Hypersensitivity I — Type I
When the response is the disease ★★★
Two French scientists, Paul Portier and Charles Richet, were trying to protect Mediterranean bathers from jellyfish stings. They purified the toxin and injected dogs with it, intending to make a vaccine. The first injection was tolerated. The second, months later and at a smaller dose, killed the dogs within minutes — vomiting, diarrhoea, asphyxia.
That was the opposite of protection, and they named it accordingly: where prophylaxis means guarding, they coined anaphylaxis — against guarding. Richet received the Nobel Prize in 1913 for it. The finding that a second exposure could be more dangerous than the first is the whole of this unit, and it is uncomfortable precisely because everything in Unit 12 said a secondary response is better.
When the immune system is re-exposed to the same antigen, the immune response is enhanced. Under some circumstances this enhanced response has deleterious effects, resulting in functional disorder, tissue damage or even death. This inappropriate or pathological immune response is termed hypersensitivity or allergy, and it is specific.Section I, 2019 AND 2020
It is tempting to think of allergy as the immune system going wrong. It is more accurate — and more useful for the exam — to see it as the immune system working exactly as designed, against the wrong target or too hard.
Every mechanism in the next three units is one you have already learnt as a defence. Type I is IgE and mast cells, which evolved against parasites. Type II is antibody plus complement and ADCC, the machinery of Unit 4. Type III is immune complexes, formed in every normal antibody response. Type IV is Th1 activating macrophages, which is how you control tuberculosis.
Nothing new is happening. The damage comes from the response, not the antigen — which is exactly the lesson of the cytokine storm and the superantigen, and the reason this unit sits under Unit 1's 'immune defence, too strong'.
- Define hypersensitivity. → An enhanced immune response on re-exposure to antigen that causes functional disorder, tissue damage or death; a pathological immune response, and specific
- Who discovered it and when? → Portier and Richet; Richet won the Nobel Prize in 1913
- Why is 'anaphylaxis' so named? → The opposite of prophylaxis — against guarding rather than guarding
- Which of Unit 1's three functions does it represent failing? → Immune defence, overshooting
The four types — Gell and Coombs ★★★
Gell and Coombs classified hypersensitivity into four types according to the mechanism. Learn the table as a whole now: three of the four exam MCQs on hypersensitivity ask you to match a disease to its type, and they are only answerable if you hold all four at once.
| Type | Name | Mediated by | Typical diseases |
|---|---|---|---|
| I | Anaphylactic / immediate | IgE | Asthma · allergic rhinitis (hay fever) · urticaria · anaphylaxis |
| II | Cytotoxic / cytolytic | IgG/IgM against cell surface | Haemolytic disease of the newborn · haemolytic anaemia · hyperthyroidism |
| III | Immune complex | Immune complexes | Rheumatoid arthritis · SLE |
| IV | Delayed-type (DTH) | T cells | Contact dermatitis · granuloma · tuberculin reaction |
Anaphylactic (I) · Cytotoxic (II) · Immune complex (III) · Delayed (IV).
And the mediator follows: types I, II and III are all antibody-mediated (humoral); only type IV is cell-mediated. That single split answers True/False Q11 and several MCQ distractors at once.
- Who classified hypersensitivity into four types? → Gell and Coombs
- Name the four types. → I anaphylactic/immediate · II cytotoxic · III immune complex · IV delayed-type
- Which types are antibody-mediated? → I, II and III. Only type IV is cell-mediated
- Which type causes asthma and rhinitis? → Type I
- Which type causes SLE and rheumatoid arthritis? → Type III
The four components of type I ★★★
| Component | Detail |
|---|---|
| 1 · Allergens | Antigens that selectively activate CD4⁺ Th2 cells and B cells and induce IgE responses. They are proteins — only proteins can be presented to T cells — and typically reach mucosal surfaces at very low doses: pollens, dust mites, spores, animal dander, foods |
| 2 · Antibody — IgE | The least abundant serum Ig; does not fix complement; binds FcεRI on mast cells and basophils through its CH2 and CH3 domains |
| 3 · Cells | Mast cells — in connective tissue, near blood and lymphatic vessels, and in skin and respiratory/GI mucosa Basophils — circulating in blood Both express FcεRI and release mediators. Eosinophils — involved in the late-phase reaction; also express FcεRI, and down-regulate type I via some of their mediators |
| 4 · Mediators | See §5 |
Note that Th2 is where this begins. Allergens are defined by their ability to drive a Th2 response — Th2 makes IL-4, IL-4 drives B cells to class-switch to IgE, and IgE arms the mast cells. That chain is the content of True/False Q11's second half, “Th2 cells are involved in type I hypersensitivity”, which is true.
- Name the four components of type I. → Allergens, IgE, mast cells/basophils/eosinophils, mediators
- Define an allergen. → An antigen that selectively activates CD4⁺ Th2 and B cells to induce an IgE response
- Which receptor binds IgE, and via which domains? → FcεRI, via CH2 and CH3
- Does IgE fix complement? → No
- Which cell is NOT involved in type I? → The NK cell — this is MCQ Q17
- What role do eosinophils play? → The late-phase reaction; they also down-regulate the response
The three phases ★★★
- ① Sensitization phase. Allergen enters the body for the first time. B cells become IgE-secreting plasma cells; the IgE binds FcεRI on mast cells and basophils. The result is sensitized target cells — a sensitized body. Nothing is felt at this stage.
- ② Excitation phase. The allergen re-enters and binds the IgE already sitting on the cell surface, causing cross-linkage of FcεR. This changes the target-cell membrane and triggers degranulation.
- ③ Effector phase. The released mediators — histamine, leukotrienes and others — act on tissue, producing the clinical picture.
The first exposure sensitizes and causes no symptoms; the second exposure causes the reaction. This is exactly Portier and Richet's dogs.
A single IgE molecule binding a single allergen does nothing at all. The mast cell only fires when one allergen bridges two adjacent IgE molecules, pulling two FcεRI receptors together. That is why an allergen must be at least bivalent — a single-epitope hapten cannot trigger degranulation on its own.
And it explains the treatment in §7. If you want to stop the reaction, you do not have to remove the allergen or the IgE — you only have to prevent two receptors being bridged at once. Giving tiny doses at short intervals lets each small amount of allergen be mopped up before it can cross-link anything, which is precisely how desensitization works.
- Name the three phases. → Sensitization, excitation, effector
- What happens in sensitization? → First allergen exposure → IgE produced → IgE binds FcεRI on mast cells and basophils
- What triggers degranulation? → Cross-linking of FcεR by allergen bridging two adjacent IgE molecules
- Why must an allergen be at least bivalent? → It must bridge two IgE molecules to cross-link the receptors
- Which exposure causes symptoms? → The second, not the first
The mediators ★★
| Class | Members | Timing |
|---|---|---|
| Preformed — made before degranulation and stored in granules | Histamine | Released immediately |
| Newly formed — synthesised after cell activation | Leukotrienes (LTs) · prostaglandin D₂ · PAF (platelet-activating factor) | Minutes to hours |
Whatever the mediator, the tissue effects are the same three: smooth-muscle contraction, vasodilation with increased vascular permeability, and mucus secretion. Everything a patient experiences is one of those three happening somewhere particular.
| Site of contact | Symptoms |
|---|---|
| Respiratory tract | Runny nose, watery eyes, sneezing, coughing, sinus congestion, constricted airways |
| Digestive tract | Cramping, diarrhoea, vomiting |
| Skin | Hives (urticaria), eczema — localised swelling |
This is worth pausing on, because it makes a long list of allergic conditions collapse into one idea. Hay fever, asthma, urticaria, food allergy and anaphylaxis are the same reaction. The mediators are the same, the cells are the same, the antibody is the same.
What differs is where the mast cells that degranulate happen to be. Nasal mucosa gives rhinitis; bronchial mucosa gives asthma; skin gives urticaria; gut gives vomiting and diarrhoea; and everywhere at once gives anaphylactic shock. Learn the mechanism once and you have learnt every disease in §6.
- Name the preformed mediator. → Histamine
- Name three newly formed mediators. → Leukotrienes, prostaglandin D₂, PAF
- What three tissue effects do the mediators produce? → Smooth-muscle contraction, vasodilation with increased permeability, mucus secretion
- Why do allergic diseases differ if the mechanism is identical? → The site of the degranulating mast cells differs
The diseases ★★★
Systemic anaphylaxis
| Cause | Examples |
|---|---|
| Drugs | Penicillin, insulin |
| Serum | Antitoxins prepared from animal antiserum |
| Venom | Bee, wasp, hornet stings |
Systemic anaphylaxis is a shock-like and often fatal state whose onset occurs within minutes. Its cause is systemic vasodilation and increased permeability — fluid leaves the circulation everywhere at once, and blood pressure drops.
The deck sets a scenario: a man bitten by a dog, with a leg wound from the dog, an arm wound from iron bars, and a facial wound of uncertain origin. The management is tetanus antitoxin within 24 hours and rabies vaccine.
Then it asks the question that matters here: what if the patient is allergic to the antitoxin? Remember from Unit 2 that horse antitoxin is a xenogeneic antigen, and from Unit 3 that it is pepsin-digested to reduce that risk. If the patient is already sensitized, giving it normally could cause anaphylaxis — and yet withholding it risks tetanus. The answer is desensitization, in §7: give the same total dose in small amounts at short intervals so that no cross-linking can occur.
Localised type I disease
| Disease | Site and mechanism |
|---|---|
| Allergic rhinitis (hay fever) | Airborne allergens meet sensitized mast cells in conjunctivae and nasal mucosa; localised vasodilation and increased capillary permeability give watery exudation, sneezing and coughing |
| Asthma | The same reaction in the lower respiratory tract: bronchial smooth-muscle contraction and mucus secretion cause bronchial constriction, airway obstruction and dyspnoea |
| Atopic urticaria (hives) | Allergen binds sensitized mast cells in the skin, causing swollen red eruptions |
| Food allergy | IgE cross-linking on mast cells along the GI tract causes localised smooth-muscle contraction and vasodilation — vomiting, diarrhoea, bellyache |
One epidemiological figure worth carrying: 20–30% of the population show type I hypersensitivity to common environmental substances. This is not a rare disease — it is the commonest immunological disorder there is.
- Name three causes of systemic anaphylaxis. → Drugs (penicillin, insulin), animal antiserum, insect venom
- Why does blood pressure fall in anaphylaxis? → Systemic vasodilation and increased vascular permeability
- Which site gives rhinitis, and which gives asthma? → Nasal mucosa and conjunctivae; lower respiratory tract
- What proportion of the population is affected? → 20–30% show type I hypersensitivity to common environmental substances
Detection and treatment ★★
Detecting type I hypersensitivity
| Method | Detail |
|---|---|
| Skin test | Small amounts of potential allergens given by intradermal injection or superficial scratching of forearm skin. After 30 minutes, a wheal and flare >5 × 5 mm is a positive result, showing the patient has specific IgE on their skin mast cells. Advantages: relatively inexpensive; screens many allergens at once. Disadvantage: in rare cases may induce systemic anaphylactic shock |
| Serum IgE by ELISA | Determines the serum level of IgE specific for a given allergen |
Principles of treatment
- Avoid contact with known allergens
- Inhibit production of IgE
- Stabilise mast cells — inhibit degranulation
- Antagonise active mediators — e.g. antihistamines
- Medication — including desensitization and hyposensitization
| Desensitization | Hyposensitization | |
|---|---|---|
| Method | Repeated injection of small amounts of allergen at short intervals (20–30 min) | Repeated injections of small doses at long intervals (5–7 days) |
| Mechanism | Gradually exhausts the active mediators | Shifts antibody production from IgE to IgG |
| Use | Emergency — e.g. giving antitoxin to an already-sensitized patient | Long-term management of allergy |
These are easy to confuse and the distinction is examinable, so anchor it on the interval.
Short interval (20–30 min) = desensitization. You are racing the system: each tiny dose triggers a little mediator release, too small to matter, and by repeating before the granules can refill you empty them. The protection is temporary and lasts only hours — which is fine, because you only need the patient to tolerate one dose of antitoxin today.
Long interval (5–7 days) = hyposensitization. You are re-educating the system: repeated small exposures shift the B-cell response from IgE to IgG. The IgG then acts as a blocking antibody, intercepting allergen before it reaches mast-cell IgE. That takes months but is lasting.
- How is a skin test read, and when? → Wheal and flare >5 × 5 mm at 30 minutes
- What does a positive skin test show? → The patient has specific IgE on their skin mast cells
- What is the risk of skin testing? → Rarely, systemic anaphylactic shock
- Desensitization — interval and mechanism? → 20–30 minutes; exhausts the active mediators
- Hyposensitization — interval and mechanism? → 5–7 days; shifts antibody production from IgE to IgG
Revision layer
The exam map for this unit
| Section | Item | From |
|---|---|---|
| I. Definitions | Hypersensitivity — set in BOTH years | §1 |
| III. MCQ Q17 | NK cells are NOT involved in type I | §3 |
| III. MCQ Q20 | Rhinitis is caused by type I | §2, §6 |
| IV. True/False Q11 | Th2 cells are involved in type I — T | §3 |
The whole unit on one screen
| Question | Answer |
|---|---|
| Define hypersensitivity | A pathological, enhanced immune response on re-exposure causing functional disorder, tissue damage or death — and it is specific |
| Who classified it? | Gell and Coombs — four types |
| Which types are antibody-mediated? | I, II, III. Only IV is cell-mediated |
| Four components of type I? | Allergen · IgE · mast cells/basophils/eosinophils · mediators |
| What defines an allergen? | It selectively activates Th2 and B cells to induce IgE |
| Which receptor binds IgE? | FcεRI, via CH2 and CH3 |
| Does IgE fix complement? | No |
| Three phases? | Sensitization · excitation · effector |
| What triggers degranulation? | Cross-linking of FcεR by allergen |
| Preformed mediator? | Histamine |
| Newly formed mediators? | Leukotrienes · PGD₂ · PAF |
| Three tissue effects? | Smooth-muscle contraction · vasodilation · mucus secretion |
| Which cell is NOT involved? | NK cell — that is type II |
| Skin test positive? | Wheal and flare >5 × 5 mm at 30 min |
| Desensitization vs hyposensitization? | 20–30 min, exhausts mediators / 5–7 days, shifts IgE → IgG |
- Define hypersensitivity. → An enhanced, pathological immune response on re-exposure to antigen, causing disorder, tissue damage or death
- Name the four Gell and Coombs types. → I anaphylactic, II cytotoxic, III immune complex, IV delayed
- Trace type I from allergen to symptoms. → Allergen → Th2 → IL-4 → IgE → FcεRI on mast cells → re-exposure cross-links → degranulation → histamine and leukotrienes
- Which cells bear FcεRI? → Mast cells, basophils and eosinophils
- Which cell is the answer to 'not involved in type I'? → NK cell
- Why do rhinitis, asthma and urticaria differ? → Same mechanism, different site of mast cells
- How would you give antitoxin to a sensitized patient? → Desensitization — small doses at 20–30 minute intervals