[Truncated abstract] With the dramatic rise in asthma and allergic disease there is an urgent need to define the early life exposures which influence developing immune responses to increase the predisposition to allergic disease. While this is clearly multifactorial, this thesis addresses the effects of maternal smoking as a major adverse, yet avoidable exposure in early life. I hypothesised that the well-documented increased susceptibility to infection in infants of smokers could indicate underlying effects on innate Toll-like receptor (TLR) mediated microbial responses which could in turn contribute to early immune dysregulation and increased risk of allergic disease. In addition to providing the first defence against microbes, TLR-mediated pathways modulate subsequent specific immune response and are of growing interest in the potential inhibition of inappropriate allergic responses. My initial interest in the potential immune effects of smoking in pregnancy was based on preliminary retrospective analyses of a previous cohort (presented in Chapter 3) which suggested possible effects on T cell cytokine responses to mitogens and allergens. Based on this, I recruited a new prospective pregnancy cohort (n=122) of smokers (n=60) and non-smokers (n=62) (as outlined in Chapter 4) to confirm this and test my novel hypothesis that maternal smoking may be affecting important innate (TLR-mediated) immune pathways. … Thus, these findings could indicate that smoking increases the early susceptibility to infection thereby increasing subsequent IgA responses. This is supported by observations that key neonatal TLR responses are attenuated in children who go onto develop wheezy illnesses and lower respiratory tract infections. Together, the study findings suggest that in addition to effects on lung growth, maternal smoking may also influence aspects of neonatal innate immune function that are now believed to play a critical role in microbial-driven postnatal immune development, highlighting that other environmental interactions are also highly relevant to the v "hygiene hypothesis". Although I saw no effects on very early allergic disease (atopic dermatitis and food allergy) longer follow up is clearly needed to more definitively examine the effects of altered early TLR function on aeroallergen sensitisation and disease, as well as allergen-specific immune development.
|Qualification||Doctor of Philosophy|
|Publication status||Unpublished - 2005|