Week 10 Part 1 - Asthma and Allergies

Question 1

Hypersensitivity

Answer 1

Excessive immune system activation -> damage
Reactions are exaggerated or inappropriate

Question 2

Allergy vs Atopy

Answer 2

Allergy = Type I (immediate) hypersensitivity reaction
Atopy = IgE-mediated hypersensitivity (affected patients are atopic)

Question 3

Type 1 Hypersensitivity

Answer 3

Immediate hypersensitivity mediated by IgE
Occurs within 30 minutes
50% of the population generate an IgE response to airborne allergens
After repeated exposure 20% develop clinical symptoms
Mild allergic reaction, to life-long debilitating disease, to severe life threatening reactions
IgE and mast cells are key players

Question 4

Steps in an Allergic Response

Answer 4

1. Sensitisation: IgE antibody is produced in response to an allergen and binds receptors on mast cells
2. Activation: re-exposure or challenge to antigen triggers mast cells to respond by releasing contents of their granules
3. Effector step: a complex response results from the effects of inflammatory mediators released by mast cells
   -> Eczema, asthma, rhinitis, allergy

Question 5

Sensitisation Step

Answer 5

Production of IgE due to airborne allergen presented at very low doses < 1ug/year
When an individual who has produced IgE in response to an antigen (allergen) re-encounters the same allergen -> allergic reaction
IgE produced by plasma cells in lymph nodes and at site of allergic reaction
- localised in tissues, low levels in serum
- bound to mast cell surfaces via high affinity FcεRI receptor -> cross-links FcεRI causing release of chemical mediators by mast cells -> allergic reaction

Question 6

Sensitisation - How is IgE Produced?

Answer 6

Certain antigens and routes of antigen presentation favour IgE production
Presenting antigen at very low doses, across a mucosal surface favours activation of Th2 over Th1 cells
Th2 cells are required for IgE generation

Question 7

Steps of how IgE is Promoted during Sensitisation

Answer 7

1. Upon first exposure to allergen, APC processes antigen and presents to Th2 cell
2. Th2 release IL-4/IL-13 which activate B cells
3. B cells differentiate into plasma cells that synthesise and secrete IgE
4. IgE binds Fc region on mast cells, sensitising the mast cells
5. Repeat exposure -> mast cells with IgE bind to antigen and release inflammatory molecules -> allergic reaction

Question 8

Steps in an Allergic Response - Activation

Answer 8

Involves mast cells and basophils can also contribute
Mast cells are located in mucosal and epithelial tissues in the vicinity of small blood vessels and subendothelial connective tissues
IgE can persist on cell surfaces for weeks, cells remain sensitised when enough IgE is bound

Question 9

Association between Activation and Effector Steps

Answer 9

Activation step triggering of mast cells by cross-linking of FcεRI receptors
Leads to degranulation and release of potent inflammatory mediators
Mast cell granules get transported to cell surface
Granule membranes then fuse with cell membrane so that the contents can be released via exocytosis
No lysis or cell death, granule content can be resynthesised
Effector step: Symptoms caused by mediators released

Question 10

Performed and Synthesised Mediators

Answer 10

Performed:
- histamine
- cytokines and chemokines
Synthesised:
- leuktrienes and prostoglandins
- PAF

Question 11

Performed Mediators in the Effector Step - Histamine

Answer 11

Binding to H1 receptors on smooth muscle causes contraction and on endothelial cells causes vascular permeability and edema
Binding to H2 receptors on respiratory mucosa triggers mucus secretion and on gut mucosa release of stomach acid

Question 12

Performed Mediators in the Effector Step - Cytokines and Chemokines

Answer 12

IL-3, IL-4, IL-5, IL-8, IL-9, TNF, GM-CSF recruit inflammatory cells
E.g. neutrophils, eosinophils, basophils, macrophages and lymphocytes

Question 13

Synthesised Mediators in the Effector Step - Leukotrienes and Prostoglandins

Answer 13

Cause contraction of bronchial and tracheal smooth muscle, vascular permeability and mucus secretion -> prolonged bronchospasm and mucus in asthma

Question 14

Synthesised Mediators in the Effector Step - Platelet Activating Factor

Answer 14

Causes platelet aggregation -> release mediators from platelets e.g. histamine

Question 15

Mast Cell Activation and Granule Release - Gastrointestinal Tract

Answer 15

Increased fluid secretion
Increased peristalsis
-> Expulsion of gastrointestinal contents

Question 16

Mast Cell Activation and Granule Release - Airways

Answer 16

Decreased diameter
Increased mucous secretion
-> Expulsion of airway contents (phlegm, coughing)

Question 17

Mast Cell Activation and Granule Release - Blood Vessels

Answer 17

Increased blood flow
Increased permeability
-> Edema, inflammation, increased lymph flow and carriage of antigens to lymph nodes

Question 18

What are the Two Phases of the Effector Step?

Answer 18

Early/Intermediate Phase: within minutes, caused by direct effects on blood vessels and smooth muscle by mediators such as histamine
Late Phase: 6-10 hours, caused by influx of inflammatory cells attracted by chemokines

Question 19

Late Phase Reactions - Overview

Answer 19

Approximately 6 hours after mast cell degranulation and persists for several days
Infiltration of eosinophils, neutrophils, macrophages, Th2 cells and basophils
Eosinophils dominate the cell infiltrate -> produced in the bone marrow and migrate to the site of an allergic reaction recruited by IL-4 and chemokines
Th2 secrete IL-3, IL-5 and GM-CSF -> growth and differentiation of eosinophils (primarily IL-5)

Question 20

Late Phase Reactions - Eosinophils

Answer 20

Express receptors for IgE (FcεRII) and Fc receptors that bind IgG
- IgG and IgE bound antigen activate eosinophils causing degranulation
- release inflammatory mediators e.g. leukotrienes, major basic protein, eosinophilic cationic protein, eosinophilic peroxidase and platelet activating factor
- cause tissue damage - particularly respiratory epithelium in asthma

Question 21

Late Phase Reactions - Neutrophils

Answer 21

Migrate in response to IL-8 from mast cells
- surface IgG Fc receptors bind antibody coated antigen -> cell activation
- phagocytosis of antibody-antigen complexes
- release of leukotrienes and lysosomal enzymes

Question 22

Late Phase Reactions - Th2 Lymphocytes

Answer 22

Infiltrate and release cytokines to exacerbate response