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SUMMARY OF EVENTS IN PATHOGENESIS OF PERIODONTAL DISEASE.

PRESENTED BY: POOJA BHASALE

INTRODUCTION
Periodontal disease is a common, complex inflammatory disease characterized by the destruction of tooth supporting soft and hard tissues of the periodontium

Although the inflammation is initiated by the bacteria, the tissue breakdown events that lead to the clinical signs of the disease results from the host imflammatory response.
Pathogenesis is defined as the origination and development of the disease.(Merriam Webster Collegiate
Dictionary)

Kornman (JOP August 2008)

A key organizing principle of systems biology is the use of multiple levels to provide a framework for defining the interactions between the cellular and molecular processes occurring at the lowest levels to the clinical presentation of disease at the uppermost level

Kornman (JOP August 2008)

BIOLOGIC SYSTEM MODEL REPRESENTING PERIODONTITIS

Offenbacher JOP 2008

Sites with clinically healthy gingiva appear to deal with continuous 7 microbial challenges without progressing to clinical gingivitis probably because of several defensive factors that include: The intact barrier provided by the junctional epithelium The regular shedding of epithelial cells into the oral cavity The positive flow of fluid to the gingival crevice which may wash away unattached microorganisms and noxious products The presence in GCF of antibodies to microbial products The phagocytic function of neutrophils and macrophages The detrimental effect of complement on the microbiota.
Clinical Periodontology & Implant Dentistry 5th edition Jan Lindhe

 The classical phases of acute and chronic inflammation are not easily applied in periodontal disease, probably because in clinically healthy gingiva a small lesion similar to an acute inflammatory reaction is already present. Subsequently developing chronic inflammatory changes become superimposed so that both acute and chronic elements coexist in most gingival lesions.

Clinical Periodontology & Implant Dentistry 5th edition Jan Lindhe

PRISTINE GINGIVA

NORMAL HEALTHY GINGIVA

INITIAL LESION (SUBCLINICAL GINGIVITIS)

Develops within 2-4 days of plaque accumulation Vascular dilation and vasculitis subsequent to the junctional epithelium Infiltration of polymorphonuclear neutrophils (PMNs) into the junction and sulcular epithleium Predominant immune cells are PMNs. Perivascular loss of collagen Alteration of the coronal part of the junctional epithelium Clinical Finding: increase in gingival fluid flow
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EARLY LESION
Vascular proliferation Rete peg formation and atrophic areas in the SE and JE. Predominant immune cells are lymphocytes (75% of the infiltrate) Increased collagen loss, 70% of collagen destroyed around the cellular infiltrate. A niche forms between the epithelium and the enamel surface and a subgingival biofilm may now form. Clinical Findings: erythema and bleeding on probing

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ESTABLISED LESION
Vascular proliferation and blood stasis More advanced area of rete peg formation and atrophic areas in the SE and JE Predominant immune cells are plasma cells Formation of small gingival pocket lined with pocket epithelium with large no. of neutrophils Continued collagen loss Elevated contents of MMPS and lysosomal contents from neutrophils Clinical Findings: changes In gingival colour, size, texture.

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 Two mechanisms are considered to be associated 14 with collagen loss: 1) Collagenases and other enzymes secreted by various cells in healthy and inflamed tissue such as fibroblasts, polymorphonuclear leukocytes, and macrophages become extracellular and destroy collagen;
2) Fibroblasts phagocytize collagen fibers by extending cytoplasmic processes to the ligament-cementum interface and degrade the inserted collagen fibrils and the fibrils of the cementum matrix

Two types of established lesion appear to exist: One remains stable and does not progress for months or years (Lindhe et al. 1975; Page et al. 1975), while The second becomes more active an converts more rapidly to a progressive and destructive advanced lesion.

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ADVANCED LESION
Marks the transition from gingivitis to periodontitis

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Predominance of neutrophlis in the pocket epithelium and pocket

Dense inflammatory infiltrate in the connective tissue Apical migration of J.E. to preserve intact epithelial barrier. Large areas of collagen depleted connective tissue Osteoclastic resorption of alveolar bone.
Carranzas Clinical Periodontology
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 Two critical factors which decide whether bone loss occurs are:
1) Concentration of inflammatory mediators 2)Inflammatory mediators must penetrate within a critical distance of the alveolar bone.

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Bone resorbs so that there is always a width of noninfiltrated connective tissue of about 0.5 to 1 mm overlying the bone. Bone resorption ceases when there is at least 2.5mm distance between the site of bacteria and the bone.(Page & Schroder 1982)
Carranzas Clinical Periodontology 11th edition

Role of dental plaque biofilm in periodontal disease :

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Most significant ramification of biofilm formation bacteria continuously release cell surface components into the oral cavity and the gingival sulcus. Gram-negative bacteria - release vesicles containing lipopolysaccharide, lipid and protein, which are found in intact outer membranes and are believed to represent normal mechanism of membrane turnover.

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LIPOPOLYSACCHARIDE(LPS)

These are MAMPS that have essential role in the pathogens ability to invade the host defense and thus are not subjected to high mutational rate.

Carranzas Clinical Periodontology 11th edition

 Bacterial material that is released in the periodontium provides a major form of communication between dental plaque and the host. Lipopolysaccharide has been reported to pass through an intact epithelial cell barrier and concentrate around blood vessels in the lamina propria.

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Bacteria can have either direct or indirect effects on host cells.

Direct effects - when the bacteria or bacterial extract directly stimulates a cell to respond Indirect effects are defined as the effects that occur when bacteria activate one cell type and then the product from that cell acts on another cell or cell type.
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 Monocytes and macrophages respond to whole dental plaque

bacteria, surface associated material, lipopolysaccharide and other soluble and particulate fractions by secreting a variety of

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inflammatory cytokines such as tumor necrosis factor a,

prostaglandin E2, IL-lb and IL-6

Cells of non-myeloid origin have a more varied response.

Dental plaque bacteria can activate these cells to produce a variety of inflammatory mediators such as IL-1, IL-6, tumor necrosis factor a & prostaglandin E2 ).
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 Lipopolysaccharide obtained from Porphyromonas gingivalis failed to elicit IL-8 or intracellular adhesion molecule expression

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Epithelial cells lose their ability to secrete IL-8, rendering the host unable to locate the source of microbial colonization .

P. gingivalis or its LPS .. inhibit monocytes chemotaxis protein one, IL-8 and intracellular adhesion molecule expression in human endothelial cells, gingival fibroblast and gingival epithelial cells (Reife et al )

Periodontology 2000( vol 14,1997)

Early stage of P. Gingivalis associated periodontitis.

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Microbial composition associated with gingival health

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Bacterial load associated with gingival health is relatively low.. (102103) Microbiota is mostly gram-positive, streptococci and actinomyces, with

about 15% gram-negative rods

Older subjects, upto 45% gram-negative species including F. nucleatum, P.gingivalis, P.intermedia, Campylobacter rectus, Eikonella corrodens, Leptotrichia and Selenomonas species (Nair, Wilson 1996 & Newman 1978)

Periodontology 2000( vol 14,1997)

Microbial composition associated with gingivitis

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Gingivitis is associated with an increased microbial load (104106 organisms) and a corresponding increase the percentage of gram-negative organisms (15-50%)

Microbial composition associated with periodontitis

Increase in the total microbial load (105-108 microorganisms)

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Elevated P. gingivalis levels differentiated periodontitis from gingivitis

(Dahlen & Manji 1992)

BACTERIAL ENZYMES AND NOXIOUS PRODUCTS

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HOW DO CELLS RECOGNIZE LPS?

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TLRs are a type of pattern recognition receptor (PRR) and recognize molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs) The discovery of TLRs and the identifi cation of their ligand repertoire have prompted the bar code hypothesis of innate recognition of microbes. According to this concept, TLRs read a bar code on microbes which is then decoded intracellularly to tailor the appropriate type of innate response. It acts as a bridge between the innate immune response and adaptive immunity
Carranzas Clinical Periodontology 11th edition

TOLL LIKE RECEPTORS

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MAHANONDA & PICHYANGKUL (PERIODONTOLOGY 2000) VOL43. 2007

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Clinical Periodontology & Implant Dentistry 5th edition Jan Lindhe

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MAHANONDA & PICHYANGKUL (PERIODONTOLOGY 2000) VOL43. 2007

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TOLL LIKE RECEPTORS

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Gingival epithelial cells express Toll-like receptor 3 and Toll-like receptor 9 (Yamada etal 2005).The presence of these Toll-like receptors provides the ability for epithelial cells to respond to both viral and bacterial nucleic acids. Human gingival fibroblasts constitutively express mRNA of Toll-like receptor 2, Toll-like receptor 4, and Toll-like receptor 9 and other Toll-like receptor-related molecules, e.g. CD14 (a co-receptor for lipopolysaccharide) and Myeloid differentiation primary-response protein 88 P. gingivalis lipopolysaccharide may be responsible for the observed upregulation of Toll-like receptor 2, Toll like receptor 4, and CD14 in periodontitis.

MAHANONDA & PICHYANGKUL (PERIODONTOLOGY 2000) VOL43. 2007

 The Expession Profile of Lipopolysaccharide-Binding Protein, Membrane-Bound CD14, and Toll-Like Receptors 2 and 4 in Chronic Periodontitis
Lei Ren,* W. Keung Leung,* Richard P. Darveau, and Lijian Jin*

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Background: This study aimed to investigate the interrelationship of in vivo expression of lipopolysaccharide-binding protein (LBP) and membrane-bound CD14 (mCD14) in human gingival tissues as well as the coexpression of Toll-like receptors (TLR) 2 and 4 in association with periodontal conditions. Methods: Gingival biopsies were collected from 43 subjects with chronic periodontitis, including periodontal pocket tissues (PoTs) and clinically healthy gingival tissues (HT-Ps), and from 15 periodontally healthy subjects as controls (HT-Cs). The expression of LBP, CD14, TLR 2, and TLR 4 was detected by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) . Results: LBP and mCD14 peptides were simultaneously detected in 91% of PoTs, 85% of HTPs, and 100% of HT-Cs. LBP and mCD14 mRNAs were simultaneously detected in 55% of PoTs, 55% of HT-Ps, and 75% of HT-Cs. The expression of LBP was confined to the gingival epithelium, whereas mCD14 was observed around the epithelium-connective tissue interface. A positive correlation existed between LBP and mCD14 peptides in both detection expression (rs = 0.608; P <0.001) and expression levels (r = 0.304; P <0.05) of these two molecules. In PoTs, TLR 2 was detected in both pocket epithelia and macrophage-like cells in connective tissues, whereas TLR 4 was predominantly detected in connective tissues. In HT-Ps and HT-Cs, a weak expression of TLR 2 was found in gingival epithelia, and no TLR 4 expression was detected. In PoTs, mCD14 was codetected on CD68-labeled macrophages in the underlying connective tissues of pocket epithelium as well as on CD1a-labeled dendritic cells in the pocket epithelium and connective tissues interface. No similar expression profile was detected in HT-Ps and HT-Cs. Conclusions: This study suggests that the in vivo expression of LBP and mCD14 may be interrelated. Altered cellular expression profiles of mCD14 and TLR 2 and 4 in periodontal pocket tissues imply that these pattern recognition receptors may play a role in periodontal pathogenesis.
Journal of Periodontology (November 2005 )

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HOST RESPONSE TO MICROBIAL CHALLENGE IN PERIODONTITIS

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Gingival health is a dynamic state that may be viewed as one scene in a play. As certain signals are given, specific players respond in a practiced manner and take their places in the scene. If diseaseinitiating signals are given, the players take positions on the stage that allow them to participate in the disease scene.

Page etal Periodontology 2000( vol 14,1997

Scene 1. Acute bacterial challenge phase: the41 epithelial and vascular elements respond to the bacterial challenge
Intact epithelial barrier of the gingival sulcular and junctional epithelium

Salivary secretions .agglutinins and specific antibodies

The gingival crevicular fluid continuously flushes the sulci or pocket and deliver complement proteins and specific antibodies.

Periodontology 2000( vol 14,1997

 A large population of B cells and plasma cells that accumulate 42 in the wall of the sulcus or pocket produce antibodies

Very high level of turnover of both the epithelium and the components of the extracellular matrix, .. permits rapid replacement of cells and tissue components damaged by the microbial challenge.

Periodontology 2000( vol 14,1997

Scene 1. Acute bacterial challenge phase

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Epithelium in health is exposed to various bacterial products

Butyric and propionic Peptides of the N-formyl-methionyl-leucyl-phenylalanine (FMLP) type which are potent chemoattractants for leukocytes, Lipopolysaccharide of gram negative bacteria

Periodontology 2000( vol 14,1997

 Histamine from perivascular mast cells, release of which is activated by LPS.

Prostaglandins and interleukins such as IL-lb, and Matrix metalloproteinases( proinflammatory mediators) from resident tissue macrophages, fibroblasts or keratinocytes.

Lipopolysaccharide can also activate the complement cascade via the indirect pathway as well as induce the production of kinins, all of which can act on the blood vessels and their endothelial cells

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The epithelium provides both signaling and protective functions

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Mucosal epithelia, provide protection due to their barrier function and

rapid cell turnover leading to constant shedding of the mucosal surface

exposed to bacterial colonization

Play a crucial role in intraepithelial recruitment of phagocytes and specific lymphocyte subsets and thus in controlling bacterial penetration through the mucosal integuments Several investigations .. specific intraepithelial leucocytes within the junctional epithelium including CD la-positive antigen-presenting cells (most likely Langerhans or dendritic cells), specific lymphocyte subsets expressing the aIELb7 integrin (mucosal T cells), the cutaneous lymphocyte antigen and the gd T-cell receptor Periodontology 2000( vol 14,1997

The bacterial challenge induces changes in the 46 epithelium to facilitate both vascular permeability and the influx of neutrophils
Cells along the tooth surface near the sulcus bottom contain acid

phosphatase positive lysosomes and manifest evidence of phagocytosis

of neutrophil granules and bacteria ICAM & LFA 3even in healthy periodontal tissue. IL-8 (chemoattractant) junctional epithelium which directs neutrophils to the gingival sulcus area MMPs & prostaglandin H synthase, which is capable of producing prostaglandin E2

Page etal Periodontology 2000( vol 14,1997

 Epithelial cells produce a range of cytokines, including IL-1a, IL-1 b, 47 granulocytes macrophage colony stimulating factor, interferon b, tumor necrosis factor a, transforming growth factor b, IL-3, IL-6, IL-7, IL-8, IL10, IL-11, and IL-12. Mucosal epithelial cells exposed to bacterial products were recently shown to produce tumor necrosis factor a, IL-6 and IL-8.

Periodontology 2000( vol 14,1997

 Neural components may be a key aspect of the early tissue response to bacterial stimuli. The neuropeptides and mast cell activation initiated by the c-fibers extending from JE may be effector mechanisms involved in early vascular response and cell replication

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Periodontology 2000( vol 14,1997

Scene 1. Acute bacterial challenge phase: the epithelial and vascular elements respond to the bacterial challenge
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Scene 2. Acute inflammatory response phase: 50 the tissues respond to the early signals
In mild inflammation, intercellular spaces are widened further and filled with fluid, which can serve as a medium for diffusion and through which neutrophil migration occurs

An increased bacterial load in the gingival sulcus increases the cell turnover rate of the sulcular epithelium (Hara etal 1991)

Infiltrating cells occupy about 1-2% of the extracellular space .gradient

Periodontology 2000( vol 14,1997

 About 30,000/min, leukocytes migrate through the JE. These are mostly neutrophils but also include monocytes and

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lymphocytes, Langerhans' cells and other HLA-DR-positive antigenpresenting cells. In most tissues.ECAM 1 is not expressed until the cells are exposed to LPS or cytokines like IL-1b

Acute phase proteins such as a2-macroglobdin have been shown to increase very early in the gingivitisprocess , indicating an increased vascular leakage.

Scene 2. Acute inflammatory response phase: the tissues respond to the early signals 52

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Fate of Extravasated Leucocytes

Leucocyte population from gingival sulcus is different from the one in

perivascular inflammatory infiltrate and junctional epithelium

Densities of neutrophils, memory/activated lymphocytes, gd T cells and CD1a+ antigen presenting cells are selectively increased in JE as compared with underlying perivascular inflammatory infiltrate

Neutrophil migration into gingival sulcus

1) 2) New developments in immunobiology have described 2 mechanisms..

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The expression of leucocyte adhesion molecules, such as ICAM 1 in epithelial cells, and Discovery of a family of low molecular weight cytokines; chemokines and IL-8 (Beckel etal 1993) ICAM 1/b2 integrin interaction is very important for neutrophil migration

Antibodies against ICAM 1& against its counter-receptor

Neutrophil migration into gingival sulcus

at mucosal sites of infection IL-8 & ICAM 1 expression represents a key step in this process

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Mucosal keratinocytes play a crucial active role in neutrophil recruitment

Biological effects of IL-8 on neutrophils.dose dependent:

- lower conc stimulate cell migration - higher conc, lead to activation of neutrophil antibacterial mechanisms

58 The inflammatory infiltrate within the tissues

Specific chemokines within the inflammatory infiltrate, such as monocyte chemoattractant protein 1partly responsible for spatial demarcation of

the area of leucocyte infiltration

In clinically healthy conditions, its size remains constant over time of exposure to bacterial plaque

Mechanism that regulates life span of leucocytes is Programmed Cell Death or Apoptosis

Summary of Scene 2

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It involves a reactive defensive response to the bacterial products Activation of adhesion molecules to enhance neutrophil migration,

Flow and activation of serum proteins into the tissues,

Movement of neutrophils out of the vessels and into the sulcus, Epithelial cell proliferation and selective accumulation of mononuclear cells in the tissues

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Scene 3. Immune response phase

Macrophages few in healthy gingiva.increase in disease Soon after inflammationendothelial cell adhesion molecule and vascular cell adhesion molecule

T cells, B cells,cytokines

Subsequently, in the presence of antigen and various cytokines, these lymphoid cells begin to enlarge and replicate to form clones of CD4' and CD8+ T cells, and the B cells are driven to differentiate into clones of antibody producing plasma cells

 With bacterial challenge..macrophage is activated through antigen

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non-specific mechanisms..

Macrophages exposed to LPS produce.IFNg, TNFa, TGF b, IL-1a and b, IL-6, IL-10, IL-12, IL-15, MCP, MIP and RANTES (regulated on activation, normal T cell expressed and secreted), MMPs and PGE2

1)Recruit additional monocytes and lymphocytes into the area 2)Alter the environment to favor collagen degradation

Molecules that mediate the immunoinflammatory 62 response become prominent in the gingival tissues
IL-1. major mediator in periodontitis IL-lb activated macrophages & fibroblasts IL-1a . Keratinocytes induced by lipopolysaccharide and other bacterial components

IL-1 is autostimulatory
IL-1..production is suppressed by bacterial metabolites..butyric and propionic acid & by IL-1 receptor antagonist produced by macrophages

 IL-1 upregulates complement and Fc receptors on neutrophils and 63 monocytic cells, and adhesion molecules on fibroblasts and leukocytes. It enhances production of itself, matrix metalloproteinases and prostaglandins by macrophages, fibroblasts and neutrophils

IL-1 upregulates MHC expression by B and T cells to facilitate their

activation IL-1b increased collagenase production by both pdl and gingival fibroblasts

 IL-2, IL-3, IL-4 and IL-5 ..differentiation of B cells to antibodyproducing plasma cells

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IL-2 is produced by T cells and antigen-presenting cells; and, in the

presence of antigen, induces the secretion of IL-3 and IL-4

IL-4 regulates IgG1 and IgE and suppresses the activated macrophages and causes their apoptosis

65 IL-6 .. Produced by macrophages, fibroblasts, lymphocytes and

endothelial cells.

Production is induced by IL-1 & LPS and suppressed by estrogen and progesteron

Through IL-6 these hormones exert their effects on gingiva

IL-6 causes

fusion

of

monocytes

to

form

multinuclear cells

that resorb bone.

 IL-8 .member of the chemokine superfamily

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Produced by LPS-activated macrophages, synovial cells, endothelium and Junctional epithelial cells.

Neutrophils, high affinity receptors.& low affinity receptorsmetabolic burst and degranulate on arrival at the site of challenge.

 Monocyte chemoattractant protein-1 is a potent attractant to monocytes.

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Transforming growth factor b produced by activated T

cells.chemoattractant for monocytes & suppresses their action

Transforming growth factor a .produced by macrophages and serves as a mitogen for fibroblasts and for epithelial and endothelial cells

 IFN gproduced by CD8+ cytotoxic T cells, recruits and activates 68 macrophages & upregulates the MHC on virally infected cells and targets them for killing

Prostaglandins & leukotreines .. Macrophages chemoattractant Platelet activating factor.

Protacycline
Thromboxane ..

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Activated complements. Matrix metalloproteinase.Zn++ dependent enzymes. Produced by macrophages, fibroblasts and keratinocytes activated by LPS or cytokines

They can digest all components of extracellular matrix

Local antibody response to bacterial challenge 70

EOP & adult periodontitis patients.humoral immune response Production of IL-4 through antigen non-specific mechanisms is an important aspect of early immune response to various pathogens.

71 Initial source of IL-4 is unclear.mast cells and basophils associated

with small blood vessels have been shown to produce IL-4 upon activation

NK cells capable of producing IL-4 are found near gingival epithelium

Scene 3. Immune response phase: activation of mononuclear cells shapes the local and 72 systemic immune response

Summary of Scene 3.
Increase in tissue lymphocytes, plasma cells and macrophages

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Shift in metabolism of the local fibroblasts to favor a reduction in collagen synthesis

Activation of the local and systemic specific immune response

Production of antibody directed against highly immunogenic bacteria

Scene 4. Regulation & resolution phase: determinants of protective components in the 74 sulcus and collagen balance in the tissues
Two conditions in which the host response becomes more destructive

at the local level

1) A specific biomass that directly inhibits key components of host defense 2) Host response modifiers such as smoking, systemic disease and genetic variation.

Scene 4. Regulation & resolution phase

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Fibroblasts shift to a state that favors destruction of extracellular matrix

Increased collagenase production by fibroblasts Increased neutrophil type (MMP-8) and fibroblast type (MMP-1)

collagenases.periodontitis compared to healthy sites (Tonetti 1993,

Ingmar 1994)

Selective cytokine expression molds the immune response

IL-5 were not detected Yamazaki et al.reported increased IL-4 in periodontitis

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Fugihashi et al 1996 found IFNg, IL-6, IL-10 & IL-13 but IL-2, IL-4 &

Agreement by several investigators..local cytokine profiles in inflamed gingival tissues are only a subset of those produced in peripheral blood of the same patients.

Scene 4. Regulation & resolution phase

Initiation and Progression of Periodontitis

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Tissues are populated with cytokines and prostanoids favor collagen and bone loss Efficiency of neutrophil migration is reduced

Scene 4. Regulation and resolution phase: determinants of protective components in the sulcus and collagen balance in the tissues 78

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HOST DERIVED INFLAMMATORY MEDIATORS

CYTOKINES AND PROSTAGLANDINS IN PERIODONTAL DISEASE: Cytokines in tissue destruction :

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IL-1 and tumor necrosis factor a are key mediators of chronic inflammatory diseases - initiate tissue destruction and bone loss IL-1 - to stimulate fibroblasts to produce collagenase. Tumor necrosis factor - mediates tissue destruction by stimulating collagenase - degradation of type 1 collagen by fibroblasts leading to connective tissue destruction. Tumor necrosis factor molecules stimulate bone resorption by inducing the proliferation and differentiation of osteoclast progenitors and activating formed osteoclasts indirectly. IL-6 also appears to have a role in bone resorption. potent stimulator of osteoclast differentiation and bone resorption and inhibitor of bone formation.
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Destructive cytokines in periodontal disease :

IL-1 levels have been shown to be elevated in the gingiva of adult periodontitis
IL-1 levels decrease after periodontal treatment. IL-6 has also been shown to be increased in the gingival crevicular fluid of patients with refractory periodontitis Hendley et al. - oral polymorphonuclear neutrophils - an important source of IL-1b in periodontal disease Keratinocytes - source of IL-1 in the gingival tissues.

Carranzas Clinical Periodontology 11th edition

Inhibitors of destructive cytokines:

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The IL-1ra is a member of the IL-1 gene family that binds IL-1 receptors without inducing apparent cell activation.

Produced by monocytes and polymorphonuclear neutrophils and keratinocytes.

Tumor necrosis factor a - induce both intracellular IL-1ra and IL-1-a by keratinocytes Soluble cytokine receptors reduce the biological effects of cytokines -decreasing the concentration of surface receptors - by binding free cytokine IL-10 - downregulate IL-1 and tumor necrosis factor a IL-4 - downregulate IL-1 and tumor necrosis factor a-gene expression

Carranzas Clinical Periodontology 11th edition

84 IL-4 - induce the death by apoptosis of IL-1 or lipoplysaccharide-stimulated monocytes

Human monocytes contribute to both the persistence and resolution of chronic inflammation - regulation of the production of monocyte mediators may have great value in healing or in reducing the immunopathogenesis of chronic inflammation. Transforming growth factor b is an anti-inflammatory agent. produced locally at the site of resorption of bone and has been shown to initiate new bone formation. An IL-1 inhibitor - by reducing the constitutive or induced level of IL-1 receptors. Major functions of IL-8 - induce the directional migration of cells, including polymorphonuclear neutrophils, monocytes and T cells -key role in the accumulation of leukocytes at sites of inflammation.

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Prostaglandins:
Prostaglandins are comprised of 10 classes, of which D, E, F, G, H and I are the most important biologically. Evidence that prostaglandins could mediate bone resorption was first reported in 1970 Prostaglandin E2 - most potent stimulator exhibits a broad range of proinflammatory effects. It contributes to the flare and wheal effects by inducing vasodilation and increasing capillary permeability

IL-1 and tumor necrosis factor activate the arachidonic acid pathway, and their effects can be attributed to prostaglandin E2.

Carranzas Clinical Periodontology 11th edition

Prostaglandins in periodontal disease:

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The production of prostaglandins - increases with inflammation and is further increased by estrogens and progesterones. Human monocytes - shown to produce prostaglandin E2 Both gingival and periodontal ligament fibroblasts secrete prostaglandin E in response to IL-1-b and to media conditioned by lipoplysaccharide-stimulated monocytes. More recent work - periodontal ligament cells produce prostaglandin E even when unstimulated, secretion is enhanced by incubation with IL-1, IL-1-b and tumor necrosis factor a and the addition of parathyroid hormone

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MATRIX METALLOPROTEINASES
Metalloproteases, are endopeptidases that contain an active site Zn2 + (hence, the prefix metallo) and are divided into subfamilies or classes based on evolutionary relationships and structure of the catalytic domain. MMPs comprise a family of currently 25 related MMP-1 and MMP-8 are both colllagenases and MMP-8 is released by infiltrating neutrophils, whereas MMP-8 expressed by resident cells. Also produced by Periopathogens but not considered as major factor in disease progression
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MATRIX METALLOPROTEINASES
Secreted in latent form and activated by proteolytic cleavage of the latent enzyme( Cathepsin G) Key inhibitors of MMP are 1 antitrypsin 1 macroglobulin TIMPS( Tissue inhibitors of MMP) Also inhibited by tetracycline class of antibiotics

The imbalance between MMPs and tissue inhibitors of matrix metalloproteinases(TIMPs) is considered to trigger the degradation of extracellular matrix, basement membrane,
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CENTRAL ROLE OF MONOCYTE MACROPHAGE SYSTEM IN PATHOGENESIS OF PERIODONTITIS 90

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Receptor activator of nuclear factor kappa-B ligand (RANKL),

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Also known as tumor necrosis factor ligand superfamily member 11(TNFSF11) TNF-related activation-induced cytokine (TRANCE) osteoprotegerin ligand (OPGL), and as a key factor for osteoclast differentiation and activation. RANKL also has a function in the immune system, osteoclast differentiation factor(ODF) Critical for adequate bone metabolism, this surface-bound molecule found on osteoblasts serves to activate osteoclasts, which are the cells involved in bone resorption.

Osteoclastic activity is triggered via the osteoblasts' surface-bound RANKL activating the osteoclasts' surface-bound receptor activator of nuclear factor kappa-B (RANK).

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Localized aggressive periodontitis

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Neutrophil and monocyte chemotaxis defects.. Decreased neutrophil chemotaxis response to both intrinsic host factors.. IL-8, C5a and leukotriene B4 and synthetic bacterial metabolic by-product peptide fragments, such as N-formyl methionyl leucyl phenylalanine Neutrophil chemotaxis abnormality..peripheral blood neutrophils and neutrophils from the lesion site. Post-receptor defects in neutrophil signal transduction pathways defective plasma membrane calcium channels, altered cytosolic calcium response, defective lipoxygenase activity, increased intracellular diacyl-glycerol and decreased diglycerol kinase activity .

100 Chronic depletion or downregulation of protein kinase C activity, has been

suggested to be pivotal in altered neutrophil function LJP neutrophils are able to phagacytose, but not kill, the engulfed Aa

A new paradigm for pathogenesis of LAP

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Neutrophil abnormalities in LAP are the result of chronic hyperactivated

or primed state of the LAP neutrophils

Neutrophil mediated injury. Activated neutrophils release oxygen radicals and proteolytic enzymes, which can directly induce tissue damage (Smith 1994, Hansen 1995) Neutrophils may release PAF, thromboxane & leukotrines that amplify

the inflammatory reaction

Oxygen radicals can affectproteins, lipids, carbohydrates and nucleic acids (Bardway & Karnovsky 1980)

CONCLUSION
Periodontitis is a family of related chronic inflammatory disease. Bacteria are necessary but insufficient to cause periodontitis. Host factors - important in determining disease development and outcome.

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The complex interplay between the bacterial challenge and innate and acquired host factors determines the outcome. Major advances have been made at the cellular, molecular and genetic levels in understanding the pathways and mechanisms by which the bacteria destroys the connective tissue of the gingival and periodontal ligament and resorbs the alveolar bone

 Acquired and environmental risk factors such as tobacco smoking as well as genetically transmitted traits modify the shared pathways - determine disease susceptibility, onset, progression, severity and outcome.

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Thus potential adjunctive therapies can be directed to modulate the host response and decrease the microbial load for treatment of periodontitis along with control of the modifiable risk factors.

REFERENCES
1. Pathogenesis of Periodontitis : Perio 2000 ; 1997

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2. Mapping the Pathogenesis of Periodontitis: A New Look Kenneth S. Kornman ( Journal of Periodontology August 2008, Vol. 79.)
3. Clinical Periodontology & Implant Dentistry 5th edition Jan Lindhe 4. Carranzas Clinical Periodontology 11th edition, 10TH edition 5. Mahanonda & Pichyangkul (periodontology 2000) vol43. 2007

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