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
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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)
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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
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9. Type-I hypersensitivity
The common allergy
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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
Kher

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
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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
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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