Cells And Mediators Of Asthma

Question 1

Context of Asthma prevalence (3)

Answer 1

o >300 million people estimated to have asthma worldwide, ≈500,000 deaths/year

o 5.5 million people being treated for asthma in the UK, 1500 deaths/year

o >50% of the 1 billion spent by the NHS on asthma is used to treat the <200,000 individuals with ‘severe asthma’

Question 2

Overview of the mechanism responsible for allergic asthma sensitisation 1st exposure (6) + 2nd (4)

Answer 2

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1st Exposure:
1) Allergen inhaled, enters airway tissue

2)Antigen-presenting cell (e.g. dendritic cell) engulfs & processes allergen + presents antigen to naïve helper T cell

3) Naïve (CD4+) helper T cell: Th2 cell interacts with B cell displaying antigen B cell

4)Mature Th2 cell: (3 paths)
- B cell
- IL-4 ( to B cell ^)
- IL-5 > Eosinophil proliferation > Eosinophil

5) B cell proliferates & produces IgE antibodies

6) IgE: binds to IgE receptor on mast cells(Antibodies bind FcεRI (IgE) on mast cells)

2nd exposure:
1) Inhaled allergen enters airway tissue

2) either:
a) Allergen binds IgE on mast cells, inducing degranulation
or
b) Further T cell activation: Th2 cell - IL-4, IL-5, IL-13

3)
a) Inflammatory mediators (PGs, LTs, chemokines) in mast cell
b) Eosinophils recruited to the airways and degranulate - Inflammatory mediators (ROS, enzymes, leukotrienes)

4) Airway inflammation reduces airflow & generates symptoms

Question 3

Additional mechanisms: alarmins (4)

Answer 3

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1) Allergen inhaled, enters airway tissue

2) Local tissue damage & antigen detection in airway epithelial cells

3)
a) Alarmins (TSLP, IL-25, IL-33) -> Group 2 innate lymphoid cells -> IL-5, IL-13
b) Antigen-presenting cell (e.g. dendritic cells ) engulfs & processes allergen + presents antigen to naïve helper T cell

4a) Naïve (CD4+) helper T cell > Mature Th2 cell

5ai) B cell > IgE
aii) IL-4
aiii) IL-5 > Eosinophil proliferation

Question 4

Additional mechanisms: Neurogenic inflammation, mucus secretion, and bronchoconstriction (4)

Answer 4

1) Activation of sensory neurones by these inflammatory mediators
2) send signal to CNS brainstem
3) send afferent signal back to various tissues (SM in airway, or mucous glands), via vagus nerve, to change their function in a secondary way
4) = Bronchial constriction and mucus secretion

(similar to asthma cough)

Question 5

Why are LAMA drugs like Tiotropium effective?

Answer 5

Long acting muscarinic antagonists block the signal (Ach) in vagus nerve = stopping smooth contraction or mucosal production

but not as effective as Beta2 antagonist because this is secondary

Question 6

Asthma is a… (2)

Answer 6

…complex & heterogeneous condition with multiple phenotypes

2012 paper: classified Type 2 and Non-Type 2 asthma

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Question 7

Inflammation vs airway dysfunction in asthma patients - variable vs consistent (5)

Answer 7

The changes to airway function are relatively consistent between asthma patients, whereas the characteristics of the inflammation can vary considerably

Inflam: variable b/w patients
1) Exposure to stimulus (allergens, cold air, NSAIDs)
2)Immune system response
3) Airway Inflammation

Airway dysfunction: Consistent b/w patients
4/1) Impaired airway function
5/2) Symptoms: Wheeze, Cough, Dyspnoea, ↓FEV1/FVC

*Relatively consistent - some variation still exists, e.g. age of onset, reversibility of obstruction, degree of remodelling and cough
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Question 8

Classic features of asthmatic inflammation are absent from some patients (3)

Answer 8

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- some have a lot of eosinophils
- a lot of patients have a lot of T cells/ Thc cells in severe asthma
-you can group patients - but they will be differing levels
- IgE; normal levels in nonallergic and high in allergic asthma

= understanding of pathphys needs to be nuanced

Question 9

Asthma syndrome definition

Answer 9

Characterised by variable and recurring symptoms, airflow obstruction, bronchial hyperresponsiveness and inflammation ( but causes that can vary considerably)

Question 10

Asthma phenotypes definition

Answer 10

Asthma subgroups defined by varying observable characteristics, e.g. early vs
late onset, specific triggers

Question 11

Asthma endotypes definition

Answer 11

Asthma subgroups defined by distinct pathophysiological mechanisms e.g. T2
high vs. T2 low or eosinophilic or non-eosinophilic

Question 12

Type 2 high vs. Type 2 low asthma named (6)

Answer 12

Type 2-high:
Early-onset allergic asthma
Late-onset eosinophilic asthma
Aspirin-exacerbated respiratory disease

Type 2-low:
Obesity-associated asthma
Very-late onset asthma
Smoking-associated asthma

Question 13

Type 2 high asthma subsets explained (9)

Answer 13

Early-onset allergic asthma:
Cause = allergen sensitisation
↑IgE, ↑Th2, ↑Eosinophils
Steroid sensitive, treatable

Late-onset eosinophilic asthma:
Cause = Staphylococcus enterotoxin-induced IgE
↑Eosinophils, ↑specific IgE
Severe from onset + frequent exacerbations. Steroid refractory

Aspirin-exacerbated respiratory disease:
Cause = Dysregulated aracidonic acid metabolism
↑Eosinophils, ↑LTE4
Severe from onset + frequent exacerbation

Question 14

Type 2 low asthma subsets explained (10)

Answer 14

Obesity-associated asthma
Risk factors = middle age, female sex
↑IL-6, ↑Neutrophils
Steroid resistant

Smoking-associated asthma
Cause = ↑oxidative stress
↑Neutrophils
Severe w/ preserved lung function ‘asthma-COPD overlap syndrome’

Very-late onset asthma
Onset after 50 years of age (or 65?)
Cause = aging associated decline in airway and immune system function
Th1/Th17 inflammation, ↑Neutrophils
Steroid resistant

Question 15

The varying characteristics of different asthma phenotypes/endotypes reflect varying pathophysiological mechanisms (4)

Answer 15

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Aspirin-associated respiratory disease
Allergic broncho-pulmonary mycosis
Cold air/exercise induced asthma
Allergic asthma

type 2 vs non type 2

Question 16

Why does it matter if there are difference in the underlying inflammation? (2)

Answer 16

o Specific therapies are more effective for specific endotypes, ∴ potential for improved treatment strategy via personalised medicine (if method of
accurate diagnosis/classification developed)

o Impact on research – both for investigation of pathophysiology and development of novel treatments (e.g. need to choose whether one is researching broad spectrum treatments/general pathology or endotype specific)

Question 17

Theoretical approaches to endotype diagnosis/classification (Carr and Kraft)

Answer 17

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diagnostically differentiate the different types of asthma - each subgroup would have a therapeutic strategy best for the physiology present

Question 18

The history of anti-IL-5 therapy illustrates… (4)

Answer 18

…the importance of understanding subgroups when researching asthma

involves monoclonal antibodies that block IL5 = plays a key role in asthma (main chemoattractant - signals causes prolif activation of eosin.)

animal model showed it helped do the job… block but had little/no effect on airway function symp’s of patients = not critical role in most

however when limited to severe eosin asthmatics = lower eosin AND LOWER AIRWAY RESTRICTION

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Question 19

Summary (3)

Answer 19

o The heterogeneity of asthma, a phenomenon that has been observed by clinicians for more than 100 years ago, is now widely understood and yielding a wealth of potential strategies for improving the effectiveness of treatment.

o This approach will enable patients to be treated with therapies that target the specific pathological changes responsible for their symptoms/disease.

o However, it first requires a clear and accurate framework for classifying patients that meaningfully differentiates them based on their varying physiology/sensitivity to individual treatments, as well as the identification of relevant biomarkers and the formulation of practical diagnostic systems.