7. Pathogenesis of asthma 2 Flashcards
What is the result of long term exposure to allergens?
- Cycles of inflammation
- Chronic asthma
What is the chronic response in asthma?
- Repeated inflammatory episodes driven by allergens lead to serious long term damage.
- This is a chronic wound.
- There is evidence of attempts at wound healing and tissue repair.
- This healing occurs to varying degrees of success.
- In the late phase of the acute response causes degranulation of eosinophils and recruitment of Th2 cells.
- In the chronic response these processes continue to cause epithelial damage over a long period of time.
What histological changes occur in the airway in chronic asthma?
- Hyperplasia of epithelium.
- Hypersecretion of mucus due to goblet cell metaplasia and hyperplasia.
- Thickening of the basement membrane mediated by myofibroblasts.
- Increased smooth muscle volume.
- Increased angiogenesis and lymphangiogenesis.
What are myofibroblasts?
A kind of mix between a fibroblast and a smooth muscle cell.
Why does the asthmatic lung have increased angiogenesis?
It makes it easier for immune cells to move from the blood into the lungs.
Why does the asthmatic lung have increased lymphangiogenesis?
- It allows dendritic cells to move more easily between the lungs and the lymph nodes.
- Allows more efficient antigen presentation of allergens/antigens in the lymph nodes.
- This activates Th2 cells and continues the inflammatory process/
When is an asthmatic’s lung function compromised?
- It can be compromised all the time even if there is not an asthma attack stimulus.
- Asthmatics are predisposed to exaggerated responses to any kind of airway challenge. eg infection or activity.
What is the role of type 2 cytokines in the pathogenesis of asthma?
- They are very important in allergic asthma and act on other cells to drive asthma.
- They act on the epithelium to cause epithelial cell damage, goblet cell hyperplasia and airway remodelling.
- 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.
- They act on smooth muscle cells to cause contraction.
- They also upregulate adhesion molecules in the endothelium to help immune cell migration.
What is the cycle of inflammation in chronic asthma?
- The environmental agent (allergen) is detected by the APC.
- Dendritic cell drives Th2 and IgE responses.
- This causes damage to the epithelium alongside environmental factors.
- The body tries to initiate repair so lots of growth factors are released.
- This activates structural and immune cells like myofibroblasts to make collagen, increase smooth muscle mass and secrete ECM components.
- Smooth muscle cells and myofibroblasts make cytokines and chemokines that drive inflammation by recruiting cells.
- Epithelial cells can make IL-5 and IL-13 that cause more tissue damage and need more tissue repair.
- This results in more inflammation and immune cell recruitment, and the cycle repeats.
What growth factors are released in chronic asthma?
- Epidermal growth factor.
- Fibroblast growth factor.
- Platelet derived growth factor.
- Transforming growth factor ß
What does asthma increase susceptibility to?
- Common respiratory viral infections.
- influenza
- Human rhinovirus
- Respiratory syncytial virus.
Why do asthmatics have increased susceptibility to respiratory infections?
- Allergic sensitisation and Th-2 driven eosinophilic inflammation could suppress anti-viral immunity.
- Epithelial cells from asthmatic patients produce less type 1 and 2 Interferons in response to human rhinovirus.
- Normal anti-viral functions of Dendritic cells are hampered by IgE resulting in less type1 IFN production.
- Th2 and Th17 cells drive eosinophilic/neutrophilic inflammation.
- This contributes to the cycle of inflammation and chronic wounding in the lung.
Why are asthmatics more susceptible to human rhinovirus?
- Epithelium in the inflamed lungs has increased ICAM-1 expression.
- Human rhinovirus binds to ICAM-1 to enter and infect the cells.
- So asthmatics are more susceptible to human rhinovirus infections.
What is the spectrum of asthma conditions?
- It is not just allergic and non-allergic.
- There is a much broader range of conditions with different clinical presentations and immunopathologies.
- Both allergic and non-allergic asthma have overlapping mechanisms.
- The only distinction between the 2 is the presence of IgE.
- There are many different asthma phenotypes and endotypes.
What is an asthma endotype?
- The different phenotypes of asthma.
- They vary by clinical manifestation, immunopathology, susceptibility and genetics.
What percentage of asthmatics have type2 immunity in their airways?
around 50%
Can type 2 cytokines be generated without the involvement of Th2 cells?
- Patients with both allergic and non-allergic asthma can have high eosinophil counts.
- If we block IL-4 and IL-5 in these patients, we see improved clinical outcomes.
- Rag-deficient mice have no T or B cells but still develop eosinophilia with challenged with an aeroallergen.
- This implies you can generate a Type 2 response without adaptive immunity.
- This is done by ILC2
What are innate lymphoid cells (ILCs)?
- These are lymphoid cells that are non-T and non-B effector cells.
- Have no TCR/BCR so no antigen specificity.
- They are derived from the common lymphoid progenitor.
- ILC and corresponding Th subsets coordinate the 3 major types of immune response.
What ILCs are involved in type 1 immunity?
- ILC1s and NK cells.
- Involved with tumour and intracellular microbe immunity.
- Targets virus, bacteria and parasites through macrophages activation and cytotoxicity.
- Mediated by IFNy, granzymes and perforin.
What ILCs are involved in type 2 immunity?
- ILC2s
- Involved with immunity to large extracellular parasites and allergens.
- Alternatively activates macrophages.
- Mediated by IL-4, IL-5, IL-13 and IL-9.
What ILCs are involved in type 3 immunity?
- ILC3s
- Involved with immunity to extracellular microbes.
- Targets bacteria and fungi through phagocytosis and antimicrobial peptides
- Mediated by IL-22, IL-17, GM-CSF and Lymphotoxin.
What are ILC2s?
- They are the innate counter part of Th2 cells.
- Both Th2 and ILC2 rely on the GATA3 transcription factor but ILC2 also relies on RORa and Notch.
- ILC2 were initially described in the gut of mice infected with helminths. They contribute to tissue eosinophilia and mucus production.
- They develop from the common lymphoid precursor in response to IL-7 and IL-33.
- They resemble Th2 cells in many ways, like producing type 2 cytokines.
What is the role of ILC2 in non-allergic asthma?
- ILC2 are activated and expand in response to epithelial derived cytokines produced in response to tissue injury.
- Injury can include things like smoking.
- Alarmins like IL-33, IL-25 and TSLP triggers ILC2 to produce type 2 cytokines like IL-5 and IL-13.
- IL-5 promotes the release of eosinophils from the bone marrow.
- IL-13 drives bronchial hyperreactivity and goblet cell metaplasia.
- This response is faster then Th2 cells as no antigen specificity is required.
- The precise signals recruiting ILC2 to the lung are unknown, but there could be some overlap with Th2, like CCR4/8.
What is the role of ILC2 in allergic asthma?
- Allergens can stimulate epithelial cells to produce IL-33.
- IL-33 activate ILC2 which produce IL-5 and IL-13 and cause eosinophilia and bronchial hyperreactivity.
- ILC2 can be activated very quickly in response to allergen exposure independent of T cells.
- This drives the defining features of asthma without Th2 cells.