Hypersensitivity

Occasionally, the immune system responds inappropriately to the presence of antigen. These responses are refered to as hypersensitivities. There are four different types of hypersensitivities that result from different alterations of the immune system. These types are classified as:

• Type I: Immediate Hypersensitivity
• Type II: Cytotoxic Hypersensitivity
• Type III: Immune Complex Hypersensitivity
• Type IV: Delayed Hypersensitivity

This page will describe the four types of hypersensitivity, giving examples of diseases that may result.

TYPE I HYPERSENSITIVITY

Type I or Immediate Hypersensitivity can be illustrated by considering the following experiment:

1. First, a guinea pig is injected intravenously with an antigen. For this example, bovine serum albumin (BSA, a protein) will be used. After two weeks, the same antigen will be reinjected into the same animal. Within a few minutes, the animal begins to suffocate and dies by a process called anaphylactic shock.
2. Instead of reinjecting the immunized guinea pig, serum is transferred from this pig to a "naive" (unimmunized) pig. When this second guinea pig is now injected with BSA, it also dies of anaphylactic shock. However, if the second pig is injected with a different antigen (e.g. egg white albumin), the pig shows no reaction.
3. If immune cells (T-cells and macrophages instead of serum) are transfered from the immunized pig to a second pig, the result is very different; injection of the second pig with BSA has no effect.

These results tell us that:

• The reaction elicited by antigen occurs very rapidly (hence the name "immediate hypersensitivity").
• The hypersensitivity is mediated via serum-derived components (i.e. antibody).
• The hypersensitivity is antigen-specific (as one might expect for an antibody-mediated reaction).

The details of this reaction can be summarized as follows (click the image to animate):

1. Initial introduction of antigen produces an antibody response. More specifically, the type of antigen and the way in which it is administered induce the synthesis of IgE antibody in particular.
2. Immunoglobulin IgE binds very specifically to receptors on the surface of mast cells, which remain circulating.
3. Reintroduced antigen interacts with IgE on mast cells causing the cells to degranulate and release large amounts of histamine, lipid mediators and chemotactic factors that cause smooth muscle contraction, vasodilation, increased vascular permeability, broncoconstriction and edema. These reactions occur very suddenly, causing death.

Examples of Type I hypersensitivities include allergies to penicillin, insect bites, molds, etc. A person's sensitivity to these allergens can be tested by a cutaneous reaction. If the specific antigen in question is injected intradermally and the patient is sensitive, a specific reaction known as wheal and flare can be observed within 15 minutes. Individuals who are hypersensitive to such allergens must avoid contact with large inocula to prevent anaphylactic shock.

TYPE II HYPERSENSITIVITY

Type II or Cytotoxic Hypersensitivity also involves antibody-mediated reactions. However, the immunoglobulin class (isotype) is generally IgG. In addition, this process involves K-cells rather than mast cells. K-cells are, of course, involved in antibody-dependent cell-mediated cytotoxicity (ADCC). Type II hypersensitivity may also involve complement that binds to cell-bound antibody. The difference here is that the antibodies are specific for (or able to cross-react with) "self" antigens. When these circulating antibodies react with a host cell surface, tissue damage may result. Click the image to animate the process.

There are many examples of Type II hypersensitivity. These include:

• Pemphigus: IgG antibodies that react with the intracellular substance found between epidermal cells.
• Autoimmune hemolytic anemia (AHA): This disease is generally inspired by a drug such as penicillin that becomes attached to the surface of red blood cells (RBC) and acts as hapten for the production of antibody which then binds the RBC surface leading to lysis of RBCs.
• Goodpasture's syndrome: Generally manifested as a glomerulonephritis, IgG antibodies that react against glomerular basement membrane surfaces can lead to kidney destruction.

TYPE III HYPERSENSITIVITY

Type III or Immune Complex hypersensitivity involves circulating antibody that reacts with free antigen. These circulating complexes can then become deposited on tissues. Tissue deposition may lead to reaction with complement, causing tissue damage. this type of hypersensitivity develops as a result of systematic exposure to an antigen and is dependent on i) the type of antigen and antibody and ii) the size of the resulting complex (click here for more information). More specifically, complexes that are too small remain in circulation; complexes too large are removed by the glomerulus; intermediate complexes may become lodged in the glomerulus leading to kidney damage. Click the image to animate the process.

One example of a Type III hypersensitivity is serum sickness, a condition that may develop when a patient is injected with a large amount of e.g. antitoxin that was produced in an animal. After about 10 days, anti-antitoxin antibodies react with the antitoxin forming immune complexes that deposit in tissues. Type III hypersensitivities can be ascertained by intradermal injection of the antigen, followed by the observance of an "Arthus" reaction (swelling and redness at site of injection) after a few hours.

TYPE IV HYPERSENSITIVITY

Type IV or Delayed Hypersensitivity can be illustrated by considering the following experiment:

1. First, a guinea pig is injected with a sub-lethal dose of Mycobacterium tuberculosis (MT). Following recovery of the animal, injection of a lethal dose of MT under the skin produces only erythema (redness) and induration (hard spot) at the site of injection 1-2 days later.
2. Instead of reinjecting the immunized guinea pig, serum is transfered from this pig to a "naive" (unimmunized) pig. When this second guinea pig is now injected with MT, it dies of the infection.
3. If immune cells (T-cells and macrophages instead of serum) are transfered from the immunized pig to a second pig, the result is very different; injection of the second pig with MT causes only erythema and induration at the site of injection 1-2 days later.
4. In a separate experiment, if the immunized guinea pig is injected with a lethal dose of Listeria monocytogenes (LM) instead of MT, it dies of the infection. However, if the pig is simultaneously injected with both LM and MT, it survives.

These results tell us that:

• The reaction elicited by antigen occurs relatively slowly (hence the name "delayed hypersensitivity").
• The hypersensitivity is mediated via T-cells and macrophages.
• The hypersensitivity illustrates both antigen-specific (T-cell) and antigen non-specific (macrophage) characteristics.

The details of this reaction can be summarized as follows (click the image to animate):

1. Initial introduction of antigen produces a cell-mediated response. Mycobacterium tuberculosis is an intracellular pathogen and recovery requires induction of specific T-cell clones with subsequent activation of macrophages.
2. Memory T-cells respond upon secondary injection of the specific (i.e. MT) antigen, but not the non-specific (i.e. LM) antigen.
3. Induction of the memory T-cells causes activation of macrophages and destruction of both specific (MT) and non-specific (LM) microorganisms.