Hypersensitivity
A damage to the host, mediated by preexisting immunity to
self or foreign antigen.
Dr. Sudheer Kher
Kher
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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.

Kher
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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
– 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
Type I : IgE type Anaphylaxis
Atopy
Type II :
Cytolytic &
Cytotoxic
Antibody mediated
damage :
Thrombocytopenia,
Agranulocytosis,
Hemolytic anemia
Arthus reaction
Serum sickness
Type III :
Immune
Complex Disease
Tuberculin
Type IV :
Contact dermatitis
Delayed
hypersensitivity
Time
Mediators
required
Minutes IgE: Histamine and other
pharmacological agents
Variable: IgG: IgM, C
Hours to
days
Variable: IgG: IgM, C, Leucocytes
Hours to
days
Hours to T cells: lymphokines, macrophages
days
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Immediate
Delayed
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 (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
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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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Cutaneous anaphylaxis
If small shocking dose is given ID to
sensitized host, there is a local weal &
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 (Weal).
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 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 antigenantibody 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
Type-III
Weal & flare reaction
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)
– Anaphylactic shock may occur.
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
time
15-30 min.
Min.-hrs
3-8 hours
48-72 hours
or longer
appearance
Weal & flare
Lysis &
necrosis
Erythema
& edema
Erythema &
induration
histology
baso- and
eosinophils
Ab and
complement
PMN and
complement
Monocytes &
lymphocytes
transfer with
antibody
antibody
antibody
T-cells
examples
hay fever,
asthma
pemphigus,
Goodpasture
farmers’
lung, SLE
Kher
TB test,
poison ivy,
granuloma
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