CD14 and development of atopic disease at 2 years of age in children with atopic or non‐atopic mothers

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Abstract
The prevalence of IgE mediated allergic diseases has drastically increased during the past few decades and there is no satisfactory explanation. A family history of allergic disease is clearly a strong risk factor, bin in view of the rapidity of the increase in allergy prevalence environmental factors are likely to have played a crucial role. This thesis aimed at elucidating the impact of maternal allergy on the in utero environment and on innate immune functions of the newborn baby. Allergic symptoms usually appear early in life. This implies an early priming for allergic disease, possibly even at the fetal level. We therefore compared the presence and production of IgE in placenta from allergic and non-allergic women. Surprisingly, numerous IgE+ cells, located primarily in the fetal villous stroma, were detected immunohistochemically in a majority of the investigated placentas irrespective of maternal allergy, maternal or fetal total scrum IgE levels. The placental IgE could not be demonstrated to be bound to IgE receptors, but was shown to be bound to fetal macrophages, possibly via FcgammaRI. No evidence was found for local fetal IgE production. The novel finding of numerous IgE+ cells in the placenta irrespective of maternal allergy could indicate a physiological role of IgE in utero during pregnancy. The placenta has been suggested to be a pregnancy-specific component of the innate immune system. We describe the novel findings of expression of Toll-like receptors 2 and 4 (TLR2 and TLR4) on villous trophoblast, whereas no immune reactivity was present in the villous core. The intermediate trophoblast was also found to express both TLR2 and TLR4. Regulation of TLR2 and TLR4 was investigated by stimulating placental explants with LPS and zymosan. Stimulation readily induced a release of IL-6 and IL-8 in the placental cultures, whereas TLR2 and TLR4 mRNA and protein expression remained at the same high level as in unstimulated explants. We believe that the TLRs and the trophoblast are important components of the innate immune system with a crucial role in the defense against placental infection, but they might also influence the cytokine environment in utero, something that could have impact on the baby's immune system. The newborn child's ability to respond to microbial stimuli in the environment is believed to be important for maturation of the neonatal immune system. We investigated how cord blood mononuclear blood cells (CBMC) from children of allergic and non-allergic women respond to microbial stimuli. Cord blood (CB) monocytes from children with allergic mothers had significantly lower expression of TLR2 and TLR4 compared to maternal peripheral blood mononuclear cells (PBMC) both before and after microbial stimulation, in contrast to CB monocytes from children with non-allergic mothers. Further, CBMCs from children with allergic mothers had a lower (p=0.03) IL-6 response after microbial stimulation than CBMCs from children with non-allergic mothers. Our results imply that CB monocytes and CBMC immune responses are influenced by maternal allergy. Based on these findings we speculate that monocytes from children with allergic mothers have a reduced capacity to respond to microbial stimuli. The soluble form of the endotoxin receptor CD14 has been shown to be negatively associated with total serum IgE levels. We investigated the levels of soluble (s) and membrane bound (m) CD14 in cord blood and at two years of age from children with allergic or non-allergic mothers and related these parameters with allergy development at two years of age. Children with allergic mothers had significantly higher sCD14 levels in CB compared to children with non-allergic mothers. At two years of age no significant differences in sCD14 levels were observed between the two groups of children and no association between sCD14 and allergic disease was found. Further, we observed large differences in sCD14 and mCD14 with respect to age. These findings highlight the complexity of the interaction between innate and adaptive immune responses. CD14 might be involved in the regulation of IgE production, but we suggest that CD14 could also be important for the maturation and development of the neonatal immune system. In conclusion, the work presented in this thesis has increased our knowledge on the in utero environment in allergic and non-allergic mothers and suggests that maternal allergy influences innate immune functions of the newborn baby