Fetal Thymus Changes in Pre-eclampsia and the Developmental Origins of Allergic Disease

Abstract

Pre-eclampsia is a systemic disorder unique to human pregnancy and a leading cause of maternal-fetal morbidity and mortality worldwide. While its exact aetiology remains unknown, maternal immune changes in pre-eclampsia, including reduced regulatory T cells (Treg), support a breakdown in maternal-fetal immune tolerance. The current immune theory for pre-eclampsia is likely to be incomplete, however, as fetal immune function is not considered. Although obvious restrictions limit access to the human fetus, the thymus, a primary immune organ, can be readily observed by ultrasound at mid-gestation. Fetal thymus changes observed via ultrasound can therefore offer non-invasive insight into fetal immunity. Beyond its immediate consequences to maternal-fetal wellbeing, pre-eclampsia has been linked to childhood allergy. This suggests fetal programming of allergic disease, a concept also supported by studies linking newborn head size with allergy. A possible explanation for this link centres on altered neurotrophin levels, including BDNF. Neurotrophins are important mediators of brain growth and development, which are also dysregulated in allergic disease. Cord blood BDNF levels are also altered in pre-eclampsia. We therefore hypothesized that pre-eclampsia would be associated with altered fetal head growth. This thesis consists of five publications. Firstly, Chapters 3 and 4, observed a smaller fetal thymus in pre- eclampsia, with a smaller fetal thymus preceding clinical disease. The third study, Chapter 5, included a large prospective study which confirmed the findings of Chapter 4. Chapter 5 also included thymus histopathology, which revealed dramatic apoptosis of thymocytes in pre-eclampsia, especially affecting Treg cells. Adding to our theory of neurotrophin dysregulation as a possible factor in fetal programming, Chapter 6 demonstrated increased fetal head growth in pre-eclampsia. Finally, Chapter 7 found reduced fetal head size at mid-gestation to be associated with childhood allergy. In summary, this research has shown fetal thymus changes to precede clinical disease in pre-eclampsia, possibly reflecting an active role for fetal immunity in disease pathogenesis. Our findings also support the developmental programming of allergic disease.