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Periodontology 2000, Vol. 43, 2007, 9–13
Printed in Singapore. All rights reserved
Ó 2007 The Author.
Journal compilation Ó 2007 Blackwell Munksgaard
PERIODONTOLOGY 2000
Host responses in periodontal
diseases: a preview
ISAO ISHIKAWA
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 ÔPeriodontal diseases and human health:
New edition in periodontal medicineÕ 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 journals have focused on the relationship between periodontal disease and systemic conditions, especially
cardiovascular diseases, diabetes and respiratory
pathosis. Progress in this field within the last few
years has been tremendous. ÔPeriodontal disease and
coronary heart disease: a reappraisal of the exposureÕ
(1), ÔHigh serum antibody levels to Porphyromonas
gingivalis predict myocardial infarctionÕ (19), ÔAntibodies to periodontal pathogens and stroke riskÕ (18),
ÔEarly carotid atherosclerosis in subjects with periodontal diseasesÕ (26), ÔGender differences in the relationship between periodontal disease tooth loss,
and atherosclerosisÕ (3), ÔPeriodontal disease and
biomarkers related to cardiovascular diseasesÕ (7),
ÔPeriodontal disease and mortality in type 2 diabetesÕ
(22) and ÔOral bacteria in the occluded arteries of
patients with Buerger diseaseÕ (6), are titles of recently published articles in medical journals, which
have identified a positive correlation between periodontal disease and systemic diseases. Stamm (27)
mentioned that practitioners of obstetrics, cardiovascular 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 periodontal 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 periodontopathic 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, complement activation products and matrix metalloproteinases. 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 consider 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
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Ishikawa
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 periodontitis, it is essential to understand how the immune 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 bacterial and viral infections (10). The authors concentrated on two topics: the cross-talk between innate
and adaptive immunity mediated by dendritic cells
via Toll-like receptors, and the antigen-specific immunoregulation by particular subsets of dendritic
cells and T cells.
T cells play an important immunoregulatory role in
the pathogenesis of periodontal diseases. In a separate 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 resorption occurs as a result of uncoupling of the
normally balanced processes of bone resorption and
bone formation. Cytokines, chemokines and prostaglandins have been identified as regulators of the
immunoinflammatory process in periodontitis. Activated 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 necrosis factor-a. These cytokines can induce bone resorption 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 resorption in inflammatory periodontal disease (28).
The recruitment of osteoclasts is dependent on the
balance between receptor activator of nuclear factor
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kappa B ligand and its decoy receptor, osteoprotegerin, 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 osteoprotegerin 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 periodontopathic 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–complement in periodontal diseases are also summarized.
Prostaglandin E2 is an important mediator of tissue 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-inflammatory 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 cyclooxygenase-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 infectious disease occurrence and severity. With recent
advances in the science of genetics, genes responsible 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 polymorphism, 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 polymorphisms in periodontitis. In addition to listing the
evidence linking genetics and aggressive and chronic
forms of periodontitis, the authors have discussed the
Host responses in periodontal diseases: a preview
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 aggregation, single nucleotide polymorphisms, polymorphonuclear leukocytes, antibodies, smoking, stress
and root morphology abnormalities (11). They suggest that increased host susceptibility in patients with
aggressive periodontitis may be caused by the combined effect of multiple genes interacting with environmental factors.
Oxidative stress has been implicated in periodontitis, 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 associated with periodontitis. Chapple & Matthews (2) explore the role of reactive oxygen and antioxidant
species in periodontal tissue destruction. They suggest 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-inflammatory mediators.
Among the environmental factors known to affect
the incidence and severity of periodontitis, smoking
stands out as one of the most significant and preventable 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 nonsmokers.
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 environment of exacerbated innate immunity. Persistent
hyperglycemia may lead to chronically activated innate 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 hostmodulation therapy. In a separate chapter, Nishimura 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 nondiabetic subjects. Taking account of all these issues,
the relationship among obesity, diabetes and periodontal disease is complicated and needs to be further
evaluated. Saito & Shimazaki (21) have reviewed the
relationship between obesity and periodontal disease. The influence of periodontal disease on obesityrelated 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 modulating 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. Environmental risk factors, such as tobacco use and diabetes,
can be significantly reduced or eliminated by smoking-cessation programs and metabolic control,
respectively. Future diagnostic and preventive
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Ishikawa
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 implications of periodontal host responses. Their
chapter may help the clinician bridge the gap between the laboratory and the clinic.
To add to this information, Kirkwood et al. (9) have
suggested novel therapeutic approaches in periodontics. Alveolar bone loss may be delayed or prevented by the use of host-modulating agents. The
feasibility of inhibiting or blocking proteolytic enzymes and pro-inflammatory cytokines are presently
being studied. Kirkwood et al. (9) mention three categories of host-modulating agents: antiproteinases,
anti-inflammatory drugs, and bone-sparing drugs.
More recently, inflammatory cell signaling pathways that generate these inflammatory and tissuedestructive proteinases have also become promising
therapeutic targets. Inhibition of signal transduction
pathways may abolish cell activation and the production of pro-inflammatory cytokines. Kirkwood
et al. (9) propose therapeutic strategies directed towards major signaling pathways, including mitogenactivated 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 effective 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 upto-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 research, aimed at a greater understanding of the
parasite–host interaction in periodontal infections,
may yield significant pay-offs in combating periodontal diseases.
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