Hypersensitivity

Li Li ( )

[email protected]
2013.12.13
 Main contents
Definition and classification
IgE-mediated(type) hypersensitivity
IgG/IgM-mediated(type ) hypersensitivity
Immune complex-mediated(type )
hypersensitivity
Delayed (type ) hypersensitivity
Definition of Hypersensitivity

An immunologic reaction which produces

cell dysfunction or tissue damage on
reexposure to antigen
 GellandCoombsClassification
Four types
Type I (immediate) (IgE-mediated)
Type II (cytotoxic) (IgG and IgM mediated)
Type III (immune complexmediated)
Type IV (Delayed-type) (cell-mediated)
 Type I (Immediate) Hypersensitivity

Results from the release of inflammatory

molecules in response to an antigen
Localized or systemic reaction
Develops soon after exposure to an antigen
Commonly called allergy
The antigens that stimulate it are called
allergens

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Type I Hypersensitivity Reaction
 Allergen (antigen)

Antigen-presenting cell (APC)

The mechanisms
phagocytizes and processes
antigen.

of a type I
hypersensitivity
APC presents
epitope to Th2 cell.

reaction:
Th2 cell
IL-4 from Th2
IL-4
cell stimulates selected
B cell clone.
B cell

B cells become plasma cells

that secrete IgE.
Plasma cell

sensitization IgE against allergen

IgE stem binds to

mast cells, basophils,
and eosinophils.

Mast cell

IgE
Sensitization Basophil Eosinophil
 The mechanisms of a type I
hypersensitivity reaction:
degranulation
Subsequent exposure
to allergen

Sensitized mast cell,

basophil, or eosinophil

Histamines, kinins,
proteases, leukotrienes,
prostaglandins, and other
inflammatory molecules

Degranulation
 Roles of degranulating cells in an allergic
reaction
Degranulation occurs after cells are sensitized
Mast cells
Basophils
Eosinophils
Degranulation releases histamine, kinins, proteases,
leukotrienes, and prostaglandins

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Mast Cell Mediators

Preformed
Vasoactive amines: histamine
Neutral proteases: tryptase, chymase
Acid hydrolases: b-hexoseaminidase
Proteoglycans: heparin, chondroitin sulfate
Newly formed
Eicosanoids: PGD2, LTC4
Cytokines: TNFa, IL-4, IL-5, IL-6
Acute Phase Allergic Reaction:

Occurs within seconds to minutes of

IgE receptor activation (mast cell
mediator release) and resolving within
an hour
Intense pruritus, edema, erythema
Almost all effects can be replicated
with histamine
 Late Phase Allergic Reaction:
A delayed inflammatory response
(peaking at 4-8 hrs and persisting up to 24 hrs)
following an intense acute phase reaction
Skin: erythema, induration, burning
Lungs: airway obstruction poorly responsive to
bronchodilators
Nose/eyes: erythema, congestion, burning
Histology
mast cell degranulation followed by influx of first
neutrophils and eosinophils followed by
mononuclear cells
Major portion of effects replicated by TNFa
edema, swelling
erythema
 Type I Hypersensitivity:
Systemic or Localized
Systemic (Anaphylaxis shock)
Symptoms include: labored breathing, drop in
blood pressure, smooth muscle contraction,
bronchiole constriction (suffocation)
Localized
Examples: Hay fever (allergic rhinitis), asthma
(allergic or intrinsic), food allergies, atopic
dermatitis (eczema)
 Clinical signs of systemic allergic reactions

Many mast cells may degranulate at once, releasing

large amounts of histamine and inflammatory
mediators
Acute anaphylaxis or anaphylactic shock can result
Clinical signs are those of suffocation
Must be treated promptly with epinephrine

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 Clinical signs of localized allergic reactions

Usually mild
Site of reaction depends on portal of entry
Small inhaled allergens may reach lungs and cause
asthma
Some foods contain allergens
May cause diarrhea and other gastrointestinal signs
and symptoms
Local skin inflammation may produce hives or urticaria

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The skin Urticaria (hives)
 Diagnosis of type I hypersensitivity

Diagnosis based on detection of high levels

of IgE against specific allergen
Alternatively, can diagnose using skin tests

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 Prevention of type I hypersensitivity

Identify and avoid allergens

Identify food allergens by eliminating suspected
foods from diet
Immunotherapy can help prevent allergic reactions
Administer a series of injections of dilute
allergen
Must be repeated every two to three years

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 Treatment of type I hypersensitivity

Administer drugs that counteract inflammatory

mediators
Antihistamines neutralize histamine
Treat asthma with a corticosteroid and a
bronchodilator
Epinephrine neutralizes many mechanisms of
anaphylaxis
Relaxes smooth muscle
Reduces vascular permeability
Severe asthma and anaphylactic shock require
emergency treatment

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 Therapy of Allergic Disease
Inhibition of IgE synthesis: Immunotherapy
Inhibition of IgE binding to receptor:
Monoclonal anti-IgE (Xolair, Omalizumab)

Inhibition of mast cell mediator release:

Topical corticosteroids
Cromolyn, nedocromil

Inhibition of mediator action:

Antihistamines
Leukotriene receptor antagonists
Topical and systemic corticosteroids
Type II Hypersensitivity Reactions
(Cytotoxic) Hypersensitivity :
Mechanisms of Tissue Damage

Complement-mediated cytolysis
Antibody-dependent cell-mediated
cytotoxicity (ADCC)
 Type II (Cytotoxic) Hypersensitivity

Results when cells are destroyed by an immune

response
Often the combined activities of complement and antibodies
A component of many autoimmune diseases
significant examples
incompatible blood transfusion and hyperacute graft
rejection
Drug-induced hemolytic anemia
hemolytic disease of the newborn
Events leading to hemolysis: transfusion reaction

Type A antigens on red Donor:TypeB

blood cells of patient
Donated red blood cells
with B antigen
Anti-B
antibody

Transfusion

Complement

Hemoglobin

Recipient:
TypeA

Agglutination and
complement binding
Hemolysis
 Type II (Cytotoxic) Hypersensitivity
Drug-induced cytotoxic reactions
Some drug molecules bind larger molecules
Stimulate the production of antibodies
Can produce various diseases
Immune thrombocytopenic purpura
Agranulocytosis
Hemolytic anemia

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 Events in the
development of immune
Drug

thrombocytopenic Platelet

purpura
Drug molecules bind to platelets,
forming drug-platelet complex.

Drug-platelet
complex Complexes are antigenic,
triggering a humoral
immune response.

Antibodies bind to drug

molecules; complement
binds to antibodies.

Complement

Membrane attack
complexes of complement
lyse platelet, which leaks
cytoplasm.
 Type II (Cytotoxic) Hypersensitivity
The Rh system and hemolytic disease of the
newborn(HDN, )
Rh antigen
Common to red blood cells of humans and rhesus monkeys
About 85% of humans are Rh positive (Rh+)
Rh woman carrying an Rh+ fetus may be at risk for
hemolytic disease
RhoGAM administered to prevent hemolytic disease
of the newborn

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Graves
disease
 Myasthenia gravis

Autoantibodies to Ach receptor

Nerve impulses trigger release bind to receptors and cause the
of Ach from the nerve ending internalization and degradation
 Type III (Immune ComplexMediated)
Hypersensitivity
Caused by formation of immune complexes
Can cause localized reactions
Hypersensitivity pneumonitis
Glomerulonephritis
Can cause systemic reactions
Systemic lupus erythematosus SLE
Rheumatoid arthritis

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 Type III Hypersensitivity
Examples of Diseases
Arthus reaction
Hypersensitivity pneumonitis
Immune complex-mediated
glomerulonephritis
Serum sickness
 Hypersensitivity Pneumonitis
Syndromes and Associated Antigens
Farmers lung (thermophilic actinomycetes)

Malt workers lung (Aspergillus spores)

Pigeon fanciers disease (avian proteins)

Cheese washers lung (Penicillium spores)

Furriers lung (fox fur)

Laboratory technicians lung (rat urine proteins)

Type III Hypersensitivity Reactions:
Serum Sickness
Occurs when antigen enters bloodstream,
circulating immune complexes form
Symptoms include:
Fever, rash, joint pain, lymphadenopathy,
occasionally glomerulonephritis
Timecourse: days to weeks after introduction of
foreign antigen
Causes: allogeneic serum, drugs, infections,
autoimmune disorders
Self
healing
1. Complement initiates
mast cell degranulation
2. Neutrophils are
chemotactically
attracted to the site
3. Neutrophils release
lytic enzyme after
failed attempts to
endocytose the immune
complex
 Type IV (Delayed or Cell-Mediated)
Hypersensitivity

Inflammation 12 to 24 hr after contact with

certain antigens
Due to actions of antigen, antigen-presenting
cells, and T cells
Delay reflects the time it takes for
macrophages and T cells to migrate to and
proliferate at the site of the antigen

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 Vedio:
DTH response
 Type IV (Delayed or Cell-Mediated) Hypersensitivity
The tuberculin response
An injection of tuberculin beneath the skin causes
reaction in individual exposed to tuberculosis or
tuberculosis vaccine
Used to diagnose contact with antigens of
M. tuberculosis
No response when individual not infected or
vaccinated
Red, hard swelling develops in individuals
previously infected or immunized
PPDskintest Measurementof
erythemadiameter
GranulomaFormation
 Type IV (Delayed or Cell-Mediated)
Hypersensitivity
Allergic contact dermatitis
Cell-mediated immune response
Results in an intensely irritating skin rash
Triggered by chemically modified skin proteins that
the body regards as foreign
Acellular, fluid-filled blisters develop in severe cases
Can be treated with glucocorticoids

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DTHreactioninallergiccontactdermatitis

Allergic contact dermatitis

 Delayed
Delayed hypersensitivity
hypersensitivity reactions
reactions

type timeof clinical histology antigenandsite

reaction appearance

contact 4872h Tcells,later epidermal:heavy

eczema macrophages
dermatitis metals,poisonivy,
rubber,latex

4872h local lymphocytes, intradermal:

tuberculin tuberculin,
induration monocytes
lepromin,etc.

granuloma 21- M,giantcells, persistentantigen

hardening
28d epitheloidcells, stimulus,chronic
fibroblasts infection
Comparison
Comparison of
of hypersensitivity
hypersensitivity reactions
reactions

characteristic TypeI TypeII TypeIII TypeIV

antibody IgE IgG, IgM IgG, IgM none
antigen Exogenous cell surface soluble cellular
response 15-30 Min.-hrs 3-8 hours 48-72 hours
time min. or longer
appearance Lysis & Erythema Erythema &
Weal &
flare necrosis & edema induration

histology baso- and Ab and PMN and Monocytes &

eosinophils complement complement lymphocytes
transfer with antibody antibody antibody T-cells
examples hayfever, pemphigus, farmers TBtest,
asthma Goodpasture lung,SLE poisonivy,
granuloma
 Questions
1. Type-I hypersensitivity is mediated by
A. IgA B. IgD C.IgE D.IgG E.IgM
2. Immediate hypersensitivity usually involves
A. Mast cells B. IgG C. antibodies to mast cells D. Th1 cells E. platelets
3. Therapy of allergic disease does not include
A. Inhibition of IgE synthesis
B. Inhibition of IgE binding to receptor
C. Inhibition of mast cell mediator release
D. Inhibition of mediator action
E. Increase T cells making IL-4
 Questions
4. Hemolytic disease of the newborn is
A. Type-I hypersensitivity B. Type-II hypersensitivity
C. Type-III hypersensitivity D. Type-IV hypersensitivity
E. Delayed hypersensitivity
5. The response of delayed hypersensitivity
A. Can be passively transferred by antibody
B. Shows erythema (redness) and induration 1-2 days after injection of the
antigen
C. Depends upon the attachment of IgE antibody to mast cells
D. Is mediated by B lymphocytes
E. Is mediated by complement system