Etiology Ibrahim.pptx

Etiology of Periodontal Diseases
Periodontal disease and gum inflammation are considered multi-factorial inflammatory
diseases.
Their development and progression depend on the complex interrelationship between
many local and systemic predisposing factors.
The amount of inflammation and severity of destruction differ widely among patients.
This variability in disease expression is the result of genetic and acquired environmental
factors that modify the host response to bacteria.
In health there is equilibrium between aggression of bacterial plaque and reparative
tissue capacity.
This equilibrium could be broken by increased amount or virulence of bacteria or
decreased defensive capacity of tissue

Periodontitis is a diseases referred to as a host –bacterial interaction attributable to:
Multiple infectious agents,
•
Interconnected cellular and humoral host immune response,
•
Local and systemic predisposing factors.

Microbial dental plaque
It is generally accepted that the primary etiology of periodontal diseases is bacterial
plaque. The composition of dental plaque varies considerably among patients and
among sites in the same patient. Saliva contains a large number of proteins and peptides
exhibiting a variety of functions, such as antimicrobial activity and lubrication. The
saliva proteins influence hard and soft tissues by forming a pellicle layer on oral
mucosa and enamel which may, in turn, initiate bacterial attachment.
Dental plaque is a general term for the complex microbial community bacteria, but it
may contain yeast , protozoa and virus found on the tooth and other oral surfaces,
embedded in a matrix of bacterial and salivary origin, so firmly adherent to tooth
surface that they resist wash off by salivary flow. Plaque develops naturally on teeth,
and forms part of the defense systems of the host by helping to prevent colonization of
enamel by exogenous (and often pathogenic) microorganisms (colonization resistance).

It is unlike any other bacterial ecosystem, in that it develops on a
nonshedding tooth surface and can form complex bacterial communities
that may harbor over 400 distinct species and contain over 1010 bacteria
per mg.Plaque may be differentiated from other deposits that may be
found on the tooth surface such as a materia alba and calculus
Materia alba; is a soft accumulations of bacteria and tissue cells that lack
the organized structure of dental plaque and are easily displaced with a
water spray.
Calculus; is a hard deposit that forms by mineralization of dental plaque
and is generally covered by a layer of un-mineralized plaque.

Supragingival plaque Subgingival plaque
Coronal : on the tooth surface
Marginal: immediate contact with
the gingival margin
.
Within the gingival crevice or
periodontal
pocket, in contrast to supragingival
plaques, subgingival biofilm residing
in a
more protected location not
subjected
to intraoral abrasion or salivary
host
defense components.
Types of dental plaque
Plaque is divided into 2 distinct types based on the relationship of the plaque to
the gingival margin
:
1.Supragingival plaque 2.Subgingival plaque

Supragingival plaque Dominated by
:
 Gram +ve facultative cocci mainly
streptococci
 Gram +ve rods mainly Actinomyces
species
Subgingival plaque subdivided into
:
 Tooth associated
 Tissue associated
 Apical bacteria lying free within the
pocket
Supragingival plaque growth being
located in contact with the oral cavity
is subject to much more oral abrasion,
which restrict its net accumulation.
Upon plaque maturation gram –ve
secondary and tertiary colonizers
predominate both sub and
subragingival plaque( see below)
A) Tooth associated: Tooth associated
or attached plaque is characterized
by
gram positive rods and cocci such as
:
 Streptococcus mitis
 Streptococcus sanguis
 Actinomyces viscosus

Supragingival biofilm is subject to
the flow characteristics of saliva,
and its host defense components
;
 IgA
 Lactoferrin
 Lysozyme
 Peroxidases
All has a wide antimicrobial
activity and serve to limit both
colonization and spread of biofilm.
A) Tissue associated: Bacteria in
this
areas are more loosely organized
than the
very dense tooth associated
region
.
It contains gram negative rods and
cocci as
well as filaments, flagellated rods
and spirochetes
.
Bacteria mostly predominate tissue
associated flora include
;
 Prophyromonas gingivalis
 Prevotella intermedia
 Actinobacellus
actinomycitimocometans
 Capnocytophaga

Dental plaque composition
1-Cells
In addition to the bacterial cells, plaque contains a small number of
Epithelial cells
,
leukocytes
,
And macrophages
2. Extracellular matrix
The cells are contained within an extracellular matrix, which is formed from
bacterial products and saliva. The extracellular matrix contains:
•
Protein ( glycoprotein , component of pellicle formation)
•
Polysaccharide (dextran as an energy storage 95
% and levan 5%)

Dental plaque composition
3. Inorganic components
Largely calcium and phosphorus which are primarily derived from saliva.
Trace amounts of sodium, potassium and fluoride derived from external
sources like water and tooth past.

MECHANISMS OF PLAQUE FORMATION
Formation of acquired pellicle Bacterial adherence
Formation of intermicrobial matrix
Bacterial colonization and plaque maturation
1. Formation of acquired pellicle:
Within the first few hours Adsorption of salivary proteins and
glycoprotein, together with some bacterial molecules to the tooth surface
to form a conditioning film (the acquired pellicle) occur
.
Components of the dental pellicle include
:
 albumin ,amylase ,lysozyme ,immunoglobulin A ,proline-rich proteins
The pellicle-coated tooth surface is colonized by Gram-positive bacteria
(Primary colonizers) such as
:
Streptococcus sanguis , Streptococcus mutans, Actinomyces viscosus
 Neisseria

Importance of acquired pellicle
a)Acquired pellicle provides specific receptors for bacterial attachment.
Ex ; streptococcus gordonii and actionomyces naeslundii, two initial
colonizers bind acidic proline rich proteins found in the pellicle
.
b)It provide surface for additional bacterial attachment, by the ability
of the two genetically identical bacteria to adhere to one another (co
aggregation) ex; attachment between gram positive cocci and rods
.
c)Surface receptors on Gram positive cocci and rods allow subsequent
adherence of Gram negative organisms which have poor ability to directly
adhere to pellicle
.
d)Supply of growth substrates for secondary colonizers
e)Reduce oxygen tension to the low level required for growth and survival
of anaerobic secondary colonizers

2. Bacterial adherence
Probably the single most important phenomenon in the development of a
biofilm is the process of microbial adhesion either to the substratum or to
other adhering cells of the same or another species
.
Reversible week attractive force between microbial cell surfaces and the
acquired pellicle occur via electrostatic and hydrophobic interactions
between opposite charges on enamel and salivary glycoproteins
.
Irreversible adhesion can occur if specific inter-molecular interactions
take place between specific inhancers of colonization called adhesins on
the bacterial cell surface (fimbria surface) and receptors on the salivary
glycoprotein (e.g. proline-rich proteins) in the acquired pellicle
.

.
3. Formation of intermicrobial matrix
Organic substances formed by bacterial enzymes from sucrose, they are
mainly polysaccharides of
:
 Glucans: The glucans is mainly dextran which is a sticky adhesive
material that plays a major role in colonization of bacteria
 Levans: Levan function as storage of polysaccharide, providing a source
of fermentable carbohydrate when hydrolyzed.

.
Division of attached cells Secondary colonizers Tertiary colonizers
Division of attached cells to
produce confluent growth,
and biofilm forming mature
plaque mass.
Mature plaque mass creating an
oxygen deprived environment
dominated by gram negative
anaerobic microorganisms which
contribute to an increased
pathogeneicty of the plaque biofilm.
After one week of plaque
accumulation, other Gram-
negative species may also be
present in plaque. These species
represent what is considered to
be the "tertiary colonizers"
Outgrowth Once attached,
pioneer species multiply. The
forming microcolony spreads
first in the plane of the
surface and then, as space
becomes limited, upwards
creating palisades of cells.
The secondary colonizers include
Gram-negative species such as:
:
Fusobacterium nucleatum,
Prevotella intermedia,
Capnocytophaga species.
Porphyromonas gingivalis
Campylobacter rectus,
Eikenella corrodens,
Actinobacillus
actinomycetemcomitans,
4. Bacterial colonization and plaque maturation
:
•Division of the attached cells
•Secondary colonizers
•Tertiary colonizers

Plaque Biofilm
The recent recognition that subgingival plaque is in fact a biofilm explains its resistance to
host defensesthat permits long term
bacterial survival even in the presence of the full range of host defenses.
•Biofilm is a barrier, meaning that when bacteria produce substances they are retained
• within the Gel like mass
•(inter-microbial matrix, derived from saliva and GCF) incorporated bacteria, increasing
the concentration of bacterial
• products, which in turn used for metabolic interactions among bacteria.

Plaque Biofilm
Factors that influence plaque formation
Host factors Bacterial factors

Plaque Biofilm
Mechanical cleansing and periodontal pocket depth Bacterial adherence
Smoking allow easier spread and growth of bacteria by affecting PMN and
AB.
Ph of the ecological niche; some bacteria
tolerate
low Ph like lactobacillus species and others
cannot like streptococci
Nature of host diet (sickness of food and frequency of intake) Oxidation reduction potential; mature plaque
provide the most suitable environment for
anaerobic growth of bacteria
Position and contour of the tooth in the arch Nutritional interactions and bacterial
metabolic inhibitors (see bacterial
interactions within a biofilm)
Axial contour of the teeth
Surface characteristics of the tooth
Surface characteristics of the gingival
Marginal ridge discrepancies
Physical space: Subgingival space available for bacterial growth is limited
in healthy periodontium and increase by more periodontal destruction and
increased pocket depth.
The innate defense system of the host
:
Intact epithelial cell barrier
 Crevicular fluid lysozyme, complement,
vascular permeability enhancers like bradykinine, thrombin, and
Role of dental plaque biofilm in periodontal disease

Role of dental plaque biofilm in periodontal disease
Dental plaque biofilm cell fragment shedding provides a constant source of bacterial
antigens that govern the innate host response.

I. Direct effect:
1. Bacterial adherence and invasion:
Bacterial adherence to host cells is of special importance for the persistence of
bacteria in the oral cavity, that is continuously cleansed by salivaOrganisms that
cannot adhere are rapidly removed by host defenses
.
Developing an understanding of these interactions will allow us to develop
prophylactic and therapeutic procedures based on interference with the
adherence reactions
-
Nonspecific adherence
:
 hydrophobic interactions
 electrostatic attractions
- Specific adherence
Involves permanent formation of many specific lock-and-key bonds between
receptor and adhesion molecules
:
.

:
.
Forms of bacterial adherence include
:
- Adherence mediated by fimbriae (adhesin), hair-like protein structures that
extend from the bacterial cell surface and bind to host cell molecules, or bacterial
surface proteins that mediate tight binding between bacteria and host cells
- Coaggregation by the attachment of microorganisms to soft and hard dental
tissues
.
- Colonization by the multiplication of the same species after attachment
.
- The formation of a biofilm, a tight coaggregation of bacteria adhering to each
other and to the host surface, helps the bacteria to colonize, to resist the host
defense and antimicrobial agents, and also provides good sites for receiving
nutrients
- Many mucosal pathogens, such as oral streptococci, produce immunoglobulin A
(IgA) proteases to cleave secretory immunoglobulin A (SIgA), which is produced
by host cells to inhibit bacterial adherence
- Irreversible adhesion by the synthesis of extracellluler polymers. Ultimately
these polymers form a significant part of the biofilm matrix. In the case of dental
plaque, these polymers comprise soluble and insoluble high molecular weight
polysaccharides synthesized from sucrose

:
.
Bacterial invasion:
- Pg, Aa, spirochetes, Bacteroides forsythus are capable of invading epithelial tissue
.
- The ability to survive within host tissue gives an advantage to pathogen to be
protected from host defense mechanisms
.
- Invasion of certain bacteria makes mechanical debridement insufficient
.
- Some investigators suggest that bursts of disease activity may be related to phases of
bacterial invasion to the tissue
.
- It was reported that IL8 production by gingival epithelial cells is inhibited following
Pg invasion, this could have a debilitating effect on innate host defense of the
periodontium
.
- "Spreading Factors" is a descriptive term for a family of bacterial toxins and enzymes
promoting the invasion of the pathogen:

:
.
2. Bacterial toxins and enzymes
:
Bacterial toxins Bacterial enzymes
Exotoxins Endotoxins Proteolytic enzymes Hydrolytic enzymes
Leukotoxins
(Aa, Cambelobacter
rectus)
Epitheliotoxin
(Pg)
Lipopolysaccaride
- Collagenase
- Gingipain
- Elastase like enzyme
- Trypsine like
enzymes
- Chemotryspsine
- Hyaluronidase
- Chondroitin sulphatase
- Acid and alkaline
phosphatase

:
.
Exotoxins (bacterial enzymes)
:
- Exotoxins may have general cytotoxic effects, or they may be targeted at a
certain host cell type as neurotoxins, leukotoxins, or hepatotoxins
- They represent a family of moleculessecreted by many Gram positive and Gram
negative bacteria with the ability to elicit massive activation of the immune
system
.
- Ex; Aa and campylobacter rectus leukotoxin and Pg epitheliotoxin
- These proteins share the ability to stimulate T cell proliferation
.
- The important feature of this interaction is the resultant production of IL-
1, TNF, and other lymphokines which appear to be the principal mediators of
periodontal destruction processes associated with these toxins.
Proteolytic enzymes
:
- Collagenase produced by Pg, Aa, and spirochetes.
- Elastase-like enzymes produced by capnocytophaga and spirochtes.
- Trypsin-like enzyme produced by Pg, B.forsythus, spirochtes.

:
.
Proteolytic enzymes induces:
o Degradation of all elements of periodontal CT including type 1 collagen,
basment mem., type VI collagen, elastin, proteoglycan and fibronectin.
o Can degrade components of the host defense system as immunoglobulin and
complements (IgG and IgA proteases).
o Some bacteria have fibrinolytic activity and so prolonging the clotting time
which provide more nutretion for certein bacteria such as Pg which use heam
for there nutretion.
Degradation of fibrin also reduce the trapping of bacteria by fibrin and so reduce surface
phagocytosis (Fibrolysin).
Bacterial proteases may activate latent host collagenases (MMP).

:
Hydrolytic enzymes
:
- Some bacteria like Pg, capnocytophega, and fusobacterium nucleatum
produce enzymes that are capable of degrading non proteinaceous elements
of the periodontal CT ( glycosaminoglycans component of proteoglycans in
the Extracellular matrix
(
- Hyaluronidase depolymerize hyaluronic acid cementing substance and
Chondrotin sulphatase depolymerize mucopolysaccaride of the ground
substance, all increasing permeability of tissue to bacterial products.
Endotoxins
:
- lipopolysaccharide complex associated with the outer envelope of Gram-
negative bacteria (Lipid A is the toxic component of LPS)
- It has direct toxic effect on tissue cells (fibroblasts, osteoblasts,
epithelial cells)
- LPS activates complement by the alternative (properdin) pathway and may
be a part of the pathology of most Gram-negative bacterial infections.

:
- Lipid A is known to react at the surfaces of macrophages causing them to
release cytokines that mediate the pathophysiological response to endotoxin
.
- Chemotactic effect either directly or via complement activation.
- Induce bone resorption either directly or indirectly through induced cytokines
3. Bacterial metabolites and toxic factors
 Butyric acid,
 propionic acid
 indole and
 ammonia
Are all metabolic end products of anaerobic bacteria and spirochetes having toxic
effects on host cells. They are all diffusible and lipid soluble and therefore could
penetrate intact epithelium
.
4. Bacterial capsule
Aa and Pg has a capsule which
:
 Resist phagocytosis and opsonization
 Is antigenic, so it can stimulate antibody production and release of IL1.
 May cause bone resorption by direct stimulation of osteoclasts.

:
Pathogenic properties (virulence factors) of periodontal bacteria
Pathogenicity: is defined as the ability of a microbe to produce disease and cause damage in
the host. What distinguish the oral bacteria that cause periodontal diseases from those that do
not is that the pathogenic organism have acquired the ability to produce what are termed
Virulence factors
,
Virulence factors: (are bacterial products that contribute to virulence) which includes
proteins and polysaccharides have the ability to avoid or destroy the normal human immune
defences which result in tissue damage

:
Bacterial Virulence is:
• The capacity to colonize
• The ability to evade antibacterial host defense mechanisms.
• The ability to produce substances that can directly initiate tissue destruction
Virulence determines the strength of the pathogenic potential and defines
1. the relative capacity of a microbe to cause damage in the host and
2. its ability to overcome host defenses .
Virulent periodontal pathogens:
Actinobacillus actinomycetemocomitans.
Prophyromonas gingivalis.
Bacteroides forsythus. (Tanarella Forsythenisis).
Prevotella intermedia.
Fusobacterium nucleatum.
Campylobacter Rectus.
Eikenella corrodens.
Spirochetes.

:
1. Actinobacillus actinomycetemcomitans:
Actinobacillus (aggregatibacter) actinomycetemcomitans is a nonmotile, gram negative,
coccobacillus (spherical or rod shaped), facultative anaerobe and capnophilic; it grows well in
5% CO2 in air or anaerobically,
It does not require X (hemin) or V (nicotinamide adenine dinucleotide) factors for growth and
grows in the absence of serum or blood
A.actinomycetemcomitans is a typical cause of periodontitis but it may also be associated with
systemic infections and it has been of current interest in relation to arterial plaques (prosthetic-
valve endocarditis, pericarditis, septicemia, Pneumonia. infectious arthritis, abscesses) , This
organism fulfills the criteria of an etiological agent of periodontitis:
Aa highly detected in localized aggressive periodontitis 90% , and to less extent chronic
periodontitis 50%.
1-High serum antibody to Aa in localized aggressive periodontitis
2-The organism eliminated when the diseases successfully treated.
3-Treatment failure associated with high level of the pathogen

:
A.a. Virulent factors:
1Lipopolysaccaride.
2Adhesins.
3Leukotoxin (protein antigen).
4Epitheliotoxin.
5Proteinase production.
6Extracellular membranous vesicles.
7Fimbriae

:
a. Lipopolysaccaride:
The LPS has a broad spectrum of immunological and endotoxic activities including:
- Mitogenic response to B lymphocytes ( IgG and IgM elevated levels).
- Macrophage activation.
- IL1 production.
- Prostaglandin E2 release by macrophages.
- Bone resorption.
b. Adhesins. (fimbriae, extracellular membranous vesicles,)
Mediation of bacterial cell adherence and attachment to epithelial cells, to other bacteria, and
to extracellular matrix proteins
c. Leukotoxin (protein antigen).
• Leukotoxin is among the most studied virulence factors of
A. actinomycetemcomitans
• The free protein is specifically cytotoxic to human polymorphonuclear leukocytes
(PMNs), monocytes, and T-lymphocytes
• It is able to become incorporated into the cell membrane of leukocytes
and macrophages, forming pores through which the white cell contents are spilled. Such loss
of immune cell function is believed to contribute to the acute severity of aggressive
periodontitis.
d. Epitheliotoxin:Aid in penetrating the sulcular epithelium.
e. Extracellular membranous vesicles:Mediation of endotoxic, leukotoxic, and bone
resorption activities.

:
a. Fimbriae
Fresh Aa possesses fimbriae of about 5 nm in diameter and several um in
length. Antibodies against the fimbriae antigen may afford protection
against Aa infection.

:
2. Prophyromonas gingivalis:
• A member of black pigmented bacteroides ( the entire colony on blood agar becomes
black due to an over production of protoheam),
• Gram negative anaerobic non motile, asaccarolytic rods ( dependent on nitrogenous
substrate for its energy) with the greatest proteolytic activity.
Pg virulence factors:
a. Capsular polysaccharide
Pg has a dense capsule (15 nm thick) around the outer membrane that consists of
polysaccharide hetropolymer providing protection to phagocytosis by PMNs.The capsule
prevent activation of alternative complement by shielding Pg LPS
b. Lipopolysaccaride
Pg LPS is different from other gram negative bacteria in that it does not have the capacity to
directly stimulate the production of E-selectin by human endothelial cells. As a consequence
leukocytes cannot bind to endothelial cells and migrate into the extra cellular compartment. By
this step Pg blocks a key step in the inflammatory response (Pg suppressing the innate host
defense response to bacteria).
• Indirect pathway of complement activation.
• Pg LPS can activate osteoclasts directly.
• Can stimulate monocytes and macrophages to release IL1b, TNF Alfa and PGE2.
c. Enzymes
Pg produces enzymes that degrade most serum proteins including immunoglobulin and
complement components. Among these:
- collagenase, and
- Protease enzymes that degrade collagen (trypsin like protease, and cysteine protease,

:
Gingipain)
• A potentially protective mechanism of most black pigmented strains
includes elaboration of superoxide dismutase. It was found to split PMN derived hydrogen
peroxide and superoxide anions and enables the organism to resist oxygen dependent intra-
leukocytic killing.
d. Gingipain
• Is a Cysteine protease virulence factor of Pg, resposible for 85% of proteolytic
activities produced by Pg.Gingipains classified into two groups based on substrate specificity
including Gingipain R that cleaves proteins after arginine residues and Gingipain K cleaves
proteins after lysine residue.
• Generally Pg Gingipains exhibit enzymatic activity against a range of host proteins
including; host immunoglobulins, extracellluler matrix proteins, proteins involved in the
coagulation, complement and host proteinase inhibitors.They help bacteria to obtain nutrients
by degrading tissue proteins including heaemogobin which result in the release of iron.
• Increase vascular permeability resulting in an increase in the flow of
gingival cervicular fluid and providing a rich source of nutrients for subgingival plaque
bacteria.Gingipains produced by Pg degraded intercellular adhesion molecules (ICAM)-1 as
well as IL-8 which disrupted trans-epithelial migration of PMN.

:
e. Fimbriae:
• Fimbriae are curled single stranded hair like protein structures with a diameter of
5nm and a length of 33 nm, present on the bacterial cell surface, enables the bacteria to bind to
human gingival tissues. This triggers a cascade of responses by cells that results in the bacteria
being tacked up into the cytoplasm. Patients with chronic periodontitis contain high titers of Pg
fimbria-specific IgG antibodies.
• Pg grown and divides within the cytoplasm (Bacterial invasion). Bacterial invasion
has been demonstrated in Aa and Pg. Invasion of host cells similar to the biofilm environment;
provide another source of (safe haven) from innate host defense.Host epithelial cells harboring
Aa and Pg my provide a source of reinfection after mechanical debridement.
f. Membrane vesicles:Membrane vesicles are shed in large numbers and carry with them the
secreted proteases which help to permeate the tissue.
g. P.g Hemagglutinin and hemolysin activity:
• Pg can utilize a broad range of hemin containing compounds such as hemoglobin. Pg
hemagglutinin and heamolysin functions to lyses RBC releasing hemin which promote
colonization by aiding the required hemin and iron. Hemin can scavenge oxygen and maintain
anaerobic environment.

:
Spirochetes
Gram negative anaerobic helical shaped , highly motile microorganisms commonly
found in periodontal pockets.
Treponema denticola, T pallidium, T vincentii are forms of spirochetes common in
periodontal diseases
In advanced periodontal lesions it constitutes up to 50% of bacteria in plaque.
Produce hydrolytic enzymes including collagenase, proteases and peptides.
It also release destructive metabolic products such as ammonia and H2S.

:
II. Indirect effect
Both of the non-specific and specific immune responses are responded to
microbial challenge in periodontitis;Although bacteria must be present for
periodontal disease to occur, a susceptible host is also required. The immune
response that develops in the gingival and periodontal tissues in response to the
chronic presence of plaque bacteria results in the destruction of structural
components of the periodontium, leading, ultimately, to the clinical signs of
periodontitis . The host response is essentially protective in nature. However, a
hyper-responsive inflammatory trait associated with an impaired host immune
response could result in enhanced tissue destru

Non specific immune response (inflammation):
1. Vascular reaction.
2. Cellular reaction.
Specific immune response:
1. Humoral immunity
2. Cell mediated immunity.
Non specific immune response (Inflammation)
The initial tissue response to any injurious agent ( periodontal pathogens) is a non
specific host reaction known as inflammation (non specific immune response)
Inflammation has 3 objectives:
1. To attack or dilute the offending agent
2. To remove the resulting dead tissue
3. repair
Inflammation include a serious of :
1. Vascular reactions
2. Cellular reactions
Caused by the liberation of pharmacologically active substances (inflammatory
mediators).
II. Indirect effect

II. Indirect effect
1.Vascular reaction
 The vessels lateral to the junctional epithelium consist of plexus of post
capillary venules.
 These vessels enlarge and proliferate in gingival periodontal inflammation.
 These alterations are most pronounced in the vicinity of the pocket
epithelium and close to the subgingival plaque associated with:
Vasodilatation, Increased capillary permeability ‫و‬ Circulatory stases
These promote an increase in blood flow to the injured area with:
a) Passage of plasma proteins from the blood vessels to the tissue resulting in
toxin dilution.
Passage of different defensive elements to the injured area including kinins,

II. Indirect effect
Mediators of vascular reactions
1. Histamine from mast cells
2. Serotonine from platelets
3. Kinins from plasma
4. Prostaglandins and leuktrines from epithelial cells, macrophages, PMNs,
keratenocytes
5. Complement products from plasma
6. IL1
7. TNF
1.Histamine
 Immediately following host periodontal bacterial injury histamine is released
from mast cells located in the gingival CT.
 Histamine release is triggered by IgE which is an antibody attached to cell
mem. of mast cells when it react with particular antigen.
 Mast cell activation and degranulation is also elicited by C3a, C5a and IL1 with
release of many inflammatory mediators such as heparin, lysosomal enzymes,
TNF, leuktrines, serotonine and prostaglandin beside histamine.

II. Indirect effect
 The most important vasoactive mediators that are stored in mast cell and
basophil granules are histamine in man, as well as serotonin or 5-
hydroxytryptamine in rodents. They both are also present in human platelets.
 Histamin has diverse functions leading to acute vascular effect including:
1.Primary, local dilation of small vessels;
1. Widespread arteriolar dilatation.
2. Local increased vascular permeability by contracting endothelial cells.
3. The contraction of nonvascular smooth muscle (bronchospasm).
4. Chemotaxis for eosinophils.
5. Blocking T lymphocyte function.
2. Serotonin
 Is also capable of increasing vascular permeability, dilating capillaries and
producing contraction of nonvascular smooth muscle.
Most serotonin is stored in the gastrointestinal tract and central nervous
system but a large amount is also stored in the dense granules of platelets.
 The increased vascular permeability mediated by these reactions probably
facilitates the capacity of antibody and inflammatory cells to arrive at the
infected site.

3. Lipid mediators
• The major constituent of cell membranes (inflammatory cell mem. Including mast cells,
neutrophil…) are phospholipids.
• Cellular phospholipases, especially phospholipase A and C, are activated
during inflammation and degrade phospholipids to arachidonic acid.
• Arachidonic acid has a short half-life and can be metabolized by two major routes,
Cyclo-oxygenase (COX)
o Lipoxygenase
The cyclo-oxygenase pathway produces:
- Prostaglandins,
- Prostacyclin, and
- Thromboxanes.
The lipoxygenase pathway produces:
- in one branch leukotrienes
- and in the second branch lipoxins .

.
Prostaglandins (PG):
 A family of lipid-soluble molecules produced by different cell types in the body.
For example, macrophages and monocytes are large producers of both PGE and
PGF, neutrophils produce moderate amounts of PGE, mast cells produce PGD.
 It is important to note that, unlike histamine, prostaglandins do not exist free in
tissues, but have to be synthesized and released in response to an appropriate
stimulus.
 Most important mediator of alveolar bone loss.
 Enhances vascular permeability.
 Is pyrogenic.
 Increases sensitivity to pain.
 And stimulates leukocyte cAMP, which can have an important suppressive
effects on release of mediators by mast cells, lymphocytes, and phagocytes.
 The use of NSAIDs can lead to inhibition of PGE2 syntheses by the direct
competitive or non competitive inhibition of the enzyme cyclo-oxygenase.
Leukotrienes:
 Causes the chemotaxis (directed locomotion) and/or chemokinesis (general cell
movement) of a number of cell types including neutrophils.

.
4. Kinines and fibrinolytic system (from plasma)
 Within one hour following the release of histamine , the vascular changes are
maintained by a vasoactive polypeptide known as bradykinine.
 The inactive precursor (prekallikrein) is released from plasma and is
activated into active enzyme (Kallikrein) by:
- Hegman factor
- Some proteolytic enzymes
- Lysosomal enzymes
- Kallikrein catalyze the liberation of plasma kinine (Bradykinin) from
kininogen.
- Bradykinine has the same effects of hestamine but for longer duration.

.
5. Complement
 The complemet system is a potent mechanism for initiating and amplifying
inflammation.
 Activated complement leads to a cascade of interactions leading to
chemotaxis, phagocytic interactions, and lytic attack of cell membrane.
 The major components are numbered as they were discovered, unfortunately
C4 was descovered before C2 and C3 so the correct sequence is listed as:
C1, C4, C2, C3, and C5 through C9.
Complement activation in periodontal pockets via:
o Antibodies to periodontal pathogens (classic pathway) or
o LPS of gram negative pathogen (alternative pathway) is believed to be
important in periodontal infections.
 Complement components and derived split products are found in abundance in
the crevicular fluid. In health, complement levels in GCF are about 1/35 of
serum, but as periodontal inflammation increases, there is a concomitant
increase in complement levels to over 25%

•Individuals with classical or alternative pathway deficiencies would be more susceptible to
periodontal infection
Functions of complement
• Complement mediated inflammation:
- C3a, C5a degranulation of mast cells
- C3b platelet release of serotonine
- C2 generation of kinines (serum bradykinine)
• Complement mediated chemotaxis:
- C3a chemotaxis of eosinophils
- C5a chemotaxis of neutrophils, eosinophiles, and macrophages.
- C5.6.7 chemotaxis of neutrophiles, and eosinophils.
• Complement mediated opsonization
- C3b promote phagocytosis.
• Complement mediated cell adherence
- C3b bind to receptor on neutrophils, macrophages and B lymphocytes.
Opsonization:
• Is a process, in which opsonins (IG or complement) adsorb to the surface of bacteria or
other particles and facilitate their adherence to the phagocyte cytoplasmic membrane through
opsonin receptors (FCr, CR3).
• Complement mediated immune regulation
- C3b bind to receptors on B lymphocytes which lead to:
Regulation of immunologic memory
Stimulation of lymphokine release

6. Tumor necrosis factor
Is produced by a variety of cell types, but activated macrophages represent the dominant source.
TNF-α activates natural killer cell cytotoxicity,
Enhances generation of cytotoxic T-lymphocytes, and activates natural killer cells to produce
interferon-γ.
TNF- α also acts on vascular endothelium to promote inflammation and thrombosis.
TNF-α is a product of Th1 T-cells; in addition to providing help in proinflammatory cell-
mediated immune responses, these cells produce delayed-type hypersensitivity reactions where
macrophages are locally recruited and activated to kill intracellular pathogens, such as certain
bacteria.
2.Cellular reaction In clinically healthy gingiva there is a continuous migration of leukocytes
from the dentogingival vessels into the junctional epithelium and the sulcus region.
This leukocyte migration is enhanced in gingival and periodontal inflammation and the cells
accumulate in the pocket epithelium and sulcus. The cells participate in the defense of the tissue
against frank invasion of bacteria.

Role of inflammatory cells in periodontal diseases
Cells of the immunity and inflammation:
Mast cells Neutrophils Monocytes/Macrophages
Lymphocytes:
T. cells, B. cells
(NK)
Peripheral dentritic cells Dermal dentrocytes

Role of inflammatory cells in periodontal diseases:
Neutrophils:
 Under normal conditions developed in the bone marrow , however during inflammation there
development is enhanced by a cytokine , granulocyte-colony stimulating factor, which is elaborated
by activated macrophages.
 Once released in the blood stream its half life is 6 to 9 hours.
 In acute inflammation, these are the first leukocytes emerges from the vessels in significant
number.
 It provides non specific effective defense against bacterial and fungal infections.
 Migration of neutrophils through the tissue to locate and destroy microorganisms are due to
chemotactic factors.
 Neutrophils moves along concentration gradient of the chemotactic factor until it reaches the
agent responsible for chemotaxis.
Neutrophils Chemotaxis
 Junctional epithelium provides a highly specialized permeable adhesive barrier that function as a
neutrophil sieve.
Capillary loops adjacent to epithelium provide a constant source of neutrophils which freely migrate
into the sulcus in response to Chemotactic components like C5a , IL8 and formylmethionyl phenylalanine
once they reached increased gradient outside capillaries

Neutrophils Chemotactic factors:
Complement dependant factors Complement independent factors
C5a
C567
Are involved in the initial recruitment of
neutrophils.
LTB4
N-formylated peptides products of
bacterial metabolism.
Bacterial stimulated macrophage IL8.
Tissue breakdown products.

Leukocyte migration
 In the dilated capillaries which has a slow blood flow , the PMN first adhere to
capillary wall ( Margination and adherence), followed by firm attachment (
pavmentation), then there is institution between the cells ( diapedesis) and
migration outside blood capillaries( emigration)
Adhesion molecules
 Activated endothelial cells express the intercellular adhesion molecule (ICAM-
1), endothelial-leukocyte adhesion molecule (ELAM-1) and vascular cell adhesion
molecule (VCAM-1) on their cell surface.
 Human PMNs, macrophages, basophiles express different integrins as receptors
for these molecules.
Integrins:
 Are a large family of transmembrane glycoproteins that attach cells to
extracellular matrix proteins of the basement membrane or to ligands on other
cells.
 Expressed in response to chemoattractants from the endothelial cells,
granulocytes , monocytes, eosinophils, and many lymphocytes.
Neutrophilphagocytosis:
 Through opsonization neutrophil becomes able to bind directly to bacteria by
means of pseudopodia where they engulf the antigen, then dimple their cell
membrane to the inside forming a concavity called phagosome that surround the
antigen.

Bacterial killing by neutrophils;
Oxygen independent Oxygen dependent
- Cationic proteins.
- Lactic acid.
- Lactoferrin.
- Lysozyme.
- Proteolytic enzymes.
- Superoxide anion
- Hydrogen peroxide
- Hypochlorous acid
- Hydrogen radicals

Oxygen dependent
- If oxygen is available, there is a respiratory burst consisting of sharp increase
in oxygen consumption.
- The respiratory burst is triggered by NADPH oxidase (Necotinamide Adenine
Dinucleotide Phosphate, enzyme situated on the membrane of phagocytic vacuole)
- The enzyme converts oxygen to oxygen metabolites that can kill bacteria.
Oxygen independent
- Following bacterial engulfment and formation of phagocytic vacuoles
(phagosome). The vacuoles fuses with the cytoplasmic granules and the granules
discharge there contents into the phagosome (degranulation).
- Netrophil granules contain a number of antibacterial factors.
- Bacterial permeability-increasing protein ;
It works through activating phospholipase which breakdown bacterial membrane
phospholipids.
-lysozyme., attack bacterial cell wall.
Collagenase, degrade collagen.
Elastase, attack bacterial cell Mem.
Gelatenase, degrade collagen.
Lactoferrin, chelator of iron, thus compete with bacteria for iron which is needed for
growth of many bacteria.

Bioactive lipids of PMN:
 It has been emphasized that PMN is a rich source of PGE2 that account for the
majority of PGE2 detected in gingival crevicular fluid of periodontitis patients.
 Pg was demonstrated to stimulate a massive influx of neutrophils accompanied
with activation of neutrophil COX0-2 followed by increased level of PGE2 level.
NEUTROPHILS AND PERIODONTAL DISEASES:
 The junctional epithelium is a transcellular adhesive barrier which provides a
highly specialized permeable barrier that functions as a neutrophil sieve.
Capillary loops adjacent to the epithelium constant source of neutrophils which
freely migrate through the epithelium into the sulcus via host and bacterial
chemotactic factors.
 Three lines of evidence support the proposal that neutrophils protect the
periodontium against periodontal bacteria:
First, primary and acquired neutrophil abnormalities have been associated with
severe periodontal destruction.
Second, otherwise healthy individuals with severe periodontal problems appear to
have defects in their neutrophils.
Third, experimental neutropenia in animals leads to rapid periodontal infection.
During PMN function, certain damage to host tissue may occur. PMN contain
collagenase (matrix mettaloprotienase-8) and other metalloproteinase, known as
gelatenases (matrix mettaloproteinase-9) and stromolysins ( matrix
mettaloproteinase-3) and possibly also matrix metalloproteinase 10 and 11.thes
enzymes degrade collagens and proteoglycans as they leak from PMN during
phagocytosis or when the cells die and degenerate. However, it is clear that the net
effect of PMN function in periodontal disease is protective.

Primary neutrophil abnormalities:
 Neutropenia and agranulocytosis associated with:
- myelosuppression,
- drugs (idiosyncratic),
- infections, and
- autoimmune disorders in which the neutrophil is the target. For example,
infection by the human immunodeficiency virus (HIV)
 Chediak-Higashi syndrome (CHS),
- Is a rare disease with an autosomal recessive mode of inheritance
- Neutropenia and depressed inflammation are observed in CHS. Depressed
inflammation is thought to be due to decreased chemotaxis, not the
neutropenia.
- Oral manifestations of this disease include severe periodontitis and oral
ulceration.

Papillon-LeFèvre syndrome (PLS):
• PLS features rapid generalized destruction of alveolar bone (both primary and
secondary dentitions affected) and palmar-plantar hyperkeratosis.
• PLS may be associated with diminished neutrophil activity.
Leukocyte adhesion deficiency,
• Inability to express leukocyte integrin essential for diabedesis and endothelial
adhesion which is usually associated with aggressive periodontitis.
Acquired Neutrophil Defects
• A number of pathogens secrete different mediators that could affect PMNs functions;
- leukotoxins,
- immunoglobulin proteases,
- lymphosuppressive factors,
- high molecular weight chemotaxis inhibitors,
- low molecular weight chemotaxis inhibitors,
- LPS and polysaccharides.
Monocytes and Macrophages
• Macrophages develop from blood monocytes, which migrate from the blood stream
into the tissues and developed into mature macrophages by the effects of inflammatory
mediators and bacterial products.
• Like neutrophils, macrophages are motile phagocytic cells, but they are long lived
(several months) and can proliferate after leaving the blood stream.
• Whereas neutrophils are the first leukocytes to enter an area of injury, the slower
macrophages because of their longer life span are often the most numerous cells in the later
stages of inflammation.

Macrophage functions
• Removal of dead and dying cells (long lived).
• Debridement (removal of damaged tissue) this paving the way for fibroblasts and
new capillaries in healing wound.
• Ingestion and processing of antigen for presentation to T cells.
- Upon recognition of foreign material, they secrete chemokines and cytokines that
further attract more immune responder cells (eg. T cells);IL1, TNF, PGE2, Leukotrienes and
Lysosomal enzymes such as collagenase and elastase.

- PGE2, Leukotrienes and Lysosomal enzymes such as collagenase and elastase.
B. specific immune response
 The junctional and pocket epithelium is highly permeable to large molecules
which trigger an immune reaction in the gingival connective tissue.
 T Lymphocytes and plasma cells generate mediators for enhanced inflammation
and tissue damage. In particular the production of cytokines .
 These substances are potent bioactive molecules which trigger a number of
tissue damaging events
 All cells of the immune system are derived from self regenerating heamopoietic
stem cells present in bone marrow and fetal liver.
 It differentiates along lymphoid pathway to give rise T and B cells.
Types of specific immunity:
Humoral immunity :Refer to the production of soluble antibodies that circulate in
the blood plasma.Upon antigen recognition B cells are stimulated to become antibody
secreting plasma cells.
Cell mediated immunity :Mediated by T lymphocytes which are produced in the bone
marrow and mature in the thymus gland.

Humoral immunity
Ag is processed and presented to its specific B lymphocytes by macrophages. B-
lymphocytes recognize the antigen where it proliferates to;
 B-cell is activated by the helper T-cell to produce antibody secreting plasma
cells that divide and produce secreted antibodies against the specific antigen
which circulate in the serum and lymph.
 Some B-cells become memory cells to produce antibody at a low rate for a long
time (long term immunity) and to respond quickly when the antigen is
encountered again.
 Immunoglobulins are secreted in the blood stream and pass from the gingival
inflammatory infiltrate to the gingival crevicular fluid. The antibodies produced
are predominantly IgG (75%), and small amount of IgM (7%).
Structure of Immunoglobulin
 The antibody molecule is composed of 2 copies of 2 different proteins
 There are two copies of a heavy chain - over 400 amino acids long
 There are two copies of a light chain - over 200 amino acids long

IgG IgM IgA IgE IgD
In serum
and body
fluids, the
main AB
80%
Small MW
so it passes
through
placental
barrier.
Neutralizes
bacterial
toxins
Activate
complement
system
Only serum (
high level in
early
infection)
Large MW
so cannot
pass through
placental
barrier
Efficient
activator of
complement
system
In serum and
body
secretions.
Passes
through
lymphatic
system to
saliva and
milk
(colostrum)
Provide
surface
protection at
MM
In mucosa and
submucosa.
Bind to mast
cells to
release
histamine and
other
mediators
In serum
(very low
conc.)
Bind to
receptors on
B-
lymphocytes-
initiate an
immune
response.
Types if immunoglobulin:

Cell mediated immunity
Ag is processed and presented to its specific T lymphocytes by macrophages or
Langerhan's cells ( antigen presenting cells), and usually appears in the early
stages of the lesion ( gingivitis) where it proliferate into:
- CD4 T helper cells: secrete lymphokines.
- CD8 T cytotoxic cells : attack and kill the antigen, TNF production.
- Memory cells.
T-lymphocyte subsets:
T lymphocyte subsets
Function
T-helper (T4) Produce cytokine
T-T enable cytotoxic cells to react to antigen.
T-B antibody production
Enhance B cell proliferation
T-macrophages interaction
T-cytotoxic (T8) Bind to and kill the target cell
Inhibit B cell proliferation
TNF production
NK cells
Involved primarily in elimination of neoplastic or tumor cells.

Cytokines
 A small protein released by cells that has a specific effect on the interactions
between cells, on communications between cells or on the behavior of cells.
They include interleukins, lymphokines and cell signal molecules, as tumor
necrosis factor and interferons, which trigger inflammation and respond to
infections.
 Lymphokines are cytokines secreted mainly by activated lymphocytes.
 The term monokines refers to analogous immunoregulators produced by
activated macrophages and Monocytes.Chemokines induce directed chemotaxis
in nearby responsive cells, hence the name Chemotactic cytokines.
 In order to unify the terminology of these factors, the term interleukin was
accepted. They are required for the initiation and regulation of all stages of
the immune response from stem cell differentiation to effector cell activation.
 Thier action is mediated by binding to specific receptor on target cells.Each
cytokine has several different activities and same activity my be produced by
different cytokines.
Some interleukins commonly associated with periodontal diseases
include:

:
IL1
 Following activation it is synthesized by varies cell types including:
- Monocytes
- Macrophages
- T-lymphocytes
- Fibroblasts
- Vascular cells
- Skin cells
 In a physiologic doses it play a role in tissue healing and remodeling since it
stimulate:
- Proliferation of fibroblasts, keratinocytes, endothelial cells
- Fibroblasts syntheses of pro-collagen and fibronectin
 Unrestricted production in an inflammatory state leads to tissue destruction.
 Stimulate gingival fibroblasts to produce collagenase and PGE2
 Potent inducer for bone resorption
 Synergize other cytokines like TNFα to induce bone resorption.

:
IL4,IL10,IL13
 Anti-inflammatory cytokines (IL-4, IL-10, IL-13) are responsible for the down-
regulation of inflammatory responses. They are able to suppress the production
of proinflammatory cytokines.
 There strong anti-inflammatory activity suggest possible utilization in
management of many inflammatory diseases
Transforming growth factor
 The production of most lymphokines and monokines such as IL-1, IL-6 and TNF-
inhibited by transforming growth factor (TGF-B ).
 TGF-B has a number of proinflammatory activities including chemoattractant
effects on neutrophils, T lymphocytes,
 TGF-B stimulates neovascularization and the proliferation and activities of
connective tissue cells and is a pivotal factor in scar formation and wound
healing.

: Local predisposing factors in periodontal diseases
Among the most important local predisposing factors that modify the tissue response to direct
and indirect bacterial effects are:
• Calculus, carious lesions, overhanging restorations, rough margins, crown contours,
tooth position, occlusal trauma, open contacts and food impaction.
• Habits; bruxism, tongue thrusting, smoking, mouth breathing
Dental calculus
Dental calculus is calcified dental plaque, composed primarily of calcium phosphate mineral
salts deposited between and within remnants of formerly viable microorganisms. A viable dental
plaque covers internalized calculus deposits.
Classification and characters:
Calculus is classified by its location into Supragingival and subgingival.
Supragingival calculus
• Contain 37% mineral by volume.
• Minerals come from saliva Usually whitish in color.
• The greatest amount of supragingival calculus is present on the lingual surfaces of
mandibular anterior teeth and decreases toward the third molars.
In the maxilla, supragingival calculus frequently forms on the buccal surfaces of the first
molars.
• In both the mandible and maxilla, these are sites that are close to the orifices of
salivary ducts.

:
Subgingival calculus:
• Contain 58% mineral by volume.
• Minerals come from sulcular fluids.
• Usually black in color Found everywhere.
• For the lingual surfaces of the teeth, the lower first molars have the most subgingival
calculus.
• For the buccal surfaces of the teeth, the mandibular anterior teeth and maxillary molar
teeth have the greatest amount of subgingival calculus.
• A more irregular subgingival cemental surface allows deposits to form into the
cemental irregularities. This makes the attachment of the subgingival calculus more tenacious
and difficult to remove.
Calculus composition:
• Supragingival and subgingival calculus contain 37% and 58% mineral content by
volume, respectively
• The matrix constitutes 15.7% of the calculus dry weight and contains 54.9% protein
and 10.2% lipid.
• Of the total lipids, 61.8% are neutral lipids,
• Glycolipids account for 28% of the total lipids
• Phospholipids, representing 10.2% of the total lipid
• The concentration of phospholipids in the saliva of heavy calculus formers
is significantly higher than that of light calculus formers . These findings suggest that
phospholipids play an important role in calculus formation

:
Dental calculus is always covered by a soft and loose layer of micro-organisms. On
supragingival calculus, this layer is dominated by filamentous micro-organisms. The filaments
are approximately perpendicular to and in direct contact with the underlying dense calculus
• By contrast, the mixture of cocci, rods, and filaments covering subgingival calculus
has no distinct pattern of orientation
• More than half of the matrix is composed of proteins of bacteria and salivary proteins.
• Carbohydrates are derived from extacellular products of bacteria (glucans) and
salivary glycoprotein's.
Inorganic component
• It has been demonstrated that octacalcium phosphate (OCP), hydroxyapatite (HAP),
and ß-tricalcium phosphate or whitlockite (WHT) form the inorganic part of both supragingival
and subgingival calculus
• Trace amounts of fluoride, sodium and magnesium
Theories of plaque mineralization:
Physico-chemical theories:
In plaque fluid, the concentrations of calcium phosphate are generally considerably greater than
in the surrounding saliva, since the ions from demineralized enamel are to some extent, likely to
remain in the plaque. The pH in plaque (5.5-6.5) is generally lower than that of saliva. The
acidic conditions that often prevail in plaque together with the high concentration of calcium and
phosphate ions make it possible for dicalcium phosphate dihydrate (DCPD) to form and
accumulate.

:
Precipitated crystallites are likely to adsorb and/or adhere to the enamel pellicle layer and plaque
bacteria which offer a large number of negatively charged binding groups. This may protect the
crystallites from dissolution and allow mineral deposition in positions where bacteria and
proteins accumulate.
Epitaxic concept (seeding theory):
This theory considers that plaque organic matrix act as a template for HA crystal formation.
Matrix protein and phospholipid surfaces may induce
nucleation by first binding calcium ions, which subsequently take up phosphate.
Plaque bacteria release relatively large amounts of lipoteichoic acid, which is likely to bind
calcium ions and to adsorb at calcium phosphate surfaces. Such interactions between
lipoteichoic acid and calcium
Phosphate may both orient the growing crystals
Inhibition theory:
Pyrophosphate salivary protein are effective inhibitors of the mineralization reactions that take
place in dental plaque, the enzyme alkaline pyrophosphate can hydrolyses pyrophosphate to
phosphate

:
Factors increasing calculus formation:
1. Elevated salivary pH.
2. Elevated salivary calcium concentration.
3. Elevated bacterial protein and lipid concentration.
4. Elevated concentration of protein and urea in submandibular salivary gland secretions.
5. Low individual inhibitory factors.
6. Higher total salivary lipid levels.
Role of Dental Calculus in Etiology of Periodontal Disease:
The primary action of calculus is that acts as a holding mechanism for dental plaque, so it
keeps plaque in direct contact with the tissues, which amplify dental plaque effects upon
periodontal tissues. Various studies clearly exclude the possibility of dental calculus as a primary
cause of periodontal disease. However, it provides an ideal surface for further accumulation of
dental plaque and amplification of effect of bacterial plaque, which initiate the pathologic
changes.

: 2. Faulty Dentistry in Etiology of Periodontal Disease
Various faulty dental procedures can participate in incidence of periodontal disease, as local
predisposing factors. They includes: Faulty restorations, Faulty prosthodontics and Faulty
orthodontics, and Hazards of dental procedures.
Faulty Restoration:
Proper dental restoration and periodontal health are inseparable and interrelated conditions.
Thus faulty restorations are considered causes of gingival inflammation for the following
aspects:
1. Restoration Margins: Placement of filling margins sub-gingivally will increase
plaque accumulation and gingival inflammation. Marginal defects, such as overhanging provide
ideal locations for dental plaque accumulation, which initiate the disease and have direct
damaging effects on gingival and periodontal tissues.
2. Restoration Contour: Both under and over – contouring of the fillings showed damaging effect
on gingival tissues.
3. Occlusion Restorations: Improper occlusion restoration may result in occlusal disharmony,
which has deleterious effects on periodontium.
4. Restorative Materials: There are some dental restoratives, e.g. acrylics, can initiate gingival
inflammation. In addition, restorative materials must have capability to obtain smooth, polished
surface otherwise their roughness will retain more plaque deposits leading to the initiation of
gingival inflammation.

:
Faulty Prosthodontics:
Partial dentures can create an ideal environment for quantitative and qualitative dental
plaque changes, which promotes development of periodontal disease. However maintenance of
proper cleaning measures can decrease dramatically this effect, and improperly fitted dentures
and/or clasps play an etiologic role in disease process.
Faulty Orthodontics:
Orthodontic appliances tend to retain dental plaque and food debris, which can initiate
gingivitis. Orthodontic bands should not extend to gingival tissue beyond attachment level, to
avoid forceful detachment. Designed orthodontic forces applied for tooth movement, should not
be excessive and rapid to avoid periodontal destruction.
Hazards of Dental Procedures:
Some dental procedures such as placing of matrix bands & rubber dam as well as mechanical
trauma during preparation for restorations can damage gingival tissues, initiating gingival
inflammatory process.

:
3. Food Impaction and Retention
Food impaction is a forceful wedging of food into periodomtium by occlusal forces. It can
cause gingival inflammation and will interfere with proper periodontal therapeutic and
preventive measures.
The following conditions can cause food impaction:
1. Absence of proximal contact or presence of unsatisfactory proximal relationship.
2. Excessive wears and flattened tooth surfaces.
3. Excessive anterior overbite.
Plunger Cusp: is tooth cusp tends to forcibly wedge food interproximally, caused from excessive
wear and flattened surface or due to shift in tooth position.
Food retention or Lateral food impaction: Lateral pressure from lips, cheeks and tongue may
force food inter-proximally. It occurs when gingival embrasure is enlarged by tissue destruction
in periodontal disease or by gingival recession.
Food impaction complications (Sequela):
1. Initiation of gingivitis and periodontal disease.
2. Aggravates the existed pathologic condition.
3. Bad odor of oral cavity (halitosis).
4. Gingival and periodontal abscesses formation.
5. Gingival recession and alveolar bone destruction.

:
4. Un-replaced Missing Teeth
Failure to replace extracted teeth initiates a series of changes, which produce varying
degrees of periodontal disease. These series includes food impaction, gingival inflammation,
bone loss in the inter-proximal area and pocket formation. These changes accompanied by
alterations in functional dental relationships as result of drifting and tilting of the adjacent teeth
and supra-eruption of opposing tooth, will result in occlusal disharmony. These changes,
collectively, are common factors in etiology of periodontal disease.
The best example of this factor is early loss of first permanent molar, which often lost in
childhood or the teen years. If this molar is not replaced, a classic set of dentition changes occurs
referred as first molar loss syndrome. Typical course of events, following such early tooth loss
includes:
1. Second and third molars drift mesially and tilt, creating a spaces and causes vertical
dimension loss.
2. The mandibular premolars drift distally and may be tilted.
3. The maxillary first molar extrudes into a space on mandibular arch.
4, Anterior overbite is increased and can lead to trauma of anterior palatal gingiva from lower
anterior teeth.
These changes create food impaction area and spaces that are difficult to clean, creating an
environment suitable for initiation of gingivitis

:
5. Teeth Crowding and Malocclusion
Crowded or malaligned teeth can be more difficult to clean than properly aligned teeth and
there is a relationship between vertical overbite and horizontal overjet and periodontal status.
Malocclusion, as determined by Angle's classification has no significant relation to periodontal
condition. However, studies reported clear association in both severity and prevalence of
periodontal disease with irregular teeth alignment, crowded teeth, displaced teeth, teeth
malocclusion and open bite.
It should be noted that malocclusion is not a cause of periodontal disease, but it may participate
in periodontal disease etiology through:
- Create conditions, which permit more dental plaque accumulation,
- Preventing proper dental plaque removal,
- Irritation to teeth – supporting structures.

:
6. Mouth Breathing and Tongue Thrust
The participation of mouth breathing in etiology of periodontal disease is unclear and
conflicting results were obtained from studies performed to clear that role. Dryness of the
mouth resulting from mouth breathing may help in initiation of gingivitis mainly at maxillary
anterior teeth. The gingiva becomes shiny erythematous, edematous and enlarged. Mouth
breathing is also associated with higher levels of plaque accumulation and gingivitis.
The best treatment is to treat the cause however palliative treatment, possibly placing of
lubricant over the tissue is helpful.
Tongue thrusting is associated with anterior open bite; during swallowing the tongue is thrust
forward against the teeth instead of being placed against the palate. When pressure against teeth
is great it can causes teeth mobility as well as spacing between the lower anterior teeth.
7. Habits
Several habits were shown to be an important factor in initiation and progression of
periodontal disease. Habits can be classified into:
1. Neuroses habits.
2. Occupational habits.
3. Miscellaneous habits.
Neurosis habits includes: Lips and cheeks biting; finger – nail and toothpick biting; and
occlusal neurosis as bruxism.
Occupational habits includes: Holding nails in mouth (carpenter), holding of music
instruments (musician) and cutting and holding of threads.
Miscellaneous habits include: Pipe and cigarette smoking and tobacco chewing, thumb
sucking, wrong tooth-brushing techniques as well as mouth breathing.

:
Trauma from Occlusion and Periodontal Disease Etiology:
Trauma from occlusion is a term used to describe the pathologic alterations or adaptive
changes, which develop in the periodontium as result of undue forces produced during
mastication. It can be termed, also, as occlusal trauma, periodontal traumatism, and traumatizing
occlusion as well as traumatogonic occlusion.
Occlusal trauma may leads to the following conditions:
1. Periodontal tissue damage.
2. Injury to TMJ, masticatory muscles.
3. Injury to pulp tissues.
Trauma from occlusion can be divided into: Primary and secondary trauma.
- Primary form of trauma from occlusion includes tissue damage elicited around teeth with
normal height of the periodontium.
- Secondary form of trauma from occlusion describes the tissue injuries caused by occlusal
forces in periodontium of reduced height.
However this division has no value, as alterations in periodontium caused by primary or
secondary occlusal trauma are similar. Several studies were carried out aimed at the clarification
of this aspect; some showed that trauma from occlusion is aggravating factor in periodontal
disease while others showed that there is no relationship between occlusal trauma and degree of
periodontal tissue destruction.
).

:
Clinical trials reported that occlusal trauma has important signs as:
1. Angular bony defects.
2. Infrabony periodontal pockets.
3. Increased teeth mobility.
In conclusion: Trauma from occlusion may have a detrimental effect on the periodontium;
however it cannot induce gingival inflammation. Teeth with progressive, plaque-associated
periodontal disease, trauma from occlusion may enhance the rate of disease progression. Trauma
from occlusion can result in resorption of alveolar bone leading to increased tooth mobility,
which can be transient, or permanent. Such bone resorption can be considered as physiologic
adaptation of tooth supporting tissues to traumatizing occlusal forces.
Bruxism:
It is a clenching or grinding of the teeth not during chewing or swallowing. Bruxism occurs
without any neurological disorder or defect, among healthy individuals. Presence of shiny, bright
facets involving teeth surfaces is usually the best indicator for diagnosis of active Bruxism. It
has been reported that, Bruxism is a knight habit (multifactorial psychosomatic phenomenon)
and it has been postulated that heredity play a role in the etiology of none stress-related Bruxism.
Both emotional stress and predisposing oral factors may act together to produce Bruxism. It can
be treated by night-guard appliance, to protect tooth surface and dissipates forces built up in
musculo-skeletal system during Bruxism.

:
Trauma from Tooth - brushing and Flossing:
Gingival alterations can occurs following improper tooth brushing technique or using too
hard new toothbrush. These alterations can be acute or chronic and varies in their appearance.
Gingival erythema, which may be diffuse, denudation of attached gingiva, formation of painful
vesicle is common sequelae of toothbrush trauma. Bristles of toothbrush may forcibly embed
into gingival tissue and can initiate acute gingival abscess. Improper use of dental floss silk,
toothpicks or wooden interdental stimulators may result in gingival inflammation.
Tobacco Use:
The use of tobacco products, particularly cigarette smoking, has been strongly identified as
a risk factor for periodontal disease; reason for this could be toxic effects of tobacco use on the
various oral structures. However, exact mechanisms by which smoking increases susceptibility
to periodontal infections are not completely known, but it is likely that smoking suppresses
certain components of immune system. Impaired neutrophil function, induced by products of
tobacco smoking, appears to be of importance.
A specific form of gingivitis termed “Gingivitis toxica,” characterized by destruction of
gingival tissue and underlying bone, is attributed to tobacco chewing (Smokeless tobacco

:
Systemic Predisposing Factors in Etiology of Periodontal Disease
I. Nutritional Factor
There are nutritional deficiencies that produce changes in oral cavity, which termed as oral
or periodontal manifestations of nutritional disease. Nutritional deficiencies themselves cannot
cause periodontal disease. However, they can create periodontal condition, which can
aggrevately affected by local irritations.
Nutritional factor participation in etiology of periodontal disease:
1. Diet nature: The composition and character of the diet may influence relative distribution of
microorganisms, their metabolic activity and pathogenecity; these effects participate in
periodontal disease etiology.
2. Some vitamins (A, B, C) deficiencies: affect oral and periodontal tissues.
Vitamin A deficiency can:
a. Affect gingival keratinization state and increases the density of alveolar bone.
c. Retard the healing of gingival wounds.
d. Predispose to leukoplakia occurrence.

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Vitamin B complex deficiency may lead to:
Gingivitis, glossitis, glossodynia, angular cheilitis and entire inflammation of oral mucosa.
Vitamin C deficiency and periodontal disease:
Its sever deficiency results in scurvy, which characterized by increased hemorrhagic tendencies
and retarded wound healing possibly due to: defective formation of collagen, retardation of
osteoid formation, impaired osteoblostic function and increased capillary permeability.
* How vitamin C deficiency can participate in etiology of periodontal disease?
* By one or more of following mechanisms:
1. Influence collagen metabolism that affects tissue regeneration and repair.
2. Interferes with bone formation leading to bone loss seen in periodontitis.
3. Increases permeability of oral tissue to toxic substances as endotoxins.
4. Decreases WBCs functions as chemotactic and migratory functions.
5. Affect the integrity of periodontal microvasculature.
6. May interfere with the equilibrium state of bacterial ecology of the plaque.
However, these mechanisms were postulated, but several studies failed to establish a clear
causal relationship between level of vitamin C with the prevalence and severity of periodontal
disease. In this respect, it can be mentioned that, role of vitamin C deficiency is aggravation of
gingival response to dental plaque, worsen edema, enlargement and bleeding tendencies.

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II. Endocrine (Hormonal) Factor
Hormones are organic substances produced by endocrine glands and secreted directly to
the bloodstream, and exerts important physiologic influences of certain biological functions.
Hormonal disturbances may affect periodontal tissues directly or indirectly as
following:
- Incidence of oral and periodontal manifestations.
- Modification of tissue response to dental plaque (Biofilm).
- Production of anatomic changes in the mouth, which favor plaque accumulation or traumatic
occlusion.
Various hormonal imbalances can participate in periodontal disease etiology such as: Hypo-
and Hyperthyroidism, Hypo-and Hyperparathyroidism, Hypo and Hyperpitutirism. The most
hormonal imbalances, which have effect on periodontal structures, are: Diabetes mellitus and
Gonads (sex hormones)
Diabetes Mellitus:
It is a metabolic disorder characterized by an impairment of functions of langerhan’s beta
cells in the pancreas, which lead to increased blood glucose level and excretion of sugar in urine.
The underlying problem in diabetes mellitus is an insufficient supply or impaired availability of
the insulin, a pancreatic hormone necessary for regulation of carbohydrate metabolism. There
are 2 main types:
a) Type I or Insulin – dependent,
b) Type II or Non-insulin-dependant type.
In these two types of diabetes mellitus, a genetic predisposition appears to be an important
factor in their development; Type II accounts for 80 to 90 % of all cases of diabetes mellitus.

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Oral manifestations of diabetes:
They differed according to controlling state of the disease, as patients with uncontrolled or
poorly controlled diabetes appear to be more susceptible to infections including periodontal
disease.
Increased susceptibility to infections among diabetics is due to PMNs deficiencies resulting in
impaired adherence.
* Uncontrolled Diabetics show the following:
1. Burning sensations, dryness, cracking or fissuring of oral mucosa.
2. Decreased salivary flow with alteration of oral flora characterized by predominance of some
species.
3. Decreased host defense mechanisms with increased susceptibility to infection leading to
destructive periodontal disease.
Thus it is common to find following manifestations: increased loss of attachment, increased
bleeding on probing increased tooth mobility and multiple periodontal abscesses.
* Controlled Diabetics: in well-controlled diabetic patients, none of the above mentioned
manifestation could be found.

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Gonads (Sex hormones):
There are several forms of periodontal alterations can be associated with gonads imbalance,
best examples are:
1. Gingival changes during puberty: Gingiva appears inflamed, bluish–red, edematous and
enlarged. These changes can be exaggerated response to local irritation caused by hormonal
imbalance state.
2. Gingival changes during menstruation: Prevalence of gingivitis during menstruation in
some females was increased. Cyclic gingival changes associated with menstruation have been
attributed to hormonal imbalance and in some instances are accompanied by a history of an
ovarian dysfunction.
3. Gingival changes during pregnancy: Pregnancy itself does not cause gingivitis but it does
accentuate gingival response to irritations and modifies resultant clinical picture. During
pregnancy gingival inflammation is markedly increased; beginning from second or third month
of pregnancy. Gingivitis becomes more sever by the eighth month and decreases during the
ninth; dental plaque accumulation follows a similar pattern. Pregnancy affects severity of
previously inflamed areas; it does not alter healthy gingiva.

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The gingival manifestations during pregnancy include:
1. Inflamed gingiva appears as bright red in color.
2. Edema of interdental and marginal gingiva.
3. Presence of discrete mass “pregnancy tumor”; it is not a true tumor.
Gingival changes are painless, unless infected. It has been suggested that, vascular alterations
associated with hormonal changes of pregnancy (i.e., elevated levels of estrogen and
progesterone) make the gingiva more susceptible to plaque-induced inflammation. Increased
progesterone levels can lead to dilatation of gingival capillaries, increased vascular permeability
and increased flow of the GCF. These changes could facilitate the entry of irritating bacterial
products from dental plaque into gingival tissue, thereby promoting gingival inflammation. Both
hormones can promote growth of certain suspected periodontal pathogens as P. intermedia.
Briefly, hormonal changes associated with pregnancy can affect the composition of sub-gingival
flora qualitatively, affect gingival resistance and promote development of gingivitis and even, in
some cases, periodontitis.

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III. Hematological Factor or Blood Disorders
Blood dysrasias is a term refers to a group of disorders that affect blood cellular elements
(red and white cells), including: aplastic anemia, agranulocytosis, cyclic neutropenia and
leukemia. Oral and periodontal changes are commonly associated with these blood disorders.
Leukemia:
It is a group of cell malignancies of bone marrow, characterized by marked increased of
immature WBCs in circulation, with widespread infiltrates in various organs as liver, spleen and
lymph nodes. Although precise causes of leukemia are unknown, some forms are linked to some
viruses or exposure to ionizing radiation. There are several forms of leukemia and major types
are; acute lymphoplastic leukemia, acute myeloblastic leukemia, chronic myeloid leukemia and
chronic lymphocytic leukemia.
The acute forms are of sudden onset and lead to death within a few months unless properly
treated. On the other hand, chronic forms develop slowly and usually have a relatively one
clinical course. Of all leukemia patients, those with chronic forms are most likely to be seen in
the dental clinics because they are often being medically managed on an outpatient basis. These
patients are suffering from marked and increased susceptibility to infections as periodontal
disease.
Leukemic patients have marked gingival enlargement due to gingival infiltration with these
immature cells. Gingiva appears bluish red and cyanotic with rounded gingival margin, enlarged
gingiva may extend to cover, partially, crown. Gingival bleeding is a common finding in
leukemia, due to thrombocytopenia that results from replacement of bone marrow cells by
leukemia cells.

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Anemia:
It is a blood disorder characterized by reduction in the number of RBCs and in the amount of
hemoglobin. It may result from blood loss, defective blood formation or increased blood
destruction. There are several types of anemia, manifested orally as marked pallor of gingiva,
atrophic changes of gingiva and alveolar bone and cyanosis of mucosa can be found in all forms
of anemia.
Agranulocytosis:
It is a depletion of granulocyte precursors in the bone marrow, characterized by
disappearance of neutrophils from peripheral blood. Because PMNs are one type of
granulocytes, severe periodontal infections and oral ulcerations are, frequently, clinical features
of this disease.
Cyclic Neutropenia:
It is a blood disorder of unknown etiology and characterized by periodic reduction of
neutrophils in the blood and bone marrow. Thus, patients with this disorder experience flare-ups
of any existing periodontal infections during the period of PMNs depletion.
Thrombocytopenic Purpura:
It is a blood disorder, characterized by marked reduction in the number of circulating
platelets. This disease is manifested by spontaneous bleeding into skin or from mucous
membranes; gingiva appears swollen, soft and friable. Gingival bleeding occurs spontaneously
or upon minor provocation and it is difficult to control. Gingival changes can be considered as
an abnormal response to local irritation as its severity can be minimized or alleviated following
irritation removal.

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IV. Immunodeficiency Disorders
Deficiencies in host defense mechanisms may lead to severe tissue destruction involving
periodontal tissues. These deficiencies are of 2 types: primary (inherited) and secondary
(acquired). The most common that may have oral manifestations:
Chediak-Higashi Syndrome:
It is a rare disease affects organelles production, of almost every cell. However,
melanocytes, platelets and phagocytes are mostly affected. It is characterized by mild bleeding
disorders and recurrent bacterial infections, including periodontitis.
Antibody Deficiency Disorders:
It is an agammaglobulinemia, is a disease results from a deficiency in B-cells, while T-cell
function is not affected. This disorder may be acquired or congenital, that is characterized by
recurrent infections including aggressive periodontitis.
Acquired Immunodeficiency Syndrome (AIDS):
It is an infection with human immunodeficiency virus (HIV). The HIV infects and
eventually kills a wide range of cells, but in particular T-helper cells, which can result in severe
immune-suppression that makes the patient susceptible to many life-threatening fungal, viral and
bacterial infections. HIV patients have severe and aggressive forms of periodontal disease, such
as necrotizing gingivitis / necrotizing periodontitis (NG / NP).

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V. Metallic Intoxications and Drugs
Metals ingestion, as mercury, arsenic, phosphorus, bismuth and lead may result in oral
manifestations; the most common one is pigmentations of the gingiva. Bismuth pigmentation of
oral tissues appears as a narrow, bluish- black discoloration of inflamed gingival margin. The
lead pigmentation of the gingiva appears as linear (burtonian line), steel gray and associated with
local irritation. Gingival pigmentation from mercury is caused by deposition of mercuric
sulfide; appears as linear blackish coloration with ulcers of gingiva and mucosa.
VI. Debilitating Diseases
Several debilitating conditions including syphilis, TB, chronic renal and hepatic failure
may predispose to periodontal disease as a result of impairment of the tissue resistance to
infections. Thus, the responses to local factors are aggravated with marked destruction of the
tooth-supporting structures.

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VII. Psychosomatic Disorders
A correlation was reported between psychiatric, anxiety, physiologic and psychological
stresses with the incidence of some forms of periodontal diseases (necrotizing gingivitis is an
example).
Disorders of psychosomatic origin may manifest in the oral cavity, through the influence of
autonomic nervous system upon somatic control of the tissue, probably, as following:
Psychological disturbance ----- functional impairment ------ cellular structural alterations -----
--- incidence of the disease.
VIII. Heredity
This aspect received attention since last three decades, but it is not completely understood.
Studies reported that, like other body systems, disease susceptibility and / or resistance might be
affected, at least to some extent, by the monogenetic backgrounds. Findings that some forms of
periodontal disease have familial pattern in occurrence and possible association with HLA
antigens confirm this idea.

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