The Allergic Lung Flashcards
List the clinical features of bronchial asthma.
- Acute attacks of shortness of breath, acute airway obstruction due to contraction of smooth muscle
- Mucus hypersecretion
- Airway inflammation
- Bronchial hyper-responsiveness
List the types and triggers of bronchial asthma.
Allergens Chemical irritants Dust, smoke Cold Post-exercise Psychogenic Post-coughing Post-hyperinflation Post-laughter Viral colds
Explain the two phases of asthma and how bronchial hyper-responsiveness is documented.
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.
Name two spasmogens.
Histamine
Methacholine
What cells are involved?
Mast cells
Eosinophils
Lymphocytes
Th1/Th2 imbalance
Describe the histology of an asthmatic’s airway. (3)
Goblet cell hyperplasia
Thick sub basement membrane
Cellular infiltrate
Pathology of asthma (1) - the antigen is inhaled and then…?
encounters dendritic cells, which then migrate to the lymph nodes and present the antigen to T and B cells.
Pathology of asthma (2) - There is then a switch by B cells to produce IgE antibodies. What are the two signals?
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.
Pathology of asthma (3) - Once synthesised and released, IgE briefly circulates in the blood then…? After binding, what happens?
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).
Pathology of asthma (4) - This activation and mediator release causes the early and late response. Explain what these are and how they occur.
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).
How does anti-IL-5 therapy work?
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.
Give two examples of anti-IL-5 therapies.
mepolizumab, reslizumab
How was omalizumab work? What has it been shown to reduce?
Omalizumab = anti-IgE mab
Reduces the days with symptoms, exacerbations, and dose of inhaled glucocorticoid.
Eosinophils originate in the … and are regulated by…?
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.
GM-CSF and IL-5 stimulate…?
the terminal differentiation of stem cells into eosinophils
Eosinophils contain proteins that damage airway epithelium, causing…?
bronchial hyperresponsiveness, and are a rich source of leukotrienes. They must migrate.
Mast cells release prostaglandin D2 - what are the three relevant receptors and where are they located?
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).
Lymphocytes are activated after allergen inhalation. What are the two types of helper CD4+ T cells?
Type 1 helper which releases IL-2 and IFN-gamma
Type 2 which releases IL-4,5,6,9,13 (allergic inflammation).
What is the effect of IL-4 and IL-13?
Stimulates B cells to produce IgE which activates mast cells and basophils
What is the effect of IL-5?
Stimulates eosinophils
What is released by activated mast cells, basophils and eosinophils?
Histamine, leukotrienes, prostaglandins, cytokines release allergic asthma.
What is meant by the Th1/Th2 imbalance paradigm?
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.
What factors favour the Th1 phenotype? (4)
- Presence of older siblings
- Early exposure to day care
- TB, measles, hep A infection
- Rural environment
What factors favour the Th2 phenotype? (5)
- Widespread use of abx
- Western lifestyle
- Urban environment
- Diet
- Sensitisation to house-dust mites and cockroaches
Why does asthma persist?
Airway remodelling – thickened airway walls, increase submucosal tissue, increase smooth muscle – and compromised repair i.e. “chronic wound”.
