L8 - Pathogenesis of asthma part 2 - Dr Bronwen Burton Flashcards
- Explain the long term consequences of asthma (immunopathology) - Describe the contribution of innate and adaptive immune cells to the spectrum of asthma endotypes, driving type 2 and non type 2 responses - Explain how our understanding of the immune processes underlying asthma immunopathology has informed the development of new therapies for the treatment of asthma
1
Q
What triggers the immediate response in allergic asthma?
A
Antigen exposure leading to cross-linking of IgE bound to FcεR1 on mast cells.
2
Q
What happens when mast cells degranulate in the acute response?
A
Release of inflammatory mediators causing tissue damage, smooth muscle constriction, and recruitment of other immune cells.
3
Q
What characterises the late-phase response in asthma?
A
Recruitment and activation of Th2 cells and eosinophils.
4
Q
What are the long-term consequences of repeated acute and late-phase responses in asthma?
A
Chronic inflammation, airway remodelling, and chronic asthma.
5
Q
What changes do the airways of chronic asthmatics exhibit?
A
Evidence of chronic wounding, with evidence of ongoing epithelial injury and repair (which try to get started and repair the injury with varying degrees of success )
6
Q
How does long-term allergen exposure affect asthma?
A
Drives repeated inflammatory episodes, leading to serious long-term illness and sustained airway damage.
7
Q
What cells are key players in the late-phase and chronic immune response in asthma?
A
Th2 cells which release cytokines and eosinophils that release their granules and proteins
8
Q
what are characteristics of acute responses
A
Iflammatory mediators cause increased mucus secretion and smooth muscle contraction leading to airway obstruction
9
Q
What are the differences between normal lung tissue and asthmatic small airways?
A
Hyperplasia of the epithelium, hypersecretion of mucus, thickening of the basement membrane, increased smooth muscle volume, and angiogenesis.
10
Q
What causes hypersecretion of mucus in asthmatic lungs?
A
Goblet cell metaplasia and hyperplasia.
11
Q
What mediates basement membrane thickening in asthma?
A
Myofibroblasts, which are cells with features of both fibroblasts and smooth muscle cells.
11
Q
what is the difference between hyperplasia and metaplasia when it comes to goblet cell hypersecretion?
A
Hyperplasia involves the increase in cell number whilst metaplasia involves the replacement of one cell type e.g. epithelial cells with goblet cells. both are adaptive responses to stimuli
12
Q
What structural change occurs in the airway smooth muscle of asthmatics?
A
Significant increase in smooth muscle volume.
13
Q
What is angiogenesis, and why is it significant in asthma?
A
Formation of new blood vessels, facilitating immune cell migration from the blood vessles into inflamed lung tissue.
14
Q
What is lymphangiogenesis, and how does it contribute to asthma pathology?
A
Formation of new lymph vessels, allowing airway DCs (APCs) to transport allergens to local lymph nodes and prime T-helper cells which go back into the lung to carry out the inflammatory processes
15
Q
What is the role of T-helper cells in asthma after lymphangiogenesis?
A
They return to the lung and perpetuate (sustain) inflammatory processes.
16
Q
What causes thickening of the basement membrane in asthmatic lungs
A
myofibroblasts
17
Q
How do these structural changes affect lung function in asthma?
A
Even without an active asthma attack, lung function can be compromised, predisposing asthmatics to exaggerated responses to airway insults.
18
Q
What are the key roles of Type 2 cytokines in allergic asthma?
A
They act on both innate and adaptive immune cells as well as non-immune cells, driving features such as epithelial cell damage, goblet cell hyperplasia, air way wall remodelling, and bronchial hyper-reactivity.
19
Q
How do Type 2 cytokines contribute to epithelial cell damage and goblet cell hyperplasia?
A
IL-5 and GM-CSF are involved in epithelial damage, while IL-4 and IL-13 promote goblet cell hyperplasia and eosinophil activation (w
20
Q
IL-4 effect from Th2 cells in asthma *
A
- Promotes goblet cell hyperplasia, leading to increased mucus production in the airways.
- Supports B-cell class switching to IgE, driving allergic responses.
- Upregulates VCAM1 and ICAM1 on endothelial cells, promoting recruitment of immune cells.
21
Q
Il-5 effect from Th2 cells in asthma *
A
- Essential for the survival, recruitment, and activation of eosinophils.
- Eosinophils release toxic granules and cytokines that cause airway tissue (epithelial) damage and inflammation.
22
Q
IL-9 effects from Th2 cells in asthma *
A
- Increases airway smooth muscle contraction, contributing to bronchial hyper-reactivity.
- Can also promote mast cell recruitment and activation, exacerbating asthma symptoms.
23
Q
IL-13 effects from Th2 cells in asthma *
A
- Drives epithelial cell damage and goblet cell metaplasia, leading to increased mucus production.
- Induces collagen deposition and airway wall remodelling through interactions with the epithelial-mesenchymal trophic unit (EMTU).
- Enhances smooth muscle contraction, worsening airway narrowing.
24
GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor) effects from Th2 cells in asthma *
Promotes the survival and activation of eosinophils, amplifying airway inflammation.
25
TNF-α effects from Th2 cells in asthma
- Contributes to vascular inflammation, enhancing the recruitment of immune cells by upregulating adhesion molecules like ICAM1.
- Supports airway remodelling by acting on non-immune cells.
26
What is the epithelial-mesenchymal trophic unit (EMTU), and why is it significant in asthma?
It refers to communication between the lung epithelium and underlying fibroblasts, driving mesenchymal proliferation and collagen deposition, leading to airway wall remodelling (very much augmented by IL-4, IL-13)
27
What initiates the cycle of inflammation in chronic asthma?
Environmental agents (allergens) trigger Type 2 immune responses involving IgE, mast cells, and eosophils. These inflammatory cells and their products, along with environmental agents, damage the lung epithelium which releases growth factors which act as pro-inflammatory mediators/ chemoattractant bringing more mast cells and eosinophils to the site which causes more damage ....
28
How does the epithelium respond to damage in chronic asthma?
The epithelium attempts repair by releasing growth factors, including:
Epidermal Growth Factor (EGF)
Fibroblast Growth Factor (FGF)
Platelet-Derived Growth Factor (PDGF)
Transforming Growth Factor Beta (TGF-β)
(these all mix activate both structural cells and cells of the immune system e.g. Mast cells and Eosinophils)
29
What is the role of myofibroblasts in chronic asthma?
Activated myofibroblasts:
- Synthesize collagen
- Increase smooth muscle cell mass
- Secrete extracellular matrix components contributing to airway remodelling
30
What structural changes occur in the airway due to chronic asthma?
- Collagen deposition and thickening of airway walls
- Increased smooth muscle cell mass
- Secretion of extracellular matrix components
31
How do smooth muscle cells and myofibroblasts contribute to inflammation?
They produce cytokines and chemokines, including IL-5 and IL-13, which recruit more inflammatory cells and drive further tissue injury.
32
How does the recruitment of inflammatory cells perpetuate chronic asthma?
Pro-inflammatory mediators and chemoattractants recruit more immune cells to the lungs, causing a cycle of ongoing tissue injury and repair, leading to chronic lung damage.
33
What is a downstream effect of chronic asthma on respiratory infections?
Asthmatic patients become more susceptible to respiratory viral infections, such as those caused by human rhinovirus, influenza virus, and respiratory syncytial virus (RSV).
34
Why do asthmatics have exaggerated responses to viral infections?
Allergic sensitisation and Th2-driven eosinophilia (driven by the inflammatory state) suppress antiviral immunity.
35
What changes occur in the epithelium and endothelium of inflamed lungs in asthma?
Increased ICAM-1 expression allows easier binding of human rhinovirus, making infection more likely.
36
How does interferon production change in asthmatic epithelial cells?
Epithelial cells from asthmatic patients produce less Type I (IFN-α/β) and Type II (IFN-γ) interferons in response to human rhinovirus infection.
37
Why Does Reduced Type I and Type II Interferon (IFN) Response in Asthmatic Patients Increase HRV Infection Rates?
Type I (IFN-α/β) and Type II (IFN-γ) interferons are crucial for initiating and maintaining antiviral defences. They trigger signalling cascades that upregulate antiviral proteins and recruit immune cells to clear viral infections. In asthmatic patients, a deficiency in these interferons significantly weakens the immune response to human rhinovirus (HRV), leading to:
Reduced Viral Clearance:
With lower IFN production, epithelial cells and immune cells are less effective at halting viral replication. HRV can more easily enter and multiply in airway epithelial cells.
Compromised Immune Activation:
Type I IFNs recruit immune cells like dendritic cells (DCs) and natural killer (NK) cells, which are pivotal in clearing viral infections. Reduced recruitment leads to delayed or inefficient immune responses.
Prolonged Inflammatory Damage:
Failure to clear the virus can trigger prolonged inflammation, exacerbating airway injury and worsening asthma symptoms.
38
How does IgE affect dendritic cells in chronic asthma?
high levels of IgE bind to dendritic cells and hamper their antiviral function, reducing their production of Type I interferons and weakening the immune response : weakened viral recognition and signalling pathways required fro robust immune responses
39
chronic Inflammation and Barrier Dysfunction:
The inflamed lung epithelium becomes structurally damaged and less capable of forming a protective barrier against viral entry.
Increased adhesion molecule expression (e.g., ICAM-1) on epithelial cells further facilitates HRV binding and entry.
40
What are the roles of Th2 and Th17 cells in chronic asthma?
Th2 cells: Drive eosinophilic infiltration through the production of cytokines like IL-4, IL-5, and IL-13, contributing to inflammation and airway remodelling.
Th17 cells: Drive neutrophilic inflammation through IL-17 production, which recruits neutrophils to the airway, further exacerbating inflammation, chronic wounding and repair ( key to chronic asthmatic lung)
41
Why is asthma considered a spectrum of conditions rather than simply allergic or non-allergic?
- Asthma encompasses a range of clinical presentations and underlying immunopathologies, from allergic to non-allergic forms.
- Many patients exhibit overlapping mechanisms, with shared immunopathology between types.
- Traditional classifications into allergic and non-allergic asthma are useful but often insufficient to describe the complexity of the disease.
- several different endotypes and phenotypes have been recognised
42
What are asthma phenotypes and endotypes, and how do they differ?
- Phenotypes: Observable characteristics of asthma, such as clinical symptoms or triggers.
- Endotypes: Subtypes of asthma defined by underlying immunopathology, susceptibility, genetics, and disease mechanisms.
- Different endotypes may overlap and share pathological features despite varying clinical presentations.
43
What percentage of asthmatic patients show evidence of Type 2 immunity, and what about the rest?
About 50% of asthmatic patients show evidence of Type 2 immunity in their airways.
The remaining patients may have alternative immune mechanisms driving their condition, such as neutrophilic or mixed inflammatory responses.
44
What is Type 2 Immunity, and what are its key features?
Defence against parasites (especially helminths) and regulation of allergic responses.
Key Cells:
Th2 cells: Release cytokines to orchestrate the immune response.
ILC2s: Act early in response to allergens or tissue damage.
Eosinophils: Release toxic granules to combat parasites but cause tissue damage in asthma.
Mast cells: Release histamines leading to inflammation and allergic reactions.
45
How can non-atopic individuals still exhibit high eosinophil counts in asthma?
Despite the absence of traditional Th2 immunity, non-atopic individuals may still develop airway eosinophilia. This can be driven by mechanisms independent of the adaptive immune system.
46
What evidence suggests that eosinophilia can occur without Th2 or adaptive immunity?
- Blocking IL-4 and IL-5 receptors: Improves clinical outcomes even in non-atopic individuals, indicating cytokine-driven eosinophilia without classic Th2 involvement.
(In simpler terms: If it doesn't have typical allergies, it can still have a disease (like asthma) characterised by high levels of eosinophils and inflammation driven by IL-4 and IL-5. Blocking the signals of these cytokines can improve their condition. This implies that there are other pathways, besides the classic allergic (Th2-IgE) pathway, that can lead to the production of IL-4 and IL-5 and subsequent eosinophilic inflammation and shows the heterogeneity of the disease)
- Rag-deficient mice experiments: These mice, which lack T and B cells, still develop airway eosinophilia when challenged with Alo-allergens. this suggests that the development of key inflammatory features / asthma isn't solely reliant on the innate immune response.
- Non-adaptive immune mechanisms: Suggest that innate immune responses can independently generate a Th2-like cytokine environment and eosinophilic inflammation.
## Footnote
Let's break down the evidence suggesting that eosinophilia can occur without classical Th2 or adaptive immunity, based on the provided points:
Understanding the Context:
Eosinophilia: An abnormally high number of eosinophils (a type of white blood cell) in the blood or tissues, such as the airways in asthma.
Th2 Immunity: A type of adaptive immune response characterized by the production of specific cytokines like IL-4, IL-5, and IL-13. This pathway is classically associated with allergic reactions (atopy) and eosinophilic inflammation in asthma. T helper 2 (Th2) cells are key players in this response.
Adaptive Immunity: The part of the immune system that learns and remembers specific pathogens or antigens. It involves T and B lymphocytes.
Innate Immunity: The first line of defense, a rapid and non-specific immune response involving cells like macrophages, neutrophils, and natural killer (NK) cells.
Evidence Suggesting Eosinophilia Independent of Classical Th2/Adaptive Immunity:
The provided points offer three lines of evidence:
1. Blocking IL-4 and IL-5 receptors: Improves clinical outcomes even in non-atopic individuals, indicating cytokine-driven eosinophilia without classic Th2 involvement.
Explanation: IL-4 and IL-5 are key cytokines traditionally associated with Th2 responses. IL-5 is a major driver of eosinophil development, recruitment, and activation. IL-4 promotes Th2 differentiation and IgE production (characteristic of atopy).
Implication: If blocking the receptors for these cytokines leads to clinical improvement (reduced inflammation, better lung function) in non-atopic individuals (those without the typical allergic triggers and IgE elevation), it suggests that eosinophilia and the associated inflammation in these individuals are still dependent on these cytokines, but not necessarily driven by a classical, allergen-specific Th2 response involving T cells and IgE.
Therefore: There must be alternative pathways, potentially involving innate immune cells or non-Th2 adaptive cells, that can lead to the production of IL-5 (and possibly IL-4) and subsequent eosinophilia in these non-atopic patients.
2. Rag-deficient mice experiments: These mice, which lack T and B cells, still develop airway eosinophilia when challenged with Alo- allergens.
Explanation: Rag (Recombination activating gene)-deficient mice are genetically engineered to lack the ability to rearrange their T cell receptor (TCR) and B cell receptor (BCR) genes. This means they cannot develop mature T and B lymphocytes, effectively lacking functional adaptive immunity.
Implication: If these mice, despite the absence of T and B cells, still develop airway eosinophilia in response to an allergen (like Alo- allergens, likely referring to Alternaria alternata or similar), it demonstrates that eosinophilic inflammation can be triggered and sustained through mechanisms that do not require T cells or allergen-specific adaptive immune responses.
Therefore: Innate immune cells or other non-classical adaptive immune cells (that might develop through Rag-independent mechanisms, although limited) must be capable of producing signals (like cytokines) that promote eosinophil recruitment and activation in the absence of a fully functional adaptive immune system.
3. Non-adaptive immune mechanisms: Suggest that innate immune responses can independently generate a Th2-like cytokine environment and eosinophilic inflammation.
Explanation: This point directly states that the innate immune system itself can produce cytokines that are typically associated with Th2 responses (like IL-5 and potentially others).
Implication: Certain innate immune cells (e.g., innate lymphoid cells type 2 - ILC2s, macrophages, epithelial cells) can be activated by various stimuli (e.g., alarmins released by damaged epithelium, fungal components, helminth products) to release IL-5 and other pro-eosinophilic cytokines. This can lead to eosinophil recruitment and activation even in the absence of a prior adaptive immune sensitization to a specific allergen.
Therefore: Eosinophilia in some contexts can be driven by the innate immune system responding to non-allergen triggers, creating a local cytokine environment that favors eosinophil development and activation, independent of classical Th2 cells and allergen-specific T cell responses.
47
Why do IL-4 and IL-5 receptor blockers improve outcomes in non-atopic asthma?
- These cytokines drive eosinophil recruitment and activation, contributing to airway inflammation and remodelling.
- Blocking these pathways can reduce inflammation and improve lung function, even in patients without traditional allergic asthma mechanisms.
48
What are Innate Lymphoid Cells (ILCs)?
ILCs, or innate lymphoid cells, are non-T, non-B effector cells that originate from a common lymphoid progenitor. They lack a T cell receptor (TCR), which means they cannot perform antigen-specific immune responses. ILCs and their corresponding T helper (Th) subsets work together to coordinate the three main types of immune responses. They are believed to play a significant role in producing T helper 2/type 2 cytokines, which contribute to asthma pathogenesis.
49
How are ILCs classified?
ILCs are classified into three functional types based on the immunity they support:
Type 1 Immunity
Type 2 Immunity
Type 3 Immunity
50
What is the role of Type 1 ILCs?
Type 1 innate lymphoid cells (ILC1) and NK cells defend against intracellular pathogens (viruses and bacteria) and tumors by activating macrophages, producing cytokines like interferon-gamma (IFN-γ), and releasing cytotoxic molecules (granzymes and perforin) to eliminate infected or malignant cells.
51
What is the role of Type 2 ILCs?
Type 2 ILCs (ILC2s) and Th2 cells protect against extracellular pathogens, particularly parasites and allergens. They promote alternative macrophage activation and release key cytokines, including IL-4, IL-5, IL-13, IL-9, and amphiregulin (AREG), to enhance immune protection and inflammation.
52
What is the role of Type 3 ILCs?
Type 3 ILCs (ILC3s) and Th17 cells defend against extracellular bacteria and fungi.
They promote phagocytosis, the release of antimicrobial peptides and key cytokines including IL-22, IL-17, GM-CSF and Lymphotoxins `
53
How do Type 2 ILCs contribute to asthma?
ILC2s produce cytokines similar to Th2 cells, contributing to asthma by causing inflammation, eosinophilia, and mucus production.
54
How are ILC2s and Th2 cells similar?
ILC2s are the innate counterparts of Th2 cells. Both produce similar cytokines involved in type 2 immune responses.
55
What factors are needed for ILC2 differentiation?
ILC2 differentiation requires the transcription factor GATA3, as well as raw alpha and notch signaling.
56
Where were ILC2s first described?
ILC2s were first described in the gut of mice infected with parasitic helminths, where they help expel the worms through tissue eosinophilia and mucus production
57
What triggers the development of ILC2s?
ILC2s develop from common lymphoid precursors in response to IL-7 and IL-33 (and IL-25)
58
How do ILC2s resemble T helper 2 cells?
ILC2s resemble Th2 cells in that they produce type 2 cytokines, such as IL-5 (promotes the release of eosinophils from bone marrow) and IL-13 (drives broncial hyperactivity and goblet cell metaplasia and hyperplasia) , despite lacking a T cell receptor. The precise signal recruits ILC2 to the lung is unknown but some overlap with Th2 cells suggested that they use CCR4 and CCR8
59
What role do epithelial-derived cytokines play in asthma?
In asthma, epithelial-derived cytokines (IL-33, IL-25, and TSLP) are produced in response to injury. These cytokines activate and expand ILC2s, especially in non-allergic asthma, triggering type 2 cytokine production
60
How are ILC2s involved in non-allergic asthma?
In non-allergic asthma, epithelial-derived cytokines directly activate ILC2s, causing them to produce IL-5, which drives the release of eosinophils from the bone marrow, contributing to inflammation.
61
How does the immune response in non-allergic asthma differ from allergic asthma?
In non-allergic asthma, ILC2s quickly produce cytokines like IL-5 without antigen-specific recognition. In allergic asthma, allergens drive epithelial damage, leading to cytokine production that conditions dendritic cells and activates Th2 cells.
62
What cytokines do ILC2s produce and how do they contribute to asthma?
ILC2s produce IL-5 (which induces eosinophil release) and IL-13 (which causes bronchial hyperreactivity and goblet cell metaplasia). These cytokines drive key features of asthma, such as inflammation and airway hyperresponsiveness.
63
How do ILC2s contribute to airway eosinophilia in asthma?
ILC2s are thought to drive airway eosinophilia in both allergic and non-allergic asthma by producing IL-5, which recruits eosinophils to the airways.
64
How are ILC2s recruited to the lungs in asthma?
While the exact mechanism of recruitment is not fully understood, it is suggested that the use of CCR4 and CCR8 may be important for the migration of ILC2s to the lungs.
65
Can ILC2s be involved in both allergic and non-allergic asthma?
Yes, ILC2s can be involved in both allergic and non-allergic asthma. In allergic asthma, they can act as an early source of type 2 cytokines, while in non-allergic asthma, they contribute to the rapid inflammatory response.
66
How do ILC2s influence asthma without T cell involvement?
ILC2s can drive asthma features, such as airway eosinophilia and bronchial hyperreactivity, by producing type 2 cytokines (like IL-5 and IL-13) without the need for T cell involvement.
67
What is difficult to determine in asthma research?
It’s difficult to determine the relative contribution of Th2 cells versus ILC2s in asthma due to complex interactions and overlapping roles.
68
What role do ILC2s play in allergic asthma?
ILC2s provide early sources of type 2 cytokines, like IL-13, which aid in T helper cell polarization during the allergic asthma response.
69
How might ILC2s act as antigen-presenting cells?
ILC2s express low levels of MHC II and costimulatory molecules, suggesting they might activate CD4 T cells during both sensitization and the effector phase of asthma.
70
What challenges do scientists face when studying ILC2s?
Studies often use rag-deficient models, which lack mature T and B cells. However, these models still have normal levels of ILC2s, enabling researchers to study these cells specifically. The drawback is that because major components of the immune system have been knocked out, it can be difficult to understand which compensatory mechanisms may be at work, potentially skewing the results.
71
What percentage of cytokine-producing cells in asthma are ILC2s (rag sufficient mice)?
In rag-sufficient mice challenged with allergens like OVA or house dust mite, about 50% of cells producing Th2 cytokines are ILC2s (shouldn't underestimate the importance of these innate like cells in driving pathology)
72
What is the suggested role of ILC2s in airway wall remodelling?
ILC2s and their cytokines might play a key role in airway remodelling in chronic asthma, as depleting CD4 T cells reduces airway eosinophilia but not remodelling.
73
What is unique about some patients with severe non-allergic asthma?
Some patients with severe non-allergic asthma show a high T helper 2 high signature but lack classic allergic responses (like IgE), and often don’t respond to steroids.
74
Why are some patients with non-allergic asthma refractory to steroids?
ILC2 production of IL-5 and IL-13 is not as easily suppressed by steroids as Th2 cell production of these cytokines would be, making steroid treatment less effective and suggesting the role of ILC2 in chronic asthma
75
How does chronic epithelial activation contribute to asthma in certain patients?
Chronic epithelial activation (due to irritants/pollutants) can lead to IL-33, TSLP, and IL-25 production, driving ILC2 responses and contributing to asthma pathogenesis.
76
What other subset of cells is important in asthma, especially in some patients?
some asthma patient show, Th17 cells and neutrophil-dominated inflammation and disease, indicating a different immune profile than the typical Th2 response.
77
What is typical of severe, late-onset asthma?
Severe, late-onset asthma often presents with neutrophil-dominated inflammation, a mixed Th1 and Th17 cytokine signature, but no Th2 response.
78
How is cytokine production by Th17 cells in asthma different from Th2 cells?
Like ILC2s, cytokine production by Th17 cells is resistant to steroid inhibition, and make many ctokines that drive neutrophilic inflammation of the airways in asthma.
79
What are the potential sources of IL-17 in severe asthma?
In some peoople IL-17 dominated disease in severe asthma may come from Th17 cells whilst in others it can come from gamma delta T cells, invariant natural killer T cells, or ILC3s.
80
What is the challenge in understanding Th17 cytokine roles in asthma?
Th17 cytokines can be protective in some models but exacerbate asthma in others. IL-17 can contribute to tissue remodelling, bronchial smooth muscle contraction in both mice and humans as and exacerbate asthma in children in response to exposure to pollutants like diesel exhaust particles ( concomitant with increased IL-17A in the serum). But on the other hand it has been found to sometimes have protective effects in mice and IL-17A or IL-22 can h bave a protective role upon experimental allergen challenge in both mice and humans.
81
How does IL-17 affect airway smooth muscle?
IL-17 can induce bronchial smooth muscle contraction, worsening airway narrowing, a harmful feature of asthma.
82
What is the role of interferon-gamma (IFN-γ) in asthma?
IFN-γ secreting CD4 + T cell levels are elevated in asthmatic patients (and rise further during asthma attacks) , and it can synergize with IL-13 to drive airway smooth muscle contraction and innate cell activation. It also promotes homing of Th2 cells to the lungs.
83
What happens when Th1 and Th2 cells are co-transferred in asthma models (as shown in some studies) ?
Co-transfer of Th1 and Th2 cells in asthma models leads to more severe asthma compared to if they were treated with Th2 cells alone, suggesting a complex interaction between these subsets. (makes you think what would happen if someone tried to block IFN-Y which hasn't been tried experimentally yet)
84
What are T helper 9 cells (Th9)?
Th9 cells are a subset of CD4 T cells that secrete high levels of IL-9, particularly in the lungs. IL-9 was once thought to be a Th2 cytokine but is now recognized as part of a unique IL-9 secreting CD4+ T cell population.
85
How does IL-9 contribute to asthma pathogenesis?
IL-9 exacerbates asthma by acting on cells of the immune system, and cells that don't belong to the immune system as well e.g. by promoting mast cell growth, enhancing IL-4-dependent antibody production by B cells, boosting Th2 responses, increases the survival of ILC2, and influencing various innate immune cell subsets.
86
What does the Tj9 number in the draining lymph nodes/ airways correlate with
asthmatic disease
87
How does IL-9 neutralisation affect asthma?
Neutralising IL-9 reduces asthma symptoms and airway remodelling in chronic asthma models, suggesting its role in the disease.
88
Can ILC2s produce IL-9?
Yes, ILC2s can also produce IL-9, though the relative contribution of ILC2s and Th9 cells to asthma pathogenesis is not well understood.
89
What role do regulatory T cells (Tregs) play in asthma?
Tregs, particularly those expressing the FoxP3 transcription factor, help maintain peripheral tolerance and prevent excessive inflammatory responses to harmless antigens. They are thought to play a role in dampening immune responses in asthma.
90
What is the role of Foxp3 in the immune system?
Foxp3 is a transcription factor essential for the development and function of regulatory T cells (Tregs), which suppress excessive immune responses and maintain immune tolerance.
91
What does the CNS-1 region of the Foxp3 gene regulate?
CNS-1 (conserved non-coding sequence 1) is required for TGF-β-mediated differentiation of peripheral regulatory T cells (Tregs).
92
How do CNS1-deficient mice relate to asthma research?
CNS1-deficient mice develop strong Th2 responses at mucosal sites due to the inability to induce peripheral Treg differentiation (TGF-B), linking Treg function to immune regulation in asthma.
93
Why is TGF-β important for Treg development?
TGF-β drives the differentiation of naïve T cells into peripheral Tregs, which are crucial for maintaining immune balance and suppressing inflammation.
94
What are the consequences of strong Th2 responses in mucosal tissues?
Increased Th2 cytokines (IL-4, IL-5, IL-13) lead to eosinophilic inflammation, mucus production, and airway hyperresponsiveness. This promotes key asthma features such as airway inflammation, mucus hypersecretion, and bronchial hyperreactivity.
95
What is the evidence for Treg involvement in asthma?
In asthma, FoxP3+ Tregs can be induced in response to inhaled allergens in the OVA mouse models, where they help dampen the immune response. Reduced Treg numbers have been observed in the sputum and blood of severe asthmatics, although lung numbers remain controversial ( with some groups saying they go up and others saying it goes down)
96
How might Treg function be compromised in asthmatic patients?
Tregs in asthmatic patients might have impaired function, making them less effective at suppressing effector cells. Some studies suggest that Tregs may regulate Th1 and Th17 responses but not Th2 responses, contributing to immune dysregulation.
97
What is the role of inhaled corticosteroids in asthma treatment?
Inhaled corticosteroids reduce airway inflammation and suppress Th2 responses. However, they are ineffective during viral exacerbations, less effective in smokers, and not effective in Th17-dominated asthma.
98
How do beta-2 adrenoceptor agonists (e.g. salbutamol) work in asthma treatment?
Beta-2 adrenoceptor agonists are short acting and work as bronchodilators that relax smooth muscle in the airways, helping to relieve chest tightness and improve breathing during active asthma episodes.
99
How do long-acting beta-2 adrenoceptor agonists (e.g. formoterol) help in asthma management?
Long-acting beta-2 adrenoceptor agonists like formoterol are used for asthma patients who do not respond well to steroids. They provide prolonged bronchodilation and help with managing asthma symptoms over an extended period.
100
What is an obvious target for people with allergic asthma
IgE
101
What is the role of omalizumab in allergic asthma treatment?
Omalizumab is a monoclonal anti-IgE antibody that binds to an IgE epitope , preventing it from binding to the FC E RI receptor on mast cells. This stops mast cell downstream effects e.g. degranulation and the inflammatory cascade associated with allergic asthma. It is licensed for moderate to severe allergic asthma and prolonged treatment reduces Th2-type cytokines in the lung tissue.
102
How does omalizumab affect IgE and mast cells?
Omalizumab binds to IgE, decreasing free IgE and preventing it from binding to FC epsilon R1 receptors on mast cells. It also reduces the expression of these receptors on mast cells, limiting inflammatory mediator release and reducing allergic inflammation.
103
How does Dapilumab work in treating type 2 asthma?
Dapilumab is an anti-human IL-4 receptor alpha antibody that blocks both IL-4 and IL-13 receptors. By doing so, it interrupts downstream signalling of type 2 cytokines. It has been shown to improve lung function and reduce exacerbation frequency in patients with type 2 high asthma who have got high blood eosinophil levels
104
What is the sturtcure of the IL-4R
The IL-4 receptor can form two different complexes:
Type I IL-4R: Composed of IL-4Rα and γc subunits; activated exclusively by IL-4.
Type II IL-4R: Composed of IL-4Rα and IL-13Rα1 subunits; activated by both IL-4 and IL-13.
105
How can eosinophils be targeted in asthma treatment?
Eosinophils can be targeted by blocking IL-5, which is responsible for the release of eosinophils from the bone marrow. This reduces eosinophilic inflammation, particularly in patients with high blood eosinophil levels.
106
What is the role of mepolizumab in severe eosinophilic asthma treatment?
Mepolizumab is a humanised monoclonal antibody targeting IL-5
. It reduces asthma exacerbations, the deposition of extracellular matrix components, and helps reduce the need for systemic steroid use. It is licensed for severe eosinophilic asthma.
107
How does targeting the IL-5 receptor with monoclonal antibodies help in asthma treatment?
Targeting the IL-5 receptor with monoclonal antibodies, like mepolizumab, depletes eosinophils through antibody-dependent cellular cytotoxicity. This effect lasts for months after a single injection, helping control eosinophilic asthma.
108
What were the outcomes of clinical trials for the IL-13 targeting antibody (lebrikizumab)?
In a phase three trial, lebrikizumab (anti-IL-13) showed significant reductions in asthma exacerbations and improvements in lung function for patients with high eosinophil or periostin levels. However, another identical trial failed to meet its endpoints, leading to the sale of development rights for the drug, with it now being tested for atopic dermatitis rather than asthma.
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How does Brodalumab, an anti-IL-17 receptor antibody, function in asthma treatment?
Brodalumab blocks IL-17RA, affecting IL-17A, IL-17F, and IL-25. While it showed poor results in a Phase II trial for asthma, it may be effective in patients with high neutrophil and TH17 levels, suggesting that targeting this subset could improve treatment outcomes.
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Why was targeting IL-33 abandoned in asthma therapy?
Efforts to block IL-33 in asthma showed no significant benefits, leading to its abandonment as a therapeutic target.
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What is Tezepeumab, and how does it help in asthma treatment?
Tezepeumab is a human anti-TSLP (thymic stromal lymphopoietin) antibody. It blocks late asthmatic responses, reduces bronchoconstriction, and lowers eosinophil counts. TSLP, produced by epithelial cells, plays a role in promoting Th2 responses and contributing to airway remodelling.
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Why is asthma considered a spectrum of conditions?
Asthma is a spectrum of conditions with significant overlap in the cells and cytokines involved in different asthma endotypes. This complexity makes it unlikely that a single drug will ever target all asthma types, necessitating more targeted treatments.
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What is meant by "regiotype" in asthma therapy?
"Regiotype" refers to the concept that regional differences in asthma endotypes may exist due to local environmental exposures such as allergens, pollutants, or other factors. This idea encourages the development of a highly personalised medicine approach for precision treatment.
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What factors need to be considered for precision treating asthma?
Precision asthma treatment requires understanding the underlying immunology, recognizing the dynamic nature of asthma pathogenesis (e.g., varying roles of ILC2 and TH2 cells over time), and developing better biomarkers to identify and target specific asthma endotypes more effectively.
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How do therapies aim to address asthma's immune pathology?
Therapies aim to address specific aspects of immune pathology by targeting immune cells, epithelial cells, and cytokines involved in tissue remodelling and inflammation. These treatments are designed to target particular asthma endotypes and reduce airway inflammation and hyperresponsiveness.
