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HYPERSENSITIVITY
Definitions
> Also known allergy (allergic reactions)
> term applied to an adaptive immune response which occurs in an exaggerated or
inappropriate form causing tissue damage.
> an unexpected, exaggerated reaction to an antigen.
> an altered state of reactivity to an allergen
> only happens when allergic antibodies are available which almost always occur during
the second exposure; exception to this rule happens when the allergen’s presence is both
sensitizing and shocking dose as what happens in serum sickness and intravascular hemolysis
(natural antibodies are involved)

ALLERGENS:
> antigen participating in allergic reactions

CLASSIFICATION: (GELL AND COOMBS)

1 Type I - immediate hypersensitivity reactions
2 Type II - cytotoxic reactions
3 Type III - immune complex-mediated reactions
4 Type IV - cell-mediated reactions or delayed type
5 Type V- stimulatory type of hypersensitivity

TYPE I HYPERSENSITIVY (IMMEDIATE) REACTIONS:

> Allergens induce the production of specific IgE antibodies in Humans during
sensitization
> initiated by antigens capable of crosslinking cell-bound antibody (IgE)
> involves the release of pharmacologically active mediators (preformed and newly
sensitized mediators) from mast cells or basophils, a mechanism that is triggered by the cross-
linking of cell-bound IgE molecules by antigens.
> Results in immune response capable of damaging the host tissues through
excessive/unnecessary reaction to second exposure to allergen (best exemplified by anaphylaxis
or anaphylactic shock)
> Manifestations are not seen during the sensitization stage but during subsequent
contact/exposure (2nd exposure or anamnesthic response)
> Mediators of hypersensitivity are released during degranulation which occurs shortly
after the allergen crosslinks two adjacent IgE
> Basophils and Mast cells are effector cells since they have possess Fcε RI
> Interleukin-4 plays a vital role in the induction of Type I hypersensitivity since it
programs B cells to switch from producing IgM/IgG to IgE (class switching)
> Certain forms of allery can be passed on through genes and as such are referred to as
atopic allergy (Atopy - refers to an inherited tendency to respond to naturally occurring inhaled
and ingested allergens with continual production of IgE)
> Type I hypersensitivity reactions are also called anaphylactic type of hypersensitivity
> It is similar to Type II and III hypersensitivity since the two are also antibody mediated
type of allergic reactions
> Severity of symptoms depend on level of IgE antibodies formed (concentration of
accumulated antibody); the higher the concentration of antibody

ALLERGENS INCLUDE SUCH DIVERSE SUBSTANCES AS:

(1 Plant pollens (e.g. ragweed) and mold spores (e.g. Alternaria, Aspergillus)
(2 House dust (e.g. excreta of house dust mites)
(3 Animal hair, dander and feathers
(4 Foods (e.g. milk, wheat, eggs, fish nuts, chocolate)
(5 Animal antiserum and hormones
(6 Insect venom (e.g. bee, wasp)
(7 Drugs and chemicals (e.g. antibiotics, antiseptics, anaesthetics, vitamins)

SKIN TESTING FOR IMMEDIATE HYPERSENSITIVITY

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method generally used to confirm specific sensitivity in patients with atopic disease or
anaphylaxis after the history has suggest the relevant allergens for testing

Methods of skin tests:

1 Cutaneous 2. Intracutaneous or intradermal
a Prick
b Scratch
c Patch

Practical application of skin tests:

DISEASES SKIN TEST

1. Brucellosis brucellergin skin test
2. Coccidioidomycosis coccidioidin skin test
3. Lymphogranuloma venerum infection Frei test
4. Histoplasmosis Histoplasmin
5. Trichinosis Trichinella skin test
Tuberculin skin test, Pirquet’s,
6. Tuberculosis
Vollmer’s, Mendel’s, Mantoux
7. Diphtheria Schick’s test
8. Scarlet fever Dick’s test
9. Glanders Hallein test
10. Toxoplasmosis Toxoplasmin skin test
11. Anthrax Ascoli test
12. Ascariasis Moan test

Important Mechanisms Related to Type I hypersensitivity

∗ Praunitz-Kustner Reaction - is the passive transfer of specific antibodies to a non-allergic
person by intradermal injection of serum from an allergic person (passive anaphylaxis)

∗ Schultz-Charlton Phenomenon - after intracutaneous injection of scarlet fever antitoxin (or

scarlet fever convalescent serum) into scarlet fever patients, a blanching of the rash (indicating that
the erythrogenic toxin produced by fever streptococci has been neutralized by the antitoxin injected)
occurs at the site of inoculation.

COMMON ALLERGENS may be classified as:

1. Inhalants - plant pollens, fungal spores, animal dander, and certain airborne particles in the home.
2. Ingestants - absorption of allergens from the alimentary tract can lead to IgE antibody production with
subsequent allergic symptoms to foods, food additives & drugs.
3. Contactants/Penetrants - direct skin contact with a pollen or food can cause localization, urticaria or
systemic allergic symptoms in a patient highly sensitive to the allergen.

CLINICAL FORMS OF ALLERGY

1. Hay fever (allergic rhinitis) 4. Angioedema
2. Asthma 5. Infantile eczema
3. Urticaria or hives 6. Food and drug allergy

MEDIATORS OF TYPE I HYPERSENSITIVITY

I Preformed Mediators
1. Histamine
a. Causes contraction of bronchioles and smooth blood vessels
b. Increases capillary permeability
c. Increases mucous gland secretion in the airway

2. Eosinophil Chemotactic Factor of Anaphylaxis (ECF-A)

- released during degranulation
- stimulates eosinophils to migrate to the site of Ag-Ab reaction
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3. Heparin - proteoglycan molecule, is found associated with histamine within mast

cell granules
- an anticoagulant

4. Neutrophil Chemotactic Factor - chemotactic for neutrophils

5. Tryptase - cleaves kininogen, inactivates fibrinogen, converts C3 to C3b

6. Chymase - converts Angiotension I to Angiotensin II

II. Newly Sensitized Mediators

- derived from membrane lipids
a. Prostaglandins
a.1 PGD2 - causes vasodilation and increase vascular permeability
a.2 PGE2, PGF2, PGI2 - vasodilation

b. Leukotrienes
b.1 LB4 - chemotactic for neutrophils and eosinophils
b.2 LC4, LTD4, LTE4 - increase vascular permeability, bronchoconstriction, mucus
secretion
- causes erythema and wheal formation

c. Platelet Activating Factor - platelet aggregation, chemotactic for neutrophils and

eosinophils

IMPORTANT TERMINOLOGIES:
1. Anaphylaxis - the severe systematic reaction which occurs upon injection of an allergen to a host
which has developed antibodies as a result of previous injection

2. Anaphylactoid reactions - are reactions which, although they resemble anaphylactic shock, are not
however antigen-antibody reactions. They may occur after the injection of colloids (or of
finely suspended materials) into the blood.

3. Passive anaphylaxis - sensitization is accomplished by transfer of serum from another animal.

4. Desensitization - a hypersensitive animal that is given several very small (subshocking) subcutaneous
injections of antigen at closely spaced intervals (one-half hour) may then be able to tolerate an
ordinarily shocking dose without severe reaction.

5. Local anaphylaxis - includes many of the disease conditions popularly known as allergies, affects
principally the skin, the respiratory tract and the gastrointestinal tract.

TYPE II HYPERSENSITIVITY
CYTOTOXIC REACTIONS

• reaction is manifested by the production of antibodies that are capable of destroying

cell surface molecules on tissue components.
• cytotoxic antibodies are IgG or IgM which bind to the cell-bound antigen which can
result in complement activation and cytolysis (antigens may be altered self antigens or
heteroantigens).
• Natural antibodies participate in this type of hypersensitivity reaction

PATHOGENIC MECHANISMS:
a Combination of IgG or IgM antibodies will epitopes on cell surface or tissue.
b Adsorption of antigens or haptens to tissues or to the cell membrane, with
subsequent attachment of antibodies to the adsorbed antigens.
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* Either two may result to :

a Lysis or inactivation of target cells via complement activation.
b Phagocytosis of target cells, with or without complement activation
c ADCC through the action of Natural killer cells

• antibody coats cellular surfaces and promotes phagocytosis by both opsonization and
activation of the complement cascade.

• Fc receptors could be found on the ff.:

(1 macrophages (3) eosinophils
(2 neutrophils (4) natural killer cells

Cellular destruction via Complement Cascade Activation

(1 Coating cells with C3b; thus facilitating phagocytosis through interaction with specific receptors on
phagocytic cells
(2 Complement-generated lysis if the cascade goes to completion.

Examples of Type II hypersensitivity reactions:

a Transfusion Reactions - ABO incompatibility involving IgM antibodies against A or B alloantigens
• causes acute massive intravascular hemolysis to an undetected decrease in red blood
cell survival.
• occurs within minutes or hours after transfusion
• as little as 10 to 15 ml of incompatible blood may cause this reaction

Factors to be considered:
1 Temperature at which antibody is most active
2 Plasma concentration of antibody
3 Immunoglobulin class
4 Extent of complement activation
5 Density of antigen on the red cell
6 Number of rbc transfused

General symptoms:
1 Fever 5. Hypotension
2 Back pain 6. Nausea
3 Chills 7. Vomiting
4 Malaise 8. Acute renal failure

b Rh incompatibility (Hemolytic Disease of the Newborn)

• IgG antibodies directed against the D antigen on fetal red cells
• causes extravascular hemolysis
• most common sensitization process occurs during delivery, when large amounts of
cord blood enter the mother’s circulation.
• sensitization against the antigen may occur during pregnancy if fetal blood leaks into
the maternal circulation
• extent of the fetal-maternal bleed influences whether antibodies will be produced
• 8% of women who are Rh negative produce anti-D after the first pregnancy and up
to 2.3% show Ab production after multiple pregnancies
• Prophylaxis: RhoGAM or anti-D immune globulin is administered prophylactically
at 28 weeks of gestation and within 72 hours following deliver.

c Autoimmune Hemolytic Anemia

• antibody to red cell epitopes
• includes:

1 Warm Antibody Hemolytic Anemia

• characterized by the formation of IgG antibody which reacts more strongly at 37 °C.
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• e.g. I.M., chronic active hepatitis

2 Cold-Antibody hemolytic anemia (IgM)

• typically found in older persons (50’s & 60’s)
• cold autoagglutinins are responsible
• mumps, Mycoplasma pneumoniae

3 Idiopathic Autoimmune hemolytic Anemia

• patient exhibits symptoms of anemia due to clearance of antibody coated rbc by liver &
spleen
• cause of antibody production is unknown

4 Idiopathic Thrombocytopenic Purpura (ITP}

• characterized by the presence of platelet specific IgG antibodies, which can lead to
various bleeding disorders (increase in platelet destruction).
• disease lasts 1 - 2 months.
• ITP can be drug-induced
a quinidine d) p-aminosalicylic acid
b quinine e) phenytoin
c sulfonamides f) sedormid
• splenectomy is the classic treatment

5 Paroxysmal Cold Hemoglobinuria (PCH)

• associated with Donath-Lansteiner antibody, a cold antibody to the IgG class directed
against red blood cell antigen P.
• Reaction is usually biphasic:
a) sensitization - usually below 15°C
b) hemolysis - when temp. is elevated to 37°C

d Goodpasture’s syndrome
• a rare progressive disease of the lungs and kidneys
• affects young men of all age groups
• deposition of Ig (usually IgG) a nd complement on alveolar and glomerular
basement membrane
• antibody to glomerular and bronchial basement membrane

e Myesthemia gravis - antibody to acetylcholine receptors

• disease resulting from faulty neuromuscular transmission
• antibodies are IgG3 isotype
• it is of the antibody-mediated cellular dysfunction

THERAPEUTIC MEASURES (type II hpy):

1 Suppression of immune response by means of corticosteroids with or without immunosuppressive
drugs (like cyclophosphamide and azathioprine), or by splenectomy
2 Removal of the offending antibodies
3 Withholding the offending drug
ITP of drug induced hemolytic diseases
4 Nephrectomy - Good Pasture’s syndrome

TYPE III HYPERSENSITIVITY

IMMUNE COMPLEX-MEDIATED REACTIONS

• initiated by antigen-antibody complexes that either are formed locally at the side of
tissue damage or are deposited there from the circulation.
• characterized by the presence of such complexes on vascular and glomerular
basement membrane.
• antibodies involved are primarily IgG & IgM that are capable of activating the
complement.
• platelets also interact with immune complexes through membrane-bound Fc
receptors which leads to platelet aggregation and microthrombus formation (release
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vasoactive amines and tissue cell growth factor which are responsible for cellular
proliferation)

• Deposition of excess antigen leads to:

a pathogenic expression
b edema
c neutrophil infiltration
d lesions in the blood vessels and kidney glomerulus

• Signs & symptoms:

a arthritis c) vasculitis
b nephritis d) skin lesions

Consequences of Ag-Ab complex formation:

a Platelet aggregation leading to the formation of microthrombi and release of vasoactive
amines.
b Activation of complement and release of anaphylatoxins (causing histamine release) and
chemotactic factors (for PMN).
c Clotting factor XII activation, leading to fibrin, plasmin, and kinin formation.

Clinical Features:
1 Arthus Reaction (Maurice Arthus, 1903)
• also called local immune-complex deposition phenomenon
• a necrotic, dermal reaction by Ag-Ab precipitation, complement fixation, and
neutrophil inflammation in tissues of an animal inoculated intracutaneously with antigen.
• immunization of rabbits with horse serum
• characterized by: foci of erythema, edema and necrosis occur at injection site;
accumulation of neutrophils plus vasculitis (destruction of blood vessel walls).

2 Serum Sickness (Systemic Immune Complex Deposition Phenomenon)

• a reaction caused by the presence of antigen at the time antibody is being formed.
• formation of antibody to foreign immunoglobulin injection
• tissue damage is also through vasculitis and vascular basement membrane
destruction
• characterized by fever, rash, splenomegaly, lymphadenopathy, arthritis, and
glomerulonephritis

3 rheumatoid Arthritis - caused by rheumatic factor which is an IgM or IgG antibody with specificity
towards IgG
• a chronic, inflammatory joint disease with systemic involvement
• general symptoms include weight loss, malaise, fever, fatigue and weakness.
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TYPE IV
HYPERSENSITIVITY REACTIONS

This type of reaction was originally demonstrated by showing that delayed hypersensitivity
could be transferred from sensitized animals to non-sensitized animals (including humans) with antigen-
reactive T cells but not with serum containing antibodies. Also known as Cell Mediated immunity.

Antibody-mediated reactions have more fluid and erythema (wheal and flare), while Cell-
mediated immune reactions are characterized by significant mononuclear cell infiltration with resultant
duration.

Two Kinds of Cell Mediated Immunity:

A Delayed type of Hypersensitivity
• effector cells are Tdth cells which recruit other cells (e.g., macrophages) that
actually do most of the tissue damage.
• usually peak 24-48 hours after exposure and manifest as inflammation at the site of
antigen exposure.

B Cell-Mediated Cytotoxicity
• effector cells are Tc cells which are themselves cytotoxic, both directly and through
the release of cytotoxic lymphokines
• also peak 24 - 48 hours after exposure and manifest as inflammation at the site of
antigen exposure.

Role of T-Cell-Mediated Immunity in disease

a Delayed hypersensitivity and Tc cell reactions can be protective as well as damaging.
They provide resistance to:
(1 Chronic intracellular bacterial infections (e.g. tuberculosis and Brucellosis)
(2 Fungal infections (e.g. blastomycosis and Histoplasmosis)
(3 Viral infections (e.g. herpes and mumps)
(4 Protozoan infections (e.g. herpes and mumps)
(5 Protozoan infections (e.g. leishmaniasis)

b Tc cells play a role in the rejection of grafted tissues and organs. Humoral immunity also
may be involved in allograft rejection.

c Sensitized T lymphocytes provide the basic mechanism of tissue injury in the ff. diseases:
(1 Contact dermatitis, which is a delayed hypersensitivity reaction that occurs in
response to exposure of the skin to certain allergens (e.g. urushiol allergen of poison
and poison sumac)
(2 Some autoimmune diseases, in which Tc cells play a major role in pathogenesis (e.g.
multiple sclerosis).

Effector Cells:

A Tdth (Delayed type of hypersensitivity cell)

> recognize foreign antigens, primarily those of intracellular pathogens
> confer resistance by secreting IFN-γ and other lymphokines, thereby
activating macrophages to cytotoxic activity and enhancing other T- and B-cell
responses.
> act through the recruitment of other cells
> CD4+ cells
> Class II MHC restriction

B Tc (Cytotoxic T cell)
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> often called Cytolytic T lymphocytes (CTLs)

> CD8+ cells
> Class I MHC restriction
> they confer resistance in two ways:
1 Secretion of IFN-γ , which induces other cells to produce antiviral proteins
2 Direct destruction of target cells (e.g. grafted tissue, tumors, and virus infected
cells) by release of perforin, with subsequent cytolysis.

N.B. IFN-γ is a major lymphokine that is important in expression of cell-mediated immunity

Helper T cells aid in the development of CD8+ cells by releasing lymphokines
(interleukins) that augment proliferative and maturational signals generated by antigen
contact.

Clinical Features:

A. CONTACT DERMATITIS - is a form of delayed hypersensitivity that accounts for approximately

40 percent of all occupationally acquired illnesses.
> due to low molecular weight compounds that are applied to the skin.
> common causes include: poison ivy, poison oak, poison sumac
> Langerhans cell, a skin macrophage, acts as antigen presenting cell
> sensitization takes several days, but once it occurs, its effects last for years.
> skin eruption is characterized by erythema, swelling, and the formation of papules which
appears anywhere from 6 hours to several days after exposure

B. HYPERSENSITIVITY PNEUMONITIS - refers to the parenchymal reaction that develops in the

lung on repeated inhalation of particulate allergens
> observed deposition of antigen-antibody complexes in target (lung) tissue during the
early phase of the disease.
> type IV (delayed hypersensitivity) reaction is involved in the pathogenesis
> symptoms include: fever, chills, chest pain, cough and dyspnea occur 4 to 8 hours after
exposure.

C. GRANULOMATOUS HYPERSENSITIVITY - results from the persistent presence in

macrophages of microorganisms or other agents that the macrophages are unable to destroy
> long term stimulus for the inflammatory response is due to the continued presence of the
antigen
> granulomas are composed of macrophages and epithelioid cells, surrounded by
lymphocytes
> neutrophils, eosinophils, and plasma cells may also be present
> lymphokines probably play a role in causing localization and activation of macrophages
at the reaction site
> diseases include tuberculosis, leprosy, leishmaniasis, leisteriosis, and deep fungal
infections (Blastomycosis)

D. TUBERCULIN TYPE HYPERSENSITIVITY - is a classic clinical example of delayed

hypersensitivity

a A small amount of antigen, usually purified protein derivative (PPD) of tuberculin, is injected
intradermally into a sensitized person
b The reaction appears slowly, about 12 - 24 hours after the injection, and reaches maximal
reactivity 24 - 48 hours later.
(1 Initially, there is erythema and a neutrophil infiltrate.
(2 Later, a mononuclear cell (lymphocyte and macrophage) infiltrate causes induration in
the region of the injection.

Major Clinical Features of Delayed Hypersensitivity Reactions:

TYPE OF REACTION
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Feature Cutaneous Basophil Contact Tuberculin Granulomatous

Hypersensitivity Dermatitis Reaction Reaction
Antigens Soluble proteins Poison ivy, Mycobacterial Immune
simple proteins complexes or
chemicals intracellular
(e.g. nickel) parasites
Time of onset 1 (one) 2 (two) 1-2 21 – 28
(days)
Skin lesion Edema Eczema Induration Induration
Systemic No No Yes Yes
manifestations
Histologic Basophils, Lymphocytes, Lymphocytes, Lymphocytes,
Features macrophages, macrophages macrophages macrophages,
lymphocytes epithelial cells,
giant cells,
fibrosis*, necrosis

Lymphokines associated with Delayed Hypersensitivity Reactions:

a Migration-inhibiting factor - inhibits migration of macrophages

b Macrophage-activating factors such as IFN-γ , granulocyte macrophage colony-

stimulating factor, and tumor necrosis factor α (TNF-α ) enhance the microbicidal and
cytolytic activity of macrophages.

c Leukocyte-inhibiting factor inhibits random migration of neutrophils

d macrophage-chemotactic factor (interleukin-8) stimulates infiltration of macrophages.

e Interleukin-2 (IL-2) - a mitogenic factor, stimulates the growth of activated T cells. It

also activates cytotoxic lymphocytes and macrophages.

f TNF-β (lymphotoxin) - has the ability to lyse certain tumor cells.

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COMPARISON OF HYPERSENSITIVITY REACTIONS:

Point of
Type I Type II Type III Type IV
Differentiation
Immune-
Complex
Immediate type Delayed type or
Cytotoxic mediated
Other name Atopic allergy cell mediated
Reactions reactions
(genetic/ inherited) reactions
(deposition
phenomenon)
Immune
IgE IgG or IgM IgG or IgM T cells
Mediator
Histamine and IL-2, TNF-β
Other preformed C3b, Ig class, Fc (lymphotoxin),
Anaphylatoxins,
and newly receptors on IL-8
Other factors platelets, clotting
sensitized MAC, PMN, (macrophage
factor XII
mediators, IL-4, Eos, NK cells chemotactic
IFN-γ factor)
Complement
No Yes Yes No
Involvement
Autologous or Autologous or
Antigen Heterologous Autologous
Heterologous Heterologous
M. tuberculosis,
Plant pollen, house Rh antigen, ABO EBV, T.
Diphtheria
Examples of dust, animal hair, antigen, drugs pallidum,
antitoxin, horse
antigen drugs, chemicals, acting as Plasmodium,
serum proteins
food, hormones haptenes DHFV, S.
pyogenes
Cytolysis due to
antibody and
complement after
Release of Deposition of
combination of
Pathologic mediators from Antigen and Release of
IgG or IgM and
mechanism basophils or mast antibody lymphokine
epitope on cell
cells complex
surfaces or
adsorption of
haptenes
Neutrophil
Lysis or infiltration and
inactivation of subsequent
In asthma hyper- Direct
target cells via release of
reactive airways destruction by
complement, lysosomal and
Cause of destroy or damage Cytotoxic T cells
phagocytosis other hydrolytic
Tissue Damage the air passages and recruitment
with or without enzymes,
causing difficulty of of macrophages
complement, destruction
breathing by Td cells
ADCC through through
Nk cells complement
involvement
EBF/HDN, ABO Contact dermatis,
and RH hypersensitivity
Asthma, Urticaria, incompatibility, Rheumatoid pneumonitis,
Hay fever, food and AIHA, arthritis, Arthus granulomatous
Clinical Forms
drug allergy, Goodpasture’s reaction, serum hypersensitivity,
anaphylaxis syndrome, sickness tuberculin type
Myesthenia of
gravis hypersensitivity