Patterns of peripheral blood mononuclear cell responses to viruses and their relationship with asthma, allergy and respiratory tract infection
File(s)
Author(s)
Regis, Eteri
Type
Thesis
Abstract
Background: Asthma is caused by a combination of genetic and environmental factors. Polymorphisms on chromosome 17q21 are associated with childhood-onset asthma and rhinovirus (RV)-induced wheezing. I hypothesised that immune responses to respiratory viruses are in part genetically determined, differ between the sexes and impact upon trajectories of asthma, allergic sensitisation and lower respiratory tract infections.
Methodology: In a population-based birth cohort, I stimulated PBMCs collected at age 16 years with three live respiratory viruses, two viral mimics and phytohaemagglutinin (PHA). I measured interferons (IFNs), IFN-induced chemokine CXCL10/IP10 and PHA-induced type 2 helper T-cell (Th2) cytokine responses in supernatants harvested at 24h post-stimulation. I ascertained the impact of sex and allergic disease status on cytokine responses using non-parametric tests. I investigated associations between virus-induced cytokines and five 17q21 single nucleotide polymorphisms (SNPs). I applied Bayesian profile regression to identify clusters of individuals with different immune response profiles and genetic variants.
Results: IFN-α responses to all viruses and viral mimics were 1.34-2.06-fold lower in males than females (P=0.018-<0.001). IFN-β, IFN-γ and IFN-induced chemokines were also deficient in males across all stimuli/viruses. All five 17q21 asthma risk alleles were significantly associated with reduced RV-A1-induced IFN-β (all P<0.012). Bayesian profile analysis identified 3 clusters which differed in the IFN-β induction to RV-A1 (low, medium, high)...
Methodology: In a population-based birth cohort, I stimulated PBMCs collected at age 16 years with three live respiratory viruses, two viral mimics and phytohaemagglutinin (PHA). I measured interferons (IFNs), IFN-induced chemokine CXCL10/IP10 and PHA-induced type 2 helper T-cell (Th2) cytokine responses in supernatants harvested at 24h post-stimulation. I ascertained the impact of sex and allergic disease status on cytokine responses using non-parametric tests. I investigated associations between virus-induced cytokines and five 17q21 single nucleotide polymorphisms (SNPs). I applied Bayesian profile regression to identify clusters of individuals with different immune response profiles and genetic variants.
Results: IFN-α responses to all viruses and viral mimics were 1.34-2.06-fold lower in males than females (P=0.018-<0.001). IFN-β, IFN-γ and IFN-induced chemokines were also deficient in males across all stimuli/viruses. All five 17q21 asthma risk alleles were significantly associated with reduced RV-A1-induced IFN-β (all P<0.012). Bayesian profile analysis identified 3 clusters which differed in the IFN-β induction to RV-A1 (low, medium, high)...
Version
Open Access
Date Issued
2023-01-31
Date Awarded
01/11/2023
License URL
Advisor
Johnston, Sebastian
Custovic, Adnan
Fontanella, Sara
Haider, Sadia
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)