Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology
The mechanistic factors responsible for the increase in allergic diseases are still not fully understood, but a reduced microbial stimulation seems to be one of the key issues. Research is now aiming at investigating the relationship between the innate immune system, involving the toll-like receptors, and allergy development. Further, the maternal influence on the child, possibly through in utero effects, but also through the breast milk, has shown to be of great importance. This thesis aimed at understanding how the maternal immune system is influenced by early exposures and allergic disease, but also to investigate the consequences of the maternal phenotype on the innate immune system of the developing child.
The Th1/Th2 cytokine pattern in allergic diseases has been extensively studied. Here we were interested in comparing the innate cytokines in allergic and non-allergic women, and to see if the allergic status was influencing the effect of pregnancy differently. We demonstrate that IL-1β, IL-6, IL-10 and IL-12 production in cells from adult women are not influenced by allergic status, neither during pregnancy nor 2 years after. However, pregnancy had an apparent effect on cytokine levels, regardless of allergic status. Also, total IgE levels in allergic women were significantly lower 2 years after pregnancy in comparison with the levels during pregnancy, pointing to the fact that pregnancy indeed has an immunomodulatory role.
We further wanted to investigate the immune system of mothers who had migrated to Sweden in comparison with indigenous mothers. The reason for our interest here was that children born from immigrated mothers have shown to have an increased risk of developing diseases such as allergy and Crohn’s disease. The results showed that immigrants from a developing country had significantly higher levels of breast milk IL-6, IL-8 and TGF-β1. Further, regardless of maternal country of birth, a larger number of previous pregnancies was associated with down-regulation of several substances, statistically significant for soluble CD14 and IL-8. The results suggest that maternal country of birth may indeed influence adult immune characteristics, potentially relevant to disease risk in offspring.
The influence of allergic status of the mother on the expression of CD14, TLR2 and TLR4 was further investigated in monocytes from mothers and their newborn babies upon microbial stimulation. We could not find any differences in monocytic TLR levels between the groups. No significant differences regarding cytokine levels between allergic and non-allergic mothers in response to stimuli were found either. However, the cytokine and chemokine release triggered by TLR2 stimulation in CB revealed that CBMC from children with maternal allergic disease released significantly less IL-6, and a trend towards less IL-8.
As we could not find differences in TLR levels attributed to maternal allergy, but an impaired IL-6 response, we turned our focus on an intracellular event taking place after TLR ligation. The results confirmed our results of decreased IL-6 levels in CB from children to allergic mothers. At 2 years of age, the children of allergic mothers still displayed a diminished IL-6 response. Additionally, they also had a decreased activity of p38 MAPK. p38 has an important role in driving Th1 responses, suggesting that the p38 pathway could be one of the responsible mechanisms behind the impaired responses correlated to allergic heredity found in CB as well as at 2 years of age.
Infancy is a crucial time period for the developing immune system. Further, the relative composition of the two major monocytic subsets CD14++CD16- and CD14+CD16+ is altered in some allergic diseases. TLR levels are different in the two subsets, proposing a possible link to the reduced responding capacity of monocytes from children with allergic heredity. We followed up our earlier studies of children at birth and at 2 years of age by looking at 5 year old children. There were no differences regarding monocytic subsets, nor in TLR levels in unstimulated cells. However, when stimulating the cells with PGN, both monocytic subsets in allergic subjects were less capable of upregulating TLR2 compared to the age-matched controls.
Taken together, the work in this thesis suggests that the maternal immune system is affected by the process of pregnancy and childhood exposures. It further suggests that maternal allergy affects the young child, in terms of impaired responses to microbial stimuli, which later in infancy correlates with allergic disease in the child. These impaired innate responses could lead to a diminished Th1 response, or alternatively to a deficiency in regulatory mechanisms, and thereby cause allergic disease.
Stockholm: Wenner-Grens institut för experimentell biologi , 2008. , 174 p.
2008-06-13, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 8 C, Stockholm, 10:00 (English)