Immunopathology of Lung Obstruction

Question 1

Describe the general process of type I hypersensitivity reactions

Answer 1

1. Primary allergen exposure via mucosal route
2. Allergen reactive B cells phagocytose allergen and present to CD4 T cells -> differentiate into Th2 helper cells (IL-4)
3. Th2 CD4+ T cells recognise antigen and bind it via MHC II and provide CD40L help to B-cell to help it undergo affinity maturation, proliferation and memory formation as well as produces IL-4 to drive IgE class switching
4. IgE antibodies from B-cells bind to mast cells that lie within the tissues
5. Secondary exposure to allergen - cross-linking of IgE on mast cells - release of histamines and other vasoactive amines
6. Smooth muscle constriction, blood vessel dilation, platelet activation, mucous production, stimulation of sensory nerve endings and eosinophil activation
7. Late stage reaction: induced by chemokines, cytokines and leukotrienes - sustained smooth muscle contraction and oedema

Question 2

What are the immediate, rapid and slow phases of mast cell action in the lungs?

Answer 2

1. Immediate: preformed mediators (30-45 secs)
   - Histamine, heparin, tryptase, TNFa
   - Histamine binds to H1 receptors
   - Bronchospasm
   - Mucous secretion
   - Vasodlation (hypotension)
   - Increased vascular leakiness
   - Pain and itching
2. Delayed release: (10-30 mins, from activation of phospholipase A2)
   - Cys-LTs and PGD2
   - Vasodilation
   - Potent bronchospasm
   - Oedema
   - Vascular permeability increase
3. Slow release: T-cell and eosinophil driven
   - IL-4, IL-5 and GM-CSF
   - Activation of eosinophils, macrophages and neutrophils
   - Inflammatory cell infiltration
   - Remodelling of airways

Question 3

What factors activate mast cells in tissues?

Answer 3

1. IgE cross-linking
2. Mechanical stimulation
3. Polybasic drugs
4. Hypotonic airway fluid (exercising asthmatic)
5. Activated complement
6. Neuropeptide
7. UV light/heat

Question 4

What is the definition of asthma?

Answer 4

• Chronic inflammatory disorder of the airways resulting in airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness and coughing
• Widespread, variable and often reversible airflow limitation
• Driven by mast cells, eosinophils, Th2 and some macrophages
• Reduced FEV1 (improves with B-agonist)

Question 5

What are some of the histological changes due to airway remodelling seen in asthmatics?

Answer 5

1. Subepithelial collagen thickening
2. Goblet cell metaplasia
3. Infiltration with inflammatory cells
4. Increased mucosal vascularity
5. Increased smooth muscle volume

Question 6

Definition of COPD?

Answer 6

• Airflow obstruction that is not fully reversible
• Abnormal inflammatory response (GCs not as effective as in asthma)
• Loss of lung parenchyma tethering bronchioles (emphysema)
• Small airway inflammation and fibrosis + thickening (chronic bronchitis)
• Squamous metaplasia of respiratory epithelium
• Driven by neutrophils, CD8+ T cells and macrophages
• Pulmonary hypertension (due to chronic hypoxia)
• Reduced FEV1

Question 7

Describe the pathogenesis of COPD:

Answer 7

• Tobacco smoke and other particulate irritants trigger oxidative stress
• ROS and other free radicals produced in large events which overwhelm anti-oxidants
• Inhibition of anti-protease proteins
• Proteolysis increased aberrantly - breakdown of elastin and reticular fibres in alveolar walls
• Increase in NF-kB leading to inflammation