17. Atopy, allergy and dth 1

Question 1

The early phase reaction

Answer 1

In allergic individuals, exposure to allergens leads to the rapid development of symptoms

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 happens after mast cell IgE ligation?

Answer 2

1. IgE binds its specific allergen
2. Cross-linking of IgE antibodies by allergen leads to clustering of FcεR1 receptors
3. The intracellular portion of the receptor becomes phosphorylated
4. The resulting intracellular cascade leads to cellular activation
5. Mast cell ‘degranulates’ releasing histamine, tryptase and other pre-formed mediators

Question 3

Leukotrienes

Answer 3

The leukotrienes produced have similar pharmacological effects to histamine

Phospholipase A2 leads to inflammation and mast cell activation

Question 4

Pharmacological effects of mast cell mediators and leukotrienes

Answer 4

Skin: wheal and flare

Nose: discharge, sneezing etc

Eyes: conjunctivitis

Lung: wheeze

Question 5

Examples of sources of allergens

Answer 5

• Pollens
• house dust mite faeces
• stinging insect venom

Allergens are almost always otherwise innocuous environmental proteins

Of the thousands of environmental proteins that we meet, only few hundred are recognised as allergens

Question 6

General characteristric of allergens

Answer 6

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 7

Clinical allergy syndromes: anaphylaxis

Answer 7

‘Generalised allergic’ reaction

Systemic release of histamine causes generalised vasodilatation & 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 8

Cardinal features of anaphylaxis

Answer 8

typical symptoms

multi-system and dramatic

rapidly follows exposure to allergen and tends to improve fairly quickly thereafter

Question 9

Clinical allergy syndromes: oral allergy syndrome

Answer 9

Most common type of food allergy amongst UK adults

IgE which is directed against pollen proteins cross-reacts with homologous proteins in plant-derived foods

Oral itching upon exposure to raw fruit, nuts and vegetables

In UK:

• Pollen = mainly birch
• Food = mainly Rosaceae fruits

Question 10

Clinical allergy syndromes: airway disease

Answer 10

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 11

The immunological tightrope

Answer 11

The immune system is constantly challenged with antigens & must somehow decide how to respond

• Self antigens vs non-self
• Dangerous infections vs commensal organisms
• Environmental allergens such as foods and pollens

Activation vs tolerance

Activation: Required for defence against infection and cancer

Tolerance: Required to prevent autoimmune and inflammatory diseases

Question 12

Origins of allergic disease

Answer 12

Allergic or atopic march = progression of disease observed from infancy

Most children outgrow eczema and many food allergies; rhinitis/ asthma may or may not be outgrown

Allergic disease may however present de novo in adults

Question 13

Chronic allergic inflammation: asthma

Answer 13

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 14

The late phase allergic reaction

Answer 14

• 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 15

T cell subsets

Answer 15

Question 16

T cell subsets and Th2 hypothesis

Answer 16

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 patients stimulated with allergen in the laboratory produce Th2 cytokines

Plenty of 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

Question 17

Th2 interleukins and allergy

Answer 17

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 18

Acute response in asthma

Answer 18

Inflammatory mediators cause increased mucus secretion and smooth muscle contraction leading to airway obstruction

Recruitment of cells from the circulation

Question 19

Chronic allergic disease: asthma

Answer 19

Activated Th2 cells and other inflammatory cells accumulate

Th2 products lead to 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

Question 20

Potential factors in asthma aetiology: genetics

Answer 20

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 21

Hygiene hypothesis

Answer 21

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 infection proposed to:

• Skew immunity towards Th2
• Reduce production of regulatory T cells