The Immunology of Preeclampsia Gustaaf A. Dekker and Baha M. Sibai The immune maladaptation hypothesis of preeclampsia is concordant with cytokine-mediated oxida- tive stress, chronology of endothelial activation, lipid changes, adverse effect of changing partners, and the protective effect of sperm exposure. Genetic factors may involve underlying hereditary thrombophilic disorders and hyperhomocysteinemia, essential hypertension and/or obesity, or con- trol of the Thl/Th2 balance and thus affect the maternal response against fetal antigens. Placental ischemia and increased syncytiotrophoblast deportation are probably end-stage disease phenomena. Copyright 9 1999 by W.B. Saunders Company p reeclampsia occurs in 3% to 5% of pregnan- cies and is a major cause (15% to 20%) of maternal mortality in developed countries and a leading cause of preterm birth and intrauterine growth retardation. 1 In this review, relevant en- dotheliai and immunologic aspects of normal pregnancy will be discussed and compared with those occurring in preeclampsia. In addition, current hypotheses regarding the etiology of preeclampsia as they relate to the primary hy- pothesis of immunologic maladaptation will be summarized. Normal Pregnancy A Vasodilatory State Generalized vasodilatation is the primary hemo- dynamic change of normal pregnancy and is already present during the luteal phase in women who subsequently become pregnant. 2 In the 1980s, pregnancy-associated biological dom- inance of prostacyclin over thromboxane-A 2 was thought to cause vascular refractoriness to vaso- constrictors and thus vasodilation. ~ More re- cently, it was demonstrated that vasodilator pros- taglandins do not mediate the attenuation of systemic and renal pressor responsiveness in pregnancy. 4,5 A number of peptide regulatory factors (cytokines, binding proteins, growth fac- tors) released in an appropriate steroid environ- From the Department of Obstetrics and Gynaecology,Free University Hospital, Amsterdam, The Netherlands; and the Department of Obstetrics and Gynecology, University of Tennessee, Memphis, TN. Address reprint requests to Baha M. Sibai, MD, Maternal-Fetal Medicine, University of Tennessee, Memphis, 853 Jefferson Ave, Suite El02, Memphis, TN 38103. Copyright 9 1999 by W.B. Saunders Company O146-0005/99/2301-0004510. 00/0 ment appear to play an integral part in this mediation, and nitric oxide may be important as final messenger. 6 In pregnant animals, pharma- cological inhibition of nitric oxide synthesis produces a preeclampsia like syndrome. 7 An endothelium-derived hyperpolarizing vasodila- tory factor is also involved in pregnancy-associ- ated vasorelaxation, s The Uteroplacental Circulation in Normal Pregnancy During the initial phases of placental develop- ment, cytotrophoblasts stream out of the tips of the anchoring villi, penetrate the overlying syn- cytiotrophoblast to form cytotrophoblast col- umns that develop into the cytotrophoblast shell. Cytotrophoblasts continue to migrate into the decidua and eventually invade the spiral ar- terioles. Endovascnlar cytotrophoblasts replace the endothelium of spiral arteries and then in- vade the media, with resulting destruction of the medial elastic, muscular, and neural tissue. The medial musculoelastic layer is replaced by a fi- brinoid matrix in which cytotrophoblasts are embedded. Eventually, cytotrophoblasts become incorporated into the wall of the vessel, and the endothelium appears to be reconstituted. These physiological changes create a low resistance to flow and absence of maternal vasomotor con- trol, which allows an enormous increase in blood supply to the growing fetus. 9 During inva- sion, cytotrophoblasts are not cytolytic but se- crete plasminogen activator and metalloprotein- ases that effect the extracellular matrix. Activity of these enzymes is influenced by mediators such as beta-human chorionic gonadotropin (/3- HCG) and cytokines2 Onset of trophoblast in- vasive behavior is associated with a shift in ex- 24 Seminars in Perinatology, Vol 23, No 1 (February), 1999: pp 24-33