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Kornman1997 Etapas de Progresion
Kornman1997 Etapas de Progresion
33
Kornman et al.
34
The host response to the microbial challenge
35
Kornman et al.
barrier function and rapid cell turnover leading to and intraepithelial leukocytes. Several investigations
constant shedding of the mucosal surface exposed have described the presence of specific intraepith-
to bacterial colonization, play a crucial role in intra- elial leukocytes within the junctional epithelium in-
epithelial recruitment of phagocytes and specific cluding: CDla-positive antigen-presenting cells
lymphocyte subsets and thus in controlling bacterial (most likely Langerhans or dendritic cells), specific
penetration through the mucosal integuments. The lymphocyte subsets expressing the dELP7 integrin
discussed evidence also indicates that keratinocytes (mucosal T cells), the cutaneous lymphocyte antigen
may play an active role in this process. ‘This is not and the y6 T-cell receptor (a subpopulation of T cells
unexpected since keratinocytes represent the inter- that has a repertoire of receptors enriched for bac-
face between the body and the external environment terial antigens) (25, 52,79, 135, 138, 147).The density
exposed to bacterial challenges. Substantial evidence of cells expressing these phenotypes is selectively in-
indicates that keratinocytes can respond to a variety creased in the junctional epithelium with respect to
of bacterial stimuli via the production of a wide array the underlying infiltrated connective tissue, sug-
of pro-inflammatory mediators, and of cytolunes in gesting that specific mechanisms able to selectively
particular (73, 124). Such ability to “sense” the exter- increase the probability of these cells to gain access
nal environment and to respond with the generation to the epithelium may be at play. The significance
of specific autocrine and paracrine messages has of the presence of these accessory cells within the
been confirmed in a series of “in vitro” investi- junctional epithelium is unknown; cells bearing
gations on mucosal and cutaneous keratinocyte cul- these specific phenotypes, however, may control the
tures. Emerging evidence indicates that interaction intraepithelial availability of proinflammatory stim-
between periodontal bacteria and keratinocytes uli and/or play an important role in antigen pro-
leads to keratinocyte activation to express a variety cessing and presentation.
of inflammatory mediators (40). These stimuli may
act locally to transmit the inflammatory message in
a centripetal direction towards the subepithelial The bacterial challenge induces changes in the
microvessels and thereby induce an inflammatory epithelium to facilitate both vascular
permeability and the influx of neutrophils
reaction.
So far, evidence that these mechanisms are at play Junctional epithelium is the structure initially most
in the marginal periodontium is sketchy. In particu- directly challenged by bacteria. Junctional epithel-
lar, evidence of the elements conferring specificity to ium is a unique structure, differing in many respects
the process is lacking. Is the ability of different bac- from all of the other oral and nonoral epithelia (117).
terial components of dental plaque to induce these It manifests a uniform interface with the underlying
centripetal stimuli essentially the same, or are speci- connective tissue without rete ridges and is roughly
fic bacteria and/or specific exo- and endocellular 15 to 18 cells thick at the sulcus bottom, tapering to
toxins needed? Further, it is unclear whether or not 4 or 5 cells at the most apical termination. Junctional
individual subjects may present differences in junc- epithelium consists of basal and suprabasal strata,
tional epithelium keratinocyte responsiveness to although all the cells are morphologically very simi-
bacterial plaque stimuli. lar. Though stratified, the cells do not undergo matu-
Besides the role of epithelial keratinocytes, more ration; they manifest differentiation markers typical
recent evidence has indicated that the presence of of simple epithelia, including production of keratin
specific leukocytes within the epithelium decreases pair K 8 and K18 (47, 80, 81). Basal cells, which pro-
the chance that bacteria can gain access to the duce the basal lamina at the interface between the
underlying connective tissue in the gastrointestinal junctional epithelium and connective tissue as well
tract. In fact, a significant increase in bacterial trans- as the interface with the tooth surface, have the ca-
location to mesenteric lymph nodes was observed in pacity to synthesize DNA and divide. The sloughing
athymic nude mice (101). Furthermore, Gautreaux et surface is at the sulcus bottom.
al. (50) have shown that experimental depletion of T Cells along the tooth surface and near the sulcus
cells in otherwise irnmunocompetent mice resulted bottom contain acid phosphatase-positive lyso-
in a significant increase in Escherichia coli translo- somes and manifest evidence of phagocytosis of
cation to the mesenteric lymph nodes. Maintenance neutrophil granules and bacteria. Since the cells
of an intact barrier function in mucosae, therefore, have neither keratohyalin- nor membrane-coating
seems to depend on complex interactions of coloniz- granules, the diffusion barrier found in most strati-
ing or infecting microorganisms with keratinocytes fied epithelia is absent. The cells can make several
36
m e host response to the microbial challenge
keratins with keratin 19 considered to be a marker jacent to small vessels. The neuropeptides and mast
for junctional epithelium (2). The cells express inter- cell activation initiated by the c-fibers extending
cellular attachment molecule and leukocyte function from the junctional epithelium may be effector
antigen 3 on their surfaces even under healthy non- mechanisms involved in the early vascular response
inflammatory conditions (27, 871, and intercellular and cell replication. The cytokines produced by the
attachment molecule 1 expression by keratinocytes responding epithelial cells are also known to activate
can be upregulated by pro-inflammatory cytokines adhesion molecules on endothelial cells and cyto-
but not by lipopolysaccharide (140, 141). IL-8 mess- kine production by endothelial cells.
enger RNA was recently found (41, 134, 138) to be Scene 1 (Fig. 1) therefore involves epithelial, and
present in gingival tissue and was localized primarily most likely local neural, responses to the bacterial
to the junctional epithelium. This localization may products. The result evident in scene 2 is enhanced
play a role in directing neutrophils to the gingival recruitment of neutrophils, proliferation of the epi-
sulcus area. The cells also express epidermal growth thelial ceUs and localized secretion of enzymes that
factor, which is especially prominent in cells ad- initiate destruction of the extracellular matrix.
jacent to the tooth surface (130), and epidermal
growth factor receptors (91) the functional role of
which is not understood.
Matrix metalloproteinases capable of degrading Scene 2. Acute inflammatory
the extracellular matrix of the periodontium have response phase: the tissues
been identified in the gingival epithelium (84), and respond to the early signals (Fig. 3)
prostaglandin H synthase, which is capable of pro-
ducing prostaglandin E2,has been identified in gin- Turnover of the junctional epithelium is unusually
gival epithelium (20). high. Cells of the junctional epithelium are connected
A mediator derived from gingival epithelial cells by fewer than half the number of desmosomes seen
has also been shown to stimulate collagenase pro- in other oral epithelia,and the extracellular spaces are
duction by periodontal ligament fibroblasts. The ac- usually wide. Most of the vacuoles and vesicles associ-
tion of the epithelial cell mediator was blocked by ated with the junctional epithelium cells on electron
IL-la-neutralizing antibody (97). micrographs are, in fact, portions of the extracellular
In addition, epithelial cells in general are known compartment (119). In mild inflammation, the spaces
to produce a broad range of cytokines, including IL- are widened further and filled with fluid, which can
la, IL- lp, granulocyte-macrophagecolony-stimulat- serve as a medium for diffusion and through which
ing factor, interferon p, tumor necrosis factor a, neutrophil migration occurs. Studies in the rat show
transforming growth factor p, IL-3, IL-6, IL-7, IL-8, that antigen placed in the gingival sulcus readily tra-
IL-10, IL-11, and IL-12 (18, 33, 39, 42, 58, 70, 108, verses the junctional epithelium (1). As with all epi-
124, 129). Mucosal epithelial cells exposed to bac- thelial surfaces, an increased bacterial load in the gin-
terial products were recently shown to produce tu- gival sulcus increases the cell turnover rate of the sul-
mor necrosis factor a, IL-6 and IL-8 (38, 58). cular epithelium (17). Infiltrating cells occupy about
In addition to inflammatory mediators, such as 1-2% of the extracellular space in human junctional
cytokines, produced by activated epithelial cells, epithelium and form a gradient with the greatest
neural components may be a key aspect of the early number of cells found coronally. Independent of this
tissue response to bacterial stimuli. Although not yet gradient, and in the absence of inflammation, large
defined in humans, the rat junctional epithelium has numbers of leukocytes, estimated to total about
been shown to include an unusually dense network 30,00O/min, migrate through the junctional epithel-
of unmyelinated nerve fibers, most likely c-fibers, ium (113). These are mostly neutrophils but also in-
that produce the neuropeptides substance P and cal- clude monocytes and lymphocytes. Langerhans’ cells
citonin gene-related peptide (15, 16, 82, 89, 131). and other HLA-DR-positive antigen-presenting cells
Many branching fibers formed a network around the are also present.
basal cells and extended through out the junctional
epithelium. These networks are the most dense yet
observed in oral tissues. These types of fibers rou- The vascular leakage enhances the localized
response
tinely form localized loops that extend from the epi-
thelium to innervate the local blood vessels and acti- Following the generation of proinflammatory affer-
vate the mast cells that are routinely resident ad- ent stimuli within the junctional epithelium, and
37
Kornman el al.
38
The hosr response to the microbial challenge
39
Komman et al.
ity of inflammatory cells to injured tissues while epithelium. In most tissues, endothelial cell ad-
avoiding unnecessary damage. Leukocyte entry into hesion molecule 1 is not expressed until the cells are
the periodontal stage requires an increase in the activated by exposure to bacterial components such
“stickiness” of leukocytes in response to the intra- as lipopolysaccharide or cytokines such as IL-1p.It
vascular release of proinflammatory agents, includ- has been reported that gingival endothelial cells of
ing IL-8, by activated endothelial cells (61, 123) (Fig. the high-endothelium microvessels express both en-
4). This induces rolling of the leukocytes on the en- dothelial cell adhesion molecule 1 and vascular cell
doluminal aspect of the venules and increases the adhesion molecule 1 even in the absence of a detect-
probability of specific interactions among vascular able inflammatory stimulus (27, 87, 136). Approxi-
cell adhesion molecules and leukocyte integrins and mately 23-28% of the microvessels that are positive
thus the chance of inducing leukocyte extravasation for intercellular attachment’molecule 1 and platelet
by diapedesis into the exuavascular spaces. Specific endothelial cell attachment molecule 1 were also
differences in the resulting inflammatory infiltrate in positive for endothelial cell adhesion molecule 1 and
various tissues indicates that this process possesses vascular cell adhesion molecule 1 (136). Production
a high degree of specificity, enabling the selective en- of these adhesion molecules in normal gingiva may
richment of specific cell types (123). The selectively be constitutive or alternatively, production may re-
of the process seems to depend on the expression sult from continuous low-level stimulation by bac-
on the endothelial cells of specific adhesins such as terial substances. This may be a critical feature for
endothelial cell adhesion molecule 1, vascular cell the continuous migration of leukocytes from the
adhesion molecule 1 and mucosal addressin cell ad- small vessels into the junctional epithelium and sul-
hesion molecule 1, whose complementary receptors cus for maintenance of normal host defense against
are expressed on specific leukocyte subpopulations. microbial challenge.
As examples, endothelial cell adhesion molecule 1
is thought to be important for the extravasation of
Fate of extravasated leukocytes
neutrophils and some lymphocytes (92, 109, 122),
while expression of mucosal addressin cell adhesion Following extravasation, leukocytes infiltrate the
molecule 1 seems to be associated with the selective perivascular connective tissue and/or migrate
enrichment of a&, lymphocytes at mucosal sites through the junctional epithelium towards the gingi-
(11). Intercellular attachment molecule 1 expression, val sulcus. Several classical investigations have ob-
on the other hand seems to confer little specificity, served that the leukocyte population retrieved from
since its complementary receptor, the p2 integrin, is the gingival sulcus is substantially different from the
expressed on all leukocytes. Intercellular attachment one observed in the perivascular inflammatory infil-
molecule 1 expression, therefore, is considered to be trate and within the junctional epithelium. Polymor-
important for the common pathway leading to diap- phonuclear leukocytes represent the majority of the
edesis, once rolling and margination have been in- cells gaining access to the bacteria present in the
duced by the more selective interactions. Endothelial gingival sulcus; mononuclear cells constitute the
cells express both intercellular attachment molecule majority of the tissue infiltrate. On the other hand,
1 and platelet endothelial cell attachment molecule both mononuclear and polymorphonuclear cells are
constitutively. Vascular cell adhesion molecule 1 is present within the junctional epithelium. These early
thought to be more specific for mononuclear leuko- observations have recently been extended; studies of
cytes. the functional phenotype of the leukocytes present
Several investigations have described the ex- in the inflammatory infiltrate, the junctional epithel-
pression of intercellular attachment molecule 1, vas- ium and the gingival sulcus have indicated that
cular cell adhesion molecule 1, and endothelial cell selective enrichments of specific phenotypes occur
adhesion molecule 1 on gingival microvessels (26- in specific topographic locations (138). A compari-
28, 51, 87, 136). Such expression has been shown to son of the density of cells expressing specific pheno-
be maximal in microvessels subjacent to the junc- types in the inflammatory infiltrate and in the junc-
tional epithelium. Interestingly, however, histo- tional epithelium found that the densities of neutro-
pathological observations indicate that only a frac- phils, memorylactivated lymphocytes (CD45RO+
tion of the microvessels express intercellular attach- cells), mucosal lymphocytes (aIELP7+ T cells), y6 T
ment molecule 1 (136). In a stable condition, cells and CD l a + antigen-presenting cells are selec-
therefore, leukocyte entry into tissues is limited to a tively increased in the junctional epithelium as com-
few venules immediately subjacent to the junctional pared with the underlying perivascular inflamma-
40
The host resvonse to the microbial challenae
tory infiltrate (25,79, 135, 138, 147). These obser- nary tract infections, neutrophil urinary counts have
vations have indicated that leukocyte infiltration and been shown to be associated with the concentrations
migration into the gingival sulcus are not random of the neutrophil chemotactic cytokine IL-8 during
diffusion processes and suggested that selective the course of naturally occurring infections or delib-
mechanisms are likely to be important (138). erate colonization in humans (4). Similar results
have been observed ex uiuo and in uitro in the gas-
trointestinal mucosa in response to Salmonella spp.,
Neutrophil migration into the gingival sdcus
Listeria monocytogenes and Helicobacter pylori infec-
Following extravasation, neutrophils seem to gain tion (29,37).Both in the urinary and gastrointestinal
access to the more coronal portion of the junctional tracts, an important source of IL-8has been shown
epithelium and to selectively migrate through this to be the mucosal epithelium.
multilayered epithelium to gain access to the bac- These facts show that mucosal keratinocytes play
terial flora. New developments in immunobiology a crucial active role in neutrophil recruitment at mu-
have described at least two mechanisms of possible cosal sites of infection and that IL-8and intercellular
importance in the regulation of neutrophil migration attachment molecule 1 expression represent key
towards the gingival sulcus or the periodontal pocket steps in this process. Recent evidence of intercellular
following neutrophil extravasation: 1) the expression attachment molecule 1 and IL-8 expression in the
of leukocyte adhesion molecules, such as the inter- gingiva supports this concept. Junctional epithelium
cellular adhesion molecule 1, in epithelial cells; and keratinocytes have been shown to express high levels
2) the discovery of a new family of low-molecular- of intercellular attachment molecule 1 and IL-8(27,
weight cytokines with potent and, to a great extent, 87, 136, 137).The intercellular attachment molecule
cell type-specific leukocyte chemotactic properties: 1 staining intensities increase within the junctional
the chemokines (88,991, and the neutrophil-selec- epithelium in an apico-coronal direction: the super-
tive interleukin 8, in particular (14). ficial keratinocytes, possibly exposed to bacterial
Intercellular attachment molecule 1 expression plaque accumulation, expressing higher staining in-
can mediate heterotypic interactions between leuko- tensities (140). Further, intercellular attachment
cytes and keratinocytes via interaction with recep- molecule 1 expression in the gingival epithelia is
tors of the p2 integrin subfamily present on leuko- limited to the junctional epithelium: the only epi-
cytes and may therefore be able to direct leukocyte thelium associated with significant neutrophil trans-
infiltration along specific haptotactic gradients (34, migration.
72, 142). The intercellular attachment molecule Substantial evidence indicates that IL-8is present
1/p2integrin interaction has also been shown to be and expressed locally in the gingiva. High concen-
a necessary step in neutrophil migration across mu- trations of IL-8 have been detected in the gingival
cosal membranes (106).In fact, neutrophil adhesion fluid (107).Investigations focused on the detection
to and migration through epithelial monolayers is of specific IL-8messenger RNA in the gingiva have
sharply inhibited by antibodies against intercellular indicated the presence of the message and its source
attachment molecule 1 (70% inhibition) and against within the junctional epithelium (134,137).The in-
its p2 integrin counter-receptor (complete inhi- tensity of the in situ signal appeared to be maximal
bition) present on the neutrophil surface (106,142). in the most superficial layers of the epithelium,
Further, a variety of mucosal pathogens whose infec- possibly because they are exposed to bacterial
tions are associated with neutrophil recruitment at plaque. In a subsequent quantitative analysis, the
mucosal sites have been shown to enhance inter- surface density of IL-8messenger RNA-positive cells
cellular attachment molecule 1 expression on mu- was significantly higher than the surface density of
cosal keratinocytes in uitro (129). leukocytes, indicating that at least part of the mess-
The chemokines, on the other hand, are thought age originated from junctional epithelium keratino-
to selectively recruit and activate specific leukocytes cytes (139).The spatial polarization of IL-8messen-
to the sites of inflammation. In this respect, emerg- ger RNA-positive cells appears to be consistent with
ing evidence on medically relevant mucosal infec- the source of a chemotactic stimulus attracting neu-
tions involving gram-negative bacteria indicates the trophils towards the superficial layers of the epithel-
importance of both the release of neutrophil chemo- ium. The biological effects of IL-8 on neutrophils
attractants and the induction of specific adhesion have been shown to be dose dependent: lower con-
molecules for neutrophil recruitment at mucosal centrations stimulate cell migration, and higher ones
sites of infection (129). For instance, in E. coli uri- lead to activation of neutrophil antibacterial mech-
41
Kornman et al.
42
The host response to the microbial challenge
43
Kornman et al.
44
The host response to the microbial challenae
~-
to be major participants in acute and chronic in- all of which are chemoattractants. It is produced by
flammation regardless of its location, and there is lipopolysaccharide-activated macrophages, synovial
strong evidence for participation of these mediators cells, endothelium and junctional epithelial cells.
in periodontitis. They are produced by activated resi- Neutrophils, the primary target cell, have high-affin-
dent gingival cells and infiltrating leukocytes and the ity receptors that can become occupied at low con-
complement cascade and kinin system in blood centrations of chemoattractant and cause the cells
plasma. Monocytes from individuals susceptible to to undergo directed migration, and low-affinity re-
or having severe periodontitis produce elevated ceptors, which become occupied at high concen-
amounts of mediators (481, and mediators are pres- trations of chemoattractant and cause the cells to
ent in inflamed gingiva and gingival crevicular fluid undergo the metabolic burst and to degranulate on
from diseased sites at elevated concentrations (93). arrival at the site of challenge. Monocyte chemoat-
Concentrations decrease following successful tractant protein 1 is a potent attractant for mono-
therapy. cytes. Monocyte chemoattractant protein l-produc-
IL-1 is a major mediator in periodontitis (104, 125, ing cells are commonly found in inflamed gingiva
126). IL-lp comes mostly from activated macro- (1551, and there is a good correlation between cells
phages and fibroblasts and IL-la from keratinocytes that produce IL-8 and monocyte chemoattractant
of the junctional or pocket epithelium. Production protein 1 and neutrophil and macrophage accumu-
is induced by lipopolysaccharide and other bacterial lation and location in gingivitis and periodontitis
components and by IL- 1 which is autostimulatory. (137).
Production is suppressed by bacterial metabolites Transforming growth factor p is produced by acti-
such as butyric and propionic acid and by IL-1 re- vated T cells. It is a chemoattractant for monocytes
ceptor antagonist, which is also produced by macro- and it suppresses their activation. Transforming
phages. growth factor p induces production of IgA and
IL- 1 upregulates complement and Fc receptors on IgG2b. Transforming growth factor a is produced by
neutrophils and monocytic cells, and adhesion mol- macrophages and it serves as a mitogen for fibro-
ecules on fibroblasts and leukocytes. It induces hom- blasts and for epithelial and endothelial cells. In con-
ing receptors for lymphoid cells in the extracellular trast, interferon y, which is produced by CD8+ cyto-
matrix and induces osteoclast formation and bone re- toxic T cells, recruits and activates macrophages and
sorption. It enhances production of itself, matrix upregulates the major histocompatibility complex
metalloproteinases and prostaglandins by macro- on virally infected cells and targets them for killing.
phages, fibroblasts and neutrophils. IL- 1 upregulates The major source of prostaglandins and leuko-
major histocompatibility complex expression by B trienes in inflamed periodontal tissues is the acti-
and T cells to facilitate their activation, clonal expan- vated macrophage, although they can also be pro-
sion and immunoglobulin production. In conjunc- duced by other cells such as fibroblasts. Prosta-
tion with tumor necrosis factor a and IL-6, 1L-1 in- glandins, especially prostaglandin EZ, comprise the
duces production of acute-phase proteins by the liver. primary pathway of alveolar bone destruction in
IL-2, IL-3, IL-4 and IL-5 are all involved, among periodontitis. Leukotrienes, especially leukotriene
other things, in lymphocyte clonal expansion, differ- B,, are potent chemoattractants for neutrophils. En-
entiation of B cells into antibody-producing plasma dothelial cells activated by cytokines or lipopolysac-
cells and isotype switching. IL-2 is produced by T charide secrete another bioactive lipid known as
cells and antigen-presenting cells and, in the pres- platelet-activating factor, which induces vasodilation
ence of antigen, induces expression of clones of spe- and platelet aggregation and degradation. The
cific T cells and secretion of IL-3 and IL-4. IL-4 regu- cells also release prostacycline, which is a potent
lates IgGl and IgE production and suppresses acti- vasodilator and inhibitor of platelet aggregation, and
vated macrophages and causes their apoptosis. IL-6 thromboxane, which causes vasoconstriction and
is produced by macrophages, fibroblasts, lympho- platelet aggregation.
cytes and endothelial cells. Production is induced by Serum proteins, such as the kinin and comple-
IL- 1 and lipopolysaccharide and suppressed by es- ment systems, provide a mechanism for rapid ex-
trogens and progesterone. It may be through IL-6 pansion of the inflammatory response. Bradykinin
that these hormones exert their effects on gingiva. enhances permeability and inflammation of vessels
IL-6 causes fusion of monocytes to form multi- of the microcirculation. It is an 8-amino acid peptide
nuclear cells that resorb bone. cleaved from a plasma protein precursor. Activation
IL-8 is a member of the chemokine superfamily, of the complement cascade either by the classic or
45
Kornman et al.
alternative pathways results in production of C3a basophils, which are routinely associated with small
and C5a which are chemotactic peptides and C3b blood vessels, have been shown to produce IL-4
which is an anaphylatoxin. upon activation (101, and natural killer cells, capable
The matrix metalloproteinases comprise a large of producing IL-4,are found near the gingival epi-
family of Zn++-dependent enzymes produced by thelium and increase in numbers in periodontitis
macrophages, fibroblasts and keratinocytes acti- (22, 45, 71).
vated by lipopolysaccharide or cytokines. Matrix Studies (150) of the antibody response in subjects
metalloproteinases collectively can digest all of the without periodontitis found that individuals with
components of the extracellular matrix. Production low antibody titers tended to have hjgh antibody
of these enzymes is tightly controlled, complex and avidity and opsonic ability, suggesting that the anti-
not well understood. Transcription is upregulated by body response in subjects with health and gingivitis
IL-1, transforming growth factor a, epidermal is capable of providing protective functions. This is
growth factor and transforming growth factor a. also consistent with the finding that antibody from
With some exceptions, transcription is down regu- gingivitis subjects recognized fewer specific I! gingi-
lated by transforming growth factor p and interferon vulis epitopes than antibody from periodontitis sub-
y. Matrix metalloproteinase activity is suppressed by jects (110).
tissue inhibitors of metalloproteinases, which are The net outcome of Scene 3 (Fig. 8) is an increase
also produced by macrophages. in tissue lymphocytes, plasma cells and macro-
phages shifts in the metabolism of the local fibro-
blasts to favor a reduction in collagen synthesis, and
The local antibody response is activated to assist activation of the local and systemic specific immune
in controlling the bacterial challenge
response, with production of antibody directed
As the bacterial challenge increases, the host tissues against highly immunogenic bacterial epitopes.
are protected by neutrophil activity in the sdcus, fa-
cilitated by specific antibody that is produced sys-
temically and in the local tissues. Circulating anti- Scene 4. Regulation and resolution
body may be far greater in amount and importance
than locally produced antibody. Most, although not
phase: determinants of protective
all, early-onset periodontitis and adult periodontitis components in the sulcus and
patients mount a systemic humoral immune re- collagen balance in the tissues
sponse to antigens of the infecting bacteria (65).This (Fig. 11)
response likely results from the access of subgingival
plaque bacteria and bacteria cell wall components The local cellular and humoral responses described
to local lymph nodes and through the circulation to above appear to be sufficiently competent in most
the spleen. Antibody titers can be remarkably high, individuals to manage a limited bacterial challenge.
although biological activity is often low, as measured There appear to be at least two conditions in which
by antibody avidity and capacity to opsonize and en- the routine host response becomes more destructive
hance phagocytosis and killing. Specific antibody at the local level. The first appears to involve a speci-
from the blood comprises a major portion of the fic bacterial biomass that directly inhibits key com-
specific antibody in gingival crevicular fluid (69, ponents of the host defense mechanism. As dis-
128). cussed by Darveau et al. in this volume, some sub-
The local antibody response is directed by the gingival biomasses and the specific bacteria that
cytokine profile within the tissues and the presen- accumulate in those ecosystems are capable of inter-
tation of antigens by professional antigen-presenting fering with neutrophil function in multiple ways, in-
cells such as the macrophage. In addition to the cluding the presence of leukocyte killing toxins (1431,
macrophage influence in shaping the T-cell and B- the production of short-chain fatty acids and poly-
cell responses within the tissues, other cells partici- amines that are toxic to neutrophils (90, 148), and
pate in essential ways in preparing the early re- the inhibition of E-selectin upregulation on endo-
sponse. Production of IL-4 through antigen non- thelial cells (30). There is also reason to believe that
specific mechanisms appears to be an important as- certain bacterial challenges are capable of shifting
pect of the early immune response to various the T-cell and B-cell responses to result in less effec-
pathogens (49). Although the initial source of local tive antibody. Selected periodontal bacteria produce
IL-4 in the gingival tissues is unclear, mast cells and proteases that cleave the Fc regions of IgG or de-
46
The host response to the microbial challenge
47
Kornman et al.
monkeys produce less total protein and collagen lagen and bone, and less effective antibody produc-
than cells isolated from noninflamed sites ( 6 2 ) .Van tion. The efficiency of neutrophil migration is re-
der Zee et al. (144) have shown that the extracellular duced, and it is likely that more neutrophils are acti-
matrix of the connective tissues surrounding bone vated within the tissue. The total impact of the above
accumulate substantial quantities of procollagenase changes is to subtly shift the scene from one in
when exposed to IL-lor alone or IL-lor plus epider- which the host is controlling the bacterial challenge
mal growth factor. At a later time the stored procol- to one in which the challenge is less well controlled
lagenase may be released in an active form by the and the tissue-destructive phase is dominant. Such
addition of plasmin. Proteases from periodontopath- factors as smoking and genetic influences on cyto-
ic bacteria have also been shown to activate latent kine expression that are capable of modifymg critical
procollagenases (120). Of perhaps major importance aspects of the neutrophil-antibody protection and/
is the cellular differentiation and production of in- or fibroblast function would be expected to alter the
flammatory mediators by fibroblasts that have been balance of the systems between protection and de-
exposed to bacterial products or an inflammatory struction.
environment (31, 32, 118).
48
The host response to the microbial challenge
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