Hypersensitivity (also called hypersensitivity reaction) is an immune response characterized by mechanisms that cause significant tissue damage or physiological dysfunction, whether directed against pathogens, harmless environmental antigens, or self-antigens that is reproducible upon re-exposure to the antigen. While hypersensitivity mechanisms can sometimes serve protective functions (such as control of infectious diseases), they are distinguished by their capacity to cause collateral tissue damage that may exceed any protective benefit. Collectively, hypersensitivities are extremely common: hay fever affects about 1 in 10 people worldwide, asthma affects hundreds of millions, and about 1 in 12 people have an autoimmune disease. In 1963, Philip George Houthem Gell and Robin Coombs introduced a systematic classification of the different types of hypersensitivity based on the types of antigens and immune responses involved. According to this system, known as the Gell and Coombs classification or Gell-Coombs's classification, there are four types of hypersensitivity:
Type I, which is an Immunoglobulin E (IgE)-mediated immediate reaction. Type II, an antibody-mediated reaction canonically involving IgG, IgM, or both. Type III, an immune complex-mediated reaction involving IgG, complement system and phagocytes. Type IV, a T cell-mediated, delayed hypersensitivity reaction. In addition to their different mechanisms, each one differs in the time to symptoms following exposure to the offending antigen. Type I hypersensitivity is also known as immediate hypersensitivity because it occurs within seconds to minutes of exposure. Type II (cytotoxic) and type III (immune complex) occur within hours of exposure. Type IV is also known as delayed-type hypersensitivity (DTH) and occurs days after exposure. Note: The Gell-Coombs classification of hypersensitivities (as well as the other ones discussed on this page) does not correspond to the modern classification of immune responses as type 1, type 2, or type 3. Type I hypersensitivities, for example, are inappropriate manifestations of type 2 immune responses (IgE, IL-4, IL-13-driven). Type IV are type 1 immune responses (IFN-γ, Th1, CD8 T cell-driven), when considering the original Gell-Coombs classification system. Type II and III can involve a mixture of different immune response types. Autoimmune diseases manifest as some form of type II, III, or IV hypersensitivity reaction as their key pathological process. It is possible to have multiple types of hypersensitivity reaction contribute to a disease at the same time, and the type of hypersensitivity reaction central to a given immunological disease can change over time (for example, acute hypersensitivity pneumonitis is thought to be a type III hypersensitivity, but as it becomes more chronic, it begins to become resemble type IV more), or even by region (allergic asthma behaves like a type IV hypersensitivity in the lower airways and like a type I hypersensitivity in the upper respiratory tract). Thus, these categories are best viewed as guides rather than absolute rules. An understanding of hypersensitivity reactions is important in guiding diagnostic and treatment decisions for the conditions that are mediated by them.
Terminology The term "allergy" has undergone significant revision over the years, originally referring specifically to type I hypersensitivities (i.e., an IgE-mediated process). However, modern professional societies define allergy to be any immunologic mechanism (whether IgE-mediated or not) that produces a hypersensitivity reaction. This has some use because some things often described as allergies or allergic diseases (e.g., nickel allergy, FPIES) are not type I hypersensitivity reactions. However, this means that anything under the Gell and Coombs classification can be considered an allergy, so long as the antigen being targeted by the hypersensitivity originates from outside the body (i.e., not autoimmune diseases). There are also non-immune hypersensitivity reactions included in classifications under more modern frameworks (type V, VI, and VII hypersensitivity under EAACI 2023 position paper classification, see below), which are not covered under Gell and Coombs's classification. These represent non-allergic hypersensitivity reactions. Despite this, many still use the term allergy specifically to describe type I hypersensitivity reactions, so it is best to obtain clarification whenever possible. Confusingly, the term "allergen" has not been updated to reflect this change in usage, and specifically refers to any antigen bound by IgE.
Gell and Coombs classification The Gell and Coombs classification of hypersensitivity is the most widely used, and distinguishes four types of immune response that result in bystander tissue damage on the basis of their mechanism.
These are elaborated upon in greater depth below in their respective sections.
Classifications beyond Gell & Coombs Note: The numerals used between the two frameworks presented below (EAACI 2023 and Pichler) overlap, but are not identical i.e., IVc in EAACI is not the same as IVc under Pichler's classification.
EAACI Proposed Categorization of Hypersensitivity reactions Over time, additional types of hypersensitivity reactions have been defined beyond the 4 proposed by Gell and Coombs. Per the most recent classification published by European Academy of Allergy and Clinical Immunology in 2023 in their position paper, hypersensitivities are classified as per the table below (type I-III are the same as in the Gell and Coombs classification, type IV is expanded, and types V-VII are new). Note that type IV hypersensitivities in this framework are not exactly the same as those in modernized Gell and Coombs' taxonomy. The table below details the additional and expanded types. EAACI 2023 groups type I-III hypersensitivities as antibody-mediated.
The expansion reflects recognition that not all adverse immune reactions fit the original antibody/cell-mediated dichotomy, particularly chronic inflammatory conditions with complex pathophysiology.
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