Host response in aggressive

periodontitis
CYELEE KULKARNI & DENI S F. KI NANE
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 <1% of any given
population (5) but in certain populations with partic-
ular genetic predispositions and environmental inu-
ences, this can reach 10% (6, 8, 69). Despite the
relatively rare occurrence, there is great clinical man-
agement interest in these early-onset forms because
of the unusual clinical presentation and the risk of
progression of the disease into adulthood. In addi-
tion, there is considerable etiopathological interest
in aggressive periodontitis as it may provide knowl-
edge on the more general chronic periodontitis that
affects a much higher percentage of the population.
Here we discuss the etiopathogenic or host response
aspects of aggressive periodontitis and our current
understanding of host susceptibility and the patho-
genesis of this condition.
Although chronic forms of periodontitis do occa-
sionally occur in a younger population, most early-
onset forms of periodontitis are typically aggressive
and rapidly progressing. Aggressive periodontitis is
characterized by three major features: noncontribu-
tory medical history; rapid attachment loss and bone
destruction; and familial aggregation of cases (3).
Additionally, aggressive periodontitis has been
claimed to be associated with secondary features
(some of which will be disputed by us in this article),
including lack of correlation between the amount of
bacterial deposits and the amount of tissue destruc-
tion, high levels of Aggregatibacter actinomycetemy-
comitans, phagocyte abnormalities and a self-limiting
pattern of disease (38, 72).
Clinically, aggressive periodontitis may present
either as localized disease or as generalized disease.
Typically, localized aggressive periodontitis occurs
circumpubertally and is limited to the rst molars
and incisors with attachment loss on at least two per-
manent teeth, one of which must be a rst molar, and
involving no more than two other teeth aside from
the molars and the incisors. Generalized aggressive
periodontitis, as its name suggests, presents more
generally. Patients with generalized aggressive peri-
odontitis are typically under the age of 30 years but
may be older (38).
Etiology
Owing to its rare occurrence, studies focused on
aggressive periodontitis have been limited by small
sample sizes and therefore much of the literature
includes case studies and anecdotal evidence. How-
ever, it is clear that periodontal disease is a complex
process which requires multiple factors to come into
play for disease to be present. In aggressive periodon-
titis, the following four factors play distinct roles in
the susceptibility of the host and thus in the manifes-
tation of disease:
bacteriahost interactions.
host defenses in aggressive periodontitis.
79
Periodontology 2000, Vol. 65, 2014, 7991 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Printed in Singapore. All rights reserved
PERIODONTOLOGY 2000
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 in
gingival 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 gingival
inammation
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 range
of 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. All
subjects 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
Kulkarni & Kinane
80
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 recall
schedule 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 common
within 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 of
genetic, environmental, host and microbial factors
(37).
Specic inammatory and immune
processes 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 immune
processes 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
Aggressive periodontitis host factors
81
how, and to what degree, these factors inuence
immune and inammatory processes. Aspects of the
inammatory and immune processes both
humoral and cellular which 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 of Prevotella 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 gingivalis and Tannerella forsythia were
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 of A. actinomycetemyco-
mitans was below the detection limit of their well-
conducted study. Multiple studies showed markedly
elevated levels of serum antibody to A. actinomycete-
mycomitans in 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 of A. actinomycetemycom-
itans were 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 molecular
study 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
Kulkarni & Kinane
82
antimicrobial is necessary then it should be broad
spectrum and effective against anaerobes and facul-
tative anaerobes. The fact that there are up to 500 dif-
ferent bacteria present in microbial plaque biolms
(55) probably makes immunization against periodon-
tal disease irrelevant. We have not yet determined
pivotal pathogenic microorganisms and thus it is not
feasible to use microbiological detection to determine
the prognosis of treatment; moreover, it is not possi-
ble to use specic microbiology as a diagnostic tool,
although Socransky et al. (67) have reported that
some groups of microorganisms are associated more
with disease than are other groups.
Much thought and discussion has gone into the
classication of periodontal diseases. However, it is
difcult to distinguish individual entities in the spec-
trum of periodontal diseases because there is signi-
cant overlap between categories. In localized
aggressive periodontitis the bacterial prole was con-
sidered somewhat distinct in comparison with
chronic periodontitis owing to the predominance of
A. actinomycetemycomitans; however, as discussed
previously, there is little compelling evidence to show
that A. actinomycetemycomitans is the universial key
pathogen in the initiation and progression of disease
and it is not indicative of disease or susceptibility in
all populations. Heller et al. (28) found that patients
with generalized aggressive periodontitis had very few
subgingival species that differed from those found in
chronic periodontitis. This lack of markedly different
pathogens between aggressive periodontitis and
chronic periodontitis further complicates the ability
of the practitioner to be able to identify susceptible
individuals based on microbial samples and pushes
us to consider the host response in aggressive peri-
odontitis being much more akin to that of chronic
periodontitis.
Clinically aggressive periodontitis often presents
with a greater amount of periodontal tissue destruc-
tion than would be expected with the amount of
microbial deposits present. This unusual presentation
further complicates the understanding of aggressive
periodontal diseases. As mentioned before, bacterial
plaque is a key factor in the development of gingivitis
and eventually of periodontitis. In the case of aggres-
sive periodontitis, the quantity of plaque may not be
as inuential as other factors. These individuals may
be more susceptible to disease because of an inap-
propriately strong host response to relatively minor
amounts of deposits. This may be the result of a
genetic predisposition to disease or exposure to an
environmental factor, or a combination of several
components.
Innate and inammatory host
immune responses to the gingival
biolm
The early host responses to infection comprise the
innate and inammatory immune systems whose role
is to provide the appropriate response to the offending
microorganisms. Later, the adaptive immune system
(comprising humoral and cell-mediated pathways)
plays a role in inammatory responses, but not in the
immediate host responses to challenge with new
microbes. In some cases there will be little or no
response when the host encounters commensals,
and in other cases a gradated response will occur,
depending very much on the hosts own determina-
tion of the pathogenic nature of the microbial insult:
and herein lies the root of variation in host responses
that govern individual susceptibility. In some individu-
als, and with some bacteria, this will be an innate-only
response, whilst others will need to invoke the inam-
matory response and yet others will require the adap-
tive immune response (cell mediated or humoral, or
both) to reduce or remove the microbial challenge. Of
course, these responses would be somewhat easier to
predict with a single pathogen challenge and will be
innitely more complex as the biolm increases in
complexity as pertains in aggressive periodontitis.
Innate immunity
Our bodys immune system comprises multiple cell
types whose primary function is to ght invading
pathogens such as bacteria, fungi, viruses, parasitic
worms and other microorganisms in order to protect
and maintain immune homeostasis. The innate
immune system provides the most immediate, and
often a completely sufcient, response when cells
encounter pathogens, and the adaptive immune
system provides a delayed, but typically effective, sus-
tained immunity. Oral infections, such as gingivitis,
chronic periodontitis and aggressive periodontitis, are
initiated by many microorganisms (35). This polymi-
crobial infection may result in chronic inammation,
which may lead to tissue destruction, as evident in
chronic periodontitis. Although many organisms are
present in the subgingival biolm, the putative patho-
gens associated with gingivitis and periodontitis may
comprise very small fractions of the total biomass.
Loe and colleagues (44) presented a positive associ-
ation of biolm with gingivitis as early as 1965.
Furthermore, Socransky and colleagues (66), Slots &
Aggressive periodontitis host factors
83
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
The eld of innate immunity has mushroomed during
the past decade, mainly because of the identication
of pathogen-recognition receptors and mechanistic
cellular 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 studied
pattern-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-like
receptor 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 the
etiology 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 polymorphonuclear
neutrophil 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 neutrophils
as a result of the absence of a crucial trafcking mole-
cule. Such diseases include PapillonLef evre 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
Kulkarni & Kinane
84
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 of
disease 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 easily
extrapolate 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.
Aggressive periodontitis host factors
85
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; whilst
necessary 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 2
cells 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 and
aggressive periodontitis
histopathology
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 may
show 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 pathogens
Antibodies 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 a
positive 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
Kulkarni & Kinane
86
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 be
associated 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 PapillonLef evre 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 and
polymorphonuclear 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 to
evaluate 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. PapillionLef evre syndrome is
characterized by hyperkeratosis of the palms and of
the 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. PapillionLef evre 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. Once
diagnosed, 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 susceptibility
to 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-
Aggressive periodontitis host factors
87
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 incisors are 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 68 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 similar
processes 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 in
diagnosis 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 microbial
deposits. 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 selection
of 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
Kulkarni & Kinane
88
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 is
unsupported. 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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