Hypersensitivity

Question 1

What is hypersensitivity?

Answer 1

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.)

Question 2

What are the four classifications of hypersensitivity?

Answer 2

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.).

Question 3

What substances can cause hypersensitivity?

Answer 3

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.

Question 4

What is type I (immediate) hypersensitivity?

Answer 4

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.

Question 5

What is the structure of monomeric IgE?

Answer 5

Usual immunoglobulin structure.
Heavy chain has 4 constant regions.
Heavily glycosylated- n-linked glycosaccarides.
Fc receptor binds to CH3 domain.

Question 6

What are mast cells?

Answer 6

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.

Question 7

What happens to mast cells during degranulation?

Answer 7

Empty out the contents of the granules- can do this quite rapidly.
Package of preformed mediators that can be released immediately.

Question 8

How does antigen binding to IgE on mast cells cause an inflammatory response?

Answer 8

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.

Question 9

What does histimine do?

Answer 9

Constricts airways, increase mucus secretion- leads to sneezing coughing and wheezing.

Question 10

What are eosinophils?

Answer 10

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.

Question 11

What are basophils?

Answer 11

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.

Question 12

What affects type I hypersensitivity symptoms?

What are some reactions and what causes them?

Answer 12

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.

Question 13

What are the shared properties of inhaled allergens?

Answer 13

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.

Question 14

How can pollen sensitisation occur?

Answer 14

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.

Question 15

What are the two stages of an allergic reaction?

Answer 15

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.

Question 16

What is the course of an asthmatic response?

Answer 16

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.

Question 17

How can the physical effects of IgE-mediated allergic reactions vary ?

Answer 17

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.

Question 18

What causes systemic anaphylaxis?

How is it treated?

Answer 18

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).

Question 19

What causes allergic rhinitis?

Answer 19

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.

Question 20

What can allergic asthma result in?

Answer 20

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.

Question 21

What are urticaria, angioedema and eczema and how are they caused?

Answer 21

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.

Question 22

What can an ingested allergen do?

Answer 22

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.)

Question 23

What are the treatments for type I hypersensitivity?

Answer 23

1. Avoidance.
2. Cromolyn sodium-stabilises mast cells, possibly other mechanisms too, prevents mast cells from being able to degranulate.
3. Anti-histamines - prevent histamine binding to H1 histamine receptors on vascular endothelium.
4. Corticosteroids -suppress leukocyte function, prevent inflammation.
5. Epinephrine – for anaphylactic reactions.
6. 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.

Question 24

What is type II hypersensitivity?

Answer 24

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.

Question 25

Describe what happens in Blood transfusion reactions when ABO incompatible blood is transferred.

Answer 25

Structures of A, B and O blood group antigens on RBC surface:
O- ceramide-Glu-Gal-GalNAc-Gal linked to a Fuc.
A- ceramide- Glu- Gal- GalNAc- Gal linked to a Fuc- GalNAc.
B- ceramide- Glu- Gal- GalNAc- Gal linked to a Fuc- Gal.
Incompatible blood groups.
Donors and recipients for blood transfusion must be matched for ABO system.

O people make anti A and anti B antibodies- an only get blood from O donor.
A makes anti-B antibodies- can get blood from O and A.
B makes anti-A antibodies- can get blood from O and B.
AB- makes no anti-antibodies- can get blood from any group.

Question 26

Describe what happens in Haemolytic disease of the newborn.

Answer 26

Results from incompatibility of Rhesus D blood antigens to RhD-negative mother.
RhD-positive RBC from 1st foetus sensitise mother usually at birth.
If subsequent foetus is RhD-positive, anti-Rh IgG produced by mother crosses the placenta and attacks foetus.
RhD-negative mothers infused with anti-RhD IgG immediately after delivery - eliminates all RhD-positive RBC before immune response occurs.

Uncontrolled- results in birth of blue babies.
Occurs in women negative for rhesus D antigen.
Occurs when partner is RhD positive- foetus may also be RhD positive.

Effect on baby: Swollen abdomen from enlargement of liver and spleen due to RBC destruction.
Elevated bilirubin (responsible for blue colour) = product of haemoglobin breakdown.
Facial petechia = haemorrhage due to platelet damage.

Cases of this have reduced over years- Reduced since introduction of treating women with anti-RhD IgG.

Question 27

What can cause type II hypersensitivity reactions?

Answer 27

Type II hypersensitivity reactions can be caused by antibodies
specific for altered components of human cells.
e.g. Penicillin and other small molecule drugs can modify human cells so that they display foreign epitopes.
Has reactive group in structure- can bind to surface of RBC- seen as foreign epitope.

Question 28

What do penicillin-protein conjugates do?

Answer 28

Penicillin-protein conjugates stimulate the production of anti-penicillin antibodies.
RBC covalently bonded to penicillin are phagocytosed by macrophages.
After processing peptides are presented to CD4 T cells.
CD4 T cells are activated to TH2 effector cells.
TH2 cells stimulate Ag-specific B cells to produce Abs against
penicillin-modified epitope.
Abs bind to penicillin-modified proteins on RBC.
Complement activation results in lysis or phagocytosis.
Sensitisation- activation of helper T cells.
Complement gets activated.

Question 29

What is type III hypersensitivity?

Answer 29

Mediated by persistence and deposition of small IgG-antigen immune complexes.

Tend to circulate in blood and become deposited in blood vessel walls.

When they accumulate, they fix complement and trigger inflammatory reactions by interacting with Fc receptors and complement receptors on leukocytes and mast cells.

C3a stimulates mast cells to release histamine causing urticaria.
C5a recruits inflammatory cells to site.
Platelets accumulate, clots form, blood vessels burst causing skin haemorrhage.

Binding of antibody to antigen.

Question 30

What causes a type III hypersensitivity reaction?

Answer 30

Localised deposition of immune complexes in tissue causes a type III hypersensitivity reaction.
Takes 1-2 hrs.
Locally injected antigen in immune individual with IgG antibody.
Local immune-complex formation activates complemet. C5a binds to C5a receptor on mast cell.
Binding of immune complex to FcyRIII on mast cell induces degranulation.
Local inflammation, increased fluid and protein release, phagocytosis, and blood vessel occlusion.

Question 31

What determines the pathology of type III hypersensitivity reactions?

Answer 31

The sites of IC deposition determine the pathology of
type III hypersensitivity reactions.

Intravenous (high dose): Results in- vasculitis- IC deposited in blood vessel walls.
Results in- nephritis- IC deposited in renal glomeruli.
Results in- arthritis- IC deposited in joint spaces.

Subcutaneous:
Results in- Arthus reaction- IC deposited in the perivascular area.

Inhaled:
Results in- Farmer’s lung- IC deposited in alveolar/capillary interface.

Symptoms persist only around period of IC formation. Once foreign antigen is cleared, the symptoms resolve.

Question 32

What is type IV hypersensitivity?

Answer 32

Delayed-type hypersensitivity- occurs 1-3 days after exposure to antigen.
Mediated by antigen-specific effector T cells.
Amount of antigen required is 100-1000 times greater than that required to produce Ab-mediated hypersensitivity reactions- need a lot more antigen to get a reaction.

Question 33

What are the two types of type IV hypersensitivity?

Answer 33

Contact:
Itchy reaction at point of contact with.
Common with metals e.g. nickel, chromate, beryllium or small haptens e.g. pentadecacatechol (in poison ivy).
Erythema, cellular infiltrate, vesicles,
intraepidermal abscesses.

Delayed-type:
Develops against protein antigen e.g insect venom, mycobacterial proteins.
Example: Tuberculin test – reaction seen following intradermal injection of tuberculin bacilli in individuals that already had immunity to Mycobacterium tuberculosis. Looking for type IV reaction.
Local skin swelling, erythema, cellular infiltrate, induration (hardening/sclerosis), dermatitis.

Question 34

What are the stages of a type IV hypersensitivity reaction?

Answer 34

Normally takes 2-3 days.
Delay- T cells specific for antigen will take time to arrive at site.

Uptake, processing, presentation by local APC.
Ag-specific memory T cells produced during previous exposure to Ag migrate to site and become activated. May take several hours for T cell of correct specificity to arrive.
Activated T cells release mediators that activate local endothelial cells, recruiting infiltrate of mainly macrophages and causing fluid and protein accumulation.

Question 35

What orchestrates a type IV hypersensitivity reaction?

Answer 35

TH1 CD4 derived cytokines orchestrate type IV hypersensitivity reactions.