Marilen Benner

GENERAL INTRODUCTION AND SCOPE OF THIS THESIS 13 1 THE ENDOMETRIUM - FERTILE GROUND ENABLING GROWTH OF A HEALTHY PLACENTA The placenta connects the fetus to the maternal circulation; a vital bond that forms the basis for all further development of the child. The placental membranes form a safe cocoon with a well- regulated internal environment for the baby to thrive in (Figure 2). Correct placenta formation is not only an essential prerequisite to avoid pregnancy loss, but also determines fetal and neonatal health. Structural impairments of the placenta cause pregnancy complications such as intrauterine growth restriction (IUGR) and pre-eclampsia (PE), with possible long-term effects on health of mother and child (16). Placenta formation depends on a complex interplay of maternal and fetal cells. Trophoblast cells of fetal origin have to invade the spiral arteries and replace their endothelium to successfully attach to the vascular system of the mother. These fetal cells are semi-allogeneic, a hybrid of half paternal and half maternal genes. The field of reproductive immunology aims to understand how these partially foreign cells evade the maternal immune system, the reactive mechanism to eliminate unfamiliar antigens. It is now established that, contrary to the initial hypothesis of Sir Peter Medawar in 1953, maternal immunity is not ignorant to the fetal cells, but tolerant (17, 18). How is this tolerance achieved? PUZZLING IMMUNITY OF THE PREGNANT UTERUS The human decidua is abundantly equipped with immune cells that may react to the semi- allogeneic fetal cells. In the peri-implantation period, Natural Killer (NK) cells (~60%), macrophages (10-20%), and T (3-10%) cells represent the most prominent local immune cell types (19-23). Upon conception, immune cells infiltrate the implantation site and levels of proinflammatory cytokines leukemia inhibitory factor (LIF), tumor necrosis factor (TNF)- α , and interleukin (IL)-6 rise in the endometrium (24). These local reactions are more than a mere side effect to the invading foreign antigens, as they belong to the physiological adaptations needed during this period. As such, increasing evidence shows that provoking a local immune reaction, by deliberately scraping the endometrial lining during in vitro fertilization (IVF), increases success rates in assisted reproductive technology (ART)(25-27). However, any inflammatory reaction of implantation, even physiological, needs to be well-contained. Excessive inflammation would threaten the baby and progression of pregnancy, leading to implantation failure, pregnancy loss, or pre-term labor (PTL). To maintain the balance between immunity and tolerance, decidual immune cells have to be equipped with extremely fine-tuned regulatory mechanisms.