L7 - Pathogenesis of asthma part 1 - Dr Bronwen Burton Flashcards
- Outline the Key features of asthma - Categorise different risk factors for asthma - Compare hypotheses explaining changes in asthma prevalence - Describe different stages of allergic asthma and explain the underlying immune response characteristic of each
1
Q
What is asthma?
A
Asthma is a chronic inflammatory disease of the lungs characterised by airway hyperreactivity, mucus overproduction, airway wall remodelling, and airway narrowing.
2
Q
How many people are affected by asthma worldwide?
A
Approximately 300 million people are affected, with an additional 100 million cases predicted by 2025.
3
Q
How many asthma-related deaths occur annually?
A
Around 250,000 asthma-related deaths are reported each year.
4
Q
What role do immune cells play in asthma?
A
Immune cells interact with epithelial cells to cause bronchial hyperreactivity (BHR), mucus overproduction, airway remodelling, and narrowing.
5
Q
What are the common symptoms of asthma?
A
Repeated episodes of wheezing, shortness of breath, and chest tightness.
6
Q
What is bronchial hyperreactivity (BHR)?
A
It refers to increased sensitivity and exaggerated contraction of the bronchial muscles in response to stimuli.
7
Q
What histological changes occur in the lungs of an asthmatic compared to a healthy lung?
A
Changes include hyperplasia of the epithelium, mucus hypersecretion, thickened basement membrane, and increased smooth muscle mass.
8
Q
What does hyperplasia of the epithelium indicate in asthma?
A
It refers to an increased number of epithelial cells, which contributes to airway narrowing.
9
Q
How is mucus production affected in asthma?
A
Mucus hypersecretion occurs, leading to excessive mucus in the airways, further narrowing them. mucus buildup can also cause turbulent airflow resulting in wheezing
10
Q
What is the significance of the thickened basement membrane in asthmatic lungs?
A
The thickening contributes to airway remodelling and reduced airway flexibility.
11
Q
How does increased smooth muscle mass affect asthmatic airways?
A
It causes excessive constriction of the airways, reducing airflow and leading to breathing difficulties .
12
Q
What is airway wall remodelling in asthma?
A
Structural changes in the airway walls that result in chronic narrowing and reduced lung function. this can lead to poor lung function even during symptom free periods
13
Q
What stain can be used to visualise the histological features of an asmatic airway and what can you see
A
Movat Pentachrome stain which visulises ( in an asthmatic lung) `
Hyperplasia of the epithelium (purplish staining).
Hypersecretion of mucus (blue staining).
Thickened basement membrane (pale pink staining).
Increased smooth muscle mass around the airway.
These changes collectively cause significant narrowing of the airway lumen, compromising normal lung function.
14
Q
What are the two traditional types of asthma?
A
Allergic asthma: Characterised by an IgE response to specific allergens.
Non-allergic asthma: Found more in adults and does not involve IgE.
15
Q
What diagnostic tool can identify allergens involved in allergic asthma?
A
A skin prick test is used to detect IgE responses to specific aeroallergens
16
Q
What percentage of asthma cases in adults and children is allergic asthma typically responsible for?
A
Allergic asthma accounts for around 50% of asthma cases in adults and the majority of cases in children.
17
Q
What is required for allergic asthma to be classified as such
A
there needs to be a particular allergen or allergerns that drives the asthma
18
Q
How does non-allergic asthma differ from allergic asthma?
A
Non-allergic asthma:
- Is less common than allergic asthma.
- Generally affects adults.
- Does not involve IgE responses.
19
Q
Why should asthma not be strictly divided into allergic and non-allergic types?
A
Asthma is now recognised as a spectrum of phenotypes with diverse pathophysiologies. Factors that vary between patients include:
- Clinical presentation
- Age of onset
- Genetic susceptibility
- Environmental response
- Degree of inflammation and bronchial hyperactivity
- Extent of tissue remodelling
- Response to therapy and prognosis
( a heterogenous disease )
20
Q
What trend was observed in asthma diagnosis in children in the UK from the mid-1970s to mid-2000s?
A
There was an upward trend in asthma diagnosis during this period across multiple centres in the UK, though diagnoses have since plateaued ( One possible reason is that asthma may have been historically overdiagnosed)
21
Q
What factors made the study from a 2007 paper on asthma prevalence in children reliable?
A
The study used:
- Consistent survey locations across time points
- The same diagnostic methods at different time points
- Can rule out confounding factors in methodology like significant change in genetics within the population
22
Q
What is the estimated percentage of the UK population diagnosed with asthma?
A
Approximately 12% of the UK population has been diagnosed with asthma.
23
Q
What types of factors contribute to the development and severity of asthma?
A
Both host and environmental factors play crucial roles.
24
Q
How heritable is asthma according to various studies?
A
Asthma heritability rates range from 35% to 95%, depending on what paper you look at
25
What are the two categories of environmental risk factors for asthma?
1. Susceptibility factors: Act on a person's genetic predisposition to trigger asthma development.
2. Precipitating factors: Set off asthma attacks in individuals who already have asthma.
26
How do genetic and environmental factors interact in asthma?
There is a complex interplay between genetic predisposition and environmental exposures that influences both asthma development and its severity.
27
What role do genetic factors play in the development of asthma?
Genetic factors increase the risk of asthma, especially if one or both parents have asthma or another atopic disease (overproduction of IgE). However, asthma is polygenic, meaning multiple genes contribute to overall susceptibility, rather than a single mutation causing it.
28
What are the categories of susceptibility genes for asthma?
1. Genes expressed in airway epithelial cells
2. Genes regulating CD4 T cell and ILC2 differentiation and function
3. Genes with other functions
29
What are example susceptibility genes expressed in airway epithelial cells for asthma
- Chemokines : CCL5
- Antomicrobial peptides : DEFB1
- Secretoglobulin family : SCGB1A1
- Epithelial barrier protein : FLG
30
what are example susceptibility genes involved in regulating CD4 T cell and ILC2 differentiation and function for asthma
- Transcription factors : GATA3, TBX21, STAT3
- Cytokines : IL-4, IL-5, IL-10 TGFb1
- Cytokine receptors: IL2RB, IL6R
- Pattern recognition receptors: CD14, TLR2, NOD1 and NOD2
- Antigen presentation : HLA-DRB1, HLA-G
- Prostaglin receptors : PDFER2 and PTGDR
*** transcription factors, cytokines and cytokine receptors are important in type 2 responses and antigen presentation affects MHC class II to CD4+ T cells
31
What are example susceptibility genes with other functions for asthma
- Proteinase or proteinase inhibitors : ADAM33
- Signaling proteins : NOTCH4
- Receptors : ADRB2
- Other
32
How do CD4 T cells contribute to asthma pathogenesis?
CD4 T cells are critical in asthma pathogenesis, as indicated by the presence of many MHC class II molecules and cytokines important for type 2 immune responses in asthma-related susceptibility genes.
33
What is the concordance rate for asthma in monozygotic (identical) twins?
The concordance rate for asthma in monozygotic twins is around 75%, although it can vary between studies. This highlights the role of both genetics and environmental factors in asthma development.
34
What are the two main categories of environmental risk factors for asthma?
1. Susceptibility factors: Environmental exposures that influence genetic predisposition to asthma (e.g. allergens, tobacco smoke, air pollutants, respiratory infections).
2. Precipitating factors: Environmental triggers that provoke asthma attacks in susceptible individuals (e.g. allergens, air pollutants, infections, emotional stress).
35
What are some common susceptibility factors for asthma?
- Indoor and outdoor allergens
- Occupational sensitizers (e.g. solvents)
- Tobacco smoke (active and passive)
- Air pollution, particularly particulate matter
- Respiratory infections, especially viral and parasitic
- Socio-economic status
- Family size
- diet and drugs
- obesity
36
What are some common prescipitating factors for asthma?
things that drive an asthma attack in an asthmatic person (there is a lot of overlap with things that increase susceptibility)
- Indoor and outdoor allergens (e.g. house dust mites with Der P1 and Der P 2 in faecal matter or grass pollen with lol p 1)
- Air pollutants and tobacco smoke
- Exercise and hyperventilation
- respiratory Infections
- Weather changes (e.g. thunderstorms)
- Sulfur dioxide exposure ( pollutant which can also be found in foods like dried fruits and wine as an antioxidant )
- Extreme emotional expression
37
What environmental factors are linked to higher asthma prevalence in more industrialised societies?
Industrialised and urbanised societies tend to have higher asthma prevalence due to greater exposure to pollution and indoor allergens.
38
What was the finding of the 1998 study on asthma prevalence in children across 56 countries?
The study found that developed countries e.g. UK had the highest prevalence of asthma in children (over 35%), while countries like Indonesia had a much lower prevalence (under 5%). This supports the idea that asthma is more prevalent in Westernised, industrialised societies.
39
What did the study suggest about countries with high asthma prevalence despite being less westernised?
In countries like Costa Rica, higher exposure to mite and cockroach allergens may explain the relatively high asthma prevalence despite being less industrialised.
40
How does asthma demonstrate a complex interaction of factors?
Asthma is polygenic, with multifactorial environmental influences shaping its development. Environmental risk factors vary by population, influencing asthma prevalence differently in various societies.
41
What is the hygiene hypothesis?
The hygiene hypothesis, suggests that higher standards of cleanliness reduce childhood infections, which may normally help prevent allergic diseases like asthma.
42
who proposed the hygeine hypothesis and when
proposed by David Strachan in 1989
43
How does household size relate to asthma prevalence according to Strachan's findings?
Strachan found that hay fever prevalence was inversely related to household size. Children in larger households with more siblings had lower rates of hay fever and asthma (this was a study done in 17,414 Bristish Children)
44
What did Strachan propose as the mechanism behind the hygiene hypothesis?
Strachan proposed that unhygienic contact with older siblings in large households exposes children to infections, which helps prevent allergic diseases like asthma by promoting T helper 1 responses.
45
What may be the reason for an increase in widespread clinical expression of atopic disease over the past century
Over the past century declining family size, improved household amenities and
higher standards of personal cleanliness have reduced opportunities
for cross- infection in young families
46
Why was the hygiene hypothesis initially not well received?
It seemed counterintuitive, as people knew that particular infections e.g rhinoviruses and RSV, rather than preventing asthma, could trigger asthma attacks.
47
How did the discovery of T helper 1 and T helper 2 cells in the 90s support the hygiene hypothesis?
The discovery of Th1 and Th2 cells showed that infections drive Th1 responses, which help fight infections, while Th2 responses can drive IgE production and promote allergic reactions. A lack of infections may lead to Th2 dysregulation, promoting asthma.
48
What is the relationship between Th1 and Th2 responses in a balanced immune system?
In a balanced system, Th1 and Th2 responses regulate each other to maintain effective immune defence without promoting allergies
49
Why is the balance between Th1 and Th2 responses crucial for immune health?
Maintaining this balance ensures protection against infections without promoting allergies or autoimmune diseases
50
How do Th1 responses inhibit Th2 responses?
Th1 cells produce cytokines, such as interferon-gamma (IFN-γ), which suppress Th2 cell activation and function.
51
How do Th2 responses inhibit Th1 responses?
Th2 cells release cytokines like IL-4 and IL-10, which can inhibit Th1 cell activity and cytokine production.
52
What can help shift the Th1/Th2 balance towards Th1 to prevent allergies?
Early exposure to infections can help promote Th1 responses, potentially reducing allergy development.
53
What does the Westernisation hypothesis propose about asthma?
Proposed by Erika Von Mutis in 1994, the Westernisation hypothesis suggests that more westernised societies have higher asthma prevalence due to exposure to indoor allergens and a more industrialised lifestyle.
54
What did Von Mutis find when comparing asthma rates in East and West Germany?
When studying asthma and allergy in children in East and West Germany, Von Mutis found that children in West Germany (more westernised) had significantly higher asthma and hay fever rates compared to children in East Germany, which was poorer, less developed, had more pollution and bronchitis
55
What environmental factor did Von Mutis link to higher asthma rates in Western societies?
Von Mutis linked higher asthma rates in Western societies to greater sensitisation to indoor allergens (aeroallergens) derived from dust mites, cats, and pollen.
56
What is Platts Mills' obesity hypothesis, and how does it relate to asthma?
The obesity hypothesis suggests that indoor lifestyles, including more exposure to allergens, overeating, and less physical activity, contribute to asthma. It aims to explain why some data doesn't fit the hygiene hypothesis
57
How does the obesity hypothesis address the relationship between hygiene and asthma in different societies?
The obesity hypothesis explains that urbanised societies with high hygiene but low physical activity (e.g. Japan) still have low asthma rates, while lower-income societies with poor hygiene may have higher asthma rates.
58
Reduced physical activity results in less deep breathing, making children more susceptible to non-specific bronchial hyperreactivity.
Reduced physical activity results in less deep breathing, making children more susceptible to non-specific bronchial hyperreactivity.
59
What disagreement with the hygiene hypothesis does Platts Mills' hypothesis address?
It explains why children in poor housing with worse hygiene (e.g. the states) might have higher rates of asthma, despite predictions from the hygiene hypothesis (It highlights that poor hygiene may coexist with factors like indoor allergens and sedentary living, leading to asthma
60
How does the obesity hypothesis expand the understanding of asthma development?
It integrates environmental, behavioural, and dietary factors alongside hygiene considerations.
61
What does the microbiota hypothesis suggest about the development of asthma?
The microbiota hypothesis suggests that a westernised lifestyle leads to changes in gut microbiota, which may alter immune responses and increase the risk of developing asthma.
62
How does dysbiosis relate to asthma risk, according to the microbiota hypothesis?
Dysbiosis, or an imbalance in gut microbiota, is associated with an increased risk of asthma. Early gut microbiota diversity is linked to asthma development, suggesting that alterations in gut bacteria may contribute to immune dysregulation.
63
What is the relationship between antibiotic use and asthma risk?
Studies show that antibiotic use is positively correlated with an increased risk of asthma and allergy, suggesting that antibiotics may disrupt normal microbiota and contribute to asthma.
64
How have animal studies supported the microbiota hypothesis in asthma development?
Animal studies have shown that germ-free mice exhibit immune system defects, and antibiotic treatments in mice promote Th2 responses and can induce asthma-like responses. Additionally, probiotics have been shown to reduce airway inflammation in mice.
65
How might changing diet or using probiotics help prevent asthma according to the microbiota hypothesis?
Altering diet or using probiotics may help to restore healthy gut microbiota, which in turn could reduce immune system dysregulation and suppress asthma development by reducing inflammation.
66
What role do changes in faecal microbiota composition play in atopy?
Altered faecal microbiota composition is correlated with increased susceptibility to atopic diseases.
67
How many microbes live on mucosal surfaces
10-100 trillion microbes all of which influence mucosal tolerance and immune responses
68
What happens to most inhaled micro-particles in the respiratory system?
They stick to mucus in the nasopharynx and upper airways, are swallowed, and become exposed to immune cells in the gut mucosa.
69
Why is mucosal tolerance important for lung health?
It prevents damaging immune responses to harmless particles, helping to maintain respiratory health and preventing immune hyperactivity and diseases like asthma
70
What study in 2019 compared farm and urban environments regarding asthma risk?
A study in Finland and Germany characterised home dust microbiota, comparing farm and urban environments to assess asthma susceptibility. It revealed that rural farms have richer home dust microbiota, which shapes lung immunity and reduces asthma risk in children.
71
What was observed about bacterial diversity between farm and urban homes in the study
Farm homes showed greater bacterial diversity, with a clear separation from urban homes. and they found that asthma risk for non-farm home children
decreases the more similar their home bacterial microbiota composition is to a
farm home.
72
: How did fungal diversity compare between farm and urban homes?
Fungal diversity showed less distinction between farm and urban homes compared to bacterial diversity.
73
What correlation was found between home microbiota composition and asthma risk in non-farm children?
Asthma risk decreased as the home bacterial microbiota composition became more similar to that of farm homes.... Identifying and therapeutically using specific bacterial strains from farm environments may help reduce asthma and allergy
74
What does the epithelial barrier hypothesis propose?
The hypothesis suggests that damage to the epithelial barrier can lead to inflammation in the epithelium and barrier damage --> colonisation of opportunistic pathogens --> Microbial dysbiosis and decreased biodiversity --> immune response to commensal and opportunistic pathogens --> and an increased risk of inflammatory and allergic diseases (which further leads to barrier damage and the cycle continues)
75
What are some examples of barrier-damaging agents in industrialised societies?
Toxins from cleaning products, enzymes, emulsifiers, processed food, pollution, and environmental toxins.
76
What happens when the healing of the epithelial barrier becomes defective?
There is increased exposure to damaging agents, perpetuating a cycle of inflammation, dysbiosis, and immune dysregulation.
77
How might climate change contribute to an increase in asthma prevalence according to Agache et al., 2024?
Climate change leads to
- increased pollen levels, longer pollen seasons, higher pollen loads
- severe asthma triggers during increased thunderstorms, wildfires, sandstorms, heatwaves, increased pollution, heat waves (heat stress) and flooding
78
How do thunderstorms contribute to severe asthma attacks?
Humidity ruptures aeroallergens into smaller particles, increasing their capacity to trigger asthma attacks.
79
What role do wildfires and dust storms play in asthma prevalence?
They release particulate matter that can damage the epithelium and trigger respiratory diseases.
80
How can flooding and heatwaves contribute to immune dysregulation?
How can flooding and heatwaves contribute to immune dysregulation?
81
What is the exposome, and how is it changing due to climate change?
The exposome includes all environmental exposures an individual encounters. Climate change is altering the exposome, increasing the risk of immune regulatory diseases, including asthma, autoimmune diseases, and cancer.
82
What type of immune disorder is asthma widely considered to be?
Asthma is widely considered a T helper 2 (TH2) mediated disorder this increases:
- the number of CD4+ T cells producing IL-4 and IL-5
- the number of Eosinohils in the respiratory tract fluids and bronchial biopsies
- the amount of serum IgE ( Il-4 driven class switching)
- Unsupervised clustering algorithms reveal Th2 (high) and Th2 (low) subtypes
83
What evidence supports the role of TH2 cells in asthma?
Increased CD4+ T cells producing IL-4 and IL-5, elevated eosinophils in respiratory samples, and high IgE levels in allergic asthmatics.
84
How does IL-5 contribute to asthma pathogenesis?
IL-5, produced by TH2 cells, drives eosinophil production, and release from the bone marrow contributing to airway inflammation.
85
How does IL-4 contribute to asthma pathogenesis?
IL-4 promotes class switching to IgE, which plays a key role in allergic responses
86
What are TH2-high and TH2-low subsets in asthmatic patients?
These are patient subgroups distinguished by the presence or absence of TH2 cytokines (IL-4, IL-5, IL-13) in airway brushings and IgE levels in the blood
87
How do mouse models help study asthma?
Mice are sensitised with ovalbumin (OVA - protein in egg whites) and adjuvants, When they are challenges with OVA aerosol they get asthma like symptoms with airway inflammation (Eosinphil inflammation, Th2 cytokines, airway hyperresponsiveness)
88
What happens when CD4+ T cells are depleted in asthma mouse models?
Depleting CD4+ T cells abolishes key features of asthma, showing their critical role in disease pathogenesis.
89
What role do TH1 cells play in relation to asthma?
TH1 cells and IL-12 suppress asthma, showing the mutually antagonistic relationship between TH1 and TH2 responses. asthma, showing the mutually antagonistic relationship between TH1 and TH2 responses.
90
What happens if TH2 cytokines (IL-4, IL-5 or IL-13) are knocked out in asthma mouse models
Mice show significantly fewer features of asthma, indicating the importance of TH2 cytokines in disease development.
91
What are some characteristics of clinically relevant allergens in allergic asthma?
Many are enzymes that directly interfere with physiological systems and can trigger life-threatening asthma attacks even at minute doses e.g. from Dermatophagoides pteronissinus
92
What is the proper scientific name for the house dust mite?
Dermatophagoides pteronyssinus ( italics)
93
What are the major allergens derived from house dust mites?
Derp1 and Derp9 which have serine and cysteine protease activity
94
How do house dust mite allergens (e.g. Derp1 and Derp9) affect the epithelial barrier?
They cleave tight junction occludin proteins, increasing epithelial permeability and allowing allergens greater access to immune cells e.g. dendritic cells (which induce Th2 responses)
95
What is the role of Derp allergens in IgE synthesis?
They cleave CD23 (FcεRII) on B cells, triggering upregulation of IgE synthesis.
96
What danger signals activate dendritic cells in the airway?
Both endogenous and exogenous signals (endogenous = produced inside an organism or cell. The opposite is external (exogenous) production.)
97
Which epithelial-derived cytokines are released in response to allergens?
epithelial cells release L-33, IL-25, and TSLP (thymic stromal lymphopoietin) when activated. This drives dendritic cells maturation and conditions them to induce Th2 responses (when they present antigens to naive T cells)
98
What are IL-33, IL-25 and TSLP known as
Alarmins
99
Why are dendritic cells important in asthma sensitisation?
They sample antigens in the airway lumen, capture allergens that breach the epithelial barrier, and migrate to the lymph nodes where they present these to naive CD4+ T cells, driving TH2 cell differentiation and responses (perpetuating inflammation). DC also recruit effector T cells to the site of inflammation in the lung by the production of chemokines, forming clusters in airways and blood vessels
100
How do dendritic cells change in asthmatic airways?
The number of activated dendritic cells increases significantly in the airways of asthmatics.
101
How do polymorphisms at HLA-DRB1 and HLA-DQA1 loci associate with asthma?
The HLA (human leukocyte antigen) system plays a crucial role in immune responses and HLA-DRB1 and HLA-DQA1 loci endoce MHC class II molecules which are involved in antigen presentation to T helper cells. Specific polymorphisms (genetic variations) at these loci have been linked to increased susceptibility to asthma.
102
how can polymorphisms at HLA-DRB1 and HLA-DQA1 influence asthma?
These variations can:
- Affect antigen binding and presentation, leading to inappropriate immune responses.
- Influence the development of Th2-skewed immunity, which promotes inflammation and IgE production — hallmarks of asthma.
- HLA polymorphisms may also shape responses to allergens and respiratory infections, contributing to disease severity.
103
sensitiation steps to Derp1 : establishing the immune response underlying asthma
1. The enzyme Derp1 cleaves occludin in tight junctions and enters the mucosa
2. Derp1 is taken up by dendritic cells for antigen presentation and Th2 priming in the lymph nodes
3. Th2 cells induce B cell switch to IgE production
4. Plasma cells travel back to mucosa and produce Derp1 specific IgE antibodies which bind to FceRI receptors on mast cells
5. Derp1 triggers cross linking and mast cell degranulation which releases inflammatory mediators e.g. histamine which cause allergic symptoms
104
Name two pre-formed inflammatory mediators released during mast cell degranulation and what they do
Histamine : acts directly on blood vessels to increase blood flow and vascular permeability
proteases : activate matrix metalloproteinases which causes tissue damage
105
How are mast cells in the airway sub-mucosa maintained
by IL-9
106
what can low levels of antigen trigger in mast cells
degranulation and release of pre formed inflammatory mediators
107
What are examples of mast cell newly synthesised inflammatory mediators
- prostaglandins
- Leukotriens
- Platelet activating factor
- Cytokines e.g. IL-4, IL-13
- chemokines
108
what do prostaglandins and leukotriens do and what do cytokines and chemokines do
Prostaglandins and leukotrienes : increase vascular permeability and smooth muscle contraction
cytokines and chemokines : recruit and influence other immune cells driving further inflammation
109
What is the immediate phase response in asthma?
It occurs within 30 minutes of allergen exposure, characterised by bronchial smooth muscle contraction and mucus hypersecretion.
110
What causes the late-phase response in asthma?
Dependent on allergen dose
* Characterised by influx of eosinophils and Th2 cells
* Continued synthesis of inflammatory mediators by mast cells perpetuates
inflammation in the lung, e.g.
– Vascular endothelial growth factor (VEGF) causes vasodilation and vascular
leakage → oedema
– Cytokines and chemokines secreted by mast cells (and others) activate and
recruit other immune cells
111
What cytokines recruit eosinophils to the lung during the late phase of asthma?
Interleukin-5 and eotaxins (CCL11, CCL24, CCL26).
112
What is the role of eosinophils in asthma?
They release toxic proteins and free radicals, causing tissue damage and perpetuating inflammation.
113
Why are eosinophils usually found in small numbers in circulation
Eosinophils are highly cytotoxic and can cause tissue damage if uncontrolled (eosinophils are dangerous)
114
How do eosinophils accumulate in asthmatic airways?
- Eosinophils are recruited to inflamed tissues in asthma.
- This process is primarily driven by Th2-mediated immune responses and chemokines like eotaxins.
115
What roles do IL-4 and IL-13 play in eosinophil recruitment during asthma?
IL-4 and IL-13 act on endothelial cells and fibroblasts, stimulating the secretion of eotaxins.
116
What are eotaxins, and what do they do in asthma?
Eotaxins (CCL11, CCL24, CCL26) are chemokines that recruit eosinophils from the blood to sites of inflammation.
They bind to the CCR3 receptor on eosinophils.
117
What is the role of CCR3 in eosinophil recruitment?
CCR3 is a receptor expressed by eosinophils and Th2 cells.
Binding of eotaxins to CCR3 promotes the migration of eosinophils to inflamed airway tissues.
CCR3 also attracts Th2 cells, further amplifying inflammation.
118
What proteins expressed on endothelial cells aid leukocyte migration into inflamed lung tissue?
ICAM-1 and VCAM-1.
119
What does histamine release during the acute asthma response increase?
Levels of P- and E-selectin for leukocyte rolling.
120
What is the process of leukocyte transmigration
1. Tethering
2. Rolling
3. Activation
4. Firm adhesion
5. Transmigration
121
Which molecules contribute to late-phase bronchoconstriction in asthma?
Eosinophil cationic protein, platelet-activating factor, and leukotrienes.
122
How do eosinophils amplify inflammation in asthma?
Through the release of cytokines that promote Th2-driven inflammation and increased eosinophil production in the bone marrow.
123
What chemokines recruit more immune cells in asthma?
CXCL8.
124
How do eosinophils contribute to airway inflammation in asthma?
By forming extracellular traps composed of DNA, histones and various proteins e.g. those from their granules (major basic protein). these are intended to capture and neutralise pathogens like parasites but in asthma they contribute to airway inflammation
125
What is the major toxic component in eosinophil granules?
MAjor basic protein which is toxic to helminths and host cells, causes mast cell and basophil degranulation, epithelial damage, increased vascular permeability, oedema, and mucus production.
126
How does major basic protein contribute to antigen access?
By opening tight junctions, allowing more antigen access and perpetuating inflammatory responses.
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