Hypersensitivity Reactions

The immune system exists to protect us, but it is a powerful weapon, and any weapon can wound the person holding it. Hypersensitivity reactions are what happen when an immune response that is normally protective becomes exaggerated, misdirected, or triggered by something harmless. The result ranges from an itchy nose in spring to a fatal collapse within minutes of a bee sting. Understanding these reactions is not academic housekeeping — it is the difference between recognising anaphylaxis and reaching for adrenaline in time, versus watching a preventable death unfold.

This page walks you through the classic Gell and Coombs classification (Types I to IV), the cellular and molecular machinery behind each, and the clinical faces they wear. We will pay special attention to allergy and anaphylaxis, and to the remarkable story of how anaphylaxis was discovered — a piece of history that gave immunology one of its foundational ideas.

Learning Objectives

• Define hypersensitivity and explain why a protective immune system can cause disease.
• Describe the four Gell and Coombs types (I–IV) by mechanism, mediator, timing, and example.
• Explain the two-phase model of Type I allergy: sensitisation and re-exposure, and the role of IgE, mast cells, and basophils.
• Recognise anaphylaxis clinically and state the immediate management priority.
• Distinguish Type II (cytotoxic) from Type III (immune complex) reactions, which students routinely confuse.
• Relate the history of anaphylaxis (Richet and Portier) to modern understanding of allergy.

Quick Answer

Hypersensitivity reactions are damaging immune responses to antigens that are either harmless (allergens) or self (autoimmunity). The Gell and Coombs system sorts them into four types. Type I is immediate, IgE-mediated allergy — mast cells and basophils release histamine within minutes (hay fever, asthma, anaphylaxis). Type II is antibody-mediated cytotoxicity, where IgG or IgM binds cells or tissue and destroys them (transfusion reactions, autoimmune haemolytic anaemia). Type III is immune-complex disease, where antigen–antibody complexes deposit in tissues and trigger inflammation (serum sickness, lupus nephritis). Type IV is delayed, T-cell-mediated hypersensitivity, taking 48–72 hours (contact dermatitis, the TB skin test, transplant rejection). Types I–III are antibody-driven and relatively fast; Type IV is cell-driven and delayed. The most urgent is anaphylaxis, treated first-line with intramuscular adrenaline.

Where It Came From

For most of history, allergy had no name and no explanation — people simply knew that some foods, plants, or stings made certain individuals ill. The concept crystallised at the turn of the twentieth century through a discovery that surprised its own discoverers.

In 1901, the French physiologist Charles Richet, working with Paul Portier aboard the yacht of Prince Albert I of Monaco, was studying the toxin of the Portuguese man-of-war and sea anemones. Their goal was to build tolerance — to protect dogs by giving small, sub-lethal doses of toxin, expecting that prior exposure would create immunity (from the Greek phylaxis, meaning protection). Instead, when a previously exposed dog received a second small dose weeks later, it collapsed and died within minutes — a dose it should easily have survived. The prior exposure had made the animal dramatically more vulnerable, not less. Richet coined the term anaphylaxis — literally "against protection" — to capture this paradox. He received the Nobel Prize in Physiology or Medicine in 1913 for the work.

The lesson was profound: the immune system does not only protect; a first "harmless" exposure can prime the body so that a second exposure becomes catastrophic. This idea of sensitisation followed by an amplified re-exposure response is the conceptual backbone of all Type I allergy. Around the same time, Clemens von Pirquet coined the word allergy (1906) to describe altered reactivity, and Robert Koch's tuberculin reaction (1890) had already demonstrated a slow, cell-mediated form of hypersensitivity. Decades later, in 1963, immunologists Philip Gell and Robin Coombs organised these scattered observations into the four-type framework students still learn today. The 1966 identification of IgE by the Ishizakas and by Johansson finally gave Type I allergy its molecular messenger.

The Gell and Coombs Framework: A Map of Four Mechanisms

The genius of Gell and Coombs was to classify hypersensitivity not by symptom but by mechanism — by which immune components do the damage. A useful memory aid is ACID: Allergic (Type I), Cytotoxic (Type II), Immune complex (Type III), Delayed (Type IV). Types I–III all use antibodies; Type IV uses T cells directly. Keep in mind that real diseases can blend types — this is a teaching map, not a rigid law of nature.

Type I: Immediate (IgE-Mediated) Hypersensitivity

Type I is what most people mean by "allergy." It unfolds in two phases separated by time.

Phase 1 — Sensitisation (no symptoms). On first exposure, an allergen (pollen, peanut protein, bee venom) is taken up by antigen-presenting cells and shown to T-helper cells. In allergy-prone individuals, these become Th2 cells, which secrete interleukins IL-4 and IL-13. These cytokines instruct B cells to class-switch and produce IgE antibodies specific to that allergen. The IgE then binds to high-affinity FcεRI receptors on the surface of mast cells (in tissues) and basophils (in blood). The person now feels completely normal but is "loaded" — primed exactly as Richet's dogs were.

Phase 2 — Re-exposure (the reaction). On the next encounter, the allergen cross-links two adjacent IgE molecules on a mast cell. This bridging triggers degranulation within seconds to minutes, releasing preformed histamine, tryptase, and heparin, followed by newly synthesised leukotrienes and prostaglandins. Histamine causes vasodilation, increased vascular permeability (swelling, wheals), smooth-muscle contraction (bronchospasm), and itch.

A late-phase reaction may follow 4–12 hours later, driven by eosinophils and Th2 cells recruited to the site — this explains why asthma or a nasal allergy can flare again hours after the initial trigger.

Clinical spectrum: localised forms include allergic rhinitis (hay fever), allergic conjunctivitis, atopic asthma, urticaria (hives), and food allergy. The systemic, life-threatening form is anaphylaxis.

Worked Example: Anaphylaxis

A 19-year-old with known peanut allergy eats a cookie containing traces of peanut. Within 10 minutes she develops widespread hives, lip and tongue swelling, a hoarse voice, wheeze, and light-headedness; her blood pressure is 80/50.

What is happening: massive, systemic mast-cell and basophil degranulation. Histamine and leukotrienes cause bronchoconstriction (wheeze), laryngeal oedema (hoarse voice — a red flag for airway compromise), profound vasodilation and capillary leak (hypotension, "distributive shock"), and urticaria.

Immediate management: intramuscular adrenaline (epinephrine) into the anterolateral thigh, without delay — it is the only first-line treatment that reverses the airway swelling and hypotension by causing vasoconstriction and bronchodilation and stabilising mast cells. Lay the patient flat with legs raised (or sitting up if breathing is the main problem), give high-flow oxygen, obtain IV access, and give fluids for hypotension. Antihistamines and steroids are adjuncts only — they are too slow and too weak to treat the acute event. Because a biphasic reaction can recur hours later, the patient must be observed and referred.

Type II: Antibody-Mediated (Cytotoxic) Hypersensitivity

Here IgG or IgM antibodies bind directly to antigens on the surface of the patient's own cells or on fixed tissue (basement membranes). The damage is done by three routes: (1) complement activation leading to cell lysis or attracting neutrophils; (2) opsonisation and phagocytosis in the spleen; and (3) antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells. A special subtype involves antibodies that alter cell function without destroying the cell.

Examples:

• ABO-incompatible transfusion reaction — recipient antibodies attack donor red cells; a true emergency.
• Haemolytic disease of the newborn — maternal anti-Rh(D) IgG crosses the placenta and destroys fetal red cells.
• Autoimmune haemolytic anaemia and immune thrombocytopenia.
• Goodpasture syndrome — antibodies against glomerular and alveolar basement membrane cause kidney failure and lung haemorrhage.
• Functional/Type V variants: Graves disease (antibody stimulates the TSH receptor, causing hyperthyroidism) and myasthenia gravis (antibody blocks the acetylcholine receptor, causing weakness).

Type III: Immune Complex Hypersensitivity

In Type III, antibody binds soluble antigen in the bloodstream, forming antigen–antibody (immune) complexes. Normally these are cleared, but when antigen is in slight excess, small complexes escape clearance and deposit in vessel walls, joints, skin, and glomeruli. There they activate complement, recruit neutrophils, and drive inflammation and tissue damage. The key distinction from Type II is where the antibody acts: Type II antibody attacks a fixed target on a specific cell; Type III antibody forms free-floating complexes that lodge in tissues far from the original antigen.

Examples:

• Serum sickness — historically after horse-serum antitoxin; fever, rash, arthralgia, and lymphadenopathy about 1–2 weeks after exposure (the delay reflects the time to make antibody). Modern equivalents include reactions to some biologic drugs.
• Systemic lupus erythematosus (SLE) — DNA–anti-DNA complexes deposit in kidneys (lupus nephritis), skin, and joints.
• Post-streptococcal glomerulonephritis.
• The Arthus reaction — a localised version: intense local inflammation where antigen is injected into a pre-sensitised individual.

Type IV: Delayed (Cell-Mediated) Hypersensitivity

Type IV is the outlier: no antibody is involved. Instead, previously sensitised T cells drive the reaction, which is why it takes 48–72 hours to appear. On re-exposure, memory T cells recognise antigen presented by macrophages and dendritic cells; CD4+ Th1 cells release cytokines (notably interferon-gamma) that activate macrophages, and CD8+ cytotoxic T cells can kill target cells directly.

Examples:

• Contact dermatitis — poison ivy, nickel, latex, cosmetics; the itchy, blistering rash appears a day or two after contact.
• The tuberculin (Mantoux) skin test — induration read at 48–72 hours; the archetype used to teach this type.
• Granulomatous diseases — tuberculosis, sarcoidosis, leprosy, where persistent antigen drives chronic macrophage activation and granuloma formation.
• Chronic transplant rejection and type 1 diabetes (T-cell destruction of islet cells).

Real-World Applications

• Emergency medicine: rapid recognition of anaphylaxis and immediate IM adrenaline saves lives; every clinician and many patients (via auto-injectors) must know this.
• Transfusion and transplant medicine: ABO/Rh matching prevents Type II reactions; anti-D immunoglobulin (given to Rh-negative mothers) prevents haemolytic disease of the newborn — a triumph of applied immunology.
• Diagnostics: skin-prick testing detects Type I sensitisation; the patch test detects Type IV contact allergy; the Mantoux test screens for TB exposure.
• Pharmacovigilance: drug reactions span all four types — penicillin can cause Type I anaphylaxis, Type II haemolysis, Type III serum sickness, or Type IV rashes, so "penicillin allergy" needs careful characterisation before it is labelled lifelong.
• Everyday life: hay fever, food labelling laws, hypoallergenic jewellery, and asthma inhalers all trace back to this science.

Common Mistakes

1. "Antihistamines are the main treatment for anaphylaxis." Wrong and dangerous. Antihistamines only ease skin symptoms and act too slowly. The correction: intramuscular adrenaline is first-line and must not be delayed while reaching for other drugs.

2. Confusing Type II with Type III. Both use IgG/IgM and complement, so students mix them up. The correction: in Type II the antibody binds a fixed antigen on a specific cell or tissue; in Type III the antibody forms soluble circulating complexes that deposit elsewhere. Target location is the discriminator.

3. Thinking all hypersensitivity is fast. Only Types I–III are relatively rapid. Type IV is delayed (48–72 hours) and antibody-free — driven by T cells. Expecting a poison-ivy rash or a positive Mantoux test to appear immediately is a classic error.

4. Believing a reaction on first exposure is "the allergy." In Type I, the first exposure usually causes only sensitisation with no symptoms; the clinical reaction needs a subsequent exposure. This is exactly the paradox Richet uncovered.

Comparison and Connections

Feature	Type I	Type II	Type III	Type IV
Mechanism	IgE, mast cells	IgG/IgM vs cell-bound antigen	Immune complexes deposit	T cells (Th1, CD8)
Main mediator	Histamine, leukotrienes	Complement, phagocytes, NK	Complement, neutrophils	Cytokines, macrophages
Timing	Seconds to minutes	Hours	Hours to weeks	48–72 hours
Antibody?	Yes (IgE)	Yes (IgG/IgM)	Yes (IgG/IgM)	No (T-cell)
Classic example	Anaphylaxis, hay fever	Transfusion reaction	Serum sickness, SLE	Contact dermatitis, TB test

Type I connects to asthma and atopic disease; Type II and III underlie much of autoimmunity; Type IV links to infection control (granulomas) and transplant immunology. All four are downstream of the adaptive immune response you study in antibody and T-cell biology.

Practice Questions

Recall

Q: Which immunoglobulin mediates Type I hypersensitivity, and which cells does it arm? A: IgE, which binds FcεRI receptors on mast cells and basophils.

Understanding

Q: Why does a Type IV reaction take 2–3 days to appear, while Type I appears in minutes? A: Type I uses preformed IgE already bound to mast cells, so mediators release instantly on allergen contact. Type IV requires memory T cells to recognise antigen, proliferate, and recruit/activate macrophages — a cellular process that unfolds over 48–72 hours.

Application

Q: A patient develops fever, rash, and joint pain 10 days after receiving an antivenom made from animal serum. Which type is this and why the delay? A: Type III (serum sickness). The delay reflects the ~1–2 weeks needed for the patient to generate antibody against the foreign serum protein, which then forms immune complexes that deposit in tissues.

Analysis

Q: Penicillin can cause four different hypersensitivity reactions. Explain how one drug can trigger all four types. A: Penicillin acts as a hapten binding host proteins, so the immune system can respond in different ways depending on the individual and route: IgE production gives Type I anaphylaxis/urticaria; IgG against penicillin-coated red cells gives Type II haemolysis; circulating penicillin–antibody complexes give Type III serum sickness; and sensitised T cells give Type IV maculopapular or contact rashes. The same antigen, different effector arm, different disease.

FAQ

Is "allergy" the same as "hypersensitivity"? Not quite. Hypersensitivity is the broad umbrella for all four exaggerated immune reactions. Allergy usually refers specifically to Type I (and sometimes Type IV contact allergy). All allergy is hypersensitivity, but not all hypersensitivity is allergy.

Can you be allergic to something the very first time you meet it? Genuine Type I allergy needs prior sensitisation, so the "first" clinical reaction reflects a hidden earlier exposure (for example, to a related food, or via the skin). Some immediate reactions to drugs can occur without classic sensitisation through direct mast-cell activation, but true IgE allergy requires priming.

Why is adrenaline injected into the muscle and not a vein for anaphylaxis? Intramuscular adrenaline in the thigh gives rapid, reliable absorption with a good safety margin. Intravenous adrenaline is reserved for specialist settings because incorrect dosing can cause dangerous arrhythmias and hypertension.

What is the difference between an intolerance and an allergy? An intolerance (for example, lactose intolerance) is a non-immune digestive or enzymatic problem — unpleasant but not immune-mediated. An allergy involves the immune system (usually IgE) and can be life-threatening. They are often confused by patients.

Why do some people get allergies and others do not? It reflects a mix of genetics (the atopic tendency to make IgE), environment, and early-life exposures. The "hygiene hypothesis" suggests reduced microbial exposure in childhood may skew the immune system toward allergic (Th2) responses, though the full picture is still being researched.

Quick Revision

• ACID: Allergic (I), Cytotoxic (II), Immune complex (III), Delayed (IV).
• Types I–III use antibodies; Type IV uses T cells and is delayed 48–72 h.
• Type I: IgE + mast cells + histamine; sensitisation then re-exposure; anaphylaxis is the emergency.
• Type II: IgG/IgM vs fixed cell/tissue antigen (transfusion reaction, Goodpasture, Graves).
• Type III: soluble immune complexes deposit in tissues (serum sickness, SLE).
• Type IV: contact dermatitis, Mantoux test, granulomas, transplant rejection.
• Anaphylaxis = IM adrenaline first, everything else is secondary.
• Richet (1901) discovered anaphylaxis — "against protection" — Nobel Prize 1913.

Related Topics

Prerequisites

• Immunology Overview
• Antibody structure and function; T-cell and B-cell biology

Related Topics

• Autoimmunity and immune tolerance
• Pharmacology of allergy and anaphylaxis
• Emergency management of anaphylaxis

Next Topics

• Immunodeficiency disorders
• Transplantation immunology and rejection
• Vaccines and immunisation