The Allergic Lung

Question 1

List the clinical features of bronchial asthma.

Answer 1

1. Acute attacks of shortness of breath, acute airway obstruction due to contraction of smooth muscle
2. Mucus hypersecretion
3. Airway inflammation
4. Bronchial hyper-responsiveness

Question 2

List the types and triggers of bronchial asthma.

Answer 2

Allergens
Chemical irritants
Dust, smoke
Cold
Post-exercise
Psychogenic
Post-coughing
Post-hyperinflation
Post-laughter
Viral colds

Question 3

Explain the two phases of asthma and how bronchial hyper-responsiveness is documented.

Answer 3

There is an early (bronchospasm) and a late phase (inflammation) of asthma.
The early phase is 0-3 hours. Late phase is 4-8 hours.
The FEV1 decreases in the early phase and then recovers, before decreasing even more in the late phase and then recovering.

Question 4

Name two spasmogens.

Answer 4

Histamine

Methacholine

Question 5

What cells are involved?

Answer 5

Mast cells
Eosinophils
Lymphocytes
Th1/Th2 imbalance

Question 6

Describe the histology of an asthmatic’s airway. (3)

Answer 6

Goblet cell hyperplasia
Thick sub basement membrane
Cellular infiltrate

Question 7

Pathology of asthma (1) - the antigen is inhaled and then…?

Answer 7

encounters dendritic cells, which then migrate to the lymph nodes and present the antigen to T and B cells.

Question 8

Pathology of asthma (2) - There is then a switch by B cells to produce IgE antibodies. What are the two signals?

Answer 8

The first signal is when T cell releases IL-4 or IL-13 (receptors share common alpha chain and common STAT-6 transduction pathway).
The second signal when CD14 on B cells binds to its ligand on T cells, which activates the B cell to produce IgE.

Question 9

Pathology of asthma (3) - Once synthesised and released, IgE briefly circulates in the blood then…? After binding, what happens?

Answer 9

binds to high affinity IgE receptors on mast cells (FcεRI) and low affinity receptors on lymphocytes, eosinophils platelets and macrophages (FcεRII).
This causes activation (when the allergen interacts with receptor-bound IgE and molecular bridging FcεRI occurs) and mediator release (e.g. histamine, leukotrienes, cytokines).

Question 10

Pathology of asthma (4) - This activation and mediator release causes the early and late response. Explain what these are and how they occur.

Answer 10

Early response (bronchospasm, oedema, acute airflow obstruction = mainly via histamine and leukotrienes).

Late response (airway inflammation, airflow obstruction, airway hyperresponsiveness = via resident inflammatory cells and recruited cells).

Question 11

How does anti-IL-5 therapy work?

Answer 11

It lowers the level of blood AND bronchial eosinophils and so reduces no. of asthma exacerbations and increases FEV1. Used in severe eosinophilic asthma. Note that there are other anti-IL-5, -4 and -13 monoclonal antibodies in development.

Question 12

Give two examples of anti-IL-5 therapies.

Answer 12

mepolizumab, reslizumab

Question 13

How was omalizumab work? What has it been shown to reduce?

Answer 13

Omalizumab = anti-IgE mab

Reduces the days with symptoms, exacerbations, and dose of inhaled glucocorticoid.

Question 14

Eosinophils originate in the … and are regulated by…?

Answer 14

Bone marrow
IL-3 and IL-5 (e.g. IL-5 controls their development in the BM and prolongs their survival)

The role of IL-5 has been demonstrated e.g. allergen challenges increase local levels of IL-5 which is associated with tissue eosinophilia.

Question 15

GM-CSF and IL-5 stimulate…?

Answer 15

the terminal differentiation of stem cells into eosinophils

Question 16

Eosinophils contain proteins that damage airway epithelium, causing…?

Answer 16

bronchial hyperresponsiveness, and are a rich source of leukotrienes. They must migrate.

Question 17

Mast cells release prostaglandin D2 - what are the three relevant receptors and where are they located?

Answer 17

DP1 receptors on bronchial vessels and dendritic cells (drug = DP1 ANTAGONIST)

DP2 receptors eosinophils and Th2 cells (drug = CRTH2 ANTAGONIST e.g. fevipiprant which lowers eosinophils)

TP receptors on airway smooth muscle cells (drug = TP ANTAGONIST).

Question 18

Lymphocytes are activated after allergen inhalation. What are the two types of helper CD4+ T cells?

Answer 18

Type 1 helper which releases IL-2 and IFN-gamma

Type 2 which releases IL-4,5,6,9,13 (allergic inflammation).

Question 19

What is the effect of IL-4 and IL-13?

Answer 19

Stimulates B cells to produce IgE which activates mast cells and basophils

Question 20

What is the effect of IL-5?

Answer 20

Stimulates eosinophils

Question 21

What is released by activated mast cells, basophils and eosinophils?

Answer 21

Histamine, leukotrienes, prostaglandins, cytokines release  allergic asthma.

Question 22

What is meant by the Th1/Th2 imbalance paradigm?

Answer 22

The Th1/Th2 imbalance paradigm describes the complex balance between Th1 and Th2 cells. Th1 cells are involved in cell-mediated immunity (protective), and Th2 cells in humoral immunity and allergic diseases e.g. asthma.

Question 23

What factors favour the Th1 phenotype? (4)

Answer 23

• Presence of older siblings
• Early exposure to day care
• TB, measles, hep A infection
• Rural environment

Question 24

What factors favour the Th2 phenotype? (5)

Answer 24

• Widespread use of abx
• Western lifestyle
• Urban environment
• Diet
• Sensitisation to house-dust mites and cockroaches

Question 25

Why does asthma persist?

Answer 25

Airway remodelling – thickened airway walls, increase submucosal tissue, increase smooth muscle – and compromised repair i.e. “chronic wound”.