Schenke in 2006

Host responses in maintainingperiodontal health anddetermining periodontal disease

HARVEY A. SCHENKEIN

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 bac-

teria 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 pro-

mote 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 contributeto 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 perio-

dontal 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 pre-

sence 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 comple-

ment, 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 patho-

gens 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 afflic-

ted 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, charac-

terized 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 polymorpho-

nuclear 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 Papillon–Lefevre

77

Periodontology 2000, Vol. 40, 2006, 77–93

Printed in the UK. All rights reserved

� 2006 The Author.

Journal compilation � 2006 Blackwell Munksgaard

PERIODONTOLOGY 2000

syndrome [85–87, 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. Papillon–Lefevre

syndrome is also characterized by early and aggres-

sive periodontitis and characteristic palmar and

plantar hyperkeratosis. It is notable that the patho-

genic mechanisms responsible for the periodontal

syndromes observed in the leukocyte adhesion defi-

ciency and Papillon–Lefevre syndromes are not

known, but the associations with defects in leukocyte

function are clear. An additional condition of interest

in this regard is Morbus–Kostmann 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 actinomyce-

temcomitans in the oral flora [175].

Additional evidence of the importance of poly-

morphonuclear leukocytes for protection against

periodontitis is provided by the observation that up

to 80% of patients with localized aggressive perio-

dontitis 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 poly-

morphonuclear 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 manifes-

tation 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 sys-

temic 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

generally appear in significant titers until after peri-

odontal 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 ques-

tion 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 patho-

gens 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 anti-

bodies 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 sero-

positive 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 perio-

dontitis 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 viru-

lence factors. Several of such studies verified that

strong antibody responses against specific bacterial

antigens, such as the lipopolysaccharide or leuko-

toxin of A. actinomycetemcomitans and the lipo-

polysaccharide or hemagglutinin of P. gingivalis,

were associated with less severe disease in patients

78

Schenkein

with aggressive or chronic periodontitis [24, 26–28].

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 meas-

ures 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 cap-

sular 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 asso-

ciations between such antibody and clinical meas-

ures of disease. Other studies did demonstrate that

colonization of specific bacteria such as A. actino-

mycetemcomitans 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 theepithelial 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. Histologi-

cally, tissues in health comprise not only epithelial

cells but also cellular sentinels such as dendritic cells

[35, 54, 108–110] and polymorphonuclear leukocytes

[197], as well as other leukocytes including lympho-

cytes 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 chemo-

attractant-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 pep-

tides including calprotectin [154], a- and b-defensins[34, 130, 237] andcathelicidin LL-37 (recently reviewed

by Dale [46]). Recent data demonstrate that perio-

dontal pathogens induce production of b-defensinsand 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 defen-

sins indirectly supporting their role in homeostasis of

the gingival sulcus in health [20, 131].

Destructive host responses toperiodontal 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 perio-

dontitis 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, cel-

lular 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 demon-

strable antigen–antibody complexes in periodontal

tissues argue that this phenomenon is not likely to be

79

Host responses in periodontal health and disease

operant in human disease [192]. Nevertheless, the

presence of high concentrations of periodontitis-

specific 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 kera-

tinocytes [241]. Though polymorphonuclear leuko-

cytes 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 proinflamma-

tory molecules such as arachidonic acid metabolites.

The presence of tissue-damaging enzymes, bone-

resorbing 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 perio-

dontitis. 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.

Macrophages

A currently accepted paradigm, explaining how the

predominantly gram-negative infection associated

with periodontitis lesions is translated into destruc-

tion of bone and connective tissue, revolves around

mononuclear phagocytes. In sites of chronic inflam-

mation, bacteria participate in attracting leukocytes

into the periodontal tissues either by directly

expressing chemoattractant peptides or by stimula-

ting 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 recep-

tors, to stimulate production of inflammatory

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 inhi-

bition 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 macro-

phages 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. Prosta-

glandin 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 per-

formed both in animal models and in human clinical

trials have demonstrated that production of prosta-

glandin E2 and loss of alveolar bone due to perio-

dontitis 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 macro-

phages 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].

Destructive host responses toperiodontal 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 des-

cribed a continuum of histologic observations that

indicated that development of destructive periodon-

titis entails a progression of cell types [167, 168]. Early

80

Schenkein

lesions of chronic periodontitis are characterized by a

cellular infiltrate comprising mainly macrophages

and T lymphocytes. More advanced lesions demon-

strating connective tissue loss and bone resorption

contain large numbers of B lymphocytes and plasma

cells. It has been proposed that the histologic com-

position, 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 produc-

tion, which in turn induces interferon-c production,

leading to macrophage activation, increased phago-

cytic activity, and protective immunity. The Th2 re-

sponse, 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. actinomyce-

temcomitans, is that some pathogens with high levels

of surface carbohydrates induce high levels of anti-

bodies 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 gin-

gival tissues for expression of cytokine mRNA or

observed the interaction of periodontal pathogens

with leukocytes. Results have frequently demonstra-

ted a mixture of Th1 and Th2 cytokines or a pre-

dominance of one type over another [69–73, 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 andTh1-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 perio-

dontal groups and healthy controls [129]. In addition,

localized aggressive periodontitis patients also dis-

play 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 70–80 lg ⁄ ml in seropositive

patients. The presence of elevated Th1-dependant

specific antibody and total IgG2 has led us to spe-

culate 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 pro-

duction 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 aggres-

sive periodontitis patients produce lower levels of

platelet-activating factor-acetylhydrolase, a platelet-

activating factor-degrading enzyme, which likely

accounts for the higher concentrations of platelet-

activating factor. Monocytes from these patients have

a tendency to differentiate into dendritic cells, which

produce lower levels of platelet-activating factor-

acetylhydrolase 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

81


production by dendritic cells as well as interferon-cproduction by natural killer cells. All of these media-

tors 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 oxy-

gen 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 pro-

tective IgG2 antibody, large amounts of probably

irrelevant IgG2, and cell-mediated immune mecha-

nisms of chronic inflammation.

Acquired immunity and bone resorption

An emerging area of research demonstrates rela-

tionships 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 pre-

cursor 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 osteopro-

tegerin [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 inflam-

matory 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 char-

acterized 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

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 ex-

pressed 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 osteoproteg-

erin 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 up-

regulate 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 ofprotective host factors

Periodontal pathogens, like other microbial patho-

gens, 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

82

Schenkein

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 patho-

genesis 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, andIL-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 bac-

terial proteases with host proteins would depend

upon the constituents of the local site at any given

time but evasion of the host antibacterial inflamma-

tory response would be a likely outcome.

Interestingly, the lipopolysaccharide of P. gingiva-

lis is unusual in both its structure and its interaction

with Toll-like receptors on leukocytes and other cells

[10, 43, 184]. Unlike Escherichia coli lipopolysaccha-

ride, which interacts mainly with Toll-like receptor-4,

P. gingivalis lipopolysaccharide interacts signifi-

cantly with Toll-like receptor-2. Recent studies

indicate that P. gingivalis lipopolysaccharide appears

to be antagonistic to Toll-like receptor-4 and com-

petes 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. actinomycetemcomi-

tans related to evasion of host responsiveness are

directed at phagocytes. A notable property of A.

actinomycetemcomitans is its toxicity to host leuko-

cytes such as neutrophils and monocytes via pro-

duction of a leukotoxin [229]. This toxin is well

characterized and strains of A. actinomycetemcomi-

tans producing high levels of the toxin are associated

epidemiologically with risk for localized aggressive

periodontitis [57, 58, 90]. This ability to kill phago-

cytes imparts obvious survival advantages to the

organism. Additionally, strains of A. actinomycetem-

comitans also produce immunosuppressive factors

that suppress specific and nonspecific immune re-

sponses as well as fibroblast proliferation [75, 123,

124, 177, 203–205, 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 thatpredispose to periodontal infection

Contribution of genes to host responsesin periodontal infection

The host response to infection depends upon both

the nature of the pathogen and its virulence charac-

teristics 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 esti-

mated that about 50% of the variance in disease

expression in the population is due to genetic influ-

ences. 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 patient’s environment to

influence the host’s response to the microflora.

Since the pathogenesis of periodontitis largely

involves host responses to periodontal microorgan-

isms, 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 vari-

ation influencing the host response to environmental

or systemic risk factors for periodontitis could also

influence the impact of such factors on disease.

83


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 lipo-

polysaccharide 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 suscepti-

bility 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 poly-

morphisms in periodontal risk in a variety of popu-

lations 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 dif-

ference 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 associ-

ation of high innate levels of IL-1 and severe disease

provide a compelling argument that this is an

important pathway from innate immunity to perio-

dontal destruction.

Polymorphisms in the gene for a second related

proinflammatory cytokine tumor necrosis factor-ahave also been examined, some studies demon-

strating 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 periodonti-

tis. 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

of the interaction of Fc receptors with immuno-

globulins, 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 cod-

ing for lower affinity receptors are more commonly

present in patients with more severe and more rap-

idly 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 perio-

dontal disease. Although the precise biological

mechanism behind this relationship are not entirely

clear, physiologic effects of smoking on vasocon-

striction, 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 sever-

ity of disease, we studied how smoking might influ-

ence 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 substan-

tially 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 perio-

dontitis. When we examined specific serum anti-

body 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 suppres-

sion of serum IgG2 and antibody response in this

84

Schenkein

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 polymorpho-

nuclear leukocyte function by tobacco and its by-

products, including chemotaxis and phagocytosis by

oral and peripheral polymorphonuclear leukocytes,

oxidative burst, and superoxide and hydrogen per-

oxide production [231]. Studies have also demon-

strated 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 mul-

tiple subforms of periodontitis that likely entail dif-

fering 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 dif-

ferent way. Furthermore, each patient with perio-

dontitis is exposed to different nonmicrobial envi-

ronmental factors that can modify the host response

to the etiologic agents of their periodontal condition.

Finally, each individual possesses amostly immutable

innate level of host susceptibility to periodontal

infections which permits disease expression in a

manner modifiable by the microflora and environ-

ment. It is clear thatmultiplemodels of host response-

based pathogenesis are likely necessary to describe

the way in which periodontal infections can lead to

destruction of hard and soft tissues. Likewise, host-

based mechanisms of maintenance of periodontal

health would vary amongst individuals depending

upon the susceptibility factors outlined above.

Acknowledgment

Supported in part by grantDE 13102 from theNational

Institute of Dental and Craniofacial Research.

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