Asthma and allergy

Question 1

What are the different types of hypersensitivity reactions?

Answer 1

• Type 1 = immediate hypersensitivity (acute allergy)
• Type 2 = Cytotoxic hypersensitivity
• Type 3 = Serum sickness and Arthus reaction
• Type 4 = delayed-type hypersensitivity, contact dermatitis

Question 2

Describe type 1 hypersensitivity

Answer 2

• Interaction between specific IgE and allergen
• Mast cells have specific IgE, allergen cross-links the IgE, causing mast cell activation and degranulation
• e.g. allergic rhinitis, asthma and anaphylaxis

Question 3

How can you test if someone is allergic to a substance?

Answer 3

• Skin prick test
• if mast cells have the specific IgE, it will recognise the allergen that you have pricked in the skin and produce a wheal response

Question 4

Describe a type II hypersensitivity

Answer 4

• Cytotoxic hypersensitivity
• IgG anti-drug antibodies
• Drug binds to RBC
• IgG binds to the drug
• Antibody-bound cells are cleared by cells such as macrophages and complement
• e.g. Some drug allergies such as penicillin
• Also special cases where IgG Abs are directed at cell-surface receptors; disrupting the normal functions of the receptor by uncontrollable activation or blocking receptor function

Question 5

Give an example of a type II reaction

Answer 5

• Graves - Ab recognises TSH receptor, induces production of thyroxine -> thyrotoxicosis

Myasthenia gravis - immune response reacts to Ach receptor, blocking synaptic transmission causing a type of paralysis

Haemolytic disease of the newborn

Question 6

What is haemolytic disease of the newborn?

Answer 6

• Caused by rhesus incompatibility
• During birth, rhesus +ve foetal erythrocytes leak into maternal blood after breakage of the embryonic chorion
• Maternal B cells are activated by the Rh antigen and produce large amounts of anti-Rh antibodies
• Rh antibody titre in mother’s blood is elevated after first exposure
• Rh antibodies are small enough to cross the chorion and attack foetal erythrocytes

Question 7

Describe a Type III reaction

Answer 7

• IgG and soluble antigen form immune complexes
• Immune complexes are cleared by phagocytosis/ complement
• e.g. Arthus reaction and serum sickness

Question 8

How does Arthus reaction occur?

Answer 8

• Locally injected antigen in immune individual forms immune complex with IgG antibody
• These bind to Fc receptors on mast cells, activating them and releasing inflammatory mediators
• Inflammatory cells invade the site, and blood vessel permeability and blood flow are increased
• Platelets also accumulate, leading to occlusion of the small blood vessels, haemorrhage and the appearance of purpura

Question 9

What is serum sickness?

Answer 9

• Caused by large IV dose of soluble antigens (drugs)
• IgG antibodies produced form small immune complexes with the antigen in excess
• Immune complexes get deposited in tissues/ blood vessel walls
• Tissue damage is caused by complement activation and subsequent inflammatory responses

Question 10

What is farmer’s lung?

Answer 10

• Farmers can become sensitised to moulds in the hay
• They inhale it and form complexes in the lung
• This can lead to severe pathology over many years

Question 11

What determines the pathology observed in type III hypersensitivity reactions?

Answer 11

• Antigen dose and route of delivery determine the pathology
• IV = vasculitis (vessel walls), nephritis (renal glomeruli), arthritis (joint spaces)
• Subcutaneous = arthus reaction (perivascular area)
• Inhaled = farmer’s lung (alveolar/ capillary interface)

Question 12

Describe type IV reactions

Answer 12

• Delayed-type hypersensitivity
• Antigen either acts on Th1 or Th2 cells
• Th1 when bound releases IFN-gamma, which activates macrophages, causing the release of chemokines, cytokines and cytotoxins - e.g. contact dermatitis
• Th2 releases IL-4,5 and eotaxin, which activate eosinophils, causing the release of proteins, enzymes and cytokines - e.g. chronic asthma, chronic allergic rhinitis

Question 13

What is IgE?

Answer 13

• Originally the first line of defence against worms - however we dont have them now so we react to things in the environment we wouldnt usually react to
• Binds to the Fc receptors on mast cells
• It pre-arms the mast cells to react when in the presence of antigen

Question 14

What is the hygiene hypothesis?

Answer 14

We live so cleanly these days that we arent exposed to enough dirt to combat allergens

Question 15

How does filaggrin?

Answer 15

• Filaggrin links skin integrity and allergen
• When it is defective, atopic dermatitis is greater
• This is due to the access of allergens

Question 16

What makes dendritic cells pro-allergenic?

Answer 16

• Langerhans are dendritic cells (APCs)
• When the skin is damaged, cytokine production is increased
• These langerhans go to the lymph nodes to present the antigens to Th2 cells

Question 17

What is the effector mechanism of the allergic immune response?

Answer 17

• We become sensitised after exposure to pollen
• Th2 cells release IL-4, which drives B cells to produce IgE in response to pollen antigens
• Pollen specific IgE binds to mast cells, priming them
• Second exposure to pollen
• mast cells are activated and release their inflammatory mediators -> allergic rhinitis
• Also IL-4 acts on eosinophils and IL-5 acts in mast cells - these cause chronic allergic reaction

Question 18

What causes the wheal and flare responses?

Answer 18

• Allergic responses have an early (wheal) and late phase (flare)
• Early is mediated by mast cells - allergen exposure triggers degranulation
• Late is mediated by T cells - activated T cells, eosinophils and basophils go to the site of allergen exposure

Question 19

What do each of the specific mediators produced by mast cells do?

Answer 19

• Histamine = increase vascular permeability and cause smooth muscle contraction
• Leukotrienes = increase vascular permeability, cause smooth muscle contraction and stimulates mucus secretion
• PGs = chemoattractants for T cells, eosinophils and basophils
• Cytokines - IL-4/13 = promotes Th2 and IgE formation. TNFa = promotes tissue inflammation

Question 20

What does mast cell activation and granule release do to different areas of the body?

Answer 20

• GIT = increased fluid secretion, increased peristalsis -> expulsion of GI contents (diarrhoea and vomiting)
• Airways = decreased diameter, increased mucus secretion -> congestion and blocking of airways, swelling and mucus secretion in nasal passages
• Blood vessels = increased blood flow and permeability -> increased fluid in tissue causing increased flow to lymph, increased cells and protein in tissues, and increased effector response in tissues.

Question 21

What are the two effector functions of eosinophils?

Answer 21

• Release highly toxic granule proteins and free radicals upon activation -> kill MOs/ parasites and cause tissue damage in allergic reactions
• Synthesise and release PGs, LTs and cytokines in order to amplify the inflammatory response by activating epithelial cells and recruiting lymphocytes

Question 22

What is allergic asthma?

Answer 22

• Asthma brought on be allergic reaction to: pollen, plants, some foods etc

Question 23

What causes the acute response in allergic asthma?

Answer 23

• Occurs within seconds of allergen exposure
• Results in airway obstruction and breathing difficulties
• Caused by allergen-induced mast cell degranulation in the submucosa of the airways

Question 24

What causes the chronic response in allergic asthma?

Answer 24

• Chronic inflammation of the airways
• Caused by activation of eosinophils, neutrophils, T cells and other leukocytes
• Mediators released by these cells cause airway remodelling, permanent narrowing of the airways and further tissue damage

Question 25

How do we treat allergy in the clinic?

Answer 25

• Blockage of effector pathways:
• Inhibit effects of mediators on specific receptors (anti-histamines)
• Inhibit mast cell degranulation (NSAID)
• Inhibit synthesis of specific mediators (lipoxygenase inhibitors)
• Steroids - act on DNA to increase transcription of anti-inflammatory mediators (IL-10) and decrease transcription of pro-inflammatory mediators
• B2 agonists
• Immunotherapy - reverses the sensitisation to allergen