Hypersensitivity Reactions

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Introduction

The human immune system is vital for defence against pathogens, but at times it can ‘overreact’ causing undesirable consequences. The effects on the body from these reactions are not due to antigens directly but from the inflammatory processes generated via immune cells.

When there is an overreaction to exogenous or ‘non-self’ antigens this can lead to allergy, and with endogenous or ‘self’ antigen this can cause autoimmunity.

By these mechanisms, hypersensitivity reactions are implicated in the pathogenesis of many diseases, and appreciating the basic cellular processes helps to understand many conditions.

There can be several factors that lead an individual to develop hypersensitivity. There may be a genetic susceptibility to these reactions or a triggering event of another kind on the immune system such as an infection.

Hypersensitivity reactions have been grouped into four types based on their mechanism, this is 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.

When an individual first encounters an antigen, their immune system may produce large amounts of IgE antibodies against this specific substance. These IgE molecules attach themselves to mast cells and basophils. The individual is now ‘sensitised’ to the antigen.

When this 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.

Clinical relevance: anaphylaxis

Anaphylaxis is a severe allergic reaction occurring rapidly and causing potentially life-threatening issues with an individual’s airway, breathing or circulation.

Common allergens that can cause anaphylaxis are foods (most commonly nuts), medications, and insect stings/venom. These allergens trigger a systemic reaction, which via the effects of mediators such as histamine can cause swelling and obstruction of the upper airways, bronchospasm and bronchodilation with respiratory failure, and vasodilation leading to hypotension and cardiac arrest.

Other systemic features may include widespread urticarial rash (‘hives’) and angioedema (swelling).

An allergic reaction causing signs and symptoms of anaphylaxis requires urgent treatment with intramuscular (IM) adrenaline (0.5mg 1:1000 in adults) to counteract the vasodilation and bronchoconstriction. Antihistamines and steroids should also be administered. 

For more information, see the Geeky Medics guide to the acute management of 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.

These antibodies can cause damage to cells or tissues (cytotoxicity) either directly by cell surface receptor binding, via activation of the complement pathway or by antibody-dependent cellular cytotoxicity.

Pathology is dependent on the target of the antibody. If antibodies are directed to cell surface antigen on red blood cells this can cause haemolytic anaemia, if they are targeted to type IV collagen in the basement membrane this can cause Goodpasture’s syndrome.

Clinical relevance: Goodpasture’s syndrome

A classic example of type II hypersensitivity is Goodpasture’s syndrome, a rare 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, but the alpha-3 subtype only occurs in certain tissues, primarily alveoli and glomeruli. There is no consistent trigger for the disease, but it is associated with certain genetics (HLA-DRB1 or DR4) and cigarette smokers.

The condition commonly presents in men, with bimodal age distribution (20 to 30 years and 60 to 70 years). Symptoms include shortness of breath, haemoptysis and signs of renal dysfunction such as decreased urine output or oedema. Goodpasture’s can lead to rapidly progressive renal failure if untreated.  

Diagnosis is made by renal biopsy and can be confirmed by blood tests for anti-GBM antibodies.

Management of Goodpasture’s involves urgent, aggressive treatment with steroids, plasmapheresis (to remove anti-GBM antibodies) and cyclophosphamide. Patients may require long-term dialysis if irreversible renal damage occurs. 


Type III hypersensitivity

Type III hypersensitivity is an antigen-antibody immune complex-mediated reaction, which can occur over hours, days or weeks. Examples include serum sickness, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and post-streptococcal glomerulonephritis.

Soluble antigen in the circulation is bound to by antibodies (most commonly IgG and IgM) forming immune complexes. These complexes can precipitate out of the circulation and deposit in certain tissues, notably blood vessels, synovial joints and the glomerular basement membrane.

These complexes trigger the classical complement pathway, leading to the recruitment of inflammatory cells including neutrophils that release enzymes and free radicals causing tissue damage. These inflammatory processes cause pathology in diseases such as rheumatoid arthritis, where immune complexes damage the filtration systems vital in synovial fluid formation.


Type IV hypersensitivity

Type IV hypersensitivity is also known as delayed hypersensitivity, as the reaction typically occurs 24 to 72 hours after antigen exposure. Unlike types I to III, it is not antibody-mediated but T cell-mediated. It is involved in the processes of contact dermatitis and the tuberculin skin test (Mantoux).

When an individual first encounters an antigen, it can be processed by antigen-presenting cells and lead to sensitisation of T helper cells.

On subsequent exposure to this antigen, these T helper cells will become activated and lead to an inflammatory response involving several immune cells such as macrophages, though there will be a delay of 24 to 72 hours as cells are recruited to the site of antigen exposure.

This can cause local tissue inflammation and damage as seen in contact dermatitis when substances such as nickel or poison ivy contact the skin, or in 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 summarised in the below table.

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

Type Mediated by Timeframe Examples

Type I hypersensitivity

IgE antibody

Immediate (minutes)

Allergy, anaphylaxis, atopy

Type II hypersensitivity

IgG or IgM antibody (cytotoxic)

Hours to days

Haemolytic disease of the newborn, autoimmune haemolytic anaemia, Goodpasture’s syndrome

Type III hypersensitivity

Antigen-antibody immune complexes

Hours to days/weeks

Serum sickness, RA, SLE, post-streptococcal glomerulonephritis

Type IV hypersensitivity

T cells

Delayed (24 to 72 hours)

Contact dermatitis, tuberculin skin test


Reviewer

Dr Dinusha Chandratilleke

Consultant Immunologist


Editor

Dr Chris Jefferies


References

  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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