Hypersensitivity

Hypersensitivity 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, 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 -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 and type III occur within hours of exposure. Type IV is also known as delayed-type hypersensitivity and occurs days after exposure.
Note: The Gell-Coombs classification of hypersensitivities 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. Type IV are type 1 immune responses, 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, or even by region. 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. However, modern professional societies define allergy to be any immunologic mechanism that produces a hypersensitivity reaction. This has some use because some things often described as allergies or allergic diseases 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. There are also non-immune hypersensitivity reactions included in classifications under more modern frameworks, 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.

Type	Alternative names	Antibodies or Cell Mediators	Immunologic Reaction	Timing	Clinical Examples
I	Immediate	IgE, mast cells	Before a type I hypersensitivity reaction may occur, sensitization is required to produce antigen -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, 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 degranulate, liberating key vasoactive mediators such as histamine, leukotrienes, as well as tryptase, platelet-activating factor, and heparin. Mast cells are the principal tissue effector cells in type I reactions.	Rapidly upon exposure to the allergen.	allergic rhinitis food allergy urticaria/angioedema venom allergy drug allergy IgE-mediated anaphylaxis α-gal syndrome
II	Antibody-dependent Cytotoxic	IgG, 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 or muscle-specific kinase prevent interactions with their target ligand.	Hours–days after re-exposure.	Autoimmune hemolytic anemia Rheumatic heart disease Erythroblastosis fetalis Goodpasture's syndrome Graves' disease Myasthenia gravis Pemphigus vulgaris Drug-induced cytopenia
III	Immune complex	Immune complexes, 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 * 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 and the cytokines produced. 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, type 2 immune responses, cytotoxicity, and type 3 immune responses.	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 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. Note that type IV hypersensitivities in this framework are not exactly the same as those in modernized Gell and Coombs' taxonomy. Because types I, II, and III are the same as with Gell and Coombs, the table below begins with type IVa to minimize redundancy. EAACI 2023 groups type I-III hypersensitivities as antibody-mediated.

Group	Class	Critical Mediators	Mechanism	Timing	Clinical Examples
Cell-mediated	Type IVa	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-mediated	Type IVb	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. There is significant overlap between type IVa hypersensitivity and type I hypersensitivity in terms of the mechanisms and players involved. The major distinctions lie in timing and the predominant role of eosinophilic inflammation via IL-5 in type IVb but not type I hypersensitivity reactions. The synthesis of IgE occurs at the end stage of type IVb hypersensitivity, whereas it is a prerequisite for type I hypersensitivity to occur. However, specific reactions may include features of both e.g., acute bronchospasm in asthma is often type I, but the chronic phase with eosinophilia and persistent inflammation via Th2s and ILC2s is more similar to type IVb. Type IVb hypersensitivity can also induce dysfunction of the epithelial barrier as in type V hypersensitivity.	Usually days–weeks; often chronic relapsing.	Atopic dermatitis endotypes asthma/CRS T2 endotypes eosinophilic esophagitis DRESS
Cell-mediated	Type IVc	T-cell–derived chemokines, GM-CSF, neutrophils	Antigen presentation elicits Th17/Tc17 responses. IL-17–family signals recruit and activate neutrophils and local innate pathways. Neutrophil enzymes and extracellular traps contribute to epithelial injury.	Delayed; typically days.	Neutrophilic asthma endotypes neutrophil-predominant dermatitis variants. Note: some drug eruptions historically labeled "Type IVd" in other taxonomies are included here in the EAACI scheme.
Tissue-driven mechanisms	Type V	Epithelial barrier defects, TSLP, IL-33, IL-25, ILC2/Th2 pathways	Barrier disruption increases allergen and microbe access. Epithelial signals activate downstream immune pathways and sustain inflammation. Chronic disease reflects ongoing barrier dysfunction with mixed immune features. In type V hypersensitivity, immunological dysfunction occurs downstream of barrier dysfunction. Loss of barrier integrity itself induces recruitment of immune cells. For example, mutations in filaggrin predispose to multiple allergic diseases regardless of pre-existing atopy. Some immunologists contest whether this represents a distinct type of hypersensitivity or just a predisposing factor to hypersensitivity.	Chronic with exposure-triggered flares.	atopic dermatitis allergic rhinitis chronic rhinosinusitis with nasal polyps asthma eosinophilic esophagitis celiac disease protein-losing enteropathy
Tissue-driven mechanisms	Type VI	Adipokines, innate cytokines, oxidative stress	Obesity and related metabolic states create systemic low-grade inflammation. This milieu modifies airway/tissue immunity and disease endotypes. Severity and treatment response can be altered. Note that this is not saying that obesity or metabolic disorders are themselves a hypersensitivity reaction, but rather that they produce conditions that induce type VI hypersensitivity. The EAACI regards type VI hypersensitivity more as a modifier of existing hypersensitivity reactions rather than a distinct type of hypersensitivity.	Chronic; tracks with metabolic stress.	Obesity-associated asthma phenotypes and related airway disease
Direct response to chemicals	Type VII	cysteinyl-leukotrienes, mast cells	Multiple, depending on the substance in question. Classic examples: COX-1 inhibition results in enhanced production of cysteinyl-leukotrienes causing bronchoconstriction Mast cells are activated directly by MRGPRX2ligands, ion channels, or other GPCR ligands independently of IgE	Minutes–hours.	AERD/N-ERD Non-allergic hypersensitivity reaction

The expansion reflects recognition that not all adverse immune reactions fit the original antibody/cell-mediated dichotomy, particularly chronic inflammatory conditions with complex pathophysiology.