Brainscape's Knowledge GenomeTM


Top Flashcards (Certified)
All Flashcards

Immunopathology and applied immunology > 7. Pathogenesis of asthma 2 > Flashcards

7. Pathogenesis of asthma 2 Flashcards

1
Q

What is the result of long term exposure to allergens?

A
  1. Cycles of inflammation
  2. Chronic asthma
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What is the chronic response in asthma?

A
  1. Repeated inflammatory episodes driven by allergens lead to serious long term damage.
  2. This is a chronic wound.
  3. There is evidence of attempts at wound healing and tissue repair.
  4. This healing occurs to varying degrees of success.
  5. In the late phase of the acute response causes degranulation of eosinophils and recruitment of Th2 cells.
  6. In the chronic response these processes continue to cause epithelial damage over a long period of time.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What histological changes occur in the airway in chronic asthma?

A
  1. Hyperplasia of epithelium.
  2. Hypersecretion of mucus due to goblet cell metaplasia and hyperplasia.
  3. Thickening of the basement membrane mediated by myofibroblasts.
  4. Increased smooth muscle volume.
  5. Increased angiogenesis and lymphangiogenesis.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What are myofibroblasts?

A

A kind of mix between a fibroblast and a smooth muscle cell.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Why does the asthmatic lung have increased angiogenesis?

A

It makes it easier for immune cells to move from the blood into the lungs.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Why does the asthmatic lung have increased lymphangiogenesis?

A
  1. It allows dendritic cells to move more easily between the lungs and the lymph nodes.
  2. Allows more efficient antigen presentation of allergens/antigens in the lymph nodes.
  3. This activates Th2 cells and continues the inflammatory process/
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

When is an asthmatic’s lung function compromised?

A
  1. It can be compromised all the time even if there is not an asthma attack stimulus.
  2. Asthmatics are predisposed to exaggerated responses to any kind of airway challenge. eg infection or activity.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What is the role of type 2 cytokines in the pathogenesis of asthma?

A
  1. They are very important in allergic asthma and act on other cells to drive asthma.
  2. They act on the epithelium to cause epithelial cell damage, goblet cell hyperplasia and airway remodelling.
  3. Type 2 cytokines act on the epithelial-mesenchymal tropic unit to cause the deposition of collagen in the lung and communicate with the fibroblasts under the epithelium to drive mesenchymal cell proliferation and tissue remodelling in the lung. This is augmented by IL-4/IL-13.
  4. They act on smooth muscle cells to cause contraction.
  5. They also upregulate adhesion molecules in the endothelium to help immune cell migration.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What is the cycle of inflammation in chronic asthma?

A
  1. The environmental agent (allergen) is detected by the APC.
  2. Dendritic cell drives Th2 and IgE responses.
  3. This causes damage to the epithelium alongside environmental factors.
  4. The body tries to initiate repair so lots of growth factors are released.
  5. This activates structural and immune cells like myofibroblasts to make collagen, increase smooth muscle mass and secrete ECM components.
  6. Smooth muscle cells and myofibroblasts make cytokines and chemokines that drive inflammation by recruiting cells.
  7. Epithelial cells can make IL-5 and IL-13 that cause more tissue damage and need more tissue repair.
  8. This results in more inflammation and immune cell recruitment, and the cycle repeats.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What growth factors are released in chronic asthma?

A
  1. Epidermal growth factor.
  2. Fibroblast growth factor.
  3. Platelet derived growth factor.
  4. Transforming growth factor ß
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What does asthma increase susceptibility to?

A
  1. Common respiratory viral infections.
  2. influenza
  3. Human rhinovirus
  4. Respiratory syncytial virus.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Why do asthmatics have increased susceptibility to respiratory infections?

A
  1. Allergic sensitisation and Th-2 driven eosinophilic inflammation could suppress anti-viral immunity.
  2. Epithelial cells from asthmatic patients produce less type 1 and 2 Interferons in response to human rhinovirus.
  3. Normal anti-viral functions of Dendritic cells are hampered by IgE resulting in less type1 IFN production.
  4. Th2 and Th17 cells drive eosinophilic/neutrophilic inflammation.
  5. This contributes to the cycle of inflammation and chronic wounding in the lung.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Why are asthmatics more susceptible to human rhinovirus?

A
  1. Epithelium in the inflamed lungs has increased ICAM-1 expression.
  2. Human rhinovirus binds to ICAM-1 to enter and infect the cells.
  3. So asthmatics are more susceptible to human rhinovirus infections.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What is the spectrum of asthma conditions?

A
  1. It is not just allergic and non-allergic.
  2. There is a much broader range of conditions with different clinical presentations and immunopathologies.
  3. Both allergic and non-allergic asthma have overlapping mechanisms.
  4. The only distinction between the 2 is the presence of IgE.
  5. There are many different asthma phenotypes and endotypes.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What is an asthma endotype?

A
  1. The different phenotypes of asthma.
  2. They vary by clinical manifestation, immunopathology, susceptibility and genetics.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What percentage of asthmatics have type2 immunity in their airways?

A

around 50%

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Can type 2 cytokines be generated without the involvement of Th2 cells?

A
  1. Patients with both allergic and non-allergic asthma can have high eosinophil counts.
  2. If we block IL-4 and IL-5 in these patients, we see improved clinical outcomes.
  3. Rag-deficient mice have no T or B cells but still develop eosinophilia with challenged with an aeroallergen.
  4. This implies you can generate a Type 2 response without adaptive immunity.
  5. This is done by ILC2
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What are innate lymphoid cells (ILCs)?

A
  1. These are lymphoid cells that are non-T and non-B effector cells.
  2. Have no TCR/BCR so no antigen specificity.
  3. They are derived from the common lymphoid progenitor.
  4. ILC and corresponding Th subsets coordinate the 3 major types of immune response.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What ILCs are involved in type 1 immunity?

A
  1. ILC1s and NK cells.
  2. Involved with tumour and intracellular microbe immunity.
  3. Targets virus, bacteria and parasites through macrophages activation and cytotoxicity.
  4. Mediated by IFNy, granzymes and perforin.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What ILCs are involved in type 2 immunity?

A
  1. ILC2s
  2. Involved with immunity to large extracellular parasites and allergens.
  3. Alternatively activates macrophages.
  4. Mediated by IL-4, IL-5, IL-13 and IL-9.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

What ILCs are involved in type 3 immunity?

A
  1. ILC3s
  2. Involved with immunity to extracellular microbes.
  3. Targets bacteria and fungi through phagocytosis and antimicrobial peptides
  4. Mediated by IL-22, IL-17, GM-CSF and Lymphotoxin.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

What are ILC2s?

A
  1. They are the innate counter part of Th2 cells.
  2. Both Th2 and ILC2 rely on the GATA3 transcription factor but ILC2 also relies on RORa and Notch.
  3. ILC2 were initially described in the gut of mice infected with helminths. They contribute to tissue eosinophilia and mucus production.
  4. They develop from the common lymphoid precursor in response to IL-7 and IL-33.
  5. They resemble Th2 cells in many ways, like producing type 2 cytokines.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

What is the role of ILC2 in non-allergic asthma?

A
  1. ILC2 are activated and expand in response to epithelial derived cytokines produced in response to tissue injury.
  2. Injury can include things like smoking.
  3. Alarmins like IL-33, IL-25 and TSLP triggers ILC2 to produce type 2 cytokines like IL-5 and IL-13.
  4. IL-5 promotes the release of eosinophils from the bone marrow.
  5. IL-13 drives bronchial hyperreactivity and goblet cell metaplasia.
  6. This response is faster then Th2 cells as no antigen specificity is required.
  7. The precise signals recruiting ILC2 to the lung are unknown, but there could be some overlap with Th2, like CCR4/8.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

What is the role of ILC2 in allergic asthma?

A
  1. Allergens can stimulate epithelial cells to produce IL-33.
  2. IL-33 activate ILC2 which produce IL-5 and IL-13 and cause eosinophilia and bronchial hyperreactivity.
  3. ILC2 can be activated very quickly in response to allergen exposure independent of T cells.
  4. This drives the defining features of asthma without Th2 cells.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

What is the relative contribution of Th2 cells vs ILC2 in allergic asthma?

A
  1. It is unclear but ILC2 accumulate in sputum following allergen challenge.
  2. ILC2 provide an early source of IL-13 which aids Th2 polarisation and help dendritic cells stimulate Th2 cells.
  3. ILC2 express low levels of MHC2 and co-stimulatory molecules so they could act as APC to activate CD4+ T cells during sensitisation and effector phases of asthma.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

What do mouse models show about the contribution of ILC2 to allergic asthma?

A

In RAG-sufficient mice OVA or house dust mite-induced asthma models, around 50% of cells producing type 2 cytokines are ILC2.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

What mouse models are used to study ILC2s in allergic asthma?

A
  1. These are done in RAG-deficient mice as they have no T cells (and no B cells).
  2. This means you can see you contribution of other cells.
  3. You also need to consider that you have knocked out a large part of the immune system so some compensatory mechanisms could skew the results.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

Why do we think ILC2s are critical for airway remodelling in asthma?

A
  1. If you knock out CD4+ T cells, you reduce eosinophilia but not airway remodelling.
  2. This suggests something else mostly controls airway remodelling.
  3. This could be ILC2.
29
Q

What is the role of the ILC2 population in asthma?

A
  1. ILC2s may be particularly important in a subgroup of patients.
  2. These are severe non-allergic asthma patients with high eosinophil levels in the blood/lungs.
  3. They also have a Th2 high signature despite lack of allergic response.
  4. These patients often don’t respond to steroid treatment.
  5. ILC2 production of IL-5 and IL-13 is not suppressed by steroids when Th2 production of these would be.
  6. It is thought these patients have chronic epithelial activation (IL-33/15 and TSLP) in response to pollutants that drive ILC2 responses.
30
Q

What is the role of the Th17 response in allergic asthma?

A
  1. Some patients show neutrophil-dominated disease and eosinophils aren’t involved.
  2. It is usually a late onset severe type of asthma.
  3. Mixed Th1 and Th17 cytokine signature and no Th2.
  4. Th17 type cytokine production is resistant to steroid treatment.
  5. Th17 type cytokines drive neutrophilic infiltration of the airways.
  6. We don’t understand where the IL-17 is coming from in this type of asthma.
  7. For different patients with Th17 type asthma different cells can be producing IL-17.
31
Q

What cells can be producing IL-17 in Th17 type allergic asthma?

A
  1. Th17 cells
  2. Gamma-delta T cells.
  3. Invariant natural killer T cells (iNKT cells).
  4. ILC3.
32
Q

How do Th17-type cytokines contribute to the pathogenesis of asthma?

A
  1. In mice IL-17 can be protective for asthma and sometimes it can exacerbate asthma.
  2. IL-17A or IL-22 can have a protective role upon experimental allergen challenge in mice and humans.
  3. Asthma exacerbation in children after exposure to diesel exhaust particles and they have increased IL-17A in serum.
  4. IL-17A contributes to tissue remodelling in some experimental models.
  5. In mice and humans, IL-17 can induce bronchial smooth muscle contraction.
33
Q

How can Th1 cells contribute to the pathogenesis of asthma?

A
  1. They airways of asthmatics have an increase in IFNy secreting CD4+ T cells (Th1)
  2. IFNy levels rise in serum during severe asthma attacks.
  3. IFNy acts with IL-13 to cause smooth muscle contraction and innate cell activation.
  4. IFNy promoted homing of Th2 cells to the lungs.
34
Q

How do mouse models show the contribution of Th1 cells in asthma?

A
  1. If you co-transfer Th1 and Th2 cells into the OVA asthma model, the asthma is worse then if you transfer Th2 cells only.
  2. This shows Th1 cells contribute to asthma but we don’t really know how.
35
Q

What are Th9 cells?

A
  1. A CD4+ T cell subset.
  2. They express high levels of IL-9.
  3. IL-9 used to be considered a type 2 cytokine, but IL-9 secreting CD4 T cells were separated into their own separate population.
36
Q

How can Th9 cells contribute to asthma?

A
  1. Th9 numbers in draining lymph nodes and airways correlate with asthmatic disease.
  2. IL-9 can act on immune and non-immune cells to exacerbate asthma.
  3. IL-9 can act as a mast cell growth factor; it can promote the IL-4 dependent generation of IgE, boost Th2 responses and increase the survival of ILC2.
  4. ILC2 can also make IL-9.
37
Q

What does targeting IL-9 in animal models show?

A
  1. If you neutralise IL-9, it reduces symptoms in the OVA-model.
  2. This reduces airway remodelling in chronic asthma models.
38
Q

What are Tregs?

A
  1. They are regulatory cells that play an important role in maintaining peripheral tolerance.
  2. They stop excessive immune responses to harmless antigens.
  3. CD4+ Tregs expressing Foxp3 may be important in asthma.
39
Q

What type of Tregs can have an effect on asthma?

A
  1. Foxp3 CNS-1 deficient mice can develop strong Th2 response at mucosal surfaces.
  2. This is due to a lack of pTreg differentiation.
40
Q

What evidence is there for Treg numbers affecting asthma?

A
  1. Reduced Treg numbers in sputum and blood of severe asthmatics.
  2. Treg cell numbers in the lungs of adults are controversial. Some say they go down and some say they go up.
  3. Tregs are detected in the airway fluids of paediatric asthmatics. They are trying to dampen the immune response by they are not working.
41
Q

What evidence is there for Treg function affecting asthma?

A
  1. The suppressive capacity of Tregs in severe asthmatics is impaired.
  2. Tregs in asthmatics may be able to regulate Th1 and Th17 responses but not Th2 type responses.
42
Q

What has our understanding of the immunopathology of asthma allowed us to do?

A

Develop effective treatments.

43
Q

What are the front-line treatments for asthma?

A
  1. Inhaled corticosteroids
  2. Inhaled ß2-adrenoceptor agonists
44
Q

How do inhaled corticosteroids treat asthma?

A
  1. They suppress Th2 responses including cytokines, chemokines and adhesion molecules.
  2. They are not effective during viral-induced exacerbation, smokers or for Th17 dominated asthma endotypes.
45
Q

How do inhaled ß2-adrenoceptors treat asthma?

A
  1. Short acting forms like salbutamol are used for active disease management.
  2. Long acting forms like formoterol are used to treat asthma endotypes not controlled well by corticosteroids. These last for 12 hours.
  3. They are bronchodilators and induce smooth-muscle relaxation.
  4. They can improve responsiveness to to corticosteroids as a combination treatment.
46
Q

How can IgE be a therapeutic target in allergic asthma?

A
  1. It is an obvious treatment.
  2. Omalizumab is a humanised anti-IgE monoclonal antibody used to treat moderate to severe asthma.
  3. It stops the IgE binding to the FcE receptor on mast cells to prevent crosslinking and degranulation.
  4. Prolonged treatment causes a reduction of Th2 cytokines in the lung tissue.
47
Q

What is Omalizumab?

A

a humanised anti-IgE monoclonal antibody used to treat moderate to severe asthma

48
Q

How does Omalizumab work?

A
  1. It binds to free IgE at an epitope that normally binds to the FcE receptor on mast cells so it prevents IgE binding to mast cells.
  2. It decreases expression of the high affinity receptor (FcER1) on mast cells.
  3. It decreases mediator release due to less degranulation.
  4. It decreases allergic inflammation and prevents exacerbation of asthma.
49
Q

How can type 2 cytokines be targeted to treat asthma?

A
  1. The IL-4Ra associates with the y chain to makes the IL-4 receptor.
  2. The IL-4Ra associates with IL-13Ra1 to make the IL-13 receptor.
  3. This means both IL-4 and IL-13 can be targeted with the same treatment.
  4. This is dupilumab.
50
Q

What is Dupilumab?

A
  1. A human anti-IL-4Ra antibody.
  2. It blocks the downstream signalling from the IL-4 and IL-13 receptors.
  3. It improves lung function in Th2 high asthma.
  4. It reduces frequency of exacerbation in patients with moderate/severe asthma with high blood eosinophil levels.
  5. Licensed to treat severe asthma with type 2 inflammation.
51
Q

How can IL-5 be blocked to treat asthma?

A
  1. Mepolizumab is a humanised monoclonal anti-IL-5 antibody.
  2. Used to treat severe eosinophilic asthma.
52
Q

What type of asthma can inhibitors of IL-5 treat?

A

Severe eosinophilic asthma

53
Q

What is mepolizumab?

A
  1. a humanised monoclonal anti-IL-5 antibody.
  2. Used to treat severe eosinophilic asthma.
  3. It reduces eosinophil numbers in the blood and frequency of exacerbation.
  4. It also reduces deposition of ECM components.
  5. It reduces the use of systemic steroid.
54
Q

What is Benralizumab?

A
  1. An anti-IL5R antibody.
  2. It depletes eosinophils for months after a single injection.
  3. Causes Antibody-dependent cellular cytotoxicity of eosinophils.
  4. Licenced for severe eosinophilic asthma.
55
Q

What does IL-5 do?

A

Drives release of eosinophils from the bone marrow.

56
Q

What is the role of IL-13 in asthma?

A
  1. It is involved in several aspects of asthma.
  2. Inflammation
  3. Promoting bronchial hyper-responsiveness.
  4. Increases mucous secretion and airway remodelling.
57
Q

How can IL-13 be targeted to treat asthma?

A
  1. By using Lebrikizumab.
  2. A humanised anti-IL-13 antibody.
  3. Didn’t work well and was abandoned
58
Q

What is Lebrikizumab?

A
  1. A humanised anti-IL-13 antibody.
  2. Was in 2 identical phase 3 trials for severe asthma in 2016.
  3. One successful trial showed reduction of asthma exacerbation and improvement in lung function.
  4. The other trial failed at every single point.
  5. Roche sold it off and is now being tested for dermatitis.
59
Q

How can IL-17 be targeted to treat asthma?

A

by using brodalumab

60
Q

What is Brodalumab?

A
  1. A human monoclonal anti-IL-17A antibody.
  2. It blocks the activity of IL-17A, IL-17F and IL-25.
  3. Didn’t control mild/moderate asthma in phase 2 trials.
  4. More targeted patient selection could respond more favourably - patients with high eosinophils and high Th17.
61
Q

What epithelial-derived cytokines can be targeted to treat asthma?

A
  1. Epithelial cells produce cytokines that promote Th2 responses.
  2. Thymic stromal lymphopoietin (TSLP) can be targeted to treat asthma.
  3. TSLP contributes to airway remodelling and activates ILC2.
62
Q

How can TSLP be targeted to treat asthma?

A

by using Tezepelumab

63
Q

What is Tezepelumab?

A
  1. A human anti-TSLP antibody.
  2. It blocks the late asthmatic response and bronchoconstriction.
  3. It reduces the eosinophil count.
64
Q

What needs to be remembered about all the different types of asthma?

A
  1. Asthma is a complex condition.
  2. There may be significant overlap in cells/cytokine profiles involved in asthma endotypes.
  3. No single drug is likely to ever be effective for all asthma.
  4. Understanding the underlying immunology leads to targeted therapy
65
Q

What did the 2019 Agache paper suggest relating to asthma treatment?

A
  1. Asthma should be treated in a highly personalised way.
  2. Asthma can exhibit regional endotypes due to the local environment and the pollutants and toxins in it.
  3. Asthma pathogenesis can be dynamic over time and a patient can switch between subtypes over time and treatment needs to change accordingly.
  4. We need to develop better biomarkers to identify asthma types and target them precisely.
66
Q

What is allergen immunotherapy?

A
  1. Administration of the allergen to the patient to help control allergic inflammation and symptoms.
  2. Sometimes also called desensitisation.
  3. It needs to occur over long periods of time to be effective.
  4. Used to treat Allergic rhinitis or asthma
67
Q

How does allergen immunotherapy work?

A
  1. It targets the respiratory tract and aids symptoms by modulating the IgE response to allergens.
  2. It regulates T and B cells, changes antibody isotypes, decreases mediator release and migration of inflammatory cells.
  3. A key mechanism of inducing tolerance is the upregulation of allergen specific Tregs and Bregs to down regulate to Th2 response and shift it to the Th1 response.
68
Q

What is the aim of allergen immunotherapy?

A

To reduce allergic mucosal inflammation by inducing immune tolerance therefor alleviating symptoms and improving quality of life.

Immunopathology and applied immunology (16 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2025 Bold Learning Solutions. Terms and Conditions