

in other patients and thus a more rigorous recallschedule may be warranted for this patient. Or per-

haps in a patient requiring a crown, the practitioner

may opt to alter the nish line to be supragingival to

prevent an unwanted localized inammatory

response in a patient who is susceptible to gingivitis

compared with one who is resistant.

In contrast to gingivitis, susceptibility to advanced

periodontitis with multiple tooth-loss is seen in only

a subset of the population (1015%) (6). It is vari-

able in that it does not affect all teeth to the same

extent, but has both a subject and a site predilec-

tion. Aggressive periodontitis is most commonwithin the rst three decades of life and, speci-

cally, localized aggressive periodontitis is typically

localized to the permanent rst molars and incisors

and often occurs circumpubertally. Retrospective

data in some studies of patients with localized

aggressive periodontitis have suggested that bone

loss in the primary dentition may be an early sign

of disease (63). The review on genetics in this vol-

ume of Periodontology 2000 may give a more com-

plete understanding of genetic susceptibility as it

pertains to clinical disease entities but at the same

time there is considerable complexity in that sus-

ceptibility to gingivitis may be related to susceptibil-

ity to aggressive or chronic periodontitis and our

clear ability to diagnose and categorize disease ef-

ciently will impact on our ability to discover and

prove underlying genetic causes.

Risk factors

The presence of a risk factor implies a direct

increase in the probability of a disease occurring.

Periodontal disease is considered to have multiple

risk factors (4). The term risk factor refers to an

aspect of personal behaviour or lifestyle, an envi-

ronmental exposure, or an inborn or inherited char-

acteristic, which on the basis of epidemiological

evidence is known to be associated with a health

related condition. Risk factors are part of the causal

chain for a particular disease or can lead to expo-

sure of the host to a disease. In periodontal disease

there are numerous pathogens that have been iden-

tied as potential key risk factors; however, it has

become clear that although necessary, the presence

of the pathogens is not sufcient for disease to

occur. The presence of microorganisms is a crucial

factor in inammatory periodontal disease, but the

progression of the disease is related to host-based

risk factors. Aggressive periodontal disease is a mul-

tifactorial process that results from a combination ofgenetic, environmental, host and microbial factors

(37).

Specic inammatory and immuneprocesses in periodontal disease

Variation in susceptibility to periodontitis is well rec-

ognized. However, the pathological basis of this

range of disease expression is poorly understood. In

particular, despite the availability of signicant infor-

mation regarding the inammatory and immuneprocesses involved in periodontitis, the differences

between the pathology of chronic periodontitis vs.

aggressive periodontitis have not been clearly identi-

ed. Thus, the task of deriving clinically important

messages is unpromising from the outset. In contrast

to gingivitis, the host response in periodontal disease

produces plasma-cell-dominated lesions. Genetic

and environmental factors modify and affect the

host response; however, it has yet to be determined

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how, and to what degree, these factors inuence

immune and inammatory processes. Aspects of the

inammatory and immune processes both

humoral and cellularwhich develop in response to

the microbial insult from dental plaque could be

important areas for therapeutics and diagnostics in

the future but are currently too poorly understood

to be of use. Whilst some inammatory and immune

responses are expected in the presence of a micro-bial biolm, the excessive plasma-cell inltrate seen

in periodontitis may be illustrative of an individuals

inability to defend against periodontal pathogens

and thus may indicate a predisposition to periodon-

titis. However, short of excising tissue we have little

way of utilizing this information diagnostically and

prognostically.

Bacterial risk factors

Examples of microbes implicated as risk factors in

periodontitis are numerous. Carlos et al. (12) found

that the presence ofPrevotella intermedia, along with

gingival bleeding and calculus, was correlated with

attachment loss in a group of Navajo adolescents,

1419 years of age. Grossi et al. (26) found that Por-

phyromonas gingivalisand Tannerella forsythiawere

associated with increased risk for attachment loss as a

measure of periodontal disease, after adjustment for

age, plaque, smoking and diabetes. The problem with

these types of microbial disease-association studies is

that the microbial plaque microbiome which is impli-cated in initiating disease has a vast and varied num-

ber of microorganisms (21), possibly also including

viruses and even, in some cases, protozoa.

In the past, the predominant microorganism found

in localized aggressive periodontitis was reported as

A. actinomycetemycomitans, but the supporting litera-

ture does not survive close scrutiny and in the paper

by Faveri et al. (20) the level ofA. actinomycetemyco-

mitans was below the detection limit of their well-

conducted study. Multiple studies showed markedly

elevated levels of serum antibody to A. actinomycete-

mycomitansin patients with localized aggressive peri-odontitis (7, 16, 43). In patients with localized

aggressive periodontitis who were treated success-

fully, there was signicant reduction or elimination

of A. actinomycetemycomitans. In those who failed

treatment, persistent levels ofA. actinomycetemycom-

itanswere found in the affected sites (47, 58). The rea-

son for this nding may be explained by the presence

of antibodies that are cross-reactive across gram-neg-

ative species, and therefore although the titers of anti-

body to A. actinomycetemycomitans were reduced,

this was a reection more of a broad reduction in

antibody titers against gram-negative anaerobic rods

than specic support for the importance of one par-

ticular bacterium over the many others in the oral

microbial biolm relevant to periodontal disease.

An important aspect of any pathogens ability to

affect a host is its virulence factor. A. actinomycete-

mycomitans has been shown to produce a leuko-toxin an exotoxin with the primary toxic effect of

leukocyte destruction, specically of polymorpho-

nuclear neurophils of the host (65, 79). This quality

has been regarded as one of the key reasons for

this species predominance in localized aggressive

periodontitis. Despite these compelling studies, the

idea that A. actinomycetemycomitans is the causa-

tive agent of localized aggressive periodontitis has

not gone undisputed. Numerous studies have

shown that although highly prevalent in most cases

of localized aggressive periodontitis, A. actinomycet-

emycomitans is not present in all cases of localized

aggressive periodontitis. Several cross-sectional

studies (13, 17, 25, 49, 75) showed that there is a

generally high prevalence of A. actinomycetemycom-

itans in many populations, particularly in develop-

ing countries. Studies have also indicated that

A. actinomycetemycomitans has been detected in

subgingival plaque in the absence of localized

aggressive periodontitis. Conversely, there have also

been reports of patients with localized aggressive

periodontitis without detectable A. actinomycetemy-

comitans, and in the comprehensive molecularstudy of the aggressive periodontitis microbiome

performed by Faveri et al. (20) they could not

detect A. actinomycetemycomitans and dismissed it

as a relevant microorganism in their population.

Clearly, A. actinomycetemycomitans has, in the past,

been considered to play an important role in local-

ized aggressive periodontitis but this is question-

able in non-black populations and calls into

question the clinical recommendation to use tetra-

cycline in the treatment of aggressive periodontitis

and the clinical relevance of the extensive studies

on leukotoxin and cytolethal distending toxin.The inammatory and immune responses in the

gingival pocket of periodontal patients are presumed

to be initiated and perpetuated by gram-negative

anaerobic rods and spirochetes. Knowledge of the

causal bacteria in periodontitis, other than the appre-

ciation that a biolm containing predominantly

gram-negative anaerobic rods and anaerobic spiro-

chetes pertains, does not as yet help in the manage-

ment of periodontitis other than suggesting that if an

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Genco (64), Tanner et al. (71) and recently Dewhirst

and colleagues (15) identied several gram-negative

bacterial species as putative pathogens in oral tissue

destruction.

Innate immunity to oral pathogens

Theeld of innate immunity has mushroomed during

the past decade, mainly because of the identication

of pathogen-recognition receptors and mechanisticcellular signaling pathways related to it. Several of

these pathogen-recognition receptors have been

identied and characterized, including toll-like

receptors, Nod-like receptors, RIG-like receptors and

dectins as pathogen sensors (50). More recently,

co-operation between different receptors (including

chemokine receptors, integrins, G-protein coupled

receptors and the complement system) and their cel-

lular signaling pathways in recognizing pathogens

and mounting an innate immune response, particu-

larly to oral pathogens have been elucidated (19). In

the context of polymicrobial infection, the immune

response triggered may be a result of the simulta-

neous activation of several cellular signaling path-

ways and it is unlikely that a signaling pathway is

activated in isolation. All of these pathways and

receptors may have a critical role in the etiology of

aggressive periodontitis and, similarly, variations in

these molecules may be induced by genetic variants

that might be the critical predisposing genetic factors

in aggressive periodontitis hereditability. Thus, they

are worthy of study.

Toll-like receptors are among the most studiedpattern-recognition receptors as a result of their role

in detecting varied pathogen-associated molecular

patterns. So far, 10 human toll-like receptors have

been identied with the ability to recognize specic

microbial structures (31). Specically, toll-like recep-

tor 4 recognizes the lipopolysaccharide of gram-

negative bacteria, and toll-like receptor 2 forms

heterodimers with toll-like receptor 1 or toll-like

receptor 6 and recognizes peptidoglycan, lipopeptide

and lipoproteins. Double-stranded RNA is recognized

by toll-like receptor 3, whereas toll-like receptor 5 can

detect bacterial agellin. Toll-like receptor 7, toll-likereceptor 8 and toll-like receptor 9 recognize bacterial

and viral molecules. Once these receptors, with the

help of co-receptors or adaptor molecules, recognize

pathogen-related biomolecules, several intracellular

signaling events occur, leading to the production of

inammatory cytokines, antimicrobial peptides, co-

stimulatory molecules, type I interferons and chemo-

kines to mount the innate immune response (11).

Any of these defensive response molecules could be

defective and be part of the specic susceptibility

associated with aggressive periodontitis [see Fig. 1

(10)].

The innate immune response is also critical in acti-

vating antigen-presenting cells and thus in stimulat-

ing the adaptive immune responses. Polymicrobial

infection seems to be much more complicated, in

terms of cellular activation, than originally thought

and again this complicates our understanding of theetiology and susceptibility in aggressive periodontitis.

Considering the diversity of microorganisms in bio-

lm colonization, activation of multiple signaling

pathways simultaneously seems to be relevant in

polymicrobial-related persistent inammation, as in

aggressive periodontitis.

Thus, the role of innate immune cells is generally to

detect microbes and maintain hostmicrobe immune

homeostasis and to induce antimicrobial defense

mechanisms. Innate immune cells, such as epithelial

cells, broblasts, dendritic cells, macrophages and

neutrophils, act as the rst line of defense against

invading pathogens and, through the actions of anti-

gen-presenting cells (dendritic cells and macro-

phages), mount an adaptive immune response. Of

these cells, the most discussed in the context of the

etiopathology of aggressive periodontitis is the poly-

morphonuclear neutrophil. A large body of literature

in the 1970s and 1980s supported the concept of pre-

disposition to juvenile periodontitis (as it was then

called) as a result of a polymorphonuclear neutrophil

chemotactic defect (24). Kinane et al. (33, 34) per-

formed an extensive study of polymorphonuclearneutrophil chemotaxis from a series of these patients

with aggressive periodontitis and found not only no

defect, but rather an overactivation of these cells in

the peripheral blood of patients with aggressive

periodontitis. Thus, although polymorphonuclear

neutrophils are critical in the defense of the peri-

odontium, as evidenced by the rapid destruction in

conditions such as leukocyte adhesion deciency, a

neutrophil chemotactic defect does not appear to be

the key mechanism. There are, however, systemic dis-

eases, in addition to leukocyte adhesion deciency,

which have defective polymorphonuclear neutrophilsas a result of the absence of a crucial trafcking mole-

cule. Such diseases include PapillonLefevre syn-

drome, in which a neutrophil antimicrobial molecule,

cathepsin C, is missing and this renders the patient

also susceptible to an early-onset form of periodontitis,

which is similar to, but different from, aggressive peri-

odontitis (37). Clearly, researchers attempting to uncover

the genetic etiology of aggressive periodontitis have

researched, and continue to research, these promising

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molecules and pathways in the search for the underlying

genetic predisposition to aggressive periodontitis.

Immune responses

Even in a state of general health, periodontal tissues

will almost always exhibit a degree of leukocyte inl-

trate because of the constant pressures of microbial

biolm and deposits adjacent to tissues. In a state ofdisease the tissues of the periodontium show

increased tissue turnover and cellular activity associ-

ated with inltrating inammatory cells (54). It has

been suggested in the literature that signicant num-

bers of B-cells and T-cells accumulate in these tissues;

however, the functions of these cells in the periodon-

tal-disease process in not well understood.

Literature describing the host response, at a cellular

level, in periodontal disease is often fraught with con-

tradictory remarks including periodontitis is a B-cell

lesion and the immunoregulatory role of T-cells in

periodontitis (46, 51, 52, 59). These observations are

often a result of immunohistochemical methods used

to determine lymphocyte subsets. While specic

observations are noted using these methods, the

inter-relationship between various types of cells can-

not be directly elucidated. For example, while T-cells

are implicated in immunoglobulin synthesis in vitro

(29, 51, 53), the results of these studies do not easilyextrapolate to in-vivo situations where complex

interactions between a variety of inltrated inamma-

tory cells occur. In these studies it is often difcult to

assess the role of the different cell types based on lim-

ited observations and immunochemical analysis, and

so the true function and inter-relationship between

the various types of cells often remains unknown.

Data suggest that both B-cells and T-cells are long

lived in gingival tissues and in periodontal granula-

Fig. 1. A simplied signaling cascade in the oral biolm,

activated by toll-like receptors and by the toll-like receptor

cross-talk pathway. Cellular signaling to oral biolms may

activate several unidentied pathways, leading to the release

of cytokines, chemokines, interferon and antimicrobial pep-

tides. These released molecules amplify the inammation

and help to kill the bacteria of the biolm, and also aid in

the recruitment of phagocytes to perform this task and ulti-

mately aid in the restoration of homeostasis to the recovered

tissues. Adapted from Benakanakere & Kinane (10). cAMP,

cyclic AMP; CXCR, CXC chemokine receptor; EDGR, epider-mal growth factor receptor; IL, interleukin; iNOS, inducible

nitric oxide synthase; IPAF, ICE protease-activating factor;

IRF, interferon regulatory factor; mTOR, mammalian target

of rapamycin; MyD88, myeloid differentiation primary

response gene (88); NALP, NALP inammasome; NF-jB,

nuclear factor-kappaB; NOD, nucleotide oligomerization

domain; PAR, protease-activated receptor; PI3K, phospho-

inositide 3-kinase; PKA, protein kinase A; RIG-1/MDA5, reti-

noid-inducible gene 1/melanoma differentiation-associated

protein 5; S1P, sphingosine-1-phosphate; Sphk1, sphingo-

sine kinase 1; TNFR, tumor necrosis factor receptor; TLR,

toll-like receptor; TRIF, TIR-domain-containing adapter-inducing interferon beta.

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tion tissues. These cells probably have the ability to

migrate between blood and lymph pathways in order

to participate in the immune response (39). This is

supported by the ndings that: (i) CD5-positive B-

cells are present in the gingiva at higher proportions

than in the blood(68); (ii) activated B-cells are present

in the periodontium(76); and (iii) CD5-positive B-cells

do not proliferate (2).

T-cells behave as a double-edged sword; whilstnecessary for host protection from bacterial invasion,

the release of excessive amounts of cytokines from T-

cells will result in damage to the host because of their

tissue-degradative properties. The function of the T-

cell in a lesion can be determined by the cytokines

that they release. T-helper (CD4+) cells can be catego-

rized into three subgroups based on their cytokine

prole: T-helper 1 cells (which secrete interleukin-2,

interleukin-12, tumor necrosis factor alpha and inter-

feron gamma); T-helper 2 cells (which secrete inter-

leukin-4, interleukin-5, interleukin-6, interleukin-10

and interleukin-13); and T-helper 17 cells (which

secrete interleukin 17 and are transforming growth

factor beta-related) (27). Numerous studies have

focused on the roles of these T-cells, particularly T-

helper 1 cells and T-helper 2 cells, in the periodon-

tium. Recent studies suggest that whilst both T-helper

1 cells and T-helper 2 cells exist in the periodontium,

T-helper 2 cells are more abundant than T-helper 1

cells in periodontal-disease sites (9, 23, 40, 48, 62, 78).

Recent studies conrm that cytokines from both T-

helper 1 cells and T-helper 2 cells are found in peri-

odontitis gingiva and granulation and that T-helper 2cells outnumber T-helper 1 cells. In particular, inter-

leukin-10, an anti-inammatory cytokine, is found in

abundance in periodontal lesions. The role of T-

helper 1 cells and T-helper 2 cells, as well as the

importance of the presence of various proinamma-

tory and anti-inammatory cytokines, is still unclear.

The possibility that the population of inltrative cells

and the types of cytokines change over the progres-

sion of the disease has been considered and, if this

concept can be further dened, could be very valu-

able in identifying the prognosis of early lesions and

susceptible individuals (21, 45, 56, 57, 60, 77).

Differences in chronic andaggressive periodontitishistopathology

In both chronic periodontitis and aggressive peri-

odontitis the cytokine proles are similar in dis-

eased tissues (57). Increased numbers of T-cells and

decreased numbers of macrophages have been

found in aggressive periodontitis compared with

chronic inammatory periodontal disease (15). It is

difcult to assess the importance of these similari-

ties because it is possible that there are temporal

changes in the prole as the disease progresses

from an early stage to a more advanced stage. Typi-

cally, only the chronic stages of disease have been

assessed, so it is possible that earlier stages mayshow a variation in cellular or cytokine proles.

These differences may also be associated with

genetic variation between subjects who have aggres-

sive periodontitis compared with those who develop

chronic periodontitis. Other considerations, includ-

ing the presence or absence of certain microorgan-

isms and the severity and duration of the disease,

may also affect cell populations.

In the progression from gingivitis to periodontitis

there is a distinct shift from a primarily T-cell lesion

to a B-cell lesion (60). There has been some consider-

ation regarding whether the progression of early

periodontal lesions to more advanced stages involves

a similar shift from cell-mediated immunity to

humoral immunity. Thus far the evidence has been

circumstantial, but the concept of this shift suggests

that T-cells may determine an individuals suscepti-

bility to advanced and possibly aggressive forms of

periodontal diseases.

The humoral immune response to

periodontal pathogensAntibodies to all known periodontal pathogens are

present in both gingival crevicular uid and serum.

The titers of these antibodies have been measured

in patients with disease and in those who have

recovered from disease. The pattern of antibody

titers appears to vary between individuals. However,

titers typically increase immediately after therapy

and then decrease thereafter, an indication of a

favorable response. Several theories have been pro-

posed regarding the interpretation of the antibody

response. A high titer could presumably indicate apositive immune response and thus an appropriate

ability to attack and remove the pathogen. On the

other hand, a high titer could be caused by the

bodys inability to remove the pathogenic source

and thus to overproduce the antibody. There is sig-

nicant interindividual variation in the antibody

response; whether this response is related to indi-

vidual genetic inuences is yet to be seen. If a cor-

relation is determined to exist, this may be a crucial

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way in which genetics and periodontal diseases are

linked (70).

Deciencies in host defenses

Particularly in the diagnosis of cases of early-onset

forms of periodontitis, systemic conditions must be

eliminated. Multiple systemic conditions may beassociated with periodontal attachment loss and

bone destruction and these need to be excluded

before a diagnosis of aggressive periodontitis is made.

Aggressive periodontitis ideally should present in

patients with a clear medical history but this is not

always the case and there is always the possibility that

a patient with, for example, leukemia, may also have

aggressive periodontitis, but this clearly complicates

the diagnosis and thankfully is rare. In some cases,

despite the absence of a signicant medical history,

there may still exist an underlying medical problem

(e.g. a polymorphonuclear neutrophil dysfunction)

and aggressive periodontitis-like features may be the

only manifestation of this disturbance. Leukocyte

adhesion deciency and PapillonLefevre syndrome

are two examples where the oral picture is inuenced

by defective leucocyte function and the diagnosis

may be confused with generalized aggressive peri-

odontitis.

During infection, polymorphonuclear neutrophils

move from blood vessels toward a chemotactic

source. In order to traverse the blood vessel, adhesion

molecules are expressed on endothelial cells andpolymorphonuclear neutrophils. This results in a

preponderance of polymorphonuclear neutrophils

within the periodontal tissues during disease, and

close examination of the histopathological features of

periodontal disease indicates that the polymorpho-

nuclear neutrophil is a critical feature of the host

defense; furthermore, in neutropenias or in leukocyte

adhesion deciency where the quantity or function of

the polymorphonuclear neutrophils are impaired,

periodontal destruction is excessive. Thus, polymor-

phonuclear neutrophils have been considered impor-

tant in aggressive periodontitis and it is necessary toevaluate deciencies and abnormalities in polymor-

phonuclear neutrophil function as they will have a

direct connection to effects on the periodontium.

However, this does not mean that we know for de-

nite that aggressive periodontitis is caused by dys-

functional polymorphonuclear neutrophils or even

by other leukocytes.

A high percentage of those with localized aggressive

periodontitis have been reported to show abnormal

chemotaxis. This has not been shown to occur in all

individuals with localized aggressive periodontitis but

there does appear to be a familial aggregation pattern

associated with this defect, suggesting that this may

be an inherited abnormality (24, 33, 34).

As mentioned previously, multiple systemic condi-

tions are associated with early-onset forms of peri-

odontal disease. PapillionLefevre syndrome is

characterized by hyperkeratosis of the palms and ofthe soles of the feet and with severe, aggressive

destruction of the periodontal tissues, resulting in

early tooth loss in both the primary and permanent

dentitions. PapillionLefevre syndrome is a result of

mutations in the cathepsin C gene. This mutation is

inherited in an autosomal-recessive manner. It has

been suggested that polymorphisms in the cathepsin

C gene may be associated with a nonsyndromic type

of aggressive periodontitis. However, despite several

studies this possibility has yet to be seen with consis-

tency.

Genetic predisposition

Aggressive periodontitis is a multifactorial disease

process in which several etiological factors are neces-

sary for clinical presentation. Bacterial and host

defenses clearly play a major role in disease. How-

ever, there is signicant support to show that a

genetic component exists in the pattern of disease

presentation within families. This has a major impli-

cation in the method in which aggressive periodonti-

tis is screened for by the practitioner. Oncediagnosed, the siblings of the child or adolescent

should also be screened.

Although bacterial invasion of the periodontal

pocket and a host immune response to the spe-

cies is necessary in the pathogenesis of periodon-

tal disease, it does not fully explain the variation

in the degree to which the disease process is

expressed in some individuals compared with oth-

ers with similar risk factors. Additionally, the

familial aggregation of cases of aggressive peri-

odontitis indicates that there may be a signicant

genetic component involved in the susceptibilityto this disease. Genetic studies in families with

aggressive periodontitis show an inheritance pat-

tern consistent with a gene of major effect. In

some cases the likelihood of a sibling having the

condition was as high as 50%. However, many of

these studies have been limited to African-Ameri-

can populations, so other patterns of inheritance

may exist in different populations. It is more likely

that aggressive periodontitis is caused by a num-

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ber of polymorphisms resulting in a similar clinical

appearance.

Pathology

Aggressive periodontitis presents very similarly to

chronic periodontitis but with some key exceptions.

As mentioned previously, there may be a dispropor-tionate amount of microbial deposits compared with

the level of tissue destruction. Additionally, in local-

ized aggressive periodontitis the areas of disease

will be limited to the incisors and the rst molars.

This localization suggests that the disease itself may

be limited in some way, either by local factors or by

age.

The most frequently affected teeth the molars and

the incisorsare the rst teeth to erupt into a mixed

dentition and this pattern may be important in the

disease process. In a typical eruption pattern the

incisors and the molars erupt in children of 6

8 years

of age. There is then a gap for approximately 12 years

before the remaining teeth erupt into the mouth

until a permanent dentition is reached by the age of

1214 years. The fact that the disease limits itself to

only the rst set of teeth may suggest that tolerance

develops to the pathogenic cause over time.

Other conditions affecting children and adoles-

cents, such as juvenile arthritis and juvenile discitis,

are time limited. These children outgrow the condi-

tions as adults. The temporality of aggressive peri-

odontitis in some patients may be caused by similarprocesses in which there is an immunological toler-

ance over time to the source or a burnout of the

lesion, resulting in a self-limiting pattern.

Relevance of the host response indiagnosis and therapy

Clinical diagnosis is the primary method by which

aggressive periodontitis is recognized but may be

supplemented with microbiological and family segre-

gation analysis. Ideally we would have a genetic diag-nostic test but this has so far been elusive and it may

be that a haplotype or group of polymorphisms may

be what genetically predisposes to aggressive peri-

odontitis. Because of the rare, yet potentially serious,

consequences of early onset forms of periodontitis,

early recognition and diagnosis is very important (3).

A thorough periodontal examination is necessary

for the diagnosis of aggressive periodontitis. Because

of the rarity of the condition it is not practical to com-

plete a thorough periodontal examination for every

child or adolescent. However, patients should be rou-

tinely screened for periodontal disease and a more

comprehensive periodontal examination would be

warranted if screening suggests that periodontal dis-

ease could be present.

In many cases of aggressive periodontitis there is a

disproportionate amount of disease progression in

comparison with the amount of localized microbialdeposits. Consequently, there may be little clinically

visible sign of disease, particularly in the early stages.

Bitewing radiographs are routinely taken in children

and adolescents and may be used for initial screening

purposes. Once aggressive periodontitis is suspected

a comprehensive periodontal examination should be

completed.

Given the high incidence of aggressive periodontitis

in families, all siblings, parents and offspring should

also be screened for the condition, as there is 50%

likelihood that the disease will be present. Although

the disease may not be identical, it is important to fol-

low patients who show even minor levels of involve-

ment as this may represent the early stages of disease.

Treatment of aggressive periodontitis can be chal-

lenging. Successful treatment is associated with early

diagnosis, elimination of the infectious organism and

maintenance. Treatment with conventional debride-

ment alone has not been shown to be effective in the

long-term elimination of aggressive periodontitis.

Antibiotic as an adjunct to debridement has been

suggested for treatment. Treatment may be empiric,

or microbiological testing may be used for selectionof appropriate antibiotics. Evidence in the literature

suggests that the use of metronidazole plus amoxicil-

lin, in combination with mechanical debridement, is

very effective in chronic periodontitis and would also

be useful in aggressive periodontitis in most cases.

Other regimens have been tested, including the use of

tetracycline, but this was based on the poorly

supported contention that this disease was pre-

dominantly caused by A. actinomycetemycomitans, a

facultative anaerobe that would need an antibiotic

capable of killing aerobes and anaerobes.

Conclusions

Aggressive periodontitis affects a small, but signi-

cant, percentage of the population. Because of the

rapidly progressing and aggressive nature of the dis-

ease process these patients require early diagnosis

and treatment in order to prevent further tissue dam-

age and tooth loss. The role of the practitioner is not

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only to treat those who already present with signi-

cant disease but to prevent and educate those who

are at high risk.

Numerous factors play a role in aggressive peri-

odontitis. Bacterial factors are well recognized as a

key factor in the pathology of periodontitis; however,

as described previously in this article, evidence to

prove that a single pathogen,A. actinomycetemycomi-

tans, is the universial primary etiology for disease isunsupported. Similarly, although host factors can also

play an enormous role in the progression of disease,

polymorphonuclear neutrophil dysfunction does not

appear to be a cause for aggressive periodontitis in

nonsyndromic individuals.

The knowledge of genetic factors may be one of the

most important aspects in the early detection of dis-

ease. Because of the high level of familial aggregation

it behooves the practitioner to screen all siblings and

family members of an affected individual.

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