Periodontal pathogenesis

PERIODONTAL PATHOGENESIS
Presented by:-
Richa Sharma

INTRODUCTION
Pathogenesis is defined as the origination and development of a
disease. It is a step-by-step process that leads to the
development of a disease, resulting in a series of changes in
the structure and function. It is the process by which the
etiologic factor causes the disease.
Carranza 11th edition

HISTOPATHOLOGY OF PERIODONTAL DISEASE
Periodontal pathogenesis
histologic appearance
Clinically healthy Inflamed periodontal and gingival tissue
gingival tissue
Even in the gingival that appear clinically normal there is a chronic low-grade
challenge presented by sub-gingival plaque bacteria.
Essential mechanism to combat the microbial challenge to prevent
bacteria and their products from infiltrating tissues.
But an excessive, dysregulated, immune-inflammatory response for a given
bacterial challenge leading to increased tissue breakdown.

CLINICALLY HEALTHY GINGIVAL TISSUES
Clinically healthy gingival tissue is not inflamed, pink in appearance, not
swollen and firmly attached to the underlying tooth/bone, with minimal
bleeding on probing. The Dento-gingival junction is a unique anatomic
feature whose function is the attachment of the gingiva to the tooth.
Epithelial portion Connective tissue portion
Both are of fundamental importance in periodontal pathogenesis.
Gingival epithelium
Junctional epithelium
Sulcular epithelium
DENTO-GINGIVAL
JUNCTION
EPITHELIAL
STRUCTURE

GINGIVAL EPITHELIUM
 Stratified squamous keratinized epithelium
 Continuous with the sulcular epithelium at the gingival crest/gingival
margin.
 Covers the gingiva and forms the clinically visible gingival tissues.
 Covers both the free and attached gingival tissues.
SULCULAR EPITHELIUM
 Stratified squamous epithelium.
 Non-keratinized
 Faces the tooth but it not attached to it.
 Forms the soft tissue lining of the gingival sulcus or periodontal pocket.

JUNCTIONAL EPITHELIUM
Unique epithelial structure
Specialized for the purpose of attachment to the tooth.
Unlike other epithelial tissues elsewhere in the body, there is no
opportunity for sloughing of cells from the surface.
The extracellular spaces between the junctional epithelium are also
greater than other epithelial tissues, with intercellular comprising
approximately 18 % of the volume of the epithelium.
This is a result of a lower density of desmosomes in the junctional
epithelium compared to the gingival epithelium, and the hence
junctional epithelium is “intrinsically leaky”.
This has great relevance in periodontal pathogenesis, as the
widened permit migration of neutrophils and macrophages from the
gingival connective tissue to enter sulcus to phagocytose bacteria,
as well as ingress of bacterial products as well as antigens.

According PAGE and SHROEDER in 1976
Low grade inflammation Sub-gingival
micro flora
Overt clinical signs of gingivitis do not develop because innate and structural
defense mechanisms, including the following:-
If the plaque accumulation increase so that these defense mechanism are
overwhelmed, then inflammation and the classic clinical signs of gingivitis
develop.
 The maintainence of an intact epithelial barrier.
Outflow of GCF from the sulcus.
Sloughing of surface epithelial cells of the junctional and sulcular
epithelium.
Presence of neutrophils and macrophages in the sulcus,
phagocytosing bacteria.
Antibodies in the GCF.

HISTOPATHOLOGY OF GINGIVITIS AND PERIODONTITIS
Infiltration of the tissues by numerous defense cells, particularly neutrophils,
macrophages, plasma cells, and lymphocytes.
Accumulation of defense cells and the extracellular release of their
destructive enzymes
There is disruption of the normal anatomy of the connective tissues resulting
in collagen depletion and subsequent proliferation of junctional epithelium.
Vasodilatation and increased vascular permeability leads to increased leakage
of fluid out of the vessels, and
facilitates the passage of defense cells from the vasculature into the tissues
which appear erythematous and edematous.

HISTOLOGIC STAGES OF GINGIVITIS AND PERIODONTITIS
Page and Schroeder; Lab Invest, 1976
INITIAL LESION EARLY LESION
Develops within 2 to 4 days
No inflammation is evident
microscopically
This lesion corresponds to
histologic picture of clinically
healthy gingival tissues.
Slightly elevated vascular
permeability and
vasodilatation.
GCF flows out of the sulcus
leading to flushing action.
Migration of leukocytes,
primarily neutrophils in small
numbers through the gingival
connective tissues into the
sulcus.
Corresponds to early
gingivitis that is evident
clinically
Develops after about 1 or 4
to 7 days week of continued
plaque accumulation
Increased vascular
permeability, vasodilatation ,
GCF flow.
Large no. of infiltrating
leukocytes mainly neutrophils
& lymphocytes.
Degeneration of fibroblasts.
Collagen destruction,
resulting in collagen depleted
areas of the connective tissue.
Proliferation of junctional
and sulcular epithelium into
collagen-depleted areas.

Established Lesion Advanced Lesion
This lesion develops from
14 to 21 days add corresponds
to chronic gingivitis.
Dense inflammatory cell
infiltrate i.e. plasma cells,
lymphocytes, neutrophils
Elevated release of MMPs
and lysosomal contents from
neutrophils.
Significant collagen
depletion and proliferation of
epithelium.
Formation of pocket
epithelium containing large
numbers of neutrophils.
It marks the transition from
gingivitis to periodontitis.
This transition is determined
by bacterial challenge, host
inflammatory response and
bacterial challenge and
susceptibility factors.
Predominance inflammatory
cells in the connective tissues.
Predominant immune cells
are plasma cells.
The basal lamina differs
from other basal laminae that
oppose connective tissue in
that type IV collagen is
absent.

INFLAMMATORY RESPONSES IN THE PERIODONTIUM
During the inflammatory response there are specific molecules which signal
tissue damage as the inflammatory response develops:-
Sub-gingival micro flora host immune-inflammatory response
The bacteria are important because they drive and perpetuate the
inflammation but they are responsible for a relatively small proportion of
tissue damage.
CARRANZA 11thedition
1) Microbial Virulence Factors
2) Host-Derived Inflammatory Mediators
3) Role of Specific Inflammatory Mediators

MICROBIAL VIRULENCE FACTORS
1) LIPPOLYSACCHARIDE
Lipid component Polysaccharide component
(Lipid A)
 Found in the outer membrane of gram-negative bacteria
 Act as endotoxins
 Elicit a strong immune response
 Have an important role in maintaining the structural integrity of bacterial
cells.
Immune system recognizes LPS through toll-like receptors(TLRs) .
TLRs are cell surface receptors that recognize microbe-associated molecular
patterns (MAMPs) which are conserved molecular structure located in
diverse pathogens.

TLR-4 recognizes LPS from gram-negative bacteria and functions as part of a complex of
cell surface molecule, including CD14 and MD-2 ( known as lymphocyte antigen 96).
Like LPS component of gram-positive cell walls lipoteichoic acid (LTA) also stimulates
immune response although less potently than LPS.
CD14/TLR-4/MD-2 LPS or LTA
increased production of inflammatory mediators
increased vasodilatation and vascular permeability, recruitment of
inflammatory cells by chemotaxis,
release of pro-inflammatory mediators by leukocytes which recruite to the area of
inflammation.
LPS in particular is a key importance in initiating and sustaining inflammatory responses in
gingival and periodontal tissues.

2) Bacterial Enzymes and Noxious Products
Plaque bacteria produce a number of metabolic waste products which
contribute directly tissue damage. These noxious agents include ammonia,
hydrogen sulfide and short chain fatty acids.
These substances have pro-found effect on host cells which are as follows:-
a) The short chain fatty acid aid P.gingivalis infection through tissue
destruction and also create a nutrient supply for the organism the
bleeding into periodontal pocket.
b) Plaque bacteria produces Proteases which are capable of break downing
the structural components of the periodontium such as collagen, elastin.
These digest proteins and provide nutrition to bacteria.

c) P.gingivalis produces 2 classes of cysteine proteases known as
GINGIPAINS
Lysine-specific gingipain Arginine-specific gingipain
Rgp A Rgp B
The gingipains modulate the immune system and disrupt immune-
inflammatory responses. Potentially leading to increased tissue damage.
These can reduce the concentration of cytokines and digest and inactivate
TNF-α.
Stimulate cytokine secretion via activation of protease activated receptors
(PARs) thereby stimulating cytokine secretion.

3) Microbial Invasion
 Periodontal pathogens such as P. gingivalis and a.a. invade the gingival
tissues including connective tissue. A. Actinomycetemcomitans can invade
epithelial cells and persist intracellularly.
J Periodontol 67:291-297,1996
 Acc. to some investigators tissue invasion is a passive translocation process
and according to the others it is an active process. But the presence of
bacteria justifies the use of antibiotics to some extent which are protected
from mechanical disruption by root surface debridement.
 The bacteria in the tissues represent the reservoir of re-infection after non-
surgical management. However the clinical relevance of bacteria being
present in the tissues is better defined, it is inappropriate to make clinical
treatment decisions (e.g., whether to use adjunctive systemic antibiotics) on
this premise alone.

4) FIMBRIAE
The fimbriae of certain bacteria particularly P. gingivalis play important role in
pathogenesis.
Major fimbrial structural component of P.gingivalis, Fim a
Secretion of IL-6. IL-8 and
TNF-α
stimulation of nuclear factor
NF-κB and IL-8 in gingival
epithelial cell line Interaction with complement
receptor-3 to activate
intracellular signalling
pathways that inhibit IL-12
production.
This may be of clinical relevance as IL-12 is important in activating natural killer
(NK) and CD8+ cytotoxic T-cells which themselves are important in killing
P.gingivalis – infected host cells such as epithelial cells.

5) Bacterial Deoxyribonucleic Acid and Extracellular Deoxyribonucleic
Acid
Bacterial DNA stimulates the immune cells via TLR-9 which recognize s
hypomethylated CpG regions of DNA. These are regions of DNA at which a
cytosine nucleotide is found next to a guanine nucleotide separated by phosphate
molecule.
Extracellular DNA plays important role in the development and structure of the
biofilm formed by oral bacteria and there are majority of eDNA released after cell
lysis.
This donated DNA is of prime importance as it acts as a means of increasing genetic
diversity , if taken up by other bacteria.
Contributing to antigenic variation and spread of antibiotic resistance,
Modulation of host immune response.
Hence eDNA is a source of genetic information for naturally transformable
bacteria in biofilm and also acts as a stimulus for host immunity.

HOST DERIVED INFLAMMATORY MEDIATORS
BY-STANDER DAMAGE
The inflammatory and immune processes that develop in the periodontal
tissues in response to the long-term presence of sub-gingival bio-film are
protective by intent but result in considerable tissue damage.
Majority of the tissue damage in periodontitis derives from the excessive and
dysregulated production of a a variety of inflammatory mediators and
enzymes which are broadly classified as follows:-
 CYTOKINES
 PROSTAGLNDINS
 MATRIXMETALLOPROTEINASES

CYTOKINES
Cytokines play a fundamental role in inflammation and are key inflammatory
mediators in periodontal disease.
 Cytokines are soluble proteins, secreted by cells, which act as messenger
molecules that transmit signals to other cells and initiate intracellular
signalling cascades resulting in phenotypic changes in cell.
 Cytokines are produced by- neutrophils, macrophages & lymphocytes
alongwith resident cells including fibroblasts and epithelial cells.
CYTOKINES
Profound biologic effects Significant overlapping activity
 signal, broadcast and amplify Cytokines function in complex
immune response networks that involve both
 Mediate connective tissue and pro-inflammatory and anti-
alveolar bone destruction through inflammatory effects that brings
induction of fibroblast & osteoclasts together both the aspects of
production of proteolytic enzyme. Innate and acquired immunity.

IL-1 Family Cytokines
IL-1β
IL-1β stimulates the synthesis of PG2, PAF, NO that causes vascular
changes associated with inflammation.
It increases the expression of ICAM-1 on endothelial cells and
stimulate the secretion of chemokines.
It synergises with other proinflammatory cytokines and PGE2 to
induce bone resorption.
It has a role in adaptive immunity and regulates the development of
antigen-presenting cells such as dendritic cells.
Key role in
inflammation
Innate immune
response
Secretion of
mediators

b) IL-1α intracellular protein & potent bone resorbing factor
An “alarmin’’ to signal the immune system during cell damage.
c) IL-1Ra - binds to IL-1 receptor (IL-R1).
 However, binding of IL-Ra does not result in signal
transduction, therefore IL-1Ra antagonizes the action of IL-1β.
 It is important in regulating inflammatory and considered to
be an anti-inflammatory cytokine.
d) IL-18 - interacts with IL-1β. It is produced by stimulated
macrophages and monocytes.
It results in pro-inflammatory responses including activation of
neutrophils.
It is a chemoattractant for T-cells, and it interacts with IL-12 and IL-
15 to induce Th1 cells cell-mediated immunity.

e) TNF-α: it is secreted by activated macrophages, particularly in
response to bacterial LPS.
Proinflammatory effects:
• Stimulation of endothelial cells to express selectins that
facilitate leukocyte recruitment.
• Activation of IL-1b production.
• Induction of PGE2 by macrophages and fibroblasts.
• GCF levels of TNF-α increases as gingival inflammation
develops.

ANTI-INFLAMMATORY CYTOKINES
 Anti-inflammatory cytokines include IL-10, TGF-β, IL-1Ra,
IL-1F5, IL-1F10.
 IL-10 family of cytokines have multiple pleiotropic effect and
possess immunosuppressive properties.
 It is produced by T reg cells, monocytes, and B-cells and it
suppresses the secretion of Th1 cells, Th2 cells, monocytes,
macrophages.
 TGF-β is a growth factor and functions as a cytokine with
immunoregulatory role.
 It plays important role in repair and regeneration, apoptosis
and angiogenesis.

CHEMOKINES
These are cytokine-like molecules that are characterized by their
chemotactic activity.
Chemokines orchestrate leukocyte recruitment in physiologic
and pathologic conditions and are therefore important in
periodontal pathogenesis.
The chemokine CXCL8, also known as IL-8, is found in the
areas of plaque accumulation as well as GCF.
Interaction between bacteria and cytokines leads to up-
regulation of IL-8 which is responsible for development of
chemotactic gradient and also stimulates neutrophil migration
in the sulcus. Similar chemotactic gradient is present in
periodontally healthy tissues.

2) Prostaglandins - It is a group of lipid compounds derived
from arachidonic acid, mainly mediated by cyclo-oxygenase
and lipo-oxygenase pathway..

 The cells primarily responsible for PGE2 production in the
periodontium are macrophages and fibroblasts.
 Its level is increased in the tissues and in GCF at sites
undergoing periodontal attachment loss.
 These are important mediators of inflammation,
particularly, PGE2, which results in vasodialation and
induce cytokine production.
 COX-2 is upregulated by IL-1b, TNF-a and LPS leading to
increased production of PGE2 in inflammed tissue.
 PGE2 results in induction of MMP’s and osteoclastic bone
resorption and has a major role in contributing to tissue
destruction that characterizes periodontitis.

3) Matrix metalloproteinase's- It is a family of proteolytic enzymes
that degrade extracellular matrix molecules such as collagen,gelatin
and elastin.
It is produced by variety of cells including macrophages, neutrophils,
fibroblasts, epithelial cells, osteoclasts.
Latent form Activated form
Proteases such as Cathepsin G
produced by neutrophils.
These MMP’s are inhibited by
• Tissue inhibitor of metalloproteinase (TIMPs)
• Glycoproteins α-1 antitrypsin and α-2 macroglobulin.
• Tetracycline class of antibiotics.

Inflamed periodontal tissues
excessive quantities of MMPs
large quantities of infiltrating cells
MMPs Inhibitors
Development of collagen depleted areas within connective
tissue
The predominant MMPs in periodontitis, MMP-8 and MMP-9
are secreted by neutrophils and are very effective in degrading
type I collagen, the most abundant type in the PDL.

If inflammation becomes more extensive because of
increase in bacterial challenge
Increased vascular permeability, vasodilatation leading to
edema, erythema.

Gingival swelling, slight deepening of sulcus further
compromises plaque removal.
Increased infiltration of inflammatory cells leads to
development of collagen depleted areas below epithelium
and the epithelium proliferates to maintain its integrity.

If the bacterial challenge persists, the cellular and fluid infiltration
continues to develop and inflammatory cells soon occupy a significant
volume of inflamed gingival tissues.
NEUTROPHILS
Phagocytose
and kill bacteria
Release large
quantities of MMP’s
leading to breakdown
of structural
components of
periodontium.
Release potent
lysosomal
enzymes,
cytokines, ROS
causing further
tissue damage.
The opportunity for repair starts getting limited. The epithelium
continues to proliferate apically, deepening the pocket further (which
is rapidly colonised by subgingival bacteria.)

As the epithelium proliferates , necrosis of epithelial
cells that are more distant from connective tissue can
lead to intraepithelial clefts and splits.
FIRST STAGE OF POCKET FORMATION
• A cycle of chronic inflammation sets in , characterized by
leucocytes, release of inflammatory mediators and destructive
enzymes, connective tissue breakdown and proliferation of
epithelium, in apical direction.

• It is an active process that results in a return to normal
haemostasis, and is mediated by specific molecules including a
class of endogenous lipid mediators, lipoxins, resolvins and
protectins.
i. Lipoxins: LX A4, B4. They also signal macrophages to
phagocytose the remnants of apoptotic cells at sites of
inflammation, without generating an inflammatory response.
ii. Resolvins: They inhibit neutrophilic infiltration and
transmigration, they inhibit production of inflammatory
mediators.
iii. Protectins: They reduce cytokine expression and also inhibit
neutrophilic infiltration.

IMMUNE RESPONSES IN PERIODONTAL
PATHOGENESIS
Immunity is defined as the resistance of a host to pathogens and their
toxic products.
 Innate factors such as complement, resident leukocytes and mast cells
play an important role in signaling endothelium, thus initiating
inflammation.
 Acute inflammatory cells (i.e. neutrophils) protect local tissues by
controlling the periodontal microbiota within the gingival crevice and
junctional epithelium.
 Chronic inflammatory cells, protect the entire host from within the
subjacent connective tissues .

Schematic illustration of the changes in the gingival tissues during the
development of gingivitis and periodontitis

 Resistance to infection which an individual possesses by
virtue of his genetic and constitutional make up.
 Prior contact with microorganisms or their products is not
essential.
 Refers to the elements of the immune response that are
determined by inherited factors (innate).
 Limited specificity
 “Fixed” (they do not change or improve during an immune
response or as a result of previous exposure to the pathogen.
 They are activated when the primary defenses are breached.
 If innate responses fail to eliminate infection, then the effecter
cells adaptive immunity (lymphocytes) are activated.

 Saliva secreted from three major salivary glands as well as from numerous
minor glands has an important role in maintaining oral health.
 It contains molecular components that contribute to host defenses against
bacterial colonization and PDL disease.
 These components include
 Saliva contains IgA to PDL pathogens that target specific Ag and inhibit
bacterial adherence
Molecules
that non
specifically
inhibit
plaque
formation
That inhibit
specific
virulence
factors eg;
Histatins that
neutralise
LPS
That
inhibit
back cell
growth
and
induce
cell death

 These are main initial site of interaction between plaque bacteria
and host.
 The keratinized epithelium of sulcular and gingival epithelial
provides protection for underlying PDL tissues ; also acts as barrier
against bacteria and their products.
 Epithelial cells stimulated with bacterial components and cytokines
produce
MMP’S
contribute to loss of connective tissue.
 Epithelial cells express antimicrobial peptides and the synthesis and
secretion of these molecules is up regulated in response to
periodontal bacteria.

 These antimicrobial peptides have a wider role in regulating
innate and adaptive immune responses to infection.
 These have chemokine-like activity, stimulating the
chemotaxis of a range of leukocytes involved in innate and
acquired immunity.
GINGIVAL CREVICULAR FLUID
It has a flushing action in gingival crevice but also likely
factions to bring the blood components of host defenses in the
sulcus
 Flow of GCF increases in inflammation, and neutrophils are
an especially important element of GCF in health and disease.

Penetration of PDL tissue by plaque, bacteria and their products
Sentinel cells recognize their presence and signal protective immune
responses
Dendritic cells express a range of pattern recognition receptors(PRPs)
that interact with specific molecular structures on microbes –
MAMP’s
Activation of immune response to provide immediate protection
Excessive and inappropriate immune response

 It is slower and reliant on complex interactions between
antigen presenting cells, T and B lymphocytes.
 Key elements:
i. Antigen specificity of the responses that facilitate specific
targeting of a diverged range of effector elements (cytotoxic
T cells and antibodies)
ii. The ability to improve during exposure to antigen.

 T cells are predominant in gingivitis and stable periodontal
lesions.
 In contrast, in active periodontitis, B cells predominate and
are associated with pocket formation and progression of
disease.

 MHC is a locus on short arm of chromosome 6 (6p21.3) that
encodes MHC classes I,II, III, which are involved in antigen
uptake, processing and presentation.
 MHC class I molecules: present intracellular antigens to
CD8+ T cells and NK cells.
 MHC class II molecules: present extracellular antigens to
CD4+ Tells.
 MHC class III molecules include complement factors B, C2
and C4.

Includes B cells, macrophages, dermal dendritic cells and
Langerhan cells
These cells naturally express MHC-II molecules to activate
specific effector T cells.
Generate antigen specific immune response to periodontal
pathogens.

Th1 Cells secrete
Th2 cells secrete
IFN gamma
Activates Cell Mediated Immunity
Macrophages NK cells CD8+ cells
IL-
4,5,13.
Activates Humoral (Antibody) mediated
Immunity.

 Specific antibodies are produced in response to increase in
bacterial challenge in periodontal disease.
 End point of B cell activation.
 High levels occur in GCF and these are produced locally by
plasma cells in periodontal tissues.
 Antibodies to periodontal pathogens are primarily IgG with
few IgM or IgA types produced.

CONCEPT OF HOST SUSCEPTIBILITY
Immune responses to the bacterial challenge never occur in isolation but take
place in the context of other host and environmental factors that influence
these responses and thereby determine the progression of disease.
HYPER-INFLAMMATORY RESPONSE TRAIT
The hyper-responder concept was originally proposed in the context of
responsiveness of monocytes to LPS challenge, suggesting the subjects
with disease possess an individual hyper-responsiveness monocytic trait,
characterized by elevated levels of inflammatory mediators released from
monocytes in response to bacterial challenge.
Individuals are considered normal for a given bacterial challenge in which
there is production of certain levels of inflammatory mediators in
periodontal tissues.
Those who are hyper-responders, the same bacterial challenge results in a
greater inflammatory response which over time would produce increased
tissue damage. & earlier presentation of clinical signs of disease.

DOSE-RESPONSE CURVE
 A certain level of bacterial challenge results in a moderate release of
inflammatory mediators which together with infiltrating defense cells have
a protective role in eliminating bacteria in the sulcus and do not trigger
periodontal disease breakdown.
 Such a steady-state scenario may persist indefinitely.
 But any alteration in the quantity and quality of bio-film or alteration of
host defense leads to increased secretion of inflammatory mediators
leading to histopathologic changes.

 There is a threshold therefore between stable and active
disease, and this varies from person to person.
 The dose-response curve for any individual can shift to left or
right according to environmental changes.
 A shift to the left would result in increase in quantities of
inflammatory mediators produced for a given bacterial
challenge. And potentially an exacerbation of disease.
 A shift to right will have an opposite effect.
 In all cases, an increase in the LPS challenge would have the
tendency to increase the production of inflammatory
mediators, which may tip the site from a stable to a
progressing periodontal lesion.

MODEL FOR PATHOGENESIS OF PERIODONTITIS
 Plaque bacteria initiate the inflammatory response but most of
the tissue damage results from the host response which is
influenced by genetic factors and environmental and acquired
risk factors.
 These factors, such as smoking, or genetic risk factors alter the
progression of the immune-inflammatory response and shift
the balance toward increased periodontal breakdown.
 This model implies that the presence of plaque bacteria does
not inevitably lead to tissue destruction and is supported by a
large number of epidemiologic studies, which confirm that
more advanced disease is usually confined to a minority of the
population.

Biologic systems model
Represents periodontal pathogenesis, which involves bacterial
components, environmental factors, specific inflammatory
mechanisms, and host-genetic variations associated with
disease.
System includes a person level, a genetic/epigenetic level, the
biologic phenotype, and ultimately the clinical phenotype

REFERENCES
1.Carranza’s Clinical Periodontology, 11th edition
2.Periodontol 200 31:167-180,2003
3. Periodontol 2000 31:167-180,2003
4. Orbans , oral histology and embryology, 12th edition
5. Acta Odontol Scand 65-13, 2007

Periodontal pathogenesis

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