The following points highlight the four important types of hypersensitivity. The types are: 1. Type I Hypersensitivity (Anaphylaxis) 2. Type II Hypersensitivity (Cytotoxic Hypersensitivity) 3. Type III Hypersensitivity 4. Type IV Hypersensitivity.
1. Type I Hypersensitivity (Anaphylaxis):
This type of hypersensitivity is the most common among all the types. About 17% of the human population may be affected, probably due to a natural proneness controlled by the genetic make-up. Anaphylaxis which literally means “opposite of protection” — is mediated by IgE antibodies through interaction with an allergen.
The allergens inciting anaphylaxis include a great variety of substances, like pollens, fibres, insect, venom, fungal spores, house-dust etc. as well as various food materials like egg, milk, fish, crab-meat, peanuts, soybean, various vegetables etc.
Generally, anaphylactic responses are of a mild type producing symptoms, like hay-fever, running nose, skin-eruptions known as “hives” or breathing difficulties. But in some cases, the responses may be severe and may even prove fatal. This latter type of response is called anaphylactic shock.
This may develop within a few minutes (2 to 30 min) and may cause death before any medical help can be provided. Anaphylactic shock is known to result from a bee-sting or intramuscular injection of penicillin. Penicillin itself is not an antigen, but it can act as a hapten.
After combination with serum proteins, it can stimulate allergenic response producing IgE molecules which can combine with the drug. A person sensitized with penicillin may be a victim to anaphylactic shock. The severe form of anaphylaxis is considered as systemic, in contrast to the milder forms which are localized.
During the sensitization phase, the immune system produces B-lymphocytes which are transformed into plasma cells in the usual way. But the plasma cells produce IgE antibodies complementary to the allergenic antigen, instead of normal IgG and IgM antibodies.
The IgE antibodies, so produced, circulate in the blood stream and they become attached to the mast cells and basophils, because IgE antibodies have special affinity for these cells. Mast cells and basophils have a richly granular cytoplasm and each cell has numerous (>100,000) binding sites for IgE molecules.
The IgE antibodies bind to these cells with their Fc domain, while the antigen-binding sites remain free. The sensitization period takes about a week’s time to be completed. During this period millions of IgE molecules are produced and fixed on the mast cells and basophils.
Manifestation of anaphylactic symptoms appears when such a sensitized person is exposed to the same allergen again. The allergen entering into body reacts with the its complementary IgE molecules bound to mast cells and basophils and combine with the antigen binding sites of the antibody.
This interaction causes degranulation of mast cells and basophils and the granules are released in the body fluids. Mast cells occur in close association with the capillaries throughout the body, particularly in the skin and respiratory tracts.
The granules released by mast cells and basophils contain several preformed chemical mediators of which the most important is histamine. The others include heparin, serotonin, bradykinin etc. In addition, some secondary mediators are also produced as a result of the interaction between IgE and an allergen. They include the leucotrienes and prostaglandins.
Degranulation of mast cells and basophils occurs when two IgE molecules are adjacent to each other on these cells and both bind to an antigen (allergen) having the same specificity, thereby forming a bridge. The chemical mediators released by the granules produce various changes associated with allergic response. One of the most important effect is the contraction of smooth muscles.
The small veins are constricted and capillary pores are dilated leading to extrascular accumulation of fluid (edema). The bronchial muscles, as well as those of GI tract, may also contract producing breathing difficulty and cramps. Mast cells present in the mucous membrane of the upper and lower respiratory tracts cause rhinitis and asthma. The events occurring during the sensitization phase and the expression of allergic symptoms after a second encounter with the allergen are diagrammatically shown in Fig. 10.58.
The susceptibility to specific allergens of an individual can be determined by skin-test. It is performed by injecting a small amount of the possible allergens below the skin. A wheal and erythema response indicated by itching, swelling and reddening of the injection spot developed within 2 to 3 minutes and reaching a maximum in about 10 minutes means that the substance is allergenic. Avoidance of the identified allergen(s) is the best way of prevention of anaphylaxis.
Another way of prevention is by desensitization. Once an allergen has been identified, the sensitive person is injected with small doses of the allergen for several weeks. The objective is to buildup immunity to the allergen through production of excess of IgG antibodies, so that they outnumber IgE antibodies. The IgG antibodies in this case are called blocking antibodies, because they block the IgE antibodies to combine with the allergen.
Anaphylaxis can also be prevented by specific drugs. Anaphylactic shock can be prevented by immediate injection of epinephrine. Drugs used for localized anaphylaxis act in two ways. A group of drugs like dexamethasone, prednisolone etc. inhibit the production or release of the chemical mediators responsible for development of allergic symptoms. The other group, mainly the anti-histamines, inhibit the action of chemical mediators, mainly that of histamine.
2. Type II Hypersensitivity (Cytotoxic Hypersensitivity):
This type of hypersensitivity involves IgG antibodies and the complement system and results in cell destruction. IgM may also take part in cell damaging reactions. Cytotoxic hypersensitivity is the result of transfusion of incompatible blood of a donor to a recipient, although this is of rare occurrence because of careful cross-matching of the donor and the recipient’s blood-groups.
A faulty cross-matching leads to hemolysis of the donor’s erythrocytes in the blood vessels of the recipient. This happens because the alloantigen’s of the donor’s erythrocytes react with the antibodies in the serum of the recipient and in combination with activated complement, the erythrocytes undergo hemolysis.
Similarly, when an Rh-negative recipient is transfused with the blood of an Rh-positive donor, Rh-antibodies develop in the recipient. In case, the same recipient receives subsequently blood from an Rh-positive donor, a rapid and extensive hemolysis occurs in the recipient due to interaction of the Rh-antigen and Rh-antibody. Precaution is necessary that an Rh-negative recipient is not transfused with Rh-positive blood more than once.
Interaction of Rh-antigen and Rh-antibody may lead to a more serious consequence when an Rh-negative mother bears an Rh-positive child, the trait of the child being acquired from an Rh-positive father. Rh-antigen of the fetus enters into mother’s circulation and provokes formation of Rh-antibody in mother.
In a succeeding pregnancy resulting in an Rh-positive fetus, these antibodies enter into the fetal circulation through placenta and react with the Rh-antigen producing serious complications, known as haemolytic disease of the newborn.
The situation leading to this disease is diagrammatically shown in Fig. 10.59:
3. Type III Hypersensitivity:
Normally, the antigen-antibody complex formed as a result of immune reactions is removed by the phagocytic activity of body. However, when bulky antigen-antibody complexes are formed and the aggregates combine with the activated complement, they chemotactically attract the polymorphonuclear leucocytes. These cells release lysosomal enzymes in large quantities to Cause tissue damage. This results in immune complex hypersensitivity (Type III hypersensitivity).
One form of this type of hypersensitivity is the Arthus Reaction. It develops due to deposition of IgG-antigen complexes in the blood vessels causing local damage. When such aggregates are deposited in blood vessels of kidney glomeruli, the result may be nephritis.
Similarly, inhalation of bacteria and fungal spores may give rise to a disease called farmer’s lung. The antigens react with IgG antibodies to form complexes in the epithelial layers of the respiratory tract giving rise to this ailment.
Another form of this type of hypersensitivity is known as lupus (systemic lupus erythematosus). It is produced as a result of interaction of IgG and the nucleoproteins of the disintegrated leucocytes (auto-antigens). Therefore, lupus is an autoimmune disease. The immune-complex may be deposited locally in the skin, or systemically in kidney or heart. Rheumatoid arthritis is another autoimmune disease developing from deposition of immune complexes in the joints.
Serum sickness is another manifestation of immune complex hypersensitivity. Antisera like anti-tetanus serum (ATS) may act as antigen in human body, because these are obtained from animals and are injected to persons for providing immediate protection. The antigen (ATS, for example) can provoke an immune response to produce IgG in the body. These IgG antibodies react with the antisera to produce immune complexes and give rise to serum sickness.
Immune complex hypersensitivity (Type III) is diagrammatically shown in Fig. 10.60:
4. Type IV Hypersensitivity:
In contrast to the first three types of hypersensitivity, Type IV is mediated by cells of immune system, mainly T-cells, but also macrophages and dendritic cells. Furthermore, lymphokines produced by T-cells play an important role. The expression of allergic manifestations takes a longer time, at least 24 hr or more.
Hence, Type IV hypersensitivity is called delayed type of hypersensitivity. The delay in appearance of allergic symptoms after a second exposure to an allergen is mainly due to the time taken by the cellular components to migrate to the site where antigen is present.
The cells involved in delayed hypersensitivity are mainly T-lymphocytes. T-lymphocytes have two main types, — the CD4+ cells and CD8+ cells. The cells involved in Type IV hypersensitivity belong to the CD4+ type. The special group of CD4+ cells taking part in this hypersensitivity are called TD-cells (D standing for delayed hypersensitivity). TD-cells are a part of the T-helper cell (TH-cells) population which constitutes the bulk of CD4+ T-cells. TH-cells are distinguished into TH-1 and TH-2 types, of which TH-2 cells are mainly responsible for activation of B-cells to produce immunoglobulin’s and TH-1 cells are involved in causing the inflammatory responses including delayed hypersensitivity reactions. So, TD-cells belong to the TH-1 type of lymphocytes.
Like the Type I hypersensitivity, Type IV also has two phases: a sensitization phase and an active phase. The allergen can be a microbial antigen or a small molecule that can act as a hapten and can combine with a tissue protein to form an active antigen. The sensitizing antigen binds to some tissue cells and these are ingested by phagocytic cells, like macrophages and dendritic cells. These cells process the antigen and present the antigenic determinants to the TD-cells.
These T-cells recognize the determinants by interacting with the determinants complexed with MHC proteins of the antigen- presenting cells (APC). The close binding between the T-cells and APCs activates the T-cells to proliferate forming a clone including some memory T-cells. Thereby, the person becomes sensitized to the particular allergenic antigen.
In the next phase, the sensitized individual expresses delayed type of hypersensitivity when exposed at din to the same allergen. The memory T-cells activate the sensitized T-cells to produce lymphokines which cause the inflammatory responses associated with Type IV hypersensitivity.
The whole process is diagrammatically shown in Fig. 10.61:
A well-known example of a microbial agent that elicits a delayed hypersensitivity is tuberculin which is a purified protein derivative (PPD) of tubercle bacilli (Mycobacterium tuberculosis). Other microbial agents that stimulate delayed hypersensitivity are Mycobacterium leprae, Brucella and fungi causing histoplasmosis (Histoplasma capsulatum) and candidiasis (Candida albicans).
The tuberculin skin test (Mantoux test) is used to determine if a person has T-cell mediated reactivity towards tubercle bacilli (also known as Koch’s bacilli). In a sensitized individual, an intradermal injection of 0.1 μg of tuberculin results in development of a progressively increasing swollen reddened circular area at the injection site attaining a maximum size in 24 to 72 hr.
Histologically, the response is due to accumulation of large number of inflammatory cells, mainly lymphocytes and macrophages. A positive response shows that the person has immunity to tuberculosis, developed either through active infection or through vaccination and, therefore, does not require BCG vaccination.
Certain low-molecular weight chemical substances can also evoke delayed hypersensitivity. Generally, the allergic symptoms are restricted to the skin and the response is called contact sensitivity. The clinical manifestation is contact dermatitis. A great many varieties of such agents causing contact dermatitis are known. Some examples are metallic nickel and copper, turpentine, formaldehyde, insecticides, detergents, cosmetics, latex, furs, protein fibres etc.
Certain plants, like poison ivy, poison oak etc. can also provoke contact sensitivity. Detection of the possible sensitizing agent can be made by a patch test in which the suspected agent is kept in contact with skin for 24 hr to 48 hr and the skin reaction is examined. Generally, avoidance of the allergenic substance or material removes the adverse effects promptly.