Schenke in 2006

Periodontology 2000, Vol.
40, 2006, 7793

Printed in the UK. All rights reserved
2006 The Author.

Journal compilation 2006 Blackwell Munksgaard
PERIODONTOLOGY 2000
Host responses in maintaining

periodontal health and
determining periodontal disease
H A R V E Y A. S C H E N K E I N
Inflammation and destruction of periodontal tissues
are largely considered to result from the response of a
susceptible host to a microbial biofilm containing
gram-negative bacterial pathogens. Many of the bacteria that can contribute to periodontitis have been
identified [206]; characteristically, their presence is
strongly associated with destructive periodontal
lesions and they display virulence factors associated
with the pathology of soft and hard tissue destruction.
Most of the bacteria that share these characteristics
are not present in healthy periodontal sites or are
present in lower concentrations than in diseased sites.
The manner in which destructive periodontal lesions
are initiated by bacteria in previously healthy sites is
not entirely clear, but likely mechanisms for
progressive destruction of previously compromised
periodontal sites have been extensively described.
As individuals are not equally susceptible to the
destructive effects of periodontal infections, it is clear
that variability in host responses among individuals
contributes significantly to the expression of these
diseases in the population [233]. This likely holds true
both for the protective host mechanisms that prevent
periodontitis or impede its progression and for the
destructive mechanisms that initiate lesions and promote progressive disease. The intent of this review is to
outline some of the host response mechanisms that
might contribute both to maintenance of periodontal
health and to initiation and progression of disease.
Host characteristics that contribute

to prevention of periodontitis
Protective host cells
polymorphonuclear leukocytes
Histologic examination of gingivitis or periodontitis
lesions reveals that the polymorphonuclear leukocyte
appears to play a key role in maintenance of periodontal health [89, 145]. These cells line the junctional
epithelium in large numbers and appear to attempt
to wall off the underlying tissues from the bacterial
biofilm. Their appearance is the result of the presence or generation of chemotactic factors in the
gingival sulcus and underlying tissues [93, 219].
Plaque bacteria are replete with chemotactic factors,
they are further capable of generating chemotactic
factors from plasma via activation of the complement, coagulation, fibrinolytic, and kinin systems or
from surrounding cells following interactions with
cellular receptors [192, 193].
The paramount importance of polymorphonuclear
leukocytes in the protective response against pathogens of the plaque biofilm is underscored by the
prevalence and severity of periodontitis in patients
with syndromes characterized by polymorphonuclear
leukocyte dysfunction. Patients with diseases such as
leukocyte adhesion deficiency, chronic neutropenia,
and cyclic neutropenia suffer from frequent and
severe extraoral infections and are frequently afflicted with severe and early onset forms of periodontitis
[4, 37, 239]. Molecular defects in polymorphonuclear
leukocytes with a variety of functional consequences
can be shown to result in accelerated periodontitis.
For example, leukocyte adhesion deficiency, characterized by total lack of, or decreased expression of,
the beta chain of CD18 or alternatively a defect in
selectin ligand expression, results in a decreased
ability of polymorphonuclear leukocytes to recognize
inflamed endothelium. The failure of polymorphonuclear leukocytes to transmigrate the endothelium
results in a greatly attenuated inflammatory response
to bacterial challenges and restricts the protective
response against periodontal pathogens [138]. A
second example is the mutation of the gene encoding
cathepsin C that results in the PapillonLefe`vre
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syndrome [8587, 227]. Cathepsin C is a lysosomal

protease found in polymorphonuclear leukocytes and
macrophages that removes dipeptides from the
amino terminus of proteins and is likely important in
the activation of other pro-enzymes. PapillonLefe`vre
syndrome is also characterized by early and aggressive periodontitis and characteristic palmar and
plantar hyperkeratosis. It is notable that the pathogenic mechanisms responsible for the periodontal
syndromes observed in the leukocyte adhesion deficiency and PapillonLefe`vre syndromes are not
known, but the associations with defects in leukocyte
function are clear. An additional condition of interest
in this regard is MorbusKostmann syndrome, an
autosomal recessive disease characterized by a lack
of the polymorphonuclear leukocyte antibacterial
cathelicidin LL-37. Patients with this disease have
been reported to have severe periodontitis and
members of one affected family have been found to
have an overgrowth of Actinobacillus actinomycetemcomitans in the oral flora [175].
Additional evidence of the importance of polymorphonuclear leukocytes for protection against
periodontitis is provided by the observation that up
to 80% of patients with localized aggressive periodontitis have a measurable decrease in chemotactic
function when compared to age- and race-matched
periodontally healthy individuals [195, 232, 234, 235].
Symptoms in such patients differ significantly from
those in patients with syndromic defects in polymorphonuclear leukocyte function. Patients with
localized aggressive periodontitis and chemotactic
dysfunction are systemically healthy, early expression
of periodontitis being the only clinical manifestation
of the defect. The chemotactic dysfunction is subtle
in that cells appear to migrate at about 50% or less of
the velocity of normal cells. Interestingly, not all
patients with clinical signs of localized aggressive
periodontitis demonstrate a reproducible defect in
chemotactic function, raising the question of whether
localized aggressive periodontitis is truly a manifestation of the polymorphonuclear leukocyte defect,
whether the association is fortuitous but unrelated, or
whether there are multiple etiologic subforms of
localized aggressive periodontitis only some of which
are related to chemotactic dysfunction.
Protective host responses antibodies

Periodontitis patients characteristically produce systemic and local antibodies reactive with a variety of
periodontal bacterial pathogens [1, 25, 61, 62, 222,
244]. It is apparent that these antibodies do not
78
generally appear in significant titers until after periodontal destruction has already occurred; clinically
periodontal healthy subjects only rarely produce high
levels of such antibodies [1, 150, 170]. This and the
observation that such antibodies persist long after
treatment of periodontal infections raises the question of whether antibodies produced during the
course of disease are functional or are merely serving
as markers of previous infection.
A series of studies of antibody responses and
specificity in aggressive periodontitis patients was
performed to address the issue of functionality of
antibodies reactive with the periodontal pathogens A. actinomycetemcomitans and Porphyromonas
gingivalis. These studies were based upon the initial
observations of Ranney and coworkers [83, 182] that
the presence or absence of high levels of such antibodies were directly associated with disease severity
as indicated by loss of attachment. Those authors
observed that aggressive periodontitis patients who
were seropositive for both A. actinomycetemcomitans
and P. gingivalis displayed significantly fewer sites
with severe attachment loss (sites with more than
5 mm attachment loss) than did patients who
were seronegative for both organisms. Patients seropositive for one or the other bacteria displayed
intermediate percentages of periodontal sites with
attachment loss. The concept that antibody function
could be related to clinical status in aggressive periodontitis was reinforced by studies demonstrating that
periodontal therapy resulting in decreased bacterial
load could induce production of antibodies to plaque
microorganisms in patients with low serum antibody
levels and decreased titer but increase antibody
avidity in patients who had high levels of specific
antibody [30]. These associations can be interpreted to
mean that the antibodies, likely raised during the
course of disease or due to therapy, diminished the
progression of periodontitis in these patients by
modifying or reducing components of the bacterial
microflora. However, in several other studies, effects
of periodontal therapy on the titers and avidities of
bacteria-specific antibodies were extremely variable
[9, 38, 47, 63, 99, 149, 151, 190, 230, 238].
To better examine the effects of antibody titer on
clinical status, studies have been performed that
assess antibody responses to specific bacterial virulence factors. Several of such studies verified that
strong antibody responses against specific bacterial
antigens, such as the lipopolysaccharide or leukotoxin of A. actinomycetemcomitans and the lipopolysaccharide or hemagglutinin of P. gingivalis,
were associated with less severe disease in patients
Host responses in periodontal health and disease
with aggressive or chronic periodontitis [24, 2628].

These antibodies were identified to be predominantly
of the IgG2 subclass. Other studies also identified the
predominant subclass response to pathogens such as
P. gingivalis to be IgG2 but failed to show that high
levels of these antibodies were associated decreased
clinical severity [243]. Despite the lack of clarity
regarding the impact of disease-induced antibody on
periodontal clinical status, several investigators have
developed vaccines based upon immunization with
whole bacteria or agents related to specific virulence
factors that appear to be effective in reducing measures of disease in animal models [19, 50, 65, 76, 78,
157, 166, 178, 185, 249]. This approach, which has
mainly targeted P. gingivalis antigens such as capsular polysaccharide and the gingipain proteases,
sheds some light on the pathogenic mechanisms of
disease in these models of periodontitis.
The protective role of local antibody production, as
detected by elevated concentrations of gingival
crevice fluid antibodies, is unclear. Studies by Tew
et al. [222] demonstrated the local production of
antibody reactive with A. actinomycetemcomitans
and P. gingivalis but failed to note significant associations between such antibody and clinical measures of disease. Other studies did demonstrate that
colonization of specific bacteria such as A. actinomycetemcomitans was lower in sites containing
locally produced antibodies [62] or that therapy
decreased local antibody production [47], but the
impact of this protective response on clinical disease
was not definitively established.
Protection of the periodontium by the

epithelial barrier
The oral epithelium, particularly the junctional and
sulcular epithelia, represents a dynamic physical and
chemical barrier against the pathologic properties of
the microbial biofilm that exists in its vicinity. The
characteristics of the junctional epithelium in health
and disease have been recently described in an
excellent review by Bosshardt & Lang [21].
Fundamentally, healthy epithelial tissues that are
challenged by bacteria react to this challenge by
mobilizing their own antimicrobial mechanisms and
by permitting cells of the innate and adaptive
immune systems to access the pathogens. Histologically, tissues in health comprise not only epithelial
cells but also cellular sentinels such as dendritic cells
[35, 54, 108110] and polymorphonuclear leukocytes
[197], as well as other leukocytes including lymphocytes and mononuclear phagocytes [196].
Cytokines that reflect innate responses of the host

to the microbial biofilm have been shown to be
expressed by cells of the junctional epithelium,
including chemotactic cytokines interleukin (IL)-8
[225, 226] and cytokine-induced neutrophil chemoattractant-2 [146], as well as IL-1 and tumor necrosis
factor-a [147]. Furthermore, cells of the junctional
epithelium and their resident leukocytes contribute
to host defense by expression of antibacterial peptides including calprotectin [154], a- and b-defensins
[34, 130, 237] and cathelicidin LL-37 (recently reviewed
by Dale [46]). Recent data demonstrate that periodontal pathogens induce production of b-defensins
and IL-8 by polymorphonuclear leukocytes [237], and
that defensins are up-regulated in tissues of patients
with chronic periodontitis [130]. However, healthy
tissues appear to have high concentrations of defensins indirectly supporting their role in homeostasis of
the gingival sulcus in health [20, 131].
Destructive host responses to

periodontal microorganisms
innate immunity
It is remarkably difficult to separate and individually
account for the relative impact of innate and
acquired host responses in the pathology of periodontitis lesions. The histopathology of periodontitis
illustrates that most stages of the disease comprise
elements of both types of responses and of both
acute and chronic inflammation. Furthermore, cellular and biochemical constituents of both categories
of response elements interact to determine the
balance of responses in such complex lesions. It is
therefore more useful to organize a discussion of
destructive host responses as a continuum of
responses of various cell types that participate in
pathologic reactions at different stages of disease and
at different locations within the lesion.
Polymorphonuclear leukocytes
Though polymorphonuclear leukocytes appear to
maintain a defensive posture in the periodontal
lesion, it is well known that these cells also can be
major players in immunopathology [16, 241]. Early
studies in animals illustrated that induction of
Arthus-type reactions in the gingiva could lead to
periodontal inflammation and attachment loss [181,
183]. However, the apparent lack of readily demonstrable antigenantibody complexes in periodontal
tissues argue that this phenomenon is not likely to be
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operant in human disease [192]. Nevertheless, the

presence of high concentrations of periodontitisspecific antibodies in the serum and gingival crevice
fluid, the abundance of opsonized bacteria in the
subgingival region, and evidence for the interaction
of bacteria with phagocytes in the periodontal lesion
argue that polymorphonuclear leukocytes are likely
to contribute to pathology in periodontitis [8, 11, 113,
145].
Polymorphonuclear leukocytes synthesize and
release a number of substances, such as lysosomal
enzymes including tissue-destructive proteases [18,
125, 135, 172, 173, 213, 242] that are associated with
the breakdown of periodontal tissues. Interactions of
polymorphonuclear leukocytes with bacteria have
been shown to damage a variety of crucial cell types,
including fibroblasts, endothelial cells, and keratinocytes [241]. Though polymorphonuclear leukocytes constitutively represent a first line of protection
against periodontal pathogens, their interaction with
overwhelming masses of biofilm lead to the release of
constitutive enzymes into the surrounding tissues as
well as the synthesis and secretion of proinflammatory molecules such as arachidonic acid metabolites.
The presence of tissue-damaging enzymes, boneresorbing lipids, and other inflammatory mediators
that are released upon encounter with bacterial
pathogens is likely to contribute to the inflammatory
response and attachment loss observed in periodontitis. It has been proposed that much of the
periodontal tissue destruction observed in aggressive
periodontitis is the result of hyperactivity or priming
of polymorphonuclear leukocytes in these patients
[112, 113, 200, 236], resulting in elevated production
of inflammatory and bone-resorbing lipids.
cytokines and other mediators. This model of tissue

destruction focuses on the production of IL-1 as a key
mediator of periodontal tissue destruction due to the
association of this cytokine with stimulation of
collagenolytic and bone-destructive processes [217].
Studies in model systems have indicated that inhibition or interruption of these pathways results in
inhibition of bacterial-mediated periodontal tissue
destruction [7, 52, 53, 81, 156, 179, 180]. This model of
pathogenesis has the particular appeal of explaining
as well some of the differences in susceptibility to
periodontitis observed in the population, due to the
presence of genetic polymorphisms in the IL-1 genes
that appear to influence the severity of periodontitis
(see below).
The interaction of lipopolysaccharide with macrophages also stimulates production of prostanoids, in
particular prostaglandin E2, which is notably found at
high concentrations in gingival crevice fluid from
sites undergoing periodontal breakdown. Prostaglandin E2 is a bone-resorbing inflammatory lipid,
and experimental data indicate that this pathway is
likely to be important in human periodontal bone
loss [79, 91, 159, 160, 161, 198, 251]. Studies performed both in animal models and in human clinical
trials have demonstrated that production of prostaglandin E2 and loss of alveolar bone due to periodontitis are substantially attenuated following local
or systemic use of nonsteroidal anti-inflammatory
drugs [92, 100, 162, 171, 245].
It is important to note that cells other than macrophages that are present in periodontal lesions (such
as fibroblasts) also produce inflammatory cytokines,
lipid mediators, and matrix metalloproteinases and
are likely to participate in the accumulation of these
molecules [59, 60, 153, 155, 164, 186, 209, 224].
Macrophages
A currently accepted paradigm, explaining how the
predominantly gram-negative infection associated
with periodontitis lesions is translated into destruction of bone and connective tissue, revolves around
mononuclear phagocytes. In sites of chronic inflammation, bacteria participate in attracting leukocytes
into the periodontal tissues either by directly
expressing chemoattractant peptides or by stimulating the production and secretion of chemoattractant
cytokines and inflammatory lipids from host cells.
This leads to accumulation of leukocytes in the host
tissue [8, 93, 94]. Bacterial lipopolysaccharide can
subsequently interact with macrophage or dendritic
cell receptors, including CD14 and Toll-like receptors, to stimulate production of inflammatory
80
Destructive host responses to

periodontal microorganisms
acquired immunity
Although current thinking ascribes a major role for
innate immune mechanisms in periodontal tissue
destruction, the histopathology of the destructive
periodontal lesion and systemic effects of periodontal
bacteria on immune factors such as antibodies and
cytokines implicates acquired immunity as playing a
role in the disease process.
The classic studies of Page and Schroeder described a continuum of histologic observations that
indicated that development of destructive periodontitis entails a progression of cell types [167, 168]. Early
lesions of chronic periodontitis are characterized by a

cellular infiltrate comprising mainly macrophages
and T lymphocytes. More advanced lesions demonstrating connective tissue loss and bone resorption
contain large numbers of B lymphocytes and plasma
cells. It has been proposed that the histologic composition, cytokine profile, and nature and specificity
of the local immune response in periodontitis lesions
reflects the presence and function of subclasses of
regulatory T cells induced by the microbial biofilm
[221, 248]. The histologic picture of the early lesion,
clinical gingivitis, is most consistent with a Th1
response [199]. Such a lesion is classically developed
in response to intracellular pathogens. On the other
hand, the histology of the advanced lesion is more
consistent with a Th2 response, which is typically
mounted to fight extracellular pathogens. The
pathogen itself may dictate which type of response is
generated through its interaction with accessory cells
and resulting production of cytokines characteristic
of the response [51, 106, 114]. For example, the Th1
response is usually characterized by IL-12 production, which in turn induces interferon-c production,
leading to macrophage activation, increased phagocytic activity, and protective immunity. The Th2 response, on the other hand, entails production of
alternative cytokines such as IL-4, IL-10, and IL-13,
leading to antibody production. An exception to this,
and one which is relevant to immune responses to
some oral microorganisms such as A. actinomycetemcomitans, is that some pathogens with high levels
of surface carbohydrates induce high levels of antibodies of the IgG2 subclass that are dependent upon
Th1 rather than Th2 cytokines for their production [2,
117].
During an immune response either the Th1 or the
Th2 cytokine profile will usually dominate, indicating
polarization of the response. The nature of this
response in periodontitis has been examined with
conflicting results. Investigators have examined gingival tissues for expression of cytokine mRNA or
observed the interaction of periodontal pathogens
with leukocytes. Results have frequently demonstrated a mixture of Th1 and Th2 cytokines or a predominance of one type over another [6973, 163, 199,
218, 220, 221, 248]. Those data would favor the
hypothesis that chronic periodontitis lesions are
more associated with the Th2 response. Results
demonstrating a mixture of Th1 and Th2 cytokines
are not surprising in view of the numerous bacterial
species that may interact with the immune system in
a periodontitis lesion. Furthermore, tissues from
lesions displaying differing histologic stages of
disease, different states of disease activity, or differing

forms of periodontitis would likely be heterogeneous
with respect to cytokine profiles.
Aggressive periodontitis and

Th1-dependent antibody production
One of the interesting aspects of the biology of
aggressive periodontitis is that patients with localized
disease have higher serum concentrations of IgG2
protein than do other age- and race-matched periodontal groups and healthy controls [129]. In addition,
localized aggressive periodontitis patients also display very high serum concentrations of specific IgG2
antibodies reactive with carbohydrate antigens of the
periodontal pathogen A. actinomycetemcomitans [26]
and IgG2 plays a predominant role in the antibody
response to P. gingivalis [27, 243]. The increase in
serum concentration of IgG2 (> 1 mg ml) found in
localized aggressive periodontitis patients is far too
great to be accounted for only by the antibody
reactive with A. actinomycetemcomitans, which
appears to average 7080 lg ml in seropositive
patients. The presence of elevated Th1-dependant
specific antibody and total IgG2 has led us to speculate that the immune response of localized
aggressive periodontitis patients may be polarized
towards Th1-dependent responses [215]. Serum IgG2
levels appear to be under genetic control, possible
explaining the predominance of Th1 responses in
localized aggressive periodontitis patients [56].
Examination of peripheral blood leukocytes from
localized aggressive periodontitis patients reveals
that adherent monocytes and soluble factors secreted
by these cells appear to direct increased IgG2 production observed in cell culture. In addition to being
controlled by Th1 cytokines such as IL-12, IL-18, and
interferon-c, IgG2 production is also influenced by
the concentrations of the inflammatory lipids
prostaglandin E2 and platelet-activating factor [2,
102, 103, 117, 215]. Monocytes from localized aggressive periodontitis patients produce lower levels of
platelet-activating factor-acetylhydrolase, a plateletactivating factor-degrading enzyme, which likely
accounts for the higher concentrations of plateletactivating factor. Monocytes from these patients have
a tendency to differentiate into dendritic cells, which
produce lower levels of platelet-activating factoracetylhydrolase than macrophages [3, 14, 215]. A
series of studies exploring the mechanism by which
platelet-activating factor influences IgG2 production
have led to the observation that platelet-activating
factor enhances prostaglandin E2, IL-12, and IL-18
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production by dendritic cells as well as interferon-c

production by natural killer cells. All of these mediators contribute to elevated Th1 responses. In addition,
the periodontal pathogen A. actinomycetemcomitans
interacts with dendritic cells and natural killer cells to
rapidly produce interferon-c and also induces high
levels of Th1 cytokines such as IL-12.
The persistence of Th1 responses can cause tissue
damage as the cytokines and inflammatory mediators
associated with this pathway can induce harmful
molecules including nitric oxide (NO), reactive oxygen intermediates, IL-1, interferon-c, and tumor
necrosis factor [106]. These factors can synergize to
induce pathology in sites of chronic inflammation
and thus may contribute to the uniquely rapid and
severe tissue destruction seen in localized aggressive
periodontitis. Thus, Th1 polarization in localized
aggressive periodontitis leads to high levels of protective IgG2 antibody, large amounts of probably
irrelevant IgG2, and cell-mediated immune mechanisms of chronic inflammation.
Acquired immunity and bone resorption

An emerging area of research demonstrates relationships between the immune system, oral bacterial
pathogens, and alveolar bone loss. Key components
of this system of bone resorption and remodeling are
tumor necrosis factor receptor superfamily proteins
including RANKL (receptor activator of nuclear factor
kappaB ligand), RANK, and osteoprotegerin. RANK,
the receptor for RANKL, is found on osteoclast precursor cells. RANKL is expressed on osteoblasts and
can be regulated by IL-1, IL-6, IL-11, IL-17, tumor
necrosis factor-a, and prostaglandin E2 as well as by
various hormones. Bone loss and remodeling are
controlled both by the balance between RANK and
RANKL and by the RANKL decoy receptor osteoprotegerin [97, 98, 211, 223]. The interplay between this
system and the immune system is demonstrated by
the observation that activated T cells express RANKL
and that bone resorption is a consequence of T-cell
activation and up-regulation of RANKL. In inflammatory diseases such as arthritis and in infectious
diseases characterized by bone resorption it is
thought that RANKL plays a key role in inducing
osteoclasts and bone resorption. In conditions characterized by both T-cell activation and inflammatory
cytokine production, bone resorption is further
enhanced by the effects of such cytokines on RANKL
expression in other cell types [223].
Links between RANK RANKL and periodontal
diseases have been established via examination of
82
gingival tissues and gingival crevice fluid as well as in

animal model systems. Gingival tissues have been
shown to express both RANKL and osteoprotegerin
mRNA with high frequency, and RANKL mRNA levels
have been shown to be highest in tissues from sites
with advanced disease, whereas osteoprotegerin
levels have been found to be very low in such sites
[127, 128]. Notably, RANKL mRNA appears to be expressed by lymphocytes and macrophages in the
gingiva. Both RANKL and osteoprotegerin have also
been quantitated in gingival crevice fluid and it has
been noted that the ratio of RANKL to osteoprotegerin is greater in fluids from diseased sites than from
healthy sites [148].
In vitro and animal studies have shown that both
A. actinomycetemcomitans and P. gingivalis can upregulate RANKL [17, 31, 107, 121, 132]. In studies
using NOD SCID mice reconstituted with human
mononuclear cells from periodontitis patients it
was shown that A. actinomycetemcomitans activates
CD4+ T cells and up-regulates RANKL, leading to
alveolar bone resorption. Likewise, P. gingivalis also
up-regulates RANKL on mononuclear cells, with
resulting bone loss.
Bacterial factors promoting evasion of

protective host factors
Periodontal pathogens, like other microbial pathogens, have evolved mechanisms that both promote
disease and enhance their own survival. The creation
and or maintenance of a biological niche suitable
for biofilm formation and survival must occur in a
manner that protects the colonizing organisms
against the host responses meant to control their
numbers. The ability of pathogenic periodontal
microorganisms to flourish appears to entail more
subtle mechanisms than simple overwhelming of the
immune system by sheer number. The pathogenic
species P. gingivalis and A. actinomycetemcomitans
exemplify this principle. Both organisms have a
common attribute of being able to invade structural
cells of the periodontium, thereby theoretically
hiding from elements of the immune system [32, 33,
67, 126, 187, 188]. However, they additionally have
interesting mechanisms for perturbing host response
mechanisms.
P. gingivalis
As described above, P. gingivalis can contribute to
periodontal inflammation and destruction through
the interaction of its lipopolysaccharide with
inflammatory cells as well as with cells of the
immune system that respond to its antigenicity.

These interactions can result in the production of
proinflammatory cytokines (IL-1b, tumor necrosis
factor-a, IL-6 and IL-8) as well as anti-inflammatory
cytokines (IL-1ra, IL-4) and promote antibody and
cell-mediated protective immune responses [12, 69,
70, 115, 116, 209, 250]. However, this species also
produces potent proteases, termed gingipains, that
utilize host proteins as nutritional substrates and that
are thought to play a significant role in the pathogenesis of periodontitis [44, 74, 101, 152, 158, 174].
Studies have demonstrated that such proteases
readily degrade host-protective molecules such as
complement proteins and immunoglobulins, thereby
evading the opsonic activities of these molecules [45,
191] and generating proinflammatory molecules such
as complement anaphylatoxins [246]. Furthermore,
these proteases can degrade cytokines and their
receptors such as tumor necrosis factor-a, IL-6, and
IL-8 [13, 29, 139, 144, 165] and cellular receptors such
as that for complement (C) 5a [104, 105] and cell
adhesion molecules on endothelial cells [202]. The
functional sequelae of the interactions of these bacterial proteases with host proteins would depend
upon the constituents of the local site at any given
time but evasion of the host antibacterial inflammatory response would be a likely outcome.
Interestingly, the lipopolysaccharide of P. gingivalis is unusual in both its structure and its interaction
with Toll-like receptors on leukocytes and other cells
[10, 43, 184]. Unlike Escherichia coli lipopolysaccharide, which interacts mainly with Toll-like receptor-4,
P. gingivalis lipopolysaccharide interacts significantly with Toll-like receptor-2. Recent studies
indicate that P. gingivalis lipopolysaccharide appears
to be antagonistic to Toll-like receptor-4 and competes with lipopolysaccharide from other species
for Toll-like receptor-4 [36, 48, 49]. It has been
hypothesized that this property could represent a
mechanism of evasion of the host innate immune
system whereby recognition of bacterial pathogens
normally recognized by Toll-like receptor-4 could be
blocked.
A. actinomycetemcomitans
Several of the properties of A. actinomycetemcomitans related to evasion of host responsiveness are
directed at phagocytes. A notable property of A.
actinomycetemcomitans is its toxicity to host leukocytes such as neutrophils and monocytes via production of a leukotoxin [229]. This toxin is well
characterized and strains of A. actinomycetemcomitans producing high levels of the toxin are associated
epidemiologically with risk for localized aggressive

periodontitis [57, 58, 90]. This ability to kill phagocytes imparts obvious survival advantages to the
organism. Additionally, strains of A. actinomycetemcomitans also produce immunosuppressive factors
that suppress specific and nonspecific immune responses as well as fibroblast proliferation [75, 123,
124, 177, 203205, 208, 214]. These properties plus its
capacity for invasion of epithelial and endothelial
cells provide substantial means for evasion of host
protective responses.
Host characteristics that

predispose to periodontal infection
Contribution of genes to host responses
in periodontal infection
The host response to infection depends upon both
the nature of the pathogen and its virulence characteristics and is significantly influenced by genetic
factors. Genetic susceptibility to most infections is a
function of the interaction of multiple genes and
environmental factors with the pathogen [39, 96].
This multifactorial etiologic and pathogenic model
appears to apply to susceptibility to periodontal
pathogens [88, 140].
Data from studies of twins and families indicate
that genes influence periodontal disease risk and
pathogenesis. Studies of chronic periodontitis in
twins indicate that there is greater concordance of
periodontal measures in monozygotic twins than in
dizygotic twins and that environmental factors do not
account for this difference [40, 141, 142]. It is estimated that about 50% of the variance in disease
expression in the population is due to genetic influences. Furthermore, family studies of patients with
aggressive periodontitis verify that there is a genetic
contribution to this form of disease as well [23, 133].
The challenge for investigators is to identify the genes
responsible and to understand how they interact with
each other and with the patients environment to
influence the hosts response to the microflora.
Since the pathogenesis of periodontitis largely
involves host responses to periodontal microorganisms, it follows that it is likely that genetic variation in
the expression of these responses or in factors that
determine the characteristics of the microflora
should influence disease expression. Genetic variation influencing the host response to environmental
or systemic risk factors for periodontitis could also
influence the impact of such factors on disease.
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Several genetic polymorphisms impacting the host

response have been examined for variants that could
be associated with periodontitis. As mentioned
above, a primary example of this relates to genetic
control of the secretion of IL-1 by macrophages. It
has been observed that polymorphic genes regulating
the production of IL-1 in response to bacterial lipopolysaccharide may impact on susceptibility to
severe periodontitis [122]. Such genetic variants of
the IL-1 A and IL-1B genes predispose macrophages
to produce varying amounts of IL-1 in response to a
given stimulus, and a higher proportion of patients
genetically programmed to produce high levels of
IL-1 appear to demonstrate increased susceptibility to increased disease severity. Interestingly, the
association observed between IL-1 polymorphic
genes and aggressive periodontitis is with the alleles
that would promote lower levels of IL-1, or otherwise
no association at all has been detected [55, 240].
Several studies have examined the role of IL-1 polymorphisms in periodontal risk in a variety of populations as well as in smoking and nonsmoking subsets
of patients with variable results [6, 42, 68, 80, 82,
134, 136, 137, 189]. These relationships appear to be
population-dependent, and also may indicate a difference in pathogenesis of chronic and aggressive
periodontitis that could relate to the role of IL-1 in
antibody production. Although it is likely that genetic
variants in the IL-1 genes are likely to be among
many other such genes that contribute to genetic risk
for periodontitis, the biology of IL)1 and the association of high innate levels of IL-1 and severe disease
provide a compelling argument that this is an
important pathway from innate immunity to periodontal destruction.
Polymorphisms in the gene for a second related
proinflammatory cytokine tumor necrosis factor-a
have also been examined, some studies demonstrating associations with periodontitis severity and
other failing to demonstrate such a relationship [41,
64, 66, 118, 201, 207, 228]. Several investigators have
examined polymorphisms in the gene coding for the
anti-inflammatory cytokine IL)10, searching for
associations with chronic or aggressive periodontitis. For the most part, these studies have not
supported a role for the tested polymorphisms in
periodontal pathogenesis [77, 95, 118, 247]. This is
also true for studies examining IL-4 polymorphisms
[111, 143].
Studies of polymorphisms that influence the
function of leukocyte Fc receptors have shown
interesting associations with disease expression and
severity. Such polymorphisms influence the affinity
84
of the interaction of Fc receptors with immunoglobulins, thereby affecting phagocytic capacity and
consequent antibacterial efficacy. FccRIIIb (CD16)
gene polymorphisms, which influence the affinity of
IgG1 and IgG3 interactions with FcRIII, have been
shown to be associated with periodontitis severity in
Japanese populations. The polymorphic alleles coding for lower affinity receptors are more commonly
present in patients with more severe and more rapidly progressing disease [119, 120, 212].
Smoking
Modification of the host response by an environmental
factor: Studies of risk factors for periodontitis clearly
implicate smoking as a potent risk factor for periodontal disease. Although the precise biological
mechanism behind this relationship are not entirely
clear, physiologic effects of smoking on vasoconstriction, revascularization of wounds, collagen and
collagenase production, oxygen transport, and
wound healing are almost certain to be important in
the effects on the periodontium. Additionally, several
studies have demonstrated that host responses may
be significantly altered in smokers and by cigarette
smoke.
We have examined the influence of smoking on the
expression of aggressive periodontitis and noted that
generalized aggressive periodontitis patients who
smoked had greater extent and severity of disease
than did patients who did not smoke [194]. As we had
previously found associations between elevated
antibody levels against the pathogens P. gingivalis
and A. actinomycetemcomitans and decreased severity of disease, we studied how smoking might influence antibody levels. Because racial groups differ in
serum immunoglobulin levels we analyzed these data
for race-matched groups of subjects. Interestingly, we
noted that IgG2, a predominant subclass of antibody
reactive with periodontal pathogens, was substantially lower in the serum of race-matched generalized
aggressive periodontitis patients who smoked than in
those who did not smoke, consistent with the clinical
findings in this group [176]. This was not the case for
other IgG subclasses nor was it true for patients with
localized aggressive periodontitis or chronic periodontitis. When we examined specific serum antibody concentrations to A. actinomycetemcomitans in
generalized aggressive periodontitis patients we
observed much lower concentrations of antibody in
serum from smokers than in serum from nonsmokers
[216]. Although the mechanism for specific suppression of serum IgG2 and antibody response in this
group of patients with severe disease is not clear,

these observations demonstrate that a risk factor for
clinical expression of disease may act by modifying
the host immune response and thereby influencing
disease expression [15].
Smoking has also been shown to influence aspects
of the inflammatory response. For example, several
studies demonstrate an impairment of polymorphonuclear leukocyte function by tobacco and its byproducts, including chemotaxis and phagocytosis by
oral and peripheral polymorphonuclear leukocytes,
oxidative burst, and superoxide and hydrogen peroxide production [231]. Studies have also demonstrated that tobacco components can stimulate the
production of proinflammatory cytokines such as
IL-1, IL-6, IL-8, and tumor necrosis factor-a, as well
as transforming growth factor-b, thereby promoting
increased fibrosis, bone resorption, and decreased
bone formation [5, 22, 84, 169, 210].
Conclusion
In attempting to synthesize the large amount of data
on host responses in periodontal diseases one must
consider several fundamental issues that complicate
our understanding of this topic. First, there are multiple subforms of periodontitis that likely entail differing combinations of pathogenic mechanisms of
tissue destruction. In addition, each periodontal site
comprises a complex microflora that may interact
with, direct, and modify the host response in a different way. Furthermore, each patient with periodontitis is exposed to different nonmicrobial environmental factors that can modify the host response
to the etiologic agents of their periodontal condition.
Finally, each individual possesses a mostly immutable
innate level of host susceptibility to periodontal
infections which permits disease expression in a
manner modifiable by the microflora and environment. It is clear that multiple models of host responsebased pathogenesis are likely necessary to describe
the way in which periodontal infections can lead to
destruction of hard and soft tissues. Likewise, hostbased mechanisms of maintenance of periodontal
health would vary amongst individuals depending
upon the susceptibility factors outlined above.
Acknowledgment
Supported in part by grant DE 13102 from the National
Institute of Dental and Craniofacial Research.
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Periodontology 2000, Vol.

40, 2006, 7793

2006 The Author.

Host responses in maintaining

Host characteristics that contribute

syndrome [8587, 227]. Cathepsin C is a lysosomal

Protective host responses antibodies

Host responses in periodontal health and disease

with aggressive or chronic periodontitis [24, 2628].

Protection of the periodontium by the

Cytokines that reflect innate responses of the host

Destructive host responses to

operant in human disease [192]. Nevertheless, the

cytokines and other mediators. This model of tissue

Destructive host responses to

Host responses in periodontal health and disease

lesions of chronic periodontitis are characterized by a

disease, different states of disease activity, or differing

Aggressive periodontitis and

production by dendritic cells as well as interferon-c

Acquired immunity and bone resorption

gingival tissues and gingival crevice fluid as well as in

Bacterial factors promoting evasion of

Host responses in periodontal health and disease

immune system that respond to its antigenicity.

epidemiologically with risk for localized aggressive

Host characteristics that

Several genetic polymorphisms impacting the host

Host responses in periodontal health and disease

group of patients with severe disease is not clear,

Host responses in periodontal health and disease

64. Endo M, Tai H, Tabeta K, Kobayashi T, Yamazaki K, Yoshie

94. Hellden L, Lindhe J. Enhanced emigration of crevicular

Host responses in periodontal health and disease

special emphasis on junctional epithelium. Scand J Dent

127. Liu D, Xu JK, Figliomeni L, Huang L, Pavlos NJ, Rogers M,

160. Offenbacher S, Heasman P, Collins J. Modulation of host

Host responses in periodontal health and disease

193. Schenkein HA, Berry CR. Activation of complement by

with chronic periodontitis. J Periodontol 2004: 75:

226. Tonetti MS, Imboden MA, Lang NP. Neutrophil migration

Host responses in periodontal health and disease

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