PATHOGENESIS OF
PERIODONTITIS AND HOST
RESPONSE I
1
Dr SC Manenzhe
BDS 3 /2019
OBJECTIVES

Discuss microbial plaque and host interaction
Microbial Virulence factors
 Kornman pathogenesis of periodontitis model of 1997
 From health=gingivitis=periodontitis Chappel model
 Periodontitis multifactorial disease


Discuss Immuno-inflammatory response

Innate and adaptive immunity interactive
relationships/the difference?






Cellular components of the immune system
Major histocompatibility complex (MHC-I & II)
Inflammatory mediators
Pattern recognition receptors
 Toll like receptors & PAMPS
Complement cascade
Osteo-immunology (RANK/RANKL/OPG)
2
INTRODUCTION

Pathogenesis =The development of a disease and the chain of
events leading to that disease


Process by which the aetiologic factor + other factors cause diseases
Disease expression and progression reflects the interplay between:

The microbial plaque (including complexes +AA), the host’s immuneinflammatory response and environmental factors

Periodontitis is polymicrobial infection

Gingivitis =precursor for periodontitis

An understanding of the aetiology and pathogenesis of
periodontitis provides a basis for treatment planning and future
risk assessment
3
HOST AND DENTAL PLAQUE INTERACTION
Microbial Attack vs. Defense Reactions by the Host

The virulence of bacteria:
 their capability to invade into
tissues
 their number and composition
 their metabolic products
(enzymes & toxins) and “signal”
substances that activate
macrophages and T-cells
Elicit reactions by the host
(immune-inflammatory
response).
Whether periodontal disease will occur, and its severity,
depends
Upon the bacterial insult and host response
4
EVOLUTION: PATHOGENESIS OF PERIODONTAL
DISEASE
1960’s
model
1980’s
model
(Source: Kornman, K.S., 2008. Mapping the pathogenesis of periodontitis: a new look.
Journal of periodontology, 79(8S), pp.1560-1568.)
Pathogenesis of periodontitis
Kornman, Page and Tonetti 1997: model of pathogenesis of
periodontitis
Critical
!!
6
DEVELOPMENT OF COMPLEXES

Bacteria no longer work as single entities: The biofilm
acts and reacts as a stable “organism.”
Pathway (A-G) leads to the “red complex,”
 Pathway (A-D) leads to Aa.

Complex development Dependent upon host response, availability of
nutritive substances, and interbacterial competition
7
VIRULENCE FACTORS OF (PG)
8
Pg is a strict anaerobe, and is therefore present in increased numbers in deep
pockets
VIRULENCE FACTORS OF (AA)
9
MICROBIAL
CHALLENGE ROLE IN PERIODONTAL TISSUE DESTRUCTION
In order to elicit periodontitis,
microorganisms must:
•
Establish themselves near the
host tissue
•
Avoid being eliminated by saliva
or exudates
•
Avoid the defense mechanisms of
the host and other
microorganisms
•
Find appropriate nutrition
•
Be capable of destroying
periodontal tissues.
Progressive periodontitis is
characterized not only
by elevated levels of bacterial
substances e.g LPS
But also by pro-inflammatory
mediators.
10


Microbial plaque biofilm=initiates and perpetuates the
inflammatory response
The nature of the immune-inflammatory response
=major determinant of sucseptibility to periodontitis


It is paradoxical that the defense mechanisms (has protective
intent) result in majority of tissue destruction seen
Susceptible host

Excessive or dysregulated host response==increased tissue
breakdown
11
MICROBIAL PLAQUE NECESSARY BUT NOT SUFFICIENT
Aetiology of Periodontitis Interaction between: Dental Plaque + the
susceptible Host
Influence the existence and the
clinical course of periodontitis
Modify immune-inflammatory response.
Time
Influence plaque
formation +
host immune
response
Influence the
systemic and psychic
well being
Influence the
immune
status.
12
13
HOST SUSCEPTIBILITY –HOST RESPONSE TO INSULT
Maintaining periodontal health involves a complex immune response to the
plaque biofilm.
Surveillance by the immune system protects an individual by
recognizing and responding to antigens,
When the immune system is overwhelmed, clinical symptoms of
disease become evident.
Responsiveness of the immune system + the amount and type microorganisms/ various antigens
• Defective immune responses
• Hyperreactive immune
BIOLOGICAL AND CLINICAL SIGNS OF
INFLAMMATION
Inflammation is a wellcoordinated process to
plaque accumulation and
includes:
Increased vascular
permeability
Classical signs of
inflammation:
Red
Swollen
Secretion of inflammatory
mediators and activation of
complement system
Painful
Hot
Migration of PMN; monocytes
(macrophage) and
lymphocytes into the tissues
Possible loss of function
HOST RESPONSE: MECHANISMS + COMPONENTS
First Axis of the Host IMMUNE System consists of:
• Phagocytes, NK cells and also diverse molecular effectors (complement, Creactive protein, etc.)
• complement
Second Axis of the IMMUNE System consists of:
• Specific immunity
• Lymphocytes (T- and B-cells)
• Antigen-presenting cells (APC) e. g., macrophages/MΦ)
• The various immunoglobulins.
Each and every cell that is involved in maintenance of
periodontal tissue integrity
• Synthesizes a large spectrum of cytokines and other mediators.
16
• Even the resident (non-mobile) cells are active in the immunologic process.
HEALTH
Homeostasis
PERIODONTITIS
Plaque
accumulation
Non-specific
17
Shift in microbial flora
Murakami et al., 2018
Clinical Flow Diagram:
From Gingivitis to
Periodontitis
18
THE TWO DISTINCT ARMS OF THE IMMUNE RESPONSE
The innate immune response
Not antigen specific (no
memory)
• Response the same
with each exposure
Physical barrier
Adaptive immune response
The distinction of the 2 has
become blurred over the years
• Responsiveness enhanced with the discovery that:
Antigen specific
with repeated antigen
exposure
• Recognition of the
pathogens (immunologic
memory)
Delayed response time
Immediate protection
Antibodies, cytokines
Cytokines, complements
The innate immune
response determines the
nature of the subsequent
adaptive response
Aspects of the adaptive
response control the
effectiveness of the innate
response
stronger
19
IMMUNITY

“Free of burdens”

In medical terms it denotes
Freedom from disease
 Resistance to infectious disease

20
HOST RESPONSE: COMPONENTS
21
Facilitates cell-cell relationships ,signal
formation, antigen presentation
22
PATHOGENESIS OF PERIODONTITIS
23
INNATE IMMUNITY RESPONSE
Components present before the onset of infection.
Disease resistant mechanisms that are not specific to a
particular pathogen
Pathogens must first breach barriers that protect host
Provides the first line defence right after exposure.
Most micro-organisms are readily cleared within a few days by
innate immune system before adaptive immune system is activated
24
INNATE DEFENSE SYSTEMS: 1ST LINE OF DEFENSE NONSPECIFIC IMMUNITY POSSESSES NO “MEMORY.”
Vascular and
cellular
inflammatory
responses
Barrier
mechanisms:
physical &
chemical
Complement
cascade
Vascular
Gingival crevicular
inflammatory events fluid
Cellular
Saliva
inflammatory events
(PMN’s)
Oral epithelium
25
SALIVA
Saliva
26
CONSTITUTION OF GCF
Cellular Elements
• Bacteria, desquamated epithelial cells, and leukocytes
(PMNs, lymphocytes, monocytes/macrophages)
Electrolytes
• Potassium, sodium, and calcium
Organic Compounds
• Carbohydrates and proteins
Metabolic and bacterial products
• Lactic acid, urea, hydrogen sulfide
27
GCF ROLE IN IMMUNITY
JE allows movement of GCF and the cells
molecules of innate immunity
 Flushing action
 Brings the blood components (e.g., neutrophils,
antibodies, and complement components) of the
host defenses into the sulcus.
 The flow of GCF increases in inflammation

28
Flushing effect
1. Flushing
action
2. Brings blood
components to
the area
29
EPITHELIAL ROLE IN IMMUNE RESPONSE
1.
Barrier
Keratinization
 Shedding

2.
Pattern recognition receptors

3.
Microbial plaque recognition molecules
Releases IL-1, IL-8 (Chemotactic for PMN)
30
LOSS OF EPITHELIAL INTEGRITY
In the depth of the active pocket bacteria
invade the connective tissue (red bars) via the
ulcerated epithelium
Tissue damage
31
Vascular and cellular immunoinflammatory responses
Barrier
mechanisms
Vascular events
Gingival
crevicular fluid
Complement
cascade
Cellular events (PMN’s, Macrophages, Saliva
Natural killer cells)
• Involves the mechanisms of
pathogen recognition, phagocytosis Oral epithelium
(killing and digesting of
• Physical
microorganisms) and acute
barrier
inflammation
Epithelial cells Via Toll like receptors
• Immunologic process
32
VASCULAR INFLAMMATORY RESPONSE
Bradykinin:
Increases
vascular
pearmeability
(Source: https://www.slideshare.net/SimbaSyed/acute-inflammation-21504202)
PATTERN RECOGNITION RECEPTORS
Family – Toll like receptors (TLRs)
Expressed predominantly in cells which mediate first-line defense.
• e.g. neutrophils, monocytes/ macrophages, and dendritic cells, as well as epithelial
cells
• The activation of PRR in this cells activates innate immune response
TLRs have the ability to recognize structures known as
pathogen‐associated molecular patterns (PAMPs) across wide variety of
pathogens
• They bind microbial cell molecules, such as lipopolysaccharides, microbial fimbriae,
and lipoteichoic acid (GRAM +VE)
The activation of TLR e.g. TLR-4 (principal LPS receptor) & TLR-2
induces the expression of a variety of cytokines that are crucial in
adaptive immune responses.
34
PATTERN RECOGNITION RECEPTORS
(PRRS)


The discovery of TLRs have prompted the “bar code” hypothesis of
innate recognition of microbes.
TLRs read a “bar code” on microbes and the interaction result in:


Intracellularly tailored appropriate type of innate responseare to plaque
biofilm
Different TLR respond to different PAMPs
35
Recognition of PAMPs
Interaction of PAMPs with TLRs
36
Connective tissue and bone destructionm
Cells with first
line of defense +
epithelial cells
PAMPs
Tissue
repair
Activation of innate
and adaptive immune
system
37
TLR ACTIVATION LEADS TO
Regulation of the innate immune response
 Regulation of the adaptive immune response
 Inflammation
 Tissue repair


Toll-like receptors interact with pathogens
and induce cytokines, which may aggravate
disease
38
PAMPS AND PRR INTERACTION
The activation of
toll-like receptors
with bacterial
components
triggers a cascade
of intracellular
signaling
mechanisms
Production of
Inflammatory
mediators
Activation of Bcells
Barros and Offenbacher, 2014
INNATE-IMMUNE RESPONSE
==MEDIATED MAINLY BY:
Neutrophils
Macrophages
40
Phagocytosis and degranulation
PMN
Protective cell
 Defective neutrophil function is associated with
periodontal destruction=increased susceptibility
to periodontitis include abnormalities in

Adherence,
 Chemotaxis


decrease of neutrophil migration in the presence of a
chemotactic gradient
Phagocytosis and bactericidal activity.
 Superoxide generation,

Deficiencies in PMN function are associated with severe and rapidly progressive
periodontitis
42
Cellular/molecular pathway signaling cytokine signaling and cell
The stimulation of macrophages (MΦ) by LPS initiates the immune
response and the inflammatory response
43
Vascular and
Barrier
INNATE DEFENSE
SYSTEMS
cellular
mechanisms
inflammatory
responses
Complement
cascade
Vascular
Gingival crevicular
inflammatory events fluid
Soluble factors C-1
to tC-9 that circulate
in the blood 7 tissue
fluids
Cellular
Saliva
inflammatory events
(PMN’s)
• Opsonization of
pathogens
• Recruitment of
inflammatory
cells
• MAC=direct
killing of
pathogens
(Bactricidal)
Oral epithelium
(pattern recognition
receptors)
44
COMPLEMENT CASCADE

Consists of plasma proteins

Bind covalently to pathogens, opsonizing them for
engulfment by phagocytes bearing receptors for
complement.

The most important action of complement is to facilitate the
uptake and destruction of pathogens by phagocytic cells
45
Activated initially independent of antibodies via the alternative pathway (APW)
later activation is dependent on antibodies via the classical pathway (CPW)
Opsonization, chemotaxis, membrane destructive -MAC
46
Schematic overview of the complement
cascade
Activation of
C3
MAC
Macrophages
and
neutrophils
phagocytosis
47
Cell/molecules
Characteristics
Functions/effects
48
CYTOKINES
Cytokines are hormone-like soluble proteins that act as
messengers that initiates / maintains an immune response
• They are key inflammatory mediators
• In combination with other mediators they build a large network responsible for
normal tissue homeostasis & immune response.
They regulate important biological processes:
• Cell proliferation, cell growth, cell activation, inflammation, immunity and repair.
Some cytokines e. g., IL-8 have a chemotactic effect on immune
cells
Members of the cytokine family include:
• Interleukins (IL)
• Cytotoxic factors (tumor necrosis factor (TNF) α and β)
• Interferons (anti-viral IFNα and β, “immune-IFNγ”)
• Colony stimulating factors (CSF)
• Growth factors (GF)
49
CYTOKINES……
Most of the cytokines primarily act locally in tissues where they are produced,
others have systemic effect e.g. TNF, IL-1, IL-6 etc.
•They can induce their own expression in an autocrine or paracrine fashion
•They pleitropic effects on different cells
Bind to specific receptors on target cells
•Initiate intracellular signaling cascades resulting in phenotypic changes
The cytokine-producing cells and their target cells exchange signals
continuously.
•Supports primarily tissue homeostasis
The host response to periodontal infection requires expression of proinflammatory (IL-1, IL-6IL-8,TNFα, IFNγ) and antiinflammatory
cytokines,(IL-1 ra (receptor antagonist), IL-10, TGFβ)
50
Cytokines are not stored but are constantly produced
, epithelial
51
52
Host-Microbial interaction NB determinant of whether disease will be
established opr not
53
The host cellular
activation as protective
against microbial
assault and the
acquired immune
activation with chronic
inflammation and
cytokine networks
modulating the
connective tissue
response.
54
INNATE IMMUNE RESPONSE
Does not require previous exposure to the
offending organism
 Important for initiating the immune response to
new exogenous microbial challenges.
 Mediate acute exacerbations of a chronic
inflammatory state
