Marilen Benner

CHAPTER 8 226 CMV seropositivity did not contribute to classification as healthy control or RPL patient. Likewise, in Chapter 3 , CMV infection did not affect the EVT’s ability to induce Treg. The human immune system is not just exploited by the virus to allow persistence, but relies on being shaped by early infection. The neonatal immune system is vulnerable to viral infections, but while not suffering from disease, the young child gets equipped with an alert immune system enabling efficient elimination of harmful pathogens (60). Lifelong CMV infection was shown to improve pathogen recognition, by allowing for recruitment of a broad cross-reactive antigen repertoire in mice (61). Pregnancy-induced training of uterine NK cells, hypothesized to be connected with improved placentation (62), was shown to be dependent on CMV-seropositivity (63). CMV seropositivity caused a segregation in frequencies of B cell subtypes of the RPL cohort. Without taking CMV status into account, switched memory B cells and naïve B cells are present at similar frequencies in control vs RPL patients. Higher frequencies of CD27 positivity of B cells, a marker for activation, were observed in the CMV pos group of the RPL cohort. Increased abundance of CD27 on B cells is a known association with CMV seropositivity (64). Unfortunately, information on CMV status was limited for donors of peripheral blood in this study. Frasca et al. compared vaccine responses based on CMV status, showing that a pre-activation of B cells, also reflected in increased intracellular TNF- α levels, negatively impacted their ability to undergo class switch recombination, and generate proper antibody and memory response (65). The authors propose that a CMV-mediated proinflammatory profile can be kept under control in young individuals, while elderly present with higher inflammatory levels. It remains to be elucidated whether CMV seropositivity poses a risk factor for RPL in case of additional deregulation of tolerance. In that case, failure to suppress a CMV-related proinflammatory profile might negatively impact implantation. An earlier study by Radcliffe et al. pointed out the difficulty to assess an association of CMV and RPL based on measuring anti-CMV antibodies as performed in Chapter 5 : the authors observed an inability of RPL patients to respond to CMV through proliferation or antibody secretion (66). The difficulty of these individuals to adequately mount a humoral response to specifically CMV infection, not to control stimulation, underlines the importance to study CMV and B cells with regard to RPL in future approaches. HUMAN REPRODUCTION AND MICROBIOTA ARE INSEPARABLE The concept that human immunity is naturally shaped through foreign influence is manifested in immunology. The term microbiom e, describes all genomes from microorganisms inside the body is often also referred to as microbiota , which describes the specific microorganisms. The microbiome does not only refer to natural colonization by bacteria, but also covers viruses, fungi, protozoa, and archaea (67, 68). The importance of microbial colonization of the human body has been extensively reviewed, focusing especially on the contribution of the gut microbiome