Hypersensitivity Reactions: Classification and Types
What is Hypersensitivity
In response to an antigen, immune response activates many cells and effector molecules that work in different ways to remove antigens from the body.
Usually, these effector molecules produce a localized inflammatory reaction that destroys the antigen without causing much harm to the body’s own tissues.
However, in some situations, this inflammatory response becomes harmful and may lead to serious tissue damage or even death.
Hypersensitivity reactions can occur during both humoral (antibody-mediated) and cell-mediated immune responses.
The term hypersensitivity is defining as exaggerated, inappropriate immune response to a substance (antigen), leading to cause significant tissue damage or physiological dysfunction.
Types of Hypersensitivity
Based on onset of symptoms, hypersensitivity reactions are classified into:
- Immediate Type Hypersensitivity
- Delayed Type Hypersensitivity
- Anaphylactic reactions that occur through the humoral branch of immunity are initiated by antibodies or antigen–antibody complexes and are classified as immediate hypersensitivity reactions. This is because the symptoms appear very quickly, usually within a few minutes to a few hours after a previously sensitized individual comes into contact with the antigen again.
- Delayed hypersensitivity develops 24–72 hours after exposure to the antigen. It is cell-mediated and does not involve antibodies. Instead, sensitized T lymphocytes (mainly TH cells) recognize the antigen and release cytokines, which attract macrophages and other immune cells to the site. This results in localized inflammation and tissue damage.
Gell and Coombs Classification
P. G. H. Gell and R. R. A. Coombs proposed a classification scheme in which hypersensitive reactions are divided into four types.
Three types of hypersensitivity occur within the humoral branch and are mediated by antibody or antigen-antibody complexes:- Type I – IgE mediated
- Type II – Antibody mediated cytotoxic
- Type III – Immune complex mediated
A fourth type of hypersensitivity depends on reactions within the cell-mediated branch, and is termed as
- Type IV – Cell mediated delayed type
Type I: IgE-Mediated Hypersensitivity
The type I hypersensitive reaction is induced by certain types of antigens referred to as allergens and mediated by IgE antibodies.
How it is generated
- At first time of allergen exposure to the body, The allergen binds with B Cells.
- B Cell present this allergen to TH (T Helper cells)
- T Helper cells release some immune mediator chemicals, which further activate B cells to convert into plasma cells and memory cells.
- As a normal Humoral immune response, Plasma cells starts the secretion of special class of IgE antibodies.
- These secreted IgE antibodies bind very strongly to special Fc receptors present on the surface of tissue mast cells and blood basophils.
- When these mast cells are covered with IgE antibodies, they are said to be sensitized.
- If the same allergen enters the body again, it binds to and cross-links the IgE molecules on the surface of these sensitized mast cells and basophils.
- This triggers degranulation of mast cells and release the contents of their granules, a process called degranulation.
- The chemicals released from these granules act on nearby tissues and cause effects such as widening of blood vessels (vasodilation) and contraction of smooth muscles.
Type I hypersensitive reactions are related to the biological effects of the mediators released during mast-cell or basophil degranulation.
These mediators are pharmacologically active agents that act on local tissues as well as on populations of secondary effector cells, including eosinophils, neutrophils, T lymphocytes, monocytes, and platelets.
| Mediator | Effect |
|---|---|
| Histamine | Increased vascular permeability; smooth-muscle contraction |
| Leukotrienes | Increased vascular permeability; contraction of pulmonary smooth muscles |
| Prostaglandins | Vasodilation; contraction of pulmonary smooth muscles; platelet aggregation |
| Proteases | Bronchial mucus secretion; degradation of blood-vessel basement membrane |
| Bradykinin | Increased vascular permeability; smooth-muscle contraction |
Type II: Antibody-Mediated Cytotoxic Hypersensitivity
Type II hypersensitive reactions involve antibody-mediated destruction of cells.
This happens in two main ways:(a) Complement-mediated Cell Destruction
Antibodies (IgG or IgM) bind to antigens present on the cell surface. This binding activates the complement system and generate complement proteins. These complement proteins creates or form holes (pores) in the cell membrane of target cell which have antigen, due to this, the cell bursts and dies.
(b) Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)
Antibodies have two portions, Fc part that binds with receptors found on immune cells and Antigen binding part Fab, which binds with antigenic proteins. Antibodies attach to antigens present on the target cell through Fab part.
Cytotoxic cells (like NK cells, macrophages, neutrophils) have Fc receptors. These Fc receptors bind to the Fc portion of the antibody. Once this combination forms (antigen - Immune Cell - Antibody), then cytotoxic cells release toxic substances, this leads to killing of the target cell.
Examples of Type II hypersensitivity
A classic example is blood group mismatch leading to hemolysis.
If a person with blood group A receives blood group B.| Blood Group | Antigen Present on RBC | Serum antibodies (Isohemagglutinins) |
|---|---|---|
| A | A | Anti-B |
| B | B | Anti-A |
| AB | A and B | None |
| O | None | Anti-A & Anti-B |
Anti-B antibodies of blood group A, bind to B antigens on donor RBCs (Blood group B).
Due to this, Antigen–antibody reaction occurs and Complement system gets activated. Within hours, this leads to complement mediated lysis of RBC, triggered by the IgM isohemagglutinins. Due to RBC lysis, free hemoglobin can be detected in the plasma; it is filtered through the kidneys, resulting in hemoglobinuria (hemoglobin in the urine). Some of the hemoglobin gets converted to bilirubin, which at high levels is toxic. Typical symptoms include fever, chills, nausea, clotting within blood vessels.Another example of Type II (antibody-mediated cytotoxic) hypersensitivity is antibodies mediated damage to the body’s own cells.
Some antibiotics such as penicillin, cephalosporins, and streptomycin can attach loosely (adsorb) to proteins present on the surface of red blood cells (RBCs). When these drugs attach to RBC membrane proteins, they form a drug–protein complex, which behaves like a hapten–carrier complex.
In some individuals, the immune system mistakenly recognizes this drug–protein complex as foreign antigen and produces antibodies against it. These antibodies then bind to the drug molecules attached to the RBC surface. Once antibodies are bound, the complement system is activated, leading to destruction (lysis) of red blood cells.Type III: Immune Complex–Mediated (Type III) Hypersensitivity
The interaction between antibodies and their corresponding antigens results in the formation of immune complexes.
Under normal physiological conditions, these antigen–antibody complexes are efficiently removed from the circulation by phagocytic cells, thereby contributing to antigen clearance. However, when immune complexes are produced in excessive amounts or are inadequately cleared, they may deposit in tissues. Such deposition can trigger inflammatory responses and tissue injury, leading to the development of immune complex–mediated (Type III) hypersensitivity reactions. Examples of Type III hypersensitivityA very common example of this is Serum sickness.
Serum sickness is a Type III (immune complex–mediated) hypersensitivity reaction that occurs when the body reacts against foreign proteins or drugs, leading to the formation and deposition of immune complexes in tissues.
When foreign serum proteins (for example, foreign serum, such as horse anti-tetanus or anti-diphtheria serum antitoxins or certain drugs like penicillin, sulfonamides) enter the body, the immune system produces antibodies against them. These antibodies bind with the antigens to form immune complexes. If these complexes are formed in large amounts, they circulate in the blood and get deposited in tissues such as blood vessels, joints, and kidneys. This deposition activates the complement system, causing inflammation and tissue damage. These symptoms include fever, weakness, generalized vasculitis (rashes) with edema and erythema, lymphadenopathy, arthritis, and sometimes glomerulonephritis.
Type IV or Delayed-Type Hypersensitivity (DTH)
Delayed-type hypersensitivity (DTH) is a cell-mediated immune reaction that occurs 24–72 hours after exposure to a specific antigen in a previously sensitized individual.
This process occurs in two phases 1. Sensitization Phase 2. Effector Phase During the sensitization phase, the antigen is taken up by antigen-presenting cells and presented to T cells, leading to the formation of memory T lymphocytes. Upon re-exposure to the same antigen, these sensitized T cells become activated and release cytokines such as interferon-γ (IFN-γ), tumor necrosis factor (TNF), and interleukin-2 (IL-2). These cytokines recruit and activate macrophages and other inflammatory cells, Macrophages are the principal effector cells of the DTH response. Activated macrophages release lysosomal enzymes and reactive oxygen species, which cause tissue injury and cell destruction. The reaction reaches its peak after 48–72 hours and is therefore termed delayed-type.