Host microbe interaction in periodontal disease

MICROBIAL INTERACTION
WITH THE HOST IN
PERIODONTAL DISEASE

Periodontal diseases
Gingivitis
Periodontitis
Inflammatory response to microorganisms in
dental plaque
Tissue destruction, Bone loss, tooth loss
01/09/15 Dr Saif Khan 2

Periodontal disease
Host-microbe disease
Interaction of Host with microrganism
determines the course and extent of the
resulting disease
Microrganism cause disease through
Direct Tissue destruction
Indirect through stimulating and modulating host
response

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

Microbe Host interaction
Local alteration and destruction of host tissue
as a result of microbe-host interaction
manifest as Periodontal disease

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

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

 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

Host tissue Invasion
Both 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

Bacteria can enter host tissue through
 Ulceration in epithelium of gingival sulcus or periodontal
pocket
 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

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

• “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

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

Periodontal bacteria neutralize or evade
host defense through numerous other
mechanism as shown in the following
table

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
Leukotoxin
Heat sensitive surface
protein
Capsule
Inhibition ofSuperoxide
Production
Inhibition of PMN
function
Programmed cell
death of PMN
Lymphocytes Aa, F nucleatum, T
forsythia, P
intermedia
Leukotoxin
Cytolethal distending
toxin
Killing of mature B
and T Cells
Apoptosis 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

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

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

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

PMN’s form a protective layer in regions where
epithelium of the gingival sulcus has been
disrupted in Gingivitis

Clinical example of established Gingivitis with
emphasis on the acute inflammatory reaction

• The chronic inflammatory cells, the
lymphocytes and monocytes orchestrate
connective tissue changes associated with
both periodontal infections and periodontal
repair and healing

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

 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

 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

Transendothelial Migration

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

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

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

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 cells

Phagocytosis
Bacterial cell ingestion by neutrophil results in
formation of Phagosome
Bacteria is killed by Oxidative or Non-
oxidative mechanism

Scanning Electron Micrograph of PMNs passing
through epithelium.
Note bacteria attached to PMNs in process of being
phagocytosed

High power view of PMN and bacteria attached
undergoing phagocytosis.

Light Microscopic view of PMNs from gingival fluid
showing evidence of phagocytosis
White spheres inside PMNs have been engulfed

Oxidative Killing by
– NADPH Oxidase,
– Myeloperoxidase,
– Nitric oxide synthase

Non-oxidative Killing by
– Defensin,
– Lysozyme,
– Neutral serine proteases
– Bacterial permeability increasing protein

DEFECT IN NEUTROPHIL
FUNCTION AT ANY STAGE LEADS
TO AGGRESSIVE PERIODONTITIS

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
DENTITION
MUTATION IN CATHEPSIN
C GENE

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

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

This patient has advanced generalized aggressive
periodontitis with deep pockets throughout the mouth.

PAPILLON-LEFEVRE SYNDROME

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

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

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

 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

• 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

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

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

• 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

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 )

 IL-1 is a potent
stimulant of osteoclast
proliferation,
differentiation, and
activation
 TNF-ά have same
effects on osteoclasts
but less potent

Prostaglandins
Arachidonic 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

• 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

Macrophages produce prostaglandin E (PGE) and (IL-1) and
lymphocytes produce Interleukin-1 (IL-1) which activate
osteoclasts by interacting with osteoblasts

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 Periodontitis

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

Periodontal Repair occurs in
overlapping phases of
1. Inflammation shutdown
2. Angiogenesis
3. Fibrogenesis

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

Source of Anti inflammatory signal

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)

 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

 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

 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

Gingivitis
Intitial lesion –Neutrophils
Early lesion – lymphocytes
Established lesion-Plasma cells

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

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

 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

 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 LAP

 Patients with elevated antibody response
(IgG2) have less loss of attachment
 Antibody response in LAP greater than
GAP(Generalised aggressive periodontitis)

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

Host microbe interaction in periodontal disease

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