Although much is known about sensitization and triggering of immune responses in human adults, a paucity of information exists regarding the normal course of these processes in fetuses. What is known about the interplay of antigens and allergens with the developing immune system in the intrauterine environment will now be presented, but much research is still required into the mechanisms of basic fetal sensitization and the neonatal triggering of normal and pathological immune responses.
Developmental studies have detailed the emergence of the human fetal immune system (reviewed in Chapter 2). Although stem cells are seen in the human yolk sac at 21 days of gestation (Hayward 1981), lymphocytes do not populate the fetal thymus until 8 to 9 weeks of gestation. They then migrate to the circulation by approximately 14 to 16 weeks of gestation (Donovan and Finn 1999). B lymphocytes appear in several organs, including the lungs and gut, from 14 weeks of gestation, and by fetal week 19-20, circulating B cells have detectable surface IgM (Hayward 1981). Circulating T cells at 22 weeks of gestation present a naïve phenotype with low expression of the cell surface antigen CD45RO and high concentrations of CD45RA (Byrne et al. 1994; Peakman et al. 1992); few third-trimester fetuses and neonates have circulating T cells expressing high levels of CD45RO, a classic "memory" cell marker (Frenkel and Bryson 1987; Hannet et al. 1992; Lewis 1998; Sanders et al. 1988).
In third-trimester fetuses and neonates, memory T cells and the production of cytokines such as IFN-gamma gradually increase. This has been attributed to an increase in antigenic exposure and T cell activation (Frenkel and Bryson 1987; Hannet et al. 1992; Lewis 1998; Sanders et al. 1988), yet the observation that both neonatal T cells and adult naïve T cells have a reduced capacity to proliferate and produce cytokines compared to memory or effector T cells may be due, in part, to their lack of antigenic experience (Donovan and Finn 1999). This review of the anatomy of—but absence of responses in—the developing immune system in fetuses provides only a general understanding of the nascent defense system. An overarching question is whether human fetuses, neonates, and newborns are innately compromised in the ability of their immune systems to respond to antigen because of defects in T cell activation, costimulation, or antigen processing (Burchett et al. 1992; Paryani and Arvin 1986; Starr et al. 1979)—i.e., developmental issues—or if their reduced capacity to respond to antigen is due to a lack of antigenic expe-rience—i.e., an exposure issue (Lewis 1998). Obviously, these two lines of argument cannot be studied using a reductionist approach, as developing and gaining experience occurs concomitantly. Immunologic "maturation" happens around the time of birth until about 6 months of age when the T helper environment within the infant is established (Hanrahan and Halonen 1998; Prescott et al. 1998). The framework for this period of maturation may be best understood by studying maternal-fetal interactions.
A somewhat compelling argument is that the maternal-fetal environment in developed countries differs from that of developing countries in the level of pathogenic exposure. Epidemiologic studies indicate that "clean," developed countries have an increase in asthma rates, suggesting a direct relationship between pathogen exposure and normal (nonasthmatic) immune system maturation. However, lack of pathogen exposure does not necessarily mean lack of antigen exposure. The debate then focuses on whether the body recognizes pathogens vs. innocuous antigens, or — more specifically for the developing immune system of a fetus—whether the mother's immune system conditions the fetus to "interpret" the antigen it encounters as a threat to be reacted against or an agent towards which tolerance should be developed. In the first scenario, the "Danger Theory" of antigenic stimulation (Matzinger 1998) envisions that sensitization of the immune system occurs to dangerous, or necrotic, events. In the second scenario, the intrauterine environment influences later maturational pathways and provides a form of imprinting on the fetus, i.e., the state of the mother's immune system influences the fetus's developing immune system. Again, resolution of these theories is difficult, as the response of a fetus to a pathogen or antigen cannot be measured out of context of the mother's immune system. Moreover, coupling native vs. maternally influenced fetal immune responses to asthma development requires a time element that allows impact of later environmental exposures to cloud the issue. Understanding the influences on fetal immune system development must be obtained despite omnipresence of antigens (pathogenic or not) and the unique pregnancy environment. It is into this realm that we focus and provide a review of the scientific data.
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