Dental - Role of Infection -

8/9/2019 Dental - Role of Infection -

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TARRSON FAMILY ENDOWED CHAIR IN PERIODONTICS


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UCLA SCHOOL OF DENTISTRY


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E. Barrie Kenney B.D.Sc., D.D.S., M.S., F.R.A.C.D.S.

Tarrson Family Endowed Chair in Periodontics.

Professor and Chairman Division of Associated Clinical Specialties UCLA

School of DentistryPathogenesis of Periodontal Disease


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G ingivitis is widespread with 54 percent of the population13 years or older having bleeding on probing.

The most common type of gingivitis is caused by Dental Plaque productssuch as Exotoxins and Endotoxins initiating inflammation of gingival

tissues.GINGIVI TIS


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Subgingival bacterial biofilm (plaque) initiates gingivalinflammation ( G ingivitis).

This in some patients may extend apically to become periodontitis

ROLE OFPLAQUE


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The first bacteria that form a biofilm on cleaned tooth surfaces areStreptococci species ( G ram positive cocci)


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W ithin two days G ram negative bacteria also appear in the subgingivalbiofilm and gingival inflammation begins


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Exotoxins are secreted by many G ram positive and G ramnegative bacteria.

Endotoxins are only seen with G ram negative bacteria


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Further examples of Exotoxins


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Some Exotoxins directly inhibit the protective effects of inflammatorycells and healing


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Bacterial Leukotoxin from some strains of ActinobaccilusActinomycetemcomitans (A.a) cause necrosis and apoptosis of

leukocytes


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Endotoxin is an important cause of gingival tissue damage by G ramnegative bacteria in the subgingival biofilm.


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Endotoxins directly destroy gingival cells. They enhance tissuedestruction due to stimulation of the immune response associated with

gingival inflammation


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ST IMULAT ION OFIMMUN E

RESPO N SE


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Established G ingivitis present in lower incisor region.

Signs of acute inflammation, redness, and swelling


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Subgingival bacteria initiate G ingivitis by their Exotoxins and Endotoxinschanging the epithelial cells lining the gingival crevice


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Scanning Electron Microscopic view of a healthy gingival sulcus.

The epithelial cells form an intact surface which acts as a barrier tosubgingival bacteria and their toxins.


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Bacterial Exotoxins such as Hyaluronidase destroy the

intercellular connections between epithelial cells liningthe gingival sulcus.

This is one of the first stages of initiation of gingivitis

The barrier effect of epithelial cells is reduced by a widening

of intercellular spaces.This allows penetration of other bacterial productsthrough the epithelium to the underlying gingivalconnective tissue


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Transmission Election Micrograph of epithelial cells from a healthygingival sulcus with narrow intercellular spaces.


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Transmission Election Micrograph of an epithelial cell from earlyG ingivitis.

The intercellular spaces are widened and the epithelial barrier hasbecome more porous.


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Scanning Electron Micrograph of epithelial f rom Early G ingivitis.

Cells of gingival sulcus showing normal areas of quiescence, other areasof widened intercellular spaces with leukocytes passing out from the

connective tissue.A area of normal quiescent epithelium.B bacteria.Cwidened intercellular spaces.

A

B

C

C

B


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High powered view with obvious widened intercellular spaces and holesthrough the epithelium.


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Other bacterial Exotoxins such as collagenase cannow penetrate through the epithelial cell barrier of thegingival sulcus.

This result in destruction of the basement membrane andareas of loss of the epithelial cell layer with ulcer formation.


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E is area of normal intact epithelial cells, U is loss of epithelial cells andulceration.A area of ulceration.E normal epithelium.

Enlargements seen below show direct exposure of gingival connectivetissue collagen to subgingival bacteria at the base of the

ulcerated epithelium. C collagen fibers of connective tissue.A E

E

C C


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Transmission Election Micrograph of G ingivitis.

Bacteria have penetrated into the connective tissue.E epithelial cellcytoplasm BM basement membrane .C connective tissue.B bacteria.

E

B

C

BM

Bacteria first contact with immune system occurs in epithelium with Langerhamscells which process antigens.


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Epithelial ulceration provides a portal for subgingival

bacteria and their products to the gingival connectivetissue.

Most subgingival bacteria that penetrate into connective

tissue in gingivitis do not proliferate in the tissue.

Bacteria may now enter blood vessels and cause abacteremia.

This is because they are anaerobic and the tissues areaerobic.


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Bacterial products that contact gingival connectivetissue initiates an acute inflammatory response withvasodilatation, edema and polymorphonuclear leukocyte (P.M. N ) activation.

G ingivitis is seen clinically as acute inflammation withredness and edema of tissues and exudates of inflammatoryfluid from the gingival sulcus.


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Early G ingivitis.

There is bleeding from the gingival sulcus with probing, brushing or mastication.

This is a result of epithelial ulceration in the gingival sulcus and acuteinflammation of the connective tissue.


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Gingival bleeding on probing is seen as early as thesecond day of initiation of G ingivitis. Bleeding on probing is a sign of active tissue destruction.

It may persist through to the later stages of Periodontitis

If G ingivitis is treated, the epithelium can heal and bleedingcan disappear after seven to ten days.


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One of the first effects of bacterial contact withgingival tissue is activation of Mast cellsMast cells are inflammatory cells of the Basophil series of granular leukocytes


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Mast cells have Toll like receptors which initiate prodution of vasoactivesubstances such as Histamine which induce vascular permeability andvasodilatation.

This vasodilatation and increased permeability of capillaries is associatedwith edema and diapedesis of leukocytes from the blood vessels into the

connective tissue of the gingiva.

Mast cells produce other inflammatory mediators such as Slow- ReactingSubstance of Anaphylaxis, Leukotriene C4, Tumor N ecrosis factor alpha(TN F).and IL6. These activate the acute inflammatory response.


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Light Micrograph of connective tissue in G ingivitis vasodilatation, edema,and migration of Leukocytes.


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Vascular tree of normal gingival tissue.

Peripheral vessels allow rapid movement of blood from the arteriolesthrough the capillaries to the venulus.

G ingiva color in health is pale pink


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W ith vasodilatation in G ingivitis terminal circulation is more convolutedso gingiva appears red and often has a purplish color


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Vasodilatation results in more complex pathways of blood f low so thatcirculation is slowed through gingival t issues.

This results in redness as well as increased reduced Hemoglobin giving apurplish color to the gingiva.


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Polymorphonuclear leukocytes (P.M. N .s) are the characteristic dominantinflammatory cells of acute inflammation of the gingiva


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In G ingivitis PM N s and edema fluid appear in the connective tissue andpass through the damaged epithelial cells into the gingival sulcus andthen into the mouth. PM N S move to the IL8 chemoattractant seen in

junctional epithelium and are attached by ICAM 1- IN TERCELLULARADHES ION MOLECULE from Langerhams cells.

GI ngival fluid is an indicator of gingival inflammation and it carriesPM N Sand antibodies into the pocket

O ne to two percent of PMNS pass through junctional epithelium each day.


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Scanning Electron Micrograph of PM N (L) passing from connective tissue(CT) through epithelium (E).

LlL

C

L

E

T


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PM N s are able to migrate through tissue towardschemotaxic substances such as peptides frombacteria, saliva, Endotoxin, IL8 and activatedcomplement.

PM N s are able to engulf bacteria by a process of phagocytosis.

This chemotaxis brings PM N s out of blood vesselsand they accumulate in connective tissue andepithelium and eventually pass into the pocket to bemoved by gingival fluid into the mouth.

Engulfed bacteria are destroyed by oxidative production of toxic reduced oxygen metabolites such as superoxideanion. N on oxidative lysosomal enzymes such as defensinsand proteases found in lysosomal granules,also kill bacteria . In the increasing anaerobiosis of thepocket oxidative killing is impaired.


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PM N s lysosomal granules can destroy bacteria intracellularly.

They can be released and cause connective tissue and bacterialdestruction extracellularly.


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Light microscopic view of G ingivitis.

PM N s seen in connective tissue and migrating through epithelium intogingival sulcus.


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High power view of PM N s in gingival fluid of gingival crevice


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Scanning Electron Micrograph of PM N s passing through epithelium.

N ote bacteria attached to PM N s in process of being phagocytosed


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High power view of PM N and bacteria attached undergoing phagocytosis.B bacteria

B


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Light Microscopic view of PM N s from gingival fluid showing evidence of phagocytosis.

W hite spheres inside PM N s have been engulfed.


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PM Ns form a protective layer in regions where epithelium of the gingivalsulcus has been disrupted in G ingivitis


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Clinical example of established G ingivitis with emphasis on the acuteinflammatory reaction


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The Basophil series are seen in G ingivitis as Mast cells, N eutrophils asPM N s.

Eosinophils are not significant contributors to plaque induced G ingivitis


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Inflammatory cells of the Agranular series of Leukocytes are also seen ingingivitis


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Monocytes become Macrophages in inflamed gingival tissue.

They exhibit chemotaxis, phagocytosis, enzyme production and bacterialkilling similar to PM N s. They are activated by bacterial products likeLIPOPOLYSACCHAR IDE LPS.

They also produce cytokines such as IL1 and TUMOR N ECROS ISFACTOR T N F which have a wide inflammatory influence as well asstimulating osteoclast proliferation,differentiation and activation.PROSTA G LAN DIN E P G E another inflammatory and osteoclast activator is also secreted in response to IL1,T N F And LPS.


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Macrophages interact with Lymphocytes by assisting in Bacterial Antigenpresentation to Lymphocytes which then produce specific antibodies (Bcells)or cytokines (T cells). Macrophages then clean up the destroyedbacterial remnants by phagocytosis.


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As G ingivitis develops the initial acute inflammatory response continuesand a chronic inflammatory response is added.

Lymphocytes and capillary proliferation characterize this chronicinflammation.


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B cells are Lymphocytes derived from Bone Marrow and produceantibodies to bacterial antigens.

T cells are lymphocytes derived from the Thymus and initiate cellmediated immunity by producing lymphokines


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B cells interact with macrophages in gingival tissue and become plasmacells which produce antibodies.

There are also B cells series that carry the memory of a particular antigenand can quickly produce antibodies, this memory is dependant on

interactions with T cells.


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Plasma cells (B cells) produce immunoglobulins within gingival tissuewhich bind to and inactivate bacterial antigens including Exotoxins.

Antibody Antigen complexes also activate Complement


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Plasma cells produce a variety of immunoglobulins with each one beingspecific for a particular bacterial antigen and have memory to become

quickly activated.

Patients with periodontal disease have high serum levels of Ig G specificfor plaque bacteria.


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Activation of complement is another part of the immune response seen inG ingivitis


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Activation of complement produces molecules such asC2a C5b that are cytotoxic, increase vascular permeability and are chemotactic for PM N s andMacrophages. Activation of complement can occur directly due to antibody

antigen complexes.

Bacterial inactivation by antibodies is also enhancedby C3b an opsonin from complement which coatsbacteria and enhances phagocytosis.

Indirectly complement is activated by Endotoxin,polysaccharides and other bacterial products.

Mast cells are activated by C3a and C5a.


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T Lymphocytes are very common in gingivitis. They interact with bacterialAntigens processed by Macrophages.

T cells then undergo proliferation and differentiation into the differenttypes of T cells.


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In Early gingivitis, T cells are the dominant Lymphocytes, but eventuallyB cells dominate.T cells have dense round nuclei with very little

cytoplasm.B cells (plasma cells) are larger than T lymphocytes and havean eccentric lighter staining nucleus with an almost equal sized

cytoplasm


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Electron Micrograph of plasma cell (B cell) with eccentric nucleus andprominent endoplasmic reticulum for protein antibody production


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Activated T Lymphocytes produce cytokines. These are bioactivemolecules that enhance inflammation and also can cause damage to

gingival and periodontal cells.

Two important cytokines are Interleukin-1 ( IL-1) and Tumor N ecrosis

Factor (TN

F).


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W ith chronic inflammation gingival blood vessels and inflammatory cellsproliferate into the areas of destroyed connective tissue.


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Established G ingivitis around lower incisors.

Acute inflammatory changes are superimposed on chronic inflammationcharges.


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The combined acute and chronic inflammation seen in G ingivitis andperiodontitis is destructive of bacteria.

It also causes damage to the connective tissue of gingiva and theperiodontal tissues


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Another mechanism of breakdown of connective tissue in Periodontaldisease involves Matrix Metalloproteinases (M.M.P).

These are produced by PM N s, Macrophages ,Fibroblasts and Epithelialcells. MMP8comes from PM N S MMP1 comes from resident cells.

G ingival Metalloproteins can be reduced by systemic administrationof low dose Doxycycline--20mg.every 12 hours .This is the basis for the use of Periostat to treat Periodontal disease,


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Examples of MMP


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The bacterial induced inflammation of G ingivitis canspread apically and involves the destruction of

connective tissue of the Periodontium including bone.

The damaged epithelium of the gingival sulcus proliferatesapically.

This is PeriodontitisAs loss of attachment of connective tissue fibers tocementum occurs the pocket epithelium migrates to line theroot surface.


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Light microscope view of lower incisor with Periodontitis.

G ingival Inflammation has spread apically and bone destruction hasoccurred.

There is apical migration of epithelium causing attachment loss andincrease of pocket depth.


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High power view with epithelium E migrated apical to bone crest B, andinflammation causing bone loss

B

E


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OSTEOBLAST -OSTEOCLASTIN TERACT IO N

Bone Loss Due toInhibition of Osteoblasts,

Stimulation of Osteoclasts.


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Macrophages produce prostaglandin E (P G E) and ( IL-1) and lymphocytesproduce Interleukin-1 ( IL-1) which activate osteoclasts by interacting with

osteoblasts.


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The mechanisms causing bone loss in Periodontitisare not well documented.

Activated osteoclasts destroy the inorganic bonecomponents by release of acid hydrolases.

Bone destruction is a result of osteoblasts or inflammatory cells signaling osteoclasts activation viacytokines such as IL-1 and T N F and Prostaglandins(P G E).

MMPs from osteoblasts destroy the organic collagenouscomponents.


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Possible mechanisms of bone loss in Periodontitisinclude:

Other mechanisms of bone loss:

Suppression of osteoblasts by inflammation withlowered bone production

Up regulation of cytokine and PG

E secretion byinflammatory cells andosteoblasts

Loss of collagen attachment with reduction of tensileforces on bone

Direct bacterial toxicity on osteoblasts and collagen

Up regulation of MMPs from inflammatory and connectivetissue cells.


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Clinical example of Periodontists with emphasis on chronic inflammatorychanges.

There were 7mm pockets after initial therapy.


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Same case being treated with flap surgery. N ote bone loss.


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Radiograph of advance Periodontitis with evidence of interproximal boneloss


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Same case with flap surgery. Extensive bone loss due to plaque inducedPeriodontitis.


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For further information use the text Carranza s ClinicalPeriodontology

9 th EditionW B Saunders 10. 2002

Chapter 7Immunity and Inflammation

Chapter 8Microbial Interactions with the host in PeriodontalDiseases

Chapter 9Molecular Biology of the host-microbe interaction inPeriodontal Diseases.

Chapter 16G ingival Inflammation

Chapter 17Clinical features of G ingivitis

Chapter 22The Periodontal Pocket

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