Hypersensitivity Reactions: The Four Types (Gell and Coombs Classification)

The immune system is built to attack threats. But sometimes it attacks too hard, or attacks the wrong thing, and the response itself causes the damage. A bee sting that kills within minutes, a mismatched blood transfusion, the joint damage of lupus, the rash of poison ivy days after contact, these are all the immune system harming its own host.

They look nothing alike, yet they sort into just four patterns based on which part of the immune system is doing the damage and how fast. Those four patterns are the Gell and Coombs classification, and learning them is the key that organizes a huge amount of clinical immunology. This article is the map: what the four types are, how to tell them apart, and where each one leads.

Hypersensitivity refers to an exaggerated or unnecessary reaction produced by the host immune system. It is an immunological dysfunction, mainly targeted at innocuous antigens with consequent tissue damage. The human immune system protects body from damage by fighting invasive substances and infections. Sometimes, however, it can ‘overreact,’ identifying harmless substances as harmful, which causes undesirable consequences. This is called a hypersensitivity response.

How the four types are organized

The Gell and Coombs classification sorts hypersensitivity by two questions: what does the damage, and how fast.

The first split is antibody versus cells.

1. Types I, II, and III are all mediated by antibodies (they are called the humoral or immediate types).
2. Type IV is different: it is mediated by T cells, not antibodies, which is why it is slower and is called delayed hypersensitivity.

Within the antibody types, the difference is what the antibody targets:

1. Type I: IgE reacts to a harmless allergen, triggering mast cells. This is allergy.
2. Type II: IgG or IgM binds an antigen on a cell surface, marking that cell for destruction. This is cytotoxic.
3. Type III: IgG or IgM binds soluble antigen, forming immune complexes that deposit in tissues. This is immune complex disease.
4. Type IV: T cells react to an antigen, recruiting macrophages and causing damage over days. This is delayed.

A widely used memory aid is ACID: Anaphylactic (I), Cytotoxic (II), Immune complex (III), Delayed (IV).

The one line that captures it: Types I to III use antibodies and act fast; Type IV uses T cells and acts slowly. Each type is covered in depth in its own article, linked in the sections below.

Types of Hypersensitivity Reactions

Figure: Different types of hypersensitivity

Type I hypersensitivity (allergic / anaphylactic)

Type I is the immediate allergic reaction. On first exposure, an allergen drives the production of IgE, which coats mast cells and basophils. On the next exposure, the allergen cross-links that IgE, and the mast cells release histamine and other mediators within minutes. This causes hay fever, allergic asthma, hives, and, at its most severe, anaphylaxis. The full mechanism, including the early and late phases, is covered in the article on type I hypersensitivity.

Type II hypersensitivity (cytotoxic)

Type II is antibody-mediated cell destruction. IgG or IgM binds an antigen on the surface of a cell, and this marks the cell for destruction by complement, by phagocytes, or by NK cells (ADCC). The result is the loss of those cells. Examples include mismatched blood transfusion reactions, hemolytic disease of the newborn, autoimmune hemolytic anemia, and Goodpasture syndrome. The full mechanism is covered in the article on type II hypersensitivity.

Type III hypersensitivity (immune complex)

Type III is caused by immune complexes. Here IgG or IgM binds soluble antigen (antigen floating free, not on a cell), forming antigen-antibody complexes. When these complexes deposit in tissues such as blood vessel walls, joints, and kidneys, they activate complement and trigger inflammation. Examples include serum sickness, the Arthus reaction, systemic lupus erythematosus, and post-streptococcal glomerulonephritis. The full mechanism is covered in the article on type III hypersensitivity.

Type IV hypersensitivity (delayed, cell-mediated)

Type IV is the odd one out: it uses T cells, not antibodies, so it develops slowly, over one to three days. Sensitized T cells recognize the antigen and recruit macrophages, which cause the tissue damage. Because no antibody is involved, it cannot be transferred by serum, only by cells. Examples include the tuberculin (Mantoux) skin test, contact dermatitis (such as poison ivy and nickel allergy), and granuloma formation in tuberculosis. The full mechanism is covered in the article on type IV hypersensitivity.

How to remember

ACID: the four types in order. Anaphylactic (I), Cytotoxic (II), Immune complex (III), Delayed (IV). The single most useful mnemonic for the classification.

The big split: antibody vs cells. Types I, II, III use antibodies and are fast. Type IV uses T cells and is slow. If it is delayed and cell-mediated, it is Type IV.

Types I to III by target: harmless allergen, cell-bound antigen, soluble antigen. Type I reacts to an allergen, Type II to antigen on a cell, Type III to antigen floating free. The target tells you the type.

Timing ladder: minutes, hours, hours, days. Type I is minutes (immediate), Types II and III are hours, Type IV is days (delayed).

Which antibody: IgE for I, IgG/IgM for II and III, none for IV. Type I is the IgE type; II and III use IgG/IgM; IV uses no antibody at all.

Key exam facts in one table

Where students get confused

"All hypersensitivity reactions are allergies." No. Only Type I is what people usually mean by allergy. Types II and III are antibody attacks on cells or tissues, and Type IV is a delayed T-cell reaction. Autoimmune diseases fall across types II, III, and IV.

"Type II and Type III are the same because both use IgG/IgM." No, and this is the key distinction. Type II antibody binds antigen on a cell surface (the cell is the target). Type III antibody binds soluble, free-floating antigen, forming complexes that then deposit in tissues. Cell-bound versus free-floating is the difference.

"Delayed hypersensitivity is delayed because the antibody is slow." No. Type IV has no antibody at all. It is delayed because it depends on T cells recruiting macrophages, which takes one to three days. The absence of antibody is why it is both delayed and non-transferable by serum.

"The lower the type number, the more severe." No. The numbers reflect mechanism, not severity. Type I includes both mild hay fever and fatal anaphylaxis; Type IV includes both a harmless skin test and severe drug reactions.

"Hypersensitivity and autoimmunity are different topics." They overlap. Many autoimmune diseases are hypersensitivity reactions against self-antigens: autoimmune hemolytic anemia is Type II, lupus is Type III, and type 1 diabetes involves Type IV. The mechanisms are the same; only the target (self versus foreign) differs.

References

1. Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular Immunology. 10th ed. Elsevier; 2022.
2. Punt J, Stranford SA, Jones PP, Owen JA. Kuby Immunology. 8th ed. W.H. Freeman; 2019.
3. Dispenza MC. Classification of hypersensitivity reactions. Allergy Asthma Proc. 2019;40(6):470–473. https://doi.org/10.2500/aap.2019.40.4274