Hypersensitivity: 4 Types Based on The Gell and Coomb’s Classification

Mast cell is important in type 1 hypersensitivity

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Hypersensitivity is an excessively exaggerated immune response against antigens. This response causes damage to the body.  The cellular damage emanates from inflammation that usually accompanies such an undesirable immune response.

Analogy of Hypersensitivity

For you to understand hypersensitivity in a better way, we shall employ a simple analogy here. If you wanted to kill a mosquito, it would be unnecessary to use a hammer to knock it against the wall.

You can kill it using the palm of your hand. The mosquito will still easily die. Using a hammer would be too much force and it would have unintended casualties – damage to the wall.

In the same way, in hypersensitivity, the immune system uses excessive force to fight relatively harmless antigens/allergens. The end result comes with massive cellular and tissue damage.

This is caused by intense inflammation. This is an undesirable effect because the immune system should only protect you but not kill your cells and tissues, right?

We have four types of hypersensitivity reactions according to classification by Coombs and Gell’s criteria. The four types are:

Type I hypersensitivity (Immediate type)

Type I hypersensitivity happens when your immune system mounts an exaggerated immune response against allergens like pollen, milk, jewelry, dust, and bee sting among others. Anaphylaxis which is a very rapid immune reaction is also an example of this type of reaction.

Allergy is a Hypersensitivity Reaction
Man talking to an allergist in a clinic (Source: Deposit Photos)

For type I hypersensitivity to happen the allergens are phagocytosed by cells your innate immunity, processed, and presented to the T cells which in turn become activated. Once activated T cells (Th2) produce IL-4 and IL-13 cytokines that help to activate the B cells.

The B cells then transform themselves into plasma cells which produce IgE antibodies. Since mast cells (Descendants of monocytes) and basophils have Fc receptors for IgE antibodies, they are primed (Attach to their surface).

In subsequent exposure to the same allergens, the mast cells and basophils are reactivated. This time the IgE antibodies already bound to their surface previously become cross-linked causing degranulation (Leaking out granules).

The granules include histamines, platelets adhesion factors, and prostaglandins which can initiate inflammation and cause cell damage. The reactions may be systemic or local. For instance, in the respiratory system, there could be effects like difficulty breathing and sneezing in asthmatic patients.

Type II Hypersensitivity (Cytotoxic or Antibody-dependent type)

Type II hypersensitivity involves the destruction of cells which may be mediated by IgG antibodies or complement fragments (e.g., C3b). In type II hypersensitivity, the reaction is caused by an immune response that sometimes causes antibody-dependent cellular cytotoxicity (ADCC) with cells in your body like the natural killer cells unleashing their cytotoxic granules.

The two commonest examples of this type of reaction are:

Incompatible ABO blood transfusion

If you are given a blood group that is incompatible, then the immune system treats the red blood cells as foreign antigens. This will cause a reaction if you already have pre-existing antibodies against those RBC surface antigens.

The RBCs will be bound by the IgG whose Fc region binds to the receptors on phagocytotic cells like macrophages and neutrophils. This reaction will be rapid because of the presence of pre-existing antibodies. It can be fatal due to anemia.

Hemolytic disease of the newborn (HDN)

This type of reaction happens to a Rhesus-negative mother when she falls pregnant with a fetus whose blood group is Rhesus positive. During delivery, the Rhesus-positive antigens leak into the mother through the placenta and are detected as foreign antigens by her immune system. The mother produces IgG antibodies against the Rhesus antigens and they remain in her blood circulation without affecting her in any way.

When she conceives again with another Rhesus-positive fetus, the anti-Rhesus antibodies may cross the placenta during pregnancy or during delivery. The antibodies bind to the newborn’s RBCs. Through the Fc receptors on the phagocytic cells, the RBCs are lysed through phagocytosis causing hemolytic disease in the newborn (HDN).

Type III Hypersensitivity (Immune complex-mediated type)

This type of reaction is mediated by immune complexes that form in your body. This type manifests in many types of systemic autoimmune diseases like rheumatoid arthritis, and systemic lupus erythematosus among others. It also manifests in some local reactions like glomerulonephritis and pneumonitis.

When Antigen-Antibody immune complexes are formed in your body, they are then removed by the phagocytic cells. However, not all of them are removed. The few remaining immune complexes can lodge on the walls of your blood vessels where they activate the complement system through the classical pathway.

Once activated some components of the complement system like C3a and C5a can help to mediate the activation of neutrophils. Then neutrophils degranulate leaking out active pharmacological components that will cause very aggressive inflammation. This inflammation will cause local as well as systemic reactions causing massive damage. 

Type IV Hypersensitivity (Delayed or Cell-mediated type)

Type IV hypersensitivity is the one that manifests in transplantation rejection reactions. It is also called delayed or cell-mediated type of hypersensitivity. The delay is such that an inflammatory reaction occurs 12 – 24 hours after exposure. The delay particularly reflects the time it takes for the antigen-presenting cells to interact with the T cells to activate them.

A typical example of delayed hypersensitivity is the tuberculin immune response. This is a test that helps to determine if someone has ever been exposed to mycobacteria tuberculosis. This exposure could have been through natural infection or vaccination with the BCG vaccine.

If the person being tested had been exposed, they will have a positive reaction. This reaction will be exhibited by an inflammatory reaction demonstrated by a red hard swelling. For someone who will not have been exposed, there will be no inflammation and no swelling.

Tuberculin Test is hypersensitivity reaction
A Patient Suffering from type 4 hypersensitivity undergoing a tuberculin test

In the graft rejection reaction, delayed hypersensitivity occurs because there is a mismatch in the MHC antigens between the donor and recipient. The closer the match (e.g., in autografts) the lower the probability of this rejection reaction. The more the donor and the recipient are not related (e.g., xenografts) the higher the probability of the hypersensitivity or rejection reaction.


The four types of hypersensitivity reactions based on Gell and Coomb’s classification are type I, type II, type III, and type IV. They all occur in different circumstances.

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