HYPERSENSITIVITY

REACTIONS
 Introduction
• An immune response inappropriate to an antigen
• Paul Portiers & Charles Richet –Problems of bathers –
stings of Portuguese Man of War –isolated jellyfish toxin
as vaccine-Instead of producing antibody-over reacted to
antigen -ANAPHYLAXIS
• These reactions are known as hypersensitivity or allergic
reaction
• Antigens that cause hypersensitivity are termed as
allergens
 Hypersensitivity Reactions
• Develop in the course of Humoral and Cell mediated
immunity
• Anaphylactic reaction –Initiated by Ab or Ag-Ab complex
–Referred to as immediate type hypersensitivity reaction –
Symptoms manifest within mins/hrs recepient encounters
the Ag
• Delayed type Hypersensitivity(DTH)-Delay of symptoms
Gell & Coomb’s Classifications
• A widely used system for categorizing these types of immune responses.

• The classification was first described by Robert Gell and Robin Coombs in the
1960s and is based on the underlying mechanisms of the immune reaction.

• The classification divides hypersensitivity reactions into four types

– Type I (Immediate) Hypersensitivity (Anaphylaxis):
– Type II (cytotoxic) hypersensitivity
– Type III (immune complex mediated) hypersensitivity-Humoral Branch
– Type IV (delayed) hypersensitivity-(Cell-Mediated): Depends on activation of T cells

• This classification system is still widely used today in the diagnosis and
understanding of hypersensitivity reactions.
 Type I:Anaphylactic reactions

• Mediated by IgE antibodies

• IgE binds to the through the Fc portion to receptors on mast
cells and basophils
• A later exposure to the same allergen crosslinks IgE on
sensitised mast cells by antigens,The IgE antibodies trigger the
mast cells and basophils to release pharmacologically active
agents causing symptoms of anaphylaxis
• pharmacologically active mediators released from granules act
on surrounding tissue causing vasodilation and smooth muscle
contraction
• Reactions are rapid,occurs within mins after reexposure to the
antigen
• Reactions range from mild manifestations associated with food allergies to
life-threatening anaphylactic shock.
– Atopic dermatitis, often referred to as eczema, is a chronic (long-
lasting) disease that causes inflammation, redness, and irritation
of the skin. It is a common condition that usually begins in
childhood; however, anyone can get the disease at any age
– Atopic allergies include hay fever, asthma, food allergies and
eczema.
– Exposure to allergens can be through inhalation, absorption from
the digestive tract or direct skin contact.
– Extent of allergic response related to port of entry, i.e., bee sting
introduces allergen directly into the circulation.
– Caused by inappropriate IgE production
• This antibody has an affinity for mast cells or basophils.
Type I Hypersensitivity Reaction
 Type I (Immediate) Hypersensitivity

Treatment
✓ Avoidance of known allergens
✓ Localized reactions use OTC antihistamines and
decongestants.
✓ Asthma uses combination – antihistamines, bronchodilators
and corticosteroids.
✓ Systemic use epinephrine
✓ Hyposensitization – inject antigen to cause production of
IgG which binds to antigen (allergen) before it reaches IgE
coated cells.
✓ Monocolonal anti-IgE – inject, binds to receptors on mast
cells blocking them from the IgE.
 Testing
In-Vivo Tests - Skin tests
• Small amount of allergen injected into skin
• Look for wheal formation of 3mm or greater in diameter
• Simple, inexpensive, can screen for multiple allergens.
• Stop anti-histamines 24-72 hours before test.
• Danger of systemic reaction
• Not for children under 3
 Type I (Immediate) Hypersensitivity
The reactions shown here demonstrate allergic response.
 Prausnitz-Kustner(P-K) test
• A test for detecting antibodies responsible for anaphylactic reaction
• In this test, serum from allergic individual is injected into the skin of a normal
person
• After 1-2 days (lag period) the site of injection is sensitized and would respond
with hive reaction when injected with that antigen to which donor was allergic
• Such a passively sensitized animals is called passive cutaneous anaphylaxis
 In-Vitro Tests

• Measure total IgE or antigen-specific IgE

• Less sensitive than skin tests.
• RIST, RAST, Allergen specific and Microarray will
be covered later.
 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)
 Type II: Cytolytic or cytotoxic reaction
• Occurs when IgM or IgG antibodies bind to antigen on the surface of
the cells and activate complement cascade
• It ends with the destruction of the cells
 Triggered by antigens found on cell surfaces
 Altered self antigens
 Heteroantigens
 Manifested by the production of IgG or IgM antibodies which coat the
antigens.
 Mechanisms
 Antibody coats cell surface promotes phagocytosis – macrophages,
neutrophils and eosinophils have Fc receptors to bind to antibody on
target cell.
 Natural Kill cells have Fc receptors, bind, results in cytotoxicity
 Complement
 Coats cells which enhances phagocytosis
 Complement cascade goes to completion results in cell lysis.
 Three Examples of Type II Hypersensitivity
Reactions
• Transfusion Reactions
– Occurs with ABO blood antigen groups
– Complement mediated lysis
• Drug Induced Hemolytic Anemia
– Occurs when an antibiotic forms a complex with red blood cell
membrane protein (similar to hapten carrier complex)
– Induces formation of antibodies
– Complement
• Hemolytic Disease of the Newborn
Type II: Cytolytic or cytotoxic reaction

 Transfusion reactions
 Hundreds of different antigens expressed on RBCs
 Antibodies can be produced naturally or through exposure,
transfusion or pregnancy most common
 Most well known example due to ABO incompatibility.
 Individuals form potent antibodies against ABO antigens not present
on their red blood cells.
 Group O individuals have anti-A and if transfused with group A
blood will have an immediate, and possibly fatal, reaction
 Other blood groups may cause delayed reaction or acute
reactions.
Type II (Cytotoxic) Hypersensitivity
 Transfusion reactions
• Antibodies to A,B and O antigens are called Isohemagglutinins(IgM)
• An individual with blood type A recognises the B like epitopes on
intestinal microorganism and produces Isohemagglutinins to the B like
epitopes
• If type A individual is transfused with blood containing type B cells a
TRANSFUSION reaction will occur
• The anti B isohemagglutinins bind to the B blood cells and mediate
their destruction by complement mediated hemolysis
 ABO Blood Group Reactivity

Genotype Phenotype Ag on erythrocytes ABO in

serum
AA, AO A A anti-B
BB,BO B B anti-A
AB AB A and B none
OO o none Anti –A&
AntiB
Transfusion reaction
Produced by mismatched blood types
➢Glycoprotein on the membrane of RBC
are encoded by different genes each of which has number of
alternate alleles
➢An individual possesing ane allelic form of blood group
antigen can recognise other allelic form as foreign and mount
a response
Destroys foreign RBC by complement-
mediated lysis triggered by IgG
Produces fever, intravascular clots,
lower back pain, Hgb in urine

Free Hgb produced has 2 fates:

passes to the kidneys –
hemoglobinuria
Breaks down to bilirubin..can be
toxic
 Hemolytic disease of the fetus and newborn

➢ Mother exposed to blood group antigens due to previous pregnancy with

antigen positive child or transfusion.
➢ Antibody must be IgG
➢ Crosses placenta and coats fetal RBCs, destruction of RBCs causes
increased bilirubin and anemia.
➢ If first pregnancy is first exposure infant usually not affected.
➢ Subsequent pregnancies have increased risk and the disease ranges from
mild to fatal.
➢ All pregnant women are screened for blood group antibodies.
 Hemolytic disease of the fetus and
newborn
• Occurs via maternal IgG Ab’s crossing the placenta
• In severe cases causes erythroblastosis fetalis
– Most commonly develops in Rh- mother with Rh+ fetus
– Exposure to Rh+ fetal RBC’s stimualtes prod of memory/plasma
– Activation of memory cells in subsequent pregnancy stim IgG Ab’s which
can cross the placenta
– mild-severe hemolytic anemia ensues along with bilirubin which affects
the brain/CNS
• Treatment centers on anti-Rh antibodies (Rhogam)
• Mothers can be tested for anti-Rh antibodies to check for a rise in titre
• Isolated fetal RBC’s can be checked for anti-Rh IgG w/ Coombs test
 Drug induced hemolytic anaemia

• Certain antibiotics (eg Penicillin,cephalosporin ,streptomycin)

• Can adsorb nonspecifically to proteins on RBC forming a complex
similar to hapten carrier complex
• In some patients such drug protein complexes induces the formation of
antibodies which then bind to the adsorbed drug on RBC inducing
complement mediated hemolysis and progressive anemia
• When the drug is withdrawn the hemolytic anemia disappears
Type III Hypersensitivity Reactions
• Similar to Type II, IgG or IgM involved and destruction is complement
mediated.
• Difference is that antigen is SOLUBLE.
• Soluble antigen and antibody combine to form complexes.
• Usually complexes cause no symptoms, quickly disappear from the
circulation.
• Size of complexes produced seems important in determining whether
they will be eliminated quickly from the body or retained long enough
to cause damage.
• In some individuals the immune complexes persist in circulation
causing clinical symptoms, some of them serious.
 Mechanism
➢ Soluble immune complexes which contain a greater proportion of antigen than
antibody penetrate blood vessels and lodge on the basement membrane
➢ At the basement membrane site, these complexes activate the complement cascade.
➢ During complement activation, certain products of the cascade are produced,`attract
neutrophils to the area. Such substances are known as chemotactic substances.
➢ Once the polymorphs reach the basement membrane they release their granules,
which contain lysosomal enzymes which are damaging to the blood vessel.
➢ This total process leads to the condition recognized histologically as vasculitis.
Type III (immune complex mediated)
Hypersensitivity
 Type III (immune complex mediated)
Hypersensitivity
• Tissues most frequently affected are:
– Glomerular basement
– Vascular endothelium
– Joint linings
– Pulmonary alveolar membranes
• Classical clinical symptoms of immune complex disease are due to
blood vessel involvement, i.e., vasculitis.
• Blood vessels of joints and the kidney are most frequently affected,
giving rise to symptoms of arthritis and glomerulonephritis.
 Type III Reactions can be localised

• Injection of an antigen intradermally or subcutaneously

into an animal that has high levels of circulating antibody
specific for that antigen leads to the formation of localised
immune complexes
• It mediates acute Arthus reaction within 4 to 8 hrs
Arthus reaction
• The Arthus reaction was discovered by Arthus in 1903.
• Arthus repeatedly injected horse serum subcutaneously into rabbits. After four
injections, he found that there was edema(Accumulation of fluid) and that the serum was
absorbed slowly. Further injections eventually led to gangrene.
• The Arthus reaction involves the formation of antigen/antibody complexes after the
intradermal injection of an antigen.
• If the animal/patient was previously sensitised (has circulating antibody), an Arthus
reaction occurs.
• This manifests as local vasculitis due to deposition of immune complexes in dermal
blood vessels. Activation of complement and recruitment of neutrophils which results in
an inflammatory response.
• Arthus reactions have been infrequently reported after vaccination against diphtheria
and tetanus.
• An Arthus reaction is a local vasculitis associated with deposition of immune complexes
and activation of complement.
• Arthus reactions are characterised by severe pain, swelling, edema, hemorrhage, and
occasionally by necrosis. These symptoms and signs usually occur 4–12 hours after
vaccination.
•
Arthus Reaction
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
 Generalized Type III Hypersensitivity
Reactions: Serum Sickness
▪ Occurs when antigen enters bloodstream, circulating immune complexes form
▪ Often observed after the administration of antitoxin containing foreign serum
(eg)Horse antitetanus serum
▪ Recipient of the foreign antiserum develops antibodies specific for the foreign
serum protein
▪ These antibodies then form circulating immune complexeswith the foreign
serum antigens
▪ Within days or weeks after exposure to the foreign serum antigens an
individual manifests a combination of symptoms called SERUM SICKNESS
▪ Symptoms include:
– Fever
– Weakness
– Rashes
– And many others
 Conditions other than serum sickness

• Chronic immune complex diseases are naturally occurring

diseases caused by deposits of immune complex and
complement in the tissues.
– Systemic Lupus Erythematosus (SLE)
– Acute glomerulonephritis
– Rheumatic fever
– Rheumatoid arthritis
 Type IV/Delayed type Hypersensitivity
reaction
• Used to describe the signs and symptoms associated with a cell mediated
immune response.
• Results from reactions involving T lymphocytes.
• Characteristics of this phenomenon are:
– Delayed, taking 12 hours to develop.
– Causes accumulation of lymphs and macrophages.
– Reaction is not mediated by histamine.
– Antibodies are not involved in the reaction
Type IV (delayed) Hypersensitivity
Positive TB Test
Inducers of Type IV Hypersensitivity
 Type IV (delayed) Hypersensitivity

• Contact dermatitis due to contact with chemicals

– Poison ivy, oak and sumac
– Nickel, rubber, formaldehyde, hair dyes, comsetics
– Latex allergies
– Function as haptens
– Causes erythema, swelling and formation of papules
• Hypersensitivity Pneumonitis
– Response of sensitized T cells to inhaled allergens.
– Caused by chronic inhalation of microorganisms.
– Occupationally related – pigeons, farmers
Poison Ivy contact dermatitis