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Pharmacy-Immunology 17 18
Hypersensitivity
Saber Hussein
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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.
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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 ofIgE; discuss
the cytotropism of IgE
6. Describe the role ofmast cells in immediatehypersensitivity reactions; explain degranulation;
distinguish between and give examples for preformed and
newly formed mediators released by mast cells
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Allergen Antigen that causes allergy: The term is
used to refer to the antigen molecule itself
or its source, such as pollen grain, animaldander, and insect venom or food products.
Many naturally occurring and syntheticchemicals have been considered allergens
Any foreign substance, which can elicit animmune response, is a potential allergen
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Hypersensitivity (Allergy)
Harmful, inappropriate or exaggerated immuneresponse
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
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Sensitization & Acute desensitization Sensitization
Immunization, especially with reference to Ags notassociated with infection
The induction ofacquired sensitivity or ofallergy
Acute desensitization This involves the administration ofvery small amounts
ofAg 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
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Chronic desensitization
Involves long-term weekly administration oftheAg to the sensitive patient
This leads to the production ofIgG-blocking
Abs in the serum, which can prevent subsequentAg from reaching IgE on mast cells
Hence under these conditions, no immediate
hypersensitive reaction would occur
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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)
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Fig 11-1: Immune effector mechanisms of the
four types of hypersensitivity
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Fig 11-1
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Type I hypersensitivity
Ag binds IgE on surfaceofmast cells & basophil
Degranulation & Release
of mediators
cAMP, cGMP and Ca++
High [cGMP] increase
degranulation
High [cAMP] decreasemediators release
Epinephrine increases
intracellularcAMP
Allergen
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Fig 11-2:
The sequence ofevents in
immediate hypersensitivity
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Fig 11-2: The sequence of
events in immediatehypersensitivity
Fig 11-2:
The sequence ofevents in
immediate hypersensitivity
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Activation ofmast cells
A. Mast cells are sensitizedby the binding ofIgE to FcIRI receptors
B. Binding of the allergen to the IgE cross-links the FcI receptors
and activates the mast cells
Fig 11-3
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The activation ofmast cells
C & D: Mast cell
activation leads todegranulation, as
seen in the light
micrographs in
which the granules
are stained with a
red dye
E, F: Degranulation
in the electronmicrographs of a
resting and an
activated mast cell
Fig 11-3
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Biochemical events in
mast cell activation
Cross-linking ofIgE on a mast
cell by an allergen initiates
multiple signaling pathways
from the signaling chains of the
IgE Fc receptor (FcIRI),including the phosphorylation
ofITAMs.
These signaling pathways
stimulate the:
release ofmast cell granule
contents (amines, proteases)
synthesis ofarachidonic
acid metabolites
(prostaglandins,
leukotrienes),
synthesis ofvarious
cytokines
These mast cell mediators
stimulate the various reactions
of immediate hypersensitivity
ITAM
Fig 11-4
Immunoreceptor
tyrosine-based
activation motif
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Mediators of Type I hypersensitivity
Preformed mediators
1. Histamine
2. Heparin
3. Eosinophil chemotactic
factor ofanaphylaxis
(ECF-A)
4. Neutrophil chemotactic
factor
5. Serotonin
Newly synthesized mediators
1. Prostaglandins
2. Thromboxanes3. Leukotrienes
Slow reacting
substance of
anaphylaxis (SRS-A)
Allergen
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Clinical manifestations ofimmediate hypersensitivity
Fig 11-5
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Treatment ofimmediate hypersensitivity
reactionsVarious drugs & their principal mechanisms of action
Fig 11-6
cAMP
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Urticaria & Eczema
An eruption ofitchingwheals
of systemic origin
It may be due to allergicreaction to:
foods
drugs
foci ofinfection physical agents (heat,
cold, light, friction)
psychic stimuli
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Histamine Present in the
preformed statein granules oftissue mast cellsand basophil
It causes:Vasodilatation
Increasedcapillary
permeability,and
Smoothmuscle
contraction
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Slow reacting substance of anaphylaxis (SRS-A)
It is composed ofseveral 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 vascularpermeability and smooth muscle contraction
Leukotrienes are the main mediators of
bronchoconstriction ofasthma
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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
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Serotonin (5-hydroxytryptamine, 5HT)
Occurs preformed in mastcells and blood platelet
When released duringanaphylaxis, it causes:
Vasoconstriction oflargeblood vessels
Capillary dilatation
Increased vascularpermeability
smooth muscle contraction
Its role is minor in humananaphylaxis
Major effects on the CNS
5-HT
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Prostaglandin & Thromboxane
Related to leukotrienes
Derived from arachidonic acid via
cyclooxygenase pathway
The effects of prostaglandin are:
Dilation
Increased permeability
Bronchoconstriction
Thromboxanes aggregate platelets
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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
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Drug Hypersensitivity
Antimicrobial agents are among the most commonagents of this type of reactions
Usually the metabolic product of the drug acts as ahapten 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 causetype I hypersensitivity
Clinical symptoms include rashes, fever, local orsystemic anaphylaxis with varying severity
The skin test can be used to test the drug sensitivity
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Atopy 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 inthe foods such as shellfish and nuts
Common symptoms: Urticaria, eczema, asthma and hay fever
The skin tests for the individuals with atopy areimmediately positive when specific antigens are used
Atopic allergy is transferable by serum only
It is antibody-mediated
Probable cause:
Reduced numbers ofsuppressor T cells
Predisposition to an abnormally high IgE responsehave been proposed as cause
Atopia = unusualness = out of place: propensity to IgE production
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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 vesselpermeability IgG & eosinophils leak to the lumen where theworm is located Abs opsonize the worm Eosinophils bind theFc degranulate kill and purge the worm
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Type II: Ab-Mediated
Ab, other than IgE, directed towards the cell surface Ags,especially on RBCs.
In this case, the IgG or IgM antibody attaches to theantigen via Fab region, and acts as a bridge to complementvia 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
Start here 3/6/08
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Types ofantibody-mediated diseases
A: Type II hypersensitivity
Antibodies (other than IgE) may cause tissue injury anddisease by binding directly to their target antigens in
cells and extracellular matrix
Fig 11-7A
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Type III hypersensitivity
Abs (other than IgE) may cause tissue injury & disease by
forming immune complexes that deposit in blood vessels
Fig 11-7B
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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 complexescause disease mainly by inducing inflammation
Fig 11-8
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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
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Effector mechanisms of Ab-mediated diseases
Abs may cause disease by interfering with normal cellularfunctions, such as hormone receptor signaling
Examples:
Graves disease
Myasthenia gravis
TSH = thyroid-
stimulating hormone
Ach = acetylcholine
Fig 11-8C: Myastheniagravis
Graves disease
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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 andhemolysis occurs
IgG and IgE antibodies in subjects allergic to penicillins recognizedifferent parts ofthe penicillin molecule
Quinine:Can attach toplatelets
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
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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
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Human antibody-mediated diseases
Itching blisters
Fig 11-9
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Human antibody-mediated diseases
Fig 11-9
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Type III: Immune-complex Hypersensitivity
Ag-Ab complexes induce an inflammatoryresponse in tissues.
Normally, the Ag-Ab complexes are removed.
Occasionally, they persist and are deposited inthe tissues.
In persistentbacterial and viral infections,
immune complexes may be deposited in theorgans such as kidneys and result in damage
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Type III hypersensitivity
Abs (other than IgE) may cause tissue injury & disease by
forming immune complexes that deposit in blood vessels
Fig 11-7B
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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
T III A h R i &
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Type III: Arthus Reaction &
Serum SicknessArthus Reaction
Local inflammatory reaction with necrosis Few hours after intradermal Ag inoculation
The inoculated animal was previously
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 excretedslowly 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 thatsymptoms develop promptly after immune-complexes are formed
Arthus Reaction
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Type IV: Delayed; Cell-mediated
It is called delayed because it starts hours or daysafter contact with the Ag and lasts for days
DH can be elicited by many innocuous substances
and can result in damage in the respondingindividual
DTH is the prime defense against intracellular
bacteria and fungi It is a function ofhelper (CD4) T lymphocytes
It can be transferred by sensitized T cells
Rxn: Macrophages andC
D4 cells and induration
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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
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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 triggeredby CD4+ and CD8+ T cells and in which tissue injury is causedby activated macrophages and inflammatory cells
B: Direct killing of target cells, which is mediated by CD8+
CTLs
Fig 11-11
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T-cell mediated diseases
Fig 11-12
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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 72hours.
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, itindicates that the person has been recently infected
PPD injected intradermal Induration & redness after 48-72 hours Positive test
PPD Test
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Type IV: Contact allergy It occurs after sensitization with certain chemicals (formaldehyde),
plant material (poison ivy), topically applied drugs (neomycin),cosmetics, soaps etc. Poison ivys allergen is Urushiol
In all cases the molecules act as hapten, enter the skin, attach to bodyproteins 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)