perio pathogenesis

1Massimo Costalonga D.M.D., Ph.D.Department of Developmental

and Surgical Sciences

Massimo Costalonga D.M.D., Ph.D.Department of Developmental

and Surgical Sciences

Pathogenesis of PeriodontitisCurrent Thinking

Pathogenesis of PeriodontitisCurrent Thinking

Healthy gingivaHealthy gingiva

Normal gingival sulcusis 2 to 3

millimeters deep

Tooth chrown

Gingiva

Root

Periodontal ligament

Alveolar bone

Advanced periodontitis

Advanced periodontitis

Bleeding Infection of the gingiva Calculus Gingival recession Loss of bone Tooth mobility Halitosis (bad breath)

Bleeding Infection of the gingiva Calculus Gingival recession Loss of bone Tooth mobility Halitosis (bad breath)

Disease that is not reversible but ONLY

controllable

Disease that is not reversible but ONLY

controllable

BackgroundBackgroundPeriodontal diseases: Infectious diseases that results in

chronic inflammation of the soft tissue surrounding the gingival pockets.

Destroys the bone and soft tissue connection between the gingiva and the root of the tooth (Kornman 1987, Suzuki 1988)

Periodontal diseases: Infectious diseases that results in

chronic inflammation of the soft tissue surrounding the gingival pockets.

Destroys the bone and soft tissue connection between the gingiva and the root of the tooth (Kornman 1987, Suzuki 1988)

Massimo Costalonga DMD, PhD DENT5301

2Chronic periodontitis is associated with a variety of

bacterial species

Chronic periodontitis is associated with a variety of

bacterial species

Bacteriological and immunological studies implicated a number of subgingival organisms associated with chronic adult periodontitis. (Red, Orange, Green, Purple and Yellow complexes) (Socransky et al. 1997)

In advanced adult periodontitis, gram-negative bacteria may compose 75% of the bacteria (Robertson 1985)

Bacteriological and immunological studies implicated a number of subgingival organisms associated with chronic adult periodontitis. (Red, Orange, Green, Purple and Yellow complexes) (Socransky et al. 1997)

In advanced adult periodontitis, gram-negative bacteria may compose 75% of the bacteria (Robertson 1985)

Modified from Socransky S. et al. 1997

Cultivable microorganisms

Cultivable microorganisms

Do you think we can culture all bacteria in periodontal

pocket ?

Do you think we can culture all bacteria in periodontal

pocket ?

Talk with the person next to you about this NOW


Most microorganisms are uncultivable

Most microorganisms are uncultivable

Kumar PS et al. 2005


316S RNA sequences separated health and disease

16S RNA sequences separated health and disease

Kumar PS et al. 2005

Bacterial challenge

Innate immunity

first

Bacterial biofilm

EpitheliumPMNs

ChemokinesCytokines

Korman KS et al. Periodontology 2000 Vol. 14 1997, 33-53

Initial Gingivitis

Acute inflammation

Initial Gingivitis

Acute inflammation

Korman KS et al. Periodontology 2000 Vol. 14 1997, 33-53

How are these microbes sensed or detected by our

body?

How are these microbes sensed or detected by our

body?




4Neutropenia = Low PMN countsNeutropenia = Low PMN counts

Downloaded from: Carranzas Clinical Periodontology (on 4 August 2006 06:34 PM)

INNATE cellular response

Monocytes/macrophages Neutrophils Natural Killer (NK)

Monocytes/macrophages Neutrophils Natural Killer (NK)

Recognition ofPathogen Associated

Molecular Patterns (PAMPs) by Pattern

Recognition Receptors (PRRs)

PRRs

IL-8 Lipid mediators of inflammationLipid mediators of inflammation

Increase vascular permeabilityIncrease smooth muscle contraction

Increase vascular permeabilityIncrease smooth muscle contraction

Increase smooth muscle contractionIncrease smooth muscle contraction


5Linoleic acid in plasma membraneLinoleic acid in plasma membranePhospholipase C Inhibited by

STEROIDS

Inhibited by NSAID

Lipid mediators ofLipid mediators of

Prostaglandins Thromboxans Leukotrienes

Prostaglandins Thromboxans Leukotrienes

Lipoxins Resolvins Protectins

Lipoxins Resolvins Protectins

Inflammation Resolution

T-cell and B-cell mediated immunity in periodontal tissues

MICROBIAL ADHERENCE

PENETRATION AND

INFECTION

INNATE IMMUNITY

DC and Macrophages

LYMPHOCYTE ACTIVATION

ANTIBODY Activated

MACROPHAGES

Toll-like receptors(TLRs)

Toll-like receptors(TLRs)


6Exogenous pathway

1. Extracellular microorganisms are phagocytosed

2. Destroyed and reduced in peptides

3. Presented to T cells via MHC class II molecules

1. Extracellular microorganisms are phagocytosed

2. Destroyed and reduced in peptides

3. Presented to T cells via MHC class II molecules

T helper cells (CD4+)T helper cells (CD4+)In the

lymph nodesT cells

recognize such

microbial peptides via

the T cell receptorand

In the lymph nodes

T cellsrecognize

such microbial

peptides via the T cell receptorand

T helper 1 (Th1)T helper 1 (Th1)

Interferon-(IFN)

Cell-mediatedimmunity

Interferon-(IFN)

Cell-mediatedimmunity

Interleukin-4(IL-4)

Antibody immunity

Interleukin-4(IL-4)

Antibody immunity

T helper 2 (Th2)T helper 2 (Th2)


7 In individuals resistant to periodontitis, neutrophils and cell-mediated immunity (Th1) limit attachment loss (Page et al. 1997).

Lack of cell-mediated immunity (IL-12, IFN and TNF-) promotes susceptibility to periodontitis (Chapple C. 1998).

Antigen Presenting Cells from patients susceptible to periodontitis may have a bias towards a Th2 response and thereby promoting an ineffective humoral immunity in periodontitis (Fokkema S. 2002).

In individuals resistant to periodontitis, neutrophils and cell-mediated immunity (Th1) limit attachment loss (Page et al. 1997).

Lack of cell-mediated immunity (IL-12, IFN and TNF-) promotes susceptibility to periodontitis (Chapple C. 1998).

Antigen Presenting Cells from patients susceptible to periodontitis may have a bias towards a Th2 response and thereby promoting an ineffective humoral immunity in periodontitis (Fokkema S. 2002).

Immune response and periodontitis in humansImmune response and

periodontitis in humans

T helper 1 cytokine IFNprotects from disease

T helper 2 cytokine IL-4does not protect from disease

T helper 1 cytokine IFNprotects from disease

T helper 2 cytokine IL-4does not protect from disease

Th1 vs. Th2in periodontal disease

Th1 vs. Th2in periodontal disease

WHY ???WHY ???

Cells in Periodontal TissuesCells in Periodontal Tissues

Gingivitis lesion: mainly T helper 1 lymphocytes (Th1)

Periodontitis lesion: mainly activated B cells and plasmacells

Activation of B cells is dependent on T helper 2 lymphocytes (Th2)

Gingivitis lesion: mainly T helper 1 lymphocytes (Th1)

Periodontitis lesion: mainly activated B cells and plasmacells

Activation of B cells is dependent on T helper 2 lymphocytes (Th2)


8 Cytokine production most important IL-1 but also TNF-, IL-6, IL-8, IL-12, IL-15 and chemokines MCP-1 and RANTES

Cytokine-induced alteration of the connective tissue metabolism

Imbalance between collagenases and matrix metalloproteinases (MMPs) activity and collagen synthesis

IL-1 and IL-6 induce fibroblast and osteoclast activation

Cytokine production most important IL-1 but also TNF-, IL-6, IL-8, IL-12, IL-15 and chemokines MCP-1 and RANTES

Cytokine-induced alteration of the connective tissue metabolism

Imbalance between collagenases and matrix metalloproteinases (MMPs) activity and collagen synthesis

IL-1 and IL-6 induce fibroblast and osteoclast activation

Destruction phaseDestruction phase

Osteoclast progenitors express the receptor activator of NF-B (RANK)

Activated T cells express the receptor activator of NF-B Ligand (RANKL)

RANK / RANKL interaction + M-CSF generates Tartarate-Resistant Acid Phosphatase positive (TRAP+) osteoclasts => BONE RESORPTION

Osteoclast progenitors express the receptor activator of NF-B (RANK)

Activated T cells express the receptor activator of NF-B Ligand (RANKL)

RANK / RANKL interaction + M-CSF generates Tartarate-Resistant Acid Phosphatase positive (TRAP+) osteoclasts => BONE RESORPTION

Induction of bone lossInduction of bone loss

RANKRANK

Osteoclast Precursor


T cell

T helper 1T helper 1

mRANKLmRANKL sRANKLsRANKL

CD4CD4B220B220 B cell

IgG2aIgG2a

Tissue Macrophage

IFNIFN

Bone

Working ModelWorking Model



RANKRANK

T cell




IgG1, IgA

UNPROTECTIVE

IgG1, IgA

UNPROTECTIVE

IL-4 and IL-10

IL-4 and IL-10

TRAP+Osteoclast

TRAP+Osteoclast

Bone Destruction

+ M-CSF+ M-CSF

Bone


9Induced Protection and Therapeutic Future

Induced Protection and Therapeutic Future

Osteoprotegrin (OPG) is a decoy receptor that binds membrane bound and soluble RANKL on activated T and B cells

Potassium channel blocker (Kaliotoxin) reduce the expression of RANKL on T cells

Osteoprotegrin (OPG) is a decoy receptor that binds membrane bound and soluble RANKL on activated T and B cells

Potassium channel blocker (Kaliotoxin) reduce the expression of RANKL on T cells



RANKRANK


T cell



TRAP+Osteoclast

TRAP+Osteoclast

Bone Destruction

+ M-CSF+ M-CSF

Osteoprotegrin (OPG)

Potassium channel blocker (kaliotoxin)

ConclusionConclusion Th1 type response IFN-mediated protects

from disease progression.

Th2 type response IL-4 and IL10-mediated are inefficient at controlling microbial biofilm.

Interference with RANK - RANKL interaction of affects the degree of bone loss

Cytokines and lipid mediators may mediate systemic effects that increase the risk of preterm birth and/or low birth weight

Th1 type response IFN-mediated protects from disease progression.

Th2 type response IL-4 and IL10-mediated are inefficient at controlling microbial biofilm.

Interference with RANK - RANKL interaction of affects the degree of bone loss

Cytokines and lipid mediators may mediate systemic effects that increase the risk of preterm birth and/or low birth weight


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