Cellular immune responses in the pathophysiology of preeclampsia

Abstract

Preeclampsia, defined as new-onset hypertension accompanied by proteinuria occurring at 20 weeks of gestation or later, is a leading cause of perinatal morbidity and mortality worldwide. The pathophysiology of this major multi-systemic syndrome includes defective deep placentation, oxidative stress, endothelial dysfunction, the presence of an anti-angiogenic state, and intravascular inflammation, among others. In this review, we provide a comprehensive overview of the cellular immune responses involved in the pathogenesis of preeclampsia. Specifically, we summarize the role of innate and adaptive immune cells in the maternal circulation, reproductive tissues, and at the maternal-fetal interface of women affected by this pregnancy complication. The major cellular subsets involved in the pathogenesis of preeclampsia are regulatory T cells, effector T cells, NK cells, monocytes, macrophages, and neutrophils. We also summarize the literature on those immune cells that have been less characterized in this clinical condition, such as γδ T cells, invariant natural killer T cells, dendritic cells, mast cells, and B cells. Moreover, we discuss in vivo studies utilizing a variety of animal models of preeclampsia to further support the role of immune cells in this disease. Finally, we highlight the existing gaps in knowledge of the immunobiology of preeclampsia that require further investigation. The goal of this review is to promote translational research leading to clinically relevant strategies that can improve adverse perinatal outcomes resulting from the obstetrical syndrome of preeclampsia.

Keywords: NK cell; T cell; gestational hypertension; hypertensive disorders of pregnancy (HDP); immune cell; macrophage; monocyte; natural killer cell; neutrophil; pregnancy; regulatory T cell.

Figure 1.

The role of innate and adaptive immune cells in the pathophysiology of preeclampsia. In the maternal circulation (upper image), a large body of evidence has implicated adaptive immune cells such as regulatory T cells, effector T cells, γδ T cells, and B cells as well as innate immune cells, namely natural killer cells, invariant natural killer T cells, neutrophils, monocytes, and dendritic cells, in the cellular mechanisms that take place in women with preeclampsia. In the decidua (lower image), studies have described alterations in natural killer cells, neutrophils, dendritic cells, mast cells, and tissue-resident macrophages as well as regulatory T cells, effector T cells, γδ T cells, and B cells that occur in women with preeclampsia. Future studies may focus on crosstalk between local and systemic immune cells to provide a more interconnected picture of cellular immune responses that occur as part of the pathophysiology of preeclampsia.

Figure 2.

An imbalance between regulatory and effector T cells in the pathophysiology of preeclampsia. During normal pregnancy, regulatory T cells in the maternal circulation (upper panel) and the decidua (lower panel) mediate effector T cell activity to prevent aberrant immune responses. Such balance is disrupted in women with preeclampsia, where systemic and local proportions of regulatory T cells are decreased and effector T cells exhibit greater activation and function.