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Microbial interaction with the host in the periodontal diseases.

Dear colleagues

I referred to 2009 scripts because the record was so bad , and there were

no slides !

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Today we'll talk about the microbial interaction with the host in the

periodontal diseases.

Getting back to talk about pathogenesis; but this time we want to stress

on the host-.. interaction; we are going to talk about it in the same

way, but here we are going to talk about the bacterial plaque and its

effect on the hosts bone, and then the host tissue will go in a host

response which is as we mentioned previously an inflammatory response.

Now the problem we have in the periodontal diseases is that most of

the problem or most of the destruction in the periodontal tissues is not

from a direct effect of the bacterial plaque; but it is from a direct effect of

the host response or immune response which is a result of the invasion

of the bacteria into the tissues.

The damage from the bacterial plaque against any other infection in the

body generally will not lead to damage because of the bacteria orbacterial plaque or pathogens generally.

So, let us ask this question: Does the immune response have a

protective effect or a destructive effect? It is here a destructive effect.

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Why do we have this destructive effect of the immune system? Simply

because the immune system is not aiming to protect the teeth or the

periodontal tissues; but the general aim of the immune system is to

protect the whole body.

We are not comparing the health of a tooth with the health of for

example cardiac tissues, both of them are important, but which one of

them is more important? Of course cardiac tissues is more important;

and because of this the immune system is always directed to protect the

cardiac tissues, the whole body, the blood stream and the vital organs in

the host tissues (generally), why the tooth and the periodontal tissuesarent considered to be of a high priority to our body, it is just too bad .

*** Important points: There is a bacterial invasion of the tissues or bacterial

plaque and an immune response, the destruction that happens due to the

immune response is what causes the problem in the periodontal tissues.

Accumulation of plaque on the gingival tissues and gingival margins and in

the gingival pocket that will cause an inflammatory response.

We have mentioned previously that it is only in the gingival tissues or in the

periodontal tissues where I have the bone as close to the outer environment,

while other bones in any other area of the body are well protected under layers

of muscles, facial and skin.

So, the presence of the dental pathogens alone is insufficient to cause the

tissue destruction seen in periodontitis, and it is the body response to the

periodontal pathogens that causes all the bone destruction seen in periodontitis.

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Now I want to mention that we have two sides of our balance; dental

plaque or bacterial plaque and immune response. As we mentioned in

the previous lecture we have some factors that may affect this balance,

so how can this balance get affected?

There are specific & non-specific theories of bacterial plaque

accumulation that causes periodontitis.

Specific is related to the number of specific bacterial type, the

virulence of the bacteria; the mechanism that bacteria colonize and

invade the periodontium regardless the amount of the bacteria. Non-

specific is related to huge amount of bacterial plaque accumulationregardless the type of bacteria.

Immune response.

We will start discussing the bacterial virulence factors and then

through that we will reach the immune response.

Bacteria virulence factor, mechanisms of bacteria to colonize and invadethat area (periodontal tissue and periodontium).

we have said before , why we have plaque accumulation in the ora

cavity on teeth but we dont have this problem in anywhere else in the

body. Why is that? Because there's shedding of soft tissues and

epithelium generally but I don't have this shedding in enamel or dentine.

Bacterial virulence factor is considered to be a minor cause of theperiodontal destruction; it is a non-specific factor.

So that the virulence factor of bacteria is not that important.

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Bacterial virulence factors can be divided into two parts; the

characteristics of the bacteria itself and the products of the bacteria.

When we talk about the characteristics of the bacteria itself we'retalking about the pathogenicity which comes from the cell membrane or

the cell wall of the bacteria, and the bacterial invasion factors; the ability

of the bacteria to penetrate into the epithelium lining or the pocket core

and the inter-radicular connective tissue; with peptides found on the

bacterial cell membrane that will cause an immune response later on.

Which types of cells are responsible of phagocytosis or presenting of

these peptides or antigens for other types of immune system cells?

Langerhans cells they are in the epithelium, the macrophages and

monocytes generally.

Talking about the bacterial products; one of the bacterial products is

exotoxin, so what is exotoxin?

It is harm proteins or potent toxins that produces by the bacteria and

released from the bacteria itself; it is not connected or associated with

the cell wall or cell membrane of the bacteria.

Second thing is enzymes, bacteria always produce enzymes; proteins

that catalyze the chemical reactions; like causing damage to the tissues

and damage to the proteins proteinases is what we call it generally

(type of enzymes), it opens the field for bacteria to invade the tissues.

Now, let's go back and talk about the bacterial side or dental plaque

side.

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Here we're talking about the bacterial colonization and plaque biofilm,

weve talked in the previous lecture about the steps or the bases of the

bacterial plaque maturation; it begins with a clean surface (after perform

brushing, scaling, polishing), then there will be a thin coated of acquiredpellicle, then building and ascending organism, and multiplication of

these cells, growth of that area, and then mature biofilm within 28 days

to complete the maturation of it; and then we will have mushroom shape

like what we see in the bacterial plaque and fluid channels.

Now, lets talk about the propagation of bacteria

How does the propagation of bacteria differ from the colonization?

Colonization is the whole procedure; from the attachment to the surface

including the propagation of the bacteria, while propagation is cell-to-cell

adherence of one colony of bacteria to one another.

In propagation, we have a sequence, it is not a random procedure,

each bacterial strain has a limited set of bacteria that it is able to adhereto it.

Sometimes they talk about it like an alphabetical ordering, for

example there are lines; line A, line B, line C, line D, and for example line

C is not allowed to set unless line B is there.

This point is very important in understanding the pathogenicity of thepathogens generally and periodontitis specifically.

According to the propagation of bacteria we can also divide the whole

process into three stages; early, intermediate and late:

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Firstly we have the pellicle on the tooth structure, and the first layer

on the early phase of propagation of the bacteria which allows other

layers to be accumulated in sequence and here some kinds of bacteriaare obviously seen.

In the early colonization the first bacteria to colonize is non-

pathogenic, this non-pathogenic bacteria is what we have after tooth

brushing, scaling or lets say after applying excellent oral hygiene

measures on the tooth surface, we call this first layer acquired pellicle.

Right after the acquired pellicle, there will be a single layer of bacteria,

and this process takes around 24 hours; this allows us to remove it when

we apply good oral hygiene measures, so we can prevent the

accumulation of the pathogenic layer of the plaque that will be formed

later on.

Here we said that the tooth surface or the hard tissues in the oralcavity generally attaches firstly to a layer of non-pathogenic bacteria, and

this layer of non-pathogenic bacteria allows the attachment of the

pathogenic bacteria; because pathogenic bacteria are always free and

floating in the oral cavity.

Because they are floating, I can divide these types of bacteria

according to the attachment into two types (attached or not attached):

1. Floating bacteria in oral cavity; and they cannot increase their number

and they cannot secrete matrix or toxin basically until they are in the

mature plaque or biofilm generally.

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2. Attached bacteria;as what we have already said, the first bacteria to

colonize are the non-pathogenic and the periodontal pathogens are

unable to colonize the biofilm alone.

The first thing we need is the acquired pellicle non-pathogenic

bacteriapathogenic bacteria to be attached to all that system.

So, this system or sequence of attachment allows me and the

researchers to work against the plaque formation chemically such as

using fluoroxidine or any other mouthwashes which is direct towards the

attachment of one of these layers.

Colonization of acquired pellicle happens first, and then the gram-

positive bacteria colonizes on it and attaches to it; which is mostly non-

pathogenic, and later on the pathogenic bacteria get attached; such as

streptococcus Sanguins the streptococcus bacteria causes other type of

diseases; for example thecaries are caused by streptococcus Mutans, sothis indicates that all this species is attached directly to the tooth surface

at the pellicle layer, and because of this these types of bacteria are

responsible for caries.

Also we have the streptococcus Sanguins or the Actinomycoses

attached to the tongue area on the bony-rich proteins of saliva coated

the tooth surface or what we call the pellicle.

Early colonization as we said is the pellicle which consists of gram-

positive; here were talking about the streptococcal species which takes

place specifically in the early colonization; and there are many of the

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streptococcal species that have the ability to attach to the tooth pellicle,

and also there're other non-streptococcus species which have the ability

to attach to tooth pellicle, also other early colonizers co-aggregate with

streptococcal species and held itself to it during colonization in the earlyphase.

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The importance of the early colonization is that the free-floating

periodontal pathogens can't cause the disease; so I have always to keep

the teeth surfaces free of these pathogenic bacteria, but how to do that?

Every time the biofilm is disturbed, the process must start all over again

with the early colonizers, so every time I apply the oral hygiene

measures, I prevent the pathogenic bacteria from attaching to the biofilm

layer presents there on the tooth surface.

Now talking about the intermediate and late colonizers; like the early

colonizers the intermediate and late bacterial colonizers must join the

biofilm in the proper sequence.

Also non-periodontal pathogens are late colonizers to the biofilm, the

intermediate propagation then induce proliferation or increase in the

number of the early colonizers; such as Streptococcus, also there will be

an increase in the number of cells to provide the environment for the

anaerobic and gram-negative bacteria that will come during the late

stage.

During the Late stage, the gram-negative organisms will come such as

Prevotella intermedia which will attach to the 1st layer, and also the

gram-negative bacteria of different late stages; such as Porphyromonas

Gingivalis.

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Here we have seen this figure more than once; talking about the

bacterial aggregation, a scientist came and divided the bacteria into

complexes, he divided them into:

1) Red complex: The most pathogenic bacteria in the oral cavity in thesub-gingival group or the sub-gingival biofilm; such as P.gingivalis,

T.forsythia and T.denticola.

2) Green complex: The least pathogenic compared to other bacteria

generally regarding the periodontal diseases.

** (these points are very important regarding the figure as Dr.Malik

said).

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Now, I want to talk about the biochemical mediators, as we said last

week there're innate and adaptive immune response, also we said that

there're stages in periodontitis; initial, early, established and advanced,

these stages start the processes to get gingivitis into periodontitis step bystep.

First there will be an invasion of the bacteria into the periodontal

tissues which will stimulate Langerhans cell, phagocytes or any other cell

that can present the antigen to the cells to start the immune response.

The immune response in the body is generally carried out throughthe biochemical mediators.

The biochemical mediators are active compounds which are secreted

from the immune cells that activate the body inflammatory response,

and they can be divided generally into cytokines, prostaglandins, and also

(MMPs) MatrixMetalloProteinases.

Note that biochemical mediators released by immune cells to activate,guide and remain the inflammatory response.

Inflammatory mediators that are important in periodontal diseases are

cytokines, prostaglandins and MMPs.

Cytokines are considered to be cell-sickled protein molecules, last

time we said there are cytokines and chemokines.

We have chemotactic effect and cytokines, chemotactic effect comefrom the pathogens generally.

Cytokines (cell signaling protein molecules) are considered to be

powerful mediators produced by the immune cells generally, influence

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the behavior of other cells and give signals to the immune system to send

more phagocytes to the site of infection, as we said it increases the

epithelial permeability of the sub-epithelial plexus.

Cytokines are produced by many different cells; especially the PMN

(PolyMorphoNuclear) cells, Macrophages, B-Lymphocytes, epithelial cells,

gingival fibroblasts and osteoblasts, and it produce the response to the

tissue injury.

Cytokines are important in the periodontal diseases and it includes IL-

1, IL-6 and IL-8, TNF-

(tumor necrosis factor-alpha), and their function is

to recruit cells such as PMN cells and macrophages to the infection sites.

So cytokines are produced by PMN cells and macrophages and they

also recruit this type of cells to the site of infection, and they increase the

vascular permeability that increases the movement of immune cells into

the tissues, and last time weve talked about the macrophages and how it

penetrate the epithelial cells towards the connective tissue where thereis injury.

So, first of all is cytokines , then there will be a penetration between 2

epithelial cells.

Later on it will initiate tissue destruction and bone loss in the site of

infection such as periodontal diseases generally.

About prostaglandins, it is also coated inflammatory mediators, we

have several groups; D, E, F, G, H and I; but the one I care about usually is

E, because most cells can produce prostaglandins, why? What are

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prostaglandins? Prostaglandins are arachidonic acid build the cell

membrane itself.

Macrophages and fibroblast produce prostaglandins, and thisprostaglandins cause bone destruction, stimulate the osteoclast which

will make bone resorption, it functions in increasing the permeability and

dilatation of blood vessel to promote and increase the movement of

immune cells and compliment to the infection site; (compliments are

proteins approximately 30 in number that disturb the cell membrane of

the bacteria), it triggers osteoclast bone consuming cells which cause

resorption of the bone, it promotes the overproduction of destructiveMMP's, enzymes and prostaglandins specially the E series to initiate most

of the alveolar bone destruction in periodontitis.

Regarding the prostaglandins they care a lot about the non steroidal anti

inflammatory drugs (NSAIDs); because generally they work against the

prostaglandins, which may reduce the inflammation in the area, andreduce the destruction of the bone. But they still do researches regarding

this information.

About MatrixMetalloProteinases, it is a family of at least 12 different

enzymes still under researches and they are produced by variant cells on

the body; like PMN cells, macrophages, fibroblast, junctional epithelial

cells, these enzymes acts together to breakdown the connective tissuematrix, which contains collagen, keratin and elastin.

And when there is a destruction of the connective tissue this will cause

edema, and there will be periodontal pocket, and recession, and these

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MMPs are present in the body in the healthy status before the diseased

status, and they are present all over -not sure- the periodonta

connective tissue matrix.

In the chronic bacterial infection they are released and there is an

overproduction of them, which will result in a breakdown of the

connective tissue of periodontium, and the high MMP level in the area

results in extensive collagen destruction of periodontal tissues, gingival

rescission and pocket formation.

Getting back to our point host response in periodontal diseases,

weve already discussed the stages of periodontitis and gingivitis; which

are initial, early, established and advanced stages from the view of

macrophages, neutrophils and the effect of them.

Now we will discuss them in another way, in the initial stage we have the

formation of the biofilm, look at this picture; here we can see the

enamel, this is epithelium, this is cementum, junctional epithelium,

sulcular epithelium, oral epithelium, this is the biofilm accumulated here,

and there are polymorphinuclear cells released in the sulcus and also

presents in some other areas.

The bacteria colonizes the tooth near the gingival margin, within 24

hours, and it will be ready in 2-4 days ( 2 - 4 ),bacteria initiates the host response, and there will be a dilation of the

blood vessels, PMN cells pass the blood stream into the gingival

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connective tissue, PMN cells release cytokines and destroy the gingival

connective tissue allowing PMN cells to move quickly towards the tissues,

also there is releasing of it in the sulcus, PMN cells migrate into the sulcus

and phagocytes the bacteria, and this is the initial stage.

Now we will discuss the early stage gingivitis, here we are still talking

about the subclinical gingivitis, in its early stage; there will be releasing of

some cytokines, interleukin 1-BETA and also interleukin 6, Tumor

Necrosis factor-alpha, prostaglandin E2. What will all of this do? It will

stimulate the immune system generally.

And the bacteria penetrate connective tissue cause releasing of

interleukins 8 from the epithelial cells, and the PMN cells release cytokine

causing more localized destruction of the connective tissue, and the

macrophages release cytokines and prostaglandins E2 and MMPs in the

area, and this will cause inflammation, redness .in the area, and there

will be formation of rete-ridges in this area.

There is penetration of bacteria into the epithelium or the soft tissue

or the connective tissue beneath the epithelial layer, here it is the

established stage (gingivitis) and then it will proceed to plaque biofilm

extend subgingivally forming a pocket, and the biofilm goes more

apically, releasing of cytokines and chemical mediators, interleukins 8,

MMPs, TNF, and started to have plasma cells, lymphocytes, which we

have in early and established stages, we have already talked about theage.

Now the host cells produce more toxic chemicals or immune

mediators and cytokines, there is an increase of the proportion of gram

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negative anaerobes; because the environment of apical region becomes

completely anaerobic, that gives the best and excellent conditions to

enhance the anaerobic bacteria growth and function.

In advance stages (periodontitis), here there is start of destruction of thebone because of macrophages and prostaglandins E2, cytokines wil

destroy the connective tissue and periodontal ligament fibers, cytokines,

prostaglandin E2 and MMPs destroy the connective tissue and bone, and

prostaglandin E2 initiate the bone destruction.

(Name of 3 bacteria the red complex)this complex is considered tobe responsible of the periodontitis generally, which is considered to be

the most pathogenic bacteria in periodontitis, and this is what we have

in the advanced stage.

The mechanism of alveolar bone destruction, when there is a

stimulation of macrophages, it releases interleukin 1-beta, TNF-alpha to

the fibroblast which will release prostaglandin E2 which will stimulate theosteoclasts, and cause stimulation of breakdown of collagen, elastin and

extra cellular matrix generally and that is done by MMPs, and it stimulate

the fibroblast to secrete MMPs to cause destruction of connective tissue,

prostaglandins E2 stimulate osteoclasts to resorb the alveolar bone.

Finally, the take home message is that, in order for the periodontium to

remain healthy, the bacterial infection must be controlled so it does nottrigger chronic exaggerated post immune response. How to control that?

By excellent oral hygiene and mechanical brushing mechanical ora

hygiene measures.

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Note that the bodys immune response to the bacteria causes most of the

tissue destruction in the periodontal tissues.

Edited By : Majd M. Hidmi