Transcript Type-I hypersensitivity

Hypersensitivity
A damage to the host, mediated by pre-existing immunity to
self or foreign antigen.
Dr. Sudheer Kher
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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
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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.

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Musts for Hypersensitivity

Contact with allergen

Sensitizing/priming dose

Induction of AMI/CMI

Shocking dose
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Classification : Hypersensitivity
reactions

Immediate hypersensitivity
– Anaphylaxis
Type I
– Atopy
– Antibody mediated cell damage
– Arthus phenomenon/reaction
– Serum sickness

Type II
Type III
Delayed hypersensitivity
– Infection (Tuberculin) type
– Contact dermatitis type
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Type IV
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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
Classification: Gell &
Coombs(1963)
Type of reaction
Clinical syndrome
Time
Mediators
required
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
Arthus reaction
Serum sickness
Variable IgG: IgM, C
: Hours
to days
Type III :
Immune
Complex Disease
Type IV :
Tuberculin
Delayed
Contact dermatitis
hypersensitivity
Variable IgG: IgM, C, Leucocytes
: Hours
to days
Hours to T cells: lymphokines, macrophages
days
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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 may be absent
and not responsible for reaction.
“Cell mediated reaction”
Circulating Ab present and
responsible for 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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Type-I hypersensitivity
The common allergy
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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
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
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
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
Mast Cells and the Allergic
Response
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Sensitization against allergens and
type-I hypersensitivity
B cell
TH2
Histamine, tryptase,
kininegenase, ECFA
Leukotriene-B4, C4, D4,
Newly
prostaglandin D, PAF
synthesized mediators
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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.
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
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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
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)
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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.
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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.
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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.
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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.
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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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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.
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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.

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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
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
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