Does paternal antigen-induced secretion of interleukin-10 by T regulatory cells mediate the birth order effect?

Childhood allergy constitutes a significant burden of disease in the Western world. The prevalence of this condition is highest in first born children, an as yet unresolved phenomenon called the "birth order effect". The hygiene hypothesis attempted to explain this differential risk by stating that less exposure to microbial agents at an early age of first born children would result in reduced activation of the immune system and subsequent polarization towards a Th2 phenotype. However, no conclusive evidence for or against the hygiene hypothesis has been found so far. Another, not necessarily conflicting, theory states that the birth order effect is already established during prenatal life and that the fetal-maternal interaction changes during successive pregnancies. Combining this theory with research on preeclampsia, another disease originating in pregnancy and also related to birth order, could suggest clues about the mechanisms underlying the birth order effect. Recent research on preeclampsia showed that preeclamptic women have higher levels of pro-inflammatory IL-6 and lower paternal antigen-induced secretion of IL-10 compared to normal pregnant women, indicating a lower number or lower functional activity of T regulatory (Treg) cells. These Treg cells play an important role in maintaining tolerance to fetal antigens in pregnancy and they are found in high numbers at the maternal-fetal interface. We hypothesize that nulliparous women have a lower activity of Treg cells specific to paternal antigens compared to parous women, either in peripheral blood or in the decidua (maternal part of the fetal-maternal interface). If this hypothesis is true, this would mean that the allergen suppressor mechanism of Treg cells is sub-optimal in first born children. This would explain at least a part of the mechanism of the birth order effect and would give us directions for developing preventive measures to prevent possibly 30% of future childhood allergies.