Pathogenic Mechanisms Ninta

8/13/2019 Pathogenic Mechanisms Ninta

1/5

PATHOGENIC MECHANISMS INPERIODONTAL DISEASEPeriodontal diseases are characterized by the progressive

destruction of the supporting tissues of

teeth in the apparent absence (at least in the early

stages) of significant tissue invasion. Tissue damage,

therefore, must also be mediated by surface

components and extracellular products of bacteria

(Table 6.8). These bacterial products can cause

destruction of gingival tissue by two mechanisms. In

one, damage results from the direct action of bacterial

enzymes and cytotoxic products of bacterial

metabolism. In the other, bacterial components

are only indirectly responsible, and tissue destruction

is the inevitable side effect of a subverted and

exaggerated

host inflammatory response to plaque

antigens; this has been termed bystander damage

(Fig. 6.15).

There is also an hypothesis proposing a role for

herpes viruses in destructive periodontal diseases.

Herpes simplex virus, human cytomegalovirus and

EpsteinBarr virus type 1 nucleic acids have been

detected in lesions from aggressive types of periodontitis.

These viruses can infect various host cells,

including polymorphonuclear leukocytes, macrophages

and lymphocytes, and they induce the

expression of potentially tissue-damaging cytokines

and chemokines. In this way, it is proposed that

these viruses could reduce the effectiveness of the

local host defences, thereby giving certain subgingival

bacteria the opportunity to escape from homeostasis

and reach clinically-significant levels. The

tissue tropism of herpes virus infections may explain

the localized pattern of tissue destruction seen in

some forms of periodontitis, while the reactivation

of these viruses may explain the episodic nature of

tissue destruction.

Indirect pathogenicityAny subgingival plaque bacterium could be considered

to be playing a role in tissue destruction via the

indirect pathogenicity route if they contribute to an

inflammatory host response. Bacterial antigens can

penetrate the crevicular epithelium and stimulate

either humoral or cell mediated immunity. Humoral

immunity results in the synthesis of immunoglobulins,

which activate the complement cascade

that leads to inflammation and the generation ofprostaglandins. Prostaglandins are inflammatory mediators, and can stimulate bone resorption. Levels

of prostaglandins in GCF correlate with periodontal

status, and can act as molecular predictors of attachment

loss. In contrast, cellular immunity leads to the

release of cytokines from activated T-lymphocytes,

and these modulate macrophage activity. Activated

macrophages release cytokines such as tumour

necrosis factor-alpha (TNF-), interferon gamma

(IFN-), and interleukin-1 (IL-1). Both IL-1 and


2/5


3/5

be a means of targeting appropriate substrates for the

release of essential cofactors for growth, such as haemin,

from host molecules. The arg-gingipains ofP.

gingivalis (see later) cleave proteins to leave exposed

arginine residues, which in turn can act as receptors

for its own fimbriae, thereby facilitating colonization

by the exposure of cryptitopes (Ch. 4).

The gingipains ofP. gingivalis can also contributeto nutrition by generating the vascular permeability

enhancement factor, bradykinin, either through

a direct action on kininogen or via activation of

pre-kallikrein, resulting in the entry of elevated levels

of plasma proteins (which can act as nutrients) into

the pocket. The lys-gingipain also plays an essential

role in nutrition by obtaining haemin from haemoglobin.

The concerted action of arg- and lys-gingipains

is necessary for the production of the black pigment

layer on the surface ofP. gingivalis (micro-oxo bishaem

layer), that protects cells against oxidative damage.

Evasion and/or inactivation of the hostdefencesPhagocytic cells form the main defence strategy by

the host against periodontal pathogens. Many strains

ofA. actinomycetemcomitansproduce a powerful leukotoxin

able to lyse human neutrophils, monocytes

and a sub-population of lymphocytes, whilst

other cell types (e.g. epithelial and endothelial cells,

fibroblasts, erythrocytes) are resistant. The leukotoxin

belongs to the RTX (repeats-in-toxin) family

of bacterial pore-forming cytolysins; Campylobacter

rectus also produces a leukotoxin. The JP2 clone ofA. actinomycetemcomitans serotype b overproduces

the leukotoxin by up to 20 times that seen in other

strains, and its presence is a significant risk factor for

localized aggressive periodontitis. The same clone

has not been isolated from Caucasians or from

healthy individuals, giving rise to the speculation

that this might represent a specific, and highly infectious,

clone of a periodontal pathogen.

Periodontal pathogens can produce a range

of molecules that cause tissue damage by inducing

host cells to produce pro-inflammatory cytokines.

These molecules, termed modulins, include

lipopolysaccharides and other less well defined cell

wall components. Other bacterial components can

inhibit the chemotaxis of polymorphonuclear leukocytes

(PMNs), and interfere with their ability to

kill bacteria or phagocytose cells. Bacteria, including

A. actinomycetemcomitans, also exert an immunosuppressive

effect, perhaps mediated by cell surface proteins,

whileP. gingivalis, possesses a capsule, which

protects cells against phagocytosis.Aggregatibacter

actinomycetemcomitans, T. forsythia,P. gingivalis, and

other pathogens may also evade the host defences

by invading epithelial cells (Ch. 4; Fig. 4.6).

The proteases ofP. gingivalisplay a critical role

in deregulating the host control of the inflammatory

response, and in evading the action of other


4/5

components of the immune system. Arg-gingipain

can inactivate both complement (e.g. by degrading

C3 and C5) and antimicrobial peptides (Ch. 2); a

range of proteases can also degrade immunoglobulins

(IgA, IgG and IgM) and interfere with the

respiratory burst of neutrophils, reducing the likelihood

of opsonization. The maintenance of tissue

homeostasis, and the coordination of the innate andadaptive immune response, is dependent on a complex

intercellular signalling network mediated by

cytokines. Components ofP. gingivalis can stimulate

the production of pro-inflammatory cytokines

such as TNF- and IL-1, but arg-and lys-gingipain

can subvert this host response by degrading these

key molecules and enzymically modifying others.

Arg-gingipain can also inactivate the two major

plasma protease inhibitors, 1-antitrypsin and 2-

macroglobulin, thereby reducing the ability of the

host to regulate the scale and ferocity of the inflammatory

response. Expression and activity of these

enzymes is up-regulated by environmental changes

(e.g. by increases in local pH and haemin concentration)that occur during the transition from a normal

gingival crevice to a periodontal pocket. Other

periodontal pathogens, including Tannerella forsythia

and Treponema denticola, also produce proteases with

arginine-x specificity. Thus, some periodontal pathogens

can subvert and deregulate the hosts attempt

to control subgingival plaque so that by-stander

tissue damage occurs, while the influx of potential

nutrients is increased so that their growth is

selectively enhanced.

Tissue-damaging enzymes and

metabolitesMembers of the subgingival microflora produceenzymes that may play a direct role in the damage

of host tissues in the periodontal pocket. For

example,P. gingivalis has been shown to produce

collagenases that can degrade collagen, although

the majority of collagenase activity in GCF is hostderived.

Once denatured, collagen may be broken

down by bacterial proteases with a broader specificity.

Other enzymes produced by subgingival bacteria

that may damage tissue matrix molecules directly

include hyaluronidase, chondroitin sulphatase, and

glycylprolyl peptidase. These enzymes can also be

detected on outer membrane vesicles of Gram negative

bacteria such asP. gingivalis; these vesicles can beshed from the bacterial cell surface during growth,

enhancing the likelihood of tissue penetration by

these enzymes. Once the integrity of the epithelium

is impaired, the increased penetration of cytotoxic

bacterial metabolites such as indole, amines, ammonia,

volatile sulphur compounds (e.g. methyl mercaptan,

H2S), and butyric and propionic acids can

induce further damage.Fusobacterium nucleatum is

the most commonly isolated species in periodontal


5/5

pockets, and it produces large concentrations of

butyrate and volatile sulphur compounds. Bone loss

is a feature of advanced forms of periodontal disease

(Fig. 6.8); bone resorption can be induced by molecules

from periodontal pathogens (e.g. LPS, lipoteichoic

acid and surface-associated proteins).

InvasionMicrobial invasion of host tissues occurs in necrotizingulcerative gingivitis (NUG), where there is superficial

invasion of the gingival connective tissues by

spirochaetes. Invasion also occurs in other forms of

periodontal disease, e.g. localized aggressive periodontitis,

advanced chronic periodontitis, and in

HIV-associated periodontal disease. The persistence of putative pathogens such asP. gingivalis in health

may be linked to their ability to invade host cells

and survive in this privileged site, out of the reach of

the host defences.

The invasion of gingival tissue byA. actinomycetemcomitans

shows some similarities to other intracellular

pathogens, such as Shigella flexneri andListeria monocytogenes,

but there are also unique features, especially

with respect to cell-to-cell spread. Contact betweenA.actinomycetemcomitans and a host cell triggers effacement

of the microvilli, formation of craters on the

host cell surface, and rearrangement of host cell actin

at the site of entry. Bacteria appear to enter the host

cell through ruffled apertures on the cell surface, and

entry occurs in a host-derived, membrane-bound vacuole.

The host-derived vacuolar membrane that initially

surrounds the internalized bacterial cells soon

disappears and cells ofA. actinomycetemcomitans grow

rapidly intracellularly, and spread to neighbouring

cells by using host cell microtubules. These protrusions

contain cells ofA. actinomycetemcomitans, and

interconnect with other host cells, enabling cell-tocell

spread of the bacteria to occur.

Documents

Pathogenic Mechanisms Ninta