Sanne Hoeks

Chapter 1 20 THIS THESIS It is clear that immune ontogeny is an emerging field. Fetal life and early infancy are increasingly recognized as a critical period to shape the immune system for life. Slowly the neonatal immune system changes its regulatory responses into effector responses. Genes, environmental factors and the epigenome will influence this maturation process and different developmental trajectories might be initiated leading to disease pathways. This concept has been recognized in the 1000 days campaign and the WHO’s Every Newborn Action Plan but pathophysiological mechanisms supporting this theory are mostly unidentified. In this thesis, we chose to study Tregs because of their indispensable role in the establishment and maintenance of immunological tolerance as shown in devastating autoimmune diseases in human and mice caused by null mutations in the X-linked Foxp3 gene. 57, 58 We explored how FOXP3 Treg contribute to antigen specific immune tolerance shortly after birth when the skin and mucosa of the child is quickly colonized by tons of (harmless) microbes and when the child is exposed to food antigens and inhaled antigens ( chapter 2 ). Next, we questioned the functionality of neonatal T H 17 cells since RORC and FOXP3 are counterbalanced ( chapter 3 ). For the studies in chapter 2 and 3 we used cord blood. Since we recognized that cord blood resembles the relatively sterile prenatal situation before immune cells have been exposed to foreign antigens but also reflects an acute phase response due to the highly stressful event of birth. Therefore we also performed a follow up study on Treg and T H 17 cells in healthy children in their first year of life ( chapter 4 ). To overcome ethical issues in retrieving blood samples from healthy children, we needed to be inventive and we collected samples from infants in need of repetitive surgery in their first year of life and samples of newborns with a viral infection (see intermezzo). In chapter 5 we questioned whether neonatal immune cells are defective or respond to strong stimuli in vivo. In the last chapter, we discuss the role of system biology in future studies ( chapter 6 ). It is clear that in overcoming the ethical issues in research on newborns and infants, we need to be inventive in sample collection but also in research methods and technical solutions.