Development Of The Newborn Immune System

Upon parturition, the immune system of the neonate becomes abruptly released from the immunosuppressive intrauterine environment (Holt 2003; Janeway Jr. et al. 1997b; West 2002) and is concomitantly exposed to a world of antigens. Unlike the situation in rodents, the human neonatal immune system has achieved a significant level of maturity (Holt and Jones 2000; Peakman et al. 1992; West 2002).

However, in comparison with the human adult immune system and with respect to the antigenic challenges facing the neonate, the neonatal immune system is considered immature (Holt and Jones 2000; Miller 1978). The neonate's susceptibility to infection has sparked the term "immunodeficiency of immaturity" (Schelonka and Infante 1998). In general, the neonate has an insignificant inflammatory response (Holladay and Smialowicz 2000), low levels of antibody (Holt and Jones, 2000), and reduced T cell reactivity (Holt et al. 1992; Pirenne et al. 1992). Moreover, the percentages of gd T cells (Peakman et al. 1992) and CD5+ B cells (Hannet et al. 1992; Holt and Jones 2000; Peakman et al. 1992) are higher in the fetus than in the adult, and they decline postnatally.

A case has been made by Kincade et al. (2002) that with respect to antigenic exposure, the emerging immune system of fetuses is not immature, but represents a unique stage of development that undergoes replacement by more reactive "adult" components in time. These authors emphasize that a direct connection has yet to be established between fetal stem cells and ones that sustain adult blood cell formation.

The neonatal period bridges the fetal and adult immune systems. Some factors governing maturational aspects of this transient period have begun to be recognized. In particular, several groups provide evidence supporting the role of antigenic exposure on regulating adaptive immune cell function through the type of cytokine response (Bjorksten 1999a; Cunningham-Rundles et al. 2002; Holt 2003; Holt and Jones 2000; Wilson et al. 1992). Microbially derived molecules not normally encountered in fetal life signal APC via specific Toll-like receptors as well as through CD14, the high-affinity receptor for bacterial lipopolysaccharide. DC appear to be the crucial type of APC influencing the immune system of the newborn from the Th2-skewed state characteristic of the fetal compartment to the more balanced (by comparison, more Th1-polarized) adult-equivalent state (Holt and Sly 2002; Holt and Jones 2000). Epidemiologic evidence supports a heightened risk for neonates both for infectious disease and allergic sensitization, and in their commentary, Holt and Sly (2002) suggest that this susceptible state results from a "generalized maturational deficit in Th1 function."

As mentioned earlier, mechanisms maintaining the Th2-skew in fetal and early postnatal life include deficient production by DC of IL-12, which is required for stabilization of the IFNg transcriptional machinery in T cells, and hypermethylation of the promoter of the IFNg gene in neonatal CD4+ T cells, which directly inhibits transcription. In addition, neonatal CD4+ T cells require higher levels of costimula-tion to achieve maximum activation. Release of these inhibitory mechanisms primarily depends on microbial exposure. Interestingly, CD8+ cytolytic T cells in neonates lack the hypermethylation of their IFNg promoter characteristic of CD4+ T cells. Moreover, the precursor frequency of CD8+ cytotoxic T lymphocytes (CTL) in neonates is comparable to that in adults, indicating a functionally mature neonatal CD8+ cytotoxic compartment. Although terminal differentiation of CD8+ T cell precursors and reactivation of CD8+ memory cells rely on cytokine "help" from CD4+ T cells, at least the primary responses of CD8+ effector cells can be utilized to provide protection during infancy (Hermann et al. 2002; Holt 2003). A description of the maturational state of the major cell types in the immune system during the neonatal period is detailed below.

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