L6 Pathology Asthma

Overview

This lecture covers asthma from its population burden through to its molecular and structural pathology: the scale of disease in New Zealand, the genetic and epigenetic basis of susceptibility, the environmental triggers (including the hygiene hypothesis and vaping), the immunological mechanisms of airway inflammation and bronchospasm, the structural changes of chronic airway remodelling, causes of exacerbation, an adult-onset/neutrophilic pathway driven by Th17 cytokines, and occupational asthma.

Epidemiology and burden (New Zealand)

• 597,000 New Zealanders take medication for asthma: 1 in 8 adults and 1 in 7 children.
• Māori, Pacific peoples and low-income families are around 3x more likely to be hospitalised for asthma.
• 7,685 hospital admissions, of which 40% were children.
• Cost to the nation exceeds $1 billion per year.
• 586,000 school days are lost each year due to asthma.
• On average, 77 New Zealanders die from asthma each year.

Spectrum of asthma subphenotypes

Asthma subphenotypes are arranged along a childhood-onset to adult-onset spectrum, split into two overarching categories:

• T2-type asthma: allergic asthma (progressing to exercise-induced asthma); late-onset eosinophilic asthma (progressing to aspirin-exacerbated respiratory disease); very late-onset asthma in women, which sits between the late-onset eosinophilic and obesity-associated branches.
• Non-T2-type asthma: obesity-associated asthma (progressing to smoking-related neutrophilic asthma); smooth-muscle-mediated paucigranulocytic asthma.

Genetics and heredity

• Children with one asthmatic parent are 3-6 times more likely to develop asthma than a child with two unaffected parents; children with two asthmatic parents are 10 times more likely.
• Twin and family studies indicate a heritable pattern.
• Some genes influence susceptibility (whether asthma develops) or severity (progression); other genes are pharmacogenetic, modifying response to therapy. Gene-environment interactions add further complexity.
• Susceptibility genes (for asthma, atopy, bronchial hyperresponsiveness) and expression genes (disease severity, pharmacogenetics) interact with environmental influences (prenatal maternal influences, allergens, respiratory infections, tobacco smoke, pollutants, prematurity, dietary factors) to produce early intermittent asthma, which progresses to chronic (persistent) asthma with reversible and irreversible changes in airway structure and function. Genetics and environment can also act directly on chronic asthma, not only via the intermittent stage.
• ADAM33 is an asthma susceptibility gene acting on three cell targets: it drives mesenchymal cells to release elastin, fibronectin and laminin, to interact with Th1/Th2 cytokines, and to modulate chemoattractant activity for eosinophils, T lymphocytes, monocytes and macrophages; it causes smooth muscle cell over-proliferation; and it drives myofibroblasts/fibroblasts to produce collagen, reticular fibres, elastic fibres, proteoglycans and glycoproteins.

Epigenetics

• Disease arises at the intersection of genetics, epigenetics and phenotype.
• Three epigenetic mechanisms converge on gene expression: RNA interference, histone modifications and DNA methylation; histone modification and DNA methylation also interact bidirectionally with each other.
• The in utero environment alters the epigenome, which is the mechanism by which the environment produces allergic disease predisposition at birth; there is also a direct interaction effect between the in utero environment and disease predisposition.
• Transgenerational epigenetic inheritance (Isle of Wight 3rd Generation study): grandmaternal gestational environment, and maternal genome/disease status/exposures together with the gestational environment, shape the maternal epigenome. The maternal epigenome shapes the neonatal epigenome, which combines with the postnatal environment and the offspring’s own genome to determine childhood allergic disease.

Triggers of asthma

• Five broad trigger categories converge on asthma: smoking and vaping, obesity, allergens (e.g. cat, dog, grass/pollen), viral infections, and air pollution.
• Vaping’s main effects on the airways: increased risk of developing asthma, increased onset of severe attacks in asthmatics, deterioration of lung function, increased airway inflammation, increased risk of respiratory infections, acute lung injury (EVALI), and long-term respiratory sequelae from toxic or carcinogenic components.
• Hygiene hypothesis: children in modern society are exposed to fewer infective agents, giving fewer stimuli to develop Th1 immunity; as a result, Th2 responses may predominate, driving allergic disease. In an immunologically naive individual with genetic predisposition (chromosomes 5, 6, 11, 12, 14): a germ-free environment, no siblings, antibiotic use, vaccination, low lactobacillus, and an industrialised society favour a Th2 response and asthma; whereas early colonisation/infection, older siblings, day-care exposure, helminth infections, hepatitis A infection, and living on farms favour a protective response and no asthma.

Airway inflammation and bronchospasm

Core features of asthma pathophysiology: airway inflammation, bronchial hyper-responsiveness, bronchoconstriction, bronchial wall oedema, excess mucous secretion, epithelial shedding, and airway remodelling.

Inflammation occurs in two phases:

• Early phase response: Type I hypersensitivity, mediated by IgE antibody bound to mast cells.
• Late phase response: Type IV hypersensitivity, a T-cell-mediated response that activates eosinophils, B cells and other cells.

Immune mechanism (sensitisation and mast cell degranulation): dendritic cells take up allergen and present it via MHC class II/TCR to a precursor T helper cell, which releases IL-4, IL-5 and IL-10; this inhibits Th1 differentiation and drives expansion of Th2-type cells. IL-4 drives B cells to produce IgE. Separately, allergen cross-links IgE already bound to FcεRI on mast cells, triggering mast cell degranulation and release of mediators of acute and chronic inflammation.

Cytokine cascade and bronchospasm: allergen presented by an APC to a CD4 Th2 cell drives release of IL-4 and IL-13, which act on B cells to produce IgE; IgE-primed mast cells then release histamine, PGD2 and LTC4/D4/E4, causing acute bronchospasm. Th2 cells also release IL-4, IL-13 and TGF-β, acting on the epithelium and airway smooth muscle, and IL-5, acting on eosinophils. The combined effects (airway hyper-responsiveness, remodelling, airway narrowing) produce chronic asthma.

Cellular recruitment: allergen activates macrophages/dendritic cells, which activate Th2 cells to recruit eosinophils, and activates mast cells directly, which recruit both eosinophils and neutrophils.

Airway wall changes seen on cross-section: epithelial shedding; mucus hypersecretion and goblet cell hyperplasia forming a mucus plug; nerve activation causing vasodilation/new vessel formation (angiogenesis) and plasma leakage/oedema; subepithelial fibrosis; fibroblast-driven sensory nerve activation triggering a cholinergic reflex; and, in airway smooth muscle, bronchoconstriction with hypertrophy/hyperplasia.

Innervation of the bronchus: parasympathetic preganglionic fibres, sympathetic postganglionic fibres and sensory afferent nerves converge on a ganglion embedded in the smooth muscle layer. The epithelium contains goblet cells and a Kultschitzky (neuroendocrine) cell; a sensory neuron connects the epithelium to the ganglion via the nexus and innervates a gland.

Airway remodelling and chronic structural changes

• Airway remodelling converts a normal airway (a single layer of epithelial cells on extracellular matrix, with airway smooth muscle beneath) into one with a thickened, disorganised epithelium producing mucus and fibrogenic growth factors, dysregulated extracellular matrix, and smooth muscle cell proliferation.
• Three-phase model of inflammation and remodelling: (a) acute phase, mast cells release leukotrienes, histamine and IL-4/IL-5 while macrophages release TNF-α, driving leukocyte recruitment and eosinophil degranulation causing airway damage/inflammation; (b) chronic phase, Th2 cells release IL-4, IL-5 and IL-13, driving further eosinophil recruitment and ongoing damage; (c) remodelling phase, Th1 and Th2 cells sustain chronic inflammation while neutrophils and activated fibroblasts produce cytokines, chemokines, prostanoids and collagen deposition, producing smooth muscle hyperplasia/hypertrophy and mucus gland hyperplasia.
• Components of airway remodelling seen together: eosinophil and lymphocyte infiltration, epithelial injury, goblet cell hyperplasia, subepithelial fibrosis, mucus gland hypertrophy, mast cells, angiogenesis, and smooth muscle hyperplasia.
• Key points to know as a checklist:
  • Chronic asthma airway histology: thickened wall, thickened basement membrane, and narrowed lumen compared to normal (normal shows blood vessel, epithelium, lumen and smooth muscle without these changes).
  • Acute attack histology: markedly folded/collapsed epithelial lining and mucus/exudate filling the narrowed lumen, with inflamed peribronchial tissue.
  • Eosinophilic infiltrate: dense eosinophil infiltration within the airway wall/submucosa.
  • Mucosal changes: epithelial and submucosal changes with inflammatory cell infiltration.
  • Curschmann’s spirals: spiral-shaped mucus casts in airway secretions, a classic finding in asthmatic sputum/airway histology.

The source slide for the mucus cast finding is titled "Cushman's spirals," but the standard/correct term is Curschmann's spirals; the slide's spelling appears to be an error.

Summary of the asthmatic airway: from outer to inner layer, the submucosa and mucosa show infiltration of inflammatory cells (mononuclear cells, eosinophils, etc.), hypertrophied smooth muscle, dilated blood vessels, eosinophils, mononuclear cells, mast cells and oedema; the lumen shows a thickened basement membrane, abnormal epithelium, and a mucus plug containing eosinophils and desquamated epithelial cells.

Causes of exacerbation

• Poorly controlled airway inflammation.
• Cold air.
• Viral infection.
• Tobacco smoke.
• Environmental allergens, indoor or outdoor (e.g. mould, animal dander/feathers, pollen, dust).

Adult-onset asthma (neutrophilic/Th17 pathway)

Four trigger categories converge on asthma via IL-17-family cytokines:

• Pollutants (diesel exhaust particles, ozone, PM2.5) generate ROS/NF-κB activation in the epithelial cell, activating γδT cells and Th17 cells to release IL-17.
• Smoking activates neutrophils to release IL-17, IL-6 and IL-8.
• Infections (viruses, bacteria, fungi) activate neutrophils/Th17 cells to release IL-17, IL-6, TNF-α and G-CSF.
• Obesity activates Th17 cells to release IL-17, IL-6 and IL-8.
  All four pathways converge to drive asthma through these cytokines.

Occupational and work-related asthma

• Work-related asthma splits into occupational asthma (caused by work exposures) and work-exacerbated asthma (pre-existing or concurrent asthma aggravated by workplace exposure to irritants, via unknown mechanisms).
• Occupational asthma further splits into sensitizer-induced (IgE-mediated or non-IgE-mediated) and irritant-induced (a single high-level exposure, or multiple high-level exposures, to irritants).
• Examples of agents and at-risk occupations: laboratory animals (scientific/animal-house work), flour (baking), biological enzymes (soap powder industry), wood dusts (saw milling, furniture manufacture), latex rubber gloves (health workers), bleaching agents/hair dyes (hairdressing), isocyanates (paint spraying, printing industry), and colophony/solder fumes (electronics industry).

The occupational allergy table on this slide appears to be cut off at the bottom; further agent/occupation rows below colophony (solder fumes)/electronics industry may not have been captured.

Self-test

1. Give the New Zealand asthma prevalence and mortality statistics quoted in the lecture (adults, children, hospitalisations, deaths, cost).
2. Distinguish T2-type asthma from non-T2-type asthma, giving an example subphenotype of each.
3. What is a child’s relative risk of developing asthma with one asthmatic parent, and with two asthmatic parents?
4. Distinguish a susceptibility gene from a gene involved in pharmacogenetics in asthma.
5. Describe the role of ADAM33 in asthma pathology, covering its three cellular targets.
6. Explain how genetics, epigenetics and phenotype together determine disease, and name the three epigenetic mechanisms that converge on gene expression.
7. Describe the transgenerational pathway by which grandmaternal and maternal factors influence a child’s risk of allergic disease.
8. State the main effects of vaping on the airways.
9. Explain the hygiene hypothesis, including the immune pathway it proposes.
10. Distinguish the early phase and late phase responses in airway inflammation, including the hypersensitivity type and key cells involved in each.
11. Describe the sequence of events from allergen exposure to IgE production and mast cell degranulation.
12. Describe how IL-4, IL-13 and IL-5 released by Th2 cells contribute to acute bronchospasm and chronic asthma.
13. List the structural changes seen in the airway wall during an asthma attack (epithelium, mucus, vessels, nerves, smooth muscle).
14. Describe the components of airway remodelling and how a remodelled airway differs from a normal airway.
15. What are Curschmann’s spirals, and what did the lecture slide call them?
16. List five causes of asthma exacerbation.
17. Describe the Th17-mediated pathway of adult-onset asthma and the four triggers that converge on it.
18. Distinguish occupational asthma from work-exacerbated asthma, and distinguish sensitizer-induced from irritant-induced occupational asthma, giving one example agent and its at-risk occupation.

Answers

Reveal answers

1. 597,000 New Zealanders take asthma medication: 1 in 8 adults and 1 in 7 children. There are 7,685 hospital admissions per year (40% children), asthma costs the nation over $1 billion per year, 586,000 school days are lost each year, and on average 77 New Zealanders die from asthma each year. Māori, Pacific peoples and low-income families are around 3x more likely to be hospitalised.
2. T2-type asthma includes allergic asthma (which can progress to exercise-induced asthma) and late-onset eosinophilic asthma (which can progress to aspirin-exacerbated respiratory disease); it also includes very late-onset asthma in women. Non-T2-type asthma includes obesity-associated asthma (which can progress to smoking-related neutrophilic asthma) and smooth-muscle-mediated paucigranulocytic asthma.
3. One asthmatic parent: 3-6 times more likely. Two asthmatic parents: 10 times more likely, compared with a child with two unaffected parents.
4. A susceptibility gene influences whether asthma develops or how severe it becomes; a pharmacogenetic gene instead modifies the individual’s response to asthma therapy.
5. ADAM33 acts on mesenchymal cells (causing release of elastin, fibronectin and laminin; interaction with Th1/Th2 cytokines; and modulation of chemoattractant activity for eosinophils, T lymphocytes, monocytes and macrophages), on smooth muscle cells (causing over-proliferation), and on myofibroblasts/fibroblasts (causing production of collagen, reticular fibres, elastic fibres, proteoglycans and glycoproteins).
6. Disease arises where genetics, epigenetics and phenotype intersect. The three epigenetic mechanisms are RNA interference, histone modifications and DNA methylation, all of which converge on gene expression (histone modification and DNA methylation also interact with each other).
7. Grandmaternal gestational environment, and the mother’s own genome, disease status, exposures and gestational environment, shape the maternal epigenome. The maternal epigenome shapes the neonatal epigenome, which combines with the postnatal environment and the offspring’s own genome to determine childhood allergic disease.
8. Vaping increases the risk of developing asthma, increases the onset of severe attacks in existing asthmatics, deteriorates lung function, increases airway inflammation, increases the risk of respiratory infections, can cause acute lung injury (EVALI), and carries long-term respiratory sequelae from toxic/carcinogenic components.
9. Children in modern society are exposed to fewer infective agents, giving fewer stimuli to develop Th1 immunity; Th2 responses then predominate, driving allergic disease. In a genetically predisposed individual, a germ-free environment, no siblings, antibiotic use, vaccination, low lactobacillus and industrialised living favour a Th2 response and asthma, while early infection, older siblings, day-care, helminth infection, hepatitis A and farm living favour a protective response and no asthma.
10. The early phase response is a Type I hypersensitivity reaction mediated by IgE antibody bound to mast cells. The late phase response is a Type IV hypersensitivity reaction that is T-cell mediated and activates eosinophils, B cells and other cells.
11. Dendritic cells take up allergen and present it via MHC class II/TCR to a precursor T helper cell, which releases IL-4, IL-5 and IL-10; this inhibits Th1 differentiation and expands Th2-type cells. IL-4 drives B cells to produce IgE. Separately, allergen cross-links IgE already bound to FcεRI on mast cells, triggering degranulation and release of mediators of acute and chronic inflammation.
12. IL-4 and IL-13 (via B cells and IgE-primed mast cells releasing histamine, PGD2 and LTC4/D4/E4) cause acute bronchospasm. IL-4, IL-13 and TGF-β acting on the epithelium and airway smooth muscle, and IL-5 acting on eosinophils, together produce airway hyper-responsiveness, remodelling and airway narrowing, i.e. chronic asthma.
13. Epithelial shedding; mucus hypersecretion/goblet cell hyperplasia forming a mucus plug; nerve-activation-driven vasodilation/angiogenesis and plasma leakage/oedema; subepithelial fibrosis; fibroblast-driven sensory nerve activation and cholinergic reflex; and airway smooth muscle bronchoconstriction with hypertrophy/hyperplasia.
14. Remodelling components: eosinophil and lymphocyte infiltration, epithelial injury, goblet cell hyperplasia, subepithelial fibrosis, mucus gland hypertrophy, mast cells, angiogenesis and smooth muscle hyperplasia. A normal airway has a single layer of epithelial cells on extracellular matrix with smooth muscle beneath; a remodelled airway has a thickened, disorganised epithelium producing mucus and fibrogenic growth factors, dysregulated matrix, and proliferated smooth muscle.
15. Curschmann’s spirals are spiral-shaped mucus casts found in airway secretions, a classic histological finding in asthma. The lecture slide title spelled the term “Cushman’s spirals,” which is not the standard/correct term.
16. Poorly controlled airway inflammation, cold air, viral infection, tobacco smoke, and environmental allergens (indoor or outdoor).
17. Pollutants generate ROS/NF-κB activation in epithelial cells, activating γδT and Th17 cells to release IL-17; smoking activates neutrophils to release IL-17, IL-6 and IL-8; infections activate neutrophils/Th17 cells to release IL-17, IL-6, TNF-α and G-CSF; obesity activates Th17 cells to release IL-17, IL-6 and IL-8. All four pathways converge on asthma via these cytokines.
18. Occupational asthma is asthma caused by work exposures; work-exacerbated asthma is pre-existing or concurrent asthma aggravated by workplace irritant exposure via unknown mechanisms. Sensitizer-induced occupational asthma is IgE-mediated or non-IgE-mediated; irritant-induced occupational asthma follows a single or multiple high-level irritant exposures. Example: flour causes occupational asthma in bakers.