Marilen Benner

SUMMARY AND DISCUSSION 231 8 uterine lymphocytes. Even co-culture of decidual lymphocytes and commercially available target cell lines hold their limitations. Decidual NK cells spare first trimester trophoblast from cytotoxicity, but not the widely-used target cell lines (121). Peripheral blood offers a source to study systemic immunity of pregnant women, as the act of drawing blood is no threat to the baby, and can be done as part of routine checkups. However, mechanisms at play at the fetal-maternal interface, in preparation for, or during, implantation or placenta formation are to a large extent unique to local immunity. Future investigations to increase our understanding of principles underlying all human life thus strongly rely on primary samples. As outlined in this thesis, patient-derived tissue can be obtained without the need for invasive biopsies. We isolated lymphocytes from menstrual blood, first and second trimester abortions, and placentae obtained upon delivery. As no additional procedures or change in behavior are required from donors, approval for use of this material by the local ethical committee can be relatively straightforward in the Netherlands (considered “ niet- wmo-plichtig ”). The use of menstrual cups as female hygiene product becomes increasingly popular, and, consequently, collection of the effluent is of limited additional effort. Increased use of the presented primary cells can also help to reduce animal studies effectively, especially since “only humans have human placentas” and other species might not present with identical mechanisms at play (122). Rather than considered waste material, menstrual blood cannot only be vital to research, but it also holds many opportunities for large-scale screenings. Prior to planned conception, especially during ART, women want to ensure that all conditions are optimal to support a healthy pregnancy. Not knowing the underlying cause of an unfulfilled child-wish comes with a large medical and emotional burden. Harnessing the diagnostic value of menstrual blood holds many opportunities. The method can only gain strength if the taboos around female health are lifted. Funding bodies might contribute to support that menstrual blood becomes just as attractive as the seemingly easier act of drawing blood for in-depth analysis. “The biologist of today […] is in much the same position as an Egyptian astronomer exploring the secrets of the universe with the naked eye.” (Roberts and Lowe, 1975, The Lancet, “Where have all the conceptions gone”) This thesis explored how understanding of reproductive immunology demands a change in perspective. A number of presented dogmas were established before holistic detection options were available. Systems biology approaches and computational analysis allow for an open approach, moving away from a biased target selection or a selective readout. Next to the presented microbiome analysis, examples of such comprehensive approaches are transcriptomics (123, 124), use of mass cytometry (27), enabling highly multiplexed flow cytometry, or mass imaging, expanding our abilities for structural analysis. Increased availability of these in-depth omics approaches will allow for a better understanding of phenotype and function of uterine immune cells. Healthy pregnancy depends on the integration of all these