Immunologic aspects of preeclampsia

Abstract

Preeclampsia is a syndrome with multiple etiologies. The diagnosis can be made without proteinuria in the presence of dysfunction of at least 1 organ associated with hypertension. The common pathophysiological pathway includes endothelial cell activation, intravascular inflammation, and syncytiotrophoblast stress. There is evidence to support, among others, immunologic causes of preeclampsia. Unlike defense immunology, reproductive immunology is not based on immunologic recognition systems of self/non-self and missing-self but on immunotolerance and maternal-fetal cellular interactions. The main mechanisms of immune escape from fetal to maternal immunity at the maternal-fetal interface are a reduction in the expression of major histocompatibility complex molecules by trophoblast cells, the presence of complement regulators, increased production of indoleamine 2,3-dioxygenase, activation of regulatory T cells, and an increase in immune checkpoints. These immune protections are more similar to the immune responses observed in tumor biology than in allograft biology. The role of immune and nonimmune decidual cells is critical for the regulation of trophoblast invasion and vascular remodeling of the uterine spiral arteries. Regulatory T cells have been found to play an important role in suppressing the effectiveness of other T cells and contributing to local immunotolerance. Decidual natural killer cells have a cytokine profile that is favored by the presence of HLA-G and HLA-E and contributes to vascular remodeling. Studies on the evolution of mammals show that HLA-E, HLA-G, and HLA-C1/C2, which are expressed by trophoblasts and their cognate receptors on decidual natural killer cells, are necessary for the development of a hemochorial placenta with vascular remodeling. The activation or inhibition of decidual natural killer cells depends on the different possible combinations between killer cell immunoglobulin-like receptors, expressed by uterine natural killer cells, and the HLA-C1/C2 antigens, expressed by trophoblasts. Polarization of decidual macrophages in phenotype 2 and decidualization of stromal cells are also essential for high-quality vascular remodeling. Knowledge of the various immunologic mechanisms required for adequate vascular remodeling and their dysfunction in case of preeclampsia opens new avenues of research to identify novel biological markers or therapeutic targets to predict or prevent the onset of preeclampsia.

Keywords: coevolution of the KIR receptors and their cognate antigens; decidual cells; decidual macrophage; decidual natural killer cells; defense immunology; endometrial stromal cells; fetal HLA-C antigens; hemochorial placenta; immunologic aspects; immunologic escape mechanisms; immunologic protection mechanisms of a transplant; immunologic protection mechanisms of a tumor process; mammal phylogeny; mechanisms of immunologic fetal escape; preeclampsia; regulation of extravillous trophoblast invasion; regulatory T cells; reproductive immunology; uterine KIR receptors; vascular remodeling of the uterine spiral arteries.

Figure 1

CTLA-4–IDO–tryptophan pathway at the maternal–fetal interface APC, antigen-presenting cell; CD4, lymphocyte CD4 T (induced expression of CTLA-4) or T regulatory cell (constitutive expression of CTLA-4); CMH, complex major histocompatibility; Treg, regulatory T cell.

Figure 2

Proportion of regulatory T cells and cytotoxic CD8 cells in the decidua of healthy pregnancy and preeclampsia In preeclampsia, the number of cytotoxic CD8 cells without expression of PD-1 increased, whereas the number of T Reg cells decreased. In healthy pregnancy, the number of non-cytotoxic CD8 cells with expression of PD-1 increased, whereas the number of T Reg cells also increased. APC, antigen-presenting cell; CMH, complex major histocompatibility; CTLA-4, cytotoxic T-lymphocyte associated protein 4; EVT, extravillous trophoblast; PD-1, programmed cell death protein-1; PDL-1, programmed cell death ligand-1; T Reg, regulatory T cell.

Figure 3

Immunologic similarities and differences between a placenta, a tumor, and a transplant APC, antigen-presenting cell, DSA, donor-specific antigen; MHC, major histocompatibility complex; NK, natural killer; TME, tumor microenvironment.

Figure 4

Interactions between NK cell and target cell in peripheral circulation and decidual microenvironment with the balance between activating and inhibitory receptors that determines the NK cell activity corresponding to cytotoxicity for circulating NK cells and to the production of cytokines for decidual NK cells LILR, leukocyte immunoglobulin-like receptor; MHC, major histocompatibility complex; NCR, natural cytotoxicity receptor.

Figure 5

Interactions between receptors expressed by decidual NK cells and HLA class I ligands expressed by extravillous trophoblast cells at the maternal–fetal interface in human with their effects on decidual NK cells LILR, leukocyte immunoglobulin-like receptor; NK, natural killer.

Figure 6

Estimation of the risk of early preeclampsia based on the combinations between uterine KIR receptors and fetal HLA-C1 and HLA-C2 antigens Adapted from Moffett et al. NK, natural killer.