Flashcards in Lecture 22 - Food Allergy Deck (47):
Characterise the prevalence of immune disorders
• Exponential increase in immune disorders
- Type I diabetes
- Crohn's disease
- Food allergy & anaphylaxis
The increase is seen across all age groups, but children 0-4 in particular
What is anaphylaxis?
Most severe form of allergic reaction
May cause death
What are the determinants of allergic disease?
2. Early life environment:
• Microbial exposure (most important)
• Vit D
• UV light
Describe the effect of genetics and environment leading to disease
1. Genes & environment
2. Epigenetic modification
3. Gene expression
4. Altered immune tolerance
Describe the observations from studies of mice in germ free conditions
"Fail to develop oral tolerance":
• Underdeveloped Peyer's patches lacking GCs
• Few IgA plasma cells and CD4+ T cells in LP
• Reduced n° of IELs
• Fail to develop oral tolerance
• Persistent Th2 responses
Window of opportunity:
• These abnormalities can be reversed, but only in the neonatal period
Compare intestinal microbiota in allergic and non-allergic children
• Decreased levels of probiotic bacteria
• Increased levels of pathogenic bacteria
• 'Good' Bifidobacterium levels reduced and less adherent to intestinal mucous
• Microbiota induce less IL-10 production
Which bacteria are probiotic?
Which bacteria are pathogenic?
• C. difficile
• S. aureus
When is abnormal microbiota seen in children?
Preceding the development of allergic disease
Describe the changes to microbiota over the first 12 months of life in children who will develop allergic disease
• decreased bifidobacteria
• decreased colonisation of Enterococci
• increased Clostridia
• increased Staphylococcus
• decreased Bacteroides
Why is microflora important for disease?
Intestinal microflora plays a vital role in:
• Immune system maturation
• Development of tolerance
Which are required to avert allergic responses
What is the prevalence of food allergy?
2% - 5% of population
Which group of people most common experience food allergy?
Food allergies resolve with age
What are the major food groups that cause allergy?
In order of increasing prevalence:
• Tree nuts & seeds
• Milk products
• Fruit & veg
• Food additives
8 major food groups cause > 90% of food allergy
What are the common food allergies in children?
Compare this with adults
• Egg, milk, peanut
• Soy, wheat, fish
• Peanut, tree nuts, fish, shellfish
What are the various clinical symptoms caused by the IgE mediated allergic reaction?
What is urticaria?
• IgE mediated allergic reaction
• Red bumps on skin
• Similar to angioedema, but only occurs in the upper dermis
What is angioedema?
Rapid swelling of dermis, subcutaneous tissue, mucosa & submucosa
What are the symptoms in the following regions due to the IgE mediated allergic reaction?
• Cardiovascular system
• Hoarse voice
• Difficultly swallowing & breathing
• Feeling of tightness in throat
• Pale and floppy
How is food allergy managed?
• Allergen avoidance
- management of allergic reactions - preparation for anaphylaxis
• Adrenaline auto-injector
Is allergen avoidance successful?
No, it's difficult
• 50% of children have accidental ingestion within 1 yr
• In fatal cases most were aware of the allergy but failed to avoid the food
• 40-100% of fatal reactions were from food prepared outside the home
Is the EpiPen widely used?
• 75% carried it
• 10% were expired
• 32% could use it correctly
Requires regular training
• Even when used, person can die:
• In 12-14% of fatal cases there were early, repeated doses of adrenaline
Describe the mechanism for loss of tolerance to food
• Increased Th2, decreased Th1
• Reduced Treg numbers & activity
1. Allergen in gut
2. Allergen taken up by DCs
3. Allergen presentation to Th2
4. Stimulation of B-cells to produce IgE
→ Food allergy
What was observed in the immune response in resolution of food allergy?
• Shift to Th1 responses
• Increased allergen specific Tregs
Compare Desensitisation & tolerance
How are they measured?
Desensitisation: the ability to tolerate a food while ingesting regular doses of the food
• Rapidly reversible
• Mediated by changes in effector cells (mast cells, basophils)
Tolerance: Ability to tolerate a food after a period of time has elapsed since ingesting the food
Expected to last for months-years after stopping therapy
Desensitisation: oral food challenge whilst still on treatment
Tolerance: oral food challenge after stopping therapy
What immunological changes occur in tolerance?
• Induction of allergen-specific Tregs
• Allergen specific anergy / clonal deletion
Describe the mechanism of immunotherapy
1. Injected allergen taken up by APC
2. Presented to Treg
3. Treg produces suppressive cytokines (IL-10, TGF-beta)
4. Suppression of Th2, stimulation of Th1
→ Reduced IgE
→ Incresed IgA & IgG4
What was seen in immunotherapy for peanut allergy?
• Desensitisation: threshold for allergen increased from 178mg to 2805mg
• High rate (39%) of serious systemic reactions
Describe efficacy of oral immunotherapy
What are the immunological changes?
What are the drawbacks?
• Majority of patients successfully desensitised
- i.e., whilst still receiving OIT they were tolerant of cow's milk
• Yet to achieve tolerance
• Decreased milk IgE
• Increased milk IgA & IgG4
• Increased IFN-gamma
• Limited ability to induce tolerance
• Allergic reactions during treatment are common
• Severe reactions (10-20%)
Describe the study of high dose Egg OIT
Aiming to induce tolerance
• Placebo group: 0% tolerance
• Treatment group: 28% tolerance
What was observed in long term follow up of OIT?
• Milk OIT for 4.5 years
• Well tolerated (desensitised)
• Regular ingestion of milk
• No evidence of tolerance
• Recurrence of allergy in subjects who discontinued OIT for period of a few weeks
How could OIT be improved?
• Higher maintenance dose
Describe the use of adjuvants in OIT
Immune response modifiers:
• Target TLRs with ligands linked to allergens
• Aims to resolve Th1 / Th2 imbalance
1. CpG-containing-DNA-allergen complexes
• Increased in allergen-specific Th1 responses
2. Monophosphoryl lipid A
• Bacterial cell wall component
• Binds TLR4
• Decreased IgE
• Increased IgG4
What is the PPOIT study?
Probiotic and Peanut OIT study
• Two groups:
1. Probiotic (LGG) + Peanut OIT
• Many samples taken at various points in time
• Oral food challenge at end of treatment course
• Skin prick tests:
• Desensitisation observed in treatment group
What is the most important environmental feature in regards to allergy?
Microbial exposure during fist few weeks and months of life
Is dysbiosis reversible?
Yes, but only in the neonatal period
How can microflora be targeted to help allergic disease?
Probiotics & diet to resolve dysbiosis
What is observed in terms of IL-10 in the MALT of people with allergic disease?
Microbiota of individuals with allergic disease induce less IL-10 production
Why are adults less commonly affected by food allergy?
Allergies can resolve over time
Which food allergies tend to resolve with age?
Which do not?
Resolve with age:
• Cow's milk
Do not resolve with age:
What is the time frame for IgE mediated allergic reaction?
30 mins - 1 hr
Describe multi-system involvement in the IgE mediated allergic reaction
What is the first clinical sign of the IgE mediated immune response?
What is the biggest treatment strategy for allergy?
• Allergen avoidance
• Having an action plan for anaphylaxis
Which cytokines released by Th2 are involved in skewing towards B cell IgE production?
What are the two types of immunotherapy?
Earlier: Subcutaneous immunotherapy
Now: Oral immunotherapy (OIT)
What were the results of the RCT of OIT for peanut allergy?
(RCT: randomised controlled trial)
No effect observed, i.e. same rates of tolerance observed in both the 'OIT' and 'avoid' groups