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. +Gell and Coombs Hypersensitivity Reactions Classification Type Alternative names Antibodies or Cell Mediators Immunologic Reaction Timing Clinical Examples (some conditions involve multiple types of hypersensitivity reactions simultaneously) I ImmediateIgE, mast cells Before a type I hypersensitivity reaction may occur, sensitization is required to produce antigen (allergen)-specific IgE.
Secreted IgE binds to the high-affinity IgE receptor on the surface of mast cells, basophils, and potentially eosinophils. IgE is predominantly bound to the surface of mast cells because of the strength of the association (KD ≈ 10−10 M), and levels in the circulation are minimal. Allergen is bound by membrane-bound IgE. IgE-allergen complex is sensed by mast cells, basophils, and eosinophils. Mast cells (as well as basophils) degranulate, liberating key vasoactive mediators such as histamine, leukotrienes, as well as tryptase, platelet-activating factor, and heparin (among other substances). Mast cells are the principal tissue effector cells in type I reactions.Rapidly upon exposure to the allergen (seconds to minutes, typically). allergic rhinitis food allergy urticaria/angioedema venom allergy drug allergy IgE-mediated anaphylaxis α-gal syndrome (delayed onset of symptoms relative to exposure) II Antibody-dependent CytotoxicIgG, IgM, complement, FcγRs, phagocytes, NK cells Type II reactions are formed against cell surface or matrix antigens.
Surface-bound antigen is recognized by pre-formed IgG or IgM antibodies. Classical pathway of complement activation is initiated on the surface of the cell. Complement activation produces opsonins that can be recognized by complement receptor-expressing phagocytes. Membrane attack complex forms a pore in the cell. Antibody-dependent cellular cytotoxicity may occur via FcγR-dependent mechanisms.
In some cases, the antibody may have an agonistic function, as in Graves disease, in which antibodies target and activate the TSH receptor, inducing hyperthyroidism.
Otherwise, the antibodies may exert a blocking function, as in myasthenia gravis, in which antibodies against the acetylcholine receptor (AchR) or muscle-specific kinase (MusK) prevent interactions with their target ligand. Hours–days after re-exposure. Autoimmune hemolytic anemia Rheumatic heart disease Erythroblastosis fetalis Goodpasture's syndrome Graves' disease (agonistic antibodies) Myasthenia gravis (blocking antibodies) Pemphigus vulgaris Drug-induced cytopenia III Immune complexImmune complexes (IgG, IgA, IgM), complement, FcγRs Type III hypersensitivities occur in response to soluble antigens.
Antigen–antibody complexes form in excess and deposit in vessel walls and other tissues e.g., the synovium. Complement activation generates anaphylatoxins that recruit and activate neutrophils. Neutrophil enzymes and ROS cause vasculitis and tissue injury.
Type III is distinguished from type II also on the basis of the fact that it is driven by immune complex deposition, whereas type II hypersensitivity does not depend on the deposition of immune complexes. Hours to days after re-exposure. Serum sickness Arthus reaction Post streptococcal glomerulonephritis Membranous nephropathy Reactive arthritis Lupus nephritis Systemic lupus erythematosus Hypersensitivity pneumonitis IV Delayed T-cells Cytotoxic T cells (CTLs) T helper cells CTLs and T helper cells are activated by an antigen presenting cell. When the antigen is presented again in the future, the memory T cells will be activated and cause an inflammatory response mediated by the effector cells activated by the T cells (e.g., CTLs, neutrophils, macrophages, eosinophils) and the cytokines produced.Le, Tau. First Aid for the USMLE Step 1 2013, p. 203-204 The classical version of type IV hypersensitivity is demonstrated with the tuberculin skin test, which is a Th1-driven reaction. In modernized versions of the Gell and Coombs framework, there are 4 subtypes of type IV hypersensitivity which are driven by type 1 immune responses (IVa), type 2 immune responses (IVb), cytotoxicity (IVc), and type 3 immune responses (IVd).Delayed; peaks ~48–72 hours after re-exposure. Contact dermatitis Mantoux test Chronic transplant rejection Coeliac disease Hashimoto's thyroiditis Granuloma annulare 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. +EAACI 2023 Hypersensitivity Reaction ClassificationsGroup ClassCritical MediatorsMechanismTimingClinical Examples (some conditions involve multiple types of hypersensitivity reactions simultaneously)Cell-mediatedType IVa (cell-mediated, type 1)Th1 cells, IFN-γ, activated macrophages Antigen is presented to memory Th1/Tc1 cells. These cells release IFN-γ and related mediators that activate macrophages. Local induration and, with persistence, granuloma-type pathology develops. Delayed; peaks ~48–72 h. Tuberculin skin test chronic phase of hypersensitivity pneumonitis celiac disease some contact dermatitis patterns non-type 2 endotypes of asthma Cell-mediatedType IVb (cell-mediated, type 2)Th2 cells, IL-4, IL-5, IL-13, eosinophils Antigen presentation favors Th2 responses. Th2 cytokines recruit and activate eosinophils and can drive IgE class switching. Eosinophil-rich inflammation leads to tissue symptoms and chronicity.