L17 Atopy, allergy and delayed type hypersensitivity - Part 1 Flashcards
The early phase reaction
- In allergic individuals, exposure to allergens leads to the rapid development of symptoms
- This reaction develops within seconds or minutes of exposure and results from the binding of allergens to pre-formed IgE antibodies on the surface of mast cells and basophils
What is an allergen
- Substance to which IgE antibodies may be produced
Events that follow mast cell IgE ligation
- IgE binds its specific allergen
- Cross-linking of IgE antibodies by allergen leads to clustering of FceR1 receptors
- The intracellular portion of the receptor becomes phosphorylated
- The resulting intracellular cascade leads to cellular activation
- Mast cell ‘degranulates’ releasing histamine, tryptase and other pre-formed mediators
Delayed mediators - leukotrienes
Membrane phospholipids –phospholipase A2 (inflammation mast cell activation)–>Arachidonic acid –(5 Lipoxygenase)–> leukotrienes
Arachidonic acid –COX1–> prostaglandins
Pharmacological effects of mast cell mediators and leukotrienes
Skin - wheal and flare
Nose - discharge, sneezing etc
Eyes - conjunctivitis
Lung - Wheeze
Mast-cell activation and granule release
GI tract –> increased fluid secretion, increased peristalsis –> expulsion of gastrointestinal tract contents (diarrhoea, vomiting)
Airways –> decreased diameter, increased mucus secretion –> congestion and blockage of airways (wheezing, coughing phlegm). Swelling and mucus secretion in nasal passages.
Blood vessels –> increased blood flow, increased permeability –> increased fluid in tissues causing increased flow of lymph to lymph nodes. Increased cells and protein in tissues. increased effector response in tissues
Examples of allergen sources
- Pollens
- House dust mite faeces
- Stinging insect venom
General characteristics of allergens
Proteins(there are a few minor exceptions) - only protein can produce a T cell(and therefore B cell) response
Physical properties that favour transition across mucus membranes - need to cross mucus membranes to activate immunity. Typically soluble and low molecular weight
Biologically active, often enzymes - interesting, but important or coincidence
Have moderate homology with self-proteins - theory is that low homology with self-protein = wouldn’t bind to MHC; high homology = would be deleted during negative selection
Clinical allergy syndromes: anaphylaxis
‘Generalised allergic’ reaction
Systemic release of histamine causes generalised vasodilation and fluid loss from circulation to tissues
- Cutaneous: hives, angioedema
- Gut histamine release: vomiting, diarrhoea
- Mucosal histamine release: laryngeal oedema, bronchoconstriction
- Circulation: vasodilatation, hypotension
Food, drugs and insect venom commonest triggers in UK
Cardinal features of anaphylaxis
Typical symptoms
Multi-system and dramatic
Rapidly follows exposure to allergen and tends to improve fairly quickly thereafter
Oral allergy syndrome
- Most common type of food allergy amongst UK adults
- IgE directed against pollen proteins cross-reacts with homologous proteins in plant-derived foods
- Oral itching upon exposure to raw fruit, nuts and veg
Airway disease
Rhinitis - sneezing, rhinorhoea, blockage due to a type 1 allergy
Lower airway obstruction - wheeze due to type 1 allergy
Allergens/symptoms may be:
Seasonal - pollens, moulds
Episodic - occupational, animal dander
When symptoms are chronic, the inflammation becomes established and cannot be explained simply in terms of mast cell degranulation
What is the immunological tightrope
The immune system is constantly challenged with antigens and must somehow decide how to respond
- Self antigens vs non-self
- Dangerous infections vs commensal organisms
- Environmental allergens such as foods and pollens
Origins of allergic disease
Allergic or atopic march = progression of disease observed from infancy
Most children outgrow eczema and many food allergies; rhinitis/asthma may or may not outgrow
Allergic disease may however present de novo in adults
Chronic allergic inflammation: asthma
- Patients with chronic asthma have on-going symptoms
- Most patients are sensitised to a variety of airborne allergens
- Biopsy shows inflammatory infiltrate and airway changes known as ‘re-modelling’ - thickened basement membrane and smooth muscle hyperplasia
- The ‘early allergic reaction’ model does not provide a good explanation by itself
Asthma - histological features
- Mucous plug with trapped inflammatory cells
- Goblet cell metaplasia
- Inflammatory cell infiltrate in submucosal layer
- Thickened basement membrane
- Thickened airway smooth muscle
- Normal parenchymal attachments
Late phase allergic reaction
- The early phase reaction to allergen is followed some hours later by a second ‘late phase reaction’
- Biopsy of the late phase shows infiltration with inflammatory cells - particularly CD4 T cells, eosinophils and mast cells: provides some insight into chronic allergic inflammation, and often used as an experimental model
T cell subsets - Naive CD4
Th1 –> IFN-g
Th2 –> IL-4,5,9 and 13
Th17 –> IL-17
Treg –> IL-10, contact-dependent mechanisms
T cell subsets and the Th2 hypothesis
Th2 responses to allergens have been consistently associated with allergic disease
- Biopsies of allergic inflammation are rich in T cells expressing Th2 cytokines
- T cells from allergic patient stimulated with allergen in the lab produce Th2 cytokines
Why are there reasons to believe that Th2 responses may be important in allergy
- IL-4 is required for B cell class switching to IgE
- IL-4 and IL-13 promote mucus hypersecretion
- IL-5 is required for eosinophil survival
- IL-9 recruits mast cells
Chronic allergic disease - asthma - acute responses
- Inflammatory mediators cause increased mucus secretion and smooth muscle contraction leading to airway obstruction
- Recruitment of cells from the circulation
Chronic allergic disease - asthma - chronic response
- Chronic response caused by cytokines and eosinophil products
- Activated Th2 cells and other inflammatory cells accumulate
- Th2 products lead to chronic disease
Th2 products and chronic disease
IL4 - mucus hypersecretion
IL-13 - Bronchial hyper-responsiveness
IL-5 - eosinophil recruitment
iL-9 - mast cell recruitment
This model suggests a true role for T cells in chronic inflammation rather than just in causing IgE production
Potential factors in the aetiology of allergy: genetics
- Childhood allergy is strongly predicted by presence of allergy in parents, but difficult to unpick relative contribution of environment
- Numerous genetic risk factors identified, but none particularly compelling
- Notable that the allergy epidemic has occurred too quickly to be explained entirely by genetics
Hygiene hypothesis: Strachan 1989
States that a lack of early childhood exposure to infectious agents, symbiotic microorganisms (such as the gut flora or probiotics), and parasites increases susceptibility to allergic diseases by suppressing the natural development of the immune system
Hygiene hypothesis: immunology
Low hygiene levels, high pathogen load, helminth infection proposed to:
- Skew immunity from Th2 to Th1
- Induce regulatory T cells
High hygiene levels, low pathogen load, absence of helminth infect proposed to:
- Skew immunity towards Th2
- Reduce production of regulatory T cells
