pathogenesis of periodontal disease 1
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SUMMARY OF EVENTS INPATHOGENESIS OF
PERIODONTAL DISEASE.
PRESENTED BY:POOJA BHASALE
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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 )
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Kornman (JOP August 2008 )
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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 )
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Offenbacher JOP 2008
BIOLOGIC SYSTEM MODEL REPRESENTING PERIODONTITIS
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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.
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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 .
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PRISTINE GINGIVA NORMAL HEALTHY GINGIVA
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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
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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
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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 .
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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
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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.
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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.
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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.
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)
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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.
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Role of dental plaque biofilm in periodontaldisease :
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LIPOPOLYSACCHARIDE(LPS)
These are MAMPS that haveessential role in the pathogensability to invade the host defenseand thus are not subjected to highmutational rate.
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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.
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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
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)
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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 )
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Early stage of P. Gin giv alis associated periodontitis.25
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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)
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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%)
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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)
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BACTERIAL ENZYMES ANDNOXIOUS PRODUCTS
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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
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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 -
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TOLL LIKE RECEPTORS 32
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MAHANONDA & PICHYANGKUL (PERIODONTOLOGY 2000) VOL43. 2007
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Clinical Periodontology & Implant Dentistry 5th editionJan Lindhe
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MAHANONDA & PICHYANGKUL (PERIODONTOLOGY 2000) VOL43. 2007
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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.
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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
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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
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HOST RESPONSE TO MICROBIALCHALLENGE IN PERIODONTITIS
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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.
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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.
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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.
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S 1 A b i l h l l
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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
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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
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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
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Th b i l h l l i d h i h
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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
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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.
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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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Scene 1 . Acute bacterial challenge phase: the epithelial and vascular
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elements respond to the bacterial challenge 49
Scene2.A cu teinf lamm atory respo ns eph ase:
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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
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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.
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Scene 2 . Acute inflammatory response phase: the tissues respond to
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y p p pthe early signals 52
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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
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N hi l i i i i i l l
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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
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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
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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
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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
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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
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With b t i l h ll h i ti t d th h ti
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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
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Molecu les tha tmediatetheimm un oinf lam m atory
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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
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IL 1 l l d F hil d
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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
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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
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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.
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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.
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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
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IFN g prod ced b CD8+ c toto ic T cells recr its and acti ates
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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 ..
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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
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Lo ca lan t ibo dy resp on setobac ter ialch al leng e
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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.
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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
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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
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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
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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
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Scene 4. Regu lat ion & reso lut ion ph ase: de term inantsofpro tec t iveco m po nents inthe
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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.
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Scene 4. Regu lat ion & resolu t ion p hase
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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)
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Selec t ive cy tok ine exp ress ion m olds the
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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.
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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
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Scene 4 . Regulation and resolution phase: determinants of protectivecomponents in the sulcus and collagen balance in the tissues
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components in the sulcus and collagen balance in the tissues 78
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HOST DERIVED INFLAMMATORYMEDIATORS
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CYTOKINES AND PROSTAGLANDINS IN PERIODONTAL DISEASE: 80
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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.
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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 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.
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Inhibitors of destructive cytokines:83
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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
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IL 4 induce the death by apoptosis of IL 1 or lipoplysaccharide stimulated 84
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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.
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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.
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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
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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
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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,
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CENTRAL ROLE OF MONOCYTE MACROPHAGE SYSTEM INPATHOGENESIS OF PERIODONTITIS 90
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Receptor activator of nuclear factor kappa-Bli d (RANKL )
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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).
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Lo cal ized agg ress ive per iod on t i t i s 99
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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-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
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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
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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)
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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
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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
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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
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