Allergy Flashcards
What is an allergic disorder?
An immunological process that results in immediate and reproducible symptoms after exposure to an allergen.
What is an allergen?
Usually a harmless substance that can trigger an IgE mediated immune response and may result in clinical symptoms.
What is sensitisation?
Sensitisation is the detection of specific IgE either by skin prick testing or in vitro blood tests: occurs more often than allergic disease.
Which immunoglobulin is clinically significant?
IgE
What is the immune response to bateria, viruses and fungi?
Microbial PAMP > Recognition of conserved microbial structure > Th1, Th17 immune response
What is the immune response to helminths, allergens and venoms?
Recognition by change in function > Th2 immune response
In contrast to immune responses to bacteria, virus and fungi, immune responses to worms, venoms and allergens tend to react to tissue damage caused by these agents rather then relying on direct recognition of the pathogen. Worms, venoms and allergens are far more diverse than bacteria.
What are the signalling cytokines in a Th2 response?
GM-CSF, IL-25, IL-33, TSLP
Which mediate
Th9 cells, ILC2, Th2 Cells
What are the effector cytokines in a Th2 response?
Th9 cells, ILC2, Th2 Cells: IL-5, IL-9, IL-4, IL-13
Tfh2 cells: IL-4, IL-21
What are the effects of these effector cytokines?
Trigger eosinophil activation
Cause B cells to release IgE and IgG4
What do mast cells release?
Histamine
Prostaglandins
Leukotrienes
Proteases
What are innate lymphoid cells?
Innate lymphoid cells found at mucosal barriers (skin, respiratory and the gastrointestinal tract) which lack antigen specific receptors.
Respond to a number of inflammatory cytokines (IL-33, TSLP, IL-25) IL-1 and IL-12 family cytokines member.
How can CD4 ILC be classified?
ILC1, ILC2, ILC3, based on their cytokine production and transcriptional profiles with ILC1s, ILC2s, and ILC3s resembling CD4+ T helper (Th)1, Th2 and Th17/22 cells, respectively.
What do ILC2 secrete?
ILC2 secrete IL-4, IL-5, IL-9, IL-13 and amphiregulin (AREG).
Secretion of type 2 cytokines by ILC2 implicated in allergic asthma, allergic rhinitis AD, food allergy and eosinophilic oesophagitis. Amphiregulin paly an important role in epithelial barrier repair in skin and respiratory tract. In allergic disease overcome steady state inhibition exerted by tissue CD4 T regulatory cells.
How do CD4 Th2 cells contribute to an allergic response?
Distinct CD4 T subset characterised by expression of the lineage determining transcription factor GATA-3 and the signal transduction protein STAT-6
- Signature cytokines are IL-4, IL-5, IL-13
- Helps B cells to produce IgE (IL-4)
- Expands and activate eosinophils (IL-5)
- Stimulate mucous secretion (IL-13)
Role in host defense against helminths, parasites and tissue repair. Contribute to late stage tissue damage in allergic disease.
What is the role of eosinophils in an allergic response?
Host defence against parasites, bacteria and viruses.
Eliminate pathogens by secretion of cytotoxic granules, RNAase proteins and extracellular traps.
IL-5 is the key cytokine in the development and expansion of eosinophils.
Implicated in late stage tissue damage in atopic dermatitis, asthma, eosinophilic oesophagitis, and granulomatous disease
What is the function of IgE in an allergic response?
IgE binds to high affinity receptor (FceR1) on mast cells, basophils, eosinophils and DC.
IgE also binds to ‘low affinity’ (FceR2) receptor on above cells as well as B cells, respiratory and gastrointestinal epithelial cells.
Protection against helminth and parasitic infection. IgE induces mast and basophil degranulation associated with immediate hypersensitivity (allergic) reactions.
What is the role of mast cells in an allergic response?
2 main subtype in human: MC (Tryptase T) skin and MC (Chymotryptase CT) in airways.
Mast cells degranulation triggered by 1) IgE/IgG receptors which respond to antibody-antigen cross linking and 2) G-protein-coupled receptors which are ligands for soluble mediators (complement and drugs).
Role in immediate and late phase immune responses to helminths, bacteria. Play an important role in allergic disorders.
What are key mast cell receptors?
FcReR1(IgE)
FcgR1 and FcgR1IA (IgG)
MRGPRX2 (opiates, quinolones)
What does cross linking of bound IgE by antigen results in?
Release of pre-formed inflammatory mediators from granules (histamine)
Release and synthesis of lipid mediators (leukotrienes, prostaglandins)
Synthesis of pro-inflammatory cytokines
What does mast cell degranulation lead to?
Recruitment of soluble proteins and inflammatory cells to site of infection.
Increase in rate of lymphatic flow back to regional lymph nodes.
Smooth muscle contraction in lungs and gut (may help to expel pathogens) and activation of sensory neurons (itch, sneeze).
What factors promote IgE production?
Antigen dose
Length of exposure
Physical properties of allergen:
- Source
- Small water soluble proteins
- Carbohydrate
- Resistance to heat, digestive enzymes
Route of exposure
What is the difference between oral exposure compared to skin and respiratory exposure?
Oral exposure promotes immune tolerance whereas skin and respiratory induces IgE sensitisation.
Which statement is correct?
A. Cutaneous exposure to allergen promote immune tolerance
B. IgE degranulation of mast cells promotes a delayed clinical response
C. IL-4 plays a crucial role in development of Th2 immune responses
D. Targeted drug therapy against IgE has not been useful in the treatment of atopic asthma
E. Secretion of IL-22 by epithelial cells induces Th2 immune responses
C: IL-4 promotes Th2 immune responses
What is allergic rhinitis?
First description in 1819 by Dr John Bostock.
Link with pollen made in 1870 however still a rare disease although by 1900 well recognized in higher income groups and epidemic in New York in 1940.
Clean water, improved food hygiene, eradication of helminths, limited exposure to farm animals and soil bacteria smaller family size, (all components of hygiene) were achieved by 1920’s in major urban centres.
Changes in farming practices late 19th century: increased dairy herds, introduction of rye grass ( generate more pollen) important for rise in grass pollen rhinitis.
What is childhood asthma?
Increased rate of asthma first recognized in 1969 in studies conducted among Birmingham school children. By 1995 it was clear that the prevalence of asthma and hospitalization had increased in children living in different climates and socio-economic conditions.
Several different allergens (HDM, cat, cockroach, fungi) were linked with exposure and sensitisation. Possible links (at least for HDM) with increase exposure to indoor allergen as child play more indoors than outdoors, exercise less and put on weight.
Other contributing factors may include increased number childhood vaccines and increased exposure to broad spectrum antibiotics.
What is the evidence that microbial environment can protect against asthma?
Amish and Hutterite communities share similar genetic background and lifestyles. Prevalence of asthma and sensitisation much lower in Amish than in Hutterites.
Increase in LPS in dust samples collected from Amish than Hutterites. Increased secretion of innate immune cytokine by PBMC exposed to LPS in Amish than Hutterites.
What are food allergies?
1990 onwards: Significant increase in number of cases of peanut allergy attending allergy clinics in the UK and the USA.
Early oral exposure will protect against development of peanut allergy. Sensitisation to peanut and wheat can occur from exposure through the skin. Differences in preparation of peanuts (roast promotes IgE whereas boiled IgG). Epidemic of delayed food allergy to red meat observed in SE USA for last 10 years: increasing case in France, Germany, Australia but not in UK to date).
Which statement is correct?
A. Incidence of all allergic disorders has significantly increased in the last 20 year.
B. Increased outdoor activities by children is believed to be linked to rising hospitalisation for asthma.
C. Hospitals in London are seeing increased cases of delayed anaphylaxis to red meat.
D. Increased secretion of pro-inflammatory innate cytokines by PBMC following exposure to environmental microbial product may protect against development of asthma.
D. Increased secretion of pro-inflammatory innate cytokines by PBMC following exposure to environmental microbial products may protect against development of asthma.
What are appropriate investigations for allergic disease?
Allergen specific IgE (Sensitisation) Tests
- Skin prick and intradermal test
- IgE blood tests
Functional allergen tests:
In vitro tests
- Basophil activation
- Serial mast cell tryptase
Ex vitro tests
- Open or blinded allergen challenge
Which allergic diseases are most likely to be present in infants?
Atopic dermatitis
Food allergy (milk, egg, nuts)
Which allergic diseases are most likely to be present in children?
Asthma (HDM, pets)
Allergic rhinitis (HDM, grass, tree pollens)
Which allergic diseases are most likely to be present in adults?
Drug allergy
Bee allergy
Oral allergy syndrome
Occupational allergy
What are the signs and symptoms of an allergic response?
Occurs within minutes or up to 3 hours after exposure to allergen
Skin: Angioedema (swelling of lips, tongues, eyelids) , urticaria ( wheals or ‘hives’), flushing and itch.
Respiratory tract: Cough, SOB wheeze, sneezing, nasal congestion and clear discharge, red itch watery eyes.
Gastrointestinal tract: Nausea, vomiting and diarrhoea.
Blood vessels and Brain: Symptoms of hypotension (faint, dizzy, blackout) and a sense of impending doom.
What are the features of IgE mediated allergic responses?
At least 2 organ systems are usually involved.
Reproducible: occurs after every exposure.
Allergic symptoms may be triggered by cofactors such as exercise, alcohol, NSAID and in children viral infection. Link between exposure and onset symptoms may not be obvious.
- House Dust mite
- Fungal skin colonisation
- Red meat ingestion
Clinical history is used to select what allergens should be tested by skin prick and/or blood tests.
What are symptoms not associated with an allergic response?
Fatigue
Migraine
Recurrent episodes of abdominal pain, diarrhoea, constipation, bloating
Hyperactivity
Depression
Symptoms which vary over time, with antigen dose and source
What are sensitisation tests?
Presence of IgE is necessary but not sufficient for diagnosis of allergic disease.
Sensitisation is far more common then allergic disease, hence detection of IgE is best considered a risk factor for an allergic disorder.
Clinical history is used to select what allergens should be order for blood test.
In the context of an appropriate history larger skin wheals and higher specific blood IgE values are more likely to be associated with allergic disorder.
Results of skin prick test or serum specific IgE do not predict the severity of reaction.
What is a skin prick test?
Expose patient to standardised solution of allergen extract through a skin prick to the forearm.
Use standard skin test solutions and positive control (histamine) and negative control (diluent).
Measure local wheal and flare response to controls and allergens.
IgE crosslinking on skin mast cells, leading to degranulation and release of histamine and other inflammatory mediators.
What is a positive response on a skin prick test?
A positive test is indicated by a wheal ≥ 3mm greater than the negative control.
High positive and negative predictive and positive skin for aeroallergens.
Allergen extracts labile for some fruit and vegetables: Prick-prick test: food and SPT.
Antihistamines and some anti-depressants should be discontinued for at least 48 hours beforehand.
What are advantages of the skin prick test?
Rapid (read after 15-20 minutes)
Cheap and easy to do
Excellent negative predictive value usually more than > 95%
Increasing size of wheals correlates with higher probability for allergy
Patient can see the response
What are disadvantgaes of the skin prick test?
Requires experience to interpret.
Risk of anaphylaxis: 1 in 3000
Poor positive predictive value: high false positive rate
Limited value in patients with dermato-graphism or extensive eczema
False negative results with labile commercial food extracts
What are intradermal tests?
Application of positive, negative controls and allergens into the skin
More sensitive but less specific than SPT
Best used to follow up negative venom and drug allergy test (better than blood tests)
Can be used if SPT to allergen is negative but convincing history
Labour intensive, greater risks of anaphylaxis.
What are sensitisation (IgE antibody) blood tests?
3 major providers (Phadia, Siemens, Hycor).
All assays have excellent technical performance. Intra-assay CV < 15% and inter-assay CV < 20%.
Lower limit of detection 0.1kUA/L although clinical significance of IgE antibody concentration remains to be determined. Results from three main testing platforms are not interchangeable: very good agreement on the presence or absence sensitisation however quantitative levels for specific allergens vary widely.
What is the risk profile of specific IgE blood tests?
Concentration: Higher levels more likely to be associated with symptoms.
Molecular target within whole extract or even individual epitope can be linked to symptoms.
Affinity (strength of binding) to target: Higher affinity associated with risk.
Capacity of IgE antibody to induce mast/basophil degranulation.
Detection of IgE is necessary but not sufficient to make a diagnosis of allergic disease.
Diagnosis of allergic disease is made by the clinician; integrates data obtained from epidemiology, history, examination, SPT, laboratory, and challenge testing.
What are indications for sensitisation blood tests?
No access to SPT and/or IDT
Patients who can’t stop anti-histamines
Patients with a history of dermatographism, extensive eczema
Patient with a history of anaphylaxis
Decision on who needs food challenge
Prediction for resolution of egg, milk, wheat allergy
Monitor response to anti-IgE therapy
What is component resolved/molecular allergen testing?
Test for IgE sensitisation against individual protein within whole allergen extract.
Increasing use of over last 10 years.
Second line: reflex test for positive whole allergen blood tests
Diagnostic use:
- Food allergy (nuts, egg, milk)
- Insect allergy (wasp and bees)
- Guide to immunotherapy (grass and HDM)
What is the food components allergy test?
Nuts
Storage proteins (2 s albumins): severe reactions. Pathogenesis-related proteins (PR10 bet v1 homologue) which are also found in tree pollens, fruits and vegetables: mild reaction.
Non specific lipid transfer proteins which are also found in in fruit (peach) , tree pollen (plane), vegetables and legumes ( can be mild or severe).
Wheat
Omega-5-gliadin more marker of specific wheat allergy than total wheat IgE.
Egg and milk
Heat stable proteins ovomucoid (egg) and caseins ( estimate who outgrow allergy).
Fish and shellfish
Parvalbumin in fish, Tropomyosin in crustaceans (cross reactive).
What is mast cell tryptase?
Tryptase: Pre-formed protein found in mast cell granules.
Systemic degranulation of mast cells during anaphylaxis results in increase in serum tryptase.
Peak concentration at 1-2 hours; returns to baseline by 6-12 hours.
Failure to return to baseline after anaphylaxis may be indicative of systemic mastocytosis.
Useful if diagnosis of anaphylaxis is not clear (hypotension + rash during anaesthesia).
Reduced sensitivity for food induced anaphylaxis.
What is the basophil activation test?
Measurement of basophil response to allergen IgE cross linking.
Activated basophils increase the expression of CD63, CD203, CD300 protein on cell surface.
Increasing use in diagnosis of food and drug allergy: surrogate marker for challenge tests.
Efforts to this standardise test to use n diagnostic laboratories to reduce need fro challenge tests.
What are challenge tests?
For food and drug allergy.
Gold standard for food and drug allergy diagnosis.
Increasing volumes of the offending food/drug are ingested.
Double blind placebo or open challenge.
Food challenges take place under close medical supervision. Very expensive in terms of clinical staff time.
Can be difficult to interpret mild symptoms. Risk of severe reaction.
A 15 year old with a history of asthma and hayfever who notices an urticarial and angioedema skin rash shortly after eating peanuts.
What is the most appropriate initial diagnostic test?
Skin prick test
A 60 year old female with hypotension and skin rash under general
anaesthesia What is the most appropriate test to diagnose anaphylaxis?
Serial mast cell tryptase
What is the difference between food allergies and food intolerance?
Food allergy: Adverse health effect arising from specific immune response that occurs reproducibly on exposure to a given food.
Food intolerance: Non-immune reactions which include metabolic, pharmacological and unknown mechanisms.
Food allergy likely affect up to 5% of adults and 8% of children.
What is the management for allergies?
Avoidance.
Education about food labelling, interaction with restaurants, school.
Nutritional input for dietary balance, growth in children.
Acknowledge anxiety, potential bullying: mental health support if needed.
Emergency management.
Anaphylaxis guidelines
Ensure allergic asthma is well controlled
Prevention
Breast feeding: Strong family of allergy
LEAP study: Early rather than delayed introduction of peanut in high risk children (moderate/severe AD and egg allergy) significantly reduces development of peanut IgE sensitisation and allergy.
What are IgE mediated food allergy syndromes?
Anaphylaxis:
- Peanut, tree nut shellfish, fish, milk and eggs are most common.
- Natural history dependent on food.
Food associated exercise induced anaphylaxis:
- Food induces anaphylaxis if individual exercises within 4-6 hours of ingestion.
- Common food triggers are wheat, shellfish, celery.
Delayed food-induced anaphylaxis to beef, pork, lamb:
- Symptoms occur 3-6 hours after eating red meat and gelatin
- IgE antibody to oligosaccharide alpha-gal (α1, 3-galactose) found in gut bacteria
- Induced by tick bites which should be avoided
Oral allergy syndrome:
- Limited to oral cavity, swelling and itch: Only 1-2% cases progresses to anaphylaxis.
- Sensitisation to inhalant pollen protein lead to cross reactive IgE to food.
- Onset after pollen allergy established: Affect adults > young children.
- Respiratory exposure to pollen (birch) results in IgE directed to homologous proteins in stone fruits (apple, pear) vegetables (carrot) and nuts (peanut, hazelnut).
- Cooked fruits, vegetables and nut cause no symptoms: Heat labile allergens detected by component allergen tests.
A 35 year old man with tree pollen hayfever and immediate lip tingling and swelling immediately after eating apples.
What is the most likely explanation for IgE hypersensitivity ?
Cross reactive IgE sensitisation between hay fever and apple allergens
