An Introduction to Hypersensitivity

Core

Hypersensitivity

Hypersensitivity is defined as an inappropriate or excessive, antigen-specific immune responses which results in harm to its host. Damage to the host results from the immune system’s heightened response rather than the presence of the antigen itself.

The hypersensitivity response can be a result of contact with intrinsic antigens (such as in autoimmune conditions), or extrinsic antigens (in response to allergens, drugs, or infectious organisms) which are usually otherwise not seen as harmful (e.g. penicillin, peanuts, or a cell surface receptor).

Hypersensitivity develops in two phases. The initial phase is known as the sensitization phase which is when the host’s immune system is first exposed to the antigen. This activates antigen-presenting cells (APCs) and effector memory T cells. The host is then said to be sensitised to the antigen. The next step is the effector phase which occurs after subsequent exposures to that same antigen and results in the activation of memory cells from the adaptive immune system. Depending on the type of hypersensitivity, this may involve antigen-specific antibodies or T-cell mediated immune responses. This process creates the ongoing hypersensitivity reactions with further exposures.

Types of Hypersensitivity Reactions

Hypersensitivity reactions are divided into 4 main types:

• Type I - an immediate allergy typically caused by environmental non-infectious antigens.
• Type II - a hypersensitivity reaction that is mediated by antibodies, meaning it is a reaction against cell-bound antigens.
• Type III - a hypersensitivity reaction that is immune complex-mediated, meaning it is a reaction against soluble antigens.
• Type IV - a delayed response that is T-cell mediated and is caused by environmental, infectious, and self-antigens.

One way to remember which type of hypersensitivity reaction correlates with which number is the ABCD method:

Type I is Allergic
Type II is antiBody-mediated
Type III is immune Complex mediated
Type IV is Delayed

Type I Hypersensitivity

Information about type I hypersensitivity makes up a large proportion of hypersensitivity. For this reason, we have split it into articles 2 and 3 of the immunology and allergy section, titled Type I Hypersensitivity Reactions and Food Allergies.

Type II Hypersensitivity

Type II hypersensitivity is mediated by IgG or IgM antibodies. These always target cell-bound antigens which can either be exogenous (from outside the body) or endogenous (from within the body). The result of the immune overreaction can vary from cell or tissue damage to physiological changes.

Examples of exogenous type II hypersensitivity reactions include:

• Haemolytic Disease of the Newborn - an IgG-mediated reaction where the natural maternal antibodies against non-self blood types pass into the baby’s circulation, causing haemolysis when the blood types do not match. It is important to know that this reaction is IgG mediated as IgG antibodies can cross the placental membranes into the foetal circulation and others cannot.
• Haemolytic Transfusion Reactions - an IgM-mediated reaction against transfused blood when the type of the donor blood and the recipient blood do not match.

Examples of endogenous type II hypersensitivity reactions include:

• Autoimmune Haemolytic Anaemia - when the body forms an antibody against its own red blood cells, leading to immune-mediated destruction of these cells and haemolysis.
• Immune Thrombocytopenia Purpura - antibodies form against platelets, resulting in a very low platelet count, resulting in a characteristic purple bruising pattern and a high risk of bleeding.
• Goodpasture’s Syndrome (Anti-glomerular Basement Membrane Disease) - a condition characterised by antibody formation against the basement membrane of the kidneys and lungs, resulting in permanent lung and kidney damage.

Plasmapheresis therapy acts to filter the blood of circulating antibodies and provides short-term relief of disease burden, allowing time for other treatments to take effect. However, antibody production continues, so plasmapheresis is generally used as a temporary or adjunctive measure in selected conditions rather than as a definitive long-term therapy.

Type III Hypersensitivity

Type III hypersensitivity involves the formation of immune complexes containing IgG or IgM antibodies binding to antigens. In type III hypersensitivity, complexes form as antibodies exclusively target soluble antigens (which can be both endogenous or exogenous), as opposed to type II hypersensitivity where antibodies bind to cell-bound antigens.

The damage here is a result of immune complexes depositing in the host’s tissues (generally the joints, kidney, small vessels, and skin), often resulting in multisystemic disease. Deposition of complexes activates the complement system leading to local inflammation and eventually release of oxygen free radicals that can cause further damage to local tissues.

Examples of diseases caused by type III hypersensitivity include Systemic Lupus Erythematosus (autoimmune) and Post-streptococcal Glomerulonephritis (extrinsic) in which immune complexes of human antibodies with streptococcal antigens deposit in the kidneys leading to impaired renal function.

Type IV Hypersensitivity

Type IV hypersensitivity is mediated by antigen-specific helper T-cells that recruit lymphocytes and macrophages which release pro-inflammatory factors causing local oedema, swelling and erythema. This type of hypersensitivity is also known as delayed hypersensitivity as the reaction can appear up to several days post-exposure.

Examples of type IV hypersensitivity reactions caused by exogenous antigens include:

• Contact Dermatitis - causes an epidermal reaction following contact with exogenous antigens (common ones being nickel, poison ivy or organic chemicals).
• Granulomatous Hypersensitivity - typically develops over weeks to months post-exposure. Common examples include tuberculosis, tuberculoid leprosy, schistosomiasis and sarcoidosis.

Examples of type IV hypersensitivity reactions caused by endogenous antigens include insulin-dependent diabetes mellitus and Hashimoto’s thyroiditis.

It is important to note that some diseases might encompass more than one type of hypersensitivity reaction mechanism in their pathophysiology. Different types of hypersensitivity reactions are not mutually exclusive and can co-exist. An interesting example of this is Hashimoto’s thyroiditis which is most commonly classed as a type IV hypersensitivity but the disease mechanism underlying this condition also presents some features of type II hypersensitivity. T-helper cells recruit B-cells which leads to cytotoxicity by producing antibodies that bind to thyroid cells, but they also recruit cytotoxic T-lymphocytes (CTLs) which cause cell apoptosis of targeted thyroid cells.

Type III and IV hypersensitivities are managed in a similar way using anti-inflammatory drugs such as NSAIDs, corticosteroids or other steroid-sparing agents (e.g. azathioprine, mycophenolate mofetil and cyclophosphamide). Recently, monoclonal antibodies have also been added to the management of some conditions (see our article on Monoclonal Antibodies).

Edited by: Dr. Maddie Swannack

Reviewed by: Dr. Thomas Burnell

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