Reproduction of a species represents a unique immunologic challenge. Despite allogeneic differences, the maternal immune response does not reject the fetus, and this situation is maintained in humans for 40 weeks of pregnancy. A body of research has demonstrated that many levels of regulation operate in a successful pregnancy. Most significantly, the placenta serves as a physical barrier, sequestering the fetus away from the mother's immune system. The trophoblast cells that form the outer layer of the placenta in contact with maternal tissues do not express classical MHC proteins, acting as a nonimmunogenic shield.
A second level of protection includes production by the placenta of immuno-modulatory molecules to actively protect the fetus. Tryptophan metabolites and IL-10 inhibit T cell activation and proliferation, and expression of FasL (CD95L) eliminates activated T cells (reviewed in: Holt 2003). Moreover, the expression by placental trophoblasts of a range of molecules such as IL-10, prostaglandin E2, and progesterone promotes T-helper 2 (Th2) responses while dampening Th1 immunity. This Th2 skew is maintained both within the innate immune system by, for instance, down-regulation of the IL-12(p35) gene expressed in neonatal DC and, in the adaptive immune system, by CpG hypermethylation of the IFNg promoter in neonatal CD4+CD45RA+ T cells (Holt and Sly 2002). The skewing of the lymphokine environment to Th2 dominance during pregnancy protects against toxicity to the placenta caused by Th1-type cytokines, particularly IFNg.
A third level of protection of the fetal immune system from negative maternal influences involves regulation of sex steroid receptors on fetal cells. Lymphocyte precursors, particularly those of B lymphocytes, decline in the mother during pregnancy when sex steroids and glucocorticoid levels are elevated (Medina et al. 1993; Medina and Kincade 1994). Protection of fetal lymphoid precursors from glucocorticoids comes from placental enzymes, but estrogen in the fetal environment is not similarly neutralized (Kincade et al. 2002). Instead, recent studies indicate that receptors for estrogen and androgen on fetal cells do not appear until after birth (Igarashi et al. 2001; Kincade et al. 2002).
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