L17 Atopy, allergy and delayed type hypersensitivity - Part 1

Question 1

The early phase reaction

Answer 1

• 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

Question 2

What is an allergen

Answer 2

• Substance to which IgE antibodies may be produced

Question 3

Events that follow mast cell IgE ligation

Answer 3

• 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

Question 4

Delayed mediators - leukotrienes

Answer 4

Membrane phospholipids –phospholipase A2 (inflammation mast cell activation)–>Arachidonic acid –(5 Lipoxygenase)–> leukotrienes

Arachidonic acid –COX1–> prostaglandins

Question 5

Pharmacological effects of mast cell mediators and leukotrienes

Answer 5

Skin - wheal and flare
Nose - discharge, sneezing etc
Eyes - conjunctivitis
Lung - Wheeze

Question 6

Mast-cell activation and granule release

Answer 6

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

Question 7

Examples of allergen sources

Answer 7

• Pollens
• House dust mite faeces
• Stinging insect venom

Question 8

General characteristics of allergens

Answer 8

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

Question 9

Clinical allergy syndromes: anaphylaxis

Answer 9

‘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

Question 10

Cardinal features of anaphylaxis

Answer 10

Typical symptoms
Multi-system and dramatic
Rapidly follows exposure to allergen and tends to improve fairly quickly thereafter

Question 11

Oral allergy syndrome

Answer 11

• 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

Question 12

Airway disease

Answer 12

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

Question 13

What is the immunological tightrope

Answer 13

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

Question 14

Origins of allergic disease

Answer 14

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

Question 15

Chronic allergic inflammation: asthma

Answer 15

• 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

Question 16

Asthma - histological features

Answer 16

• 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

Question 17

Late phase allergic reaction

Answer 17

• 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

Question 18

T cell subsets - Naive CD4

Answer 18

Th1 –> IFN-g
Th2 –> IL-4,5,9 and 13
Th17 –> IL-17
Treg –> IL-10, contact-dependent mechanisms

Question 19

T cell subsets and the Th2 hypothesis

Answer 19

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

Question 20

Why are there reasons to believe that Th2 responses may be important in allergy

Answer 20

• 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

Question 21

Chronic allergic disease - asthma - acute responses

Answer 21

• Inflammatory mediators cause increased mucus secretion and smooth muscle contraction leading to airway obstruction
• Recruitment of cells from the circulation

Question 22

Chronic allergic disease - asthma - chronic response

Answer 22

• Chronic response caused by cytokines and eosinophil products
• Activated Th2 cells and other inflammatory cells accumulate
• Th2 products lead to chronic disease

Question 23

Th2 products and chronic disease

Answer 23

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

Question 24

Potential factors in the aetiology of allergy: genetics

Answer 24

• 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

Question 25

Hygiene hypothesis: Strachan 1989

Answer 25

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

Question 26

Hygiene hypothesis: immunology

Answer 26

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