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Comparison of neutrophilfunctions in aggressive and

chronic periodontitisMA R K I . RY D E R

In the history of medicine and dentistry, there have

been major paradigm shifts in the understanding of

the underlying pathogenic mechanisms of a variety of

diseases and conditions. In the study of aggressive vs.

chronic periodontitis, one of the most significant

paradigm shifts has centered on the role of alterations

in neutrophil function, either due to inherent chan-

ges, external factors or a combination of both, in the

pathogenesis of these two broad disease categories.

The earliest pioneering work on neutrophil functions

and periodontal diseases in general and aggressive

periodontitis in particular (11, 14, 25, 51, 64, 81)

indicated an impairment of neutrophil functions

responsible for host protection. For the next decade,

the prevailing view was that impaired neutrophil

functions, as well as impaired functions of other cellsof the host response, were a central mechanism in the

progression of chronic and aggressive forms of

periodontitis. However, in subsequent decades, the

concept of a primedor hyperactive neutrophil, par-

ticularly in aggressive periodontitis, began to emerge

(21, 29, 43, 56), leading to a new perspective on the

role of neutrophils in aggressive periodontitis, as well

as the destructive role of inflammatory cytokines from

the cell-mediated response. This new perspective

emphasized the role of the destructive aspect of

inflammation in general, and neutrophil-mediated

tissue damage and bone resorption in particular, inthe pathogenesis of aggressive periodontal diseases,

and perhaps to a lesser extent for chronic periodon-

titis. More recently, the concept of the primedneu-

trophil has suggested new avenues of research for the

diagnosis and treatment of aggressive as well as

chronic forms of periodontitis. This review describes

the evolution of our understanding of the role of

alterations in neutrophil functions in periodontal

diseases, with particular emphasis on those studies

that have compared neutrophil functions between

aggressive and chronic forms. The objective of this

review is to bring the reader up to date on the current

understanding of the role of neutrophils, particularly

in chronic and aggressive forms of periodontitis, and

the implications for the diagnosis and treatment of

these diseases.

Several complex issues emerge when comparing

the roles of neutrophil functions in aggressive peri-

odontitis, chronic periodontitis and periodontal

health. Foremost among these is the variation in

definitions and terminologies used to define what we

now call localized and aggressive forms of peri-

odontitis. Researchers in the field of complex systems

refer to this problem of shifting opinions on defini-

tions of disease conditions as a

dancing landscape

(44). The concept of a dancing landscape is appro-

priate when drawing comparisons between studies

from over 30 years ago to today. For example, previ-

ous diagnostic terms for localized and generalized

periodontitis have included Gottleibs cementopa-

thia, periodontosis, localized juvenile periodontitis,

generalized juvenile periodontitis, rapidly advancing

periodontitis and early-onset periodontitis. In order

to avoid unnecessary confusion, the more recent

terminology of localized aggressive periodontitis and

generalized aggressive periodontitis will be used in

this review as a replacement for the disease namesused in previous studies. While such a simplification

may cause problems in terms of overlaps or gaps

compared with previous terms for the disease, using

the terms localized and generalized aggressive dis-

eases allows us to combine observations from this

relatively large body of work over the past few

decades.

In considering the role of alterations of selected

neutrophil functions in the pathogenesis of

124

Periodontology 2000, Vol. 53, 2010, 124137

Printed in Singapore. All rights reserved

2010 John Wiley & Sons A/S

PERIODONTOLOGY 2000


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aggressive vs. chronic periodontitis, a description of

these various functions is warranted. While a more

comprehensive review of these functions is available

(15), the most relevant and most studied functions

are briefly reviewed here for the purposes of dis-

cussing possible differences in neutrophil functions

between aggressive and chronic periodontitis. In the

absence of a specific stimulus such as microbial

colonization in the gingival crevice periodontalpocket, neutrophils flow within the terminal circula-

tion system in the periodontal tissue, with a propor-

tion of these neutrophils rolling along the endothelial

lining. This rolling motion along the endothelial lin-

ing is facilitated through weaker binding of selectins

on the neutrophil surface to lectins on the endothe-

lial lining (Fig. 1). Neutrophils respond to binding of

microbial products or antigens resulting from

microbial colonization of the tooth surface, such as

the small bacterial chemotactic peptide N-formyl-

methionyl-leucyl-phenylalanine (referred to here as

f-Met-Leu-Phe), and binding of these peptides or

antigens to specific receptors or neutrophil binding at

a variety of inflammatory mediators released in

response to the microbiota to neutrophil receptors.

One of the first responses to such binding is shedding

of the selectins on the neutrophil surface, with a

concomitant increased expression of integrins of the

CD11 CD18 (cluster determinant 11 18) family on

the neutrophil cell surface (Fig. 2). These integrins

enable the neutrophil to adhere more tightly to

intercellular adhesion molecules on the surface of

endothelial cells, and facilitate migration of neu-

trophils through the endothelial lining and into the

lamina propria of the periodontal tissues (Figs 2 and

3). The actual movement of neutrophils into the tis-

sue is driven by an actin filament motor through

polymerization and depolymerization of intracellularactin filaments. Neutrophils then move out of the

lamina propria into the gingival crevice periodontal

pocket, where they attempt to engulf phagocytose

and kill the bacteria on the tooth surface (Fig. 4). This

process of engulfing the bacteria via phagocytosis

and eliminating them by intracellular killing is facil-

itated by two neutrophil processes: (i) release of en-

zymes such as myeloperoxidase and a variety of

proteolytic enzymes from lysosomal granules, and (ii)

the oxidative burst, which entails the synthesis and

release of superoxide and hydroxyl radicals, and

subsequent conversion of these products to hydrogen

peroxide (Figs 4 and 5). In addition, as part of this

first line of defense against microbial colonization in

the periodontal pocket, neutrophils secrete other

bactericidal substances such as calprotectins and

cathelicidins as part of the innate immune system.

In order to understand the potential protective

and or destructive role of these neutrophil functions

in aggressive or chronic periodontitis, I would like to

Plaque biofilm

Junctional epithelium

Lamina propria

L-selectin

CD 11/18 integrin

Vessel lumen

rolling

firm attachment

Fig. 1. Early events of neutrophil chemotaxis in perio-

dontal tissues. Neutrophils attach to, and roll along, the

endothelial cells in the terminal circulation via relatively

weak selectin-mediated binding. In response to a micro-

bial and or pro-inflammatory stimulus, selectins are

shed and surface integrins are up-regulated to create a

firm attachment to the endothelial lining of the blood

vessel and to promote migration of neutrophils from the

blood vessel into the lamina propria of the gingiva. This

migration is facilitated by polymerization and depoly-

merization of actin filaments (Arrows).


Lamina propria

Vessel lumen

LcLcN

LcLc

LcLc NN

Fig. 2. Transmission electron micrograph showing neu-

trophil (N) migration out of a blood vessel and into the

lamina propria. Two extensions of the neutrophil (red

arrows) into the lamina propria were observed (pseudo-

podia). A proportion of these neutrophils migrate through

the lamina propria, where several lymphocytes (Lc) are

observed, and through the basal lamina (blue arrows) into

and through the junctional epithelium. A proportion of

neutrophils in the junctional epithelium will then migrate

into the gingival crevice periodontal pocket in an

attempt to neutralize bacteria in the plaque biofilm.

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take some poetic license and draw an analogy be-

tween the schools of thought on impaired neu-

trophils vs. primed hyperactive neutrophils and the

1986 remake of the movie The Fly, in which a sci-

entists DNA is mixed with the DNA of the fly in an

accident during a teleportation experiment. At first

the scientist becomes very weak, and has difficulty

walking across the room or performing the simplest

of tasks. His weakened state is similar to the earlier

hypothesis of neutrophils as impaired cells that

cannot perform the functions of migrating toward a

microbial pathogenic plaque in the periodontal

pocket, and phagocytosing and killing the bacteria.

This impairment of the host defenses would lead to

substances from the microbial plaque biofilm over-

whelming the other host mechanisms, and tissue

invasion of the microbiota with more rapid perio-

dontal breakdown. However, as the scientist contin-

ues to evolve into a fly, he becomes stronger, similar

in a sense to the primed hyperactive neutrophil. In

this hyperactive state, he demonstrates how he eats

food by placing a pastry on the table, then spewing

Fig. 4. Scanning electron micrograph of a neutrophil

migrating towardStreptococcus mutanson a glass surface.

In this in vitro environment, the leading edge of the

neutrophil on the left is seen to extend toward and

phagocytose the bacteria.

Plaque biofilm

ENZYMES


H2O2

H2O2

H2O2

H2O2

H2O2

O2-

O2-

O2-

Lamina propria

ENZYMES

ENZYMES

Vessel lumen

Fig. 3. Later stages of the neutrophilresponse. In an attempt to isolate

and or kill bacterial plaque in both

the plaque biofilm and the overlying

planktonic suspension, neutrophils

attempt to phagocytose individual

bacteria, release superoxide (O2)) as

part of the oxidative burst process,

which is converted to hydrogen

peroxide (H2O2), and release a series

of enzymes that may have anti-

microbial and or tissue-destructive

effects.

Plaque Biofilm

Wall of Neutrophils

Fig. 5. Neutrophils in the periodontal pocket forming awall against the plaque biofilm. In contrast to Fig. 4,

neutrophils cannot engulf the large biofilm structure

in vivo. The formation of a wall against the biofilm may

be a protective mechanism. Nevertheless, an attempt is

made to engulf the surface layer of this biofilm (yellow

arrows). During this process of frustrated phagocytosis,

enzymes within neutrophil lysosomal granules (red ar-

rows), products of the oxidative burst, and other prom-

inflammatory substances may be released directly into the

pocket and or the underlying tissue, where they have a

predominantly destructive effect.

126

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enzymes from his mouth to digest the pastry, and

absorbing as much of the dissolved pastry as possible

through his now primitive mouth. Not only does this

process dissolve the pastry, but also the surface of the

table. The effects of the eating method of the hyper-

active fly are comparable with the action of neu-

trophils and the outcome of aggressive periodontitis,

whereby the pastry is the bacteria and the table is the

supporting periodontal tissue, both of which arebroken down in this process. Thus, these two aspects

of neutrophil function are discussed in this review

with the aim of developing a current understanding

of how both impaired neutrophils and primed

hyperactive neutrophils may play a role in the

pathogenesis of aggressive and chronic periodontitis.

The impaired neutrophil model inaggressive periodontitis

Before considering impairment of neutrophil func-

tion per se as an underlying mechanism for the

pathogenesis of aggressive forms of periodontitis, it is

necessary to address the question of whether there is

a reduced number of neutrophils or proportion of

neutrophils in the whole leukocyte population that

may in turn impair the host response to the sub-

gingival microbiota. There is clear evidence that pa-

tients who have low counts of circulating neutrophils

due to rare conditions such as cyclic neutropenia

present with a pattern and progression of loss of

periodontal attachment that is similar to that ofaggressive forms of periodontitis (24). However, low

neutrophil counts have not been demonstrated in

either chronic or aggressive forms of periodontitis (9,

33). Some authors have reported elevated neutrophil

counts in patients with generalized aggressive peri-

odontitis (33). Others found that the numbers and

proportions of neutrophils in serum are similar in

aggressive and chronic forms of periodontitis (9).

Thus the relevance of neutrophil counts in aggressive

periodontal diseases remains unresolved.

The earliest studies on a possible impairment of

neutrophil function centered on impaired chemo-taxis in response to signals from bacterially derived f-

Met-Leu-Phe peptides. Most of these early studies,

which were performed on peripheral neutrophils (i.e.

those isolated from serum), revealed a pattern of

reduced chemotaxis (directed migration) to f-Met-

Leu-Phe at concentrations of 10)9 to 10)7 M in a

significant proportion of aggressive periodontitis

patients (7286%), but unaltered or increased

random migration (5, 11, 14, 51, 64, 65, 82). Defects in

neutrophil chemotaxis were also observed in a skin

window test on patients with localized aggressive

periodontitis (66). Similar chemotaxis defects were

observed in studies that examined both crevicular

neutrophils and peripheral neutrophils in the same

patient (75, 76). In addition, patients with defective

chemotactic responses to f-Met-Leu-Phe and endo-

toxin-activated serum also showed impaired che-

motaxis to leukotriene b4 (62). A similar pattern ofreduced neutrophil chemotaxis in aggressive perio-

dontitis patients was observed in vivo using an

external skin window test without f-Met-Leu-Phe

stimulation, and this pattern of chemotaxis was

unaltered on addition of f-Met-Leu-Phe (66). By

contrast, in studies that compared neutrophil

chemotaxis in chronic and aggressive periodontitis

patients, the patients in the chronic periodontitis

group exhibited either a normal or elevated chemo-

taxis response (5, 78).

Given this general pattern of normal random

migration chemokinesis and impaired chemotaxis

in aggressive but not in chronic forms of periodon-

titis, the consensus is that the chemotaxis defect may

involve faulty surface receptors for chemotactic

stimulants. This could be due to (i) a reduction in the

number of receptors on the neutrophil cell mem-

brane, (ii) an inherent or acquired defect in the

f-Met-Leu-Phe membrane receptor itself and or co-

receptors for the f-Met-Leu-Phe receptor such as

GP110 (glycoprotein 110) or CD38 that facilitate and

enhance the chemotatic response (84), or (iii) a

combination of both. Early indications supported adecrease in the number of neutrophil receptors for

both f-Met-Leu-Phe and the GP110 co-receptor (84).

Studies on expression of the membrane co-receptor

CD38 in unstimulated neutrophils showed no differ-

ence between periodontally healthy patients and

localized aggressive periodontitis patients. However,

there was a significant decrease of CD38 expression

in f-Met-Leu-Phe-stimulated neutrophils in localized

aggressive periodontitis patients compared to normal

individuals (22). However, these membrane receptor

defects do not appear to influence the function of the

motorof neutrophil motility, the actin cytoskeleton,as the patterns of actin polymerization and depoly-

merization were normal (12).

In addition to impaired chemotaxis, some early

studies demonstrated impaired phagocytosis and

killing in patients with localized or generalized

aggressive periodontitis compared to individuals

with chronic periodontits. In one study, a propor-

tion of patients with localized aggressive periodon-

titis (53%) and generalized aggressive periodontitis

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(46%) showed consistently lower percentages of

neutrophils with phagocytosed particles and lower

numbers of phagocytosed particles per neutrophil

compared to chronic periodontitis patients (45).

This reduced function had not altered after treat-

ment, implying an inherent defect that is not af-

fected by changes in serum factors that could be

altered after periodontal treatment. (45) In another

study, the number of phagocytosing cells obtainedfrom generalized aggressive periodontitis patients

did not differ from that obtained from periodontally

healthy controls. However, when challenged in vitro

with one strain ofPorphyromonas gingivalisand two

strains of Aggregatibacter actinomycetemcomitans,

crevicular phagocytes harvested from healthy indi-

viduals ingested significantly more bacteria than

phagocytes obtained from affected sites in patients

with generalized aggressive periodontitis (18). In

addition, intracellular killing of P. gingivalis and

both strains ofA. actinomycetemcomitans was de-

creased in the periodontitis group (18).

In the innate immune system, neutrophils are an

important source of potent broad-spectrum anti-

microbials such as defensins and LL-37 cathelicidin.

In gingival crevicular fluid from some patients with

aggressive periodontitis, LL-37 cathelicidin was

reduced or absent, and there were lower levels of

human neutrophil peptide 13 defensin compared to

gingival crevicular fluid and neutrophils obtained

from patients with chronic periodontitis (71). In an-

other study, the level of human neutrophil peptide 3

defensin was significantly reduced in neutrophilsfrom patients with generalized aggressive periodon-

titis (20). However, in the latter study, the reduction

in these defensins was considered to be minor and

not to have a significant impact on the pathogenesis

of aggressive periodontal diseases (20).

A third area of study of neutrophil function that has

yielded contradictory results involves possible alter-

ations in the initial adhesion of neutrophils to

endothelial cells of capillaries. As described in the

Introduction, this process involves both shedding of

selectins, and increased cell surface expression of

CD11 18 integrins, which promote firmer adherenceand fixation of the neutrophil to the endothelial lin-

ing and subsequent chemotactic migration into the

tissue. For example, unstimulated and f-Met-Leu-

Phe-stimulated neutrophils from localized aggressive

periodontitis patients demonstrated higher adhesion

to culture plates than did periodontally healthy

controls (34). By contrast, other studies that exam-

ined CD18 CD11a and CD18 CD11b expression on

peripheral and crevicular fluid neutrophils in local-

ized aggressive and chronic periodontitis patients

demonstrated no marked differences in expression

nor a deficiency of these adhesion integrins (60, 67,

86). In addition, expression of intercellular adhesion

molecules on the endothelial surface of blood vessels

that bind to neutrophils in aggressive periodontitis

patients was comparable to that of a periodontally

healthy control group (68).

Evidence also began to emerge indicating that, insome patients with aggressive periodontitis, these

chemotaxis defects were genetically inherent and

could not be reversed by treatment (57). However,

in other patients with aggressive periodontal dis-

eases, these defects were acquired through exposure

to inflammatory mediators in the serum and or

microbiota, and were subsequently fully or partially

resolved by periodontal treatment. For example, one

early study demonstrated that 86% of localized

aggressive periodontitis patients showed impaired

neutrophil chemotaxis due to an intrinsic abnor-

mality, while 48% of generalized aggressive perio-

dontitis patients showed an abnormality related to

the composition of their serum (51). In subsequent

studies, it was shown that the serum of localized

aggressive periodontitis patients down-regulated

chemotaxis and the surface expression of f-Met-Leu-

Phe receptors (3, 33). This effect was eliminated by

antibodies to tumor necrosis factor alpha and

interleukin-1 (1, 3). Reported defects in phagocytosis

in generalized aggressive periodontitis patients may

also be influenced by the bacterial strains associated

with the disease. For example, a leukotoxic A. ac-tinomycetemcomitans strain associated with gener-

alized aggressive periodontitis was phagocytosed to

a lesser degree than corresponding non-leukotoxic

strains (18). It has also been shown that major

inflammatory cytokines such as tumor necrosis

factor alpha and interleukin-1 modulate the

expression of neutrophil CD11 CD18 adherence

molecules (2). This effect was markedly reduced by

use of antibodies to these cytokines (2). Similarly,

incubation of neutrophils with A. actinomycetem-

comitansdecreased the expression of f-Met-Leu-Phe

receptors, in conjunction with increases in CD11 CD18 adhesion molecules (6). Other studies have

demonstrated that both extrinsic and intrinsic fac-

tors for neutrophil function may be involved in the

same patient. For example, in a study that examined

the modulatory effects of serum from either local-

ized aggressive periodontitis patients or periodon-

tally healthy controls, there was normal phagocyto-

sis in both groups but impaired killing of

A. actinomycetemcomitans by neutrophils incubated

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with serum from the healthy controls, indicating an

intrinsic defect (38).

The intrinsic neutrophil defects found in some but

not all patients with aggressive periodontitis may

have a genetic basis, as suggested by some of the

earliest early studies of neutrophil function (57).

Initial genetic studies showed that some patients with

clinical signs of aggressive periodontitis had an

inheritable neutrophil chemotaxis defect, whereasmembers of other families who presented with clin-

ical signs of aggressive periodontitis did not have this

inheritable defect (83). A more comprehensive dis-

cussion of comparative studies of genetic suscepti-

bility in chronic vs. aggressive forms of periodontitis

is presented elsewhere in this issue, but some com-

ments are warranted regarding the inheritability of

defects and or altered expression of f-Met-Leu-Phe

receptors as reported in several studies of aggressive

periodontitis (30, 37, 72, 88). Some of these studies

noted single nucleotide polymorphisms at specific

loci. For example, DNA sequencing of 30 localized

aggressive periodontitis patients compared to 20

controls found two single nucleotide polymorphisms

in the f-Met-Leu-Phe receptor DNA: a thymine to

cytosine substitution at base 329 in 17 patients, and a

cytosine to guanine substitution at base 378 in five

patients (30). However, in another study, the single

nucleotide polymorphisms at these two sites did not

correlate with clinical signs of aggressive periodon-

titis (88). Studies on the corresponding amino acid

substitutions at the receptor site reported that an

amino acid substitution at the 110 and 126 positionsof the f-Met-Leu-Phe receptor may be a predictor for

more severe forms of aggressive periodontitis (30, 37).

In addition, polymorphisms between the f-Met-Leu-

Phe receptor and G protein coupling may also be

involved in inherited alterations of neutrophil func-

tion. For example, in a recent study on neutrophils

from patients with localized aggressive periodontal

disease, there was an almost complete loss of G(i)

protein coupling in patients with amino acid substi-

tutions at positions 110 and 126 (72). However, the

authors proposed that such a loss of f-Met-Leu-Phe

receptor function is not usually life-threatening, asthe defect is readily compensated for by redundan-

cies in the innate immune system (72).

In addition to the f-Met-Leu-Phe receptor, poly-

morphisms in the neutrophil membrane receptor for

the Fc gamma fragment of antibody may play a role

in defective phagocytosis in aggressive periodontitis.

Polymorphisms in the Fc gamma receptor occurred

at a significantly higher rate in neutrophils from

patients with aggressive periodontitis vs. those of

periodontally healthy controls (39, 61). Patients with

this polymorphism showed decreased phagocytosis

of periodontopathic bacteria (39).

Emergence of the concept of ahyperactive or primed neutrophil

Most of the earlier studies on aggressive periodontitisreported defects in neutrophil chemotaxis and

phagocytosis, either inherent and or acquired, but

there were early indications that impaired chemo-

taxis resulting from a defect in membrane receptors

or other mechanisms could not fully explain the

possible role of neutrophils in aggressive periodon-

titis, nor could they fully account for the rapid tissue

destruction in aggressive compared to chronic forms

of periodontitis. For example, some early studies in

aggressive periodontitis patients reported no signifi-

cant correlation between neutrophil chemotaxis and

the severity of periodontal disease (13, 47, 48), but an

elevated neutrophil chemotaxis response was seen in

other aggressive periodontitis patients (14, 42, 43, 72).

In one comparative study, elevated neutrophil che-

motaxis was seen in two of 32 patients with localized

aggressive periodontitis and two of eight patients

with generalized aggressive periodontitis, compared

to ten of 23 patients with chronic periodontitis, a

much higher proportion (81). In another study, neu-

trophils from aggressive periodontitis patients

showed normal random migration and chemotaxis

when compared with neutrophils from patients withchronic periodontitis or periodontally healthly con-

trols (58). A more recent study examining a panel of

neutrophil, cytokine and microbial parameters be-

tween various periodontal conditions found no dif-

ferences in neutrophil chemotaxis, phagocytosis,

superoxide production or adhesion in patients with

various forms of aggressive periodontitis compared

to patients with chronic periodontitis and periodon-

tally healthy controls (78). These observations led

investigators to examine other possible alterations of

neutrophil function that may lead to the more rapid

breakdown of the periodontal support in aggressiveforms of periodontitis compared to chronic forms.

In recent decades, most data have supported the

concept of a hyperactive primed neutrophil that

leads to increased tissue destruction in aggressive

forms of periodontitis (42). Such priming could in-

volve increased neutrophil adhesion, enzyme release

and, perhaps most importantly, an elevated oxidative

burst. This concept of a primed hyperactive neu-

trophil or elevation of neutrophil function began to

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emerge in the earliest studies on defects in chemo-

tactic receptors. For example, although expression of

f-Met-Leu-Phe receptors is impaired, appears that

integrin-mediated cell adhesion may be enhanced in

patients with either aggressive or chronic periodon-

titis (34).

Evidence for increased enzyme activity is sup-

ported by studies of neutrophils from patients with

aggressive forms of periodontitis who have increasedintracellular levels of beta-glucuronidase, an enzyme

characteristic of azurophil lysosomes (69). Patients

with generalized aggressive periodontitis had greater

beta-glucuronidase activity in crevicular fluid than

individuals with localized aggressive periodontitis,

whose levels were in turn greater than found in

periodontally healthy controls. These higher levels

of beta-glucuronidase could lead to increased

periodontal breakdown in aggressive periodontal

diseases (4). Myeloperoxidase is another enzyme se-

creted by neutrophils that may play a central role in

the activation of neutrophil proteases, and in inacti-

vating constitutive tissue and serum inhibitors of

protease activity, particularly matrix metalloprotein-

ases. This would tilt the balance of tissue homeostasis

toward a situation favoring tissue breakdown or

resorption (87). In patients with aggressive perio-

dontitis, baseline levels of myeloperoxidase were

highly correlated with the presence of bleeding and

suppurating sites, although no specific comparisons

were made between aggressive and chronic perio-

dontitis patients (40). On the other hand, studies that

examined the activities of selected neutrophil-de-rived matrix metalloproteinases such as MMP-8

found no difference in tissue or crevicular fluid levels

of this enzyme between chronic and aggressive

periodontitis patients (79). In addition, the levels of

MMP-25 and MMP-26, two newly identified neutro-

phil matrix metalloproteinases involved in extra-

cellular matrix breakdown and turnover, were

comparable between aggressive and chronic perio-

dontitis patients (19).

Perhaps the most characteristic event in neutrophil

priming or hyperactivity is an increase in the syn-

thesis and release of oxidative burst products, such assuperoxide, hydroxyl radicals and hydrogen peroxide,

from both resting and stimulated cells. As in other

neutrophil function studies in aggressive and or

chronic periodontitis, there is no clear consensus as

to whether the oxidative burst is increased, decreased

or unchanged in unstimulated, stimulated or both

unstimulated and stimulated neutrophils than in in-

dividual patients. Much of this confusion centers on

the isolation methods used to collect neutrophils and

the variety of oxidative burst assays used, such as

chemoluminescence and dye reduction. In addition,

whether this priming effect is unique to aggressive

cases is open to question, as comparable priming

events have been observed in chronic periodontitis

patients (46). Some studies have shown no difference

in chemoluminescence in either stimulated or

unstimulated neutrophils from aggressive periodon-

titis patients (59). In an early study, no significantdifferences were found between stimulated neu-

trophils from chronic or aggressive periodontitis pa-

tients (59). In addition, although unstimulated re-

lease of oxidative burst products may be increased in

aggressive periodontitis patients compared to

chronic periodontitis patients, the oxidative burst

stimulated by agents such as opsonized zymosan or

by the process of phagocytosis may be decreased in

aggressive periodontitis patients. For example, neu-

trophils from patients with localized aggressive peri-

odontitis showed decreased chemoluminescence

during phagocytosis of opsonized zymosan (26). In

another study, neutrophils from chronic periodontitis

patients released significantly more reactive oxygen

species than neutrophils from patients with aggres-

sive periodontitis when exposed to P. gingivalisand

A. actinomycetemcomitans (28). On the other hand,

some studies have demonstrated a comparative in-

crease in the stimulated oxidative burst in aggressive

periodontitis patients (36, 55, 73). One study dem-

onstrated a larger receptor-independent respiratory

burst and higher phagocytotic activity in neutrophils

from patients with generalized aggressive periodon-titis compared to neutrophils from chronic perio-

dontitis patients and periodontally healthy controls

(36). These investigators postulated that the intrinsic

intracellular activity of the nicotinamide adenine

dinucleotide phosphate oxidase system may account

for the continued periodontal breakdown (36).

Some studies have demonstrated an increased

chemoluminescence response in stimulated neu-

trophils that appears to be unrelated to alterations in

membrane receptors. For example, increased respi-

ratory burst activity is associated with normal

expression of IgG-Fc receptors and complementreceptors in peripheral neutrophils from patients

with localized aggressive periodontitis (55). In this

study, the neutrophils from localized aggressive

periodontitis patients generally showed more intense

chemoluminescence with all activators than those

of controls. In particular, the chemoluminescence

responses induced by non-opsonized zymosan

particles and f-Met-Leu-Phe were significantly higher

(55).

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Neutrophil priming in aggressive periodontitis may

be due to an inherent defect or acquired from

substances in the serum and or exposure to oral

microbiota. The serum of localized aggressive peri-

odontitis patients contains a neutrophil-priming

substance that is capable of triggering the release of

superoxide from neutrophils. Superoxide generation

by neutrophils is also enhanced by exposure to f-

Met-Leu-Phe and pre-incubation with P. gingivalis(73). The priming agent in serum may be a microbial

product. For example, one study implicated prior

exposure to A. actinomycetemcomitans as a priming

agent for the oxidative burst in neutrophils in the

unstimulated state (7). Neutrophil priming by

inflammatory cytokines in serum has also been

implicated in aggressive periodontitis. In one study,

increased interleukin-8 plasma levels in aggressive

periodontitis patients were correlated with increased

production of hydrogen peroxide by neutrophils, and

decreased L-selectin shedding, implicating interleu-

kin-8 in serum as a priming factor for the neutrophil

oxidative burst (23). However, other studies have not

found this pattern of increased inflammatory cyto-

kines in serum to be a priming factor. One study re-

ported that the levels of interleukin-1 and tumor

necrosis factor alpha were not increased in the serum

of 29 localized aggressive periodontitis patients, of

whom 20 had a chemotaxis defect (74).

As with the question of defective neutrophils and

alterations in chemotactic receptors, gene expression

studies have focused on possible under- or over-

expression of mRNAs that may contribute to aprimed neutrophil profile. One study identified three

aggressive periodontitis-related genes involved in

neutrophil adhesion and expression of tumor necro-

sis factor alpha (49). Another study found an increase

in expression of genes associated with NADPH oxi-

dase, which is responsible for the synthesis of oxi-

dative burst products in both chronic and aggressive

forms of periodontitis (61). The authors speculated

that this may also be an explanation for the altered

neutrophil response that is characteristic of aggres-sive periodontitis (61).

Defective or primed neutrophils:insights from intracellularsignaling

Over the past few decades, new insights into the

intracellular signaling pathways that drive the func-

tions of adhesion, chemotaxis, phagocytosis and

intracellular killing have shed light on possible

underlying mechanisms for impaired neutrophil or

primed neutrophils. This subject has been extensively

reviewed (41), and Fig. 6 summarizes the current

understanding of these intracellular signaling mech-

anisms. There are several pathways, substances or

nodes in the intracellular scheme that could be

investigated, but this review focuses on the three

pathways and nodes that have received the most

attention: calcium homeostasis, the phosphorylation

of proteins by protein kinase C, and the central role

of diacylglycerol and diacylglycerol kinase.

Calcium homeostasis and alterations of intracel-lular pH play a critical role in a variety of neutrophil

CalciumAgonist

G-protein

Receptor

1Phospholipase C

inositol 1,4,5 phosphate ReceptorPhosphatidyl inositol4,5 phosphate

Phosphatidyl inositol phosphate

CalciumIntracellular

stores of

calcium

Diacylglycerol

Diacylglyce

rol

kinase

Phosphaditic acid

Phosphatidyl inositol 2

Protein kinase C

Phosphorylation of selected protiens

Stimulation or inhibition of neutrophil functions

Fig. 6. A summary of the major

intracellular signaling pathways thathave been assessed in neutrophil

function studies in aggressive and

chronic periodontitis. The major

components of these pathways dis-

cussed in this review, including in-

flux of calcium ions (1), release of

intracellular calcium stores (2),

diacylglycerol, diacylglycerol kinase

and protein phosphorylation, are

highlighted in red. Adapted with

permission from (41).

131



9/14

functions, including the chemotactic response, cell

motility in migration and phagocytosis, and selected

intracellular signaling pathways. Several studies have

demonstrated impairment of the initial intracellular

release of calcium and the influx of extracellular

calcium into the neutrophil. Although some studies

have demonstrated that the release of intracellular

sequestered calcium in the early phase of the calcium

response appears to be intact in neutrophils fromlocalized aggressive periodontal patients (16), the

second phase of the calcium response, associated

with membrane channel activation and influx of

extracellular calcium, appears to be compromised

(16). In a comparative study, rapid responses to

f-Met-Leu-Phe or interleukin-8 as measured by

changes in cytoplasmic calcium and pH were greater

in neutrophils from localized aggressive periodontitis

patients compared to chronic periodontitis patients

(32). However, redistribution of the rapidly released

calcium and alkalinization of the cytoplasm was

impaired in the neutrophils from aggressive perio-

dontitis patients compared to healthy controls (32). A

possible candidate that may explain the underlying

mechanism of this defect in calcium influx is a newly

described calcium influx factor (75). This calcium

influx factor is hypothesized to be a second mes-

senger for the opening of membrane calcium chan-

nels when intracellular calcium stores are depleted.

The activity of this calcium influx factor is decreased

in localized aggressive periodontitis patients com-

pared to patients with chronic periodontitis or

healthy controls (75).Alterations in protein kinase C and subsequent

clinical effects on both unstimulated and stimulated

chemotaxis have also been observed. One study re-

ported that the total calcium-dependent protein ki-

nase C activity of neutrophils from patients with

localized aggressive periodontitis and decreased

chemotactic migration to a f-Met-Leu-Phe gradient

was lower than in neutrophils from healthy controls

(50). The synthesis and breakdown of the secondary

messenger diacylglycerol (DAG) may play a central

role in this intracellular signaling process, and the

reported alterations in DAG kinase levels in neu-trophils from aggressive periodontitis patients may

have a variety of effects. Because DAG is an endog-

enous activator of protein kinase C, increased and

prolonged generation of DAG could lead to an

abnormal pattern of protein kinase C-regulated

neutrophil functions, explaining the parallel hypo-

and hyperactivities (53, 54). DAG is converted to

phosphatidic acid by DAG kinase. Thus reduced DAG

kinase levels imply increases in intracellular DAG

levels and subsequent neutrophil priming (27, 63).

This role for DAG in intracellular signaling in neu-

trophils from aggressive periodontitis patients is

supported by studies demonstrating that the DAG

levels increased by 67 and 111% from the basal level

following stimulation with f-Met-Leu-Phe and non-

opsonized zymosan particles, respectively, in neu-

trophils from localized aggressive periodontitis pa-

tients, while the mean increases were 36 and 65%,respectively, in control cells. This may be due to

impairment of the DAG kinase levels or activity. In

one study, neutrophils from three of five patients

with localized aggressive periodontitis did not show a

rise in DAG kinase activity upon chemoattractant

stimulation (35). These differences may be due to

differential expression of isoforms of DAG kinase, as

reported in a population of localized aggressive

periodontitis patients (63).

Implications for diagnosis andtreatment

Earlier in this review, reference was made to the

difficulties in defining localized and aggressive peri-

odontitis in view of the historical names given to

these conditions, some which are still in use today.

This is an example of a concept referred to in com-

plexity theory as a dancing landscape (44). This

dancing landscape makes the development of spe-

cific diagnostic criteria for aggressive periodontitis

based on clinical signs alone a challenging proposi-tion. The question arises as to whether use of a lab-

oratory-based assessment of neutrophil function,

other elements of the host immune response, such as

the cellular or humoral response and or microbial

parameters may improve the accuracy of diagnosis of

aggressive vs. chronic periodontal diseases. One early

approach involved determination of the number of

chemotactic receptors on the neutrophil surface as a

possible diagnostic tool for aggressive periodontal

diseases. Early studies suggested that a reduction of

GP110 and f-Met-Leu-Phe receptors on neutrophils is

specific to localized aggressive periodontitis patientswho exhibit neutrophil chemotaxis abnormalities

(84), and may be a useful disease marker for localized

aggressive periodontitis (85). In another study, seven

monoclonal antibodies were selected on the basis of

their reactivity with the 68 kDa receptor component,

and, of these, five showed reduced binding to

neutrophils from chemotaxis-defective localized

aggressive periodontitis patients compared to their

reactivity against neutrophils from patients with

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11/14

aggressive periodontitis did not respond to molecules

of the lipoxin series, but Resolvin E1 did inhibit

superoxide generation (31).

Conclusions and future directions

With regard to neutrophil functions in aggressive and

chronic forms of periodontitis, the role of either animpaired or primed hyperactive neutrophil in the

progression of aggressive periodontitis in particular

has been extensively studied. Whether defective

neutrophil functions, such as chemotaxis, phagocy-

tosis and intracellular killing of microbial pathogens,

or primed neutrophils with elevated functions (e.g.

increased oxidative burst and destructive enzyme

release) are the predominant contributor to pro-

gression of aggressive and chronic forms of perio-

dontitis is still open to debate. In addition, one must

take into consideration that the neutrophil per se is

just one component of the first line of defense,namely the innate immune system in the periodontal

tissues. As discussed in other reviews in this volume

ofPeriodontology 2000, other components of the in-

nate immune system as well as the entire repertoire

of cytokines and chemokines from the acquired im-

mune response may also play significant and perhaps

sometimes different roles in the pathogenesis of

aggressive and chronic periodontitis.

Nevertheless, despite the complexity in determin-

ing the most important inflammatory and immune

pathways in these diseases, an understanding of

neutrophil function can aid in the development of

new diagnostic and treatment approaches. In par-

ticular, the potential to reverse acquired neutrophil

defects using a variety of approaches from basic

mechanical debridement to the strategic therapeutic

use of newly identified anti-inflammatory agents may

lead to more cost-effective approaches to treating

both aggressive and chronic forms of periodontitis.

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