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Hypersensitivity Dr. Sudheer Kher

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1 Hypersensitivity Dr. Sudheer Kher
A damage to the host, mediated by pre-existing immunity to self or foreign antigen. Dr. Sudheer Kher Kher

2 Learning objectives 1. Classify the hypersensitivity reactions
2. List the diseases associated with hypersensitivity reactions 3. Describe the mechanisms of damage in hypersensitivity reactions 4. List the methods for diagnosing conditions due to hypersensitivity 5. Describe the modes of treating diseases due to hypersensitivity and their rationale Kher

3 What is hypersensitivity?
Injurious consequences in the sensitized host, following contact with specific antigen Deals with injurious aspect of heightened and exaggerated immune response leading to tissue damage, disease or even death Concerned with what happens to the host rather than what happens to the antigen. Kher

4 Musts for Hypersensitivity
Contact with allergen Sensitizing/priming dose Induction of AMI/CMI Shocking dose Kher

5 Classification : Hypersensitivity reactions
Immediate hypersensitivity Anaphylaxis Atopy Antibody mediated cell damage Arthus phenomenon/reaction Serum sickness Delayed hypersensitivity Infection (Tuberculin) type Contact dermatitis type Type I Type II Type III Type IV Kher

6 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

7 Classification: Gell & Coombs(1963)

8 Immediate Type I, II & III
Delayed Type IV Appears and recedes rapidly Appears slowly, lasts longer Induced by Ag/haptens by any route Induced by infection, injection of Ag /hapten intradermally or with Freund’s adjuvant or by skin contact Circulating Ab present and responsible for reaction Circulating Ab may be absent and not responsible for reaction. “Cell mediated reaction” Passive transfer possible with serum No transfer with serum. Transfer possible with T - Cells or transfer factor Desensitization easy but short lived Desensitization difficult but long lasting Kher

9 Type-I hypersensitivity
The common allergy Kher

10 Type I: Immediate hypersensitivity
* 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

11 Anaphylaxis * 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

12 Atopy * 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

13 Pathogenic 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

14 Mast Cells and the Allergic Response

15 Sensitization against allergens and type-I hypersensitivity
IL13 B cell TH2 Histamine, tryptase, kininegenase, ECFA Leukotriene-B4, C4, D4, prostaglandin D, PAF Newly synthesized mediators Kher

16 Type I (Anaphylactic) Reactions
Antigens combine with IgE antibodies bound to mast cells and basophils, causing them to undergo degranulation and release several mediators: Histamine: Dilates and increases permeability of blood vessels (swelling and redness), increases mucus secretion (runny nose), smooth muscle contraction (bronchi). Prostaglandins: Contraction of smooth muscle of respiratory system and increased mucus secretion. Leukotrienes: Bronchial spasms. Anaphylactic shock: Massive drop in blood pressure. Can be fatal in minutes.

17 Type I Reactions Humans –
Itching of scalp & tongue, flushing of skin, difficulty in breathing, nausea, vomiting, diarrhea, acute hypotension, loss of consciousness, death (rare) Causes Serum therapy, antibiotics, insect stings Treatment Adrenalin 0.5 ml (1 in 1000 solution) SC/IM repeated up to 2 ml in 15 min Kher

18 Pathogenic 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

19 Mechanism of anaphylaxis
Mediators of anaphylaxis – Primary mediators Preformed contents of Mast cells & Basophils Histamine, serotonin, eosinophils chemotactic factor of anaphylaxis (ECF-A), Neutrophil chemotactic factor (NCF), Heparin & various proteolytic enzymes Secondary mediators – Newly formed after stimulation by Mast cells, Basophils & other leucocytes Slow reacting substance of anaphylaxix (SRS-A), Prostaglandins & Platelet activating factors (PAF) Kher

20 Primary Mediators of Anaphylaxis
Histamine – Most important vasoactive amine of Human anaphylaxis, formed from histidine found in granules. Released into skin, causes burning & itching. Causes vasodilatation & hyperemia by an axon reflex (Flare) and edema by increasing capillary permeability (Wheal). Induces smooth muscle contraction of diverse tissues & organs. Kher

21 Primary Mediators of Anaphylaxis
Serotonin (5-HT) –Role in human not clear. Base derived by decarbolxylation of Tryptophan. Found in intestinal mucosa, brain & platelets. Causes smooth muscle contraction, ↑ Vascular permeability & vasoconstriction. Important in rats & mice. Kher

22 Primary Mediators of Anaphylaxis
Chemotactic factors – ECF-A released from mast cell granules are strongly chemotactic for eosinophils. Accounts for high eosinophil counts in many hypersensitivity reactions. NCF – Attracts neutrophils Enzymatic mediatores such as proteases & hydrolases are also released from the mast cell granules. Kher

23 Secondary mediators of anaphylaxis
Prostaglandins & leukotrienes – Derived from Arachidonic acid formed from the disruption of mast cell membrane, other leucocytes Lipoxygenase pathway - Leukotrienes Cycloxygenase pathway - Prostaglandins One of the family of Leukotrienes is SRS-A (slow reacting substance of anaphylaxis) Prostaglandins are bronchoconstrictors/broncodilators, affect secretions of mucus glands, platelet adhesion, permeability, dilatation of capillaries & pain threshold. Kher

24 Secondary mediators of anaphylaxis
Platelet activating factor – PAF Low mol wt lipid released from basophils Causes aggregation of platelets and release of their vasoactive amines Other mediators – Anaphylatoxin – Released by complement activation Bradykinin & Other kinins formed from plasma kininigens Kher

25 Cutaneous anaphylaxis
If small shocking dose is given ID to sensitized host, there is a local wheal & flare reaction (local anaphylaxis). Used for Testing for hypersensitivity Identification of allergens for atopy Precaution – Keep adrenalin injection ready to combat severe fatal reaction. Kher

26 Anaphylactoid reaction
Intravenous injection of peptone, trypsin & certain other substances causes clinical reaction like anaphylaxis. Resemblance due to participation of same chemical mediators. Difference – Anaphylactoid shock has no immunological basis. It is nonspecific reaction involving activation of complement & release of anaphylatoxin. Kher

27 Methods 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

28 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 mast cell degranulation

29 Animation & Quiz



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