Sanne Hoeks

General Introduction 13 1 CHARACTERISTICSOFTHEPERINATAL IMMUNESYSTEM: SOPHISTICATED BUT VULNERABLE Maintaining the delicate balance between immune tolerance against newly encountered but harmless antigens on the one hand and induction of potent immune responses against pathogens on the other hand seems to be an exceptionally complicated challenge of the neonatal immune system. Specific characteristics of perinatal immune cells are involved in this task. In the first place, neonates harbor an immune phenotype with complex immune regulatory mechanisms that match the unique environmental pressure and challenges during pregnancy and in the first days of life. 12 Myeloid-derived suppressor cells (MDSC) are present at high frequencies in early human life and could therefore play an important role in immune homeostasis. Soluble regulatory mediators are produced at high levels. These regulatory mediators, like adenosine, Transforming Growth Factor (TGF)β and prostaglandin E2 together with progesterone from the yellow body, encourage T H 2 cytokine production. 13-15 Additionally, fetal and neonatal T cells have a strongly regulated interferon (IFN)γ gene expression and are highly sensitive for interleukin (IL)-4. 16 Besides this T H 2 polarization, high circulating concentrations of IL-10 and high frequency of forkhead box P3 (FOXP3) regulatory T cells (Tregs) with corresponding immune suppressive capacities, are present respectively in neonatal blood and at mucosal sites. 17, 18 Infants have limited exposure to antigens in utero. As a consequence, neonatal T- and B-cell populations consist of mainly naive cells. The sophisticated regulated perinatal immune responses come with a price. The neonatal immune system is shown to be less effective to clear infections upon microbial invasion. Intracellular pathogens cause more severe disease (e.g. disseminated herpes infections and tuberculosis in neonates) or replicate at higher levels in the fetus and young child as compared to the adult. Especially premature infants are at much higher risk for infection and this risk is inversely related to the gestational age. This is exemplified by infections with coagulase-negative staphylococci (CoNS), which are most common in infants born at gestational age below 30 weeks irrespective of confounding clinical factors and explained by the developmental difference in activity of toll-like receptor (TLR)-2. 19, 20 Most of the fetal and neonatal T-cells and B-cells are in a naive state and not equipped for a fast and adequate immune response. Furthermore, innate immunity although relatively high in numbers, is functionally not as effective as the adult innate immune system. 21 Antimicrobial immune recognition and antigen presentation are significantly impaired because of reduced numbers of dendritic cells (DC) and other antigen presenting cells (APC), as well as reduced receptor expression and reduced intracellular signaling in these cells. 22, 23 Neonatal DCs express less MHC class I and II, have decreased co-stimulatory capacity and an impaired IL12p70 production. 24-26 Components promoting pro-inflammatory T cell responses such as the complement system, are produced at lower levels in early life. In general fewer cytokines