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MICROBIAL INTERACTIONS

WITH THE HOST IN


PERIODONTAL DISEASES
The interaction between the microorganism
with the host determines the course and
extent of the resulting disease.

Microorganisms exerts their pathogenic effect


by
directly by tissue destruction.
Indirectly by stimulating &modulating host
responces.
Host responses mediated by host microbial
interaction & inherent characteristic of host. E.g
genetic factors.

Functions in protective role by preventing local


infection to progress in systemic, life threatening
infections.

Interaction between host-microorganism leads to


local alteration and destruction of host tissue-
manifests periodontal disease.
Because of the varying balance between
beneficial and harmful effects of pathogenic
microorganism and host.

Wide variety of patterns and tissue changes in


patients.
Host microbe interaction
MICROBIOLOGICAL ASPECTS OF THE
HOST-MICROBIAL INTERACTION
The specific microorganisms found to be
associated with differing states of health and
diseases.

According to socransky, established a criteria to


identify periodontal pathogens,as
Association
Elimination
Host responses
Virulence factor
Animal studies
Studies of microbial interaction with host
includes:
Analysis of host response
Ability of microorganism to cause disease in
animal model

Virulence factor- the properties of a


microorganism that enable it to cause disease
is referred as virulence factor.
Virulence properties are broadly classified into
2 groups:

1. factors enable bacteria to colonize &


invades host tissue. And

2. factors that enable a bacterial species to


cause host tissue damage directly or
indirectly.
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.
Bacterial colonization & survival in
periodontal region
Bactrerial adhesion
Adherence as a virulence factor for periodontal
pathogen.
Surfaces for attachment of bacteria are
Tooth, root, tissues and pre-existing mass.
Attachment to the tooth is established by saliva
or pelicle coating of tooth surface. For e.g
actinomyces viscosus and p gingivalis though
fimbraie on bacterial surface and proline rich
protein on on saliva coated teeth surface.
in pre existing plaque mass bacteria may
adhere by properties like co aggregation
E.g adherence of a.viscous through fimbriae
to polysacchride receptors on cell of s. sanguis
Host tissue invasion
Bacteria may enter host tissue in two ways-
1.through ulceration in epithelium &
gingival sulcus or pocket.

2. direct penetration of bacteria in epithelial


or connective Tissue cell. For e.g p. gingivalis,
t.denticola invades tissue directly.
Ability to inavde---key roledistinguishing
pathogenic from non pathogenic bacteria.
Certainly localisation of bacteria to the host
tissues provide ideal position from which
bacterial toxins and enzymes are deliverd to
to the host cell.
& this may be the significans of invasion as a
virulence factor.
Some investigators found bursts of disease
activity in phase of bacterial invasion.
BACTERIAL EVASION OF HOST
DEFENCE MECHANISM
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 for e.g
Ability to adhere allows bacteria to avoid

displacement by host secretions


Invasion by which they disrupt the natural barriers

formed by host tissue cells.

Periodontal bacteria neutralize or evade host

defense through numerous other mechanism as


shown in the following table
MICROBIAL MECHANISM OF HOST
TISSUE DAMAGE
Some bacterial product inhibit the growth or
alter the metabolismm of host tiisue cells .

Ammonia, volatile sulfer compounds &fatty


acids peptides, indoles.
Variety of enzymes.
Immunological
aspects
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 &


organise 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
The chronic inflammatory cells, the

lymphocytes and monocytes organize connective

tissue changes associated with both

periodontal infections and periodontal repair

and healing.
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 cellincreses in gcf

Mast cell constitutely transcribe TNF-,

TNF-, IL-4, IL-6

When stimulated induce produce

Proinflammatory cytokines such as IL-1, IL-6,

INF-
Stimulation of endothelial cells by C5a,

IL-1, TNF- 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
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
Disorders of neutrophils are associated with
invasive periodontal infection and aggressive
periodontitis.

These defects can be in neutrophil chemotaxis or


phagocytosis.
DEFECT IN NEUTROPHIL FUNCTION AT ANY
STAGE LEADS TO AGGRESSIVE PERIODONTITIS
Transepithelial migaration

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) deposition of c3b on surface


Recognized by CR3 neutrophil receptor

phagocytosis.
Antigen presenting cells such as
Peripheral Dendritic cells
(langerhans,macrophages,B cells) are
abundant in gingival cells, high titre of
serum IGg .
phagocytosis
Entrapment of the bacterial cell into
membrane delimnated structure known as the
phagosome.

May be killed by oxidative or non oxidative


mechanisms.
Oxidative Killing by
NADPH Oxidase,
Myeloperoxidase,
Nitric oxide synthase
Non-oxidative Killing by
Defensin,
Lysozyme,
Neutral serine proteases
Bacterial permeability increasing protein
Conn.tissue alteration and tissue
destruction
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.
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.


5/15/17 Dr Saif Khan 40
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.

5/15/17 Dr Saif Khan 41


MMPs are inactivated by -macroglobulin found in

serum and GCF and by Tissue inhibitor of MMPs


(TIMP) produced by many cell types and common
in host tissue and fluids.
Other proteinases are neutrophil serine proteinase

,elastase, cathepsin G.
Tetracycline also inactivates MMPs and have

significant therapeutic role.

5/15/17 Dr Saif Khan 42


Cathepsin G is elevated in gingival tissue and

GCF.--bactericidal
Elastase degrades a wide range of molecules

including Elastin, Collagen, and Fibronectin.


Elevated Elastase level are associated with active

Periodontal attachment loss.

5/15/17 Dr Saif Khan 43


Cytokines
Three pro inflammatory cytokines IL-1, IL-6 and TNF-
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- is also produced by activated macrophages,
mast cells or lymphocytes, fibroblasts in response to
Bacterial LPS.
5/15/17 Dr Saif Khan 44
Also TNF- and IL-1 can activate macrophage IL-1

production
TNF- is primarily produced by Th1 subset of

CD4+ T cells that have been activated by antigen


or mitogen.

5/15/17 Dr Saif Khan 45


Proinflammatory effect of IL-1 and TNF-
are
Stimulation of endothelial cells slectins
recruitment of leukocytes.

Activation of IL-1production

Induction of prostaglandin .

Bone resorption and induction of tissue degrading

proteinases

5/15/17 Dr Saif Khan 46


IL-1 is a potent

stimulant of osteoclast
proliferation,
differentiation, and
activation
TNF- have same

effects on osteoclasts
but less potent
5/15/17 Dr Saif Khan 47
Prostaglandins
Arachidonic metabolite generated by

cyclooxygenase (COX-1, COX-2).


Found in plasma membrane of mast cells.

COX-2 is upregulated by IL-1, TNF- and bacterial

LPS leading to formation of PGE2 associated with


inflammation and attachment loss in periodontal
disease.

5/15/17 Dr Saif Khan 48


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

5/15/17 Dr Saif Khan 49


Macrophages produce prostaglandin E (PGE)
and (IL-1) and lymphocytes produce
Interleukin-1 (IL-1) which activate osteoclasts
by interacting with osteoblasts
5/15/17 Dr Saif Khan 50
PGE2 is released from monocytes of patients with

severe or aggressive periodontitis than patients

with little or no 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
5/15/17 Dr Saif Khan 51
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.


5/15/17 Dr Saif Khan 52
Periodontal Repair occurs in overlapping
phases of
1. Inflammation shutdown

2. Angiogenesis

3. Fibrogenesis

5/15/17 Dr Saif Khan 53


Inflammation shutdown
In post inflammatory healing process, shut down

of inflammatory processes and initiation of post


healing is organsied by leukocytes.
Anti inflammatory signals generated by leukocyte

are IL-1 receptor antagonist (IL-1ra) and


Transforming growth factor- (TGF-).
IL-4, IL-10, IL-11 also depress inflammatory

response

5/15/17 Dr Saif Khan 54


Source of Anti inflammatory
signal
IL-1ra

5/15/17 Dr Saif Khan 55


Angiogenesis and Fibrogenesis
IL-1 and TNF- participate both in inflammation

and healing
IL-1 and IL- 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).

5/15/17 Dr Saif Khan 56


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.

5/15/17 Dr Saif Khan 57


Also TGF- promotes the elaboration of fibroblast

extracellular matrix adhesion.

TGF- is potent inhibitor of osteoclast formation

Osteoclast differentiation and activation are

inhibited by interferon- (INF- ) which is secreted


by natural killer cells, Th1 cells and macrophages.

5/15/17 Dr Saif Khan 58


The main effect of INF- appears to be inhibition

IL-1 and TNF- induced osteoclast activation.


IL-1ra also effective in blocking IL-1 and TNF-

induced osteoclast activation

5/15/17 Dr Saif Khan 59


Microbiology and immunology
in gingival health
Gram positive facultative microorganismas .
E.g actinomyces and streptococcus.
Gram negative species and spirochetal forms also
found.
Serum antibodies to microorganisms low in titre
indicating minimal antigenic stimulation.
In health-gingival tissues show some of evidance
of inflammation.
Physical mechanisms of host defense include the
integrity of the epithelial cell layer, as well as the
shedding of epithelial cells and the flow of
crevicular fluid, which may function to clear
bacteria and their products from the subgingival
environment.

It is likely that the complement, neutrophils, and


antibody production contribute to controlling the
sulcular microbiota.
gingivitis
The most common is plaque-induced gingivitis.
Common clinical findings in gingivitis include
erythema, edema, tissue enlargement, and
bleeding.
Two forms of plaque-induced gingivitis have been
investigated:
a naturally occurring gingivitis and
Experimental gingivitis.
Experimental gingivitis is a longitudinal clinical
model that has been widely used in human and
animal studies."
In humans, experimental gingivitis is induced
through abstinence from oral hygiene measures;
in animal studies a soft diet favoring plaque
accumulation is instituted.
The studies of experimental gingivitis have clearly
demonstrated that plaque accumulation invariably
causes gingivitis and that gingivitis is reversible
with removal of the plaque deposits
Page and Schroeder reviewed the histopathology
of human and animal experimental gingivitis in a
classic article that delineated three temporal
stages of gingivitis:
initial, early, and established lesions

Intitial lesion Neutrophils

Early lesion lymphocytes

Established lesion-Plasma cells


Specialized forms of gingivitis include those
with hormonal changes, with medications, and
associated with systemic disease.

in these cases, evidence exists of an altered


host environment that appears to contribute
to an increase in host susceptibility to
gingivitis.
For example, the inflammatory response to
plaque during pregnancy appears to be
exaggerated, with an increased prevalence and
severity of gingivitis beyond that expected
for the level of plaque accumulation.
Alterations in the microbiota and the host
immune response to bacterial antigens during
pregnancy have been reported.
For example, increases in hormone levels appear
to correlate with increases in the subgingival
proportions of P. intermedia
Chronic periodontitis.
Bacterial etiology-
P.gingivalis, t.forsythia, p.intermedia,c.rectus,
F. nucleatum ,t.denticola. Actinobacillus
actinomycetemcomitans.

Involve activation of alternative pathway of


complement system with c3 and c3b clevage in
gingival fluid .

Increased collagen activity with periodontal


destruction.
Increased mmp -8 level whereas level of TIMP-1 is
not elevated.
Collagenase activity is 6 times greter than in
gingivitis.

Systemic factors that modify susceptibility to


periodontitis
include conditions such as diabetes and human
immunodeficiency virus (HIV) infection and
environmental
influences such as smoking and stress."
Aggressive periodontitis
Two forms localised and genralised
bacterial etiology
A.actinomycetemcomitans.
Other organisms like p.gingivalis, e.corrodence
,c.rectus, f.nucleatum, capnocytophaga species
and spirochetes.
Virulence factors- leukotoxin productionbind to
phagocytes and cause lysis.
Inhibit lymphocyte function
Immunological considerations.

Numerous mechanisms are available of serum


mediated bacterial killing including lysis of
membrane attack complex of complement and
enzymes like lysozyme.

Studies of LAP have revealed a number of aspects


of neutrophil function that may result in
compromised bacterial killing and have been key
in demonstrating the importance of neutrophil
function in periodontal health and disease.
Approximately 75% of patients with LAP have
dysfunctional neutrophils, involving a
decreased expression of G-protein coupled
receptors.

The defect is evident as a decrease in the


chemotactic response to several chemotactic
agents, including the complement component
C5a, N-formyl-methionvl leucyl phenylalanine
(FMl.P), and leukotriene B4.
The defect is associated with a membrane
glycoprotein, GP110, on the neutrophil surface.
function of GP110 is unknown, but diminish
GP110 expression associated with diminished
surface expression of all G protein coupled
receptors.
For this reason, this neutrophil defect has been
called a global membrane receptor detect.
The precise dysfunction caused by the (,-protein
coupled
receptor deficiency responsible for disease has
not been
However, neutrophil transendothelial migration,
transepithelial migration, chemotaxis, secretion,
and priming can be affected.
in lAP the predominant collagenase found in
tissues and crevicular fluid is MMP-I, and elevated
levels of TIMP-1 are present.
Elevated level of antibodies.
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