| dc.description.abstract | Atopic eczema (AE) or atopic dermatitis (AD) is a chronic relapsing skin disease. The pathogenesis of AE is multifactorial resulting from a complex interaction between genetic, immunological, and environmental factors. Filaggrin (FLG) mutations are the most important genetic risk factor implicated in AE. It encodes a large protein that is degraded sequentially to a FLG monomer responsible for the normal epidermal barrier structure. The FLG monomer is further processed to Natural moisturizing factors (NMFs) essential for maintaining skin hydration. Tower Hamlets Eczema Assessment (THEA) is a large cross-sectional clinical and environmental study in AE patients of Bangladeshi ancestry. The clinical phenotype observed in these children is usually of the severe type with higher risk of complications. This has been attributed to enrichment in variation of FLG mutations. Our first aim was to assess the impact of this disease on patients and their families through quality of life (QoL) questionnaires. To date, this is the largest QoL study in this specific ethnic group in the UK. We recruited 460 Bangladeshi children and 98 adult patients from paediatric dermatology/allergy and adult dermatology outpatient clinics at the Royal London Hospital in East London. Our results show that many external factors other than disease severity affect QoL of patients and their families, especially those who face different linguistic and cultural barriers. The effect of pollutants on the incidence and prevalence of atopic eczema (AE) is controversial with different causative proposed inflammatory mechanisms and sensors in skin such as oxidative stress, the aryl hydrocarbon/artemin (AhR/ARTN) and Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways. Carbonylated proteins (CPs) are irreversible aldehyde and ketone groups generated on protein side chains when oxidized. My second aim was to evaluate CP expression as a general oxidative marker by western blotting in skin tape strips in patients and controls and correlate it with FLG genotype status. In addition, FLG and cytokeratin 10 (CK10) expression were evaluated. Results of 49 AE patients and 10 normal controls recruited through THEA show significant difference in CP level between wild type controls/patients and patients with biallelic FLG mutations. The number of FLG mutations correlated positively and significantly with CP expression level suggesting that patients with enrichment in FLG mutations might be more susceptible to inducible oxidative stress by environmental stimuli. Interestingly, there was a significantly increased FLG dimer level as well in those patients compared to wild type and 4 compound heterozygous patients/controls, which might suggest aberrant FLG processing and abnormal degradation and accumulation of FLG intermediates in AE patients. Ambient exposure of THEA patients to commonly studied meteorological variables and pollutants showed that long-term exposure to ground-level Ozone (O3) has the strongest association with eczema severity. Acute exposure to toxic O3 concentrations is well known to result in skin inflammation mimicking eczema, however the effect of daily ground low level O3 on the skin requires further research. My third aim was to study the effect of long-term exposure to low levels of O3 on keratinocytes in 2D/3D cultures by means of western blotting, immunofluorescence staining and bulk RNA sequencing. Our data suggest that repeated exposure to O3 induces oxidative stress that leads to inflammatory, proliferative, and apoptotic changes in keratinocytes. | en_US |
