Atopy, allergy and delayed type hypersensitivity 1

Question 1

The early phase allergic 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 from the binding of allergens to pre-formed IgE antibodies on the surface of mast cells and basophils

Question 2

Allergen definition

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 FcεR1 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

Leukotrienes

Answer 4

Delayed mediators

Have similar effects to histamine

Question 5

General characteristics of allergens

Answer 5

Proteins (there are a few minor exceptions)

Physical properties that favour transition across mucus membranes

Biologically active, often enzymes

Have moderate homology with self-proteins

Question 6

Anaphylaxis

Answer 6

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: vasodilation, hypotension

Food, drugs and insect venom commonest triggers in UK

Question 7

Cardinal features of anaphylaxis

Answer 7

Typical symptoms

Multi-system and dramatic

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

Question 8

Oral allergy syndrome

Answer 8

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, nut and vegetables

In UK:

• pollen= mainly birch
• food= mainly rosaceae fruits

Question 9

Airway disease

Answer 9

Rhinitis
- sneezing, rhinorrhoea, 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 10

The immunological tightrope

Answer 10

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

• self antigens vs non self
• dangerous infections vs commensal organisms
• environmental allergens such as foods and pollens

Question 11

Allergic or atopic march

Answer 11

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 12

Asthma

Answer 12

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

Early allergic reaction model does not provide a good explanation by itself

Question 13

Late phase allergic reaction

Answer 13

The early phase reaction to allergen is followed some hours later by a second late phase reaction

Biopsy of the late phase shows infiltrate 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 14

T cell subsets

Answer 14

All from naive CD4

Th1- IFN-g

Th2- IL4,5,9,13

Th17- IL17

Treg- IL10, contact dependent mechanisms

Question 15

T cell subsets and the Th2 hypothesis

Answer 15

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

• IL4 is required for B cell class switching to IgE
• IL4 and IL13 promote mucus hypersecretion
• IL5 is required for eosinophil survival
• IL9 recruits mast cells

Question 16

Asthma: acute responses

Answer 16

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

Recruitment of cells from the circulation

Question 17

Asthma: chronic response

Answer 17

Activated Th2 cells and other inflammatory cells accumulate

Th2 products lead to chronic disease

• IL4: mucus hypersecretion
• IL13: bronchial hyper-responsiveness
• IL5: eosinophil recruitment
• IL9: mast cell recruitment

Question 18

Genetics and allergy

Answer 18

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 19

Hygiene hypothesis: immunology

Answer 19

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 Th2
• reduce production of regulatory T cells