Periodontology 2000, Vol.

43, 2007, 278293

Printed in Singapore. All rights reserved

Copyright ! Blackwell Munksgaard 2007

PERIODONTOLOGY 2000

Clinical relevance of the host

responses of periodontitis
D E N I S F. K I N A N E & P. M A R K B A R T O L D

The purpose of this chapter is to outline the etiology

and pathogenesis of periodontal disease in a manner
that is clinically relevant to practitioners of periodontics and general dentistry. To accomplish this, it is
important to review with clarity several processes
involved in periodontal pathogenesis and to discuss
the concepts of susceptibility to and risk of disease.
The host response in periodontal disease can be
considered in many ways, i.e. as the processes that
render a subject susceptible to disease or as the
pathology of the lesions or as the processes involved
in the acute and chronic inflammatory lesion of periodontitis. If we consider all of these categories of !host
response" we are then set a difficult task in determining which ones are truly of !clinical relevance",
defined as !those features which if present change our
clinical decision-making or patient management".
Clearly, there are different forms of periodontitis,
different rates of susceptibility to these forms, different responses, different genetics and risk factors at
play and different modifiers of these diseases. All of
these factors are based on variations or modifications
of the host response and are thus pertinent to this
current review. This overview will revisit what we
know about the pathology, tissue remodeling, and
healing events of periodontal diseases and susceptibility to them and will attempt to assist the clinician
by emphasizing important aspects that should be
considered in the management of the disease.
The term !periodontal diseases" refers to both gingivitis and periodontitis (chronic and aggressive) and
to a variety of rare conditions, the more common being
necrotizing gingivitis or periodontitis. This review will
be confined to these named entities and will not
address the rarer forms such as desquamative gingivitis and gingival manifestations of other conditions.
The most recent European Workshop in Periodontology (49) has declared that gingivitis and periodontitis are a continuum of the chronic inflammatory

278

condition affecting the supporting structures of the

teeth. In the past, gingivitis was considered inevitable
following the build-up of microbial plaque on teeth;
we now accept that certain patients will be more
susceptible than others to gingivitis and indeed periodontitis. Periodontitis follows gingivitis and is
strongly influenced by the individuals immune and
inflammatory responses. It is initiated by microbial
plaque, but it occurs in only a fraction of the population (1015%). Periodontitis involves the destruction of the supporting structures of the teeth
including the periodontal ligament, bone and gingival tissues. Clearly, periodontitis is the most significant of these diseases because it can lead to tooth
loss but prevention of gingivitis is the primary
preventive measure for preventing periodontitis
and may be more important than we previously
considered.

Concept of susceptibility
For many years, it was noted that subjects differ in
their response to bacterial plaque. Some individuals
might be very susceptible and will develop aggressive
forms of periodontitis at a relatively young age, while
others might be resistant and will never develop
periodontitis (51). Most of the population lies between these extremes, and will develop a degree of
periodontitis over time when exposed to plaque. In
some cases, the disease will progress slowly, and
periodontal destruction during their lifetime will be
minimal, while in others the rate of periodontal bone
loss will endanger the function of their dentition and
may even result in tooth loss. Shapira et al. suggest
that an excessive monocyte/macrophage response
can be found in periodontitis patients compared to
subjects with no periodontitis (30, 102). Engebretson
et al. (27) have shown that probing depth and

Clinical relevance of the host responses of periodontitis

attachment levels are strongly correlated with

inflammatory cytokine levels in gingival crevicular
fluid but as yet none of these features of inflammation are diagnostically useful and there is much work
still to be done to determine a diagnostic test or a
therapy based on these inflammatory aspects which
would be clinically useful.
Clearly, periodontal disease is multifactorial in
nature and incorporates various etiological factors,
host factors, environmental factors, and genetic factors. Microbial dental plaque/bacteria variations may
account for only 20% of the risk which means that
other factors (environment, genetic, host, etc.) must
come into play before clinical disease manifests and,
worse, progresses.

Susceptibility to gingivitis
During experimental gingivitis studies it has long
been noted that subjects vary in their rates of gingival
inflammation (gingivitis) development. Weidmann
et al. reported that in a group of 62 subjects that were
subject to a period of withdrawal from oral hygiene
measures, eight were !resistant" and did not develop
gingivitis within 21 days, while another group of 25
subjects were found to be !susceptible" and exhibited
substantial gingival inflammation within 14 days
(114). The remaining subjects, the intermediate
group, developed gingival inflammation by day 21.
Kinane & Hart described a group of subjects that
consistently exhibited greater than average gingival
inflammation, with another group consistently below
average, representing a !resistant" group (51). The
difference in gingivitis susceptibility between the two
groups was completely independent of quantitative
plaque accumulation differences or qualitative differences in plaque. A consistent estimate across
studies is that approximately 13% of subjects represent a !resistant" group (102). Trombelli et al. (111)
and Engebretson et al. (27) have shown through
experimental gingivitis studies that while all individuals will develop some degree of inflammation, there
are inter-individual differences in response to dental
plaque. Some individuals developed gingival inflammation more rapidly and/or in a more intense
manner. These inter-individual differences may be
explained by genetics, environmental factors, or a
combination of these effects. Using the !twin study
approach" (27) did not demonstrate a strong association between gingival inflammation and genetics,
perhaps because of the cross-sectional nature of this
study. In addition, preliminary genetic evidence

supports the possibility that there are inter-individual

differences in the ability to develop gingival inflammation and showed that specific genetic characteristics [for example carriage of certain interleukin-1
polymorphisms, !composite genotype positivity"] may
contribute to exacerbated gingival inflammation in
response to plaque accumulation (114). Gingivitis
susceptibility may influence periodontitis susceptibility but the state of current knowledge does not
permit us to say which way the relationship goes. For
example, one might presume that those developing
excessive gingivitis in response to plaque may also
develop excessive periodontitis or aggressive periodontitis, but in many cases of aggressive periodontitis
the periodontal destruction is not accompanied by
excessive gingival inflammation. Rather, reports
indicate an absence of obvious signs of inflammation
in many cases. Another possibility is that gingivitis
may be the normal host response that holds the effects of microbial plaque in check and does not
permit further destruction of the periodontal tissues.
To further complicate matters, both gingivitis and
periodontitis could be independent of each other
both pathologically and with respect to risk factors
(33). As will be discussed later, gingivitis or gingival
inflammation is masked by smoking, probably because of restriction of the blood flow and/or hypoxia
of the tissues, whereas periodontitis is more common
in smokers. In summary, gingivitis susceptibility and
indeed resistance are now accepted entities, but we
do not know how these relate to periodontitis. The
clinical relevance of this is that certain patients will
develop gingivitis more readily. For example, in
crown preparation where the gingival margin is involved, we may need to exercise care in whether we
place a margin subgingivally in some patients compared with others. In orthodontics, we must be aware
that certain children will develop overt gingivitis
readily following band placement and plaque accumulation and thus we need to maintain oral hygiene
rigorously in this group. All of the studies to date
point to the likelihood of genetically based host
modulation of gingival inflammation and practitioners should be aware of this although the long-term
ramifications of this are as yet unclear.

Susceptibility to periodontitis
In contrast to gingivitis, advanced/severe periodontitis is seen in only a subset of the population (10
15%). It is variable in that it does not affect all teeth
evenly, but has both a subject and site predilection.

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Kinane & Bartold

Recent epidemiological studies of periodontal disease

suggest that relatively few subjects in any age group
suffer from advanced periodontal destruction and
only specific sites in these individuals are affected
(73, 112). When considering changes in attachment
level over time, it is also peculiar that relatively
few sites actually undergo extensive periodontal
destruction during any given observation period (36,
112). Lindhe et al. (60) reported that 70% of the sites
deteriorated by 3 mm or more during a 2-year
monitoring period, but this occurred in only 12% of
the subjects examined. Susceptibility to periodontitis
will undoubtedly have both genetic and environmental components and these modifiers will be
addressed in this review.

Risk factors for periodontitis

Periodontal disease is considered to have multiple risk
factors. The term !risk factor" refers to !an aspect of
personal behavior or lifestyle, an environmental
exposure, or an inborn or inherited characteristic,
which on the basis of epidemiological evidence is
known to be associated with a health-related condition" (64). Risk factors are part of the causal chain for a
particular disease or can lead to the exposure of the
host to a disease (84). The presence of a risk factor
implies a direct increase in the probability of a disease
occurring. Although specific microorganisms have
been considered as potential periodontal pathogens, it
has become apparent that pathogens are necessary,
but not sufficient, for disease activity to occur (60).
Destructive periodontal disease is a consequence of
the interaction of genetic, environmental, host, and
microbial factors (57). The presence of microorganisms is a crucial factor in inflammatory periodontal
disease, but the progression of the disease is related to
host-based risk factors. Other risk factors include
genetics, age, gender, smoking, socio-economic factors, and certain systemic diseases. Indeed the periodontal diseases are now recognized to be eco-genetic
diseases, which highlights their multifactorial nature.

Clinical relevance of specific

inflammatory and immune
processes in periodontal disease
The inflammatory and immune processes in periodontitis are complex (Fig. 1) and although much
information is currently available many questions

280

remain. Thus, the task of deriving clinically important

messages is from the outset unpromising. Variation
in human susceptibility to periodontitis has long
been accepted, although the pathological basis of this
is poorly understood, as is the difference if any
between the pathology of chronic and aggressive
periodontitis. Genetics and environmental influences
will play a role, but if and how this translates through
the immune and inflammatory processes to produce
the plasma-cell-dominated lesions that differentiate
gingivitis from periodontitis, remains to be elucidated. Aspects of the inflammatory 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 they are currently too poorly
understood. A tendency for an individual or site to
form an extensive plasma cell infiltrate may indicate
an inability to defend against periodontopathogens
and thus a predisposition to periodontitis but short of
excising tissue we have little way of utilizing this
information either diagnostically or prognostically.

Bacterial risk factors

Examples of microbes implicated as risk factors in
periodontitis are numerous. Carlos et al. (19) found
that the presence of Prevotella intermedia, along with
gingival bleeding and calculus, was correlated with
attachment loss in a group of Navajo adolescents
aged 1419 years. Grossi et al. (38) found that Porphyromonas 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. Numerous
additional examples exist such that the cumulative
risk for a given microflora can be estimated.
The inflammatory 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
appreciation that a biofilm containing predominantly
gram-negative anaerobic rods with anaerobic spirochetes pertains, does not as yet help in the management of periodontitis other than suggesting that if an
antimicrobial is necessary than it should be broad
spectrum and effective against both anaerobes and
facultative anaerobes. The fact that there are up to
500 different bacteria present in microbial plaque
biofilms (85) probably makes immunization against
periodontal disease irrelevant. We have not yet

Clinical relevance of the host responses of periodontitis

Microbial Challenge

NO Synthase
Inhibitors

NSAIDs
Host Cells

Cytokines

Prostaglandins

Osteoclasts

Nonantimicrobial
Tetracyclines

Cytokine
Receptor
Antagonists

Connective Tissue
Breakdown
Bone Resorption

Bisphosphonates

Nitric Oxide

MMP Release from

Fibroblasts and Monocytes

Nonantimicrobial
Tetracyclines

Clinical Signs of Disease

Initiation and Progression
Fig. 1. Role of molecular mediators in the development of periodontitis and potential sites for chemotherapeutic host
modulating medications. NSAID, non-steroidal anti-inflammatory drugs; MMP, matrix metalloproteinase.

determined pivotal pathogenic microorganisms and

thus it is not feasible to use microbiological detection
to determine prognosis of treatment nor can specific
microbiology be used as a diagnostic tool although
Socransky & Haffajee (104) have reported groups of
microorganisms that are more associated with disease than others.

The microbial plaque biofilm

Perhaps one of the most significant conceptual advances in periodontics in the last 15 years has been
the recognition that the subgingival plaque exists as
a biofilm. Short-term clinical studies have shown
that microorganisms quickly colonize tooth surfaces
when an individual stops oral hygiene procedures
and within a few days, microscopic and clinical
signs of gingivitis become apparent. The inflammatory changes can be resolved when adequate oral
hygiene is resumed (51, 111). Microorganisms that
form dental plaque and cause gingivitis probably do
so by the release of bacterial products that induce
tissue inflammation both directly and indirectly.

Clinical trials emphasize the need to remove both

supra- and subgingival microbial plaque in the
treatment of gingivitis and periodontitis. Furthermore, animal experiments have indicated that gingivitis only develops in animals that accumulate
bacterial deposits. Clearly, gingivitis is a prerequisite
for the development of periodontitis and thus prevention of gingivitis is also a primary preventive
measure for periodontitis. As stated earlier, not all
patients develop periodontitis and for those who do,
it is the result of a mixture of environmental and
genetic factors that affect their host response to
microbial plaque. This provides a research challenge
for those interested in the pathogenesis of this
multifactorial disease. The site specificity and predilection in periodontitis and gingivitis probably
relate to the retention of plaque in specific areas
such as restoration overhangs, poor crown margins,
etc. The type of plaque, i.e. the specific organisms
present, and its quantity, may be a crucial environmental influence in periodontal disease, but at
the same time it could be the individual host response, or a mixture of the two. However, the

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Kinane & Bartold

weighting of these predisposing and modifying factors needs to be tested experimentally.

Complex inflammatory and immune responses are
involved in the progression of periodontitis. Tissue
activity within the diseased periodontium comprises
epithelial and connective tissue turnover and the
cellular activity associated with the infiltrating
inflammatory cells (82). Previous work has suggested
that B cells and T cells accumulate in large numbers
in the periodontal tissues although much about their
functions in the disease process is not clearly
understood.
While T cells are implicated in vitro in immunoglobulin synthesis (42, 72, 79), the results of these
studies do not easily extrapolate to in vivo situations
where complex interactions between varieties of
infiltrated inflammatory cells occur. Furthermore, it
may also be presumptive to assess the role of the
different cell types and their inter-relationships at
inflammatory sites from limited observations of
morphology and immunochemical analysis of cell
surface markers. Immunohistochemical methods
have been used to determine lymphocyte subsets (45,
72, 87, 88) and the paradigms that !periodontitis is a
B-cell lesion" and the !immunoregulatory role of T
cells in periodontitis" have been proposed following
such studies (69, 72, 78, 99). One drawback of this
sort of study is that the activity of the cells under
investigation remains unknown.
The data support the view that B cells in the gingiva
are long-lived cells. They probably possess the ability
to migrate between the blood and lymph nodes to
participate in the periodontal immune response. Our
more recent findings indicate that B cells in the
periodontal granulation tissue behave in a similar
fashion (55). These observations are supported by the
findings that: CD5-positive B cells are present in the
gingiva at higher proportions than in blood (106),
activated B cells are present in the periodontium
(116) and CD5-positive B cells do not proliferate (2).
There was no clustering of CD3-positive or of
CD45RO-positive cells in any of our sections of gingiva or granulation tissue. The above observations
also appear to be true for T cells. While, some authors
have demonstrated that activation of T cells occurs in
periodontitis (45, 87), Longhurst et al. (65) have
shown that T blasts are rare in transmission electron
micrographs of periodontal tissue, although they
have been observed in the infiltrated connective tissue adjacent to the junctional epithelium of slightly
inflamed prepubertal gingiva (103).
Human T-cell functions can be estimated by
studying their cytokine profiles. Basically, three sub-

282

sets of T-helper cells (CD4-positive) cells have been

characterized by their cytokine profile (67, 92).
Typical secretory products of T helper type 1 (Th1)
cells are IL-2, IL-12, tumor necrosis factor-a, and
interferon-c; those of Th2 cells are IL-4, IL-5, IL-6, IL10, and IL-13; and Th3 cells are known to secrete
transforming growth factor-b. In the last few years a
large number of studies have investigated the role of
Th1 and Th2 cells in the periodontium. While some
conflicting reports have been published on the
expression of IL-2 and IL-4 by T cells in the gingiva,
many recent studies on the immunology of periodontal disease support the concept that Th2 cells are
more abundant than Th1 cells in periodontitis lesions
(4, 31, 56, 70, 103, 118).
The relative importance of the Th1 and Th2 subsets
in periodontal disease is poorly understood. Early
reports have suggested that IL-2 messenger ribonucleic acid is not expressed by T cells in the gingiva
(29, 66) and other studies suggest that gingival T cells
express the protein (98, 117). Our recent observations
(95) have confirmed the view that Th2 cells outnumber Th1 cells in periodontal lesions. We have
also confirmed that typical products of both Th1 cells
(IL-2, interferon-c, IL-15) and Th2 cells (IL-4, IL-6,
and IL-10) are detected in periodontitis gingiva and
granulation tissue. In addition, we have confirmed
the earlier observation (91) that the anti-inflammatory cytokine IL-10 is very widely expressed in periodontal tissue. What role proinflammatory and antiinflammatory cytokines play in this disease process is
still unclear. The concept that different cytokine
profiles may characterize different stages in the
development of periodontal disease has not been
answered. That different populations of T cells in
tissue lesions are associated with the gingivitis in the
majority of people that does not progress into periodontitis and the gingivitis that ultimately leads to severe periodontitis in the minority of individuals is an
important clinical consideration that remains difficult
to address.

Differences in chronic and

aggressive periodontitis
histopathology
We have observed increased numbers of T cells and a
reduced number of macrophages in early-onset or
aggressive periodontitis lesions when compared with
chronic or adult periodontitis (23). We have not
observed any differences in the cytokine profiles

Clinical relevance of the host responses of periodontitis

between these two diseases (95). However, it is

possible that differences might be present at earlier
stages in the disease process and we must concede
that only the later chronic phases of the disease have
been investigated in our studies. Differences in the
cell populations are likely to be the result of a large
number of factors including the genetic background
of the individual, the presence of pathogenic and/or
absence of particular commensal microorganisms,
the severity of the initial insult, and the duration and
the severity of the disease.
It is well known that there is a shift from a predominantly T-cell lesion to a B-cell lesion in the
progression from gingivitis to periodontitis. It is
interesting to speculate that a shift from cell-mediated immunity (Th1) to humoral immunity (Th2)
occurs during the development of periodontal disease. At present, the evidence is mainly circumstantial. It is apparent that in gingivitis T cells probably
exceed cells of the B-cell lineage, and when this
progresses into periodontitis, B cells/plasma cells
then predominate. The susceptibility factor in
periodontitis may reside with T regulatory cells and
whether they produce Th1 or Th2 responses may
determine whether a patient has periodontitis or is
resistant to the ravages of this disease.

Immunoglobulin subclasses in the

periodontium
Antibody production, especially of immunoglobulin
G (IgG) and IgA, is considered to have a protective
role in the pathogenesis of periodontal disease, but
the precise mechanisms are still unclear. Certain
questions need to be considered, for example: what
proportion of the antibodies in the gingival sulcus/
pocket region comes from the systemic circulation
and which antibodies are locally produced? To
determine local IgG and IgA production, we investigated the human IgG and IgA subclass messenger
ribonucleic acid-bearing plasma cells within periodontal tissue by in situ hybridization in gingival
samples from periodontitis patients (66). In addition,
the concentrations of IgG and IgA subclass proteins
and digested IgA1 Fab portions were measured in the
pocket fluid that corresponded to the sites from
which the tissues were taken (98). Cells expressing
IgG1 messenger ribonucleic acid were predominant
(mean 63%) and cells expressing IgG2 messenger
ribonucleic acid were present at around 23% of total
IgG plasma cells and IgG3 and IgG4 were present to a

lesser extent (3% and 10%, respectively). Similar

proportions of IgG subclass proteins were detected in
pocket fluid, which were also consistent with typical
serum levels. In terms of IgA expression, IgA1 messenger ribonucleic acid-positive cells were the greater
(mean 65.1%, P < 0.001). In contrast, IgA2 protein in
the pocket fluid samples was present at higher concentrations than IgA1 (P < 0.001) and IgA1 Fab fragments were detected more than intact IgA1. There
was good correlation between the amounts of IgG
subclass proteins in pocket fluid and the number of
IgG subclass messenger ribonucleic acid-positive
cells in the same sites, but not between IgA subclass
proteins and the number of IgA subclass messenger
ribonucleic acid-positive cells.
These data suggest that IgG and IgA subclass proteins can be produced locally in the periodontium
and in addition to serum-derived immunoglobulin
they contribute to the antibody levels found in the
gingival pocket or crevice.

The humoral immune response to

periodontal pathogens
This is a large area that has been covered extensively
in the literature and the reader is referred to recent
reviews on this subject (108). In summary, antibodies
against all the known periodontal pathogens are
found in both the serum and the gingival crevicular
fluid. Titers of antibody vary greatly between patients
and also vary before and after therapy (during which
there is often an initial increase in titer and then a
drop following successful therapy). More consistently, antibody titer tends to increase following
therapy and this is considered to indicate a favorable
response to therapy. There are several theories
regarding the significance of the antibody responses
in periodontal disease. In some cases, it can be
considered to reflect exposure to periodontal pathogens. However, a high titer could be considered to
reflect a positive immune response by the patient,
but a high titer could also reflect an inability of the
immune system to rid the body of the pathogen. It is
clear that there is large inter-individual variation in
the humoral immune response in humans, indicating
a possible genetic control of the response. Eventually,
it may be found that the immune response is a crucial way in which genetics and periodontal disease
are linked. Antibody avidity is a measure of the
effective function of the immune response and
measuring avidity may prove the most useful method

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Kinane & Bartold

of assessing individual susceptibility related to the

immune response.
Although many studies have investigated the numbers of immunoglobulin-bearing lymphocytes and
plasma cells in periodontal tissues, it is important to
consider the function and target of these cells. The
products of B cells and plasma cells in the tissues include antibodies that may bind to components and
metabolites of periodontal pathogens (16). Investigation of plasma cells and their targets in the diseased
tissues, which are infection-specific and have undergone affinity maturation and migration to the site, may
elucidate the most important pathogens and immune
response-inducing antigens in periodontal disease.

periodontitis, and that the level of diabetic control is

an important factor in this relationship. Further
studies have suggested that periodontal treatment
influences diabetes control positively and that diabetics with severe periodontal disease are much more
at risk of renal and cardiovascular complications
(110).
From this, the clinically relevant messages are that
periodontitis patients are more likely to have diabetes, and that the presence of active or untreated
periodontitis can actually worsen diabetes. Thus,
treatment for either disorder is likely to help the other.

Medications

Systemic modifiers of periodontitis

Microbial dental plaque is the initiator of periodontal
disease but whether it affects a particular subject,
what form the disease takes, and how it progresses,
are all dependent on the host defenses to this challenge. Systemic factors modify all forms periodontitis
principally through their effects on the normal immune and inflammatory defenses. The possible role
of systemic diseases and systemic exposures in
initiating or modifying the progress of periodontal
disease is clearly a complex issue. It is, however,
generally agreed that several conditions may give rise
to an increased prevalence, incidence, or severity of
gingivitis and periodontitis.

Diabetes mellitus
Diabetes is considered to be a modifier of existing
periodontitis rather than a disease that causes periodontitis. Periodontal disease has been called the
sixth complication of diabetes (62), a view supported
by several reviews which conclude that the bulk of
evidence indicates there is a direct relationship
between diabetes mellitus and periodontal disease
(50, 86). Another report (80) also concluded that the
preponderance of evidence from studies conducted
throughout the world suggests that some diabetics
are at increased risk of periodontitis. A cross-sectional study of 1,426 subjects (38) reported that
diabetes mellitus was the only systemic disease positively associated with attachment loss, with an odds
ratio of 2.32. A 1995 study confirmed that metabolic
control might be the most important factor in the
association between periodontitis and diabetes (3).
Thus, it would appear that both type 1 and type 2
diabetes are associated with an increased risk of

284

Membrane ion channel blockers

This group of drugs works on the ion channels of
human cells and has profound effects through this
route. The membrane ion channel blockers have
relatively similar effects in that they are considered to
influence gingival fibroblasts to overproduce collagen
matrix and ground substance when stimulated by
gingival inflammation following plaque build-up
(26). They clearly have major effects in terms of gingival overgrowth and, although it could be argued
that an unfavorable gingival form and false pocketing
may be plaque retentive and thus might be local
modifiers of periodontitis, i.e. increased susceptibility
may ensue, this has not been shown in published
studies. Thus, it is important to bear in mind that,
although there is evidence supporting the effects of
these drugs on gingival overgrowth, there is as yet no
evidence linking the use of these medicines with
periodontitis.
Anti-epileptic drugs
Some degree of gingival enlargement is present in
3667% of patients who take the anticonvulsant drug
sodium 5,5-diphenylhydantoinate (phenytoin, Dilantin") (53). Generally, the gingival tissue around the
labial surfaces of the anterior teeth is more severely
affected than that around the posterior teeth (110). It
occurs primarily in young individuals and is reported
to be seen rarely in persons over 40 years of age (1,
47). The onset of gingival overgrowth is generally
3 months after the start of phenytoin therapy (10)
and approximately 50% of phenytoin users develop
these lesions (110), although this incidence is higher
in institutionalized epileptics (40). More recent
studies have also implicated alternative anti-epileptic
drugs such as valproic acid (5) and vigabatrin (48) as
also causing gingival overgrowth.

Clinical relevance of the host responses of periodontitis

Antihypertensive calcium antagonists

Nifedipine is used extensively in the management of
angina and occasionally hypertension and gingival
overgrowth often accompanies its use. The overgrowth associated with nifedipine is clinically and
histochemically similar to phenytoin-induced overgrowth. Other calcium antagonists such as diltiazem
have been shown to have similar effects (17).
Cyclosporine
Cyclosporine is an immunosuppressant which acts
solely on the cell-mediated immune responses (13). A
widely recognized side effect of cyclosporine is
gingival overgrowth (12, 93). Clinically and histopathologically, it resembles phenytoin-induced
overgrowth. Other similarities are that the overgrowth occurs in 30% of individuals, is related to the
serum concentration of the drug, and tends to appear
within 3 months of commencing the drug regimen
(100).
Combination therapies
Combination therapy of cyclosporine and nifedipine
is widely used in the management of organ transplant
patients. One study examined the prevalence and
severity of gingival overgrowth in cardiac transplant
patients and found significantly higher gingival
overgrowth scores and periodontal probing depths
in patients medicated with the combination of
cyclosporine and nifedipine than those medicated
with cyclosporine alone (26). Calcium channel blockers will result in gingival overgrowth in a proportion of
patients and may increase periodontal destruction in
patients who are otherwise susceptible to the disease,
but whether they actually increase the risk of periodontitis in non-risk patients is not known (109).
Steroids
Studies relating steroid therapy to periodontal disease and alveolar bone loss are conflicting. From one
study it was reported that, although long-term prednisone therapy may predispose the patient to osteoporosis, no loss of alveolar bone was observed (18). In
contrast, another study (61) concluded that hydrocortisone induced periodontal breakdown by
impairing collagen and mucopolysaccharide synthesis in bone. Hydrocortisone acetate significantly
decreased the gingival concentrations of hyaluronic
acid, chondroitin sulfate, and heparin in rats (54).
The effects of prednisone therapy on gingival
inflammation and periodontitis have been investigated in a group of patients taking steroids for up to

4 years (94). Comparisons were made between this

group, patients given non-steroidal therapy, and
healthy controls and no differences were found in
either the frequency or severity of periodontal disease, indicating the lack of influence of steroids on
periodontal disease.

Hormones
It is well established that pregnancy causes a modification in the hosts response to dental plaque but
this is largely confined to the soft tissues and manifests as an increase in chronic gingivitis. Several
studies have shown that the incidence and severity of
gingival redness, swelling, bleeding, and exudation
increase from the second month of gestation to the
eighth month and then decrease (20, 63). It is evident
that with more gingival overgrowth false pocketing
will increase and thus both the quantity and anaerobic level of the microflora will increase but there are
no published studies which might implicate periodontitis as a sequelae to sex hormone-induced
chronic gingivitis (46).
Other clinical indications of a hormonal effect
include the effects of oral contraceptives on the gingiva and fluctuations in gingivitis with phases of the
menstrual cycle (41, 59). Furthermore, puberty is
often accompanied by increased gingival inflammation and this heightened response to plaque has been
attributed to the concentration of circulating sex
hormones (107). An alternative explanation for
increased gingivitis during puberty is that this is a
period of mixed dentition where erupting and exfoliating teeth present many sites for plaque retention.
The fact that gingivitis decreases after puberty may
reflect the general improvement seen in children as
they improve their dexterity and become more aware
of oral hygiene. Evidence suggests that sex hormone
levels may alter the inflammatory response to plaque
and, although this predominantly results in gingivitis
alone, an increased risk of periodontitis in these
patients cannot be ignored (77, 113).
The clinical message regarding pregnancy gingivitis is that the lesions are modified by plaque and that
the treatment for this condition is primarily to reduce
inflammation by improving plaque control before
removing the lesion surgically. Excising the lesion
without improving the oral hygiene results in excessive and possibly uncontrolled bleeding because of
the excessive angiogenesis in this lesion. Improving
oral hygiene does two things, first it reduces the
lesion and its inflamed and hemorrhagic and vascular
nature, and second it helps prevent recurrence by

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teaching the patient to reduce inflammation and thus

the swelling and angiogenesis does not recur.
Human immunodeficiency virus infection
Among the oral lesions associated with acquired
immunodeficiency syndrome (AIDS) are several
periodontal findings. Individuals infected with
human immunodeficiency virus (HIV) may exhibit
the following conditions: linear gingival erythema,
necrotizing ulcerative gingivitis (NUG), severe
localized periodontitis, and severe destructive
necrotizing stomatitis affecting gingiva and bone
(similar to noma or cancrum oris) (96115). It is
possible that these lesions are neither HIV nor AIDS
specific, but that they are necrotizing forms of periodontal disease which may be more exaggerated in
immuno-suppressed patients, although many HIVinfected individuals do not have any form of
periodontitis. Interestingly, HIV-infected individuals
with CD4-positive cell counts <200 cells/mm3 may
have more severe and extensive chronic periodontitis related attachment loss (8, 90). This suggests
that in immunocompromized HIV patients, preexisting periodontitis may be exacerbated and thus
HIV infection can be considered a modifier of
periodontitis.
Smoking
Numerous investigations of the relationship between
smoking and the periodontal diseases have been
performed over the past 15 years and both crosssectional and longitudinal studies provide strong
epidemiological evidence that smoking confers a
considerably increased risk of periodontal disease.
Numerous studies of the potential mechanisms
whereby smoking tobacco may predispose to periodontal disease have been conducted and it appears
that smoking may affect the vasculature, the humoral
immune system, the cellular immune system, and the
inflammatory system. A 10-year longitudinal radiographic study of alveolar bone loss showed that
smoking was a significant predictor of future bone
loss (15), and in a 5-year study of attachment loss,
smokers were found to be at an increased risk (11). In
a further 1-year longitudinal study, smokers exhibited
both greater attachment loss and bone loss when
compared with their non-smoking counterparts (68).
Smokers were also shown to be at significantly
greater risk of further attachment loss when compared with non-smokers. Thus both cross-sectional
and longitudinal studies indicate a strong relationship between smoking and increased risk of periodontal breakdown.

286

A study examining the relationship between

smoking and attachment loss demonstrated a dosedependent response; the odds for more severe
attachment loss in smokers compared with nonsmokers ranged from 2.05 for light smokers to 4.75
in heavy smokers (80). These support the findings of
a later study that reported that probing depth was
significantly correlated with smoking !pack years"
(7). Furthermore, years of exposure to tobacco
products has been shown to be a statistically significant risk factor for periodontal disease in 1,156
community-dwelling elderly subjects in New England, regardless of other social and behavioral factors (43). Thus, factors such as quantity of cigarettes
smoked and duration of the habit may need to be
considered in assessing risk of periodontitis due to
smoking.
Emotional stress
The incidence of acute NUG increases during periods
of physiological (28) and emotional (35) stress. Green
et al. (37) studied individual !life events" such as
divorce and bereavement and concluded that an
increase in the incidence of stressful events led to a
greater prevalence of periodontal disease. These
conclusions are supported by a more recent study
(22), which looked at the relationship between life
events and adult (chronic) periodontitis and found
that both psychosocial factors and oral health risk
behaviors, such as poor oral hygiene and smoking,
clustered together as important determinants of
periodontitis. The intervening physiological mechanisms between stress and increased susceptibility to
periodontal disease are not well documented but are
probably related to impaired immune function during stress. It is recognized that stress may increase
the levels of circulating corticosteroids (24), which
may have effects on the periodontium. Stress is not
an easily measured factor, but corticosteroid levels in
urine can be measured and were found to be higher
in acute NUG patients (21). Maupin and Bell found
significant elevation of 17-hydroxycorticosteroids in
patients with acute NUG and reductions when the
disease was resolved (71). Recent studies suggest that
stress may influence the inflammatory response to
P. gingivalis infection in mice (101). More severe and
extensive adult periodontitis was also seen in
psychologically depressed human subjects who
smoked and had high titers of IgG against T. forsythia,
the authors explained this by the negative influence
depression has on the immune system (74). Further
studies with experimental gingivitis volunteers suggested that proinflammatory cytokine levels are

Clinical relevance of the host responses of periodontitis

increased in stressed subjects (25). A study of adult

periodontitis patients found that those resistant to
therapy were more stressed than those who responded to therapy, which highlights the potential contribution of stress to adult periodontitis (6). The
concept of a role for psychoneuroimmunology in the
pathology of chronic periodontitis has also been
raised (9).
Genco et al. (32) evaluated the association of
stress, distress, and coping behaviors with periodontal disease in 1,426 subjects, aged 2574 years.
They found that psychosocial measures of stress
associated with financial strain are significant risk
indicators for periodontal disease in adults. Interestingly, stress may also significantly change
behavior and behavior-related parameters such as
oral hygiene, which may further affect the periodontal condition.

Alterations to the periodontal

connective tissues with the
development of periodontal
inflammation
Notwithstanding the important influx of inflammatory cells detailed in this review, other prominent
features of the inflammatory periodontal diseases are
the qualitative and quantitative changes in the
molecular composition of the periodontal connective
tissues, especially in the gingiva. While recognizing
that not all individuals develop gingivitis with the
accumulation of plaque to the same extent and
severity, a number of important changes within the
periodontal connective tissues have been observed in
those individuals who do develop gingivitis. With
development of the initial inflammatory cell response
to the accumulation of dental plaque adjacent to the
gingival margin, connective tissue destruction commences (32). This early response in the tissues can
result in up to 70% loss of collagen within the foci of
inflammation. With further development of the initial
inflammatory response, the destruction expands
deeper towards the periodontal ligament and alveolar
bone. Simultaneous with this destruction, a form of
frustrated repair is initiated with fibrosis and scarring
coexisting at foci of inflammation (10). It is at this
stage that a combination of factors, including
the connective tissue response together with the
inflammatory cell regulation and function, results in
this lesion being contained with no further development of bone loss and loss of attachment.

However, if the lesion does progress from a contained gingivitis into a more progressive periodontitis
lesion, biochemical analyses have demonstrated that
numerous quantitative and qualitative changes occur
to the fibrous and non-fibrous components of the
gingival connective tissues (76).
Within other compartments of the periodontium
(ligament, bone, and cementum) the changes associated with the development of periodontitis have
been less well characterized. The periodontal ligament manifests subtle topographical changes in the
number of extracellular matrix components (52).
Changes to the hard tissue matrices of bone and
cementum differ significantly because of their different anatomical location. Cementum may become
altered as a result of its exposure to the oral or pocket
environment in which there is a loss of periodontal
attachment and changes in both the organic and
inorganic content (105).
An often overlooked, but nonetheless important
part of the tissue reaction to the developing periodontal lesion is the apical migration of the junctional
epithelium and associated formation of pocket epithelium. This process requires not only coordinated
cell proliferation but also migration of the cells over
the connective tissue substratum, which has been
modified by the inflammatory process. These processes are most likely regulated to a large extent by
the variable expression of integrands and other
adhesion molecules at the epithelial/connective tissue interface (39).
The above observations indicate that the tissue
response is highly regulated and is usually a wellcontrolled process with little scope for clinical
intervention. However, through a better understanding of the molecular and cellular events
associated with these processes many opportunities
will arise for pharmaceutical control using diseasemodifying anti-inflammatory drugs. In particular,
the molecular events associated with both soft and
hard tissue destruction offer promise as adjuncts to
the management of inflammatory conditions of
which the periodontal diseases could be considered
to be prime targets (Figure 1). Moreover, the
opportunities to clinically intervene by adding or
supplementing tissues, tissue growth factors, and
materials designed to augment the normal host
recovery process to provide clinically improved
healing have added another dimension that we
need to consider in periodontal management. This
is an area of the host response, that is the healing
and repair and regeneration area, where future
advances are likely and much needed.

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Degradation and remodeling of the

connective tissue matrix
It is important to recognize that destruction of the
extracellular matrix is effected via a number of different, but often interrelated, pathways, and mechanisms. In general, degradation occurs via the activity
of matrix metalloproteinases and reactive oxygen
species or through phagocytosis of matrix components (14, 89). Of particular interest to the molecular
pathways of tissue remodeling, repair, and regeneration are the processes associated with matrix metalloproteinase activity and activation.
Matrix metalloproteinase activity is controlled
in vivo through four separate mechanisms. First, the
enzymes are synthesized and secreted as inactive
precursors and conversion to their active forms
requires activation by plasmin, trypsin, or other proteinases (75). Second, a number of growth factors and
cytokines regulate the production of matrix metalloproteinase. In particular, IL-1 and transforming
growth factor-b are key regulators of matrix metalloproteinase production in inflamed tissues (81). Third,
serum and tissue inhibitors are able to neutralize the
activity of matrix metalloproteinase in tissues. The
major serum inhibitor is an a2-macroglobulin, which
covalently cross-links with and inactivates target
matrix metalloproteinases. Fourth, a group of protein
inhibitors of matrix metalloproteinase, known as tissue inhibitors of metalloproteinases (TIMP), play a
significant role in regulating matrix metalloproteinase
activity in tissues by preventing the conversion of
precursor forms of matrix metalloproteinase to their
active forms (14). Each of these processes offers sites
of potential control from a pharmacological point of
view. Examples to date would be the chemically
modified tetracycliness, IL-1 antagonists, and transforming growth factor antagonists.

hydrolysis, activation of protein kinase C, and tyrosine phosphorylation of focal adhesion kinase. This
cascade of events results in the activation of cell
migration, cell attachment, DNA synthesis, and
matrix synthesis. In addition, target genes for other
cytokines or growth factors may be activated, which
in turn further influence and regulate the activities of
cells and cell-to-cell interactions (83).

Clinical relevance of host-mediated

changes to the periodontal connective
tissues
Risk assessment
Recognizing that periodontitis is a multifactorial disease resulting from an intricate interplay between
etiological factors (bacteria), environmental factors
(modifying factors) and host factors (host response),
and genetic predisposition it is clear that no single test
is ever going to be able to reliably predict periodontal
risk. Nonetheless, it is very likely that a battery of tests
developed into a risk assessment matrix will be
developed. It is within this context that monitoring of
connective tissue changes at a given time-point may
prove helpful. It is well known that components
associated with disuse destruction (both effectors and
products) appear in the gingival crevicular fluid. This
fluid is easily collected and is relatively simple to
analyze for its constituent components. Analysis of
gingival crevicular fluid as a means of diagnosis and
risk assessment has been disappointing to date. The
lack of any one specific marker together with the naive
assumption that one test will provide all the information we need has hampered progress in this field.
With the rapidly expanding field of proteomic
screening for disease identification it is possible that
this approach could be applied to the gingival
crevicular fluid in the near future.
Disease modification

Effects of soluble mediators on

connective tissue cells
Of the myriad cytokines and growth factors known to
affect fibroblast function, platelet derived growth
factor, insulin-like growth factor, transforming
growth factor-b, IL-1, prostaglandin E2, interferon-c,
and tumor necrosis factor-a are amongst the most
potent. These cytokines and growth factors influence
cellular activities in several ways. Through their
binding to specific cell surface receptors a variety of
signaling events are activated including Ca2+ mobilization, receptor phosphorylation, inositol phosphate

288

Improved understanding of the molecular events

involved in the inflammatory responses and the
associated tissue destruction offers considerable
opportunities for management of the periodontal
diseases. Nonetheless, it can be expected that problems will be encountered for similar reasons to those
alluded to above. Namely, that there is a plethora of
molecular pathways involved and it is very unlikely
that control of only one pathway will prove to be the
panacea. Nonetheless, the opportunity exists for
medications to be used as an adjunct to mechanical
therapy and regulation of other predisposing and

Clinical relevance of the host responses of periodontitis

modifying factors. It may be that in the future the

disease may show considerable individual heterogeneity such that individual deficiencies in molecular
pathways can be identified and then managed
appropriately rather than providing a one treatment
fits all philosophy.
Clearly, many of these biological agents, which
target specific molecular events associated with acute
and chronic inflammation, have significant potential
to alter clinical outcomes in periodontal disease.
With the emerging understanding that periodontitis
is a multifactorial disease, combination therapies that
target multiple disease outcomes are also emerging.
For example, combination therapy to control both
MMP and cyclooxygenase activities has been proposed and studied for the management of periodontitis (58).
Nonetheless, it must be remembered that while
host modification of disease processes is possible for
periodontitis, controlling the bacteria that cause
periodontal infections remains a significant focus
for periodontal treatment and prevention. At best,
host modification can only be an adjunct treatment
for periodontitis.
Tissue regeneration
Once the destructive phase of periodontitis reaches
the deeper periodontal structures, regeneration of
the damaged tissues becomes an important clinical
issue. However, to date, periodontal regeneration has
proven to be a very elusive goal. One of the major
challenges at present is to understand the extraordinarily complex molecular and cellular events
associated with periodontal regeneration. This anatomical site is unique; for new connective tissue
fibers to insert into the cementum and bone, the
healing components of both the soft tissues and the
hard tissues of the periodontium need to be coordinated and integrated. Very little is known about the
signals that regulate these interactions.
With these concepts in mind a number of novel
approaches to periodontal regeneration have been
proposed and developed over the past 15 years.
These have included the concepts of guided tissue
regeneration, root surface conditioning and application of growth factors (notably platelet-derived
growth factor/insulin-like growth factor and bone
morphogenetic proteins) and the use of enamel
matrix proteins. Recently, adult stem cells have been
isolated and characterized from periodontal ligaments from several species including humans. Whether these cells have the capacity to be used clinically
for regeneration remains to be established.

Notwithstanding these elegant developments, there

is no doubt that the desired clinical end point is predictable regeneration of the periodontal tissues
damaged by inflammation to their original form and
function. To date, this has been elusive. For regeneration to occur there will need to be the coordinated
deposition of specific matrix molecules consistent
with both soft and hard connective tissue formation
and this will be largely driven by soluble cytokines and
growth factors. To understand the rational basis of
regenerative procedures, more information is needed
on the variety of molecular and cellular processes
associated with the formation of each periodontal
component. In particular, very little is known about
cementogenesis and the mechanisms necessary for
reattachment. While the use of growth factors shows
some promise in this area, these suffer from being
very broad in their range of activity and thus lack a
degree of tissue specificity. Therefore, it seems reasonable to continue to probe local factors that may be
specific for the development (and therefore regeneration) of the periodontal tissues. To this end, efforts to
characterize cementum components have provided
new perspectives and possibilities for the role that
local factors may play in periodontal regeneration.
More recently, advances in tissue engineering
strategies including development of novel scaffolds
for cell and drug delivery (34, 44) are providing
important new vistas in the field of periodontal tissue
regeneration. Finally, the identification of stem cell
populations within the periodontal ligament opens
up the potential to utilize the regenerative potential
of these cells for regenerative purposes (97).

Summary
The purpose of this chapter was to outline the etiology, pathogenesis, and tissue changes resulting from
periodontal disease in a manner that is clinically
relevant to practitioners of periodontics and general
dentistry. Thus, we reviewed several processes involved in periodontal pathogenesis and tissue
destruction and healing and to discuss the concept of
susceptibility and risk of disease. It is clear that there
are different forms of periodontitis, different rates of
susceptibility to these forms, different responses,
different genetics and risk factors at play and different modifiers of these diseases, and variations in
healing and tissue destruction. In terms of what are
the most relevant of these aspects for clinicians and
which of these factors will impact on clinical judgment, probably the most relevant is the concept of

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differing subject susceptibility. Humans differ in their

susceptibility to both periodontitis and gingivitis. We
do not understand the genetics and environmental
aspects sufficiently but clearly numerous risk factors,
including plaque or oral hygiene modifications, systemic health including diabetes and HIV, socio-economics, stress, obesity, and smoking are all relevant
and may interact to render subjects at increased risk
of periodontal disease. The healing and regeneration
of tissues is a further area of variation we need to
consider, as is the concept of diagnosis and which of
the multitude of host factors that we can use with
utility for assessing periodontal disease presence
and progression. Extensive microbiological research
tends to indicate specific pathogens but there are a
multitude of unknowns, difficult to detect and cultivate microorganisms including viruses and Archaea,
which may be crucial in disease causation and
exacerbation. Alternatively, it may be that in future
we will consider the plaque biofilm as the main agent
of disease and thus develop strategies and detection
procedures based on dealing with this multi-microorganism conglomeration rather than specific
microorganisms per se.
Possibly, the most important clinical messages
include the fact that systemic modifiers such as
smoking and diabetes may adversely affect the
disease process, the ability to diagnose disease and
the healing following tissue destruction. Also, that
aggressive periodontitis is autosomal dominant in
its transmission and thus siblings, parents and
offspring of affected persons are 50% more likely to
have the disease, and that both gingivitis and periodontitis are chronic inflammatory conditions initiated and perpetuated by the microbial plaque
biofilm and thus mechanical or chemical antimicrobial therapies will be useful for both conditions.
Also, that control of gingivitis is a primary preventive measure for the control of periodontitis.
With respect to the extensive immunological,
microbiological, and diagnostic and tissue regeneration research efforts, we are unfortunately still
some way from elucidating accurately the disease
and healing processes but in time we will undoubtedly utilize these to develop better diagnostic
and therapeutic management of patients.

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