Nulliparous women have a high risk of preeclampsia compared to multiparous women (Robillard et al.,1993; Skjaerven et al., 2002) and this protective eﬀect of multiparty is lost with a change of partner (Robillard et al., 1993; Trupin et al., 1996; Dekker, 2002). Furthermore, among nulliparous women, a previous spontaneous or induced abortion has a substantial protective eﬀect against preeclampsia, but nulliparous women who had an abortion with a diﬀerent partner were at the same risk as primigravidas (Dekker,2002). These ﬁndings suggest that paternal antigen-speciﬁc tolerance is induced during the ﬁrst pregnancy, and these memory T cells, which induce paternal antigen-speciﬁc tolerance, quickly expand in the next pregnancy resulting in low risk of maladaptation of pregnancy. Indeed, it has been shown that maternal T cells acquire a transient state of tolerance speciﬁc for paternal alloantigens during pregnancy in mice (Tafuri et al., 1995).
As second piece of epidemiological evidence, semen exposure over a long period, decreases the risk of preeclampsia. A short duration of sexual cohabitation is associated with an increased risk of preeclampsia (Robillard et al., 1994 but long term cohabitation with condom use increases the risk of preeclampsia (Klonoﬀ-Cohen et al., 1989).
Koelman et al. (2000) reported that soluble MHC-class I antigens are present in seminal ﬂuid. These antigens could be taken up by vaginal or uterine antigen presenting cells (APCs and these APCs may induce paternal MHC class I speciﬁc tolerance. Furthermore, soluble MHC class I antigens are reported to induce apoptosis of T cells (Zavazava and Kronke, 1996); therefore, soluble paternal MHC class I antigens may reduce alloreactive maternal T cells. This may play an important role
in the induction of paternal MHC class I speciﬁc tolerance. Furthermore, seminal plasma contains abundant immunosuppressive cytokines, transforming growth factor (TGF)-b, and this cytokine could play an important role in implantation and induction of tolerance (Robertson et al., 2003).
Semen consists of sperm and seminal ﬂuid. In intracytoplasmic sperm injection (ICSI) using ejaculated sperm, women are exposed to sperm and seminal ﬂuid for a long time, but in ICSI using surgically obtained sperm, sperm exposure is negative although seminal ﬂuid exposure is positive. Wang et al. (2002) reported a risk of preeclampsia in these cases. Interestingly, the risk of preeclampsia in ICSI using surgically obtained sperm was very high (11%) and this risk was signiﬁcantly higher than that in conventional IVF cases (4%) and in ICSI using ejaculated sperm (4%). This ﬁnding suggests that sperm exposure is more important for the reduction of preeclampsia. Recent data shows that MHC class I antigens and MHC class II antigens are expressed on the surface of human and murine sperm, although their expression is low (Mori et al., 2000; Martin-Villa et al., 1996). We can speculate that MHC class I and MHC class II antigens on the sperm might induce MHC-class I- and MHC-class II-speciﬁc tolerance, and soluble MHC class I might induce MHC-class I-speciﬁc tolerance.
Persistent oral intake of a small amount of antigens induces tolerance, and this is called ‘oral tolerance’. Koelman et al. (2000) examined the frequency of oral sex in primipara preeclamptic cases and primipara normal pregnancy subjects. They found that the frequency of oral sex or swallowing semen were signiﬁcantly lower in preeclamptic cases compared to those in a control group. Induction of oral tolerance by semen intake might partly reduce the risk of preeclampsia .