Host responses in periodontaldiseases: a preview

IS A O IS H I K A W A

Ten years have passed since a paradigm shift in the

pathogenesis of periodontitis was proposed by Page

& Kornman (16). A plethora of research papers has

since revised our previous concepts in this field. In

particular, important information has appeared on

cellular, molecular and genetic aspects of destructive

periodontal disease. Recent conceptual and technical

advances have provided us with further insights into

the infectious agents and the characteristics of the

host immune response in periodontal diseases. The

information gained may help to improve our ability

to diagnose and treat such diseases.

In 1997, a symposium at North Carolina Chapel

Hill entitled �Periodontal diseases and human health:

New edition in periodontal medicine� advanced the

notion that oral infections may have powerful and

multiple influences on the occurrence and severity of

systemic conditions and diseases (27). Since then,

numerous publications in dental and medical jour-

nals have focused on the relationship between peri-

odontal disease and systemic conditions, especially

cardiovascular diseases, diabetes and respiratory

pathosis. Progress in this field within the last few

years has been tremendous. �Periodontal disease and

coronary heart disease: a reappraisal of the exposure�(1), �High serum antibody levels to Porphyromonas

gingivalis predict myocardial infarction� (19), �Anti-

bodies to periodontal pathogens and stroke risk� (18),

�Early carotid atherosclerosis in subjects with perio-

dontal diseases� (26), �Gender differences in the re-

lationship between periodontal disease tooth loss,

and atherosclerosis� (3), �Periodontal disease and

biomarkers related to cardiovascular diseases� (7),

�Periodontal disease and mortality in type 2 diabetes�(22) and �Oral bacteria in the occluded arteries of

patients with Buerger disease� (6), are titles of re-

cently published articles in medical journals, which

have identified a positive correlation between perio-

dontal disease and systemic diseases. Stamm (27)

mentioned that practitioners of obstetrics, cardio-

vascular disease and periodontics are collaborating in

scientific progress in ways not previously imagined.

Recently, it has been suggested that herpesviruses

comprise an important source for triggering perio-

dontal tissue destruction. Herpesvirus infections may

initiate or accelerate periodontal breakdown via their

ability to stimulate cytokine release from host cells,

or they might impair host defense mechanisms,

resulting in heightened virulence of resident perio-

dontopathic bacteria (24). In the light of the potential

importance of mammalian viruses in periodontal

diseases (23–25), a discussion of virally induced host

responses is also included in this volume.

Microbial antigens and virulence factors elicit an

immediate inflammatory and immune response from

the host. The host reacts to microbial insults by

producing cytokines, eicasonoids, kinins, comple-

ment activation products and matrix metallopro-

teinases. Some of these inflammatory mediators

participate in periodontal ligament and bone

destruction. In turn, the inflammatory response is

regulated by genetic and environmental modifiers. As

reported by Page et al. (17), bacteria are essential in,

but not sufficient to cause, periodontitis, and host

factors, such as heredity, and environmental factors,

such as smoking, are important determinants of

periodontal disease occurrence and severity. Bacteria

may cause periodontal tissue destruction indirectly

by activating various components of the host defense

system. When activated, these host systems may

provide protection at the cost of some level of

periodontal destruction. Periodontal researchers

have extensively studied this double-edged sword

phenomenon, and the concepts thus derived consi-

der the involvement of intrinsic and induced host

factors. In addition, cell-specific receptors and their

pathways have been identified. In this volume of

Periodontology 2000 we have compiled the latest

9

Periodontology 2000, Vol. 43, 2007, 9–13

Printed in Singapore. All rights reserved

� 2007 The Author.

Journal compilation � 2007 Blackwell Munksgaard

PERIODONTOLOGY 2000

information on host responses in periodontitis. A vast

amount of knowledge provided by research experts

has been gathered in a format that we hope is clear

and illustrative for the readers.

In order to investigate the pathogenesis of perio-

dontitis, it is essential to understand how the im-

mune system reacts towards microbial infections. To

familiarize readers with this topic, Mahanonda &

Pichyangkul (10) have prepared an article on the

fundamental mechanisms of host responses to bac-

terial and viral infections (10). The authors concen-

trated on two topics: the cross-talk between innate

and adaptive immunity mediated by dendritic cells

via Toll-like receptors, and the antigen-specific im-

munoregulation by particular subsets of dendritic

cells and T cells.

T cells play an important immunoregulatory role in

the pathogenesis of periodontal diseases. In a sep-

arate article dealing with T cells in periodontal

diseases, Gemmell et al. (5) suggest that T cells have

a homeostatic role and that autoimmunity is an

important component of chronic periodontal

inflammation. They discuss various mechanisms by

which T cells are involved in the destruction and

repair processes of chronic periodontitis. In their

article, they advance the concept that T cells have a

homeostatic role, rather than a defensive or

destructive role, in periodontal diseases (5).

Periodontitis is characterized by destruction of the

periodontal ligament and bone. Alveolar bone re-

sorption occurs as a result of uncoupling of the

normally balanced processes of bone resorption and

bone formation. Cytokines, chemokines and prosta-

glandins have been identified as regulators of the

immunoinflammatory process in periodontitis. Acti-

vated lymphocytes, macrophages and neutrophils

infiltrate inflamed gingival tissue and secrete

inflammatory mediators, including interleukin-1 and

prostaglandin E2. In addition, T helper 1- and T

helper 2-type T lymphocytes, which are present in

periodontal lesions, up-regulate the production of

the pro-inflammatory interleukin-1 and tumor nec-

rosis factor-a. These cytokines can induce bone re-

sorption indirectly by promoting the differentiation

of osteoclast precursors and by activating osteoclasts.

Udagawa et al. (28) have prepared a chapter on

signal transduction of lipopolysaccharide-induced

osteoclast differentiation. Lipopolysaccharide, being

the major constituent of gram-negative bacteria, is

proposed to be a potent stimulator of bone resorp-

tion in inflammatory periodontal disease (28).

The recruitment of osteoclasts is dependent on the

balance between receptor activator of nuclear factor

kappa B ligand and its decoy receptor, osteoproteg-

erin, in osteoblasts. Receptor activator of nuclear

factor kappa B ligand is thought to be a major

mediator of alveolar bone resorption in periodontitis.

Nagasawa et al. (12) have discussed the role of

receptor activator of nuclear factor kappa B, receptor

activator of nuclear factor kappa B ligand and oste-

oprotegerin in periodontal bone resorption. The

potential importance of differences in receptor

activator of nuclear factor kappa B ligand and

osteoprotegerin expression among human gingival

fibroblasts, periodontal fibroblasts and osteoblasts is

also addressed. In addition, Nagasawa et al. (12)

review recent concepts of antibodies against perio-

dontopathic bacteria, especially the diagnostic value

of antibacterial antibodies, which are becoming

important not only in periodontal diagnosis but also

in the risk assessment of coronary heart disease and

peripheral vascular disease (4,18). New insights into

the classic axis of neutrophils–antibodies–comple-

ment in periodontal diseases are also summarized.

Prostaglandin E2 is an important mediator of tis-

sue destruction in periodontitis. Prostaglandin E2

stimulates pro-inflammatory responses, including

osteoclastogenesis, by enhancing the expression of

receptor activator of nuclear factor kappa B ligand.

However, prostaglandin E2 also has anti-inflamma-

tory effects, including inhibiting the production of

pro-inflammatory cytokines, such as tumor necrosis

factor-a, and can elicit anabolic actions on bone. An

article by Noguchi & Ishikawa (15), discussing the

periodontal roles of prostaglandin E2 and cyclo-

oxygenase-2, has been included. The authors suggest

that prostaglandin E2 has the ability to down-regulate

hyper-inflammation occurring in periodontal lesions,

and to stimulate wound healing.

Similarly to environmental factors, host factors,

such as heredity, are a major determinant of in-

fectious disease occurrence and severity. With recent

advances in the science of genetics, genes res-

ponsible for various diseases have been identified

and mapped. Genetic traits that may be associated

with an increased risk for periodontitis include

abnormal phagocyte function, a reduced capacity

to produce immunoglobulin G2, hFc-gamma-RIIa

polymorphism, tumor necrosis factor-a polymorph-

ism, interleukin-1a polymorphism and prostaglandin

endoperoxide synthase 1 gene polymorphism (17). In

this volume of Periodontology 2000, Yoshie et al. (29)

have reviewed the possible role of genetic polymor-

phisms in periodontitis. In addition to listing the

evidence linking genetics and aggressive and chronic

forms of periodontitis, the authors have discussed the

10

Ishikawa

polymorphisms identified in the cytokine family

and receptor genes, and addressed the issues and

concerns about the candidate gene approach of study

in periodontitis.

Aggressive periodontitis is characterized by a

young age of disease onset and severe periodontal

tissue destruction. Meng and co-authors (11) have

reviewed the determinants of host susceptibility in

aggressive periodontitis, focusing on family aggrega-

tion, single nucleotide polymorphisms, polymor-

phonuclear leukocytes, antibodies, smoking, stress

and root morphology abnormalities (11). They sug-

gest that increased host susceptibility in patients with

aggressive periodontitis may be caused by the com-

bined effect of multiple genes interacting with envi-

ronmental factors.

Oxidative stress has been implicated in periodon-

titis, obesity, type II diabetes, vascular diseases and

the events that lead to adverse pregnancy outcome.

In recent years, reactive oxygen species have also

been implicated in the pathogenesis of periodontitis.

The overproduction of reactive oxygen species may

be a key component of hyper-inflammation associ-

ated with periodontitis. Chapple & Matthews (2) ex-

plore the role of reactive oxygen and antioxidant

species in periodontal tissue destruction. They sug-

gest that oxidative stress not only leads to direct

tissue damage, but may also activate key nuclear

transcription factors, such as receptor activator of

nuclear factor kappa B and Ap-1, which subsequently

can induce gene transcription for key pro-inflam-

matory mediators.

Among the environmental factors known to affect

the incidence and severity of periodontitis, smoking

stands out as one of the most significant and pre-

ventable risk factors. Tobacco smoking increases

the risk of periodontal destruction by stimulating

inflammatory responses and impairing protective/

reparative host responses. In an elaborate review,

Ryder (20) deals with the influence of smoking on the

immune response in periodontal disease. He suggests

that host-modulating agents, such as tetracyclines,

may partly alleviate the destructive effects of tobacco

products on host responses. Research in the field of

tobacco smoking and its effects on the host immune

system may also help to identify host-modulating

agents that may be beneficial in the treatment of

periodontal disease in both smokers and non-

smokers.

Diabetes is an extensively researched risk factor for

periodontitis. Diabetic subjects are known to respond

to microbial challenges in an exaggerated manner

compared with nondiabetic subjects. Exaggerated

inflammatory responses in diabetic subjects appear

to increase the risk for vascular disorders. Nassar

et al. (13) have proposed the interesting hypothesis

that long-term hyperglycemia supports anaerobic

infection in periodontal sites owing to an environ-

ment of exacerbated innate immunity. Persistent

hyperglycemia may lead to chronically activated in-

nate immunity and chronic inflammation in the

periodontium by either blocking or suppressing

pathways of resolution. Nassar et al. (13) examined

the role of innate immunity, inflammation and

resolution of inflammation as essential components

in the development of diabetic complications,

including periodontal disease. They also proposed

several therapeutic approaches, including host-

modulation therapy. In a separate chapter, Nishim-

ura et al. (14) summarize the current knowledge on

the bidirectional relationship between diabetes and

periodontal disease, and discuss future strategies for

the prevention and treatment of periodontal disease

in diabetic subjects. Periodontal disease has been

considered to be the sixth complication of diabetes.

Recent studies suggest that obesity is associated

with periodontal disease. Obesity increases the risk of

various systemic diseases and of type 2 diabetes, and

raises patient mortality. Conversely, periodontal

disease has been reported to influence the serum

glucose level, not only in diabetic but also in non-

diabetic subjects. Taking account of all these issues,

the relationship among obesity, diabetes and perio-

dontal disease is complicated and needs to be further

evaluated. Saito & Shimazaki (21) have reviewed the

relationship between obesity and periodontal dis-

ease. The influence of periodontal disease on obesity-

related metabolic disorders, such as glucose and lipid

metabolism, and associated glucose intolerance and

dyslipidemia, are highlighted (21).

With the emergence of immense knowledge at the

basic science level, the clinician is left to think about

the relevance of the available information. The road

from the laboratory bench to the clinic seems

sometimes to be exceedingly long. Nonetheless, the

information regarding host responses and modu-

lating factors in periodontitis may be used for

therapeutic purposes. With the paradigm rapidly

changing, the focus in periodontics is shifting from

diagnosis and treatment to prevention and health

promotion. Identifying and managing the risk factors

for periodontitis is of utmost importance. Environ-

mental risk factors, such as tobacco use and diabetes,

can be significantly reduced or eliminated by smo-

king-cessation programs and metabolic control,

respectively. Future diagnostic and preventive

11

Host responses in periodontal diseases: a preview

approaches appear to be in the application of

the genetic information to determine the inherent

susceptibility of individuals to periodontal disease.

Kinane & Bartold (8) have discussed the clinical im-

plications of periodontal host responses. Their

chapter may help the clinician bridge the gap be-

tween the laboratory and the clinic.

To add to this information, Kirkwood et al. (9) have

suggested novel therapeutic approaches in period-

ontics. Alveolar bone loss may be delayed or pre-

vented by the use of host-modulating agents. The

feasibility of inhibiting or blocking proteolytic en-

zymes and pro-inflammatory cytokines are presently

being studied. Kirkwood et al. (9) mention three ca-

tegories of host-modulating agents: antiproteinases,

anti-inflammatory drugs, and bone-sparing drugs.

More recently, inflammatory cell signaling path-

ways that generate these inflammatory and tissue-

destructive proteinases have also become promising

therapeutic targets. Inhibition of signal transduction

pathways may abolish cell activation and the pro-

duction of pro-inflammatory cytokines. Kirkwood

et al. (9) propose therapeutic strategies directed to-

wards major signaling pathways, including mitogen-

activated protein kinase and receptor activator of

nuclear factor kappa B. Finally, they consider novel

protein antagonist strategies in the treatment of

periodontal diseases to disrupt the receptor activator

of nuclear factor kappa B ligand/receptor activator of

nuclear factor kappa B/osteoprotegerin axis. These

novel therapies may eventually provide more effect-

ive means to manage chronic periodontitis.

In this volume of Periodontology 2000, we have

tried to incorporate the most recent information

regarding the host responses in periodontitis.

Comprehensive reviews of each study subject have

been included. Experts in the field of immunology

have contributed their valuable time and effort to

complete this task. We hope that this volume is up-

to-date and of help to the researcher as well as the

clinician. As a result of rapidly advancing technology,

it may soon be possible to apply the new information

for diagnostic and therapeutic purposes. Further re-

search, aimed at a greater understanding of the

parasite–host interaction in periodontal infections,

may yield significant pay-offs in combating perio-

dontal diseases.

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Host responses in periodontal diseases: a preview