Hypersensitivity

A damage to the host, mediated by preexisting immunity to

self or foreign antigen.

Dr. Sudheer Kher

Kher 1
 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 2
 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
– Atopy
– Antibody mediated cell damage
– Arthus phenomenon
– Serum sickness
 Delayed hypersensitivity
– Infection (Tuberculin) type
– Contact dermatitis type

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 Classification: Gell &
Coombs(1963)
Type of reaction Clinical syndrome Time Mediators
required
Type I : IgE type Anaphylaxis Minutes IgE: Histamine and other
Atopy pharmacological agents
Type II : Antibody mediated Variable: IgG: IgM, C
Cytolytic & damage : Hours to
Cytotoxic Thrombocytopenia, days
Agranulocytosis,
Hemolytic anemia
Type III : Arthus reaction Variable: IgG: IgM, C, Leucocytes
Immune Serum sickness Hours to
Complex Disease days
Type IV : Tuberculin Hours to T cells: lymphokines, macrophages
Delayed Contact dermatitis days
hypersensitivity

Kher 5
 Immediate Delayed
Appears and recedes rapidly Appears slowly, lasts longer

Induced by Ag/haptens by any Induced by infection, injection of

Ag /hapten intradermally or with
route Freund’s adjuvant or by skin
contact
Circulating Ab present and Circulating Ab may be absent
responsible for reaction and not responsible for reaction.
“Cell mediated reaction”

Passive transfer possible with No transfer with serum. Transfer

serum possible with T - Cells or
transfer factor

Desensitization easy but short Desensitization difficult but long

lived lasting
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Type I (Anaphylactic) Reactions
– Occur within minutes of exposure to antigen
– 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 ( IgE
Mediated)
 Anaphylaxis –
– Classical immediate reaction
– Sensitization
 Most effective when Ag introduced parenterally
 May occur by any route exposure to Ag
 Minute quantities are enough
 Interval of 2-3 wks needed between sensitizing &
shocking dose
 Once sensitized it remains so for long time
 Shocking dose most effective by IV route then IP,
then SC then ID
 The shocking Ag must be same or similar to
Sensitizing Ag
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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

Kher 10
 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 11
 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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 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) –
– Base derived by decarbolxylation of
Tryptophan.
– Found in intestinal mucosa, brain & platelets.
– Causes smooth muscle contraction, ↑ Vascular
permeability & vasoconstriction.
– Important in rats & mice.
– Role in human not clear.

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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
– Heparin – Acidic mucopolysaccharide.
Contributes to anaphylaxis in dogs but
apparently not in man.
– 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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Type-I hypersensitivity

The common allergy

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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 a nonspecific reaction
involving activation of complement & release of
anaphylatoxin.

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Type II (Cytotoxic) Reactions
– Involve activation of complement by
IgG or IgM binding to an antigenic cell.
– Antigenic cell is lysed.
– Transfusion reactions:
 ABO Blood group system: Type O is
universal donor. Incompatible donor cells
are lysed as they enter bloodstream.
 Rh Blood Group System: 85% of
population is Rh positive. Those who are
Rh negative can be sensitized to destroy Rh
positive blood cells.
– Hemolytic disease of newborn: Fetal cells are
destroyed by maternal anti-Rh antibodies that
cross the placenta.
 Type II Reactions : Cytolytic,
Cytotoxic & Cell Stimulatory
 Involve reaction between IgG (rarely IgM) & Ag
determinant on the surface of cells.
 Leads to cytolytic or cytotoxic effect.
– Autoimmune anemias
– Hemolytic disease of the new born
– Drug induced hemolytic anemias
– Drug induced thrombocytopenic purpura
– Drug induced agranulocytosis
 Rarely normal cell function may be disrupted
– Agonist effect -Cell stimulatory effect seen (LATS in
Graves’ disease).
– Antagonist effect – Myasthenia gravis

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Type III (Immune Complex) Reactions
– Involve reactions against soluble
antigens circulating in serum.
– Usually involve IgA antibodies.
– Antibody-Antigen immune complexes
are deposited in organs, activate
complement, and cause inflammatory
damage.
 Glomerulonephritis: Inflammatory kidney
damage.
– Occurs when slightly high antigen-
antibody ratio is present.
Immune Complex Mediated
Hypersensitivity

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 Type III Reaction: Immune
Complex Disease
 Arthus Reaction – Localized manifestation
of generalized hypersensitivity
– Ag+Ab precipitates cause C activation and
release of inflammatory molecules. Leads to ↑
vascular permeability & neutrophil infiltrate.
Leucocyte-platelet thrombi formed which
reduce blood supply leading to necrosis.
– Clinical example – Farmer’s lung & other
hypersensitivity pneumonitis following inhaled
Ag like Actinomycetes.

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 Arthus reaction

Arthus reaction Wheal & flare reaction

Type-III Type-I

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 Type III Reaction: Immune
Complex Disease
 Serum Sickness – Systemic form of Type III
reaction.
– Takes place following serum therapy
– e.g. ADS, ATS, AGGS, Hyperimmune globulin, Anti
Snake venum.
– Clinically Fever, lymphadenopathy, splenomegaly,
arthritis, glomerulonephritis, endocarditis, vasculitis,
urticarial rashes, abdominal pain, nausea, vomiting.
– Pathogenesis – Formation of immune complexes, its
deposition on the endothelial lining of BVs all over the
body, leads to inflammation.

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 Serum Sickness (contd)
 Plasma concentration of C falls due to massive
activation and fixation to Ag+Ab complexes.
 Disease self limited.
 Single dose of Antiserum can serve both as
sensitizing & shocking dose.
 Can also be seen after administration of
penicillin or other antibiotics.
 Immune complexes occur in many bacterial,
viral, parasitic infections e.g. poststreptococcal
glomerulonephritis, Hepatitis B & Malaria. Also
seen in disseminated malignancies &
autoimmunity.

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Serum sickness

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Type IV (Cell-Mediated) Reactions
– Involve reactions by TD memory cells.
 First contact sensitizes person.
 Subsequent contacts elicit a reaction.
– Reactions are delayed by one or more days
(delayed type hypersensitivity).
 Delay is due to migration of macrophages and T
cells to site of foreign antigens.
– Reactions are frequently displayed on the
skin: itching, redness, swelling, pain.
– Tuberculosis skin test
– Poison ivy
– Metals
– Latex in gloves and condoms (3% of health care
workers)
 Type IV Reactions: Delayed
Hypersensitivity
 One aspect of CMI
 Provoked by specific Ag, involves lymphocytes &
Macrophages.
 Not induced by circulating Ab but by sensitized
lymphocytes.
 Sensitized lymphocytes release lymphokines
which have biological effects on leucocytes,
macrophages & tissue cells.
 Transfer possible thru’ lymphocytes / transfer
factor.

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 Type IV Reactions: Delayed
Hypersensitivity
 Two types –
– Tuberculin (Infection) type
– Contact dermatitis type
 Tuberculin type –
– ID inoculation of PPD in sensitized indivisual leads to
induration & inflammation in 48-72 hrs. This is not
same as skin test done for Type I hypersensitivity.
– Used for diagnosis / exclusion of diagnosis of many
bacterial / fungal / parasitic / viral and autoimmune
diseases.

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Granuloma in a leprosy patient

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 Contact dermatitis
 Ag possibly enters thru’ sebaceous glands
 Lesions vary from macules & papules to
vesicles which subsequently breakdown
leaving weeping surface typical of acute
eczematous dermatitis.
 Detected by patch test

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Contact dermatitis reaction

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 Allergic Contact Dermatitis
Response to Poison Ivy Hapten

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 Comparison of hypersensitivity
reactions
Characteristic Type-I Type-II Type-III Type-IV
Antibody IgE IgG, IgM IgG, IgM none
Antigen exogenous cell surface soluble intracellular
Response 15-30 min. Min.-hrs 3-8 hours 48-72 hours
time or longer
Appearance Weal & flare Lysis & Erythema Erythema &
necrosis & edema induration

Histology baso- and Ab and PMN and Monocytes &

eosinophils complement complement lymphocytes
Transfer with antibody antibody antibody T-cells
Examples hay fever, pemphigus, farmers’ TB test,
asthma Goodpasture lung, SLE poison ivy,
granuloma

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