Maternal-Fetal Immunology and Preeclampsia

Preeclampsia is a disease unique to pregnant humans characterized by elevated blood pressures (BPs) and proteinuria. The mild form of preeclampsia is defined as BPs >140/>90 on two occasions, 6 hours apart, as well as >300mg of protein in the urine when collected over 24 hours. When a patient meets the criteria for severe preeclampsia her BPs are >160/>110 with >5 grams of protein in a 24 hour urine collection. These findings must occur at > 20 weeks of pregnancy.
While preeclampsia only affects 5-8% of pregnancies, it is responsible for major maternal and fetal morbidity and mortality worldwide due to: seizures (eclampsia), stroke, renal failure, pulmonary edema, placental abruption, and hemorrhage. Currently, the only “cure” for preeclampsia is delivery. Since preeclampsia also can occur in pregnancies that do not contain a fetus (i.e. molar pregnancies) and is more common in multiple gestations (i.e. twins, triplets, etc.), it is believed that the placenta is the main perpetrator in the pathogenesis of the disease. (1,2)
The placenta is therefore under intense study in attempt to understand the etiology of preeclampsia. The Maternal-Fetal immune interface involves several areas of placental growth and development that are likely pivotal in the development of preeclampsia. The human placenta is the organ that connects the mother’s blood supply, via the uterus, to the developing fetus, via the umbilical vein.
One cell type pertinent to placental immunology is the syncytiotrophoblast. These cells line the fetal “capillaries,” aka the chorionic villi. Syncytiotrophoblasts are unique in that they express no HLA. Therefore, they are “immunologically privileged” in that they cannot be recognized by the maternal immune system and do not present foreign antigen (i.e. fetal antigen). Syncytiotrophoblasts are the barrier between the fetal circulation and the intervillous space, which is where the maternal blood supply empties, creating the main communication between the mother and growing fetus.(3)
As the human placenta develops, invasive cytotrophoblasts (cells generated from the developing embryo) penetrate into the muscular layer of the uterus (myometrium) that contains a copious blood supply. It is thought that uterine Natural Killer (uNK) cells aid in this invasion. The uNK cells are specialized to produce cytokines and growth factors that promote cytotrophoblast growth and invasion, but they are only weakly cytotoxic.(4)
Ultimately, the cytotrophoblasts alter the architecture of the maternal “spiral” arteries (those arteries that penetrate the myometrium and “empty” into the intervillous space) and become essentially the endothelial lining of these arteries. This converts uterine blood flow to the spiral arteries from a high velocity, high resistance area in the non-pregnant state into a low-velocity, low resistance area in pregnancy that aids in the perfusion of the placenta and, thus, the fetus.(5)
Tremendous research is going into the investigation of preeclampsia and how cytotrophoblastic invasion of the myometrium is involved in the development of this disease. Cytotrophoblasts (which are fetal) can express HLA-C, HLA-E, or HLA-G. It is the combination of these with the highly polymorphic uNK cell Ig-like receptors (KIRs) that have been implicated heavily in the facilitation or inhibition of the cytotrophoblastic invasion. Proper or improper invasion either protects against or stimulates the pathogenesis of preeclampsia. This depends on how well the fetal HLA type “interacts” with the maternal uNK KIRs.
Uterine NK KIRs recognize HLA-C. However, as the KIRs genes are polymorphic, they can be variable in their ability to express activating receptors. For example, individuals with the KIRs “AA” phenotype usually have no activating receptors while those individuals who express the “B” haplotype have copious activating receptor expression. So, depending on the maternal KIRs phenotype and fetal HLA-C epitopes expressed, invasion of the maternal vasculature by cytotrophoblasts is either hindered or facilitated.(6)
If invasion into the maternal vasculature by cytotrophoblasts is hindered, development of the placenta is impaired. Early in pregnancy, this triggers oxidative stress in the placenta in its attempt to improve communication with the maternal blood supply. This oxidative stress leads to the release of many of the factors identified previously in the serum of women who will ultimately develop the clinical syndrome of preeclampsia. These factors include sFlt-I (soluble VEGF-receptor I), syncytiotrophoblastic debris, complement, endothelial microparticles, as well as other yet unidentified players. Release of these factors also contributes to the clinical characteristics of the disease.
The release of these factors by a “sick” placenta leads to endothelial dysfunction in the maternal circulation and an amplified maternal systemic inflammatory response that is manifested as labile elevated blood pressures and proteinuria resulting from intermittent vasospasm.(7,8) In preeclampsia, therefore, the maternal-fetal immune response is deranged. Initiated by poor placentation, preeclampsia begins as a local pathology early in pregnancy that becomes amplified and systemic in the third trimester. The resultant cascade of events, including endothelial damage and metabolic derangement, represent the clinical illness that we ultimately diagnose as preeclampsia. (9)


1 Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK. Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol 1989; 161(5): 1200-4.
2 Redman CWG, Sargent IL. Latest advances in understanding preeclampsia. Science. 2005;308:1592-1594.
3 Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005;365(9461):785-99.
4 Redman CWG. Immunology of preeclampsia. Society of Gynecologic Investigation annual meeting. Feb 2006:19-20
5 Redman CWG, Sacks GP, Sargent IL. Preeclampsia: an excessive maternal inflammatory response to pregnancy. Am J Obstet Gynecol. 1999;180:499-506.
6 Hiby, SE, Walker JJ, O’Shaughnessy KM, et al. Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success. J Exp Med. 2004;200:957-965.
7 Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004; 350(7):672-83.
8 Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 2003;111(5):649-58.
9 McMaster MT, Zhou Y, Fisher SJ. Abnormal placentation and the syndrome of preeclampsia. Semin Nephrol 2004; 24(6):540-7.