Thesis
The role of interleukin-5 in the aetiology of the late-onset endo-phenotype of eosinophilic asthma
- Abstract:
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Background: The aetiology of late-onset eosinophilic asthma is largely unknown
Objectives: (1) To understand the additional effects of oral corticosteroids (OCS) on top of inhaled corticosteroids in type-2 (T2) high asthma to understand why late-onset eosinophilic (LOE) patients are more OCS dependent. (2) To assess IL-5 and solubilised IL-5-receptor-α (sIL-5Rα) in the blood and airway of eosinophilic asthmatics to understand if the IL-5/IL-5Rα axis may be leveraged to dampen IL-5 basal signalling. (3) To assess the burden of rare, high impact mutations in genes related to IL-5 signalling, and look for clonal haematopoiesis of indeterminate potential (CHIP) in LOE asthma.
Methods: (1) A prospective observational trial was performed comparing adjunctive 30 mg prednisolone daily for 10 days with the effects of initiating 200 mcg beclomethasone twice-daily for 8 weeks in T2-high asthmatics. (2) IL-5 and sIL-5Rα were measured in blood and sputum of 50 eosinophilic asthmatics and 17 healthy controls. Flow sorted 7eosinophils from blood and sputum were examined for expression of mIL-5Rα (n=7). (3) 123 patients with LOE asthma and 30 healthy controls were deep-sequenced for high-impact variants in IL-5 signalling genes, and for CHIP mutations, using bespoke panels.
Results: (1) OCS produced greater inhibition of blood eosinophils while ICS produced greater inhibition of FeNO. OCS had a broader suppressive effect on T2-mediators in sputum and serum. (2) There was no relationship between plasma sIL-5Rα and IL-5. Levels of sIL-5Rα were significantly lower in sputum than plasma for eosinophilic asthmatics (p < 0.05). There was marked loss of eosinophil mIL-5Rα expression in sputum (p < 0.0001). (3) Six missense variants were identified in IL17RA and 2 high-impact mutations (one frameshift, one missense) were identified in THRA in LOE asthma patients: this did not reach Bonferroni significance.
Conclusion: Further work is required to understand the onset and maintenance of high T2-signalling in LOE asthma patients.
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(Preview, Dissemination version, pdf, 11.3MB, Terms of use)
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Authors
Contributors
+ Hinks, T
- Institution:
- University of Oxford
- Division:
- MSD
- Department:
- NDM
- Sub department:
- NDM Experimental Medicine
- Role:
- Supervisor
+ Pavord, I
- Institution:
- University of Oxford
- Division:
- MSD
- Department:
- NDM
- Sub department:
- NDM Strategic
- Role:
- Supervisor
- ORCID:
- 0000-0002-4288-5973
- DOI:
- Type of award:
- DPhil
- Level of award:
- Doctoral
- Awarding institution:
- University of Oxford
- Language:
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English
- Keywords:
- Subjects:
- Deposit date:
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2026-06-13
- ARK identifier:
Terms of use
- Copyright holder:
- James Melhorn
- Copyright date:
- 2026
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