Pharmacy-Immunology 17 ± 18 Hypersensitivity

Saber Hussein

1. Define:
i. ii. iii. iv. v. vi. Allergy Anaphylaxis Atopy Sensitization Desensitization Shocking dose

2.Know the four types of hypersensitivity, their immunological bases; give examples of each:
i. ii. iii. ii. Type I: immediate (anaphylactic) hypersensitivity Type II: antibody-dependent cytotoxic hypersensitivity Type III: immune complex-mediated hypersensitivity Type IV: cell-mediated (delayed type) hypersensitivity.

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

‡ 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 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:

Fig 11-2: The sequence of events in immediate 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 FcIRI receptors B. Binding of the allergen to the IgE cross-links the FcI receptors and activates the mast cells

The activation of mast cells
C & D: Mast cell activation leads to 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 Fig 11-3

Biochemical events in mast cell activation
‡ Cross-linking of IgE on a mast cell by an allergen initiates multiple signaling pathways from the signaling chains of the IgE Fc receptor (FcIRI), including the phosphorylation 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

Fig 11-4

ITAM Immunoreceptor
tyrosine-based activation motif



Mediators of Type I hypersensitivity
Preformed mediators
1. 2. 3. Histamine Heparin Eosinophil chemotactic factor of anaphylaxis (ECF-A) Neutrophil chemotactic factor Serotonin Prostaglandins Thromboxanes Leukotrienes ‡ Slow reacting substance of anaphylaxis (SRS-A)


4. 5. 1. 2. 3.

Newly synthesized mediators

Clinical manifestations of immediate hypersensitivity
Fig 11-5

Treatment of immediate hypersensitivity reactions
Various drugs & their principal mechanisms of action


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 ± ± ± ±

‡ 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 ‡ When released during anaphylaxis, it causes:
± Vasoconstriction of large blood vessels ± Capillary dilatation ± Increased vascular permeability ± smooth muscle contraction 5-HT

‡ 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

‡ ‡ ‡ ‡

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 Fc 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 = thyroidstimulating 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 Reaction ‡ 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 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)

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