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Hypersensitivity Reactions

M. Asghar Pasha, M.D.


Associate Professor of Medicine and Pediatrics
Division of Allergy and Immunology
Department of Medicine
E-mail: pasham@mail.amc.edu

OBJECTIVES
1. To be able to explain the mechanisms of hypersensitivity
types I-IV and give examples of each.
2. To be able to explain the distinctive features of the four
types of hypersensitivity (I-IV).
3. To be able to list how each hypersensitivity type I-IV is
treated.

What is Hypersensitivity?
Definition, Initiation, & Types
Definition: An adaptive immune response occurs in an exaggerated or
inappropriate form to a harmless environmental antigen. Hypersensitivity
reactions are the result of normally beneficial immune responses acting
inappropriately, and sometimes cause inflammatory reactions and tissue
damage.
Initiation: Hypersensitivity reactions can be provoked by many antigens,
and the cause of a hypersensitivity reaction will vary from one individual to
the next. Hypersensitivity is not manifested on first contact with antigen,
but usually appears on subsequent contact.
Hypersensitivity Types: There are four types of Hypersensitivity (I, II, III,
IV). The first three types are antibody-mediated; the fourth is mediated
mainly by T cells and macrophages.

Hypersensitivity Type I = Immediate hypersensitivity


Type I Hypersensitivity: Mediated
by IgE bound to its Fc receptor on
mast cells.
Characterized by an
allergic
reaction
that
occurs
immediately following contact with
antigen referred to as an allergen.
Allergy: A clinical, immune-mediated
immediate hypersensitivity reaction to
a protein antigen (allergen).

Allergic Rhinitis

Hypersensitivity Type I: IgE, Heredity, & Common Allergens


IgE:
Normal individuals usually
produce IgE in response to parasitic
infections. Some individuals have a
regulatory defect that allows IgE to be
produced against nonparasitic antigens.
Atopy: A hereditary predisposition to
the
development
of
immediate
hypersensitivity
reactions
against
common environmental antigens. This is
perhaps the most important determining
factor.
Allergen:
Specifically refers to
nonparasitic
antigens
capable
of
stimulating Type I Hypersensitivity.
Most allergens are small soluble
proteins; environmental allergens often
proteases, food allergens heat-stable,
drugs small chemicals that bind human
proteins (haptenate) first.

Hypersensitivity Type I: A Mechanistic Overview


Mast Cells and Basophils:
The cells that bind IgE and are
responsible for the clinical
manifestations
of
Hypersensitivity
Type
I.
Basophils comprise 0.5-1.0% of
the circulating white blood
cells. Mast cells are formed in
the bone marrow and carried
throughout
almost
all
vascularized tissue where they
mature.
The skin contains
10,000 mast cells/mm3.

Hypersensitivity Type I: Inflammatory Mediators

Hypersensitivity Type I: Consequences

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Hypersensitivity Type I: Food/Drug/Hymenoptera Allergy and


Systemic Anaphylaxis

Onset within minutes to 2 hours of


consuming the food
Hives are commonly seen, skin
symptoms not always present
Mild-severe symptoms
Anaphylaxis is a severe allergic
reaction that is rapid in onset and
may cause death
Two or more organ system
involvement
Anaphylaxis can be caused by:
food allergy
insect stings
medications (antibiotics,
NSAIDs)
latex

URTICARIA
Circumscribed, raised, erythematous and
pruritic lesions that blanch with pressure
10-20 % Of general population
(Sheldon et al; J Allergy 25:525-560)
(Champion et al; Br J Dermatol 81:588-597)

0.5-1% persists daily for 6 weeks


(Zuberbier et al; 2005 EAACI/GA LEN/EDF guideline)

Common in adults than children


Female- male ratio

2-24 hours

Immediate

Hypersensitivity Type I:
Asthma
Clinical Aspects:
A common
disease that effects 5% of Americans
in the United States. For some
unknown reason asthma is increasing
in incidence and severity in the
United States, especially among
African-American children in the
inner-city. The mortality is highest
among children.

Congestion
Edema
Neutrophils
T Cells

Genetics: Atopic individuals are


most susceptible, but only 10-30%
get asthma. There appears to be
multiple genes involved as well as
environmental factors.
Environment: A combination of
cockroach allergy and the presence of
cockroach allergens has been
demonstrated to play a role in the
high incidence of asthma in inner-city
children. Defects in the public health
system in these cities has also been
shown to contribute.
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Hypersensitivity Type I: Skin Prick and Intradermal Test

Advantages: Low cost screening in a short time.


High sensitivity.
Disadvantages: Anaphylaxis (rare), Late phase
reactions.

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Hypersensitivity Type I: Radioimmunoassay


Radioimmunosorbent Test: Measures nanogram levels of IgE. IgE is precipitated with anti-IgE
beads followed by I125-anti-IgE (RIST). This can also be done with allergen-coated beads (RAST).
RIST

RAST

Measures Total IgE

Measures Allergen-Specific IgE

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Hypersensitivity Type I: Asthma treatment

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Hypersensitivity Type I: Treatment


Prevention: Currently at equipoise for foods: avoidance or exposure?
Avoidance: When foods/drugs are involved, strict avoidance. With
environmental allergens, attempt to minimize exposure to the allergen.

Subcutaneous Immunotherapy: Injection of Low Dose Ragweed Allergen


Hyposensitization:
Repeated
injections of increasing doses of
allergen.
Mechanism: There is a gradual
switch to higher levels of IgG
and lower levels of IgE. The
IgG competes with the IgE for
allergen forming IgG-allergen
complexes which are removed
by phagocytes. A switch from
Th2 to Th1 cells may also be
involved.
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IgE-Dependent Release of Inflammatory Mediators

Allergens

IgE
FcRI
FcRI
binding site

Immediate Release
Granule contents:
Histamine, TNF-,
Proteases, Heparin

Sneezing
Nasal congestion
Itchy, runny nose
Watery eyes

Over Hours
Over Minutes
Lipid mediators:
Prostaglandins
Leukotrienes

Cytokine production:
Specifically IL-4, IL-13

Mucus production
Eosinophil recruitment

Wheezing
Bronchoconstriction

EARLY ALLERGIC REACTION

LATE ALLERGIC REACTION

Anti-IgE (Omalizumab)
FcRI

IgE

+ Anti-IgE (Omalizumab)

Allergic Symptomatology

Hypersensitivity Type II: General


Description
Type II Hypersensitivity: Mediated by
IgG or IgM binding to specific cells or
tissues.
Hemolytic Disease of the Newborn (HDNB)

Enlarged liver and spleen and elevated bilirubin


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Hypersensitivity Type II: Transfusion Reactions


Mechanism: An individual with one allelic form of blood group antigen can
recognize other allelic forms as foreign when transfused with them. Binding of
antibodies to red blood cells activates complement leading to massive intravascular
hemolysis. Antibodies are due to normal exposure to bacterial antigens similar to
those on red blood cells.
Isohemagglutinins: Antibodies to the A,B,O blood groups, usually of the IgM subclass.
Immediate: A,B,O related. Triggered by IgM antibodies.
Within hours free hemoglobin is detected in plasma.
Symptoms include: fever, chills, nausea, blood clotting,
lower back pain, and hemoglobin in urine.
Delayed: Usually involves IgG responses to blood group
antigens other than A,B,O (Rhesus, Kell, Kidd, Duffy),
following repeated transfusions.
IgG-dependent
complement-mediated lysis is less efficient and lysis tends
to occur at extravascular sites. Thus hemoglobin is not
usually detected in plasma or urine. Symptoms include:
fever, low hemoglobin, increased bilirubin, mild jaundice,
and anemia.
Treatment: Termination of
transfusion and diuretics to
maintain urine flow.

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Hypersensitivity Type II: Hemolytic Disease of The Newborn


Mechanism: HDNB is caused by maternal IgG antibodies to fetal blood group antigens
which cross the placenta and destroy fetal red blood cells.
Erythroblastosis Fetalis: Severe HDNB most commonly occurs when the mother is Rh- and the fetus is Rh+.

Clinical Manifestations: Mild to severe anemia can develop and become fatal.
Bilirubin can accumulate in the brain and cause brain damage.

(24-48 h after delivery)

Treatment:
Transfusions until
or after delivery.
UV
light
to
remove bilirubin.

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Hypersensitivity Type III: General Description


Type III Hypersensitivity: Mediated by immune complexes which
persist and are deposited in a range of tissues and organs. This then
results in complement and effector-cell-mediated damage.
Examples (antigen):
Systemic lupus erythematosus (DNA, nucleoproteins)
Poststreptococcal glomerulonephritis (streptococcal cell wall antigens)
Serum sickness (various proteins, i.e. drugs)
Arthus reaction (various proteins, i.e. mold)

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Hypersensitivity Type III:


The Arthus reaction
Clinical Manifestations:
Insect Bites: In sensitive individuals initially a
Type I reaction may occur at the site. Four to
eight hours later, a typical Arthus reaction also
develops at the site, with pronounced erythema
and edema.
Farmers Lung: An intrapulmonary Arthustype reaction which develops after inhalation of
thermophilic actinomycetes from moldy hay.
Results from
Pigeon Fancier s Disease;
inhalation of a serum protein from pigeons in
dust derived from pigeon feces.

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Hypersensitivity Type IV: General Description


Type IV Hypersensitivity: Takes more than 12 hours to develop, and
involves cell-mediated immune reactions rather than humoral (antibodymediated) immune reactions.
Classical T cell-mediated inflammatory reaction is called delayed-type
hypersensitivity (DTH), which is an injurious cytokine-mediated
inflammatory reaction resulting from the activation of T cells.

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Type IV hypersensitivity reation (Immune response in allergic contact dermatitis)


Haptens
Afferent limb

Efferent limb

LC

LC

IFg

IL-2
Th1

IFNg
Blood
vessel

LC

GM-CSF

Th0
Beltrani et al, Contact dermatitis: Ann
Allergy Asthma Immunol 1997:78:160-75

Lymph Node

Th1
sensitized
Th1

unsensitized

Hypersensitivity Type IV: The Allergens

Note: This response is designed to eliminate parasites and intracellular pathogens.


Problems arise when the response is prolonged as a result of failure to eliminate the
pathogen.

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Hypersensitivity Type IV: Contact dermatitis


Contact Dermatitis: This results from small molecules which are not normally immunogenic
complexing with skin proteins forming a hapten-carrier-like complex. These complexes are then
presented by professional antigen presenting cells (Langerhan's cells) to TDTH cells.
Contact Dermatitis-Inducing Agents: Formaldehyde,
trinitrophenol, nickel, turpentine, cosmetics, hair dye,
poison oak, and poison ivy.

Type IV hypersensitivity
Allergic reaction to
Rubber gloves
(Carba Mix
&
Thiuram Mix)

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Type IV hypersensitivity reactions


Diagnosis:
Patch test for the diagnosis of allergic contact dermatitis

Treatment:
Topical steroids
Systemic steroids

Penicillin may elicit Hypersensitivity reactions I-IV

Wheal and Flare


(Type I)

Arthus (Less definedType III)

Red Induration (Hardening)


(Type IV)

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Hypersensitivity Types I-IV:


Summary of Distinguishing Features

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Hypersensitivity Reactions

Thank you!
M. Asghar Pasha, M.D.
Associate Professor of Medicine and Pediatrics
Division of Allergy and Immunology
Department of Medicine
E-mail: pasham@mail.amc.edu

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