Pathogenesis of Periodontal disease Dr.

Eman Magdy

Lecture 3,4,5
Pathogenesis of Periodontal diseases:
Pathogenesis: how the disease occurs,
Periodontal disease= Periodontal tissue destruction (epi., C.T., Bone resorption)
So, we are going to study how the periodontal tissue destruction occurred.

Direct Mechanism: (bacteria)

Bacterial Invasion
Bacterial Virulence
Indirect Mechanism: (immunity-inflammation)
Vascular response
Cellular response

Bacteria
Bacterial invasion:
Bacteria may invade tissue or intracellular invasion.
Tissue invasion: Epithelium/ Connective tissue
Bacteria needs to pass the epithelium and get into the Connective tissue for
survival (Blood supply) to do this they may invade para cellular or transcellular
For bacteria to invade para-cellular into epithelium (Figure 1) they must have a
certain weapon (Virulence factor) to degenerate desmosomes. For junctional
epithelium there is a unique feature that makes it easy for bacteria, JUNCTIONAL
EPITHELIUM IS LEAKY (LOOSE). So, Para-cellular passage is easy.

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Figure 1: Tight epithelium and leaky epithelium during bacterial invasion

For transcellular epithelial invasion to the connective tissue, the bacteria must
have the power to adhere and bind certain receptor to enter the epithelial cells.
Toll- Like receptors (TLRs) and Microbe associated molecular pattern (MAMPs).
To enter the epithelial cell, Bacteria must have certain characters (Virulence
factors) to cross the cell membrane. Bacteria may bind to certain Toll- like
receptor (TLRs) on the cell wall paying part of their molecular structure – Microbe
associated- Molecular Pattern- (MAMPs) for the TLRs to open and allow microbial
passage. (Figure 2).

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MAMP
s

Figure 2: Toll-like receptor and Microbe-associated molecular pattern

For example: Aggregatibacter Actinomycetemcomitans or A.a Bacteria as G-ve

bacteria they possess Lipopolysaccharides (LPS) which are MAMPs can bind TLRs
and open the gates for A.a. entry through the epithelial cells in a trans-epithelial
invasion to pass to the C.T. (Safe passage) allowing temporary escape from
antibiotic and mechanical wash.
Factors that allows bacteria to invade the epithelial tissues (Para-cellular and
Trans-cellular) are for example:
1- The “leaky nature of junctional epithelium”
2- Bacterial motility to move between epithelial cells. (Fimbria)
3- Bacterial adhesion: Bacteria secret Adhesins- Proteoglycans which act as a
glue. Other bacteria bind through fimbria mechanically to the cell).
4- Bacterial toxins (Endotoxins/exotoxins) – Act as MAMPs
5- Bacteriocins: Kill beneficial bacteria which are competitive with them.
The connective tissue invasion:
Passing the epithelium bacteria now needs to colonize and create an ecologic
system or a biofilm. Bacteria needs a substrate to eat and live on they start C.T.
degradation and degeneration. To perform this function, they must evade the

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immune system. To do this Bacteria will interfere with the function of the
immune cells, and kill immune cells.
Factors that allow the bacteria to interfere with / kill immune cells function:
1- Leukotoxins: directly kill PMNs
2- Chemotaxis inhibitors
3- Immunoglobin (Ig) inhibitors: Bind Fc (Complement) part on the Ig
Factors that allow bacteria to destroy host tissue and prevent repair:
1- Proteases: bacteria may secret wide range of proteases that may degradate
the C.T. matrix either direct or by provoking immune cell reaction.
2- In addition, bacteria may secret toxins to inhibit fibroblast and osteoblast
activity to prevent tissue repair.
An example to be remembered:
Remember 1:
Spirochetes (NUG), Aggregatobacter actinomycetemcomitans, Porphyromonas
gingivalis and Tannerella forsythia , Prevotella intermedia, Fusobacterium
nucleatum can invade oral epithelial cells.
Remember 2:

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Figure 3: Upon bacterial invasion, the first cell to meet them is dendritic cell
(Tissue resident- Macrophage) which is a major secretory cell (IL-1β-TNF-α- IL-8)
initiates the inflammatory response.

Bacterial Virulence factors:

Virulence factors of Bacteria include (Figure 4):
Endotoxins.
Exotoxins.
Bacterial enzymes and noxious products.
Low molecular weight substances
Surface components
Capsule.

Figure 4: Notice endotoxin and exotoxin

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Pathogenesis of Periodontal disease Dr. Eman Magdy

(1) Endotoxins:
Endotoxins are released from bacterial cell upon cell death or during cell
division. These are lipopolysaccharides (LPS) present in the cell wall of Gram –ve
bacteria.
LPS play main role in periodontal destruction since they can:
Stimulate bone resorption either directly through activation of osteoclasts or
indirectly through stimulation of the release of osteoclast activating factors
(OAF) from the host cell. OAF includes tumor necrosis factors  (TNF-),
interleukin. I (IL-I) and prostaglandin E2 (PGE2).
Activate complement system through alternative pathway that has numerous
biological activities. Among the actions of complement system are neutrophil
chemotaxis and tissue damage.
Induce toxic effect on osteoblast, fibroblast and epithelial cells.
Increase the kinin formation (increases the inflammatory mediators to
propagate the condition).
Act as antigen, stimulating the immune response and resulting in release of
catabolic cytokines that cause tissue damage

Complement activation
Chemotoxis of neutrophils
Endotoxin Kinin production
Antigenic
Bone resorption
Toxic to host cell

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(2) Exotoxins:
There are proteins released from living bacteria. Examples for exotoxins are
leukotoxin and epitheliotoxin. Leukotoxin is released from A. actinomycetem
comitans and. Epitheliotoxin is released from P. gingivalis.

(3) Bacterial enzymes:

Degradation of periodontal tissue is induced by proteolytic enzymes and other
hydrolytic enzymes of bacterial origin.
* Proteolytic enzymes: produced by plaque bacteria can degrade:
i) all the elements of periodontal connective tissue including:
Type I collagen
Type IV collagen
Elastin
Basement membrane.
Proteoglycans.
Fibronectin.
ii) Components of host defense systems including:
Immunoglobulin
Complement.
The following table illustrates some of the bacterial proteases and their origin.
Table (1):
Enzyme Bacteria

Collagenase P. gingivalis
A. actinomycetem comitans
Spirochetes
Elastase-like enzyme Spirochetes

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Capnocytophaga

Trypsine-like enzyme P. gingivalis

B. forsythus
Spirochetes
Chemotrypsin-like enzyme Spirochete
Capnocytophaga
Aminopeptidase Capnocytophaga
Spirochetes
Dipeptidyl peptidase P. gingivalis
P. intermedia
Capnocytophaga

* Other hydrolytic enzymes:

Plaque bacteria also produce enzymes capable of degrading the non-
proteinaceous elements of the periodontal tissues.

Enzyme Producing bacteria Action

Hyaluronidase & F. nucleatum, Hydrolyse glucosomino-glycans in
chondroitinase P. gingivalis, spirocretes extracellular matrix
Sialidase B. forsythus, Attack sialoproteins in the
P. gingivalis epithelium increasing its
permeability to bacterial products
Phospholipase P. gingivalis, Damage the surface of epithelium
P. intermedia
Phosphatase P. gingivalis, Contribute in bone resorption
P. intermedia

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(4) Small moleculear weight components:

These components are metabolic end products produced by anaerobic bacteria
such as butyric acid, h2s, ammonia, urea and
They are readily diffusable due to their small molecular weight and lipid solubility,
thus they can penetrate intact epithelium. They are toxic to host cells.
(5) Capsules:
• P. gingivalis is surrounded by capsule which resists phagocytosis.
• Bacterial capsule acts as antigen that can stimulate immune response resulting in
the release of catabolic cytokines capable of tissue destruction.
Indirect damage: The Immune system
Inflammation:
Vascular response
- Vasodilation
- Increased vascular permeability
Upon bacterial invasion, Macrophage signaling IL-1 and TNF will induce
Vasodilation, IL-8 (LAF) or NAF: is the major leukocyte activator and will activate
neutrophil or PMNs.
The step is further augmented by Mast cell activation and Histamine release (Very
fast from primary cellular granules) then slower release of serotonin and
bradykinin will follow along with the activation of arachidonic acid metabolites
including Prostaglandins. ALL ARE KNOWN AS Pro-Inflammatory mediators
Remember 3:

Vaso-active amines: It’s a name given to mediators which have an

active role on blood vessels e.g: Histamine, Adrenaline
The vasodilation will increase the vascular permeability to cells, and
inflammatory mediators (Figure 5).

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Pathogenesis of Periodontal disease Dr. Eman Magdy

Figure 5: The inflammatory response, Notice PMNs and Macrophage emigration

and CRP (inflammatory mediator), Notice the Prostaglandin (PG) and Leukotrienes
(LT) acting on the blood vessel wall to induce vasodilation and increase vascular
permeability

The cellular response:

The step is followed by: Margination, rolling and diapedesis, emigration,
chemotaxis (LAF &Complement), phagocytosis (Macrophage-Microphage) (Figure
6) then killing (Intra-cellular). Failure of phagocytosis will activate extracellular
killing and frustrated killing or cell suicide by Microphages or PMNs and result in
massive tissue damage.

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Figure 6: The phagocytic cells- Cellular response

Neutrophil, Poly-morph-nuclear Lymphocyte (PMNL), Microphage:

Neutrophil-microbe interaction: Possible scenarios:

Phagocytosis is the main function of PMNs:

Phagocytosis means that PMNs succeed to engulf the microbe
- Either intracellular (Microbe killed inside the cell) killing will occur: It’s safe
killing away from host cell and result in no tissue damage.
Remember 4:
The intracellular killing is either: Oxygen dependent (Reactive oxygen species or
ROS such as NO, Myeloperoxidase) or Oxygen independent (Lysozymes) (Figure
7)

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Figure 7: Oxygen dependent and oxygen independent killing

Failure to phagocytosis: NETosis will result

Neutrophil tries to immobilize the microbe through a net of elastin fibers and
start degranulation (Result in tissue damage) what we know as extra-cellular
killing.
Failure to engulf the microbe or failure to kill the microbe after phagocytosis both
conditions will end by apoptosis and again degranulation will result in massive
tissue damage.

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PMNL

Phagocytosis

Macrophage:
1- Phagocytosis: Same as PMNs
2- Antigen presentation to T-Lymphocyte
3- Secretion of Cytokines to activate cells IL-1, IL-6, TNF-α, IL-8, colony
stimulating, growth factors (CSGF), prostaglandins (PG), Leukotrienes (LT).
Macrophages secret matrix metalloproteinases (MMPs) MMPs are a family
of proteolytic enzymes that degrade matrix molecules. They are produced
by resident cells & inflammatory cells. Collagenases , Matrilysins, and
Stromolysins are good examples.
4- Scavenger cells to remove the inflammatory exudates.
T- Lymphocyte:
T-Clones are activated upon antigen recognition by Scanning Macrophage’s Major
histocompatibility complex II (MHC II).
T-Helper: Upregulation of the immune system (activation), secretion of cytokines
or interleukins (IL), B- cell activation.
T-Cytotoxic: execution of dis-functioning cells.
T-Suppressor: down regulate the immune system.
T- Memory: to remember the microbe for secondary response
B- Lymphocyte:
1- Antigen recognition
2- Formation of Immunoglobins (Plasma cell)
3- Memorizing Microbe (B- Cell memory)

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The Inflammatory mediator:

Pro-inflammatory cytokines: IL-1, IL-6, IL-8, TNF-α
Cell of origin: T-cell and Macrophages
 Increase vascular permeability.
 Activation of endothelial cells. There is increased synthesis & expression of
surface adhesion molecules.
 Chemotaxis & activation of neutrophils.
 Potent activators of MMPs secretion associated with C.T. remodeling.

Alveolar bone resorption

• We have pro-osteoblast (P-ob) it may convert into Osteoblast or osteoclast.
This mechanism of differentiation is guided by cell wall receptor ligand-
binding.
• The cell wall receptor is called receptor activator of nuclear factor kappa
beta (RANK), RAANK may bind one ligand.
Receptor activator of nuclear factor kappa beta Ligand (RANKL)
Binding may convert P-ob into osteoclast.
To interfere with this receptor- ligand mechanism an enzyme known as
Osteoprotegrin (OPG). OPG may bind RANKL prevent its binding to RANK and thus
stop osteoclastic formation (Figure 8).
• OAFs: The expression of RANKL is stimulated by proinflammatory cytokines
as IL-1β, TNFα, IL-17, PG E2, IL-11.
• Its expression is inhibited by IL-4, IL-10, IL-13, INFγ & TGFβ.

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