Pharmacy-Immunology 17 – 18

Hypersensitivity
Saber Hussein
 Objectives
1. Define:
i. Allergy
ii. Anaphylaxis
iii. Atopy
iv. Sensitization
v. Desensitization
vi. Shocking dose
2.Know the four types of hypersensitivity, their
immunological bases; give examples of each:
i. Type I: immediate (anaphylactic) hypersensitivity
ii. Type II: antibody-dependent cytotoxic hypersensitivity
iii. Type III: immune complex-mediated hypersensitivity
ii. Type IV: cell-mediated (delayed type) hypersensitivity.
 Objectives
3. Understand that in immediate hypersensitivity reactions,
the immune system itself provokes tissue damage by
responding to false alarm.
 4.Differentiate between primary and secondary exposure to
antigen in immunity and in hypersensitivity
 5.Explain the structure-function relationship of IgE; discuss
the cytotropism of IgE
6. Describe the role of mast cells in immediate
hypersensitivity reactions; explain degranulation;
distinguish between and give examples for preformed and
newly formed mediators released by mast cells
 Allergen
• Antigen that causes allergy: The term is
used to refer to the antigen molecule itself
or its source, such as pollen grain, animal
dander, and insect venom or food products.
• Many naturally occurring and synthetic
chemicals have been considered allergens
• Any foreign substance, which can elicit an
immune response, is a potential allergen
 Hypersensitivity (Allergy)
• Harmful, inappropriate or exaggerated immune
response
• The first contact of the Ag with the host is
necessary for sensitization
– During this phase the Ag induces the Ab formation
• The second contact of the same Ag will result in
allergic response
– Such an individual is hypersensitive to that specific Ag
– The clinical manifestation of the typical symptoms
depends on the individual
 Sensitization & Acute desensitization
• Sensitization
– Immunization, especially with reference to Ags not
associated with infection
– The induction of acquired sensitivity or of allergy
• Acute desensitization
– This involves the administration of very small amounts
of Ag at 15 minutes intervals
– Few Ag-IgE complexes are formed, so mediator release
is so low that it cannot give major allergic reaction
– Used for administering drugs in sensitive patients
– This is a temporary situation
– Hypersensitivity is restored after a few days
 Chronic desensitization
• Involves long-term weekly administration of the
Ag to the sensitive patient
• This leads to the production of IgG-blocking
Abs in the serum, which can prevent subsequent
Ag from reaching IgE on mast cells
• Hence under these conditions, no immediate
hypersensitive reaction would occur
 Types of hypersensitivity
• Type I, II, III reactions are antibody-mediated
• Type IV reactions are cell mediated
1. Type I: Immediate/Anaphylactic Hypersensitivity
• IgE is involved
2. Type II:Cytotoxic Hypersensitivity: IgG or IgM
3. Type III:Immune-Complex Hypersensitivity
4. Type IV:Cell-mediated Hypersensitivity (Delayed)
Fig 11-1: Immune effector mechanisms of the
four types of hypersensitivity
Fig 11-1
 Type I hypersensitivity
• Ag binds IgE on surface
of mast cells & basophil
• Degranulation & Release Allergen
of mediators
• cAMP, cGMP and Ca++
• High [cGMP]  increase
degranulation
• High [cAMP]  decrease
mediators release
• Epinephrine increases
intracellular cAMP
 Fig 11-2:

The sequence of events in

immediate hypersensitivity
 Fig 11-2: The sequence of
events in immediate
Fig 11-2:
hypersensitivity

The sequence of events in

immediate hypersensitivity
 Activation of mast cells
Fig 11-3

A. Mast cells are sensitized by the binding of IgE to FcRI receptors

B. Binding of the allergen to the IgE cross-links the Fc receptors
and activates the mast cells
 The activation of mast cells
C & D: Mast cell
activation leads to
Fig 11-3
degranulation, as
seen in the light
micrographs in
which the granules
are stained with a
red dye

E, F: Degranulation
in the electron
micrographs of a
resting and an
activated mast cell
 Biochemical events in
mast cell activation Fig 11-4
• Cross-linking of IgE on a mast
cell by an allergen initiates
multiple signaling pathways
from the signaling chains of the
ITAM
Immunoreceptor
IgE Fc receptor (FcRI), tyrosine-based
including the phosphorylation activation motif
of ITAMs.
• These signaling pathways
stimulate the:
• release of mast cell granule
contents (amines, proteases)
• synthesis of arachidonic
acid metabolites
(prostaglandins,
leukotrienes),
• synthesis of various
cytokines
• These mast cell mediators
stimulate the various reactions
of immediate hypersensitivity
 Mediators of Type I hypersensitivity
Preformed mediators
1. Histamine
Allergen
2. Heparin
3. Eosinophil chemotactic
factor of anaphylaxis
(ECF-A)
4. Neutrophil chemotactic
factor
5. Serotonin
Newly synthesized mediators
1. Prostaglandins
2. Thromboxanes
3. Leukotrienes
• Slow reacting
substance of
anaphylaxis (SRS-A)
 Clinical manifestations of immediate hypersensitivity

Fig 11-5
 Treatment of immediate hypersensitivity
reactions
Various drugs & their principal mechanisms of action

cAMP↑

Fig 11-6
 Urticaria & Eczema

• An eruption of itching
wheals
• of systemic origin
• It may be due to allergic
reaction to:
– foods
– drugs
– foci of infection
– physical agents (heat,
cold, light, friction)
– psychic stimuli
 Histamine
• Present in the
preformed state
in granules of
tissue mast cells
and basophil
• It causes:
– Vasodilatation
– Increased
capillary
permeability,
and
– Smooth muscle
contraction
Slow reacting substance of anaphylaxis (SRS-A)

• It is composed of several leukotrienes, which do

not exist in the preformed state and are released
during anaphylactic reactions
• This explains in part the slow action of SRS-A
• Leukotrienes are synthesized from arachidonic acid
by the lipoxygenic pathway
• Leukotrienes also cause increase vascular
permeability and smooth muscle contraction
• Leukotrienes are the main mediators of
bronchoconstriction of asthma
 Eosinophil chemotactic factor of anaphylaxis
(ECF-A)
• A tetrapeptide exists in preformed state in mast cell
granules
• When released, it attracts eosinophils that are prominent in
immediate allergic reactions
• The role of eosinophil in Type I hypersensitivity is
unknown
• Eosinophils do release
– Histaminase, which degrades histamine
– Arylsulphatase, which degrades SRS-A
• Eosinophil may be involved in reducing the severity of the
type I response
 Serotonin (5-hydroxytryptamine, 5HT)
• Occurs preformed in mast
cells and blood platelet
5-HT
• When released during
anaphylaxis, it causes:
– Vasoconstriction of large
blood vessels
– Capillary dilatation
– Increased vascular
permeability
– smooth muscle contraction
• Its role is minor in human
anaphylaxis
• Major effects on the CNS
 Prostaglandin & Thromboxane
• Related to leukotrienes
• Derived from arachidonic acid via
cyclooxygenase pathway
• The effects of prostaglandin are:
– Dilation
– Increased permeability
– Bronchoconstriction
• Thromboxanes aggregate platelets
 Anaphylactoid Reaction
• Clinically, they are similar to anaphylactic
reactions
• The mechanism is different
• They are not IgE mediated
• The drugs or iodinated chemicals directly
induce the mast cells to release the mediators
 Drug Hypersensitivity
• Antimicrobial agents are among the most common
agents of this type of reactions
• Usually the metabolic product of the drug acts as a
hapten and binds to body protein and act as a
sensitizing antigen
• On Re-exposure to the drug, the resulting antibody
reacts either with the intact drug or hapten to cause
type I hypersensitivity
• Clinical symptoms include rashes, fever, local or
systemic anaphylaxis with varying severity
• The skin test can be used to test the drug sensitivity
 Atopy Atopia = unusualness = out of place: propensity to IgE production

• This includes type I reactions that exhibit familial predisposition

• Associated with high levels of IgE
• Genetically based disorders
• Induced by exposure to specific allergens; e.g., pollens, dust; or in
the foods such as shellfish and nuts
• Common symptoms: Urticaria, eczema, asthma and hay fever
• The skin tests for the individuals with atopy are
immediately positive when specific antigens are used
• Atopic allergy is transferable by serum only
• It is antibody-mediated
• Probable cause:
– Reduced numbers of suppressor T cells
– Predisposition to an abnormally high IgE response
have been proposed as cause
IgE, IgG, mast cell & eosinophilia in parasite purging
• Mast cell in the mucosa are coated with IgE specific for worm Ags
• IgE bind worm Ags  Trigger degranulation
• ECF-A & NCF & histamine  Eosinophilia, blood vessel
permeability↑  IgG & eosinophils leak to the lumen where the
worm is located  Abs opsonize the worm  Eosinophils bind the
Fcγ  degranulate  kill and purge the worm
 Type II: Ab-Mediated
Start here 3/6/08
• Ab, other than IgE, directed towards the cell surface Ags,
especially on RBCs.
• In this case, the IgG or IgM antibody attaches to the
antigen via Fab region, and acts as a bridge to complement
via the Fc region.
• This results in complement-mediated lysis
• Killer cells can be involved with ADCC
• Examples:
– hemolytic anemia
– ABO transfusion reactions
– Rh hemolytic disease
 Types of antibody-mediated diseases
A: Type II hypersensitivity

Fig 11-7A

• Antibodies (other than IgE) may cause tissue injury and

disease by binding directly to their target antigens in
cells and extracellular matrix
 Type III hypersensitivity

Fig 11-7B

• Abs (other than IgE) may cause tissue injury & disease by
forming immune complexes that deposit in blood vessels
 Effector mechanisms of Ab-mediated diseases
• Abs may cause disease by inducing inflammation at the
site of deposition
• All three mechanisms are seen with antibodies that bind
directly to their target antigens, but immune complexes
cause disease mainly by inducing inflammation

Fig 11-8
 Effector mechanisms of Ab-mediated diseases
• Abs may cause disease by opsonizing cells for phagocytosis
• Opsonins involved:
– IgG antibody
– C3b complement fragment

Fig 11-8
 Effector mechanisms of Ab-mediated diseases
• Abs may cause disease by interfering with normal cellular
functions, such as hormone receptor signaling
• Examples:
– Graves disease
– Myasthenia gravis

Fig 11-8C: Graves disease Myasthenia

gravis

•TSH = thyroid-
stimulating hormone
•Ach = acetylcholine
 Type II: Drugs adverse reactions
• Penicillins (haptens):
– Can attach to surface proteins on RBCs,
– Become immunogenic & elicit Ab synthesis including
• IgE (type I)
• Autoimmune IgG Abs interact with the cell surface and
hemolysis occurs
• IgG and IgE antibodies in subjects allergic to penicillins recognize
different parts of the penicillin molecule
• Quinine:
– Can attach to platelets
– Induce autoantibodies formation
– Lead to thrombocytopenia with bleeding tendency
• Hydralazine:
– May modify host tissues
– Favoring the production of autoantibodies directed at DNA,
– Resulting disease resembles SLE
 Type II: Autoimmune diseases

• In rheumatic fever, antibodies against Group A

streptococci cross-react with cardiac tissue
• In Mycoplasma pneumoniae infection, antibodies
are formed that cross-react with RBCs, which
results in hemolytic anemia
• In Goodpasture syndrome, Abs to basement
membrane of the kidneys and lungs are formed,
which lead to severe damage to the membrane via
complement-attracted leukocytes
Human antibody-mediated diseases

Fig 11-9

Itching blisters
Human antibody-mediated diseases

Fig 11-9
Type III: Immune-complex Hypersensitivity
• Ag-Ab complexes induce an inflammatory
response in tissues.
• Normally, the Ag-Ab complexes are removed.
• Occasionally, they persist and are deposited in
the tissues.
• In persistent bacterial and viral infections,
immune complexes may be deposited in the
organs such as kidneys and result in damage
 Type III hypersensitivity
• Abs (other than IgE) may cause tissue injury & disease by
forming immune complexes that deposit in blood vessels

Fig 11-7B
 Type III: Immune-complex hypersensitivity &
immune complex Disease
• In autoimmune diseases, "self" Ags may produce antibodies that bind
to an organ antigen or deposit in organs as complexes
• This can occur in:
– Joints  arthritis
– Kidneys  nephritis
– Blood vessels  vasculitis
• Deposited immune complexes activate the complement system
• Attracted PMNs cause inflammation and tissue injury
Fig 11-10
 Type III: Arthus Reaction &
Serum Sickness
Arthus Reaction
• Local inflammatory reaction with necrosis
• Few hours after intradermal Ag inoculation
Arthus
• The inoculated animal was previously Reaction
immunized to the same Ag
• Immunized animal has high titers of precipitating IgG Abs
Serum Sickness
• After injection of a foreign serum or certain drugs, Ag is excreted
slowly leading to Ab production
• Ag + Ab  Ag-Ab complex
• These complexes may circulate or be deposited at various sites.
• Symptoms: fever, urticaria & lymphadenopathy
• Symptoms develop after few days to 2 weeks
• Serum sickness is classified as immediate reaction due to the fact that
symptoms develop promptly after immune-complexes are formed
 Type IV: Delayed; Cell-mediated
• It is called delayed because it starts hours or days
after contact with the Ag and lasts for days
• DH can be elicited by many innocuous substances
and can result in damage in the responding
individual
• DTH is the prime defense against intracellular
bacteria and fungi
• It is a function of helper (CD4) T lymphocytes
• It can be transferred by sensitized T cells
• Rxn: Macrophages and CD4 cells and induration
 Mechanisms of T cell-mediated tissue injury
• T cells may cause tissue injury and disease by two mechanisms:
• A: Delayed hypersensitivity reactions, which may be triggered by
CD4+ and CD8+ T cells and in which tissue injury is caused by
activated macrophages and inflammatory cells
• B: Direct killing of target cells, which is mediated by CD8+ CTLs

Fig 11-11
 Mechanisms of T cell-mediated tissue injury
• T cells may cause tissue injury and disease by two mechanisms:
– A: Delayed hypersensitivity reactions, which may be triggered
by CD4+ and CD8+ T cells and in which tissue injury is caused
by activated macrophages and inflammatory cells
– B: Direct killing of target cells, which is mediated by CD8+
CTLs

Fig 11-11
 T-cell mediated diseases
Fig 11-12
 Type IV: Tuberculin test
• A patient previously exposed to Mycobacterium tuberculosis is injected
intradermally with a small amount of tuberculin (PPD)
• Gradually, induration and redness develop and peak in 48 to 72 hours.

• Positive test indicates previous infection/exposure

• It does not confirm the presence of current disease
• If a person with previously negative test gives a positive test, it indicates
that the person has been recently infected
• PPD injected intradermal  Induration & redness after 48-72 hours
 Positive test

PPD Test
 Type IV: Contact allergy
• It occurs after sensitization with certain chemicals (formaldehyde), plant
material (poison ivy), topically applied drugs (neomycin), cosmetics, soaps etc.
– Poison ivy’s allergen is Urushiol
• In all cases the molecules act as hapten, enter the skin, attach to body proteins
and become complete antigens (allergens)
• Cell-mediated reaction develops in the skin
• Sensitized person develops erythema, itching, eczema and necrosis of the skin
within 12-48 h

Contact dermatitis (poison ivy)