Host microbe interaction in periodontal disease
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Transcript of Host microbe interaction in periodontal disease
MICROBIAL INTERACTION
WITH THE HOST IN
PERIODONTAL DISEASE
Periodontal diseases
GingivitisPeriodontitisInflammatory response to microorganisms in
dental plaqueTissue destruction, Bone loss, tooth loss
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Periodontal disease
Host-microbe diseaseInteraction of Host with microrganism
determines the course and extent of the resulting disease
Microrganism cause disease throughDirect Tissue destructionIndirect through stimulating and modulating host
response
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Host Response
Mediated by Microbial interaction and inherent characteristic of host including genetic factors which vary among individuals
In general host response is protective it prevents local infection from progressing to systemic, life threatening infections
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Microbe Host interaction
Local alteration and destruction of host tissue
as a result of microbe-host interaction
manifest as Periodontal disease
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Microbial Aspect of Microbial Host Interaction
Gram negative anaerobes are pathogenic
organisms associated with disease
The properties of microorganism that enable it
to cause disease is called Virulence Factor
Bacteria must colonize the host tissue and
then cause destruction of the host tissue
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Bacterial Colonization and Survival in Periodontal region
• Bacterial Adherence– GCF flows outwards from the base of pocket– Bacterial species that colonize this region must
attach to available surfaces to avoid displacement– Surfaces available for attachment are tooth or
root, tissue, and preexisting plaque mass– Eg: A viscosus and Pgingivalis through fimbrae on bacterial surface to
proline rich proteins found on saliva-coated tooth surface
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P gingivalis binds to epithelial cells and fibroblasts
The ability of Porphyromonas gingivalis to attach
to other bacteria, epithelial cells, and connective
tissue components fibrinogen and fibronectin add
to virulence of this periopathogen
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Host tissue InvasionBoth gram-positive and gram- negative
bacteria, including cocci, rods, filaments and
spirochetes have been seen in gingival
connective tissue and alveolar bone
Presence of bacteria in periodontal tissue in
gingivitis, advanced chronic periodontitis
and Aggressive Periodontitis
Presence of bacteria in host tissue in NUG
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Bacteria can enter host tissue through
Ulceration in epithelium of gingival sulcus or periodontal
Observed in intercellular spaces of gingival tissues
Direct penetration of bacteria into hosts epithelial or
connective tissue cell
Eg: A actinomycetemcomitans, P gingivalis, F nucleatum,
Treponema denticola to invade tissue cell directly
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Bacterial species that have been identified as
capable of tissue invasion are strongly
associated with disease
Ability to invade has been proposed as a key
mechnism that distinguishes pathogenic from
non- pathogenic gram negative species
Localization of bacteria to the tissue provides
an ideal position from which organism can deliver
toxic molecules & enzymes to host tissue
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• “Burst of disease activity” may be related to
phases of bacterial invasion of the tissue
• Mechanical debridement alone is insufficient, and
systemic antibiotic in combination with surgical
therapy is required to eliminate A
actinomycetemcomitans from lesion in aggressive
periodontitis
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Bacterial Evasion of Host Defense System
To survive in periodontal environment
bacteria neutralize or evade host mechanism
involved in bacterial clearance and killing
Bacterial adherence and invasion are
strategies through which bacteria accomplish
this task
Ability to adhere allows bacteria to avoid
displacement by host secretions
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Periodontal bacteria neutralize or evade
host defense through numerous other
mechanism as shown in the following
table
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Host Defense Mechanism
Bacterial Species Bacterial Property Biologic effect
Specific Antibody Pg, Pi, P melanogenica, Capnocytophaga sp
IgA and IgG degrading protease
Degradation of Specific antibody
Polymorphonuclear leukocytes (PMNs)
Aa, F nucleatum, P gingivalis, T denticola
LeukotoxinHeat sensitive surface proteinCapsuleInhibition ofSuperoxide Production
Inhibition of PMN functionProgrammed cell death of PMN
Lymphocytes Aa, F nucleatum, T forsythia, P intermedia
LeukotoxinCytolethal distending toxin
Killing of mature B and T CellsApoptosis of lymphocytes and mononuclear cells
Release of IL-8 P gingivalis Inhibition of IL-8 production by epithelial cells
Impairment of PMN response to bacteria
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Bacterial enzymes capable of Degrading Host Tissue
1. Collagenases
2. Trypsin like enzymes
3. Aryl sulfatase
4. Neuraminidase
5. Fibronectin –degrading Enzyme
6. Phospholipase -A
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Immunological aspect of Microbial-Host interaction
Involves following factors in response to bacterial infection– Innate factors such as complement, resident
leukocyte and especially mast cell play significant role in signalling endothelium thus initiating inflammation
– Acute inflammatory cells (neutrphils) protect local tissue by controlling the periodontal microbiota within the gingival crevice and junctional epithelium
– Chronic inflammatory cells, macrophages, and lymphocytes protect the entire host from within the subjacent connective tissue and do all that is necessary to prevent a local infection from becoming systemic and life threatening
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Periodontal disease is a well-regulated
response to protracted bacterial infection
directed by inflammatory cells of the host
immune system
Neutrophils primarily function as antimicrobial
cells, and chronic inflammatory cells orchestra
adaptive responses
Neutrophils function to contain microbial
challenge through phagocytosis and killing and
may contribute to local tissue changes by
release of tissue-degrading enzymes
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PMN’s form a protective layer in regions where epithelium of the gingival sulcus has been
disrupted in Gingivitis
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Clinical example of established Gingivitis with emphasis on the acute inflammatory reaction
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• The chronic inflammatory cells, the
lymphocytes and monocytes orchestrate
connective tissue changes associated with
both periodontal infections and periodontal
repair and healing
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Innate factors and initiation of inflammation
Onset of inflammation there is edema and
erythema leading to vascular changes
Complement activation in response to bacterial
infection result in generation of C3a and C5a
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Degranulation of Mast cell
Mast cell constitutely transcribe TNF-ά,
TNF-β, IL-4, IL-6
When stimulated induce produce
Proinflammatory cytokines such as IL-1, IL-6,
INF-γ
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Stimulation of endothelial cells by C5a,
IL-1β, TNF-ά and bacterial lipopolysacchrides results
in expression of selectins on the luminal surface of
endothelial cells and release of chemokine from the
endothelial cells These process are central in transendothelial
migration
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Transendothelial Migration01/09/15 Dr Saif Khan 29
Complement levels
• In healthy patients complement levels in GCF
are about 3% of that serum as periodontal
inflammation increases the complement level
of C3 and C4 increases to 25% and 85% of
that in serum
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Controlling Bacterial Challenge primary role of Neutrophils
• Neutrophils are the first leukocyte to arrive at site of inflammation
• Neutrophils control bacterial inflammation through– Transendothelial migration– Transepithelial migration– Opsonization– Phagocytosis– Intraphagolysosomal killing
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Transepithelial migration
• 1-2% neutrophils migrate across the junctional epithelium daily through chemotactic gradient of IL-8 and ICAM-1 expressed by junctional epithelium
• Porphoromonas gingivalis impedes transepithelial migration of neutrophils by preventing epithelial cells to secrete IL-8 in response to bacterial challange
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Opsonization
Coating of bacteria by host proteins to facilitate
phagocytosis
Bacteria are coated with complement components
(iC3b, C3b)
Recognized by CR3 neutrophil receptor
Antigen presenting cells such as Peripheral
Dendritic cells (langerhans,macrophages,B cells)
are abundant in gingival cells01/09/15 Dr Saif Khan 33
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Phagocytosis
Bacterial cell ingestion by neutrophil results in
formation of Phagosome
Bacteria is killed by Oxidative or Non-
oxidative mechanism
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Scanning Electron Micrograph of PMNs passing through epithelium.
Note bacteria attached to PMNs in process of being phagocytosed
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High power view of PMN and bacteria attached
undergoing phagocytosis.
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Light Microscopic view of PMNs from gingival fluid showing evidence of phagocytosis
White spheres inside PMNs have been engulfed
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Oxidative Killing by – NADPH Oxidase, – Myeloperoxidase, – Nitric oxide synthase
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Non-oxidative Killing by – Defensin, – Lysozyme, – Neutral serine proteases– Bacterial permeability increasing protein
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DEFECT IN NEUTROPHIL FUNCTION AT ANY STAGE LEADS TO AGGRESSIVE PERIODONTITIS
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Systemic neutrophil abnormalities associated with Aggressive Periodontitis
CONDITION NEUTROPHIL ABNORMALTY
PERIODONTAL MANIFESTATION
NEUTROPENIA,AGRANULOCYTOSIS
DECREASED NO. OF NEUTROPHILS
SEVERE AGGRESSIVE PERIODONTITIS
CHEDIAK HIGASHI SYNDROME
DECREASED NEUTROPHIL CHEMOTAXIS AND SECRETION NEUTROPHILS FUSE TO FORM CHARACTERISTIC GIANT GRANULES CALLED MEGABODIES
SYNDROME CAUSED BY MUTATION IN THE VESICLE TRAFFICKING GENE ,LYST
PAPPILON-LEFEVRE SYNDROME
MULTIPLE FUNCTIONAL NEUTROPHIL DEFECTS, INCLUDING MYELOPEROXIDE DEFICIENCY, DEFECTIVE CHEMOTAXIS, AND PHAGOCYTOSIS
SEVERE AGGRESSIVE PERIODONTAL DESTRUCTION AT EARLY AGE, INVOLVES PRIMARY AND PERMANENT DENTITIONMUTATION IN CATHEPSIN C GENE
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LEUKOCTE ADHESION DEFICIENCY TYPE-1 (LAD-1)
DEFECTS IN LEUKOCYTE FUNCTION CAUSED LACK OF INTEGRIN β-2 SUBUNIT (CD-18).NEUTROPHIL DEFECTS INCLUDE IMPAIRED MIGRATION AND PHAGOCYTOSIS. HISTOLOGICALLY ALMOST NO EXTRAVASCULAR NEUTROPHILS ARE EVIDENT IN PERIODONTAL LESION
AGGRESSIVE PERIODONTITIS AT AN EARLY AGE AFFECTING PRIMARY AND PERMANENT DENTITION, IN INDIVDUAL WHO ARE HOMOZYGOUS FOR THE DEFECTIVE GENE
LEUKOCTE ADHESION DEFICIENCY TYPE-2 (LAD-2)
NEUTROPHILS FAIL TO EXPRESS LIGAND (CD15) FOR P- AND – E SELECTIN, RESULTING IN IMPAIRED TRANSENDOTHELIAL MIGRATION IN RESPONSE TO INFLAMMATION
AGGRESSIVE PERIODONTITIS AT YOUNG AGE
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The clinical photo and the X-Ray of this 28 year-old
man show the advanced alveolar bone loss in the
absence of significant gingival inflammation, typical
of the localized aggressive periodontitis
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This patient has advanced generalized aggressive
periodontitis with deep pockets throughout the mouth.
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PAPILLON-LEFEVRE SYNDROME
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These photos show the Palmo-plantar Hyperkeratosis
present in patients with the Papillon Lèfevre
Syndrome. These lesions remain for life but improve
when treated with retinoic acid
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Connective tissue alteration: Tissue destruction in Periodontitis
Connective tissue alteration: Tissue destruction in Periodontitis
The fundamental event in the transition from
gingivitis to periodontitis is the loss of the
soft tissue attachment to the tooth and
subsequent loss of bone
Mediators produced as part of host
response contribute to tissue destruction
include Proteinase,Cytokines, Prostaglandins
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Proteinases• Matrix Metalloproteinases(MMP) are primary
proteinases involved in periodontal tissue
destruction by degrading extracellular matrix
molecules
• MMPs are family of Proteolytic enzymes found
in neutrophils, macrophages,fibroblasts, epithelial
cells, osteoblasts and osteoclasts
• MMPs degrade extracellular matrix molecules,
such as collagen, gelatin, and elastin
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MMP-1 is expressed by resident periodontal
tissue such as fibroblasts, monocytes,
macrophages and epithelial cells
MMP-8 is released by infiltrating neutrophils
MMP are activated by chymotrypsin-like
protease produced by Treponema denticola
as well as host enzymes such as neutrophil
cathepsin G
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• MMPs are inactivated by ά-macroglobulin
found in serum and GCF and by Tissue
inhibitor of MMP’s (TIMP) produced by
many cell types and common in host tissue
and fluids
• Tetracycline also inactivates MMPs and have
significant therapeutic role
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Other Proteinases associated with
Periodontitis include neutrophil serine
proteinases, Elastase and Cathepsin G
Cathepsin G is elevated in gingival tissue and
GCF
Elastase degrades a wide range of molecules
including Elastin, Collagen, and Fibronectin
Elevated Elastase level are associated with
active Periodontal attachment loss
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Cytokines• Three proinflammatory cytokines IL-1, IL-6
and TNF-ά have a central role in Periodontal
tissue destruction
• IL-1 is produced primarily by activated
Macrophages or Lymphocytes
• Bacterial LPS is potent activator of
Macrophage IL-1 production
• TNF-ά is also produced by activated
macrophages in response to Bacterial LPS
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• Also TNF-ά and IL-1 can activate macrophage
IL-1 production
• TNF-β is primarily produced by Th1 subset of
CD4+ T cells that have been activated by
antigen or mitogen
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Proinflammatory effect of IL-1 and TNF-α are
Stimulation of endothelial cells to express
selectins that facilitates recruitment of
leukocytes
Activation of Macrophage IL-1 Production
Induction of Prostaglandin E2 (PGE2 )
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IL-1 is a potent
stimulant of osteoclast
proliferation,
differentiation, and
activation
TNF-ά have same
effects on osteoclasts
but less potent
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ProstaglandinsArachidonic metabolite generated by
cyclooxygenase (COX-1, COX-2)
Arachidonic acid is a 20-carbon
polyunsaturated fatty acid found in
plasma membrane of most cells
COX-2 is upregulated by IL-1β, TNF-β and
bacterial LPS leading to formation of
PGE2 associated with inflammation
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• PGE2 is increased in periodontal sites demonstrating inflammation and attachment loss
• PGE2 also induces MMPs and osteoclastic Bone Resorption
• PGE2 is elevated in gingivitis and Periodontitis in active disease
• PGE2 is partly responsible for bone loss associated with periodontitis
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Macrophages produce prostaglandin E (PGE) and (IL-1) and
lymphocytes produce Interleukin-1 (IL-1) which activate
osteoclasts by interacting with osteoblasts01/09/15 Dr Saif Khan 63
PGE2 is released from monocytes of patients
with severe or aggressive periodontitis
High risk patient display “Monocyte Hyper
secretory trait” leading to exaggerated response
both locally and systemically to bacterial LPS
Use of NSAID as an inhibitor of Prostglandins
synthesis has therapeutic role in preventing
bone loss in Periodontitis01/09/15 Dr Saif Khan 64
Connective tissue alteration: Healing Process in Periodontitis
The chronic immune system plays an important role in
healing process, which consists regeneration and
repair
Regeneration involves the replacement of tissue with
new, identical tissues that function same as the
orignal tissue
Repair involves replacement of one tissue with
another tissue, such as fibrous connective tissue
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Periodontal Repair occurs in overlapping phases of
1. Inflammation shutdown
2. Angiogenesis
3. Fibrogenesis
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Inflammation shutdown
• In post inflammatory healing process, shut down
of inflammatory processes and initiation of post
healing is orchestrated by leukocytes
• Anti inflammatory signals generated by
leukocyte are IL-1 receptor antagonist (IL-
1ra) and Transforming growth factor-β
(TGF-β)
• IL-4, IL-10, IL-11 also depress inflammatory
response
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Source of Anti inflammatory signal
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Angiogenesis and Fibrogenesis
• IL-1β and TNF-β participate both in
inflammation and healing
• IL-1β and IL-ά are indirectly involved in
inducing fibroblast proliferation and collagen
synthesis by stimulating the production of PGE2
or release of secondary cytokines such as
Platelet derived growth factor (PDGF)
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PDGF is a protein complex formed by different
combinations of A,B, C and D chains (PDGF-
AA,AB,BB,CC,DD)
PDGF is structurally and functionally related
to vascular endothelial growth factor(VEGF),
an important factor in endothelial proliferation
PDGF activates fibroblasts and osteoblasts
resulting induction of protein synthesis
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Also TGF-β promotes the elaboration of fibroblast
extracellular matrix adhesion
TGF-β is potent inhibitor of osteoclast formation
Osteoclast differentiation and activation are
inhibited by interferon-γ (INF- γ ) which is
secreted by natural killer cells, Th1 cells and
macrophages
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The main effect of INF-γ appears to be inhibition
IL-1 and TNF-ά induced osteoclast activation.
IL-1ra also effective in blocking IL-1 and TNF-ά
induced osteoclast activation
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Gingivitis
Intitial lesion –Neutrophils
Early lesion – lymphocytes
Established lesion-Plasma cells
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Chronic Periodontitis
• Characterised by Alternative pathway activation of complement C3 and C3B in gingival fluid
• Increased MMP-8 and decreased TIMP-1• Collagenase activity is 6 times more than
gingivitis
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Aggressive periodontitis
Caused by Actinobacillus
actinomycetemcomitans (Aa)
Humoral response to Aa is elevated
Most common serotype B, then A
Incidence of Aa is greater in younger than older
patients
Younger patient have more destructive disease
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Aa can be identified by electron microscopy,
immunoflouresence and culture from LAP lesion
within gingival connective tissue
Aa is quite virulent releases leukotoxin,
Collagenases, Phosphatases and Bone Resorbing
factors
Positive correlation between elimination of
bacteria and resolution of the lesion
Global Membrane Receptor Defect
Defect associated with 40% defect in 110-kd
membrane glycoprotein on neutrophil
surface, Gp110
Gp110 is G-protein coupled receptor
75% of patients with LAP have dysfunctional
neutrophils, involving decreased expression of
G-protein coupled receptor
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Localised Aggressive Periodontitis (LAP)- MMP-1
is increased
Chronic Periodontitis- MMP-8 is increased
In LAP antibody to Aa is increased and
predominant antibody is IgG2
Variant of Fc receptor on neutrophils(R131 allele
of FcγRII-α) does not bind efficiently to IgG2
leading to LAP01/09/15 Dr Saif Khan 78
Patients with elevated antibody response
(IgG2) have less loss of attachment
Antibody response in LAP greater than
GAP(Generalised aggressive periodontitis)
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Socransky criteria
• Proposed criteria by which periodontal microorganism may be judged to be potential pathogens
1. Must be associated with disease, as evident by increase in the number of organisms at diseased sites
2. Must be eliminated or decreased in sites that demonstrate clinical resolution of disease with treatment
3. Must demonstrate a host response, in the form of an alteration in the host cellular or humoral immune response
4. Must be capable of causing disease in experimental animal model.
5. Must demonstrate virulence factors responsible for enabling the microorganism to cause destruction of periodontal tissue
Dr Saif Khan 8001/09/15