Hypersensitivity Reactions

Hypersensitivity Reactions

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The human immune system defends against pathogens, but it can sometimes overreact causing undesirable consequences. These effects are not caused by antigens but from inflammatory processes generated by immune cells.

An overreaction to exogenous or ‘non-self’ antigens can lead to allergy, and with endogenous or ‘self’ antigen this can cause autoimmunity. Hypersensitivity reactions are implicated in the pathogenesis of many diseases and can be caused by a genetic susceptibility or a triggering event of another kind on the immune system.

Hypersensitivity reactions have been classified into four types known as the Gell and Coombs classification. This article will cover the four types of hypersensitivity reactions.

Type I hypersensitivity

Type I hypersensitivity is an immediate reaction (within minutes) mediated by IgE antibody, which results in allergy, anaphylaxis and atopic disease.

The immune system produces large amounts of IgE antibodies against an antigen. These IgE molecules attach themselves to mast cells and basophils, sensitizing the individual to the antigen.

When the antigen is encountered again, it will cause cross-linking of the bound IgE and degranulation of mast cells and basophils, releasing potent vasoactive molecules such as histamine. This leads to the signs and symptoms of allergy, and if severe can cause anaphylaxis.

Type II hypersensitivity

Type II hypersensitivity is an IgG or IgM antibody-mediated cytotoxic reaction occurring in hours to days, which results in pathologies such as haemolytic disease of the newborn, autoimmune haemolytic anaemia and Goodpasture's syndrome.

An individual may possess or develop IgG and IgM antibodies directed against cell surface or extracellular matrix antigen.

Type I to III Hypersensitivity

Type I to III hypersensitivity are antibody-mediated reactions. They can cause damage to cells or tissues (cytotoxicity) through direct cell surface receptor binding, activation of the complement pathway, or antibody-dependent cellular cytotoxicity.

Pathology varies depending on the target of the antibody. For example, if antibodies are targeted toward red blood cell surface antigen, it can cause haemolytic anaemia. If they are targeted to type IV collagen in the basement membrane, it can cause Goodpasture's syndrome.

Clinical Relevance: Goodpasture's Syndrome

A classic example of type II hypersensitivity is Goodpasture's syndrome, an autoimmune condition caused by antibodies against the alpha-3 chain of type IV collagen found in the basement membrane. Type IV collagen is a major structural component of all basement membranes, though alpha-3 subtype only occurs in specific tissues like alveoli and glomeruli.

No consistent trigger has been found, but it has been associated with certain HLA-DRB1 or DR4 genetics and cigarette smokers. The condition commonly affects men in two age groups (20 to 30 years and 60 to 70 years). Symptoms include shortness of breath, haemoptysis, signs of renal dysfunction (e.g. decreased urine output or oedema), potentially leading to rapid renal failure if left untreated.

Diagnosis is made by renal biopsy and anti-GBM antibodies in the blood. The treatment involves aggressive urgent use of steroids, plasmapheresis and cyclophosphamide to remove anti-GBM antibodies. Patients may require long-term dialysis if irreversible renal damage occurs.

Type IV Hypersensitivity

Type IV hypersensitivity, also known as delayed hypersensitivity, is a T cell-mediated reaction that typically occurs 24 to 72 hours after antigen exposure. It is involved in contact dermatitis and the tuberculin skin test (Mantoux).

When a person first encounters an antigen, it can be processed by antigen-presenting cells and lead to sensitisation of T helper cells. When exposed to the antigen again, these T helper cells are activated and lead to an inflammatory response involving various immune cells, such as macrophages, with a 24 to 72 hour delay as cells are recruited to the antigen exposure site.

Hypersensitivity Reactions

Certain substances can cause local tissue inflammation and damage when they come into contact with the skin. This situation can be seen in contact dermatitis when elements like nickel or poison ivy come into contact with the skin. Another example is the Mantoux test, where proteins from M. tuberculosis are injected intradermally and an indurated area forms in individuals who have been previously exposed to the bacteria.

Key Points

The four types of hypersensitivity reactions, as per the Gell and Coombs classification, are outlined in the following table.

Table 1. The key features of the four types of hypersensitivity reaction.

  • Type I hypersensitivity: Mediated by IgE antibody. Immediate (minutes). Examples: Allergy, anaphylaxis, atopy.
  • Type II hypersensitivity: Mediated by IgG or IgM antibody (cytotoxic). Hours to days. Examples: Haemolytic disease of the newborn, autoimmune haemolytic anaemia, Goodpasture's syndrome.
  • Type III hypersensitivity: Mediated by antigen-antibody immune complexes. Hours to days/weeks. Examples: Serum sickness, RA, SLE, post-streptococcal glomerulonephritis.
  • Type IV hypersensitivity: Mediated by T cells. Delayed (24 to 72 hours). Examples: Contact dermatitis, tuberculin skin test.


  1. Justiz Vaillant AA et al. Immediate Hypersensitivity Reactions | StatPearls. Published 2021. Available from: LINK
  2. Dispenza MC. Classification of hypersensitivity reactions | Allergy Asthma Proc. Published 2019. Available from: LINK

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