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HypersensitivityHypersensitivity

A damage to the host, mediated by A damage to the host, mediated by pre-existingpre-existing immunity to self or foreign antigen.immunity to self or foreign antigen.

Dr. Sudheer KherDr. Sudheer Kher

Learning objectivesLearning objectives

1. C1. Classify the hypersensitivity reactions lassify the hypersensitivity reactions

2. List the diseases associated with 2. List the diseases associated with hypersensitivity reactions hypersensitivity reactions

3. Describe the mechanisms of damage in 3. Describe the mechanisms of damage in hypersensitivity reactions hypersensitivity reactions

4. List the methods for diagnosing conditions 4. List the methods for diagnosing conditions due to hypersensitivity due to hypersensitivity

5. Describe the modes of treating diseases 5. Describe the modes of treating diseases due to hypersensitivity and their rationale due to hypersensitivity and their rationale

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What is hypersensitivity?What is hypersensitivity?

Injurious consequences in the Injurious consequences in the sensitized hostsensitized host, following contact with , following contact with specific antigenspecific antigen

Deals with Deals with injurious aspect injurious aspect of of heightened and exaggerated immune heightened and exaggerated immune response leading to tissue damage, response leading to tissue damage, disease or even deathdisease or even death

Concerned with Concerned with what happens to the what happens to the host host rather than what happens to the rather than what happens to the antigen.antigen.

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Musts for HypersensitivityMusts for Hypersensitivity

Contact with allergenContact with allergen

Sensitizing/priming doseSensitizing/priming dose

Induction of AMI/CMIInduction of AMI/CMI

Shocking doseShocking dose

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Classification : Hypersensitivity Classification : Hypersensitivity reactionsreactions

Immediate hypersensitivityImmediate hypersensitivity– AnaphylaxisAnaphylaxis– AtopyAtopy– Antibody mediated cell damage Antibody mediated cell damage – Arthus phenomenon/reactionArthus phenomenon/reaction– Serum sicknessSerum sickness

Delayed hypersensitivityDelayed hypersensitivity– Infection (Tuberculin) typeInfection (Tuberculin) type– Contact dermatitis typeContact dermatitis type

Type I

Type II

Type III

Type IV

Hypersensitivity Reaction

Hypersensitivity or allergy * An immune response results in exaggerated

reactions harmful to the host

* There are four types of hypersensitivity reactions:

Type I, Type II, Type III, Type IV

* Types I, II and III are antibody mediated * Type IV is cell mediated

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Classification: Gell & Classification: Gell & Coombs(1963)Coombs(1963)

Type of reaction Clinical syndrome Time required

Mediators

Type I : Anaphylaxis Atopy

Minutes IgE: Histamine and other pharmacological agents

Type II : Cytolytic, Cytotoxic& Cell stimulatory

Antibody mediated damage : Thrombocytopenia, Agranulocytosis, Hemolytic anemia, LATS

Variable: Hours to days

IgG: IgM, C

Type III : Immune Complex Disease

Arthus reaction Serum sickness

Variable: Hours to days

IgG: IgM, C, Leucocytes

Type IV : Delayed hypersensitivity

Tuberculin Contact dermatitis

Hours to days

T cells: lymphokines, macrophages

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Immediate Type I, II Immediate Type I, II & III& III

Delayed Type IVDelayed Type IV

Appears and recedes rapidlyAppears and recedes rapidly Appears slowly, lasts longerAppears slowly, lasts longer

Induced by Ag/haptens by any Induced by Ag/haptens by any routeroute

Induced by infection, injection of Induced by infection, injection of Ag /hapten intradermally or with Ag /hapten intradermally or with Freund’s adjuvant or by skin Freund’s adjuvant or by skin contactcontact

Circulating Ab present and Circulating Ab present and responsible for reactionresponsible for reaction

Circulating Ab may be absent Circulating Ab may be absent and not responsible for reaction. and not responsible for reaction. “Cell mediated reaction”“Cell mediated reaction”

Passive transfer possible with Passive transfer possible with serumserum

No transfer with serum. Transfer No transfer with serum. Transfer possible with T - Cells or possible with T - Cells or transfer factortransfer factor

Desensitization easy but short Desensitization easy but short livedlived

Desensitization difficult but long Desensitization difficult but long lastinglasting

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Type-I hypersensitivityType-I hypersensitivityType-I hypersensitivityType-I hypersensitivity

The common allergy

Type I: Immediate Type I: Immediate hypersensitivityhypersensitivity

* An antigen reacts with cell fixed antibody (Ig E) leading to release of soluble molecules An antigen (allergen) soluble molecules (mediators)

* Soluble molecules cause the manifestation of disease

* Systemic life threatening; anaphylactic shock

* Local atopic allergies; bronchial asthma, hay fever and food allergies

AnaphylaxisAnaphylaxis* Systemic form of Type I hypersensitivity

* Exposure to allergen to which a person is previously sensitized

* Allergens: Drugs: penicillin Serum injection : anti-diphtheritic / anti-tetanus serum/ AGGS, Anti

snake venum Anesthesia or insect venom * Clinical picture: Shock due to sudden decrease of blood pressure, respiratory

distress due to bronchospasm, cyanosis, edema, urticaria

* Treatment: corticosteroids injection, epinephrine, antihistamines

AtopyAtopy* Local form of type I hypersensitivity

* Exposure to certain allergens that induce production of specific Ig E

* Allergens : Inhalants: dust mite faeces, tree or pollens, mould

spores. Ingestants: milk, egg, fish, chocolate Contactants: wool, nylon, animal fur Drugs: penicillin, salicylates, anesthesia, insect venom

* There is a strong familial predisposition to atopic allergy

* The predisposition is genetically determined

Pathogenic mechanismsPathogenic mechanisms* First exposure to allergen Allergen stimulates formation of antibody (Ig E type) Ig E fixes, by its Fc portion to mast cells and basophils

* Second exposure to the same allergen It bridges between Ig E molecules fixed to mast cells

leading to activation and degranulation of mast cells and release of mediators

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Mast Cells and the Allergic Mast Cells and the Allergic ResponseResponse

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Sensitization against allergens Sensitization against allergens and type-I hypersensitivityand type-I hypersensitivity

Sensitization against allergens Sensitization against allergens and type-I hypersensitivityand type-I hypersensitivity

B cell

Histamine, tryptase, kininegenase, ECFA

Leukotriene-B4, C4, D4, prostaglandin D, PAF

Newly

synthesized mediators

TH2

IL13

Type I (Anaphylactic) ReactionsType I (Anaphylactic) Reactions

Antigens combine with IgE antibodies Antigens combine with IgE antibodies bound to mast cells and basophils, bound to mast cells and basophils, causing them to undergo causing them to undergo degranulationdegranulation and release several mediators:and release several mediators: HistamineHistamine: Dilates and increases : Dilates and increases

permeability of blood vessels (swelling and permeability of blood vessels (swelling and redness), increases mucus secretion (runny redness), increases mucus secretion (runny nose), smooth muscle contraction (bronchi). nose), smooth muscle contraction (bronchi).

ProstaglandinsProstaglandins: Contraction of smooth : Contraction of smooth muscle of respiratory system and increased muscle of respiratory system and increased mucus secretion.mucus secretion.

LeukotrienesLeukotrienes: Bronchial spasms.: Bronchial spasms.

– Anaphylactic shockAnaphylactic shock: : Massive drop in blood Massive drop in blood pressure. Can be fatal in minutes.pressure. Can be fatal in minutes.

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Type I ReactionsType I Reactions

Humans –Humans –– Itching of scalp & tongue, Itching of scalp & tongue,

flushing of skin, difficulty flushing of skin, difficulty in breathing, nausea, in breathing, nausea, vomiting, diarrhea, acute vomiting, diarrhea, acute hypotension, loss of hypotension, loss of consciousness, death consciousness, death (rare)(rare)

– Causes Causes Serum therapy, Serum therapy,

antibiotics, insect stingsantibiotics, insect stings– TreatmentTreatment

Adrenalin 0.5 ml (1 in Adrenalin 0.5 ml (1 in 1000 solution) SC/IM 1000 solution) SC/IM repeated up to 2 ml in repeated up to 2 ml in 15 min15 min

Pathogenic mechanismsPathogenic mechanisms

* Three classes of mediators derived from mast cells: 1) Preformed mediators stored in granules (histamine)

2) Newly synthesized mediators: leukotrienes, prostaglandins, platelets activating factor

3) Cytokines produced by activated mast cells, basophils e.g. TNF, IL3, IL-4, IL-5 IL-13, chemokines

* These mediators cause: smooth muscle contraction, mucous secretion and bronchial spasm, vasodilatation, vascular permeability and edema

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Mechanism of anaphylaxisMechanism of anaphylaxis Mediators of anaphylaxis –Mediators of anaphylaxis –

– Primary mediatorsPrimary mediators Preformed contents of Mast cells & BasophilsPreformed contents of Mast cells & Basophils

– Histamine, serotonin, eosinophils chemotactic Histamine, serotonin, eosinophils chemotactic factor of anaphylaxis (ECF-A), Neutrophil factor of anaphylaxis (ECF-A), Neutrophil chemotactic factor (NCF), Heparin & various chemotactic factor (NCF), Heparin & various proteolytic enzymesproteolytic enzymes

– Secondary mediatorsSecondary mediators – – Newly formed after stimulation by Mast Newly formed after stimulation by Mast

cells, Basophils & other leucocytescells, Basophils & other leucocytes– Slow reacting substance of anaphylaxix (SRS-A), Slow reacting substance of anaphylaxix (SRS-A),

Prostaglandins & Platelet activating factors (PAF)Prostaglandins & Platelet activating factors (PAF)

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Primary Mediators of Primary Mediators of AnaphylaxisAnaphylaxis

HistamineHistamine – –– Most important vasoactive amine of Most important vasoactive amine of

Human anaphylaxis, formed from Human anaphylaxis, formed from histidine found in granules. Released histidine found in granules. Released into skin, causes into skin, causes burning & itchingburning & itching. . Causes vasodilatation & hyperemia by Causes vasodilatation & hyperemia by an axon reflex (an axon reflex (FlareFlare) and edema by ) and edema by increasing capillary permeability increasing capillary permeability ((WhealWheal). Induces smooth muscle ). Induces smooth muscle contraction of diverse tissues & organs.contraction of diverse tissues & organs.

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Primary Mediators of Primary Mediators of AnaphylaxisAnaphylaxis

Serotonin (5-HT)Serotonin (5-HT) – –Role in human not clear.Role in human not clear.

– Base derived by decarbolxylation of Base derived by decarbolxylation of Tryptophan.Tryptophan.

– Found in intestinal mucosa, brain & Found in intestinal mucosa, brain & platelets.platelets.

– Causes smooth muscle contraction, Causes smooth muscle contraction, ↑ ↑ Vascular permeability & vasoconstriction.Vascular permeability & vasoconstriction.

– Important in rats & mice.Important in rats & mice.

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Primary Mediators of Primary Mediators of AnaphylaxisAnaphylaxis

Chemotactic factors –Chemotactic factors –– ECF-AECF-A released from mast cell released from mast cell

granules are strongly chemotactic for granules are strongly chemotactic for eosinophils. Accounts for high eosinophils. Accounts for high eosinophil counts in many eosinophil counts in many hypersensitivity reactions.hypersensitivity reactions.

– NCFNCF – Attracts neutrophils – Attracts neutrophils– Enzymatic mediatores such as Enzymatic mediatores such as

proteasesproteases & & hydrolaseshydrolases are also are also released from the mast cell granules.released from the mast cell granules.

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Secondary mediators of Secondary mediators of anaphylaxisanaphylaxis

Prostaglandins & leukotrienes Prostaglandins & leukotrienes ––– Derived from Arachidonic acid formed from the Derived from Arachidonic acid formed from the

disruption of mast cell membrane, other leucocytesdisruption of mast cell membrane, other leucocytes Lipoxygenase pathway -Lipoxygenase pathway - Leukotrienes Leukotrienes Cycloxygenase pathway -Cycloxygenase pathway - Prostaglandins Prostaglandins

– One of the family of Leukotrienes is One of the family of Leukotrienes is SRS-ASRS-A (slow (slow reacting substance of anaphylaxis)reacting substance of anaphylaxis)

– ProstaglandinsProstaglandins are are bronchoconstrictors/broncodilators, affect secretions bronchoconstrictors/broncodilators, affect secretions of mucus glands, platelet adhesion, permeability, of mucus glands, platelet adhesion, permeability, dilatation of capillaries & pain threshold.dilatation of capillaries & pain threshold.

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Secondary mediators of Secondary mediators of anaphylaxisanaphylaxis

Platelet activating factor – PAFPlatelet activating factor – PAF– Low mol wt lipid released from basophilsLow mol wt lipid released from basophils– Causes aggregation of platelets and Causes aggregation of platelets and

release of their vasoactive aminesrelease of their vasoactive amines Other mediators – Other mediators –

– AnaphylatoxinAnaphylatoxin – Released by – Released by complement activationcomplement activation

– Bradykinin & Other kininsBradykinin & Other kinins formed from formed from plasma kininigensplasma kininigens

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Cutaneous anaphylaxisCutaneous anaphylaxis

If small shocking dose is given ID to If small shocking dose is given ID to sensitized host, there is a local wheal sensitized host, there is a local wheal & flare reaction (local anaphylaxis).& flare reaction (local anaphylaxis).

Used for Used for – Testing for hypersensitivityTesting for hypersensitivity– Identification of allergens for atopyIdentification of allergens for atopy

Precaution – Keep adrenalin injection Precaution – Keep adrenalin injection ready to combat severe fatal ready to combat severe fatal reaction.reaction.

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Anaphylactoid reactionAnaphylactoid reaction

Intravenous injection of peptone, trypsin & Intravenous injection of peptone, trypsin & certain other substances causes clinical certain other substances causes clinical reaction like anaphylaxis.reaction like anaphylaxis.

Resemblance due to participation of same Resemblance due to participation of same chemical mediators.chemical mediators.

Difference – Anaphylactoid shock has no Difference – Anaphylactoid shock has no immunological basis. It is nonspecific immunological basis. It is nonspecific reaction involving activation of reaction involving activation of complement & release of anaphylatoxin.complement & release of anaphylatoxin.

Methods of diagnosisMethods of diagnosis

1) History taking for determining the allergen involved

2) Skin tests: Intradermal injection of battery of different allergens A wheal and flare (erythema) develop at the site of allergen to which the person is allergic

3) Determination of total serum Ig E level

4) Determination of specific Ig E levels to the different allergens

Management Management

1) Avoidance of specific allergen responsible for condition

2) Hyposensitization: Injection gradually increasing doses of extract of allergen - production of Ig G blocking antibody which binds allergen and prevent combination with Ig E - It may induce T cell tolerance

3) Drug Therapy: Corticosteroids injection, epinephrine, antihistamines,

leukotriene receptor blockers, Chromolyn sodium inhibits leukotriene receptor blockers, Chromolyn sodium inhibits mast cell degranulation mast cell degranulation

Animation & QuizAnimation & Quiz

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