allergy

Question 1

mechanisms of tolerance (3)

Answer 1

1. clonal selection
   Positive thymic T cell selection: in cortex, T cells undergo apoptosis if TCR does not bind to HLA (failure to recognise self)
   Negative thymic T cell selection: in medulla, T cells that bind to self-antigens from various tissues in the body undergo apoptosis (no tolerance/reactivity to self)
2. anergy:
   T-lymphocyte activation requires complex signalling through both the TCR complex and ligation of CD28 by CD80/86 on the antigen-presenting cell (APC)
   Lack of the CD28 costimulatory signal results in anergy rather than activation
3. T regulatory cells
   Produce suppressive cytokines such as IL-10 and TGFb

Question 2

methods of allergy prevention (6)

Answer 2

1. breastfeeding: only slight effect on eczema in early life
2. hydrolysed formula: no evidence
3. probiotics -> decreased eczema when given to mother during lactation
4. parasites: anti-helminthic treatments e.g. albendazole increase rates of ezcema
5. early introduction of allergenic foods: oral tolerance
6. daily emollient: evidence that decreases eczema

Question 3

WHO recommendation for breastfeeding

Answer 3

6 months exclusive, 24 months w complimentary foods

Question 4

which route of exposure and dosing -> development of allergy or tolerance

Answer 4

allergy: intermittent low-dose, inhaled, skin contact
tolerance: regular high doses, sublingual, oral

Question 5

indications for immunotherapy (4)

Answer 5

1. insect stings
2. rhinitis, conjunctivitis (hayfever)
3. food allergy (not yet widely used due to safety concerns re: anaphylaxis)
4. asthma

Question 6

factors to consider for new treatments (3)

Answer 6

1. cost-effectiveness (cost per QALY)
2. safety
3. acceptability to patient

Question 7

main function of

1. IL-12
2. IL-10

Answer 7

1. IL-12: Th0 -> Th1

2. IL-10: downregulation of Th1

Question 8

definition of hypersensitivity

Answer 8

Immune & inflammatory responses that are harmful to the host

Question 9

definition of allergy

Answer 9

Symptomatic immune response to harmless environmental antigen

Question 10

definition of atopy

Answer 10

Genetic predisposition to become sensitised and produce IgE antibodies in response to ordinary exposures to allergens

Question 11

T helper cell subsets (4)

Answer 11

1. Th1 for intracellular microorganisms → cytotoxic lymphocytes, macrophages
2. Th2 for parasites and allergic diseases → mast cells, basophils, eosinophils (which all degranulate), B cells
3. Th17 for extracellular microbes (bacteria, fungi) → neutrophils
4. T regulatory cells: actively control/suppress function of other cells (usually inhibitory effect) + ∴ prevent overreaction of the immune system, autoimmunity and allergy

Question 12

benefits of breastfeeding

Answer 12

1. Optimal nutrition; no overfeeding
2. contains Abs, WBCs -> fewer infections
3. contains traces of food proteins that could promote tolerance
4. reduced risk of breast cancer for mother
5. associated w higher IQ

Question 13

allergy tests (3)

Answer 13

1. skin tests: skin prick test or intradermal skin test
2. blood tests: basophil activation test or specific IgE
3. in vivo challenge (provocation testing)

Question 14

advs (5) + disadvs (4) of skin tests in allergy diagnosis

Answer 14

Advantages
1. Inexpensive
2. Quick, painless
3. Easy to perform
4. Immediate results
5. High NPV / fair PPV
Disadvantages
1. Small risk of systemic reaction (intradermal > SPT)
2. Results may not be accurate in pts w dermatographism or on antihistamines
3. Results can vary with circadian rhythm, seasonal variation and quality of allergen extracts
4. Excessive physical force or insufficient entry into skin gives rise to false positives and false negatives

Question 15

advs (2) + disadvs (5) of blood tests for allergy diagnosis

Answer 15

Advantages
1. Can be done in pts w severe skin disease or dermatographism
2. Can be done in pts w recent anaphylaxis or on antihistamines
Disadvantages
1. More expensive than skin tests
2. Blood sample required; difficult in children
3. Slower result turnaround than skin tests
4. Lower NPV than SPT
5. False +ve w high IgE

Question 16

management of anaphylaxis (5)

Answer 16

1. Adrenaline IM
2. Oxygen
3. IV fluids if ongoing hypotension
4. H1 antagonist and corticosteroids may help reduce biphasic response
5. Nebulised salbutamol may be used for lower airway obstruction

Question 17

how can environmental exposure have different effects in individuals w different genetic predispositions on development of asthma (5)

Answer 17

Endotoxin (in gram -ve bacteria cell wall) can be used as measure of exposure to microbes

1. Low endotoxin exposure → C allele is risk allele for sensitisation
2. High endotoxin exposure → T allele is risk allele for sensitisation (i.e. ↑asthma)
3. T-allele → day-care strongly protects against asthma
4. A-allele homozygotes → day-care increases risk of asthma
5. TLR2 variants → day-care protective in some and risk factor in others

Question 18

epigenetic effects on asthma

Answer 18

1. children have greater risk of asthma when their grandmother smoked during their mother’s foetal period
2. ↑methylation in cord blood of functional IL2 CpG site → ↑asthma hospital admissions
   (IL2 important for immune response to viral infection, which is involved in asthma exacerbations)

Question 19

association between antibiotics and asthma development

Answer 19

Antibiotics in infancy → ↑wheezing and asthma exacerbations

However effects may be due to infants w more severe symptoms being taken to doctors and prescribed ABx more often

Question 20

filaggrin

1. function
2. mutations -> ?

Answer 20

Critical to the conversion of keratinocytes to the protein / lipid squames that compose the stratum corneum
Important for aggregation of keratin filaments; key for keeping skin moist
FLG mutations → ↑risk of eczema, peanut allergy, asthma

Question 21

factors that contribute to eczema development (3)

Answer 21

1. defects in skin barrier
2. defects in skin innate immunity
3. enhanced response to food and inhalant allergens

Question 22

outside-inside / inside-outside hypotheses for eczema development

Answer 22

Outside-inside hypothesis: Xerosis (skin dryness) and abnormal permeability of skin barrier drives eczema with secondary sensitisation

Inside-outside hypothesis: Inflammatory response to irritants and allergens drives eczema with secondary barrier disruption

Question 23

changes to skin barrier in eczema (6)

Answer 23

1. Disorganised keratinocytes in stratum corneum
2. Abnormal lipids: ↓ceramides, free fatty acids, cholesterol
3. Break down of corneodesmosomes
4. ↓Tight junctions
5. ↓Protease inhibitors
6. ↑proteases

Question 24

influence of staph aureus on the skin barrier

Answer 24

S. aureus produces serine proteases which can degrade the skin barrier by damaging tight junctions
Temporal shifts in skin microbiome associated w disease flares & Tx in children with AD
acute AD flares → ↑expression of Staph Aureus strains in lesional skin

Question 25

ezcema treatment (3)

Answer 25

stepwise treatment

1. emollients
2. topical corticosteroids
3. topical calcineurin inhibitors (retains and restores skin barrier integrity)

Question 26

mechanism of tolerance vs allergy

Answer 26

Tolerance: usual allergen response: APCs process Ags and present to T cells → T cell differentiation to Th1, Treg → IL-10, TGFβ → suppress immune response
Allergy: APCs → T cells differentiate to Th2 → IL-4,5,13 → B cells produce IgE → eosinophil and mast cell response sensitisation
Degranulation on secondary Ag exposure → histamines, prostaglandins, leukotrienes, cytokines

Question 27

mechanism of IgE allergy

Answer 27

1. Sensitisation:
   APC processes Ags and migrates to lymph node → presents on MHC to T cells → T0 differentiation into Th2 cells → IL-4, IL-5, IL-13 → B cells → IgE produced and binds to mast cells
2. Allergic reaction:
   Secondary Ag exposure → mast cells and eosinophils degranulate → histamines, prostaglandins, leukotrienes, cytokines →
   a. Activation of sensory nerve endings → itchiness
   b. Smooth muscle cells → bronchoconstriction
   c. Crampy abdominal pain
   d. Small blood vessels → ↑permeability → oedema
   e. Vasodilatation → redness