W10L13 - Asthma and Allergies

Question 1

Hypersensitivity Introduction

Answer 1

Excessive immune system activation → damage
Reactions are exaggerated or inappropriate
Two arms of adaptive immunity
May be humoral or cell mediated response
Type I hypersensitivity
- immediate hypersensitivity mediated by IgE
- occurs within 30 minutes
Allergy = type I (immediate) hypersensitivity reaction
Atopy = IgE mediated hypersensitivity (affected patients are atopic)

Question 2

Type 1 Hypersensitivty

Answer 2

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 3

Steps in an Allergic Reaction

Answer 3

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 4

Steps in an Allergic Reaction - Sensitisation

Answer 4

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 5

How is IgE produced at the Sensitisation step?

Answer 5

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
Steps:
1. Respiratory or gut mucosal surfaces
- antigen presenting cells drive helper T cells to Th2
2. Th2 release IL-4/IL-13
3. B cells differentiate into plasma cells → IgE
4. IgE binds Fc region on mast cells
5. Repeat exposure  IgE production: individual sensitised

Question 6

Steps in an Allergic Reaction - Activation

Answer 6

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
Basophils are present in the circulation in mature form
IgE can persist on cell surfaces for weeks, cells remain sensitised when enough IgE is bound

Question 7

Summary of Activation and Effector Steps

Answer 7

Activation step triggering of mast cells by cross-linking of FcεRI receptors
Degranulation and release of potent inflammatory mediators
Transport of mast cell granules to cell surface
Granule membranes fuse with cell membrane
Contents released via exocytosis
No lysis or cell death, granule content can be resynthesised
Effector step: Symptoms caused by mediators released

Question 8

Steps in an Allergic Reaction - Effector Step Preformed Mediators

Answer 8

Histamine
- 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
Cytokines and chemokines:
- 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 9

Steps in an Allergic Reaction - Effector Step Synthesised Mediators

Answer 9

Leukotrienes and prostaglandins
- contraction of bronchial and tracheal smooth muscle, vascular permeability and mucus secretion
- → prolonged bronchospasm and mucus in asthma
Platelet activating factor (PAF)
- platelet aggregation → release mediators
- e.g. histamine

Question 10

Steps in an Allergic Reaction - Effector Step Pathway Consequences

Answer 10

Physiological consequences of IgE-mediated mast cell degranulation depends on dose of antigen and route of entry - site of allergic reaction
Mast cell activation and granule release in:
1. Gastrointestinal tract
- increased fluid secretion and peristalsis
- => expulsion of gastrointestinal contents (diarrhoea, vomiting)
2. Airways
- decreased diameter
- increased mucous secretion
- => expulsion of airway contents (phlegm, coughing)
3. Blood vessels
- increased blood flow and permeability
- => edema, inflammation, increased lymph flow and carriage of antigen to lymph nodes

Question 11

Effector Step Phases

Answer 11

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 12

Effector Step - Late Phase Reactions

Answer 12

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)
Detected in haematoxylin and eosin staining
- eosinophils have orange/red/pink cytoplasm

Question 13

Late Phase Reactions - Actions of Eosinophils, Neutrophils and Th2 Lymphocytes

Answer 13

Eosinophils
- 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
Neutrophils
- 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
Th2 lymphocytes
- infiltrate and release cytokines to exacerbate response

Question 14

Allergy Clinical Tests

Answer 14

Skin prick testing
- small amounts of potential allergens introduced at skin sites
- if allergic, mast cells degranulate
- wheel and flare reaction within 15 minutes
- late phase reaction can occur 6 hours later
Serum levels of IgE specific for an allergen
- allergen coupled to an ELISA plate → serum added → specific IgE binds allergen → anti-IgE antibody tagged with a label which can be quantitated
Serum levels of total IgE
- anti-IgE coupled to an ELISA plate → serum added → second anti-IgE antibody tagged with a label which can be quantitated

Question 15

Anaphylaxis

Answer 15

Allergy may be life threatening
- e.g. systemic anaphylaxis and severe asthma
Anaphylaxis can be fatal: triggered by allergen introduced into blood or gut or skin
Occurs rapidly
- type I hypersensitivity reaction from IgE-mediated release of inflammatory mediators from mast cells and basophils
Plasma histamine is a critical mediator
- rises after 5 mins and remains elevated 30-60 mins
- increased vascular permeability → urticarial (hives) and angioedema (skin swelling, mucosa, submucosa)
- increased heart rate, coronary artery vasospasm
- contraction of bronchial tract and GI tract → wheezing, shortness of breath, nausea, vomiting, diarrhoea
Massive edema, shock and bronchiole constriction → major causes of death

Question 16

Signs and Symptoms of Anaphylaxis

Answer 16

Swelling of conjunctiva
Runny nose
Swelling of lips, tongue and/or throat
Skin
- hives
- itchiness
- flushing
CNS
- light headedness
- loss of consciousness 
- confusion
- headache
Respiratory
- SOB
- hoarseness
- pain when swallowing
Gastrointestinal 
- crampy abdominal pain
- diarrhoea
- vomiting
Loss of bladder control

Question 17

Anaphylaxis Drugs

Answer 17

Epinephrine/adrenaline is drug of choice

• relaxes smooth muscle and stops vascular permeability
• improves cardiac output, stopping vascular collapse
• change in blood pressure during systemic anaphylaxis, following treatment with epinephrine

Question 18

Clinical Consequences of Allergy - Food Allergy

Answer 18

Mast cell mediators lead to localised smooth muscle contraction and vasodilation
Vomiting and diarrhoea

Question 19

Clinical Consequences of Allergy - Atopic Dermatitis (Eczema)

Answer 19

Loss of skin barrier function: filagrin mutations
Allergens enter the skin → Th2 response
Mast cells induce chemotaxis of inflammatory cells
Mostly eosinophils → inflammatory skin lesions
Eczema → increased risk of allergic rhinitis and asthma
Treatment: corticosteroid creams

Question 20

Clinical Consequences of Allergy - Allergic Rhinitis

Answer 20

Allergens diffuse across mucous membranes of nasal passages
Activate mucosal mast cells
Local edema and nasal discharge of mucus rich in eosinophils
Irritation due to histamine release
Treatment: anti-histamines or intra-nasal corticosteroids
Allergy has a key role in most asthma

Question 21

Asthma

Answer 21

Chronic disease of the lower airways, episodes of reversible airflow limitation
Airway hyper-reactivity (wheeze) due to late phase reactions: IL-13, histamine, leukotrienes
- IL-13 stimulates mucus secretion
- bronchial contraction by non-specific stimuli (e.g. histamine)

Question 22

Asthma - Late Phase Reactions

Answer 22

Eosinophils lead to chronic inflammation of bronchial mucosa
IL-5 essential for development and proliferation of eosinophils IL-5, IL-4, IL-13 and eotaxin regulate eosinophil accumulation in tissues
Mucus build-up, edema, sloughing of epithelium
- → occlusion of bronchial lumen

Question 23

Allergic vs Non-Allergic Asthma

Answer 23

Heterogenous with several distinct phenotype: allergic and non-allergic
Non-allergic asthma: exposure to air pollution, cigarette smoke, diesel particles, infection
Innate lymphoid cells (ILCs)
- family of cells that parallel types of T cells in adaptive immunity
- however, ILCs lack antigen-specific receptors and react to a wide range of innate signals
ILC2s: non-allergic asthma
- secrete large quantities of IL-5, IL-13 and have receptors for IL-33 and IL-25
- function similar to Th2 cells

Question 24

Non-Allergic Asthma

Answer 24

Irritant or infection acts on lung epithelium
Triggers release of IL-33
Activates ILC2s through IL-33 receptors → type 2 cytokines IL-5 and IL-13
Induce inflammatory cell infiltration, mucus production and airway hyper-responsiveness