Before the fetus has even a rudimentary immune system, the maternal immune response has had to adapt to permit development of a child whose paternal antigens are cause for immune rejection. Evidence exists in both murine and human studies that during pregnancy, TH2 immune responses dominate in the mother, reducing TH1 type reactions that would presumably mediate rejection of the fetus (reviewed in: Donovan and Finn 1999; Warner and Warner 2000). In support of this idea, Sills and coworkers demonstrated a relationship between the TH1-associated cytokine TNF and infertility. In that report, chronic therapy for infertility using biologic agents to block TNF was associated with successful induction of ovulation, conception, and normal delivery (Sills et al. 2001). Pregnant women have been shown to have compromised cell-mediated immunity (Weinberg 1984), impaired lymphocyte proliferation (Matthiesen et al. 1996), and a loss of peripheral blood mononuclear cell proliferative responses to recall antigens (Bermas and Hill 1997). However, the TH2 response, which promotes antibody production, functions effectively; production of maternal antibodies specific for paternal antigens occurs. A lack of these antibodies in women with spontaneous abortion is associated with a TH1 autoimmune response (Bermas and Hill 1997; Donovan and Finn 1999). Overall, data indicate that successful pregnancy requires a TH2-biased maternal immune response.
Fetal development also supports a TH2 environment during pregnancy. The fetal trophoblast only expresses low-affinity receptors for TH1 cytokines, such that TH2 responses predominate at the maternal-fetal interface (Lin et al. 1993; Raghupathy 1997). Moreover, the TH2 cytokine IL-4 is produced by human amnion epithelium (Jones et al. 1995), and IL-10 and IL-13 from the placenta are detectable during the second trimester of pregnancy (Cadet et al. 1995; Jones et al. 1995; Williams et al. 2000). It has also been thought that common environmental allergens that cross the placenta prime T cells of the fetus in utero (Kay 2001) and that this contributes to TH2-domination of the immune response in virtually all newborns (Prescott et al. 1998).
The observations that the in utero environment supports TH2-type immune responses has given rise to a hypothesis that atopy in children derives from a persistence of this bias beyond birth (Donovan and Finn 1999; Holt et al. 1992; Holt and Macaubas 1997; Prescott et al. 1998a; Prescott et al. 1998b). Normally, a shift occurs in an infant's immune system shortly after birth to favor the adult TH1-mediated responses. This developmental phenomenon is termed "immune deviation" (Holt et al. 1999). Atopic infants instead may increase the TH2 cells that were primed in utero (Kay 2001). Because macrophages that engulf microbes secrete IL-12, a cytokine that induces Natural Killer (NK) cells to produce IFNg and in general promotes TH1-type cells, it is believed that microbes are the chief stimulus of protective TH1-mediated immunity (Kay 2001). This idea leads into the hygiene hypothesis discussed earlier proposing that lack of immune deviation is due to an overly clean environment, that is, one deprived of microbial antigens that stimulate TH1 cells (Rook and Stanford 1998). A potential contributing factor to this situation in Western countries is the overuse of antibiotics for minor illnesses in early life. Another indication that repeated immune stimulation may protect against atopic allergy is the observation that atopic allergic diseases are less common in younger children who have three or more older siblings, and among children who have had measles or hepatitis A (Openshaw and Hewitt 2000). This hygiene hypothesis is supported by evidence that exposure of young children to older children at home or to other children at day-care can protect against development of asthma in childhood (Ball et al. 2000). However, in contrast, an increased prevalence among poor blacks in the United States of atopic asthma is associated with sensitization to cockroaches and house dust mites (Levy et al. 1997).
While many other factors may also favor the persistence of the TH2 phenotype, Kovarik and colleagues have shown that microbial CgP oligodeoxynucleotides (ODN) can circumvent this polarization in neonatal responses to vaccines, although they may fail to fully redirect TH2 responses established by neonatal priming (Kovarik et al. 1999).
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