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Next Lesson - Type 1 Hypersensitivity
Contents
Abstract
- There are 4 classical (Gell and Coombs) types of hypersensitivity reaction, which play a key role in the pathogenesis (how a disease develops) of several diseases.
- They are classified based on the underlying pathophysiology (the body processes behind the disease) and the immune mediators (the antibodies or cells that cause the damage).
- Hypersensitivity reactions are not mutually exclusive; some diseases involve more than one type of hypersensitivity mechanism.
Core
Hypersensitivity is defined as an inappropriate or excessive, antigen-specific immune response 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 directed at intrinsic antigens (also called endogenous antigens: molecules from the body itself, such as a cell surface receptor in autoimmune conditions). It can also be directed at extrinsic antigens (also called exogenous antigens: molecules from outside the body, such as allergens, drugs or infectious organisms, for example penicillin or peanuts).
Hypersensitivity develops in two phases. The initial phase is known as the sensitisation phase which is when the host’s immune system is first exposed to the antigen. This activates antigen-presenting cells (APCs, cells that show pieces of antigen to T cells) which present antigen to naive antigen-specific T cells (T cells, a type of lymphocyte, that have not yet met their antigen), leading to formation of effector and memory populations (effector cells act against the antigen, and memory cells remember it). 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 classically divided into 4 main types (the Gell and Coombs classification). A 2023 European allergy nomenclature paper extends this to nine types, splitting type IV into subtypes and adding types V to VII, but this article covers the four classical types:
- Type I - an immediate allergy mediated by IgE (immunoglobulin E, the class of antibody involved in allergy), typically caused by environmental non-infectious antigens.
- Type II - a hypersensitivity reaction that is mediated by antibodies, meaning it is mainly a reaction against cell-bound antigens.
- Type III - a hypersensitivity reaction that is immune complex-mediated (an immune complex is an antibody bound to its antigen), 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 is a large topic, so we cover it in articles 2 and 3 of the immunology and allergy section. They are titled Type I Hypersensitivity Reactions and Food Allergies respectively.
Type II hypersensitivity is mediated by IgG or IgM antibodies (immunoglobulin G and immunoglobulin M, two classes of antibody). These target antigens on the surface of cells or in the extracellular matrix (the supporting material around cells), 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 Fetus and Newborn (HDFN, also called haemolytic disease of the newborn) - an IgG-mediated reaction. The mother makes antibodies against blood group antigens that her baby has inherited from the father and that she lacks (for example the rhesus D antigen). These maternal antibodies pass into the baby’s circulation, causing haemolysis (breakdown of red blood cells) 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 fetal circulation and the other antibody classes cannot.
- Haemolytic Transfusion Reactions - a reaction mediated by IgM or IgG antibodies against transfused red blood cells when the type of the donor blood and the recipient blood do not match. In a delayed reaction, antibodies that were previously undetectable become active again on re-exposure to the antigen.
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 (ITP, formerly called idiopathic thrombocytopenic purpura) - antibodies form against platelets, so the platelets are removed faster than normal. This causes a low platelet count (thrombocytopenia), purpura (purple-red spots and patches caused by bleeding into the skin) and episodes of bleeding.
- Goodpasture’s Syndrome (Anti-glomerular Basement Membrane Disease) - a condition characterised by antibody formation against the basement membrane (the thin supporting layer under the lining cells) of the kidneys and lungs. It causes glomerulonephritis (inflammation of the kidney’s filters) and, in about half of cases, bleeding into the lungs. The kidney damage may be permanent, especially if treatment is delayed. Anti-GBM disease can affect the kidneys alone, and the name Goodpasture’s syndrome is used when the lungs are involved too.
Plasmapheresis (also called plasma exchange) filters circulating antibodies out of the blood. It does not stop the body making new antibodies, so in anti-GBM disease it is given together with immunosuppressive drugs (drugs that damp down the immune system), such as cyclophosphamide and corticosteroids. This combination has greatly improved outcomes, particularly in people who do not yet need dialysis (a treatment that does the kidneys’ filtering job). In other type II conditions, plasmapheresis is generally kept for severe cases.
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 target soluble antigens (which can be both endogenous and exogenous). In type II hypersensitivity, by contrast, antibodies bind to antigens fixed on cells or in tissues.
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 (affecting several body systems). Deposition of complexes activates the complement system (a group of blood proteins that help destroy targets and trigger inflammation) leading to local inflammation and eventually release of oxygen free radicals (highly reactive molecules) that can cause further damage to local tissues.
Examples of diseases caused by type III hypersensitivity include Systemic Lupus Erythematosus (an autoimmune disease that can affect many organs) and Post-streptococcal Glomerulonephritis (extrinsic), which is inflammation of the kidney’s filters after a streptococcal infection. In this disease, immune complexes of human antibodies with streptococcal antigens deposit in the kidneys, leading to impaired renal function.
Type IV hypersensitivity is mediated by antigen-specific T-cells, mainly helper T-cells (CD4+ cells) and also cytotoxic T-cells (CD8+ cells, which kill other cells). The helper T-cells recruit lymphocytes and macrophages which release pro-inflammatory factors (cytokines, chemical messengers that drive inflammation) causing local oedema, swelling and erythema (redness). This type of hypersensitivity is also known as delayed hypersensitivity as the reaction typically appears 48 to 72 hours after exposure, although some take weeks to develop.
Examples of type IV hypersensitivity reactions caused by exogenous antigens include:
- Allergic Contact Dermatitis - causes an epidermal reaction (inflammation of the outer layer of the skin) following contact with exogenous antigens (common ones being nickel, fragrances, hair dye and plants such as primula, or poison ivy in North America). Irritant contact dermatitis is not an immune reaction, so it is not a type IV hypersensitivity.
- Granulomatous Hypersensitivity (forming granulomas, which are small nodules of immune cells) - typically develops over weeks to months post-exposure. Common examples include tuberculosis, tuberculoid leprosy and schistosomiasis (a parasitic infection). Sarcoidosis (a multisystem disease that forms granulomas) is also grouped here, but its cause is unknown. It may be an inflammatory response to an environmental agent or infection in people who are genetically predisposed.
Examples of type IV hypersensitivity reactions caused by endogenous antigens include type 1 diabetes mellitus (previously called insulin-dependent diabetes mellitus) and Hashimoto’s thyroiditis (an autoimmune inflammation of the thyroid gland).
It is important to note that some diseases involve 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. It 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 (the cells that make antibodies), which produce antibodies that bind to thyroid cells and lead to cytotoxicity (killing of the cells). The T-helper cells also recruit cytotoxic T-lymphocytes (CTLs), which cause apoptosis (programmed cell death) of targeted thyroid cells.
Management depends on the condition and its cause, not just on the type of hypersensitivity. The usual aims are to remove the trigger, support the affected organ and, in more severe disease, damp down the immune response. For example, allergic contact dermatitis is treated by avoiding the allergen, using emollients (moisturisers) and sometimes topical corticosteroids. Immune-mediated kidney disease (glomerulonephritis) may need corticosteroids or other immunosuppressants, and NSAIDs (non-steroidal anti-inflammatory drugs, such as ibuprofen) are generally avoided because they can impair kidney function. Some severe conditions need steroid-sparing agents (drugs that allow a lower steroid dose), for example azathioprine, mycophenolate mofetil and cyclophosphamide. Monoclonal antibodies (laboratory-made antibodies aimed at one target) are also used in the management of some conditions (see our article on Monoclonal Antibodies).
Edited by: Dr. Maddie Swannack
Reviewed by: Dr. Thomas Burnell and Dr. Marcus Judge
Quiz
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