Pharm Immuno17 Hypersensitivity POR

8/7/2019 Pharm Immuno17 Hypersensitivity POR

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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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Abs may cause disease by opsonizing cells for phagocytosis

Opsonins involved:

IgG antibody

C3b complement fragment

Fig 11-8


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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)

Pharm Immuno17 Hypersensitivity POR

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