Gene expression of the constant region of the heavy chain of immunoglobulin G (IgG CRHC) is down-regulated in human decidua in association with preeclampsia

Abstract

An aberrant interaction at the maternal/fetal interface between the genetically distinct fetal trophoblast cells and cells of the maternal decidua has been proposed as an initiating factor in one of the major complications of human pregnancy, preeclampsia. Biochemical and epidemiological studies suggest that the immune system plays an important role in preeclampsia. Thus, the aim of this study was to determine the decidual gene expression status in preeclampsia of one of the key components of the adaptive immune system. Total RNA was extracted from decidua collected from women with normal pregnancies and those complicated by preeclampsia. Reverse Northern analysis was performed on 72 cDNAs from human decidua and differentially expressed genes identified were analysed further using semi-quantitative RT-PCR and Northern blot analysis. Expression of the gene encoding the constant region of the heavy chain of immunoglobulin G (IgG CRHC) was shown to be down-regulated in association with preeclampsia. These data support the hypothesis that immune maladaptation may play an important role in the pathogenesis of preeclampsia.

Introduction

Human pregnancy is a complex and precisely choreographed process; from conception and implantation of the blastocyst, formation of the placenta, maternal adaptation to pregnancy, through fetal development, and finally to labour and birth. One of the crucial elements in a successful pregnancy is the accommodation by the mother of her genetically distinct offspring. This unique state of immunological tolerance encompasses the interaction of the paternal/fetal allograft with maternal tissues at the time of mating, conception, implantation and throughout gestation (Sibai, 1991). It is the intimate and complex interaction between the fetal cells of the placenta and the maternal cells that line the pregnant uterus (decidua) that has generated considerable interest. It is in this milieu that genetically distinct cells must accommodate each other for their mutual benefit. An inability to do so may contribute to a number of complications of pregnancy, including preeclampsia.

Preeclampsia is the most common serious medical disorder of pregnancy, affecting 2–10% of all human births. Occurring in the mid-to-late stages of pregnancy, preeclampsia is traditionally diagnosed by three clinical signs: pregnancy-induced hypertension, proteinuria and generalised oedema. If untreated, preeclampsia leads to severe clinical deterioration marked by maternal multisystem organ dysfunction and fetal compromise (Roberts and Redman, 1993, Working Group on High Blood Pressure in Pregnancy, 2000). Delivery of the baby and placenta, irrespective of gestation, remains the only definitive treatment. Due to the complex maternal, paternal/fetal and unknown linking factors interacting within a framework of genetic susceptibility, the exact cause of preeclampsia is still not known. However, for more than a century investigators have postulated that immunologic factors play a role in preeclampsia. Evidence from epidemiological studies proposes a link between the immune system and preeclampsia, in particular focussing on the contribution of paternal/fetal antigens. The concept of an immune response to paternal/fetal antigens is largely based on observations such as: (1) approximately 75% of women with eclampsia are nulliparous (Chesley, 1984); (2) the risk of preeclampsia/eclampsia is decreased after the first normotensive pregnancy (Cooper and Liston, 1979, Eskenazi et al., 1991, Jacobs et al., 2003); (3) the protective effect of multiparity is largely lost with a change in partner (Trupin et al., 1996, Robillard et al., 1999, Saftlas et al., 2003); (4) artificial donor insemination and donor oocyte pregnancies lead to an increased risk of preeclampsia (Need et al., 1983, Blanchette, 1993, Smith et al., 1997); and (5) increased exposure to semen (e.g. length of cohabitation, use of oral contraceptives) may be protective (Klonoff-Cohen et al., 1989, Robillard et al., 1994).

Evidence to date suggests that an aberrant interaction between the genetically distinct cells at the maternal/fetal interface may be the initiating factor. During implantation and placentation, foreign antigens are expressed on fetal trophoblast cells which interact with the maternal system; cytotrophoblast and syncytiotrophoblast populations are bathed in maternal blood within the intervillous space while the invasive trophoblasts are in intimate contact with the maternal cells of the decidua, including the uterine spiral arteries. A key morphological lesion associated with preeclampsia is the reduced penetration and remodelling of the uterine spiral arteries by trophoblasts (Brosens et al., 1970, Pijnenborg et al., 1991, Meekins et al., 1994). One hypothesis is that, in preeclampsia, the normal function of the fetal trophoblast cell is compromised by an aberrant maternal immune attack on these foreign cells. MacGillivray (1958) stated that “a first pregnancy confers considerable immunity since the incidence of preeclampsia is so low in a second pregnancy”. To date, there has been no conclusive evidence of the involvement of an antibody, traditionally associated with adaptive immunity, in an aberrant maternal immune response in preeclampsia. In this study, we provide the first evidence of altered expression of a component gene of the adaptive immune system in association with preeclampsia.