MCB 307 (IMMUNOLOGY) BY DR. M.B.

ODEBISI-OMOKANYE (2022/2023)

HYPERSENSITIVITY REACTIONS

Hypersensitivity is an exaggerated or excessive, undesirable (damaging, discomfort-

producing and sometimes fatal) immune response that results in tissue damage and is

manifested in the individual on a second or subsequent contact with an antigen. It is an

exaggerated or inappropriate immune responses in a sensitized individual on re-exposure to the

same antigen. Both the humoral and cell-mediated arms of the immune response may

participate in hypersensitivity reactions.

Hypersensitivity essentially has two components. First priming dose (first dose) of antigen is

essential, which is required to prime the immune system, followed by a shocking dose (second

dose) of the same antigen that results in the injurious consequences.

Depending on the time taken for the reactions and the mechanisms that cause the tissue damage,

hypersensitivity has been broadly classified into immediate type and delayed type.

In the immediate type, the response is seen within minutes or hours after exposure to the antigen

and in the delayed type, the process takes days together to manifest as symptoms.

Hypersensitivity reactions are classified into four categories by Gell and Coombs (1963) based

on the time elapsed from exposure of antigen to the reaction and the arm of immune system

involved.

Types I, II, and III are antibody-mediated and are known as immediate hypersensitivity

reactions, while type IV is cell-mediated (i.e., mediated by cell-mediated immunity) and is

known as delayed hypersensitivity reactions.

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Type I Hypersensitivity

It is also known as immediate, allergic or anaphylactic hypersensitivity and is mediated by IgE.

The reaction occurs on exposure to allergen second time. The first exposure (sensitizing dose)

results in sensitization of host to allergen and subsequent exposure (s) (shocking dose) will

cause reaction. The reaction may involve skin (urticaria and eczema), eyes (conjunctivitis),

nasopharynx (rhinorrhea, rhinitis), bronchopulmonary tissues (asthma) and gastrointestinal

tract (gastroenteritis). The reaction is always rapid, occurring within minutes of exposure to an

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allergen, it may cause a range of symptoms from minor inconvenience to death. The reaction

usually takes 15 - 30 minutes from the time of exposure to the antigen, although sometimes it

may have a delayed onset (10 - 12 hours) and always involves IgE-mediated degranulation of

basophils or mast cells.

Mechanism of Type-I hypersensitivity

Allergic reactions occur when an individual who has produced IgE antibody in response to the

initial exposure to an antigen (allergen) subsequently encounters the same allergen. Upon

initial exposure to a soluble allergen, B cells are stimulated to differentiate into plasma cells

and produce specific IgE antibodies with the help of TH cells. This IgE is sometimes called a

reagin, and the individual has a hereditary predisposition for its production. Once synthesized,

IgE binds to the Fc receptors of mast cells (basophils and eosinophils can also be bound) and

sensitizes these cells, making the individual sensitized to the allergen. When a subsequent

exposure to the allergen occurs, the allergen attaches to the surface-bound IgE on the sensitized

mast cells, causing mast cell degranulation. Degranulation releases physiological mediators

such as histamine, leukotrienes, heparin, prostaglandins, PAF (platelet activating actor), ECF-

A (eosinophil chemotactic factor of anaphylaxis), and proteolytic enzymes. These mediators

trigger smooth muscle contractions, vasodilation, increased vascular permeability, and mucus

secretion.

Type I Reaction occur in 2 phases:

Phase I:

- Sensitization phase: allergen or Antigen enter the tissue, typically low-dose via mucous

membranes (respiratory, GI). Allergen enter tissues, induce an immune response. B – cells

transform to plasma cells & produce IgE. IgE bind to receptors on Mast cells and basophiles

(receptors). individuals become: “Sensitized.

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Phase II :

Elicitation (Re-exposure) i.e Challenge phase: Subsequent encounter with same allergen cross

– link IgE on Mast cells. This generate an intracellular signal that prompts the Mast cells to:

Degranulate”. Degranulation of cells result in the synthesis and secretion of chemical mediators

such as platelet-activating factor (PAF), leukotreins, bradykinins, prostaglandins, and

cytokines. These chemical mediators released from the mast cell granules are the direct causes of hives

(urticaria), hay fever (allergic rhinitis), asthma, anaphylactic shock, and other allergic manifestations.

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Manifestation of Type 1 hypersensitivity reaction can either be systemic (generalized) or

atopic (localized).

Anaphylaxis is the name given to allergic reactions caused by IgE-mediated release of chemical

mediators from mast cell granules.

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Systemic anaphylaxis is a generalized response that occurs when an individual sensitized to

an allergen receives a subsequent exposure to it. Antigen enters the bloodstream and becomes

wide-spread. Instead of being localized in areas of the skin or respiratory tract, the reaction

affects almost the entire body, causing a drop in blood pressure that can result in anaphylactic

shock. The reaction is immediate due to a sudden burst in the release of mast cell mediators.

Usually there is respiratory impairment caused by smooth muscle constriction in the

bronchioles. The arterioles dilate which greatly reduces arterial blood pressure and increases

capillary permeability with rapid loss of fluid into the tissue spaces. These physiological

changes can be rapid and severe enough to be fatal within a few minutes from reduced venous

return, asphyxiation, reduced blood pressure, and circulatory shock (anaphylactic shock).

Common examples of allergens that can produce systemic anaphylaxis include penicillin drugs,

passively administered antisera, peanuts, and insect venom from the stings or bites of wasps,

hornets, or bees.

Localized anaphylaxis is localized in an area. The symptoms that develop depend primarily

on the route by which the allergen enters the body.

Hay fever (allergic rhinitis), marked by itching, teary eyes, sneezing, and runny nose, occurs

when allergic persons inhale an antigen such as ragweed pollen to which they are sensitive.

The mechanism is similar to that of hives and is also blocked by antihistamines.

Bronchial Asthma is an example of atopy involving the lower respiratory tract. Common

allergens can be the same as for hay fever. An allergen reacting with IgE-sensitized mast cells

causes their degranulation and release of chemical mediators. The mediators cause spasms of

the bronchi, which interfere with breathing. Mediators other than histamine, mainly lipids such

as leukotrienes and prostaglandins, and protein cytokines, are responsible for bronchospasm

and increased mucus production. Eosinophils recruited to the area also release leukotrienes and

contribute to an inflammatory response. Antihistamines are therefore not effective in treating

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asthma, but several other drugs are available to block the reaction, such as bronchodilating

drugs that relax constricted muscles and relieve the bronchospasm. An example is albuterol, a

bronchodilator usually delivered by an inhaler. Cortisone-like steroids are often used to

decrease the inflammatory reaction.

Hay fever (allergic rhinitis) is a good example of atopy involving the upper respiratory tract.

It is marked by itching, teary eyes, congested nasal passage, coughing, sneezing and runny

nose. Initial exposure involves airborne allergens—such as plant pollen, fungal spores, animal

hair and dander, and house dust mites—that sensitize mast cells located within the mucous

membranes of the respiratory tract. Re-exposure to the allergen causes localized anaphylactic

response. Antihistamine drugs are used to help alleviate these symptoms.

Hives (urticaria) (eruptions of the skin) is an allergic skin condition characterized by the

formation of a wheal and flare; the wheal is an itchy swelling generally resembling a mosquito

bite, surrounded by redness, the flare. The wheal and flare reaction is seen also in

positive skin tests for allergens. Hives may occur, for example, when a person allergic to lobster

eats some of the seafood. Lobster antigen absorbed from the intestinal tract enters the

bloodstream and is carried to tissues such as skin, where it reacts with mast cells that have anti-

lobster IgE antibody attached to them. Reaction between antibody and antigen on the mast cell

surface releases histamine, which in turn causes dilation of tiny blood vessels and the leaking

of plasma into skin tissues. Once established, type I food allergies are usually permanent but

can be partially controlled with antihistamines because histamine is a major mediator in this

situation, the reaction is blocked by antihistamine medications or by avoidance of the allergen.

Skin testing can be used to identify the antigen responsible for allergies.

Diagnostic tests for immediate hypersensitivity include skin (prick and intradermal) tests

resulting in wheal and flare reaction, measurement of total IgE and specific IgE

antibodies against the suspected allergens by ELISA, Radioallergosorbent test (RAST)

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Type II Hypersensitivity

Type II hypersensitivity are antibody mediated cytotoxic reactions. Antibodies react with

molecules on the surface of a person’s cells (usually RBCs) and trigger destruction of the cells.

The reaction time is minutes to hours. It is generally called a cytolytic or cytotoxic

hypersensitivity because it results in the destruction of host cells, either by lysis or toxic

mediators and may affect a variety of organs and tissues. The antigens are normally endogenous,

although exogenous chemicals (haptens, such as ivy or drugs) that can attach to cell membranes

can also lead to type II hypersensitivity. It is mediated, primarily, by antibodies of IgM or IgG

class and complement. Cell destruction can occur through activation of the complement system

or by antibody-dependent cellular cytotoxicity (ADCC), in which the antibody-coated target

cells are destroyed by the mononuclear phagocyte system. Two common examples of type II

sensitivity reactions are transfusion reactions and haemolytic disease of the new-born

(erythroblastosis fetalis).

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Transfusion Reactions:

Erythrocytes (red blood cells) have various antigenic determinants on their surface that differ

from one person to another. On transfusion, of mismatched blood (transfusion of red blood

cells antigenically different from his or her own), red blood cells will be coated with iso-

haemagglutinins (anti-A, anti-B or both) the immune system attacks those cells and cause

severe reactions. Occasionally, the complement system is activated via the classic pathway and

life-threatening rapid destruction of transfused red blood cells occurs by membrane attack

complexes. Matching the blood of donor and recipient to ensure compatibility minimizes the

possibility of a transfusion reaction. Transfusion reactions generally involve antigens of the

ABO blood group system.

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People are designated as having blood type A, B, or O, depending on which, if any, specific

polysaccharides are present on their red blood cells. People who lack A or B antigens have

antibodies against those antigens they do not have. Thus, people with blood type O have both

anti-A and anti-B antibodies; those who have blood type A have anti-B antibodies, and those

with blood type B have anti-A antibodies. These antibodies are called natural antibodies

because they are present without any obvious cause. Anti-A and anti-B antibodies are not

present at birth but generally appear before the age of six months. These natural antibodies are

mostly of the class IgM, and therefore cannot cross the placenta. These probably arise because

of multiple exposures to substances similar to blood group antigens that occur in environmental

materials such as bacteria, dust, and food.

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Haemolytic Disease of the New-born: Antigens of the rhesus (Rh) system represent another

important kind of erythrocyte antigen, first described in rhesus monkeys. If a Rh antigen is

present on a person’s erythrocytes, he or she is termed “Rh-positive”; if no Rh antigens are

present, that person is “Rh-negative.” Just as donor and recipient bloods are matched for the

ABO system, they are also matched for Rh system antigens, so that serious transfusion

reactions are uncommon. A problem can develop when an Rh-negative woman is pregnant

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with an Rh-positive fetus. If the woman has anti-Rh IgG antibodies, they can cross the

placenta and damage the developing fetus, causing hemolytic disease of the newborn

(erythroblastosis fetalis). A Rh-negative woman is likely to become sensitized to the Rh

antigen during delivery of her first Rh-positive baby when enough of the baby’s erythrocytes

enter her circulation to cause an immune response. Sensitization can also occur during

pregnancy in some cases, and after induced or spontaneous abortion. The anti-Rh antibodies

formed by the mother do her no harm because her red blood cells lack the Rh antigen. However,

the antibody response can damage her fetus during subsequent pregnancies. With each new

pregnancy with an Rh-positive fetus, the mother produces large quantities of anti-Rh IgG

antibodies that cross the placenta and enter the fetal circulation. Reaction with the Rhesus

antigen on the foetal RBC leads to their destruction through opsonic adherence resulting in

haemolytic disease of the new-born. To prevent haemolytic disease of the newborn, Rh-

negative women who are carrying a Rh-positive foetus are injected with anti-Rh antibodies

once during pregnancy and again shortly after delivery. The anti-Rh antibodies bind to any Rh-

positive erythrocytes that may have entered the mother’s circulation from the baby, thereby

preventing the development of a primary immune response. Injecting anti-Rh antibody is not

effective if the individual is already sensitized to Rh antigen.

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Drug-Induced Haemolysis

Certain drugs (such as penicillin, quinidine, phenacetin, etc.) may induce haemolysis of red

blood cells. They attach to the surface of red blood cells and induce formation of IgG

antibodies. These autoantibodies then react with red blood cell surface, causing haemolysis.

Similarly, quinacrines attach to surface of platelets and induce autoantibodies that lyse the

platelets, causing thrombocytopenia.

Goodpasture’s Syndrome

Autoantibodies of IgG class are produced against basement membrane of the lungs and kidneys

in Goodpasture’s syndrome. Such autoantibodies bind to tissues of the lungs and kidneys and

activate the complement that leads to an increased production of C5a, a component of the

complement. The C5a causes attraction of leukocytes, which produce enzyme proteases that

act on lung and kidney tissues, causing damage of those tissues.

Rheumatic Fever

In this condition, antibodies are produced against group A streptococci that cross-react with

cardiac tissues and activate complement and release of components of complement, which

in turn causes damage of cardiac tissues.

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Type III Hypersensitivity

Type III hypersensitivity involves the formation of immune complexes. An immune complex

consists of IgG or IgM antibody bound to antigen, often with some complement components

and usually adhere to Fc receptors on cells of the mononuclear phagocyte system. These

complexes are then engulfed and destroyed effectively by the fixed monocytes and

macrophages of the monocyte-macrophage system especially if they are large. Under ordinary

circumstances, this rapidly removes them from circulation. In conditions where there is

presence of moderate excess of some soluble antigens over antibody, the antigen-antibody

complexes may not be efficiently removed and destroyed but persist in circulation or at their

sites of formation in tissue. Immune complexes possess considerable biological activity. They

initiate the blood clotting mechanism, and they activate components of the complement system

that attract neutrophils into the area and contribute to inflammation. Proteases released from

the neutrophils then damage tissue. Circulating immune complexes are commonly deposited

in skin, joints, and the kidneys. Immune complexes are responsible for the rashes, joint pains,

and other symptoms seen in a number of diseases, such as farmer’s lung, bacterial endocarditis,

early rubella infection, and malaria. When they are deposited in the kidneys they cause

glomerulonephritis. Immune complexes can also precipitate a devastating condition,

disseminated intravascular coagulation, in which clots form in small blood vessels, leading

to failure of vital organs. Immune complex disease may arise during a variety of bacterial, viral,

and protozoan infections, as well as from inhaled dusts or bacteria and injected medications

such as penicillin.

There are two forms in which Type 3 hypersensitivity reaction exists which include: Arthus

reaction and Serum sickness.

Arthus reaction: in this type, immune complexes are formed locally in the tissue in relative

antibody excess at the site of introduction of antigen. This is responsible for the localized injury

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or death of tissue, known as the Arthus reaction. This occurs if antigen is injected into the

tissue of a previously immunized person with high levels of (excess) circulating specific

antibody. Examples include: a) Farmer’s lung in which there is severe respiratory difficulties

which occur within 6 to 8 hours of exposure to the dust from mouldy hay. The patients are

sensitized to thermophilic actinomycetes present in the hay. b) Pigeon Fancier’s disease where

the antigen is believed to be serum protein present in dust from fried faeces. Both examples are

examples of allergic alveolitis.

Serum sickness: in this case, antigen-antibody complexes are formed in the circulation in

antigen excess and then deposited in the tissues. This results from the deposition of soluble

antigen-antibody complexes formed in antigen excesses and deposition is a dynamic affair and

long lasting disease is seen only when the antigen is persistent as in chronic infections and

autoimmune disease e.g Hashimoto’s thyroiditis.

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They are wholly or partly responsible for contact dermatitis (such as from poison ivy and

poison oak), tissue damage in a variety of infectious diseases, rejection of tissue grafts, and

some autoimmune diseases directed against antigens of self.

Type IV Hypersensitivity

Type IV hypersensitivity Harmful effects produced by the mechanisms of cell-mediated

immunity are referred to as delayed hypersensitivity. The name reflects the slowly developing

response to antigen; reactions peak at 2 to 3 days rather than in minutes as in immediate

hypersensitivity. Delayed hypersensitivity reactions can occur almost anywhere in the body.

Delayed Hypersensitivity reactions are of two types: contact hypersensitivity (contact

dermatitis) and tuberculin-type hypersensitivity reactions.

CONTACT HYPERSENSITIVITY

Contact hypersensitivity is a manifestation of DTH occurring after sensitization with certain

substances. These include drugs, such as sulfonamides and neomycin; plant

products, such as poison ivy and poison oak; chemicals, such as formaldehyde and nickel; and

cosmetics, soaps and other substances. This reaction manifests when these substances acting

as haptens enter the skin and combine with body proteins to become complete antigens to which

a person becomes sensitized. On second exposure to the same antigen, the immune system

responds by attack of cytotoxic T cells that cause damage, mostly in the skin. The condition

manifests as itching, erythema, vesicle, eczema, or necrosis of skin within 12–48 hours of the

second exposure.

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Tuberculin-type hypersensitivity reaction

Tuberculin reaction is a typical example of delayed hypersensitivity to antigens of

microorganisms, which is being used for diagnosis of the disease.

Tuberculin skin test:

A partially purified protein called tuberculin, which is obtained from the bacterium that causes

tuberculosis, is injected into the skin of the forearm (intradermal injection). The response in a

tuberculin-positive individual begins in about 8 hours, and a reddened area surrounding the

injection site becomes indurated (firm and hard) within 12 to 24 hours. The TH1 cells that

migrate to the injection site are responsible for the induration. The reaction reaches its peak in

48 hours and then subsides. The size of the induration is directly related to the amount of

antigen that was introduced and to the degree of hypersensitivity of the tested individual. Other

microbial products used in type IV skin testing to detect disease are the proteins histoplasmin

to detect histoplasmosis, coccidioidin to detect coccidioidomycosis, lepromin to detect leprosy,

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and brucellergen to detect brucellosis. Several important chronic diseases involve cell and

tissue destruction by type IV hypersensitivity reactions. These diseases are caused by viruses,

mycobacteria, protozoa, and fungi that produce chronic infections in which the macrophages

and T cells are continually stimulated. Examples are leprosy, tuberculosis, leishmaniasis,

candidiasis, and herpes simplex lesions.

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