Pathogenesis of Periodontal Disease 1

7/28/2019 Pathogenesis of Periodontal Disease 1

1/105

SUMMARY OF EVENTS INPATHOGENESIS OF

PERIODONTAL DISEASE.

PRESENTED BY:POOJA BHASALE

1


2/105

INTRODUCTIONPeriodontal disease is a common, complexinflammatory disease characterized by thedestruction of tooth supporting soft and hardtissues of the periodontium

Although the inflammation is initiated by thebacteria, the tissue breakdown events that lead tothe clinical signs of the disease results from the

host imflammatory response.

Pathogenesis is defined as the origination anddevelopment of the disease .(Merriam Webster CollegiateDictionary )

2


3/105

3


4/105

Kornman (JOP August 2008 )

4


5/105

key organizing principle of systems biology is the use of multiple levels torovide a framework for defining the interactions between the cellular andolecular processes occurring at the lowest levels to the clinical presentation

f disease at the uppermost level

Kornman (JOP August 2008 )

5


6/105

Offenbacher JOP 2008

BIOLOGIC SYSTEM MODEL REPRESENTING PERIODONTITIS

6


7/105

Sites with cl in ical ly heal thy gin giva appear to deal with continuousmicrobial challenges without progressing to clinical gingivitis probablybecause 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 awayunattached 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 5 th edition Jan Lindhe

7


8/105

The classical phases of acute and chronicinflammation are not easily applied inperiodontal disease, probably because inclinically healthy gingiva a small lesion similar to an acute inflammatory reaction is alreadypresent. Subsequently developing chronicinflammatory changes become superimposedso that both acute and chronic elements co-exist in most gingival lesions .

Clinical Periodontology & Implant Dentistry 5 th edition Jan Lindhe

8


9/105

PRISTINE GINGIVA NORMAL HEALTHY GINGIVA

9


10/105

INITIAL LESION ( SUBCLINICAL GINGIVITIS )Develops within 2-4 days of plaqueaccumulation

Vascular dilation and vasculitissubsequent to the junctionalepithelium

Infiltration of polymorphonuclear

neutrophils (PMNs) into the junctionand sulcular epithleium

Predominant immune cells arePMNs.

Perivascular loss of collagen

Alteration of the coronal part of the junctional epithelium

Clinical Finding : increase ingingival fluid flow

Carranzas Clinical Periodontology 10 th edition

10


11/105

11


12/105

EARLY LESIONVascular proliferation

Rete peg formation and atrophic areasin the SE and JE.

Predominant immune cells arelymphocytes (75% of the infiltrate)

Increased collagen loss, 70% of collagen destroyed around the cellular infiltrate.

A niche forms between the epitheliumand the enamel surface and asubgingival biofilm may now form.

Clinical Findings : erythema andbleeding on probing

Carranzas Clinical Periodontology th

12


13/105

ESTABLISED LESIONVascular proliferation and blood stasis

More advanced area of rete pegformation and atrophic areas in the SEand JE

Predominant immune cells are plasmacells

Formation of small gingival pocketlined with pocket epithelium with largeno. of neutrophils

Continued collagen loss

Elevated contents of MMPS andlysosomal contents from neutrophils

Clinical Findings : changes In gingivalcolour, size, texture .


13


14/105

Two mechanisms are considered to be associated withcollagen loss:

1) Collagenases and other enzymes secreted byvarious cells in healthy and inflamed tissue such asfibroblasts, polymorphonuclear leukocytes, andmacrophages become extracellular and destroycollagen;

2) Fibroblasts phagocytize collagen fibers by extendingcytoplasmic processes to the ligament-cementuminterface and degrade the inserted collagen fibrils andthe fibrils of the cementum matrix

14


15/105

Two types of established lesion appear toexist: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 anconverts more rapidly to a progressive and

destructive advanced lesion.

15


16/105

ADVANCED LESIONMarks the transition from gingivitis toperiodontitis

Predominance of neutrophlis in thepocket epithelium and pocket

Dense inflammatory infiltrate in theconnective tissue

Apical migration of J.E. to preserveintact epithelial barrier.

Large areas of collagen depletedconnective tissue

Osteoclastic resorption of alveolar bone.


16


17/105

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.

Bone resorbs so that there is always a width of noninfiltratedconnective tissue of about 0.5 to 1 mm overlying the bone.

Bone resorption ceases when there is at least 2.5mmdistance between the site of bacteria and the bone.( Page &Schroder 1982)


17


18/105

Most significant ramification of biofilm formation -bacteria continuously release cell surface componentsinto the oral cavity and the gingival sulcus.

Gram-negative bacteria - release vesicles containinglipopolysaccharide, lipid and protein, which are found inintact outer membranes and are believed to represent

normal mechanism of membrane turnover.

Periodontology 2000( vol 14,1997 )

Role of dental plaque biofilm in periodontaldisease :

18


19/105

LIPOPOLYSACCHARIDE(LPS)

These are MAMPS that haveessential role in the pathogensability to invade the host defenseand thus are not subjected to highmutational rate.


19


20/105

Bacterial material that is released in the periodontium provides amajor form of communication between dental plaque and the host.

Lipopolysaccharide has been reported to pass through an intactepithelial cell barrier and concentrate around blood vessels in thelamina propria.

Bacteria can have either direct or indirect effects onhost cells.

Direct effects - when the bacteria or bacterial extract directlystimulates a cell to respond

Indirect effects are defined as the effects that occur when bacteriaactivate one cell type and then the product from that cell acts onanother cell or cell type.

Periodontology 2000( vol 14,1997)

20


21/105

21


22/105

Monocytes and macrophages respond to whole dental plaque

bacteria, surface associated material, lipopolysaccharide and

other soluble and particulate fractions by secreting a variety of

inflammatory cytokines such as tumor necrosis factor a ,

prostaglandin E 2, 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 E 2 ).Periodontology 2000( vol 14,1997)

22


23/105

23


24/105

Lipopolysaccharide obtained from Porphyromonas gingivalis failed to elicit IL-8

or intracellular adhesion molecule expression

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 )


24


25/105

Early stage of P. Gin giv alis associated periodontitis.25


26/105

Microbia l co m po s i t ion ass oc iated w i th g in giv al health

Bacterial load associated with gingival health is relatively low.. (10 2-

10 3)

Microbiota is mostly gram-positive, streptococci and actinomyces, withabout 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)


26


27/105

Microbia l co m po s i t ion ass oc iated w i th g ing iv i t i s

Gingivitis is associated with an increased microbial load (10 4-

10 6 organisms) and a corresponding increase the percentage

of gram-negative organisms (15-50%)

27


28/105

Micro bial com po s i t ion ass oc iated w i th per iodont i t i s

Increase in the total microbial load (10 5-10 8 microorganisms)

Elevated P. gingivalis levels differentiated periodontitis from gingivitis

(Dahlen & Manji 1992)

28


29/105

BACTERIAL ENZYMES ANDNOXIOUS PRODUCTS

29


30/105

30


31/105

HOW DO CELLS RECOGNIZELPS?

TLRs are a type of pattern recognition receptor (PRR) and recognizemolecules that are broadly shared by pathogens but distinguishable fromhost molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs)

The discovery of TLRs and the identifi cation of their ligand repertoirehave prompted the bar code hypothesis of innate recognition of microbes.

According to this concept, TLRs read a bar code on microbes which isthen decoded intracellularly to tailor the appropriate type of innateresponse.

It acts as a bridge between the innate immune response and adaptiveimmunity Carranzas Clinical Periodontology 11 th edition

31
http://en.wikipedia.org/wiki/Pattern_recognition_receptorhttp://en.wikipedia.org/wiki/Pathogenhttp://en.wikipedia.org/wiki/Pathogen-associated_molecular_patternhttp://en.wikipedia.org/wiki/Pathogen-associated_molecular_patternhttp://en.wikipedia.org/wiki/Pathogen-associated_molecular_patternhttp://en.wikipedia.org/wiki/Pathogen-associated_molecular_patternhttp://en.wikipedia.org/wiki/Pathogen-associated_molecular_patternhttp://en.wikipedia.org/wiki/Pathogen-associated_molecular_patternhttp://en.wikipedia.org/wiki/Pathogenhttp://en.wikipedia.org/wiki/Pattern_recognition_receptor


32/105

TOLL LIKE RECEPTORS 32


33/105

MAHANONDA & PICHYANGKUL (PERIODONTOLOGY 2000) VOL43. 2007

33


34/105

Clinical Periodontology & Implant Dentistry 5th editionJan Lindhe

34


35/105


35


36/105

36


37/105

TOLL LIKE RECEPTORSGingival epithelial cells express Toll-like receptor 3 and Toll-like receptor 9 ( Yamada etal 2005 ).The presence of these Toll-like receptors providesthe ability for epithelial cells to respond to both viral and bacterial nucleicacids.

Human gingival fibroblasts constitutively express mRNA of Toll-likereceptor 2, Toll-like receptor 4, and Toll-like receptor 9 and other Toll-likereceptor-related molecules, e.g. CD14 (a co-receptor for lipopolysaccharide) and Myeloid differentiation primary-response protein88

P. gingivalis lipopolysaccharide may be responsible for the observed up-regulation of Toll-like receptor 2 , Toll like receptor 4, and CD14 inperiodontitis.


37

The Expession Profile of Lipopolysaccharide-Binding Protein, Membrane-BoundCD14 d T ll Lik R t 2 d 4 i Ch i P i d titi


38/105

CD14, and Toll-Like Receptors 2 and 4 in Chronic Periodontitis

Lei Ren, * W. Keung Leung, * Richard P. Darveau, and Lijian Jin *

Background : This study aimed to investigate the interrelationship of in vivo expression of lipopolysaccharide-binding protein (LBP) and membrane-bound CD14 (mCD14) in humangingival tissues as well as the coexpression of Toll-like receptors (TLR) 2 and 4 inassociation with periodontal conditions.Methods: Gingival biopsies were collected from 43 subjects with chronic periodontitis, includingperiodontal pocket tissues (PoTs) and clinically healthy gingival tissues (HT-Ps), and from 15periodontally healthy subjects as controls (HT-Cs). The expression of LBP, CD14, TLR 2, andTLR 4 was detected by immunohistochemistry and reverse transcription-polymerase chainreaction (RT-PCR).Results: LBP and mCD14 peptides were simultaneously detected in 91% of PoTs, 85% of HT-Ps, 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 gingivalepithelium, whereas mCD14 was observed around the epithelium-connective tissue interface. Apositive correlation existed between LBP and mCD14 peptides in both detection expression (r s =0.608; P


39/105

HOST RESPONSE TO MICROBIALCHALLENGE IN PERIODONTITIS

39


40/105

Gingival health is a dynamic state that maybe viewed as one scene in a play. As

certain signals are given, specific playersrespond in a practiced manner and take

their places in the scene. If disease-

initiating signals are given, the players takepositions on the stage that allow them toparticipate in the disease scene.

Page etal Periodontology 2000( vol 14,1997

40


41/105

Scene 1. A cu te bacter ial c hal leng e ph ase: th e ep i the lial and vascu lar e lem ents resp on d to the

bac ter ial ch al leng e 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

41


42/105

A large population of B cells and plasma cells that accumulate 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.


42

S 1 A b i l h l l


43/105

Scene 1. A cu te bacter ial c h al len ge phase

Epi the lium in h eal th i s exp os ed to v ar iou s bacter ial prod uc ts

Butyric and propionic

Peptides of the N-formyl-methionyl-leucyl-phenylalanine (FMLP) type

which are potent chemoattractants for leukocytes,

Lipopolysaccharide of gram negative bacteria


43


44/105

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

LPS.

Prostaglandins and interleukins such as IL-l b , 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

Periodontology 2000( vol 14,1997 44


45/105

The ep i the lium pro vides bo th s igna l ing and pro tec t ive func t ions

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 a IELb7 integrin (mucosal T cells), the cutaneous lymphocyte antigen and

the gd T-cell receptor Periodontology 2000( vol 14,1997

45

Th b i l h l l i d h i h


46/105

The bacter ial chal leng e ind uc es ch anges in th e epi th el ium to fac i l i tate bo th v asc ular permeabi l i ty and the in f lux of neu t roph i l s

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 3 even 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 E 2

Page etal Periodontology 2000( vol 14,1997

46


47/105

Epithelial cells produce a range of cytokines, including IL-1 a , IL-1 b ,

granulocytes macrophage colony stimulating factor, interferon b , tumor

necrosis factor a , transforming growth factor b , IL-3, IL-6, IL-7, IL-8, IL-

10, 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.


47


48/105

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


48

Scene 1 . Acute bacterial challenge phase: the epithelial and vascular


49/105

elements respond to the bacterial challenge 49

Scene2.A cu teinf lamm atory respo ns eph ase:


50/105

Scene 2. A cu te inf lamm atory respo ns e ph ase: the t is s ues resp on d to th e ear ly s ig na ls

In mild inflammation, intercellular spaces are widened further and filledwith 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


50


51/105

About 30,000/min, leukocytes migrate through the JE.

These are mostly neutrophils but also include monocytes and

lymphocytes, Langerhans' cells and other HLA-DR-positive antigen-presenting cells.

In most tissues.ECAM 1 is not expressed until the cells are exposed to

LPS or cytokines like IL-1 b

Acute phase proteins such as a2-macroglobdin have been shown to

increase very early in the gingivitisprocess , indicating an increased

vascular leakage.

51

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


52/105

y p p pthe early signals 52


53/105

53


54/105

54


55/105

Fate of Extravasated L euc o cy tes

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

55

N hi l i i i i i l l


56/105

Neutrop hi l migra t ion in to g ing iva l su lcus

New developments in immunobiology have described 2mechanisms..

1) The expression of leucocyte adhesion molecules, such as ICAM 1 inepithelial cells, and

2) Discovery of a family of low molecular weight cytokines; chemokinesand IL-8 ( Beckel etal 1993)

ICAM 1/ b2 integrin interaction is very important for neutrophilmigration

Antibodies against ICAM 1& against its counter- receptor

56


57/105

Mucosal keratinocytes play a crucial active role in neutrophil recruitment

at mucosal sites of infection

IL-8 & ICAM 1 expression represents a key step in this process

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

- lower conc stimulate cell migration

- higher conc, lead to activation of neutrophil antibacterial mechanisms

Neut rop hi l m igrat ion in to g ing iva l su l cus

57


58/105

The inf lam m atory inf i l t ra te w i th in th e t i ss ues

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 Programm ed Cel l

Dea th o r Apo ptos i s

58


59/105

Summary of Scene 2

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

59


60/105

Scene 3. Im m un e resp on se ph ase

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' andCD8+ T cells, and the B cells are driven to differentiate into clones of

antibody producing plasma cells

60

With b t i l h ll h i ti t d th h ti


61/105

With bacterial challenge..macrophage is activated through antigen

non-specific mechanisms ..

Macrophages exposed to LPS produce. IFNg, TNF a , TGF b , IL-1 a 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 PGE 2

1)Recruit additional monocytes and lymphocytes into the area

2) Alter the environment to favor collagen degradation

61

Molecu les tha tmediatetheimm un oinf lam m atory


62/105

Molecu les tha t mediate the imm un oinf lam m atory resp on se becom e pro m inent in the g ing ival t i s sues

IL-1. major mediator in periodontitis

IL-lb activated macrophages & fibroblasts

IL-1a . Keratinocytes

induced by lipopolysaccharide and other bacterial componentsIL-1 is autostimulatory

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

62

IL 1 l l d F hil d


63/105

IL-1 upregulates complement and Fc receptors on neutrophils and

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

63


64/105

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

producing plasma cells

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

64


65/105

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.

65


66/105

IL-8 .member of the chemokine superfamily

Produced by LPS-activated macrophages, synovial cells, endothelium

and Junctional epithelial cells.

Neutrophils, high affinity receptors .& low affinity

receptors metabolic burst and degranulate on arrival at the site of

challenge.

66


67/105

Mono cyt e chem oat t ractant prote in-1 is a potent attractant to

monocytes.

Transform ing grow th fac tor b produced by activated T

cells. chemoattractant for monocytes & suppresses their action

Transform ing grow th fac tor a .produced by macrophages and

serves as a mitogen for fibroblasts and for epithelial and endothelial cells

67

IFN g prod ced b CD8+ c toto ic T cells recr its and acti ates


68/105

IFN g produced by CD8+ cytotoxic T cells, recruits and activates

macrophages & upregulates the MHC on virally infected cells and targets

them for killing

Prostaglandins & leukotreines .. Macrophages chemoattractant

Platelet activating factor .

Protacycline

Thromboxane ..

68


69/105

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

69

Lo ca lan t ibo dy resp on setobac ter ialch al leng e


70/105

Lo cal an t ibo dy resp on se to bac ter ial ch al leng e

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.

70


71/105

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

71

Scene 3 . Im m un e resp on se ph ase: ac t iv at ion o f m on on c learce l lss hapesth eloc aland


72/105

m on on uc lear ce l ls s hapes th e loc al and sy s t em ic im m une r espons e

72


73/105

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

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

73

Scene 4. Regu lat ion & reso lut ion ph ase: de term inantsofpro tec t iveco m po nents inthe


74/105

determ inants of p ro tec t ive co m po nents in the su lcus and co l lagen ba lanc e in the t is s ues

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.

74

Scene 4. Regu lat ion & resolu t ion p hase


75/105

g p

Fibro blasts sh if t to a s ta te that favo rs

des t ruc t ion of ext racel lu lar m atr ix

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)

75

Selec t ive cy tok ine exp ress ion m olds the


76/105

imm une respons e

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

IL-5 were not detected

Yamazaki et al.reported increased IL -4 in periodontitis

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.

76

Scene4.Regu lat ion& resolu t ionp hase


77/105

Scene 4. Regu lat ion & resolu t ion p hase

Ini t ia t ion and Pro gress ion of Per iodon t i t i s

Tissues are populated with cytokines and prostanoids favor collagen

and bone loss

Efficiency of neutrophil migration is reduced

77

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


78/105

components in the sulcus and collagen balance in the tissues 78


79/105

HOST DERIVED INFLAMMATORYMEDIATORS

79

CYTOKINES AND PROSTAGLANDINS IN PERIODONTAL DISEASE: 80


80/105

PERIODONTAL DISEASE:Cytokines in tissue destruction :

IL-1 and tumor necrosis factor a are key mediators of chronic inflammatorydiseases - initiate tissue destruction and bone lossIL-1 - to stimulate fibroblasts to produce collagenase.

Tumor necrosis factor - mediates tissue destruction by stimulating

collagenase - degradation of type 1 collagen by fibroblasts leading toconnective tissue destruction.

Tumor necrosis factor molecules stimulate bone resorption by inducing theproliferation and differentiation of osteoclast progenitors and activating formedosteoclasts indirectly.

IL-6 also appears to have a role in bone resorption.potent stimulator of osteoclast differentiation and bone resorption andinhibitor of bone formation.


80

81


81/105

81

82


82/105

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 beincreased in the gingival crevicular fluid of patients with refractory periodontitis

Hendley et al. - oral polymorphonuclear neutrophils - an important source of IL-1-b in periodontal disease

Keratinocytes - source of IL-1 in the gingival tissues.


82

Inhibitors of destructive cytokines:83


83/105

The IL-1ra is a member of the IL-1 gene family that binds IL-1 receptors withoutinducing apparent cell activation.

Produced by monocytes and polymorphonuclear neutrophils and keratinocytes.

Tumor necrosis factor a - induce both intracellular IL-1ra and IL-1- a bykeratinocytes

Soluble cytokine receptors reduce the biological effects of cytokines -decreasingthe 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


83

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


84/105

IL-4 - induce the death by apoptosis of IL-1 or lipoplysaccharide-stimulatedmonocytes

Human monocytes contribute to both the persistence and resolution of chronic inflammation - regulation of the production of monocyte mediators mayhave great value in healing or in reducing the immunopathogenesis of chronicinflammation.

Transforming growth factor b is an anti-inflammatory agent.produced locally at the site of resorption of bone and has been shown to initiatenew bone formation.

An IL-1 inhibitor - by reducing the constitutive or induced level of IL-1receptors.

Major functions of IL-8 - induce the directional migration of cells, includingpolymorphonuclear neutrophils, monocytes and T cells -key role in theaccumulation of leukocytes at sites of inflammation.


84

85


85/105

Prostaglandins:

Prostaglandins are comprised of 10 classes, of which D, E, F, G, H and I are themost important biologically.

Evidence that prostaglandins could mediate bone resorption was first reported in1970

Prostaglandin E2 - most potent stimulator exhibits a broad range of proinflammatory effects.

It contributes to the flare and wheal effects by inducing vasodilation and increasingcapillary permeability

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


85

Prostaglandins in periodontal disease: 86


86/105

Prostaglandins in periodontal disease:

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-stimulatedmonocytes.

More recent work - periodontal ligament cells produce prostaglandin E even whenunstimulated, secretion is enhanced by incubation with IL-1, IL-1- b and tumor necrosis factor a and the addition of parathyroid hormone


86

87


87/105

MATRIX METALLOPROTEINASES

Metalloproteases, are endopeptidases that contain an active siteZn2 + (hence, the prefix metallo ) and are divided intosubfamilies or classes based on evolutionary relationships andstructure of the catalytic domain.

MMPs comprise a family of currently 25 related

MMP-1 and MMP-8 are both colllagenases and MMP-8 isreleased by infiltrating neutrophils, whereas MMP-8 expressed

by resident cells.

Also produced by Periopathogens but not considered as major factor in disease progression

Carranzas Clinical Periodontology 10 th

edition

87

88


88/105

MATRIX METALLOPROTEINASES

Secreted in latent form and activated by proteolytic cleavage of the latentenzyme( Cathepsin G)

Key inhibitors of MMP are1 antitrypsin1 macroglobulinTIMPS( Tissue inhibitors of MMP)

Also inhibited by tetracycline class of antibiotics

The imbalance between MMPs and tissue inhibitors of matrixmetalloproteinases(TIMPs) is considered to trigger the degradation of extracellular matrix, basement membrane,


88

89


89/105

89

CENTRAL ROLE OF MONOCYTE MACROPHAGE SYSTEM INPATHOGENESIS OF PERIODONTITIS 90


90/105

90

91


91/105

9

92


92/105

Receptor activator of nuclear factor kappa-Bli d (RANKL )

93


93/105

ligand (RANKL ),

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, osteoclastdifferentiation factor (ODF)

Critical for adequate bone metabolism, this surface-bound moleculefound on osteoblasts serves to activate osteoclasts, which are the cells

involved in bone resorption.

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

94


94/105

95


95/105

96


96/105

97


97/105

98


98/105

Lo cal ized agg ress ive per iod on t i t i s 99


99/105

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-productpeptide fragments, such as N-formyl methionyl leucyl phenylalanine

Neutrophil chemotaxis abnormality..peripheral blood neutrophils andneutrophils from the lesion site .

Post-receptor defects in neutrophil signal transduction pathwaysdefective plasma membrane calcium channels, altered cytosolic

calcium response, defective lipoxygenase activity, increased intracellular diacyl-glycerol and decreased diglycerol kinase activity .

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


100/105

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

A a

A new parad igm for pa thog enes is o f LA P 101


101/105

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 102


102/105

CONCLUSIONPeriodontitis is a family of related chronic inflammatorydisease.

Bacteria are necessary but insufficient to causeperiodontitis.

Host factors - important in determining diseasedevelopment and outcome.

The complex interplay between the bacterial challenge andinnate and acquired host factors determines the outcome.

Major advances have been made at the cellular, molecular and genetic levels in understanding the pathways andmechanisms by which the bacteria destroys the connectivetissue of the gingival and periodontal ligament and resorbsthe alveolar bone

A i d d i t l i k f t h t b103


103/105

Acquired and environmental risk factors such as tobaccosmoking as well as genetically transmitted traits modify theshared pathways - determine disease susceptibility, onset,

progression, severity and outcome.

Thus potential adjunctive therapies can be directed tomodulate the host response and decrease the microbial loadfor treatment of periodontitis along with control of themodifiable risk factors.

REFERENCES 104


104/105

REFERENCES1. Pathogenesis of Periodontitis : Perio 2000 ; 1997

2. Mapping the Pathogenesis of Periodontitis: A New Look KennethS. Kornman ( Journal of Periodontology August 2008, Vol. 79.)

3. Clinical Periodontology & Implant Dentistry 5 th edition Jan Lindhe

4. Carranzas Clinical Periodontology 11 th edition, 10 TH edition

5. Mahanonda & Pichyangkul (periodontology 2000) vol43. 2007

105


105/105

THANK YOU

Documents

Pathogenesis of Periodontal Disease 1