Journal of Reproductive Immunology 46 (2000) 155���166 Hypothesis Correlation between oral sex and a low incidence of preeclampsia: a role for soluble HLA in seminal fluid? Carin A. Koelman a, Audrey B.C. Coumans b, Hans W. Nijman b, Ilias I.N. Doxiadis a, Gustaaf A. Dekker b, Frans H.J. Claas a,* a Department of Immunohematology and Blood Bank, Leiden Uni6ersity Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands b Department of Obstetrics and Gynaecology, Free Uni6ersity Hospital, Amsterdam, The Netherlands Received 12 January 1999 received in revised form 20 October 1999 accepted 24 November 1999 Abstract The involvement of immune mechanisms in the aetiology of preeclampsia is often suggested. Normal pregnancy is thought to be associated with a state of tolerance to the foreign antigens of the fetus, whereas in preeclamptic women this immunological tolerance might be hampered. The present study shows that oral sex and swallowing sperm is correlated with a diminished occurrence of preeclampsia which fits in the existing idea that a paternal factor is involved in the occurrence of preeclampsia. Because pregnancy has many similarities with transplantation, we hypothesize that induction of allogeneic tolerance to the paternal HLA molecules of the fetus may be crucial. Recent data suggest that exposure, and especially oral exposure to soluble HLA (sHLA) or HLA derived peptides can lead to transplantation tolerance. Similarly, sHLA antigens, that are present in the seminal plasma, might cause tolerance in the mother to paternal antigens. In order to test whether this indeed may be the case, we investigated whether sHLA antigens are present in seminal plasma. Using a specific ELISA we detected sHLA class I molecules in seminal plasma. The level www.elsevier.com/locate/jreprimm * Corresponding author. Tel.: +31-71-5263800 fax: +31-71-5216751. E-mail address: ihbsecr@euronet.nl (F.H.J. Claas) 0165-0378/00/$ - see front matter �� 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0165-0378(99)00062-5

C.A. Koelman et al. / Journal of Reproducti6e Immunology 46 (2000) 155���166 156 varied between individuals and was related to the level in plasma. Further studies showed that these sHLA class I molecules included classical HLA class I alleles, such as sHLA-A2, -B7, -B51, -B35 and sHLA-A9. Preliminary data show lower levels of sHLA in seminal plasma in the preeclampsia group, although not significantly different from the control group. An extension of the present study is necessary to verify this hypothesis. �� 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Soluble HLA sHLA-I Preeclampsia Sperm Tolerance Oral sex 1. Introduction Presently, there is plenty of circumstantial, mostly epidemiologic evidence that immune mechanisms are involved in the etiology of preeclampsia. Genuine preeclampsia is primarily a disease of first pregnancies. A previous normal pregnancy is associated with a significantly decreased incidence of preeclampsia in subsequent pregnancies (Campbell, 1985). Even a previous abortion provides some protection (Strickland, 1986). The protective effect of multi parity, however, is lost with change of partner (Feeney, 1980 Ikedife, 1980 Chng, 1982 Campbell, 1985 Robillard et al., 1993 Dekker et al., 1998). Additionally, preeclampsia occurs more frequently in pregnancies induced by artificial insemination by a donor (Serhal and Craft, 1987). Moreover, the length of unprotected sexual cohabitation before conception appears to be inversely related to the incidence of pregnancy-induced hypertensive disorders (Marti and Herrmann, 1977 Klonoff-Cohen, 1987 Robillard, 1994). Thus, preeclampsia may be a problem of primipaternity rather than primigravidity (Robillard et al., 1993). These findings support the idea that males might tolerize the female partner prior to gestation. It was shown before that sHLA class I molecules are detectable in seminal plasma by ELISA techniques using a monomorphic monoclonal antibody (Schaller et al., 1993), but it is not known whether these represent classical HLA class I molecules. Pregnancy has many similarities with tolerance induction to a transplanted graft whereby a certain tolerization state to foreign HLA molecules is important for graft survival. Blood transfusions (contact with foreign HLA molecules) have a beneficial effect in developing transplantation tolerance (Opelz et al., 1973) and is also associated with a decreased occurrence of preeclampsia (Feeney, 1977). In addition, it has been reported that sHLA molecules can induce specific tolerance by the induction of apoptosis in alloreactive T cells (Zavazava and Kronke, 1996). Because it is well known that especially oral exposure to antigens can induce tolerance (Sosroseno, 1995 Brandtzaeg, 1996) we wondered if this way of tolerance induction might play a role in pregnancies. Exposure of