T1 L17 and 18 Atopy, allergy and DTH Flashcards
What is an allergen?
Substance to which IgE antibodies may be produced
What are the steps of the early phase reaction?
1) Specific antigen binds to IgE
2) Cross-linking of IgE antibodys by allergen causes clustering of FceR1 receptors
3) Intracellular portion of receptor becomes phosphorylated
4) Resulting intracellular cascade leads to cellular activation
5) Mast cell degranulates releasing histamine, tryptase and other pre-formed mediators
Describe the effects of mast cell activation and granule release on the GI tract
Increased fluid secretion
Increased peristalsis
Leading to:
Expulsion of gastrointestinal contents (diarrhoea, vomiting)
Describe the effects of mast cell activation and granule release on the airways
Decreased diameter
Increased mucus secretion
Leading to:
Congestion and blockage of airways (wheezing, coughing, phlegm)
Swelling and mucus secretion in nasal passages
Describe the effects of mast cell activation and granule release on blood vessels
Increased blood flow
Increased permeability
Leading to:
Increased fluid in tissues causing increased flow of lymph to lymph nodes
Increased cells and proteins in tissues
Increased effector response in tissues
Give examples of allergen sources
Pollens
House dust mite faeces
Stinging insect venom
What are the general characteristics of allergens?
Proteins
Physical properties that favour transition across mucus membranes
Biologically active, often enzymes
Have moderate homology with self-proteins
What is anaphylaxis?
Generalised allergic reaction
Systemic release of histamine leads to generalised vasodilation and fluid loss from circulation to tissues
What are some common triggers for anaphylaxis?
Food
Drugs
Insect venom
What are the cardinal features of anaphylaxis?
Typical symptoms Multi-system Dramatic Rapidly follows exposure to antigen Tends to improve fairly quickly
What is oral allergy syndrome?
Most common type of food allergy across UK adults
IgE directed against pollen proteins cross-reacts with homologous proteins in plant-derived food
Exposure to raw fruits, nuts and vegetables causes oral itching
What is rhinitis?
Blockage due to type 1 allergy
Sneezing and rhinorrhoea
What is lower airway obstruction?
Wheeze due to type 1 allergy
What are examples of seasonal allergens?
Pollens
Moulds
What are examples of episodic allergens?
Occupational
Animal dander
Why is tolerance required?
To prevent autoimmune and inflammatory diseases
What is allergic / atopic march?
Progression of disease observed from infancy
Eczema –> food allergy –> rhinitis –> asthma
Allergic disease can present de novo in adults
What would asthma show on biopsy?
Inflammatory infiltrate and airway changes known as re-modelling
Thickened basement membrane
Smooth muscle hyperplasia
What does IL-4 lead to?
Mucus hypersecretion
What does IL-13 lead to?
Bronchial hyper-responsiveness
What does IL-5 lead to?
Eosinophil recruitment
What does IL-9 lead to?
Mast cell recruitment
What is the late phase allergic reaction?
Occurs hours after early phase reaction
What would be shown in a biopsy of late phase allergic reaction?
Infiltration with inflammatory cells:
CD4 T-cells
Eosinophils
Mast cells
What is the evidence that Th2 responses are important in allergy?
IL-4 required for B-cell class switching to IgE
IL-4 and IL-13 promote mucus hypersecretion
IL-5 required for eosinophil survival
IL-9 recruits mast cells
Describe the genetics of asthma
Childhood allergy strongly predicted by presence of allergy in parents
Numerous genetic risk factors identified, none particularly compelling
Allergy epidemic occurred too quickly to be entirely explained by genetics
Describe the hygiene hypothesis
Strachan 1989
Low hygiene levels, high pathogen load and helminth infections proposed for skew immunity from Th2 to Th1 and induce regulatory T-cells
High hygiene levels, low pathogen load and absence of helminth infection proposed for skew immunity towards Th2 and reduce production of regulatory T-cells
What factors contribute to developing countries having less allergies?
Large family size Rural homes, livestock Intestinal microflora are variable and transient Low antibiotic use High helminth burden Poor sanitation, high orofaecal burden
What factors contribute to westernised countries having more allergies?
Small family size Affluent urban homes Intestinal microflora are stable High antibiotic use Low or absent helminth burden Good sanitation, low orofaecal burden
What did the LEAP study look at?
Is exposure to peanuts protective?
High risk infants recruited and tested for peanut allergy at baseline
After 6 months of age they were randomised to either peanut avoidance or regular consumption and followed to 5 years
What were the results of the LEAP study?
Those exposed had peanut in the gut
Those not been exposed may be exposed to peanuts through the skin in future. If they already have asthma and skin is already inflammed, then allergen gets presented in an inflammatory context.
What is in vivo skin testing?
Allergen extract applied as drops
Top layers of epidermis are punctured with lancet
Positive result if wheal and flare occurs within 15 minutes
Results need interpretation in clinical context
What is in vitro testing?
ELISA
Give the 4 main steps of the ELISA
1) Plastics coated with purified allergen of interest
2) Incubate with patient serum
3) IgE antibodies in sera of sensitised patient bind to allergens
4) Immobilised IgE antibodies detected with polyclonal anti-IgE detection antibody
Give examples of allergy treatments that only resolve symptoms
Nasal decongestants e.g. oxymetazoline
Beta2 agonists e.g. salbutamol
Epinephrine
What is the mechanism of oxymetazoline?
Acts on alpha1 adrenoreceptors causing vasoconstriction
What is the mechanism of salbutamol?
Acts on beta 2 adrenoreceptors in lung causing smooth muscle relaxation
What type of drugs act on early phase mediators?
H1 antihistamines
Leukotriene receptor antagonists
Mast-cell stabilisers
Give an example of a H1 antihistamine
Chlorpheniramine - 1st generation
cetirizine, loratadine, desloratadine, fexofenadine
Why can 1st generation antihistamines only be given in hospital?
High risk of sedation and drug interactions
Give an example of a leukotriene receptor antagonist
Montelukast
Give an example of a mast-cell stabiliser
Sodium cromoglicate
Describe the mechanism of corticosteroids
1) Steroid receptors found in cytoplasm are complexed with heat-shock protein Hsp90
2) Steroids cross cell membrane and bind to steroid receptor complex which releases Hsp90
3) Steroid receptor complex crosses nuclear mechanism
4) In nucleus, steroid receptor binds to specific gene regulatory sequences which activates transcription.
Give examples of inhaled corticosteroids
Beclomethasone
Fluticasone
Give examples of nasal corticosteroids
Beclomethasone
Mometasone
Fluticasone
What is omalizumab?
Monoclonal antibody directed against IgE
How does omalizumab word?
Binds to free IgE decreasing cell-bound IgE
Decreases expression of high-affinity receptors
Decreases mediator release
Decreases allergic inflammation, prevents exacerbation of asthma and reduces symptoms
What is allergen-specific immunotherapy?
Large doses of allergen are administered y subcutaneous injection or sublingually which produces multiple immunological effects
What immunological effects occur in allergen-specific immunotherapy?
Induce regulatory T-cell responses to allergens Reduced Th2 responses Induced allergen-specific IgG antibodies Reduction in mast cell responsiveness Reduce allergen-specific IgE levels
What is contact dermatitis
Type IV hypersensitivity reaction
Describe the process of sensitisation in CD
Sensitising agents penetrate skin and react with self-proteins to create protein-happen complexes. These are picked up by Langerhans cells and migrate to regional lymph nodes
Langerhans cells process and present antigens with MHC II
Activated T-cells then migrate to dermis
What is a hapten?
Small molecule which can’t produce an immune response by itself but can bind to a protein to alter its immunogenicity
Describe the process of elicitation in CD
Chemokines recruit macrophages
Th1 cells secrete IFN-gamma which increases expression of vascular adhesion molecules and activates macrophages.
TNF-alpha/beta causes local inflammation
What is pentadecatechol?
Poison ivy lipid that may cross skin and modify intracellular proteins
What is patch testing?
Done for contact dermatitis
Antigen-impregnated patch placed on back and results read after 2 days.
Examples include nickel, chrome, cobalt, expose resin, lanolin.
What is the difference between the clinical features of type I and type IV allergy?
Type I has various features consistent with mast cell degranulation
Type IV is an eczematous skin reaction
What is the difference between the temporal aspect of type I and type IV allergy?
Type I closely follows exposure then improves rapidly
Type 2 has a delay between exposure and symptoms
What is the difference between the causative agents of type I and type IV allergy?
Type I is almost always a naturally occurring protein or closely related to one
Type IV is various, often synthetic molecules
What is the difference between the effector mechanism of type I and type IV allergy?
Type I has specific IgE, mast cell degranulation
Type IV has antigen-specific effector Th1 cells
How is type I and type IV allergy assessed?
Type 1 in allergy clinic. History, skin prick testing, serology for antigen-specific IgE
Type IV in dermatology clinic or allergy clinic. History or patch testing.
How are type I and type IV allergy managed?
Type I is avoidance, pharmacotherapy and immunotherapy
Typve IV is avoidance
When should a skin-prick test be done?
History suggestive of IgE mediated allergy
What is the test format of skin-prick testing?
Allergen extract drops applied to skin, skin punctured. Read after 15min
What is a positive result of the skin prick testing?
Wheal and flare response
When should a patch test be done?
History suggestive of contact dermatitis
What is the test format of patch testing?
Test antigen applied under occlusive dressing. Read after 48h.
What is a tuberculin skin test used for?
To determine exposure to TB
What is tuberculin?
Complex mixture of antigens derived from MTB which is injected intradermally in the TST.
Why is the tuberculin skin test a poor test for active TB?
TB is unlikely to be in the skin so the test will be negative
What is the mechanism of the tuberculin skin test?
1) Antigen injected into subcutaneous tissue and processed by local antigen presenting cells
2) Th1 effector cell recognises antigen and releases cytokines which act on vascular endothelium
3) Recruitment of phagocytes and plasma to site of antigen injection causes visible lesion
What are there results of IGRA test if there is no previous TB exposure?
No primed effector memory T-cells specific for MTB
No interferon gamma produced in such a short timeframe
What are the results of IGRA test if there is previous TB exposure?
Effector memory Th1 cells recognise antigen
Secondary immune response means cytokines are released within short timeframe.
