Hypersensitivity Flashcards
What is hypersensitivity?
Hypersensitivity = exaggerated, inappropriate adaptive immune response to harmless environmental antigens.
Sometimes inflammatory reactions and tissue damage result.
Can be provoked by range of antigens.
Not manifest on first contact with Ag.
Usually appears on subsequent contact.
(Response to what would normally be harmless. Non-pathogenic.
Features will not manifest on first contact with antigen- features happen on subsequent contact.)
What are the four classifications of hypersensitivity?
Type I, II, III and IV.
Types I, II, III - Antibody mediated.
Type IV - mediated by T cells and macrophages.
May have more than one occurring at same time.
Order here- occurs fastest to slowest (eg. I is fastest, then II, III, IV etc.).
What substances can cause hypersensitivity?
Inhaled materials: plant pollens, dander of domesticated animals, mold spores, feces of very small animals eg. house dust mites.
Injected materials: insect venoms, drugs, therapeutic proteins.
Ingested materials: food, orally administered drugs.
Contacted materials: Plant leaves, industrial products made from plants, synthetic chemicals in industrial products, metals.
What is type I (immediate) hypersensitivity?
IgE response (sensitization) to innocuous environmental antigens- pollen, house dust mite feces, animal proteins.
IgE is located mainly in tissues, binds to FceRI (Fc receptor that binds IgE) on mast cells, basophils and activated eosinophils.
Second encounter with allergen triggers release of inflammatory mediators.
produces acute inflammatory reaction within minutes- effects seen straight away.
Symptoms of varying severity, from running nose (rhinitis) to breathing difficulties and even death by asphyxiation.
What is the structure of monomeric IgE?
Usual immunoglobulin structure.
Heavy chain has 4 constant regions.
Heavily glycosylated- n-linked glycosaccarides.
Fc receptor binds to CH3 domain.
What are mast cells?
Resident in mucosal and epithelial tissues lining body surfaces.
Present in all vascularized tissues except CNS and retina.
Maintain tissue integrity.
Alert immune system to local trauma and infection.
Facilitate repair of damage caused by infection or wounds.
50-200 granules fill the cytoplasm.
Vesicles contain histamine and other inflammatory mediators.
What happens to mast cells during degranulation?
Empty out the contents of the granules- can do this quite rapidly.
Package of preformed mediators that can be released immediately.
How does antigen binding to IgE on mast cells cause an inflammatory response?
IgE has long half life of residency (2 weeks) when bound to receptor.
High affinity interaction- (Kd ~ 10^10M-1) – means binding is very long lived.
Mast cells primed with IgE.
IgE would have binding sites for specific anitgen (when encountered once), for if it encounters it again.
Immobilise Fc receptors in clusters.
Signalling pathways triggered- receptor cross-linking -> Lyn and syk kinases-> Degranulation and release of histamine, prostaglandins,
leukotrienes and other mediators of allergic response.
Long binding is why response is so immediate.
What does histimine do?
Constricts airways, increase mucus secretion- leads to sneezing coughing and wheezing.
What are eosinophils?
Release toxic mediators in IgE response.
Mostly resident in connective tissue underlying mucosal epithelia.
Have a characteristic staining pattern in histological sections.
In inflammatory response, cytokines and chemokines at site induce eosinophils to express FcεRI.
Also have granules- can also degranulate.
Stain with eosin
Fc expresssion- can now respond to IgE.
Activated eosinophils secrete toxic proteins contained in their granules and also produce cytokines and inflammatory mediators.
Usually very effective at killing parasites, but turn on our own tissues in hypersensitivity.
What are basophils?
Granules contain similar, but not identical, set of mediators to those of mast cells.
Recruited to tissue under appropriate stimulation.
Similar effector function to eosinophils.
What affects type I hypersensitivity symptoms?
What are some reactions and what causes them?
Type I hypersensitivity symptoms vary with site of entry of allergen.
Systemic anaphylaxis (most severe form of type I hypersensitivity): caused by drugs, serum, venoms, peanuts. Causes oedema, increased vascular permeability, tracheal occlusion, circulatory collapse, death.
Wheal and flare (swelling and redness): caused by insect bites, allergy testing. Causes local increase in blood flow and vascular permeability.
Allergic rhinitis (hayfever): caused by pollens, dust mite feces. Causes oedema, nasal mucus, irritation of nasal mucosa.
Bronchial asthma: caused by pollens, dust mite feces. Causes bronchial constriction, increased mucus production, airway inflammation.
Food allergy: caused by shellfish, milk, eggs, fish, wheat etc. Causes vomiting, diarrhoea, itching, hives, anaphylaxis.
What are the shared properties of inhaled allergens?
Usually proteins, as they only induce T-cell responses (molecular type).
Often proteases (function).
Favour activation of IL-4-producing CD4 Tcells (low dose).
Allergen can diffuse out of particle into mucus (low molecular weight).
Allergen is readily eluted from particle (high solubility).
Allergen can survive in desiccated particles (high stability).
Contains peptides that bind host MHC class II- required for T cell priming.
How can pollen sensitisation occur?
Antigens that leach from inhaled pollen are taken up by APC in airway mucosa. (Pollen can leach across epithelium and be picked up by antigen presenting cells.)
These activate naive T cells to become TH2 effector cells, which secrete IL-4.
IL-4 binds to the B cell’s IL-4 receptor.
B cell is induced to switch Ig isotype and secretes IgE.
IgE binds to FcεRI on mast cells. Mast cells now primed with antigen specific IgE.
What are the two stages of an allergic reaction?
Allergic reactions have an immediate reaction followed by a late-phase reaction.
Bi-phasic response.
Immediate- localised swelling at point of injection, redness (wheal and flare- 15 mins).
Late- 6 hrs- generalised swelling.
What is the course of an asthmatic response?
Immediate asthmatic response in lungs finishes within 1 h.
Followed by late-phase reaction about 6 h later.
High peak expiratory flow rate before allergen encounter, drop in immediate response, will go back up, the decrease again in late phase.
How can the physical effects of IgE-mediated allergic reactions vary ?
Vary with the site of allergen exposure.
Gastrointestinal tract: Increase fluid secretion, increased peristalsis- expulsion of gastrointestinal tract contents (diarrhoea, vomiting).
Airways: decreased diameter, increased mucus secretion- expulsion of airway contents (phlegm, coughing).
Blood vessels: increased blood flow, increased permeability- oedema (swelling), inflammation, increased lymph flow and carriage of antigen to lymph nodes.
What causes systemic anaphylaxis?
How is it treated?
Systemic anaphylaxis is caused when allergens reach the bloodstream and activate mast cells throughout the body.
Very severe reaction.
Loss of consciousness due to circulation being compromised.
Difficulty in breathing, wheezing- most common cause of death due to anaphylaxis.
Systemic anaphylaxis should be treated immediately with epinephrine (adrenaline).
What causes allergic rhinitis?
Allergic rhinitis is caused by allergens entering the respiratory tract.
Inhaled antigen taken up in lungs, enters mucosa, and act on mast cells locally.
Mast cell activation causes blood vessel permeability and activation of epithelium.
Eosinophils are recruited from blood and enter nasal passages with mucus.
Histamine and other mediators released by activated mast cells
These increase permeability of local capillaries and activate nasal epithelium to produce mucus.
Eosinophils attracted into the tissues from the blood are activated- release of inflammatory mediators.
Streaming nose.
What can allergic asthma result in?
Allergic asthma can result in chronic inflammation of airways.
In sensitized individuals, specific IgE on mast cells in airways is crosslinked by allergen.
Inflammatory mediators secreted.
Bronchial smooth muscle contracts, increased mucus secretion.
Airways obstructed.
Elevated blood vessel permeability- oedema & influx of eosinophils and TH2 cells.
Eosinophil degranulation causes further tissue injury.
End result is chronic inflammation, and possibly irreversible damage to airways.
Inflammation of the airways in chronic asthma restricts breathing.
What are urticaria, angioedema and eczema and how are they caused?
Urticaria, angioedema, and eczema are allergic reactions in the skin.
Allergen introduced into the skin of a sensitized individual causes mast cells in the connective tissue to degranulate.
Released histamine dilates local blood vessels, causing rapid swelling.
What can an ingested allergen do?
Ingested allergen can cause vomiting, diarrhea, and urticaria.
Localized reactions are caused by the action of histamine on intestinal epithelium, blood vessels, and smooth muscles.
Urticaria is caused by antigen that enters blood vessels and is carried to the skin.
(Histimine released from mast cells.)
What are the treatments for type I hypersensitivity?
- Avoidance.
- Cromolyn sodium-stabilises mast cells, possibly other mechanisms too, prevents mast cells from being able to degranulate.
- Anti-histamines - prevent histamine binding to H1 histamine receptors on vascular endothelium.
- Corticosteroids -suppress leukocyte function, prevent inflammation.
- Epinephrine – for anaphylactic reactions.
- Desensitisation- Try and introduce small quantities of known antigen to individual to get them to make another antigen response (eg. IgG instead of IgE). Carefully controlled, but risky.
What is type II hypersensitivity?
Antibody-dependent cytotoxic hypersensitivity.
Occurs in 12-18 hours of exposure to antigen.
Occurs when IgG or IgM binds to either a
self-antigen or a foreign antigen on human cells- Phagocytosis, killer cell activity or complement-
mediated lysis.
Damage is restricted to particular cells/tissues
bearing the antigen.
Occurs more slowly than type I.
