mechanisms of tolerance (3)
- 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) - 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 - T regulatory cells
Produce suppressive cytokines such as IL-10 and TGFb
methods of allergy prevention (6)
- breastfeeding: only slight effect on eczema in early life
- hydrolysed formula: no evidence
- probiotics -> decreased eczema when given to mother during lactation
- parasites: anti-helminthic treatments e.g. albendazole increase rates of ezcema
- early introduction of allergenic foods: oral tolerance
- daily emollient: evidence that decreases eczema
WHO recommendation for breastfeeding
6 months exclusive, 24 months w complimentary foods
which route of exposure and dosing -> development of allergy or tolerance
allergy: intermittent low-dose, inhaled, skin contact
tolerance: regular high doses, sublingual, oral
indications for immunotherapy (4)
- insect stings
- rhinitis, conjunctivitis (hayfever)
- food allergy (not yet widely used due to safety concerns re: anaphylaxis)
- asthma
factors to consider for new treatments (3)
- cost-effectiveness (cost per QALY)
- safety
- acceptability to patient
main function of
- IL-12
- IL-10
- IL-12: Th0 -> Th1
2. IL-10: downregulation of Th1
definition of hypersensitivity
Immune & inflammatory responses that are harmful to the host
definition of allergy
Symptomatic immune response to harmless environmental antigen
definition of atopy
Genetic predisposition to become sensitised and produce IgE antibodies in response to ordinary exposures to allergens
T helper cell subsets (4)
- Th1 for intracellular microorganisms → cytotoxic lymphocytes, macrophages
- Th2 for parasites and allergic diseases → mast cells, basophils, eosinophils (which all degranulate), B cells
- Th17 for extracellular microbes (bacteria, fungi) → neutrophils
- T regulatory cells: actively control/suppress function of other cells (usually inhibitory effect) + ∴ prevent overreaction of the immune system, autoimmunity and allergy
benefits of breastfeeding
- Optimal nutrition; no overfeeding
- contains Abs, WBCs -> fewer infections
- contains traces of food proteins that could promote tolerance
- reduced risk of breast cancer for mother
- associated w higher IQ
allergy tests (3)
- skin tests: skin prick test or intradermal skin test
- blood tests: basophil activation test or specific IgE
- in vivo challenge (provocation testing)
advs (5) + disadvs (4) of skin tests in allergy diagnosis
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
advs (2) + disadvs (5) of blood tests for allergy diagnosis
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
management of anaphylaxis (5)
- Adrenaline IM
- Oxygen
- IV fluids if ongoing hypotension
- H1 antagonist and corticosteroids may help reduce biphasic response
- Nebulised salbutamol may be used for lower airway obstruction
how can environmental exposure have different effects in individuals w different genetic predispositions on development of asthma (5)
Endotoxin (in gram -ve bacteria cell wall) can be used as measure of exposure to microbes
- Low endotoxin exposure → C allele is risk allele for sensitisation
- High endotoxin exposure → T allele is risk allele for sensitisation (i.e. ↑asthma)
- T-allele → day-care strongly protects against asthma
- A-allele homozygotes → day-care increases risk of asthma
- TLR2 variants → day-care protective in some and risk factor in others
epigenetic effects on asthma
- children have greater risk of asthma when their grandmother smoked during their mother’s foetal period
- ↑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)
association between antibiotics and asthma development
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
filaggrin
- function
- mutations -> ?
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
factors that contribute to eczema development (3)
- defects in skin barrier
- defects in skin innate immunity
- enhanced response to food and inhalant allergens
outside-inside / inside-outside hypotheses for eczema development
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
changes to skin barrier in eczema (6)
- Disorganised keratinocytes in stratum corneum
- Abnormal lipids: ↓ceramides, free fatty acids, cholesterol
- Break down of corneodesmosomes
- ↓Tight junctions
- ↓Protease inhibitors
- ↑proteases
influence of staph aureus on the skin barrier
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
