Hypersensitivity Reactions
Hypersensitivity Reactions
 When the immune system "goes wrong" .
 Immune response should be protective.
 In this process damage to host occurs.
 Hypersensitivity denotes a state of increased reactivity of the host
to an antigen and implies that the reaction is damaging to the host.
 The individual must first have become sensitized by previous exposure to
the antigen.
 On second and subsequent exposures, symptoms and signs of a
hypersensitivity state occur.
Hypersensitivity Reactions
 Immediate hypersensitivity refers to antibody
mediated reactions – symptoms develop within minutes
to hours
 Delayed hypersensitivity refers to cell mediated
immunity, symptoms not observed for 24 to 48 hours.
Four Classifications
 Type I (Immediate) Hypersensitivity
 Type II (cytotoxic) hypersensitivity
 Type III (immune complex mediated) hypersensitivity
 Type IV (delayed) hypersensitivity
Type I (Immediate) Hypersensitivity
 Distinguishing feature short lag time.
 Key reactant is IgE
 Antigens which trigger response called atopic antigens or allergens.
 Atopy – inherited tendency to immunologically respond to
inhaled or ingested allergens with increased IgE production.
Type I (Immediate) Hypersensitivity
 IgE primarily synthesized in lymphoid tissue of respiratory
and GI tract.
 Regulated by T helper cells.
 Specific interleukins are involved in development of
eosinophils and promote development of mast cells.
 All act to stimulate overproduction of mucus.
 Basophils and mast cells have highest number of receptors for
Fc portion of IgE on surface.
Type I (Immediate) Hypersensitivity
 Reactions range from mild manifestations associated with food
allergies to life-threatening anaphylactic shock.
 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 (Immediate) Hypersensitivity
Type I (Immediate) Hypersensitivity
 When IgE meets its specific allergen it causes the mast
cell to discharge its contents of vasoactive substances
into the circulation.
 This release leads to symptoms of:
 sneezing,
 runny noses,
 red watery eyes and
 wheezing.
 Symptoms subside when allergen is gone.
 The most common immunological abnormality
seen in medical practice, estimated that 30% of
US population has allergies.
Type I (Immediate) Hypersensitivity
 Anaphylactic shock is the most serious and fortunately the rarest
form of this Type I hypersensitivity.
 Symptoms are directly related to the massive release of vasoactive
substances leading to fall in blood pressure, shock, difficulty in
breathing and even death.
 It can be due to the following:
 Horse gamma globulin given to patients who are sensitized to
horse protein.
 Injection of a drug that is capable of acting as a hapten into a
patient who is sensitive, ie, penicillin.
 Following a wasp or bee sting in highly sensitive individuals.
 Foods – peanuts, shellfish, etc.
Type I (Immediate) Hypersensitivity
Anaphylaxis
Type I (Immediate) Hypersensitivity
Anaphylaxis
Type I (Immediate) Hypersensitivity
Anaphylaxis
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.
Type I (Immediate) Hypersensitivity
Epipen
Type I (Immediate) Hypersensitivity
 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
Doctors sometimes use skin tests to diagnose allergies.
Type I (Immediate) Hypersensitivity
The reactions shown here demonstrate allergic response.
Type I (Immediate) Hypersensitivity
 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 II (Cytotoxic) Hypersensitivity
 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.
Type II (Cytotoxic) Hypersensitivity
 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
 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.
Type II (Cytotoxic) Hypersensitivity
 Autoimmune hemolytic anemia
 Patients form antibodies to antigens on their on RBCs.
 Warm antibodies react at 37C
 Cold antibodies react best in-vitro at 4C and will dissociate at
37C
 This will be discussed in detail during Immunohematology.
 Drug induced hemolysis
 Some drugs may act as haptens, attach to the RBC membrane
causing antibodies to be formed.
 Antibody reacts with drug on RBC causing hemolysis.
Type II (Cytotoxic) Hypersensitivity
Peripheral Smear
Type II (Cytotoxic) Hypersensitivity
 Tests
 Coomb’s or anti-human globulin test.
 Direct Coomb’s
 Add anti-IgG to washed drop of RBCs
 If cells are coated with IgG then agglutination will occur.
 Indirect Coomb’s
 Incubate patient serum with RBCs of known antigenic make
up.
 Wash and add anti-IgG
 If patient has antibody against antigen on RBC agglutination
will occur.
Type II (Cytotoxic) Hypersensitivity
 Some individuals make antibody which cross reacts with self
antigens found in both the lung and kidney.
 Goodpasture syndrome most well known example
 Antibody produced against basement membrane protein.
 This protein present in lungs and kidneys.
 Antibody binding results in inflammation
 Symptoms are hemoptysis and hematuria.
 Others will be discussed later
 Hashimoto’s disease
 Myasthenia Gravis
 Diabetes mellitus
Type II (Cytotoxic) Hypersensitivity
Type III (immune complex mediated)
Hypersensitivity
 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.
Type III (immune complex mediated)
Hypersensitivity
 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 (immune complex mediated)
Hypersensitivity
Arthus Reaction
 Immunized rabbits to antigen
 Rabbits then injected intradermally with antigen
 Localized inflammatory reaction occurred followed by hemorrhagic necrotic lesion.
 Occurred due to immune complexes depositing in dermal blood vessels.
 Complement, neutrophils and platelets caused toxic affects.
 Rare in humans.
 Serum Sickness
 Due to passive immunization with animal serum, bovine or horse.
 Vaccines and bee stings may also trigger.
 Symptoms appear 7 – 21 days after exposure to animal serum.
 Headache, fever, nausea, vomiting, joint pain, rashes and lymphadenopathy.
 Symptoms due to antibody being formed at same time antigen is present = immune complexes form.
 Benign, self limiting, 7-30 days for recovery.

Type III (immune complex mediated)
Hypersensitivity
 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) Hypersensitivity
 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
 Most well known is the Koch Phenomenon
 Inject tuberculoprotein (PPD test) intradermally
 Reaction results in an area of induration of 5 mm or more in
diameter and surrounded by erythema
 Reaction which occurs within 48 hours is a positive.
Type IV (delayed) Hypersensitivity
Positive TB Test
Type IV (delayed) Hypersensitivity
 Contact dermatitis due to contact with chemicals
 Poison ivy, oak and sumac give off urushiol.
 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
Type IV (delayed) Hypersensitivity
Type IV (delayed) Hypersensitivity
Summary
References
 http://www.thebody.com/nih/immune_system.html
 http://pathmicro.med.sc.edu/ghaffar/hyper00.htm
 http://home.kku.ac.th/acamed/kanchana/bsi.html