[MID] Chapter 13: Hypersensitivity

Hypersensitivity heightened state of immune responsiveness

Classification:

Immunology & Serology

C.
D.

Promoting the development of mast cells

Stimulating the overproduction of mucus

IL-4 A, C, D

Type 1 cell-bound antibody reacts with antigen to release

physiologically active substances
Type 2 free antibody reacts with antigen associated with cell
surfaces

IL-5 B

IL-9 B, C, D

IL-13 A, D

While cytokines regulate antibody synthesis, MHC genes are

responsible for the response to specific allergens.
MHC Class II molecules such as HLA-DR2, DR4, and DR7 are
associated with a high response to individual allergens.

Type 3 antibody reacts with soluble antigen to form complexes that

precipitate in the tissues

***HLA-D molecules are known to play a role in antigen presentation.

Type 4 - sensitize T cells rather than antibodies are responsible for the
symptoms that develop

People who are prone to allergies exhibit variations in the gene found
on chromosome 11q,that codes for receptor for IgE.

***Complement plays a major role in producing tissue damage in in

Types 2 and 3 reactions.

***Types 1-3 reactions are also called immediate hypersensitivity

(development of symptoms within a few minutes to a few hours)
***Type 4 reaction is also called delayed hypersensitivity (symptoms
develop within 24 to 48 hours)
TYPE 1 HYPERSENSITIVITY
Distinguishing feature = short time lag between exposure to antigens
and the onset of clinical symptoms

Langerhans and Dendritic cells internalize and process allergens

from the environment and transport the allergen-MHC class II complex
to local lymphoid tissue.
Binding of IgE to cell membranes increases the half-life of the IgE
molecule from 2 or 3 days to up at least 10 days.
-

Key reactant = IgE, which are called atopic antigens, or allergens.

-

Atopy inherited tendency to respond into naturally

occurring inhaled and ingested allergens with continue
production of IgE.

Production of large amount of IgE in response to a small

concentration of antigen is often observed in patients who exhibit
allergic or immediate hypersensitivity reactions.
Passive cutaneous anaphylaxis - a reaction that occurs when serum
is transferred from an allergic individual to a nonallergic individual, and
consequently the second individual is challenged with a specific
antigen
Triggering of Type 1 Reactions by IgE:
IgE is primarily synthesized in the lymphoid tissue of the respiratory
and gastrointestinal tracts; with normal values having a range of 150
ng/mL
Type II T helper cells (Th2) are the regulators of IgE production
Type I T Helper cells (Th1) have the function of triggering normal
immune response by the production of interferon gamma
-

Interferon gamma, as well as IL-12 and IL-18 may

suppress production of IgE.

In people with allergies, Th2 will produce IL-3, IL-4, IL-5, IL-9, and IL-

Polymorphism in the beta-chain of such receptors are linked

to atopy.
The high affinity receptors, FCE-RI receptors, bind the Fc
region of the epsilon heavy chain, and are found on
basophils and mast cells.

Once binded, IgE acts as an antigen receptor on mast cells

and basophils, and cross-linking of at least two of the
antibodies by an antigen triggers the release of mediators
from such cells.
o
Once
cross-linking
occurs,
multiple
phosphorylation reactions cause an increase in
calcium, which then promotes sysnthesis of
arachidonic acid from membrane lipids, as well as
promote cytokine synthesis.

Role of Mast Cells and Basophils:

Mast Cells are the principle effector cells of immediate
hypersensitivity. They are prominent in connective tissue, the skin, the
respiratory and the gastrointestinal tract.
-

Histamine comprises 10% of the total weight of granular

constituents, and is found in 10 times greater supply per cell
than in basophils.
Mast cell populations differ in different sites, but they all
release a variety of cytokines and other mediators that
enhance the allergic response.

Basophils represent 1 percent of the WBCs in peripheral blood, with a

half-life of about 3 days.
-

Histamine rich, and they respond to chemotactic stimulation,

and accumulate in tissues during inflammatory reactions.

Mediators Released from Granules:

Preformed Mediators:

13. Such interleukins are encoded by chromosome 5.

Functions of the Interleukins:
A.
B.

Final differentiation that occurs in B cells

Involvement in the development of eosinophils

Cross linking of surface bound IgE by a specific allergen releases

mediators from the cytoplasmic granules.

[MID] Chapter 13: Hypersensitivity

Primary or preformed mediators include:
histamine, heparin,
eosinophil chemotactic factor of anaphylaxis (ECF-A), neutrophil
chemotactic factor, and protease
-

Release of such substances accounts for the early phase

symptoms seen in allergic reactions.

The effects of histamine appear within 30 to 60 seconds, and are

dependent on activation of four different types of receptors found on
cells.
1)

2)

3)
4)

H1 receptors contraction of smooth muscles in bronchioles,

blood vessels, and the intestines, and generally induces
proinflammatory activity
H2 receptors increases gastric acid secretion, airway
mucus production, and permeability of capillaries and
venules
H3 receptors found on central and peripheral neural tissue
H4 receptors involved in immune regulation

Immunology & Serology

IL-4 = recruits T cells, basophils, eosinophils
and monocytes
IL-5 also recruits eosinophils
o

Th2 cells, mast cells, basophils, and macrophages exit the circulation
and infiltrate allergen-filled tissues.
Clinical Manifestations of Immediate Hypersensitivity:
Clinical manifestations vary from a localized skin reaction to a systemic
response known as anaphylaxis (without protection).
-

***Histamine is also responsible for local erythema or redness and

wheal and flare formation.
ECF-A attracts eosinophils to the area and induces expression of
eosinophil receptors for C3b
Tryptase cleaves kininogen to generate bradykinin, which induces
prolonged smooth muscle contraction and increases vascular
permeability and secretory activity

Anaphylaxis most severe type of allergic response

because it is an acute reaction affecting multiple organs.
o
Typically triggered by glycoproteins or large
polypeptides
o
Typical agents include venom from insects, drugs,
and foods such as shellfish, peanuts, or dairy
products
o
Latex sensitivity can also trigger anaphylaxis
o
Clinical signs begin within minutes after antigenic
challenge, and the severity of the reaction
depends on the # of previous exposures to the
antigen with consequent buildup of IgE on
mast cells and basophils
o
Massive release of reactants is responsible for the
ensuing symptoms
o
Death may occur from asphyxiation due to upper
airway edema and congestion, irreversible shock,
or a combination of such symptoms.

Newly Synthesized Mediators:

Synthesized from the breakdown of phospholipids in the cell
membrane, and are responsible for late phase allergic reactions within
6-8 hours after exposure to antigen
Newly formed mediators include: cytokines, platelet-activating
factor (PAF), prostaglandin (PG) D2, leukotrienes (LT) B4, C4, and
E4.
PGD2 is the major product of the cyclooxygenase pathway. It mimics
the effects of histamine, causing bronchial constriction and
vasodilation. It is, however, more potent than histamine, albeit being in
smaller quantities.

The symptoms depend on variables such as route of exposure,

dosage, and frequency of exposure.
Rhinitis is the most common form of atopy. Its symptoms include
paroxysmal sneezing, rhinorrhea, nasal congesting, and itching of the
nose and eyes.
Pollen, mold spores, animal dander and dust mites are examples of
airborne foreign particles that act directly on the mast cells.
Particles no longer than 2-4 um such as pollens, dust, or fumes may
cause asthma.
-

Leukotrienes result from the 5-lipoxygenase pathway of arachidonic

acid metabolism.
-

C4, D4, and E4 were also known as slow-reacting substances

of anaphylaxis (SRS-A), with LTC4 and LTD4 being 1000
times more potent than histamine
LTB4 is a potent chemotactic factor for neutrophils and
eosinophils

PAF is released by monocytes, macrophages, neutrophils, eosinophils,

mast cells and basophils. Its main function include platelet
aggregation, chemotaxis of eosinophils and neutrophils,
increased vascular permeability and contraction of smooth
muscles in the lungs and intestines
Cytokines alter the local microenvironment, leading to increase in
inflammatory cells.
-

IL-3 and IL-4 = increase IgE production

o
IL-3 = growth factor for mast cells and
basophils

Asthma
- recurrent airflow obstruction that leads to
intermittent sneezing, breathlessness, and occasionally a
cough with sputum production.
o
Often treated with a combination of therapeutic
reagents
such
as
antihistamines
and
bronchodilators
followed
by
inhaled
corticosteroids.

Food allergies is also an example of type 1 immediate hypersensitivity,

and may cause eczema, which is an itchy red skin rash.
Treatment of Immediate Hypersensitivity:
Avoidance of known allergens is the first line of defense.
Localized allergic reactions such as hay fever, hives, or rhinitis can
be treated with antihistamines and decongestants.
Hyposensitization small quantities of sensitizing antigen are
injected into the patient with the idea of building up IgG antibodies.

[MID] Chapter 13: Hypersensitivity

Use of anti-IgE monoclonal antibody in order to block sites that IgE
would normally bind to on a mast cell. The blockage can help alleviate
allergic symptoms, as mast cells cant release mediators.
Testing for Immediate Hypersensitivity:
In vivo skin test methods are the least expensive and most specific.
There are two forms cutaneous and intradermal.
-

Cutaneous (lesser amount of antigen are used):

1. Small drop of material is injected into the skin
2. The spot is examined and the reaction is recorded after
15 minutes
o
A (+) reaction is formation of a wheal that is 3mm
greater in diameter than the negative control
(saline)
Intradermal (greater amount of antigen, more sensitive
than cutaneous):
1. Using a 1 mL tuberculin syringe, 0.01 to 0.05 mL of test
solution is administered between layers of the skin
2. After 15-20 minutes, the site is observed for erythema
and wheal formation.
a. A positive result is wheal formation of greater
than 3mm

In vitro tests involve measurement of either total IgE or antigenspecific IgE. These are less sensitive than skin tests.
-

Immunology & Serology

IgG and IgM are the two main reactants responsible
-

Complement plays a major role in Type 2 hypersensitivity.

Transfusion Reactions:
Cellular destruction that result from
heteroantigens

Interpretation of Total IgE Results:

o
Infants: Normal serum level of Ige are less than 2
kIU/L; increase up to 10 kIU/L is indicative of
allergic disease
o
After the age of 14, IgE levels in the range of 400
kIU/L are considered to be abnormally elevated.

Anti-A and Anti-B are naturally occurring antibodies, also

known as, isohemagglutinins
o
Triggered by contact with identical antigenic
determinants on microorganisms
o
Type A blood contains anti-B
o
Type B blood contains anti-A
o
Type O contains both anti-A and anti-B

A transfusion reaction occurs when a patient is given blood

for which antibodies are present, and such reactions are
dependent on the following factors:
1.
2.
3.
4.
5.
6.

Allergen-specific IgE testing is a noncompetitive solid-phase

immunoassay in which the solid phase is coated with
specific allergen and reacted with patient serum.

Microarray Testing allows for multiallergen diagnosis with a low

sample volume and a high throughput capacity.
-

Its principle is the same as noncompetitive immunoassays,

in that patient serum with possible IgE is reacted with the
microarray of allergens, and then an anti-IgE with a
fluorescent tag is added. Presence of color indicates a (+)
result.
TYPE 2 HYPERSENSITIVITY

Temp at which antibody is most active

Plasma concentration of antibody
Particular immunoglobulin class
Extent of complement activation
Density of the antigen on the RBC
Number of RBCs transfused

***It is important to detect antibodies that react at 37C

Acute hemolytic transfusion reactions may occur within minutes or
hours after receipt of incompatible blood.
-

The original commercial testing method for determining specific IgE

was known as radioallergosorbent test (RAST).
-

with

The ABO blood group is an important consideration in transfusion

reactions.

Noncompetitive solid-phase immunoassay, antihuman

igE is bound to a solid phase such as cellulose, a paper disk,
or a microtiter well.
o
Patient serum is added and allowed to react, and
then a labeled anti-igE is added to detect the
bound patient IgE.
Total serum IgE is used as a screening test, as well as aiding
in diagnosis of allergic rhinitis, asthma, or other allergic
conditions.

antibody combining

The major groups involved with transfusion reactions include the ABO,
Rh, Kell, Duffy, and Kidd systems.

The Competitive radioimmunosorbent test (RIST) uses

radiolabeled IgE to compete with patient igE for binding sites
on a solid phase coated with anti-igE.

Triggered by altered self-antigens and heteroantigens,

found on cell surfaces.
Promotes phagocytosis and activation of complement

Reactions that begin immediately are most often associated

with ABO blood group incompatibilities.
Intravascular hemolysis occurs after antigen is introduced to
the patient, due to complement activation
Delayed hemolytic reactions occur within the first 2 weeks
following a transfusion, and are caused by a secondary
response to the antigen
o
IgG is the antibody present
o
Rh, Kell, Duffy, and Kidd blood groups are most
associated with this type of reaction.
o
Intravascular hemolysis does not occur, as IgG is
not efficient in activating the complement
system.

Hemolytic Disease of the Newborn

Appears in infants whose mothers have been exposed to blood-group
antigens on the babys cells that differ from their own
-

As a result, IgG production starts, which destroy fetal red

cells.

Erythroblastosis fetalis severe HDN in which D antigen is the most

common antigen involved

[MID] Chapter 13: Hypersensitivity

-

Immunology & Serology

Treatment involves an exchange transfusion to replace

antibody-coated red cells.

HDN due to ABO compatibility is milder, as IgM antibodies are formed,

which cannot cross the placenta.
Exposure occurs during the birth process, due to fetal cells leak in the
mothers circulation.
-

First child is usually unaffected.

Later children, however, are susceptible due to an
anamnestic response
The extent of the first bleeding influences the amount of
antibodies formed.
o
If enough, memory B-cells develop, which then
mature to IgG to cross the placenta
o
The amount of antibodies formed affects the
childs mortality or its likelihood of developing a
disease.
Kernicterus can occur if there is bilirubin build up

Screening of pregnant women can prevent the consequences of HDN.

Antibody reaction with basement membrane, and the

glomeruli, as well as the pulmonary alveolar membranes
are affected
o
Complement cascade occurs in the two areas, and
inflammation occurs
o
Treatment = corticosteroids

Testing for Type 2 Hypersensitivity:

Direct antiglobulin testing (DAT) performed to detect transfusion
reactions, hemolytic disease of the newborn, and autoimmune
hemolytic anemia
Polyspecific antihuman globulin (mixture of antibodies to IgG and
complement components) initial testing
Indirect Coombs test crossmatching of blood to prevent
transfusion reaction
TYPE 3 HYPERSENSITIVITY

Autoimmune Hemolytic Anemia:

IgM and IgG are the main antibodies involved, however, unlike in Type
2 hypesensitivity, the antigen is soluble.

Type 2 hypersensitivity reaction directed against self-antigens, due to

the production of antibodies to an individuals own RBC.

Complexes that precipitate out of the serum are formed when soluble
antigen combines with antibody

Two groups:
antibodies

Warm

reactive

antibodies

and

Cold

reactive

Warm autoimmune hemolytic anemia accounts for 70% of

autoimmune anemia.
-

Characterized by formation of IgG antibody, which react

strongly at 37C.
May or may not be associated with other diseases
Underlying cause of antibody production is unknown and is
referred to as idiopathic autoimmune hemolytic anemia.
Symptoms of anemia as a result of clarance of antibody
coated RBCs by the liver and spleen
Hemolysis is extravascular
Treated with corticosteroids or splenectomy

Cold autoagglutinins less frequent, found in people in their fifties

and sixties
-

Triggered by antigens on microorganism, as antibodies

form following Mycoplasma pneumonia and infectious
mononucleosis
Antibodies belong to the IgM class and are specific for Ii
blood groups
Reactions are seen only if the individual is exposed to the
cold, and temp of circulation falls below 30C
If complement is activated, intravascular hemolysis occurs
Treatment = keeping the patient warm

Type 2 Reactions Involving Tissue Antigens:

Some type 2 reaction involve destruction of tissues because of
combination with antibody
Goodpastures syndrome an example of an organ specific
autoimmune disease in which antibody is directed against a particular
tissue.

If complexes arent phagocytized, they deposit in the

tissues and bind complement, causing damage
Excess antigen sites on antibody molecules become
filled before cross-linking occurs
Excess antibody no lattice formation
Precipitating complexes occur in mild antigen excess, and
are most likely to deposit in the tissues.

Complement binds to the complexes in the tissues causing the release

of mediators.
If target cells are large, and are unaffected by phagocytosis, granule
and lysosome contents are release by exocytosis
Long-term changes include loss of tissue elements that cannot be
regenerated.
Arthur Reaction:
Localized type 3 reaction characterized by erythema and edema,
which peaks within 3-8 hours, and is followed by a hemorrhagic
necrotic lesion that may ulcerate.
-

Caused by antigen-antibody combination, and formation

of complexes that deposit in small dermal blood vessels
Complement is fixed, attracting neutrophils and causing
aggregation of platelets.
o
Neutrophils release free radicals and proteolytic
enzymes
Activation of complement is essential for such reaction to
occur.

Serum Sickness:

[MID] Chapter 13: Hypersensitivity

Result from passive immunization with animal serum, usually a horse
or bovine, used to treat infections like diphtheria, tetanus, and
gangrene
-

Symptoms (heache, nausea, fever, joint pain etc.) occur 721 days after injection of the animal serum, and recovery
takes between 7 and 30 days
In this disease, the sensitizing and the shocking dose of
antigen are one and the same, because antibodies develop
while antigen is still present
o
High levels of antibody form immune complexes
that deposit in the tissues.

Autoimmune Disease:
Autoimmune diseases that fall into type 3 hypersensitivity reactions
include:
1)

2)

Systemic lupus erythematous antibodies are directed

against constituents such as DNA and nucleohistones.
a. Complex deposition involves multiple organs, but
the main damage occurs at the glomerular
basement membrane of the kidney
Rheumatoid arthritis rheumatoid factor, an antibody, is
directed against IgG.
a. Complex deposition occurs in the membranes of
joints.

Testing for Type 3 Hypersensitivity:

Agglutination reactions detects SLE and rheumatoid arthritis
Fluorescent staining of tissue sections determine deposition of
immune complexes
Measuring complement levels general method determining
immune complex diseases
TYPE 4 HYPERSENSITIVITY
Differs from the other three types of hypersensitivity in that sensitized
T cells, usually a subpopulation of Th1 cells, play the major role in its
manifestations.
***Antibody and complement are not directly involved
Sensitization phase of 1-2 weeks, and symptoms occur several after
subsequent exposure, and peak at 48-72 hours

Immunology & Serology

Reactions are usually due to low-molecular weight compounds that
touch the skin
Most common causes include: poison ivy, poison oak, and poison
sumac
Other common compounds: nickel, rubber, formaldehyde, hair dyes;
cosmetics; antiseptics and antibiotics; latex
Most of the aforementioned substances are haptens that bind to
proteins on skin cells
The Langerhans cell act as the antigen-presenting cell, which migrate
to regional lymph nodes and generate sensitized Th1 cells.
After repeat exposure, cytokine production causes macrophages to
accumulate, and a skin eruption characterized by erythema, swelling,
and formation of papules appear between 6 hours to several days after
exposure.
Dermatitis is initially limited to skin sites exposed to the antigen, but
then it spreads out to adjoining areas. It can last for 3-4 weeks until
antigen has been removed
-

Hypersensitivity Pneumonitis:
Mediated predominantly by sensitized T-lymphocytes that respond to
inhaled allergens. IgG & IgM play a minor role.
It is an allergic disease of the lung parenchyma, characterized by
inflammation of the alveoli and interstitial spaces and is caused by
inhalation of a variety of antigens
The reaction is most likely due to microorganisms, especially bacterial
and fungal spores.
Symptoms include: dry cough, shortness of breath, fever, chills
Alveolar macrophages and lymphocytes trigger a chronic condition
characterized by interstitial fibrosis with alveolar inflammation.
Tuberculin-Type Hypersensitivity:
Testing for exposure to tuberculosis is based on the principle that
soluble antigens from M. tuberculosis induce a reaction in people who
have or have had tuberculosis.
-

Transferred only through the transfer of T-lymphocytes.

Langerhans cells and macrophages capture and present the antigen to
T helper cells of the Th1 subclass, and once activated, the Th1 cells
release cytokines, which recruit macrophages and neutrophils
-

Cytotoxic T cells are also recruited and they bind with

antigen-coated target cells to cause tissue destruction

Allergic skin reactions to bacteria, viruses, fungi and environmental

antigens like poison ivy are examples of this reaction.

Systemic corticosteroids can be used to treat dermatitis

Previously sensitized individuals develop an area of

erythema on the injection sites as a result of T-lymphocytes
and macrophages into the area

Tuberculin skin test use of M. tuberculosis antigen prepared by a

purified filtrate from the cell wall of the organism.
-

The Purified Protein Derivative is injected under the skin

and the reaction is read 48 -72 hours later
o
Positive result indicates that the individual has
been exposed to the bacteria.

Contact Dermatitis:
Testing for Delayed Hypersensitivity:

[MID] Chapter 13: Hypersensitivity

Patch Test gold standard in testing for contact dermatitis
-

Positive result = redness with papules or tiny blisters

Mantoux Method Used for testing Candida albicans, tetanus

toxoid, tuberculin, and fungal antigens.
-

Performed in the same manner as testing for the presence of

IgE
o
Antigen is injected intradermally, and the test site
is read at 48 and 72 hours for the presence of
induration

Immunology & Serology

o

Positive result = >5mm of induration