Asthma Pathogenesis -

Question 1

What is the first immune cell to detect an allergen in the airway?

Answer 1

The antigen-presenting cell (APC) detects the allergen, endocytoses it, and presents it on MHC-II.

Question 2

What happens after the APC presents the allergen?

Answer 2

A naïve T lymphocyte recognizes the antigen and becomes activated, initiating sensitisation.

Question 3

What type of T cell does the naïve T cell differentiate into during allergic asthma?

Answer 3

It differentiates into a Th2-type cell.

Question 4

What cytokines are released by Th2 cells to stimulate B cells?

Answer 4

Interleukin-4 (IL-4) and Interleukin-13 (IL-13).

Question 5

What is the function of IL-4 and IL-13 in asthma pathogenesis?

Answer 5

They stimulate B lymphocytes to proliferate and produce immunoglobulin E (IgE) antibodies.

Question 6

What does IgE bind to after it is produced by B cells?

Answer 6

IgE binds with high affinity to FcεRI receptors on the surface of mast cells, priming them.

Question 7

What additional role does IL-13 play in asthma pathogenesis besides B cell stimulation?

Answer 7

IL-13 promotes the survival and activation of mast cells.

Question 8

What cytokine from Th2 cells recruits eosinophils?

Answer 8

Interleukin-5 (IL-5) recruits and promotes the maturation of eosinophils.

Question 9

What type of white blood cells are eosinophils, and what is their role in asthma?

Answer 9

Eosinophils are granulocytes and are the dominant inflammatory cells in allergic asthma.

Question 10

What happens during a second exposure to the allergen in a sensitised individual?

Answer 10

IgE-primed mast cells degranulate, releasing a cascade of inflammatory mediators.

Question 11

What pre-formed mediators are released by mast cells during degranulation?

Answer 11

Histamine, proteases, and cytokines.

Question 12

What newly synthesized eicosanoids are released by mast cells?

Answer 12

Leukotrienes, prostaglandins, and thromboxanes.

Question 13

What do eosinophils release that contributes to asthma symptoms?

Answer 13

Pro-inflammatory mediators that contract smooth muscle and damage tissue.

Question 14

What are the effects of the mediators released by eosinophils and mast cells?

Answer 14

• Bronchoconstriction
• Microvascular leakage (oedema)
• Airway remodeling/obstruction

Question 15

What are the clinical symptoms of asthma caused by this immune cascade?

Answer 15

Wheezing, chest tightness, cough, and breathlessness.

Question 16

Predominant characteristics of allergic (TH2-type) asthma

Answer 16

1. Airway obstruction
2. Increased airway hyperresponsiveness
3. Chronic eosinophilic airway inflammation.

Question 17

Name the major inflammatory cells involved in airway inflammation.

Answer 17

• Mast cells
• Eosinophils
• Th2 cells
• Basophils
• Neutrophils
• Platelets

Question 18

What are the key structural cells involved in airway inflammation?

Answer 18

Epithelial cells
Smooth muscle (Sm) cells
Endothelial cells
Fibroblasts
Nerves

Question 19

Name the main chemical mediators released during inflammation in asthma.

Answer 19

• Histamine
• Leukotrienes
• Prostanoids
• Platelet-activating factor (PAF)
• Kinins
• Adenosine
• Endothelins
• Nitric oxide
• Cytokines
• Chemokines
• Growth factors

Question 20

What are the physiological effects of these inflammatory mediators in the airways?

Answer 20

• Bronchospasm
• Plasma exudation
• Mucus secretion
• Airway hyperresponsiveness (AHR)
• Structural changes

Question 21

Which cells are responsible for producing histamine, leukotrienes, and cytokines in asthma?

Answer 21

Mainly mast cells and eosinophils.

Question 22

What is airway hyperresponsiveness (AHR) and how is it triggered?

Answer 22

AHR is an exaggerated airway narrowing in response to stimuli. It is triggered by inflammatory mediators (e.g., histamine, leukotrienes) and cellular damage.

Question 23

What is the underlying cause of airway obstruction in allergic asthma?

Answer 23

Chronic inflammation involving Th2-type cells, eosinophils, mast cells, and structural changes such as smooth muscle hypertrophy, goblet cell hyperplasia, oedema, and mucus hypersecretion, all contribute to narrowing the airway lumen.

Question 24

What triggers the Th2-type immune response in allergic asthma?

Answer 24

Exposure to allergens (e.g. pollen, dust mite faeces), which are presented by antigen-presenting cells to naïve T cells, leading to Th2 cell differentiation and cytokine release.

Question 25

Which cells and mediators are predominantly involved in allergic asthma?

Answer 25

**Cells: **Th2 cells, eosinophils, mast cells, B cells **Mediators: **IL-4, IL-5, IL-13, histamine, leukotrienes, prostaglandins, IgE

Question 26

What is airway hyperresponsiveness (AHR) in asthma?

Answer 26

AHR is the exaggerated constriction of airway smooth muscle in response to non-specific stimuli like methacholine or histamine.

Question 27

What structural changes occur in chronic asthma?

Answer 27

* Goblet cell hyperplasia * Smooth muscle hypertrophy and hyperplasia * Basement membrane thickening * Angiogenesis * Increased mucus and plasma leakage

Question 28

How do short-acting beta-2 agonists (SABAs) work?

Answer 28

They activate beta-2 receptors → increase cAMP → activate PKA → decrease intracellular calcium → relax airway smooth muscle → relieve bronchospasm.

Question 29

What are common side effects of SABAs?

Answer 29

Tremor, palpitations, tachycardia (at high doses), potential beta-receptor downregulation with overuse.

Question 30

Why are LABAs always combined with inhaled corticosteroids (ICS)?

Answer 30

LABAs provide long-term bronchodilation, but without ICS, they don’t treat the underlying inflammation, which can worsen outcomes.

Question 31

What is the mechanism of inhaled corticosteroids (ICS)?

Answer 31

ICS bind to glucocorticoid receptors → translocate to nucleus → alter gene expression → reduce inflammatory cytokines and increase anti-inflammatory proteins (e.g. annexin-1, beta-2 receptors).

Question 32

What are adverse effects of ICS?

Answer 32

Dysphonia, oral thrush (minimized by rinsing mouth), possible systemic effects at high doses (osteoporosis, diabetes risk, glaucoma).

Question 33

What is the role of leukotriene receptor antagonists (e.g., montelukast)?

Answer 33

They block leukotriene-1 receptors to reduce bronchoconstriction, mucus, and eosinophil recruitment — used as add-on therapy or in aspirin-induced asthma.

Question 34

What are precautions with leukotriene receptor antagonists?

Answer 34

Neuropsychiatric effects, especially in children (e.g., nightmares, mood changes).

Question 35

What are biologics used for in asthma treatment?

Answer 35

* **Omalizumab:** binds IgE → prevents mast cell priming * **Mepolizumab/Benralizumab: **block IL-5 or its receptor → reduce eosinophils * **Dupilumab: **blocks IL-4/IL-13 → reduces inflammation These are for severe, treatment-resistant asthma.

Question 36

Why is combination therapy necessary in asthma?

Answer 36

Asthma has both bronchoconstrictive and inflammatory components. * Bronchodilators (e.g., SABAs, LABAs) relieve acute symptoms * Anti-inflammatory drugs (e.g., ICS) prevent chronic inflammation and structural changes. Combination therapy targets both for optimal control.

Question 37

What is the benefit of inhaled delivery in asthma drugs?

Answer 37

Direct delivery to airways → faster onset, lower dose needed, fewer systemic side effects.

Question 38

Why are β₂-adrenoceptor agonists used in asthma treatment?

Answer 38

They directly relax airway smooth muscle and reverse bronchoconstriction, which is the cause of acute asthma symptoms like wheezing and chest tightness. Their effect opposes that of constrictor mediators such as histamine, leukotrienes, and acetylcholine.

Question 39

What role do β₂ agonists play in asthma management?

Answer 39

*** Short-acting β₂ agonists (SABAs)** are used for relief of acute symptoms *** Long-acting β₂ agonists (LABAs) **are used for maintenance therapy and prevention of bronchospasm

Question 40

How do β₂-adrenoceptor agonists cause smooth muscle relaxation?

Answer 40

1. Bind to β₂-adrenoceptors (Gs protein-coupled receptors) 2. Activate adenylyl cyclase → increases cAMP 3. cAMP activates protein kinase A (PKA) 4. PKA decreases intracellular calcium → leads to relaxation of airway smooth muscle 5. Result: bronchodilation and widened airway lumen

Question 41

How is this different from cardiac muscle response to β-agonists?

Answer 41

In cardiac tissue, β-adrenoceptor activation increases intracellular calcium, leading to increased contraction force. In airway smooth muscle, it decreases calcium, leading to relaxation.

Question 42

What are common adverse effects of β₂-adrenoceptor agonists?

Answer 42

* Muscle tremor (most common) * Palpitations * Tachycardia (especially at high doses due to β₁ stimulation or reflex) * Hyperglycaemia (from increased glycogenolysis and reduced insulin)

Question 43

What precautions should be taken with β₂ agonists in certain patients?

Answer 43

* Cardiovascular disease (e.g., hypertension, heart failure) → risk of worsened symptoms * Diabetes → risk of increased blood glucose * Frequent SABA use may indicate poor asthma control and can lead to β-receptor downregulation

Question 44

Why are asthma drugs delivered via inhalation?

Answer 44

* Direct action on airway target cells * Rapid onset of effect * Lower effective dose needed * Minimizes systemic side effects

Question 45

What improves inhaler delivery efficiency?

Answer 45

* Use of spacers * Correct inhaler technique These reduce oropharyngeal deposition and improve lung delivery.