Basic Immune12121212121212121212121212122

Basic Immunology
(Understanding Immune System)
Prof. Abdel-Fattah Amer
Dept. of Oral Medicine & Periodontology,
Faculty of Dental Medicine, Al-Azhar University

Immunology
 Study Of Immune System
 Latin Word immunis =“exempt”
 Pasteur Was First To Successfully Apply
Vaccination
 It is the branch of biology concerned with
the ability of the body to defend against
external as well as internal invaders.

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Immune Response
 The immune processes in most cases, lead to the
elimination of antigens without producing
clinically detectable inflammation.
 Development of clinically apparent inflammation
indicates that immune system has encountered
either:
 An unusually large amount of antigen (Antigen in an
unusual location)
 Or antigen that is difficult to digest .

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Immune Response
 Normal Response:
It is capability of responding to foreign substance
entering the body and recognize it as non-self.
 Immune Hyperactivity:
o Allergy
o Autoimmunity
 Immune Hypoactivity:
o Immunodeficiency
o Infections
o cancer

Host Defense (Non-specific & Specific)
Defense
Mechanisms
Innate
Inborn independent of previous
experience
Acquired
Naturally
acquired
Active
Adoptive
Passive
Active
Adoptive
Passive
after natural
exposure to a foreign
agent
placental transfer
immune cells in
colostrum
Artificially
acquired
Specific
immunization
administration of
preformed antibodies
Bone marrow
transplant
immune cells in
colostrum

Two Types of Immunity
 Innate
– It is effective but not specific and is not
enhanced by previous exposure to foreign
substance.
– “possessed at birth, possessed as an essential
characteristic”
– Always present
 Acquired (Adaptive)
– Created and modified

Innate immunity
o Present at birth (Termed
innate).
o Is the main, first-line
defense against invading
organisms, in which
microorganisms are
detected and destroyed
within hours by defensive
mechanisms that are not
antigen specific.
Acquired immunity
• Absent at birth and has
specificity and memory
(Termed adaptive).
• If an infectious agent
overcomes the early lines of
defense (innate immunity),
acquired immunity will
respond through antigen
specific cells.

Characteristics of Innate and Acquired immunity
 Non-specific, is present at
birth and does not change in
intensity with exposure.
 Protects from pyogenic
bacteria, fungi and parasites.
 Composed of mechanical
barriers, secreted products
and cells (Granulocytes and
NK cells)
 Specific responses, acquired
from exposure and increases in
intensity with exposure.
 Protects from bacteria including
intracellular infection, viruses
and protozoa.
 Composed of secreted products
and cells (Lymphocytes)
Innate Immunity Acquired Immunity

Innate Immunity: Components)
 Protection by Skin and Mucous Membranes
 Phagocytic Cells
o Remove debris: Macrophages, Neutrophils, Monocytes
 N K Cells
o Lymphocytes that kill virally infected cells & tumours
 C System
o A group of >30 proteins found in the blood
 Physiologic Barriers
– pH (stomach); Temperature (fever)
– Soluble Factors (interferons, lysozyme)
 Inflammatory Barriers
– Vasodilation, Capillary permeability, Leukocyte Infiltration

o C-Reactive Protein (liver)
o Histamine (vasodilation, increased permeability)
o Kinins
• Small peptides normally inactive in blood
• Ex. Bradykinin (causes pain)
Mediators Of Inflammation

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2nd line of defense
Phagocytic cells and the immune response
Neutrophils
 Under normal conditions developed in bone marrow ,
however during inflammation there development is
enhanced by Granulocyte-colony stimulating factor,
which is elaborated by activated Macrophages.
 Once released into blood stream its half life is 6 to 9
hours.
 In acute inflammation, they are the first leukocytes
emerges from the vessels in significant number.
 It provides non specific effective defense against
bacterial and fungal infections.

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Neutrophils Chemotaxis
 Migration of Neutrophils
through the tissue to locate
and destroy microorganisms
are due to Chemotactic
factors.
 Neutrophils moves along
concentration gradient of
chemotactic factor until it
reaches the agent responsible
for chemotaxis.
PMN
Chemotaxis
Phagocytosis

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Neutrophils chemotactic factors
Complement dependent
factors
I. C5a
II. C567
are involved in the initial
recruitment of neutrophils.
Complement independent
factors
I. LTB4
II. N-formylated peptides
products of bacterial
metabolism.
III. Bacterial stimulated
macrophage IL8.
IV. Tissue breakdown
products.

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

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 Bacterial killing by Neutrophils
Oxygen independent
o Bacterial permeability-increasing protein
it works through activating phospholipase which
breakdown bacterial membrane phospholipids.
o lysozyme, attack bacterial cell wall.
o Collagenase, degrade collagen.
o Elastase, attack bacterial cell Mem.
o Gelatenase, degrade collagen.
o Lactoferrin, chelator of iron, thus compete with
bacteria for iron which is needed for growth of many
bacteria.

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Bacterial killing by Neutrophils
Oxygen dependent
• If O2 is available, there is a respiratory burst consisting
of sharp increase in oxygen consumption.
• Respiratory burst is triggered by NADPH oxidase
(Enzyme situated on membrane of phagocytic vacuole)
• The enzyme converts O2 to O2 metabolites that can kill
bacteria.
• Following bacterial engulfment and formation of
phagocytic vacuoles (Phagosome), vacuoles fuses with
Cytoplasmic granules and granules discharge their
contents into phagosome (Degranulation).
• Neutrophil granules contain a number of antibacterial
factors.

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Monocytes and Macrophages
 Like Neutrophils, Macrophages they are motile
phagocytic cells, but they are long lived (several
months) and can proliferate after leaving the blood
stream.
 Neutrophils are the first leukocytes to enter an area
of injury
 Macrophages because of their longer life span are
often the most numerous cells in later stages of
inflammation.

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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.
 Major Macrophage Products:
1. IL1
2. TNF
3. PGE2
4. Leukotrienes
5. Lysosomal enzymes as Collagenase and Elastase.

Adaptive Immunity
 Two Components of Adaptive Immune System
I. Humoral (humoral mediated immunity)
– B-Cells  Plasma Cells  Antibodies
II. Cellular (cellular mediated immunity)
– CD8+ T-Cells  Direct Cellular Killing
– CD4+ T-Cells  Recruitment of other immune cells
(inflammatory response)
 4 Characteristics
Memory Diversity
Antigenic Specificity Self/non-self recognition

Principles of Adaptive Immunity
1) Specificity
ability to discriminate between different antigenic
epitopes and respond to those that necessitate a response
rather than making a random response.
2) Self-non self discrimination:
ability to recognize body proteins (self) and differentiate
them from cells or tissues of other people e.g. blood
transfusion, graft rejection.
3) Memory:
ability to recall previous contact with a particular antigen
giving protection against it which is long-lasting or even
life-long e.g. meningitis, measles.
4) Adaptiveness:
ability to respond to previously unseen antigen which may
never have existed before.

 Close collaboration between Innate &
Acquired / Adaptive Immunity , exists
as:
o Macrophages can secret cytokines that affect the
type of adaptive immunity
o Macrophages/DCs Present Antigen
o Lymphocytes Increase Effectiveness of
Macrophages

~ 60% Neutrophils (50% - 70%)
~ 3% Eosinophils (>0% - 5%)
~ 0.5% Basophils (>0% - 2%)
~ 5% Monocytes (1% - 9%)
~ 30% Lymphocytes (20% - 40%)
Frequency of Leukocytes Different Types in Healthy
Individuals

 Granulocytes (Neutrophils, Eosinophils & Basophils),
Monocytes and Lymphocytes (T & B).
 Antigen presenting cells
 Lymphocytes
• T cells, mature in Thymus (CD3, CD4, CD8)
• Two Major subsets, TH (CD4) and TC (CD8)
• Mature T cell expresses TCR
• TCR cannot recognize antigen on its own
• MHC I (all nucleated cells) or MHC II (APCs) is
required
• TH cells secrete cytokines
• TC less cytokines, more cytotoxic
Cells Of Immune System

• B cells, mature in Bone Marrow (CD19,
CD20)
• in periphery they express a unique surface
antibody
• Plasma cells differentiated B cell, short
lifespan, antibody factory
• Memory B cell (CD45RO), long life span

 Antigen Presenting Cells
• Number of Cells capable of Antigen
Presentation
• Dendritic Cell (DC) professional APC
• Macrophages, B cells
• APCs are a safeguard against autoimmunity

 First Protein Antigens Must Be Broken Down
 Form Complexes With MHC I or II
• Exogenous Antigens
– Binding of Ags To MHC II
– Expression of MHC II+Ags On Surface
– CD4 T Cells Recognize Ag Thru Class II MHC
 Endogenous Antigens
– Produced Within Cell, Ex. Virus Ag, Cancer Ag
– MHC I Molecules Bind Ag in ER
– CD8 T Cells Recognize Ag Thru MHC I
Processing & Presentation of Antigens

Lymphoid System
 Collection of tissues and organs designed to bring B
and T cells in contact with antigens
In order for body to mount appropriate response,
immune cells must encounter antigen
 Lymphoid system includes
– Lymphatic vessels
– Secondary lymphoid organs
– Primary lymphoid organs

 Lymphatic vessels { Carry lymph to body tissues }
– Lymph travels through vessels to lymph nodes
 Material such as protein is removed ………. Fluid portion
empties back into blood stream
 Secondary lymphoid organs { Sites where lymphocytes
gather to encounter antigens}; include:
 Lymph nodes Spleen Tonsils Adenoids Appendix
 Allows for initiation of immune response from nearly any
place in body.
 Primary lymphoid organs { Bone marrow and thymus are
primary lymphoid organs}
– B cells mature in bone marrow
– T cells mature in thymus
 Once mature, cells leave primary lymphoid organs and
migrate to secondary lymphoid organs

 Immunogen (Antigen)
• Is a substance which when introduced into the body is
able to produce specific immunological response
(production of antibodies) and is able to react with the
products of that response.
* Hapten: (Incomplete or Partial Antigen)
Antigen with a small molecular weight, alone has no antigenicity
e.g. most drugs, but when introduced in the body it combines with
body proteins forming Hapten (body – protein conjugate that can
provoke an immune response).

Antigen
 A substance that is capable of reacting with products of a
specific immune response (antibody or specific sensitized T-
lymphocytes).
 A “self” component may be considered an antigen, even though
one does not generally make immune responses against them.
 Foreign substances: Mainly proteins, often microorganisms and
their toxins.
 Human cells that have been transformed: may be tumor cells, or
cells infected with viruses.
 Human tissue: Organ transplants, tissue grafts, incompatible
blood types during a transfusion.
o Autoimmune diseases: Tissue from person’s own body becomes
an antigen.

Characters of Antigen (Immunogen)
1. Foreignness to the animal.
2. High molecular weight: Most potent antigens are
those with a molecular weight over 10.000 Dalton.
3. Chemical nature: The more the chemical complexity, the
more potent the antigen. amino-acid are poor immunogen.
4. Antigenic determinant: Antigen should have antigenic
determinant (epitopes) to react with lymphocytes receptors.
5. Dose and route of administration: once the threshold has
exceeded, increasing the dose increase the immune response.
Subcutaneous (S.C.) & Intramuscular (I.M.) routes of
administration are the safest while Intravenous (I.V.) is most
dangerous.
6. Genetic constitution
Ability of the body to respond to antigen varies with genetic
make up (inherited as an autosomal dominant trait).

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3nd line of defense
Acquired (specific) immunity
 Humoral immunity
 Cellular immunity
 Complement activation

Antibodies
 Soluble glycoproteins that exhibit antigen-binding
ability belonging to a group of large polypeptides
termed Immunoglobulins.
 All antibodies are immunoglobulins, however, not all
immunoglobulin molecules necessarily have
demonstrated antigen-binding (i.e. antibody) function.
 Antibody: “a Y-shaped protein, found on surface of B-
Cells or free in the blood, that neutralize antigen by
binding specifically to it”
 Also known as an Immunoglobulin
Antigen

 Structure of Antibody (Ab)
◦ Basic Y-shaped structure
◦ Made of 4 chains of amino acids held together by
disulfide bonds:
 Two chains are heavy & Two chains are light
◦ Each heavy and light chain has a constant region :
known as Fc region
◦ Each heavy and light chain has a variable region: is
unique to each Ab; binds to a specific Antigen and is
known as “Fab” region

1. IgM
• First Ab to respond to infection
• 5 – 13% of Ab in circulation
• Only Ab that can be formed by the fetus
2. IgG
• Dominant Ab in circulation: 80 – 85% Ab in circulation
• Only Ab that can cross the placenta
• The antibody of memory!!!!!
3. IgA
• Found in secretions, 10 - 13 % of Ab in circulation
4. Ig D
• <1% of total Ab in circulation
• Maturation of antibody response
5. Ig E
• Barely detectable in circulation, Active in allergic reaction
Classes of Antibodies

Antibodies Production:
B-cells produce antibody through two mechanisms:
a) T-cell dependent antigen:
- Where antigen needs help from T-h to stimulate B cells
to produce antibodies.
- Antigen is processed by antigen presenting cells to T-h
together with (MHC).
- T-h becomes activated and produces cytokines
including B-cell growth factor (BCGF) and B-cell
differentiating factor (BCDF).
- BCGF and BCDF (with IL-2, 4, 5, 6) stimulate B cells to
differentiate into plasma cells to produce Abs.
b) T-cell independent antigens:
Where antigen is capable of directly stimulating B cells
e.g. Lipopolysaccharides of gram –ve bacteria.

 Characteristic of Primary response:
– Lag period of 10 to 12 days occurs before antibody
detection in blood
 Activated B cells proliferate and differentiate
into increasing numbers of plasma cells as long
as antigen is present
– Net result is slow steady increase in antibody titer
B Lymphocyte and Antibody Response

 Formation of Memory
o B cells that have undergone class switching
 Produce IgG antibody (Memory Ab)
 IgG antibody can circulate in body for years
allowing protection against specific antigens
 Characteristics of Secondary response
o Memory cells responsible for swift effective
reaction of secondary response
o Some memory B cells will differentiate into plasma
cells … rapid production of Abs
B Lymphocyte and Antibody Response

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Functions of immunoglobulin
I. Toxin neutralization.
II. Opsonization: enhancement of
Phagocytosis.
III. Complement fixation (Activation).
IV. Mast cell degranulation (Ig E).

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Cell Mediated System
T-lymphocytes
 T-cells mature in Thymus
o Over a million different kinds of T-cells;
each producing a different receptor in the
cell membrane .
 CD8+ T-Cell
– Stimulated  Direct Killing
 CD4+ T-Cell
– Th1  Stimulated  Macrophage
Activation
– Th2  Stimulated  B-Cell Activation

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T CD4 helper subsets
 Th1 involved in Macrophage dependent
immune response and secrete IL2 and
interferon gamma.
 Th2 facilitate syntheses of other types of
antibodies, they synthesize IL4 and IL5
o IL12 promote syntheses of Th1 and IL4
promote production of Th2

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T-lymphocyte subsets
T lymphocyte subsets Function
T-helper (T4)
T-cytotoxic (T8)
NK cells
Large granular lymphocytes
Produce cytokine
T-T enable cytotoxic cells to react to
antigen.
T-B antibody production
(enhance B cell proliferation)
T-macrophages interaction
Bind to and kill the target cell
Inhibit B cell proliferation
TNF production
Involved primarily in elimination of
neoplastic or tumor cells.

T Lymphocytes Antigen Recognition & Response
 General characteristics of T cells
o Have multiple copies of T cell receptors ,
which have variable sites of antigen
bonding
o Role of T cells different from B cells
 T cells never produce antibodies
 T cells armed with effectors that interact
directly with antigen
 T cell receptor does not react with free
antigen
 Antigen must be present by APC

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Cytokines & Lymphokines
 Cytokines are hormone like glycoprotein involved in
communications between cells.
 Lymphokines are cytokines secreted mainly by activated
lymphocytes.
 Monokines refers to analogous immunoregulators
produced by activated Macrophages and Monocytes.
 In order to unify the terminology of these factors, the
term interleukin was accepted.
 They are required for initiation and regulation of all
stages of immune response from stem cell
differentiation to effector cell activation.
 Their 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.

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 IL-1 and TNF- together with IL-6 serve as endogenous
pyrogens. The up-regulation of inflammatory reaction is
also performed by IL-11, IFN-gamma.
 Anti-inflammatory cytokines (IL-4, IL-10, IL-13) are
responsible for down-regulation of inflammatory
responses.
 They suppress production of proinflammatory
cytokines.
 Their strong anti-inflammatory activity suggest possible
utilization in management of many inflammatory
diseases.
 IL-10 protect mice from endotoxin-induced shock, a
lethal inflammatory reaction mediated by TNF- & IL-1

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Transforming growth factor
 Production of most Lymphokines and Monokines 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 proliferation
and activities of connective tissue cells and is a pivotal
factor in scar formation and wound healing.

 Natural killer cells descend from lymphoid stem cells
› They lack antigen specificity
 No antigen receptors
 Recognize antigens by means of Fc portion of IgG
antibodies
 Allow NK cells to attach to antibody-coated cells
 Actions augment adaptive immune response
› Important in process of antibody dependent cellular
toxicity
 Enable killing of host cells with foreign protein in membrane
 Natural killer cells recognize destroyed host cells with
no MHC class I surface molecules
› Important in viral infection
Natural Killer Cells

INSummary
 Humoral
– Antibody Production – B-Cells ….. Plasma cells
……… Abs
 Cellular
– CD8+ T-Cells  MHC-I  Cytotoxic
– CD4+ Th1-Cells  MHC-II  Activate
Macrophages
– CD4+ Th2-Cells  MHC-II  Activate B-
Cells…… Plasma cells …..produce Antibody

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Complement
 Potent mechanism for initiating & amplifying Inflam.
 The major components are numbered as they were
discovered, unfortunately C4 was discovered before C2
and C3 so the correct sequence is listed as:
C1, C4, C2, C3, and C5 through C9
 Activated C leads to a cascade of interactions leading to
chemotaxis, phagocytic interactions, lytic attack of cell
membrane.
 Consists of > 30 various glycoprotein's present in serum.
 These are present in blood serum in an inactive state and
are activated by :
 immune complexes: (Classical pathway),
 By bacterial carbohydrates: (Lectin pathway),
 By bacterial origin, LPS,: (Alternative pathway) .

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 Classical Pathway
 C1 activated by complex of Ag, Ab (IgG, IgM).
 When Ag Ab complex bind to C1, C4 and C2 are cleaved
into C4a , C2b in addition to formation of a complex of
C4b2a which is termed C3 convertase.
 C3 convertase has the ability to cleaves C3 into 2
biologically important fragments C3a and C3b.
 C3a is called Anaphylatoxin and it causes the release of
histamine from mast cells and basophils.
 C3b serves to continue the cascade , its release result in
activation of C5 to C9.
 Cleavage of C5 to C5a & C5b; C5a is another
Anaphylatoxin.
 C5b binds C6, C7; C5b,6,7 bind C8 and C9 where they
penetrate target cell mem. (Membrane attack complex,

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 Alternative pathway
 It can be stimulated directly by
Microorganisms and is important
in early stages of infection before
the production of antibody.
 C3 activation by microorganisms
split C3 into C3a, C3b.
 C3b bind factor B and factor D
(only complement factors present
in the body fluids as an active
enzyme) split off small fragments
of C3bBb and C3 convertase that
cleaves C5 through 9 to activate
the MAC.

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Function of Complement
 Complement mediated Inflammation:
o C3a, C5a degranulation of mast cells
o C3b platelet release of serotonine
o C2 generation of kinines (serum bradykinine)
 Complement mediated Chemotaxis:
• C3a chemotaxis of eosinophils
• C5a chemotaxis of neutrophils, eosinophiles, macrophages.
• C5.6.7 chemotaxis of neutrophiles, eosinophils.
 Complement mediated Opsonization
o C3b promote phagocytosis.
 Complement mediated Cell adherence
o C3b bind to receptor on neutrophils, macrophages, B cells.
 Complement mediated Immune regulation
o C3b bind to receptors on B lymphocytes which lead to:
• Regulation of immunologic memory
• Stimulation of lymphokine release

Immunopathology
(Study of immune reactions involved in disease)
• Immune system can malfunction and cause
tissue damage:
o Hypersensitivity (Hyper reactivity)/ Allergy
o Autoimmune diseases
o Immune deficiencies

ALLERGY
 It is derived from Greek Allos ergos = altered reactivity
 Allergy is an altered reactivity of tissues of certain individual,
caused by exposure to an agent that is innocuous to others.
 Allergen Is an antigen (foreign substance) that can elicit allergic
symptoms However, Since first exposure to an antigen results in
production of antibody primary Ig E (Type I hypersensitivity
reaction), re-exposure to allergen triggers an allergic response.
 So, allergy can be defined as: “Altered reactivity on second contact
with allergen”.
 Allergen can be defined as: “A class of antigen that can elicit Ig E
production in some individuals”.
 Hapten: is incomplete antigen that has low molecular weight and
binds with body protein to form complete antigen.

 Sensitizing Dose
o Patient is initially exposed to antigen … lead to formation of
specific IgE.
o A latent period of variable duration (several hrs, days, years)
during which IgE continues to be produced and attached to
basophils and mast cells.
o After this latent period…. high levels of IgE sensitized basophils
and mast cells are present.
o IgE interact only with particular antigen or with chemically
related antigen (called Cross reactivity).
 CROSS REACTIVITY:
 Is the reaction of antibody with an antigen other than the one
which induced its formation.
 Allergy to chemically related drugs, i.e, patient allergic to one
drug is also allergic to the chemically related drugs, e.g: 1.
Procaine and Sulpha (Same Para Aminobenzoic acid nucleus) 2.
Penicillin and Cephalosporine.

 Classification of Hypersensitivity reactions on basis
of mechanisms involved in their production
 According to effector mechanisms thought to be involved,
hypersensitivity reactions was originally classified by Gell &
Coombs in 1970s into four categories:
o Type I Anaphylactic
o Type II Cytotoxic
o Type III Immune complex (Serum sickness like)
o Type IV Cell mediated (Delayed)
 Immediate allergic reactions include types I, II, III of Gell
& Coombs classification system.
 Type IV reaction is an example of delayed reaction.

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Allergic Acute inflammation
 Type I hypersensitivity is characterized by an allergic
reaction that occurs immediately following contact
with antigen, which is referred as allergen.
 In some individuals certain allergens have a propensity
to stimulate production of IgE antibodies.
 Ig E antibodies bind nonspecifically, via their high
affinity Fc receptors, to Mast cells and Basophiles.
 Subsequent attachment of antigen to the Fab portion
of cell-bound Ig E antibodies results in release of
contents of cytoplasmic granules from mast cells and
basophiles: (e.g. Histamine, prostaglandin), as well as
in synthesis and secretion of biologically active cellular
lipid mediators of Arachidonic acid (e.g. Leukotrienes).

 Mast cells, IgE,
and the allergic
response.

Eosinophils & Their Role in Allergy
 Eosinophils are important in allergic diseases.
 Blood or local tissue Eosinophilia is a useful clinical test
for allergy (while they normally comprise 1-3% of
circulating leukocytes, in allergic patients eosinophils
reach 10-20%).
 Mast cells & Basophils release Eosinophil chemotactic
factor (ECF-A) and IL-5 that attract Eosinophil to allergic
inflammation area.
 Eosinophils exert a negative feedback control on allergic
reactions by limiting amount of mediators.

Mast cell & Basophil Granules (Mediators)
A. Preformed granules B. Synthetized substances
 Preformed granules
1. Histamine
2. Proteoglycans:
a. Heparin in mast cells.
b. Chondroitin sulphate in basophils.
Action: i. Anticoagulant. ii. Activate C1q
3. Protease enzymes mainly tryptase
Action: i. Increase vascular permeability. ii. Activates C3
4. Platelet activating factor (PAF)
5. Eosinophil chematactic factor (ECF)
6. Neutrophil chemotactic factor (NCF)

 Synthetized substances from Mast cell wall
These substances are produced by 2 pathways through
activation of phospholipids by action of phospholipase:
Phospholipids (Action of Phospholipase)
……Arachidonic acid (Metabolized by two pathways):
1. Lipo-oxygenase Pathway 2. Cyclo-oxygenase Pathway
Leukotreins Prostaglandin
LTB4 PG: D2, E2, F2
LTC4
LTD4 (SRS-A)
LTE4
TXA2
Thromboxanes ……….. Aggregate platelets

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 Histamine
 Has diverse functions leading to acute vascular effect including:
• Local dilation of small vessels; widespread arteriolar dilatation;
• Local increased vascular permeability by contracting endothelial
cells; Contraction of nonvascular smooth muscle (bronchospasm);
• Chemotaxis for Eosinophils;
• Blocking T lymphocyte function.
 Serotonin
o Capable of increasing vascular permeability, dilating capillaries
and producing contraction of nonvascular smooth muscle.
o Most serotonin is stored in GIT and CNS but a large amount is also
stored in dense granules of platelets.
 Increased vascular permeability mediated by these
reactions probably facilitates the capacity of antibody
and inflammatory cells to arrive at the infected site.

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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 and Lipoxygenase pathways:
o Cyclo-oxygenase pathway produces Prostaglandins,
Prostacyclin, and Thromboxanes;
o Lipoxygenase pathway produces Leukotrienes and Lipoxins .

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Prostaglandins (PG)
 A family of lipid-soluble molecules produced by different
cell types.
 Macrophages & Monocytes are large producers of both
PGE and PGF, Neutrophils produce moderate amounts of
PGE, Mast cells produce PG.
 Unlike histamine, PGs do not exist free in tissues, but
have to be synthesized and released in response to an
appropriate stimulus.
 PGE enhances vascular permeability,Is pyrogenic,
 Increases sensitivity to pain,
 May an have an important suppressive effects on release
of mediators by mast cells, lymphocytes, phagocytes.

68
Thromboxane A (TXA)
o Produced by Monocytes, Macrophages, Platelets.
o It causes platelets to aggregate and constrict BVs and airways.
o These effects are somewhat opposed by action of Prostacyclin
(PGI) which is a potent vasodilator.
 Leukotrienes
 Causes Chemotaxis (directed locomotion) and/or Chemokinesis
(general cell movement) of a number of cell types including PMNs.
 Lipoxins: LXA and LXB
• Stimulate changes in microcirculation: For example, LXA induces
rapid arteriolar dilation and can also antagonize LTD-induced
vasoconstriction.
• LXA may regulate the action of vasoconstrictor Leukotrienes.
• LXA can block Neutrophil chemotaxis.
• Both LXA and LXB inhibit Cytotoxicity of Nk cells.

Bradykinin
 Action of Bradykinin
 Vasodilatation of the B.V. & increased capillary
permeability
 Contraction of smooth muscles.
 Stimulation of glandular secretion (including
bronchi) as histamine
 Stimulation of pain fibers.

Inflammatory Mediators released during allergic conditions
1.Histamine: Vasodilatation of B.V.; Increased vascular permeability;
Contraction of smooth muscles; Stimulation of gastric acid secretion.
2. Prostaglandin: Vasodilatation of B.V. , increased capillary permeability,
Bronchial constriction and bronchial edema. Pain.
3. Leukotriens (derived from lipo-oxygenase pathway of arachidonic acid
metabolism) slow releasing substance of anaphylaxis: LTB4 (Potent
chemotactic), LTC4, LTD4, LTE4 (SRS-A ).
Action: Vasodilatation of B.V. & increased capillary permeability; Contraction of
smooth muscles; Bronchial mucosal edema; Mucous hypersecretion; Chemotaxis.
SRS-A: a mixture of leukotriens (LTC4, LTD4, LTE4). This effect is 6000 times
as potent as that of histamine. Their effect is prolonged bronchial smooth muscle
contraction: Not diminished or reversed by antihistaminics.
4. Platelets Activating Factor (PAF): Activation and aggregation of
platelets. Vasodilatation of B.V. & Increased vascular permeability. Chemotaxis,
Activation & degranulation of Neutrophils, Eosinophils, Activate complement,
Potent broncho-constrictor.

71
Immediate Hypersensitivity
o Acute systemic immediate reaction to allergen, typically
mediated by Ig E antibodies.
o Agents that induce IgE-mediated anaphylaxis include,
Penicillin, Insect venoms, Foods, and occasionally
immunotherapy (i.e. injection of allergen to which a person is
allergic, in order to treat allergic diseases).
 Types of Anaphylaxis
 Localized Anaphylaxis:
o Urticaria,
o Seasonal rhinitis,
o Asthma,
 Systemic Anaphylaxis:
• Where large amounts of Antigens (Allergens) enter the host
circulation, Systemic Anaphylaxis (Anaphylactic Shock).

o N.B: Skin test for allergy in atopy (to detect IgE
circulating antibodies)
1. Serum of a sensitized atopic person (contains IgE) is injected
S.C. into a tissue a normal personal.
2. Ab will bind to mast cells and remain fixed up to 4 – 5 days in
skin.
3. If specific allergen (to be tested) is introduced into same site
after a 24 hours … a local wheel develops indicating a positive
reaction.
- Skin test may give false- positive results, produced by localized
release of histamine in response to skin puncture by the needle.
- Negative response means that patient can safely receive tested
drug.
- Skin of allergic patient can not used for allergic test(e.g. test
for LA , because of possibility that might precipitate an
immediate anaphylaxis.

Type I Hypersensitivity
Immediate (Anaphylactic type)
– Reaction occurs within minutes after exposure to an antigen.
– Plasma cells produce Ig E.
 Ig E causes mast cells to release histamine, causing
increased dilation and permeability of blood vessels and
constricting smooth muscle in lung bronchioles .
– Reaction may range from hay fever to asthma and life-
threatening anaphylaxis.
 Anaphylactoid Reactions
 Identical symptoms, which are not immune mediated, are
sometimes termed Anaphylactoid.
 Anaphylactoid reactions may be caused by radiocontrast dye
(used for x-ray studies) and exercise.

 Type I Hypersensitivity Reactions is mediated by
IgE.
 SO
 What are Mechanisms that favor switching of humoral
immune response for production of IgE (antibody response
become dominated by IgE which is normally 0.004%) ?
 How IgE mediates allergic reactions in relation to cells as
eosinophils, mast cells & basophils ?
 What are pathophysiological mechanisms of allergic
reactions ?

 1- Principles that elicit Ig E production:
A. Role of TH2, IL-4 and IL-13 B. Genetic factors.
A. Role of IL-4 and IL-13 & TH2 :
IL-4 & IL-13 (same effect as IL-4) action: 1. B cell proliferation (
activation & differentiation of B cells into plasma cells) to produce
antibodies.; called B cell growth factor. 2. A growth factor for TH2
(switch antibody isotype from IgM to Ig E). 3. Inhibitory for TH1 4. In
allergy provide a potent stimulus for B cell switching to produce Ig E.
5. Control proliferation and activities of Eosinophils and Mast cells.
N.B. Allergens when enter body (even at a very low doses by diffusion
across mucosal surfaces) can trigger Naïve T cells to develop into TH2
in presence of IL-4. These TH2 cells (allergen specific TH2 cells) can
switch antibody isotype from IgM to Ig E.
• Antigen that evoke TH2 cells to drive an Ig E response is called
allergen.
• TH2 – driven Ig E responses can be inhibited by TH1 cells that
produce INF- γ

B. Genetic factors
 Production of Ig E may be enhanced by host genetic
factors, this state is called atopy.
 Atopy is a group of allergic diseases of hereditary
tendency, e.g. bronchial asthma and hay fever.
 Atopic individuals have higher level of Ig E &
Eosinophils than normal counts.
 Defect on loci on long arm of chromosome 11 is
responsible for abnormal Ig E response.
 Infants who subsequently developed allergic diseases
produce less IFN- γ than normal.
 IFN- γ is one of cytokines which regulate Ig E
production.

Allergen ……Trigger TH2 response in presence of IL-4 & IL-13
B cells
Switch antibody isotype to produce …….. Ig E
Can be inhibited by TH1, IFN- γ……
•

78
Anaphylactic Shock (Generalized Anaphylaxis)
o The most dangerous drug reaction.
o Usually starts within 30 seconds-1/2 hour.
o The quicker the onset, the more sever the reaction.
 Clinical Features
• Some or all of the features of generalized anaphylaxis;
• Paresthesia of the face
• Coldness of the extremities
• Wheezing (bronchospasm)
• Facial edema
• Peripheral circulatory failure , pale, sweating, faint pulse.
 In severe cases
a- Rapid fall of blood pressure. b- Pallor and sweating. c- Rapid pulse
and weak. d- Loss of consciousness.
3. Later the patient becomes: a- Pulse less. b- Cyanotic from
inadequate oxygenation of blood. c- Death may occur within few
minutes.

 Management
1- Lay patient in supine position to improves venous return and
increases blood flow to brain.
2- Adrenaline.
3- Oxygen & monitoring of vital signs until an improvement in
patient status (BP & Pulse rate).
 These 3 steps (Position, Adrenaline and Oxygen) are only steps
during life-threatening phase.
4. Hydrocortisone sodium succinate 200 mg I.V.
5. Antihistaminic. 6. Call ambulance.
 The 4th and 5th steps (cortisone & histamine blockers function to
prevent recurrence of symptoms and to decrease need for continuous
administration of adrenaline. They are not administered during acute
phase of reaction. They may be given on arrival in office or after
transporting the victim to ER for definitive care.

Drugs used to Treat Hypersensitivity
A. Adrenaline
 Action: 1. Bronchodilator. 2. Vasoconstrictor 3. Decrease capillary
permeability, thus reduce edema. It acts within few minutes
leading to increased blood pressure & stimulation of heart muscle
(life saving in anaphylactic shock).
 Dose and route of administration: 0.5 ml of 1/1000 conc. S.C. or
I.M. Repeated every 5 minutes if there is no improvement with
maximum dose 1.5 ml (3 injections over a period 10 – 15 minutes).
- Never injected I.V. to avoid Ventricular fibrillation.
- Smaller doses for children 0.1 – 0.3 ml (infant 0.075 ml).
 Site for I.M. injection: Intra-lingual or floor of mouth, even in
presence of hypotension, will provide rapid absorption than in
traditional I.M.
o Adrenaline is only injectable drug needs to be kept in a preloaded
form.
o More than 3-4 injections carry potential risk of excessive adrenaline
administration, which lead to excessive cardiovascular stimulation.

B. Coticosteroids
Action: (dose 200 mg I.V.)
1. Used to prevent recurrence of symptoms.
2. Anti-inflammatory and immunosuppressive
Mechanism of Action
- Cortisone enters the cells by passive transfusion.
- Binds to cytoplasmic receptors & combination enters nucleus.
- Nucleus will be stimulated to produce (m- RNA) …lipocortin
synthesis.
Action of Lipocortin
- Inhibits phospalipase enzyme so interfere with inflammatory
mediator release i.e. reduce synthesis of leukotreins (SRS-A) and
PGE.
- Inhibit production of IL-2 …. suppression of cell mediated
immunity.
- Inhibitions of lymphokines.
- Interferes with function of macrophages.

C. Antishistaminics
- Antihistaminics are of no value in emergency treatment
since .
- They are slowly acting drugs; they antagonize one
mediator only (histamine); they restore the vasomotor tone
without producing potential vasoconstriction.
Antihistaminics include e.g. Promethazine HCI:
 20-50 mg oral or I.M. every 24 hours.
 Long acting 20-24 hours.
 Highly sedative 8-12 hours.
 Best taken at night.

Localized Anaphylaxis
 In general, Atopy is a hereditary feature manifested by abnormal
immediate - type hypersensitivity to a certain allergen or a group
of allergens. 1. Angioedema 2. Bronchial asthma
Angioedema
• It is attack of non-inflammatory edema involving subcutaneous
and submucosal tissues in various parts of body (rapid
development of edematous swelling of skin, subcutaneous
tissue & sub mucosal CT).
Mechanism of Angioedema
Vasodilatation of BVs & increased capillary permeability brought
about by release of allergic mediators with subsequent transudation
of plasma subcutaneously or submucosally resulting in a large
swelling under normally looking skin or mucous membrane.
 Kinins .. vasodilatation .. Increases capillary permeability ..
leakage of fluid .. edema under normal looking skin or MM.

84
• Angioedema is of Two Forms:
1. Hereditary form due to inherited deficiency of C1 esterase
inhibitor…….continued complement activation and kinine-like
substance formation ……… increased capillary permeability and
edema.
2. Non hereditary form.
 Types of Hereditary Angioedema (HAE)
1. Type 1 HAE: Represent 85% of cases, due to absence of C1
esterase inhibitor.
2. Type 2 HAE: Represent 15% of cases, present of non-
functioning C1 esterase inhibitor.
 Etiology
C1 Estrase inhibitor: Absence.
Present but non function.
Consumed in coagulation & fibrinolytic system.

Angioedema
 Clinical Picture:
1- Rapidly developing edema in less than
½ an hour and may last one or several
days. a. Edema of face involve: eyes, chin,
lips & parotid gland resulting in facial
disfigurement.
b. Swelling of tongue (posterior part),
nasopharynx and larynx result in
respiratory problems.
2- Swelling appear smooth, diffuse,
painless, no change in color /temperature
of affected part (non-inflammatory).
Treatment
1. Hereditary: raise level of C1 Estrase inhibitor
enzyme (blood transfusion).
2. Non Hereditary: a- Mild cases: Adrenaline 0.5
ml SC followed by Corticosteroids 50 mg 4
times/day. b- Tracheotomy may be life saving.

Bronchial Asthma
Allergy characterized by recurrent attacks of acute breathlessness.
Mechanism
Patient is abnormally sensitive to various substances inhaled or
ingested. Presence of dental foci may aggravate the condition.
Allergic reaction result in release of leukotreins (SRS-A) which is
main mediator in bronchial asthma, resulting in: Spasm of smooth
muscles of bronchi. Swelling of bronchial mucosa. Mucous
secretion, mucous blugg (interfere with flow of air during
respiration.
Clinical Features:
 Sudden onset & lasts from half an hr to several hrs.
Short forceful inspiration, followed by a longer easily heard
wheezing expiration.
Expiration is not capable of deflating chest which becomes
distended, fixed in position of full inspiration.
Pallor, cyanosis of face, lips, ear, nose and extremities.
Prolonged attacks are called status asthmatics which may last for
days without remission (life-threatening)

Management:
 If asthmatic attack occurs in dental office:
Stop dental procedure.
Check air way passage and remove intra oral devices .
Permit patient to sit upright position to allow mucous
secretion to get down by gravity.
Loosen tight clothes.
Ensure that the room is airy and cool.
Drugs; (patients usually carry their own drugs).
a- Pressurized aerosol: (bronchodilators)
i- Adrenaline. ii- Tablets isoprenaline 20 mg sublingual.
Dentist can give a adrenaline 0.5 ml 1/1000 Conc., Sc. Or I.M.
(usually if two doses of aerosolized bronchodilator fail).

 Status Asthmatics: Severe prolonged life – threatening
attack, so:
• Hospitalization. Oxygen inhalation.
• Corticosteroids. I.V. Aminophyline.
• Sedation.
- Sedative drugs in severe or prolonged asthmatic attacks are
contraindicated as they depress CNS and respiratory systems.
- Potential respiratory depression produced by sedative agents may
be accentuated by concurrent hypoxia and respiratory arrest may
occur.
- In less severe cases ,use of sedatives, e.g., diazepam may be
used.
N.B. Antihistamines: are of no value since Leukotrienes (not
histamine) are important mediators of the reaction.

Urticaria
A common allergic reaction on skin varying from
small localized papules to large coalescing
erythematous plaque with itching.
 Mechanism
Food, drugs or certain bacteria act as allergen,
resulting in IgE mediated release of histamine &
histamine like substances from the mast cells to
act on superficial vasculature.
 Treatment: If possible, avoidance of the
causative factor.
• Antihistaminic & Corticosteroids in severe
cases.
• N.B. Septic foci may be the cause for chronic
urticaria.

Hay fever
 Recurrent form of allergy to wind-born pollen grains of grasses and
trees, certain food or dust. Familial predisposition to allergy and
has a seasonal incidence particularly in early summer.
 Mechanism:
IgE mediated reaction with release of histamine & other
mediators in m.m. of upper respiratory tract & conjunctiva.
 Clinical Features
• Itching of nose with profuse watery nasal discharge.
• Paroxysms of sneezing & coughing.
• Conjunctival irritation & lacrimation. Headache & depression.
 Treatment * Avoid contact with causative pollen.
*Antihistaminic & steroids in cases refractory to Antihistamines
* Desensitization may be performed.

Type II Hypersensitivity
Antibody-dependent (Cytotoxic Type)
 Acute inflammation mediated by cytotoxic Abs occurs when
antibody binds to either self antigen or foreign antigen on cells,
and leads to phagocytosis, killer cell activity or complement-
mediated lysis.
• Antibody combines with an antigen bound to surface of tissue
cells, usually a circulating RBCs.
o Activated complement components, IgG and IgM antibodies in
blood, participate in this type of hypersensitivity reaction.
 This destroys the tissue that has the antigens on the surface of
its cells (e.g., Rh incompatibility).

92
Immune Complex Complement Activation
o Antibody directed against cell surface or tissue antigens forms
immune complex which interacts with Complement and a
variety of effector cells to bring about damage to Target cells.
AB Dependent Cell Mediated Cytotoxicity
o Antibodies can link Target cells (Ag) to effector cells, as
Macrophages, Neutrophils, Eosinophils, NK cells, by means of
Fc receptors on these effector cells.
o This is so-called antibody-dependent cell-mediated cytotoxicity
(ADCC).

93
 N.B.
 Both Type II and Type III Hypersensitivity are caused by IgG
and IgM antibodies.
 Main distinction is that Type II reactions involved antibodies
directed to antigens on surface of specific cells or tissues,
whereas type III reactions involve antibodies against widely
distributed soluble antigens in serum.
 Thus, damage caused by Type II reactions is localized to a
particular tissue or cell type, whereas damage caused by
Type III reactions affects those organs where antigen-
antibody complexes are deposited.

Type III Hypersensitivity
Immune Complex Type (Serum sickness)
– Immune complexes are formed between
microorganisms and antibody in circulating blood.
 These complexes leave the blood and are deposited
in body tissues, where they cause an acute
inflammatory response.
– Tissue destruction occurs following phagocytosis by
neutrophils.
 Type III hypersensitivity develops when immune
complexes are formed in large quantities, or cannot
be cleared adequately by Reticulo-endothelial
system, leading to serum-sickness type reactions.

Type IV Hypersensitivity
 Cell-mediated type (Delayed)
– T lymphocytes that previously have been introduced to an
antigen cause damage to tissue cells or recruit other cells.
– Responsible for the rejection of tissue grafts and
transplanted organs.
All those hypersensitivity reactions which take more than 12
hours to develop, and which involve cell-mediated immune
reactions rather than Humoral immune reactions.
 Type IV hypersensitivity reaction Stomatitis Venenata /
Dermatitis Venenata (Contact allergy)
Definition: It is a delayed allergic reaction of skin or oral
mucosa to local contact with foreign substance (allergen).
o Dermatitis venenata……. Skin.
o Stomatitis venenata ……. Oral cavity.

96
Type IV or Delayed Type Hypersensitivity Chronic
inflammation
 Unlike other forms of hypersensitivity, Type IV
hypersensitivity cannot be transferred from one animal
to another by serum (since it is not an AB serum
components), but can be transferred by T cells.
 T cells necessary for producing delayed response are
cells which have become specifically sensitized to the
particular antigen by a previous encounter, and they act
by recruiting other cell types to the site of the reaction.

Mechanism
 Caused by hapten first contact with antigen and epithelial cell
protein and on second contact with allergen, immunologically
mediated by TH1 & TC tissue damage occur through release of
cytokines; Mainly TNFα.
 Contact allergy is thought to occur in oral cavity less frequently
than skin, even when same allergen has contacted both skin and
oral mucosa.
 Reasons for decreased rate of contact allergy in OM than skin:
1. Presence of saliva: dilutes allergen, washes allergen from surface
of mucosa & digests allergen with enzymes.
2- Allergen are only in brief contact with oral mucosa.
3- High vascularity of oral mucosa lead to rapid absorption &
dispersion of allergen.
 Thick keratin layer of skin serves a better source of protein for
combination with hapten forming antigen complex, compared with
the relatively thin layer of keratin (or absence of keratin) in most
areas of the oral cavity

Etiology
Stomatitis venenata may be induced by patient or by dentist.
1) Induced by dentist: (iatrogenic)
a- Dental materials: Plastic filling material (acrylic resin) due to
sensitization of the oral mucosa to liquid methyl methacrylate.
- Denture base material due to liquid monomer, Amalgam
filling.
b- Dental therapeutics: Antiseptic lozenges, phenol, alcohol,
Topical antibiotics & Iodine, formaline.
2) Induced by patient
a- Dental cosmotic preparations: Dentifrices, Denture powders
& Mouth washes
b- Chewing gum & lip sticks
c- Food: Candy, Melon & Shell fish

Clinical Features
Erythema, edema; in severe cases ulceration of site of contact.
While itching is a characteristic complaint of the skin, burning
is the common complaint in the oral mucosa.
Cheilitis, dry scaled lip, localized atrophy of tongue coating
may occur.
N.B. Dermatitis venenata
 May affect perioral skin (itching, burning, erythema vesicles,
ulceration, urticaria).
 May affect dentist’s or technician’s fingers when handling
dental materials.
 Latex sensitivity become a significant problem among all
health professionals including dentists (and probably their
patients).
 Use of Vinyl gloves as latex substitute has minimized
occurrence of allergic reactions.

100
Stomatitis Medicamentosa
 Appears as eruptive lesions of the oral mucosa resulting from
systemic administration of allergen (drug or food).
May involve skin alone….dermatitis medicamentosa.
Mouth alone ……………stomatitis medicamentosa.
Skin and mouth
o Acute multiple vesicles/ulcers similar to Erythema multiform
anywhere in body ( attributed to immune complex mediated
injury (Type III Reaction.)
o Angiodema on the lip and tongue (Type1), Urticaria of lip and
oral mucosa (Type 1), Fixed drug reaction (Type 1)
Oral Manifestations:
- Vesicles, ulcers & lesions similar to erythema multiform.
- Angioedema. Urticaria of lip. Chelitis, stomatitis, Glossitis
(Tongue is enlarged with indentation markings around its
lateral margins, with loss of filiform papillae.
Stomatitis: Oral mucosa is fairy red in color, vesicles & ulceration
may occur.

102
Stomatitis/Dermatitis venanata
Predisposing factors
 Allergic reaction of skin or MM to local contact with foreign
substance (allergen).
 Dental cosmetics ( dentifrices, MW, denture powder)
 Dental materials ( impression M, perio. pack, mercury)
 Dental therapeutics ( topical AB, iodine, procaine,.. )
 Clinical Features
o Localized , mild/sever burning and itching at site of contact.
o Erythema, edema, or vesicle formation, erosion, ulceration.
o Lip; sever edema, cheilitis, angular cheilitis.
o Tongue; localized atrophy of coating.
• Find out precisely cause of allergic reaction (Patch test)
• Dermatologist Consultation.
• Active dermatitis is usually treated with the following:
• Emollient creams
• Topical steroids
• Topical or oral antibiotics for secondary infection
• Oral steroids, usually short courses, for severe cases

Patch test
Only test distinguish contact allergy from other lesions as chronic
Atrophic Candidiasis. It may be performed on skin or oral mucosa.
a- Dermal test: Allergen (e.g. scrapping of denture) is applied to
skin with moist gauze on one arm and control moist gauze alone on
other side ………. Allergic individuals show erythema within 24-72
hours at contact site.
- Erythema, sloughing or ulceration at contact site .. Positive patch
test.
b- Epimucous test : Application of allergen to oral mucosa via:
- a- Rubber suction cup applied to cheek mucosa.
- b- Incorporation into orabase in mucobuccal fold.
- c- Incorporation into oral adhesive spray.
- d- Placing it on palatal aspect of denture.
 Mantoux reaction
 best known example of cell-mediated hypersensitivity
 Obtained by injection of tuberculin into skin of an individual in whom previous
infection with mycobacterium had induced a state of cell-mediated immunity.
 Characterized by erythema and induration which appears only after several
hours and reach a maximum at 24--48 hours, thereafter subsiding.

Diagnosis of Contact Allergy
 History of contact with allergen.
 Clinical examination: Erythema, Edema, Vesicle &
Ulceration. Positive patch test.
 Treatment of Stomatitis Venenata
1. Elimination of causative agent (allergen).
In mild case: removal of allergen will be sufficient
In severe cases: Antihistaminics. Topical corticosteroids
(even systemic) corticosteroids may be needed in more
sever resistant cases).
2. Symptomatic treatment: in presence of severe
manifestations as oral ulceration, sloughing.
- Analgesics or topical anesthetics to relief pain.
- Orabase, to protect the ulcer during healing.
- Antiseptic agent, to minimize secondary infection.

Differentiation between Allergy & Denture Sore Mouth (DSM)
Allergy
History: New denture
Clinical examination:
- Erythema is seen under upper
& lower denture (more in
upper).
- Erythema involve denture
bearing & denture contacting
areas (inner aspect of lip,
cheek, tongue).
- Special investigations:
- Patch test is +ve
Therapeutic drug
- Antihistaminic
Candidosis (DSM)
Old denture. Inadequate cleaning
of Denture fittings surface.
Wearing of denture for day& night.
- Erythema is seen confined to
upper denture bearing area
only.
- More in upper denture than
lower.
- 1. Patch test is –ve.
- 2. Bacterial smear.
- 3. Bacterial culture.
- 4. High candidal antibody titre
in serum & salvia
- Antifungal drugs.

Hypersensitivity to Drugs
 Most drugs are of too low MW to be directly immunologic, but
they act as a Haptens (incomplete antigen), bonding with
body proteins to form complexes that act as allergen.
 Drugs can act as antigens.
– Topical administration may cause a greater number of
reactions than oral or parenteral routes.
– But the parenteral route may cause a more widespread and
severe reaction.
 Clinical manifestations of Drug allergy
o Generalized anaphylactic shock
o Angioedema & Urticaria
o Serum sickness
o Drug fever
o Erythema nodosum & Erythema multiform
o Hematologic disorders (Leukopenia, Eosinophilia)
o Disseminated vasculitis

Fixed Drug Eruptions
 Single or multiple slightly raised, reddish patches or clusters of
macules on skin, or MM, May have pain or pruritis.
 Lesions appear in same site each time a drug is introduced
Generally appear suddenly after a latent period and subside
when the drug is discontinued
 A type of allergic reaction (Type III), Immune complexes are
deposited along the endothelial walls of blood vessels.
Inflammation causes vasculitis with damage to the vessel wall.
This creates erythema and edema in superficial layers of skin or
mucosa.
 Mechanism: Drug is conjugated with body protein in vascular bed
supplying this particular area.
Site: Tongue is most common site for fixed drug eruption.
Drug: Phenolphthaline (most common) & Barbiturates .
 Treatment
Drug causing reaction should be identified and discontinued.

Prevention of Drug Allergy
It is impossible to prevent drug allergy but to minimize the risk.
1- Careful Case History :- Previous drugs (allergen) reaction. - Taking into
consideration nature of allergens and cross reactivity. - History of atopic
allergic diseases (Hay fever, asthma) or any allergic reactions.
2- The patient must be informed about the his hypersensitivity to a certain
drug or L.A.
3- Drugs which can be taken I.M. or S.C. should not be taken I.V.
4- Serious reaction occurs within first 30 minutes after I.V. administration
of the drug, keep patient under observation for 30 minutes after injection.
5- Dentists must be ready and equipped by:
a. good medical information.
b. Suitable medications.
c. Good equipments: preloaded syringe of adrenaline for emergency use.

Adverse Reaction To Local Anesthetics
According to chemical structure, LA could be divided into:
1- Ester Group: “Paraaminobenzoid acid esters” (PABA)
- Procaine (Novocain) - Tetracaine (Pontocain)
- Benzocaine - Amethocaine
2- Amide Group: “non – ester type”
- Lidocaine (xylocaine)
- Mepivacaine (carbacaine) or (Scandonest)
- Prilocaine (Citanest)
- Articaine (ultracaine) or (Astracaine).
 Ester type of anesthetics cross react with each other, cross
reaction does not occur between ester and amide types of local
anesthetics.
 If the Pt is allergic to both groups:
• 1% solution of diphenhydramine (Antihestaminic) and 1/100.000 Epinephrine

110
Unwanted Effects to Local Anesthetics
Hypersensitivity to LA
 Immediate: in form of anaphylactic shock.
 Latent: (after minutes or hours) in the form of
asthma, urticaria, angiodema.
 Delayed: in the form of contact dermatitis due
to frequent handling of LA ointment.

Unwanted effects of Local Aneasthetics
A. In Normal individuals: Due to L.A. itself Not due to L. A
1. CNS: a. stimulation
b. depression
1. Psychomotor & Vasovagal
syncope,
2. Vasopressor
2. Cardiovascular:
a- Cardiac arrest.
b- Peripheral Vascular collapse.
B. In Abnormal individuals:
Hypersensitivity, Intolerance, Idiosyncracy

Unwanted effects of L.A. due to L.A itself
A. In normal individual
I- Cardiovascular System: LA at toxic dose or I.V or rapid injection
lead to:
a. Cardiac arrest due to its depressant effect on conduction system.
Management: Artificial respiration. Cardiac massage (injection of
adrenaline into heart)
b. Peripheral vascular collapse
L.A is vasodilator …… decrease blood pressure.
Management
- Vasopressor drug to elevate blood pressure.
Toxicity reactions usually occur if LA are given in a dose or in a
manner that produces an excessive serum concentration.
Toxic overdose of local anesthetic is about 10 cartilages.
Certain factors are present and may predispose to develop an
overdose reaction.

113
Cardiovascular
 If the LA injected accidentally into a vein it may
reach the heart leading to cardiac arrest due to
its depressing effect on the conduction system. It
needs cardiac massage and artificial respiration.
 It may be distributed throughout the peripheral
circulation leading to peripheral vascular
collapse. Need vasopressor drugs.

 During injection of LA to an individual, Dentist
should :
1- Inject slowly & Aspirate first.
2- Better to inject one or two drops of solution first, withdraw
needle and wait 5 minutes to observe reaction. If normal
reaction, complete injection.
3- Limit dose of LA to reasonable quantities i.e. least amount
of L.A. necessary to produce intensity and duration of pain
control required to complete planned surgical procedure.
4- Use vasoconstrictors (with certain exceptions) to slow
entry of L.A. into blood.
5- Patient’s age, weight, liver function and pathologic
processes, history of previous problems with local anesthetic
must be considered while choosing the dose of L.A.
6- Semisupine position (30 – 45 degree) of patient while
taking L.A. prevent vasovagal syncope.

II- Central Nervous System
- LA at toxic dose ………. CNS stimulation
- Very high dose ………… CNS depression
A. CNS stimulation
1. Mild: talkative, confusion or euphoria.
2. Moderate: headache, tinnitus, nausea or feeling of coldness.
3. Severe: muscle twitching and convulsions & loss of conscious.
Management
1. Put patient in supine position, with leg elevated.
2. Ask patient to hyperventilate with or without O2
administration.
Management of convulsions : 2.5 - 5 mg valium IV (diazepam).

116
CNS stimulation
 Apprehension, excitement, confusion or
euphoria.
 Headache, tinnitus, feeling of coldness.
 Muscle twitches and convulsions which
treated by IV 50mg of 2.5% thiopentone.

B- CNS Depression
May follow stimulation or occurs from the start it is seen as:
a- Drop in blood pressure.
b- Loss of consciousness.
c- Respiratory depression.
Management
1. Put patient in supine position, with leg elevated.
2. Artificial respiration.
3. Vasopressor drugs e.g. 5mg phenylephrine I.M to maintain
blood pressure.
4. Cardiac massage (if needed).
N.B.
D.D. between anaphylactic shock no talking, no CNS
stimulation.

AFM AMER 118
CNS Depression
 May follow stimulation or occurs from the
start in the form of
Drop in BP
Loss of consciousness
Respiratory depression
Pt. in flat position, vasopressor drug, artificial
respiration, cardiac massage if needed.

B. In abnormal individuals
I. Hypersensitivity
- Don’t use L.A for many times …….. lead to allergy.
- If a patient gives history of allergy with a L.A … give L.A. of other
group.
- While ester types of local anesthetics cross react with each other,
cross reaction does not occur between ester and amide types.
- While procaine (ester type) has the highest incidence of allergic
reactions, true allergy to amide type is rare.
Excessive use of topical anesthetics:
1- Risk of including sensitization of the patient. Subsequent exposure
to the same or chemically related local anesthetic injection can lead
to dramatic hypersensitivity response including the possibility of
anaphylactic shock.
2- Particularly lozengenges and especially in children, may lead to a
dangerous degree of anesthesia of oropharynx with consequent
inhalation of food into respiratory tract during eating.

II. Intolerance
- It means low threshold to normal pharmacological dose of a
drug. Patient can’t tolerate normal dose.
i.e. normal dose will cause toxicity (over dose).
III- Idiosyncrasy
- It means abnormal bizarre reaction to drug (usually normal
dose) due to genetic abnormality.
- Nausea, vomiting may occur.
2. Unwanted reaction not due to local anesthesia
I- Psychomotor
Some patients may faint or act hysterically at sight of needle.
Management
a- Patient in semi supine position during injection…. maintain
good supply to brain.
b- Patient is handled sympathetically but firmly.
c- Sedation may be needed.

Management of vasovagal Syncope
a- Patient should be placed in supine position.
b- Respiratory stimulant as aromatic ammonia may be useful.
c- Place a cool moist towel on this patient’s forehead.
Stimulus e.g. dental syringe should be away from patient’s field of
vision.
II. Vasopressors
Vasoconstrictor to L.A. (adrenaline or noradrenaline) may lead
to:
A. Local adverse effect
- Vasoconstriction may lead to pallor of tissues and local cyanosis with
reduction of oxygen tension.
- Hyperaemia which may increase risk of postoperative bleeding.
B. General adverse effect
- Adrenaline may lead to palpitation, apprehension & rise of blood
pressure.

122
Treatment of drug hypersensitivity reactions
 Adrenaline:
o The first line of treatment in emergency situations as
angioedema and anaphylaxis it antagonize inflammatory
mediators leading to ;
• Bronchial relaxation & Vasoconstriction (increasing BP).
• Decreasing capillary permeability reducing edema.
• Stimulate heart muscle increasing cardiac output.
 Corticosteroid:
• Life saving in sever Bronchial Asthma & Anaphylaxis
because of:
• Inhibition of the production of inflammatory mediators and
lymphokines
• Inhibition of the response to the inflammatory mediators
• Stabilization of cell membrane and decreasing capillary
permeability leading to decreased edema

Contact Mucositis & Dermatitis
Lesions resulting from contact of an allergen
with skin or mucosa.
Involves CMI (cell-mediated immunity)
Mucosa initially becomes erythematous and
edematous.
Often there is burning and pruritus
Later, the area becomes white and scaly.
Treatment
Topical and/or systemic corticosteroids

Autoimmune Diseases
 Immunologic tolerance
– The body learns to determine self from
nonself.
 Autoimmune disorder
– The recognition mechanism breaks down;
some body cells are not tolerated and are
treated as foreign antigens.

Immunodeficiency
 An immunopathologic condition
– A deficiency in number, function, or
interrelationships of the involved WBC’s and
their products
– May be congenital or acquired
– Infections and tumors may occur as a result
of the deficiency.

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