Overview
This lecture covers allergy as Type I hypersensitivity: its definition, the allergens that trigger it, the historical Prausnitz-Küstner experiment establishing IgE as the serum factor, and the full sensitisation-to-effector pathway from first allergen exposure through mast cell activation. It covers the airway changes seen in asthma, what makes an allergen effective, and genetic and environmental (hygiene hypothesis) contributors to susceptibility. It then covers the rationale behind allergy/asthma therapies including allergen-specific immunotherapy (desensitisation), before closing by placing allergy within the four hypersensitivity types, briefly covering Types II-IV with clinical examples, and a case study on the immunology of insect bite itch.
Allergy and Type I hypersensitivity
- Allergy is an inappropriate immune response, made by genetically predisposed hosts, to non-pathogenic antigens (allergens).
- Allergy is a Type I hypersensitivity reaction, but is often associated with a Type IV late-phase reaction (T cell infiltration).
- Three components are required for allergy: allergen, serum factor (IgE), tissue factor (mast cells).
- Prausnitz-Küstner experiment (1921): Küstner was highly sensitive to fish. Prausnitz injected Küstner’s serum into his own skin, then challenged himself with fish extract, producing a reaction. This showed sensitivity could be transferred by a serum factor (later identified as IgE) - the Prausnitz-Küstner test.
- Examples of Type I hypersensitivity: allergic rhinitis (hayfever/seasonal rhinitis), asthma (chronic lung disease), eczema/urticaria (skin disorders), anaphylaxis (acute and systemic).
- Skin testing shows two temporal phases in the same limb: an immediate reaction (Type I, IgE mediated) and a late-phase reaction (Type IV, T cell mediated).
Airway pathology in asthma
- Normal airway: relaxed smooth muscle, open lumen.
- Asthmatic airway: wall inflamed and thickened, narrowed lumen.
- Asthmatic airway during an attack: smooth muscle contracts, lumen narrows further, and air becomes trapped in the alveoli.
Allergens
- Allergens are typically small soluble proteins or glycoproteins.
- Often proteases, possibly including those from parasitic helminths (the lecturer poses this link as a question rather than a settled fact).
- Common sources: dust mite faeces, food (milk, nuts, eggs, fish), insect saliva, plant excretions, chemicals (cosmetics, metals, hair dyes), drugs (e.g. penicillins).
- Penicillin’s life-threatening allergic response is due to reaction of the beta-lactam ring with self-proteins.
- Features of inhaled allergens that promote TH2 priming:
- Protein, often with carbohydrate side chains - only proteins induce T cell responses.
- Enzymatically active - allergens are often proteases.
- Low dose - favours activation of IL-4-producing CD4 T cells.
- Low molecular weight - can diffuse out of the particle into mucus.
- Highly soluble - readily eluted from the particle.
- Stable - survives in a desiccated particle.
- Contains peptides that bind host MHC class II - required for T cell priming.
- Dust mite faeces contain Der p1, a protease. Pollen is a major allergen source and often contains proteases.
- Bee venom allergy in beekeepers: risk factors are stings in the first years of beekeeping and in spring, fewer than 10 annual stings, skin sensitivity with bee venom-specific IgE alongside low venom-specific IgG, a history of atopic disease, and upper respiratory tract allergy symptoms while working in beehives. Apiarists are advised to launder their clothes separately from family clothing. This relates to the low-dose priming theory of allergy development.
Sensitisation and the allergic response pathway
Allergen priming (skin/airway epithelium): an allergen particle contacts the epithelium, penetrates between epithelial cells, and is taken up by a dendritic cell (DC) beneath the epithelium. The DC migrates to the draining lymph node (LN), generating an allergen-specific immune response.
Full sequence from first exposure to effector response:
- First exposure to allergen.
- Allergen is presented by a DC to TH2 cells, which stimulate IgE class switching in B cells.
- IgE is produced by the class-switched B cells.
- IgE binds to the high-affinity receptor FcεRI on mast cells, coating them (sensitised, resting mast cell).
- On repeated exposure to allergen, allergen cross-links the IgE bound on the mast cell surface.
- This activates the mast cell, causing release of mediators: histamine and other vasoactive amines/lipid mediators, and cytokines.
- Mediator release produces two outcomes:
- Immediate hypersensitivity reaction (minutes after repeat exposure), driven mainly by histamine and other vasoactive amines/lipid mediators (vascular and smooth muscle effects).
- Late-phase reaction (2-4 hours after repeat exposure), driven mainly by cytokines (inflammation).
- Because mast cells lack a high-affinity Fc receptor for IgG, only IgE-mediated cross-linking triggers this activation pathway.
Genetic and environmental susceptibility
- Atopy is a genetic predisposition to allergy, affecting up to 10% of people in the USA.
- Genes associated with atopy:
- IL-4 (promoter variant) - alters expression of IL-4.
- IL-4 receptor alpha chain (structural variant) - increased signalling in response to IL-4.
- High-affinity IgE receptor beta chain (structural variant) - alters the consequences of IgE ligation by antigen.
- MHC class II genes (structural variants) - enhanced presentation of particular allergen-derived peptides.
- Hygiene hypothesis: first-world countries have a higher incidence of allergy. More siblings (especially older siblings), growing up on farms, having pets, and early infection or bowel colonisation are protective; antibiotic use in childhood appears only as an additional, unconfirmed option in the underlying question, and is most plausibly the predisposing factor by elimination of the other (protective) options, rather than something the transcript directly states. Mechanisms are not fully clear, and there is not a close link between poverty and protection. An example cited for this link is caesarean-section delivery and the resulting neonatal gut metabolome being associated with increased childhood asthma risk.
- Model combining genetic susceptibility and environment:
- High genetic susceptibility + hygienic/high-exposure environment -> atopic outcome, associated with conjunctivitis, rhinitis, eczema, asthma.
- Low genetic susceptibility + unhygienic/low-exposure environment -> non-atopic outcome, associated with exposure to hepatitis A virus, primary tuberculosis, measles, and early bowel colonisation with commensal bacteria.
Therapy of allergy and asthma
- Avoidance of the allergen (e.g. avoiding pets).
Slide 22 is an image-only humorous slide (a "grumpy cat" photo) continuing the pet-avoidance joke from the avoidance slide, with no additional textual content.
- Blocking mast cell triggering: isoprenaline, cromoglycate.
- Corticosteroids (e.g. Beconase): inhibit inflammatory genes.
- Immunotherapy:
- Allergen-specific immunotherapy (SIT), see below.
- Anti-IgE therapy (omalizumab).
Allergen-specific immunotherapy (SIT) / desensitisation
- SIT can shift the T cell response from Th2 to Th1.
- High-dose antigen may inactivate B cells and induce production of T regulatory cells.
- High-dose antigen can inactivate IgE-producing B cells via BCR cross-linking in the absence of T cell help; this can occur within hours.
- Development of allergy vs desensitisation, by dose/route:
- Repetitive low-dose allergen stimulation -> Th2 response (IL-4, IL-5, IgE) -> development of allergy.
- Escalating allergen doses given subcutaneously -> Th1 response (IFN-γ, IgG2a/b), which antagonises the Th2 response -> desensitisation.
- Mechanism of desensitisation: (1) lowers IgE levels; (2) IgG binds the antigen, preventing IgE from binding it. Because mast cells lack a high-affinity Fc receptor for IgG, IgG-bound allergen cannot trigger mast cell activation.
- Antibody dynamics over time: without therapy, repeated allergen contact causes IgE to rise progressively with each exposure while IgG stays low; giving SIT later causes a sharp rise in IgG. With early/prophylactic SIT (given at or near birth), IgG rises steadily to a high sustained level from early on while IgE stays low throughout - keeping the IgG:IgE balance favourable compared to late conventional treatment.
Hypersensitivity Types II-IV
- Type II: antibodies recognise self-antigens on the cell surface. Examples: haemolytic anaemia, some drug reactions.
- Complement-dependent mechanism (the diagram is explicitly labelled “A. Complement-dependent”, implying other Type II mechanisms exist): antibody coats the target cell -> complement activation (C1423, then C5-9) -> two outcomes: the membrane attack complex (C5-9) causes osmotic lysis, and C3b deposition causes opsonisation; opsonised cells are recognised by macrophage Fc receptors and C3b receptors and undergo phagocytosis.
- Example: anti-basement membrane antibody-mediated glomerulonephritis, with autoreactive IgG detected in patient serum by immunofluorescence tracing the glomerular basement membrane.
- Type III: antibody reacting with soluble antigen, forming immune complex disease. Examples: vasculitis (SLE), serum sickness, rheumatoid arthritis.
- Mechanism: antigen circulates in the blood vessel -> B cells bind antigen and differentiate into plasma cells producing free antibody -> antibody binds circulating antigen forming immune complexes -> complexes deposit in/near the vessel wall -> complement activation and neutrophil recruitment, with platelet aggregation at the deposit site -> neutrophils release lysosomal enzymes causing fibrinoid necrosis of the vessel wall.
- Example: the “butterfly rash” of SLE - a symmetrical erythematous rash across the cheeks and nose bridge - reflects this vasculitis.
- Type IV (delayed-type hypersensitivity, DTH): T cell mediated.
- Sensitisation: antigen enters the skin; a dendritic cell takes up the antigen and migrates to the draining lymph node, where T cell activation occurs.
- Challenge: on re-exposure, the activated T cells migrate from the vessel into the tissue at the antigen site.
- Examples: the widespread thickened, plaque-like skin lesions of leprosy; occupational contact dermatitis (e.g. severe dermatitis of a hairdresser’s hands from reactive chemicals modifying skin proteins); contact dermatitis to nickel from a jeans stud, appearing as a localised red patch at the site of skin contact with the metal.
Insect bite itch (case study)
- The itch from sandfly and mosquito bites is caused by an immune response to proteins in the insect’s saliva, which act as vasodilators or anticoagulants.
- The first bite does not itch; an immune response to the salivary proteins develops only after one or more bites.
- The bite reaction has two phases, mediated by different cells and molecules: an early hypersensitivity-like reaction that subsides after a few hours, followed by a swelling and intense itch appearing 1-2 days later, caused by T cells migrating into the bite site and causing additional inflammation in response to residual salivary proteins.
- Proposed evolutionary advantage: the itch response provokes a behavioural response that helps dislodge biting insects, and the immune response to bite proteins may also help control the entry of parasites carried in the saliva.
Part of the source text for this section (a headline and a short middle passage) is cut off/obscured in the transcript, so some of the mechanistic detail on how salivary proteins interact with host antibodies is incomplete.
Self-test
- Define allergy.
- What three components does the Prausnitz-Küstner experiment show are required for allergy, and how did the original experiment demonstrate the role of the serum factor?
- List the features of an inhaled allergen that promote TH2 priming, giving the mechanism for each.
- Describe the steps from first allergen exposure to mast cell sensitisation, and then the steps from repeat exposure to mediator release, naming the mediators released.
- Distinguish the immediate hypersensitivity reaction from the late-phase reaction in terms of timing and the mediators driving each.
- Why does IgE, but not IgG, trigger mast cell activation?
- Describe how the airway changes across a normal airway, a chronically asthmatic airway, and an asthmatic airway during an acute attack.
- A patient who keeps bees develops upper respiratory allergy symptoms while working the hives despite fewer than 10 stings a year. What underlying process links her low sting frequency to sensitisation, and what practical advice would you give her regarding her clothing?
- List the genes associated with atopy and the mechanism by which each polymorphism contributes to allergic susceptibility.
- According to the hygiene hypothesis, which childhood exposures are protective against allergy, which factor predisposes to it, and which combination of genetic susceptibility and environment produces an atopic outcome?
- Explain the mechanism by which penicillin can cause a life-threatening allergic reaction.
- Describe the mechanism by which allergen-specific immunotherapy (SIT) produces desensitisation, from the change in T cell response through to how IgG blocks the allergic reaction at the mast cell.
- Distinguish the antibody dynamics seen with late conventional SIT from those seen with early/prophylactic SIT.
- List the four hypersensitivity types with one example condition for each.
- Describe the complement-dependent mechanism of Type II hypersensitivity, from antibody binding to the two possible outcomes for the target cell.
- Describe the steps by which circulating immune complexes cause vessel wall damage in Type III hypersensitivity.
- Describe the sensitisation and challenge phases of Type IV (delayed-type) hypersensitivity.
- A hairdresser develops severe dermatitis on the hands after prolonged chemical exposure. Which hypersensitivity type is responsible, and what is happening at the level of the antigen and the T cell?
- Explain why the first mosquito or sandfly bite does not itch but subsequent bites do, and describe the two phases of the itch reaction that follows repeated bites.
Answers
Reveal answers
- Allergy is an inappropriate immune response, made by genetically predisposed hosts, to non-pathogenic antigens.
- Allergen, serum factor (IgE) and tissue factor (mast cells). Prausnitz injected himself with serum from Küstner, who was highly sensitive to fish, then challenged himself with fish extract and reacted, showing that sensitivity could be transferred by a serum factor alone.
- Protein with carbohydrate side chains (only proteins induce T cell responses), enzymatically active/protease activity, low dose (favours IL-4-producing CD4 T cells), low molecular weight (diffuses into mucus), highly soluble (readily eluted), stable (survives desiccation), and contains peptides that bind host MHC class II (required for T cell priming).
- First exposure: allergen is presented by a dendritic cell to TH2 cells, which drive IgE class switching in B cells; IgE is produced and binds FcεRI on mast cells, sensitising them. Repeat exposure: allergen cross-links the IgE on the mast cell surface, activating it and triggering release of histamine and other vasoactive amines/lipid mediators, and cytokines.
- The immediate reaction occurs within minutes of repeat exposure and is driven mainly by histamine and other vasoactive amines/lipid mediators; the late-phase reaction occurs 2-4 hours later and is driven mainly by cytokines.
- Mast cells lack a high-affinity Fc receptor for IgG, so only IgE bound to FcεRI and cross-linked by allergen can trigger mast cell activation.
- Normal airway: relaxed smooth muscle, open lumen. Asthmatic airway: wall inflamed and thickened, lumen narrowed. During an attack: smooth muscle contracts, narrowing the lumen further, with air trapped in the alveoli.
- Her low sting frequency (fewer than 10 stings a year) is a risk factor that relates to the low-dose priming theory of allergy development. She should launder her beekeeping clothes separately from the family’s clothing.
- IL-4 promoter variant alters IL-4 expression; IL-4 receptor alpha chain structural variant increases signalling in response to IL-4; high-affinity IgE receptor beta chain structural variant alters the consequences of IgE ligation; MHC class II structural variants enhance presentation of particular allergen-derived peptides.
- Protective factors: more (especially older) siblings, growing up on a farm, having pets, and early infection/bowel colonisation. Antibiotic use in childhood is the most likely predisposing factor, by elimination of the other (protective) options, though the transcript does not confirm this directly. High genetic susceptibility combined with a hygienic, high-exposure environment produces an atopic outcome (conjunctivitis, rhinitis, eczema, asthma).
- Reaction of the beta-lactam ring with self-proteins produces the life-threatening allergic response.
- SIT can shift the T cell response from Th2 towards Th1; high-dose antigen may inactivate IgE-producing B cells (via BCR cross-linking without T cell help) and induce T regulatory cells. Escalating subcutaneous doses drive a Th1 response (IFN-γ, IgG2a/b) that antagonises the Th2 response, lowers IgE, and produces IgG that binds the allergen and blocks IgE from binding it, so mast cells (which lack a high-affinity FcR for IgG) are not activated.
- With late conventional SIT, IgE rises progressively with each exposure before treatment, and IgG only rises sharply once SIT is finally given. With early/prophylactic SIT (near birth), IgG rises steadily to a high sustained level from the start while IgE stays low throughout.
- Type I: IgE-mediated, e.g. allergic rhinitis/asthma/anaphylaxis. Type II: antibody against cell-surface self-antigen, e.g. haemolytic anaemia. Type III: antibody-soluble antigen immune complex disease, e.g. SLE vasculitis/serum sickness/rheumatoid arthritis. Type IV: T cell-mediated delayed-type hypersensitivity, e.g. contact dermatitis or the reaction seen in leprosy.
- Antibody coats the target cell, activating complement via C1423 and then C5-9 (this is the complement-dependent route, labelled “A.” on the slide, implying other Type II mechanisms exist). This produces either the membrane attack complex (C5-9), causing osmotic lysis, or C3b deposition, causing opsonisation; opsonised cells are recognised by macrophage Fc and C3b receptors and phagocytosed.
- Circulating antigen is bound by antibody to form immune complexes, which deposit in or near the vessel wall. This activates complement and attracts neutrophils, with platelet aggregation at the deposit site; neutrophils then release lysosomal enzymes that cause fibrinoid necrosis of the vessel wall.
- Sensitisation: antigen enters the skin, is taken up by a dendritic cell, which migrates to the draining lymph node where T cells are activated. Challenge: on re-exposure to antigen, the activated T cells migrate from the vessel into the tissue at the antigen site.
- Type IV (delayed-type) hypersensitivity. Reactive chemicals modify skin proteins, creating antigens that are recognised by sensitised T cells, which then infiltrate the skin and drive the dermatitis.
- The first bite does not itch because no immune response to the salivary proteins has yet developed; sensitisation occurs after one or more bites. On subsequent bites, an early hypersensitivity-like reaction to the salivary proteins occurs and subsides within a few hours, followed 1-2 days later by swelling and intense itch caused by T cells migrating into the bite site and driving further inflammation.