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3 authors, including:
Kenneth Kornman
Maurizio Tonetti
Interleukin Genetics
SEE PROFILE
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C o p y r i g h t 8 Munksgaard 1997
PERIODONTOLOGY 2000
ISSN 0906-6713
General comments
Efforts to delineate the pathogenic processes of a
complex chronic disease have some inherent limitations and require many assumptions based on
cross-sectional observations from the specific disease and knowledge from general biological mechanisms.
Bacteria have generation times that allow an evolutionary adaptation to an inhospitable environment.
Thus, many of the bacteria in the gingival sulcus
have evolved mechanisms to avoid and manipulate
the host defense mechanisms. SimilarIy, the host has
developed countermeasures against these microorganisms. In an encounter between the host and a
single subgingival bacterial species, the sequence of
events in the host response may be reasonably well
defined. In a bacterial ecosystem as complex as the
gingival sulcus, however, the co-evolutionary processes between the diverse bacterial species and the
host have most likely produced a variety of host molecules to cope with the bacterial challenge. This
phenomenon is only one of the factors that makes it
extremely difficult to determine which host factors
are actually destructive or protective.
In addition, once periodontitis has established in
the tissues, it is reasonable to assume that substantial feedback mechanisms are at play to ultimately
regulate and control the immunoinflammatory responses. Such mechanisms are finely tuned, so that
the synthesis and inhibition of various cytokines and
other mediators will undergo repeated changes to
allow a response that properly limits the bacterial
challenge but is then modulated to limit tissue destruction and allow repair. Most importantly, the immunoinflammatory response in adult periodontal
disease should not be viewed as a one-dimensional
process that leads to destruction, but rather an iter-
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Kornman et al.
Fig. 1. The epithelial and vascular response to early bacterial accumulations is shown diagrammatically in Scene
1. The bacteria release normal metabolic products, including fatty acids and the peptide N-formyl-methionylleucyl-phenylalanine(FMLP) and the lipopolysaccharides
(LPS) of gram-negative bacteria. These products activate
junctional epithelial cells to release various inflammatory
mediators, including interleukin-8 (IL-8), interleukin-la
(IL- la), prostaglandin E2 (PGE2), matrix metalloproteinases (MMP) and tumor necrosis factor a (TNFa). In addition, neural components originating in the epithelium
release neuropeptides that influence the local vascular response. The bacterial products and epithelial response activates perivascular mast cells to release histamine and
activates vascular endothelial cells to release IL-8 within
the vessels to assist in localizing neutrophils.
34
mediately deep to the junctional epithelium becomes inflamed, leukocytes exit the post-capillary
venules and there is a very large increase in the
numbers of leukocytes, especially neutrophils, migrating through the junctional epithelium and into
the sulcus or pocket. The collagen and other components of the perivascular extracellular matrix are
destroyed. As supragingival plaque extends apically
into the gingival sulcus, the coronal cells of the junctional epithelium are stimulated to proliferate, and a
gingival pocket is formed. Later on, the apical cells
of the junctional epithelium are induced to proliferate and extend apically along the root surface, subsequently to be converted into an ulcerated pocked
epithelium. At an early stage, there is an enlarging
leukocyte infiltrate dominated by lymphocytes, including B cells and T cells with characteristics of
both T-helper 1 (Thl) and Th2 cells. Subsequently,
the lesion becomes dominated by B cells but also
present are T cells, macrophages and neutrophils, all
of which become activated. B and T cells are antigenically or mitogenically activated to replicate to
give rise to clones, and B cells are driven to differentiate into clones of antibody producing plasma cells.
As the disease worsens, periodontal pockets deepen,
the components of the extracellular matrix of the
gingiva and periodontal ligament are destroyed and
alveolar bone is resorbed.
Fig. 2. Schematic drawing of the relationships of the gingival sulcus. Note the microbial plaque (P) on the tooth surface at the entrance to the gingival sulcus. Neutrophils are
leaving vessels in the connective tissue (CT) and emigrating chemotactically through the junctional epithelium
(JE) but not through the oral sulcular epithelium (OSE) of
the lateral wall of the sulcus. Source: Schroeder HE, Attstrom R. Pocket formation: an hypothesis. In: Lehner T, Cimasoni M, ed. Borderland between caries and periodontal
disease, Vol. 11. Orlando: Grune and Stratton, 1980).
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Kornman et al.
36
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Kornman el al.
including IL- 1p or tumor necrosis factor a, the endothelial cells of the microcirculation become activated
(13) (Fig. 4, 5). The vessels of the microcirculation
become inflamed, dilated and engorged with blood,
and the blood flow slows. The endothelial cell junctions open and protein-rich fluid leaves the vessels
at the site of the post-capillary venules and accumu-
early in the local inflammatory response, subepithelial venules are activated and display: an increase
in vascular permeability; the expression of leukocyte
cell adhesion molecules; and the release of specific
leukocyte-activating agents. The effects of these
phenomena are thought to be an increased leakage
of plasma components, including acute-phase proteins, into the gingival crevicular fluid and leukocyte
extravasation, leading to the formation of a perivascular connective tissue infiltrate.
In the presence of lipopolysaccharide or cytokines
38
Fig. 4. Schematic drawing illustrating the process of diapedesis. Endothelial cells of the venules become activated
by lipopolysaccharide (LPS) as well as by the proinflammatory cytokines IL-18 and tumor necrosis factor fl (not
shown) and are induced to express E-selectin. Neutrophils
constitutively express sialyl Lewis-X, which forms a loose
binding to E-selectin, resulting in slowing of the leukocyte
to a rolling motion along the endothelial surface. Leukocyte adhesion receptors (CD11118) form a tight binding
with the intercellular adhesion molecule (ICAM), which is
constitutively expressed by the endothelial cells, and initiates movement of the leukocyte between the endothelial cells into the extravascular compartment. (Figure
courtesy of Richard Darveau)
39
Komman et al.
40
epithelium. In most tissues, endothelial cell adhesion molecule 1 is not expressed until the cells are
activated by exposure to bacterial components such
as lipopolysaccharide or cytokines such as IL-1p.It
has been reported that gingival endothelial cells of
the high-endothelium microvessels express both endothelial cell adhesion molecule 1 and vascular cell
adhesion molecule 1 even in the absence of a detectable inflammatory stimulus (27, 87, 136). Approximately 23-28% of the microvessels that are positive
for intercellular attachmentmolecule 1 and platelet
endothelial cell attachment molecule 1 were also
positive for endothelial cell adhesion molecule 1 and
vascular cell adhesion molecule 1 (136). Production
of these adhesion molecules in normal gingiva may
be constitutive or alternatively, production may result from continuous low-level stimulation by bacterial substances. This may be a critical feature for
the continuous migration of leukocytes from the
small vessels into the junctional epithelium and sulcus for maintenance of normal host defense against
microbial challenge.
Fate of extravasated leukocytes
Following extravasation, leukocytes infiltrate the
perivascular connective tissue and/or migrate
through the junctional epithelium towards the gingival sulcus. Several classical investigations have observed that the leukocyte population retrieved from
the gingival sulcus is substantially different from the
one observed in the perivascular inflammatory infiltrate and within the junctional epithelium. Polymorphonuclear leukocytes represent the majority of the
cells gaining access to the bacteria present in the
gingival sulcus; mononuclear cells constitute the
majority of the tissue infiltrate. On the other hand,
both mononuclear and polymorphonuclear cells are
present within the junctional epithelium. These early
observations have recently been extended; studies of
the functional phenotype of the leukocytes present
in the inflammatory infiltrate, the junctional epithelium and the gingival sulcus have indicated that
selective enrichments of specific phenotypes occur
in specific topographic locations (138). A comparison of the density of cells expressing specific phenotypes in the inflammatory infiltrate and in the junctional epithelium found that the densities of neutrophils, memorylactivated lymphocytes (CD45RO+
cells), mucosal lymphocytes (aIELP7+
T cells), y6 T
cells and CD l a + antigen-presenting cells are selectively increased in the junctional epithelium as compared with the underlying perivascular inflamma-
tory infiltrate (25,79, 135, 138, 147). These observations have indicated that leukocyte infiltration and
migration into the gingival sulcus are not random
diffusion processes and suggested that selective
mechanisms are likely to be important (138).
Neutrophil migration into the gingival sdcus
Following extravasation, neutrophils seem to gain
access to the more coronal portion of the junctional
epithelium and to selectively migrate through this
multilayered epithelium to gain access to the bacterial flora. New developments in immunobiology
have described at least two mechanisms of possible
importance in the regulation of neutrophil migration
towards the gingival sulcus or the periodontal pocket
following neutrophil extravasation: 1) the expression
of leukocyte adhesion molecules, such as the intercellular adhesion molecule 1, in epithelial cells; and
2) the discovery of a new family of low-molecularweight cytokines with potent and, to a great extent,
cell type-specific leukocyte chemotactic properties:
the chemokines (88,991, and the neutrophil-selective interleukin 8, in particular (14).
Intercellular attachment molecule 1 expression
can mediate heterotypic interactions between leukocytes and keratinocytes via interaction with receptors of the p2 integrin subfamily present on leukocytes and may therefore be able to direct leukocyte
infiltration along specific haptotactic gradients (34,
72, 142). The intercellular attachment molecule
1/p2integrin interaction has also been shown to be
a necessary step in neutrophil migration across mucosal membranes (106).In fact, neutrophil adhesion
to and migration through epithelial monolayers is
sharply inhibited by antibodies against intercellular
attachment molecule 1 (70% inhibition) and against
its p2 integrin counter-receptor (complete inhibition) present on the neutrophil surface (106,142).
Further, a variety of mucosal pathogens whose infections are associated with neutrophil recruitment at
mucosal sites have been shown to enhance intercellular attachment molecule 1 expression on mucosal keratinocytes in uitro (129).
The chemokines, on the other hand, are thought
to selectively recruit and activate specific leukocytes
to the sites of inflammation. In this respect, emerging evidence on medically relevant mucosal infections involving gram-negative bacteria indicates the
importance of both the release of neutrophil chemoattractants and the induction of specific adhesion
molecules for neutrophil recruitment at mucosal
sites of infection (129). For instance, in E. coli uri-
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Kornman et al.
Fig. 8. Scene 3 depicts the increase in hfhmrnatory cellular activity in the tissues and the epithelial changes associated with a gingival pocket. Soon after inflammation
starts, the exudate from the vessels becomes predominated by mononuclear cells. In addition to the activation
of macrophages and serum proteins, as in Scene 2, T cells,
B cells and plasma cells become evident in the tissue. Activated T cells produce cytokines that help to shape the immune response, including interleukins 2 , 3 , 4, 5, 6, 10 and
13 (IL-2, IL-3, IL-4, IL-5, IL-6, IL-10 and IL-13), tumor necrosis factor a (TNFa), transforming growth factor b
(TGFB), interferon-y (IFNy) and a series of chemotactic
substances: monocyte chemoattractant protein (MCP),
macrophage inflammatory protein (MIP) and RANTES
(regulated on activation, normal T-cell expressed and secreted). Plasma cells become prominent in the tissues and
produce immunoglobulins, such as IgG, and cytokines interleukin-6 (IL-6) and tumor necrosis factor a. Some of
the polymorphonuclear leukocytes (PMNS) become activated in the tissue and produce IL-la, IL-la, IL-6 and IL8, tumor necrosis factor a, leukotrienes (LT) and matrix
metalloproteinases (MMP). Fibroblasts are shown producing collagen, matrix metalloproteinases and tissue inhibitors of matrix metdoproteinases (TIMP). FMLP: N-formyl-methionyl-leucyl-phenylalanine; PGE,:
prostaglandin E2.
42
hesion molecule 1, activated endothelial cells express vascular cell adhesion molecule 1, which selectively binds mononuclear cells, allowing them to exit
the small blood vessels and become a part of the
extravascular exudate. Very soon after the initiation
of the acute inflammatory response, small lymphocytes consisting of both T cells and B cells predominate in the tissue infiltrate. Subsequently, in the
presence of antigen and various cytokines, these
lymphoid cells begin to enlarge and replicate to form
clones of CD4' and CD8+ T cells, and the B cells
are driven to differentiate into clones of antibodyproducing plasma cells. In studies of gingival specimens obtained from patients with adult periodontitis, Meikle et al. (84) observed that CD4+ cells
were present in larger numbers than CD8+ cells. The
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Kornman et al.
44
forming growth factor @ (661, IL-la and p (12,33),IL6 (132, 145), IL-10 (9, 86), IL-12 (59, 152), IL-15 f53),
the chemokines monocyte chemoattractant protein,
macrophage inflammatory protein and RANTES
(regulated on activation, normal T-cell expressed and
secreted), matrix metalloproteinases and prostaglandin E2. Some of the factors from monocytes, in
particular IL-lp, tumor necrosis factor a and prostaglandin E2 are prominent components of the periodontitis lesion and have been strongly implicated in
the pathogenesis of periodontal diseases (94).
The macrophage products substantially alter the
local environment in several ways. First, the macrophages in the gingival area have been shown to produce chemokines (155) that would recruit additional
monocytes and lymphocytes into the local area.
Second, the factors produced by lipopolysaccharide-activated macrophages in vitro, such as prostaglandin E2, matrix metalloproteinases and various
cytokines, are certainly capable of altering the environment to favor collagen degradation. The gingival macrophages, when stimulated, are known to
produce matrix metalloproteinases (82). Matrix
metalloproteinases and tissue inhibitors of matrix
metalloproteinases play a major role in determining
the progress of destruction of the components of the
extracellular matrix. In addition, the macrophage
products may alter collagen metabolism of the local
fibroblasts. For example, recent studies have demonstrated that IL- 1@ increased collagenase production
by both periodontal ligament and gingival fibroblasts (5, 96), decreased collagen synthesis (64) and
increased fibroblast cell-associated products that
were capable of increasing collagenase production
and activating bone resorption in experimental test
systems (98). Prostaglandin E2 also decreased collagen synthesis by gingival fibroblasts (6).
Third, antigen-specific CD4+ T-lymphocytes
would be activated by the macrophage activity and
differentiate to cytokine producing T cells that are
capable of providing help for B-cell differentiation
and antibody production. IgG is detectable in the
gingival crevicular fluid of gingivitis sites, and increases are associated with the development of gingivitis (36, 54).
~-
to be major participants in acute and chronic inflammation regardless of its location, and there is
strong evidence for participation of these mediators
in periodontitis. They are produced by activated resident gingival cells and infiltrating leukocytes and the
complement cascade and kinin system in blood
plasma. Monocytes from individuals susceptible to
or having severe periodontitis produce elevated
amounts of mediators (481, and mediators are present in inflamed gingiva and gingival crevicular fluid
from diseased sites at elevated concentrations (93).
Concentrations decrease following successful
therapy.
IL-1 is a major mediator in periodontitis (104, 125,
126). IL-lp comes mostly from activated macrophages and fibroblasts and IL-la from keratinocytes
of the junctional or pocket epithelium. Production
is induced by lipopolysaccharide and other bacterial
components and by IL- 1 which is autostimulatory.
Production is suppressed by bacterial metabolites
such as butyric and propionic acid and by IL-1 receptor antagonist, which is also produced by macrophages.
IL- 1 upregulates complement and Fc receptors on
neutrophils and monocytic cells, and adhesion molecules on fibroblasts and leukocytes. It induces homing receptors for lymphoid cells in the extracellular
matrix and induces osteoclast formation and bone resorption. It enhances production of itself, matrix
metalloproteinases and prostaglandins by macrophages, fibroblasts and neutrophils. IL- 1 upregulates
major histocompatibility complex expression by B
and T cells to facilitate their activation, clonal expansion and immunoglobulin production. In conjunction with tumor necrosis factor a and IL-6, 1L-1 induces production of acute-phase proteins by the liver.
IL-2, IL-3, IL-4 and IL-5 are all involved, among
other things, in lymphocyte clonal expansion, differentiation of B cells into antibody-producing plasma
cells and isotype switching. IL-2 is produced by T
cells and antigen-presenting cells and, in the presence of antigen, induces expression of clones of specific T cells and secretion of IL-3 and IL-4. IL-4 regulates IgGl and IgE production and suppresses activated macrophages and causes their apoptosis. IL-6
is produced by macrophages, fibroblasts, lymphocytes and endothelial cells. Production is induced by
IL- 1 and lipopolysaccharide and suppressed by estrogens and progesterone. It may be through IL-6
that these hormones exert their effects on gingiva.
IL-6 causes fusion of monocytes to form multinuclear cells that resorb bone.
IL-8 is a member of the chemokine superfamily,
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Kornman et al.
46
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Kornman et al.
48
lagen and bone, and less effective antibody production. The efficiency of neutrophil migration is reduced, and it is likely that more neutrophils are activated within the tissue. The total impact of the above
changes is to subtly shift the scene from one in
which the host is controlling the bacterial challenge
to one in which the challenge is less well controlled
and the tissue-destructive phase is dominant. Such
factors as smoking and genetic influences on cytokine expression that are capable of modifymg critical
aspects of the neutrophil-antibody protection and/
or fibroblast function would be expected to alter the
balance of the systems between protection and destruction.
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