Alloimmune Causes of Recurrent Pregnancy Loss: Cellular Mechanisms and Overview of Therapeutic Approaches

Abstract

Recurrent pregnancy loss (RPL) is a complex early pregnancy complication affecting 1-2% of couples and is often linked to immune dysfunction. Aberrations in T and B cell subpopulations, as well as natural killer (NK) cell activity, are particularly influential, with studies showing that abnormal NK cell activation and imbalances in T and B cell subtypes contribute to immune-mediated miscarriage risk. Successful pregnancy requires a tightly regulated balance between pro-inflammatory and anti-inflammatory immune responses. In the early stages, inflammation supports processes such as trophoblast invasion and spiral artery remodeling, but this must be tempered to prevent immune rejection of the fetus. In this review, we explore the underlying immune mechanisms of RPL, focusing on how dysregulated T, B, and NK cell function disrupts maternal tolerance. Specifically, we discuss the essential role of uterine NK cells in the early stages of vascular remodeling in the decidua and regulate the depth of invasion by extravillous trophoblasts. Furthermore, we focus on the delicate Treg dynamics that enable the maintenance of optimal immune homeostasis, where the balance, and not only the quantity of Tregs, is crucial for fostering maternal-fetal tolerance. Other T cell subpopulations, such as Th1, Th2, and Th17 cells, also contribute to immune imbalance, with Th1 and Th17 cells promoting inflammation and potentially harming fetal tolerance, while Th2 cells support immune tolerance. Finally, we show how changes in B cell subpopulations and their functions have been associated with adverse pregnancy outcomes. We further discuss current therapeutic strategies aimed at correcting these immune imbalances, including intravenous immunoglobulin (IVIg), glucocorticoids, and TNF-α inhibitors, examining their efficacy, challenges, and potential side effects. By highlighting both the therapeutic benefits and limitations of these interventions, we aim to offer a balanced perspective on clinical applications for women facing immune-related causes of RPL.

Keywords: NK cells; T cells; alloimmune; immunotherapy; killer cell immunoglobulin-like receptors; recurrent pregnancy loss.

Figure 1

Tolerogenic immune interactions at the maternal–fetal interface: role of extravillous trophoblasts in regulating dNK cells. The figure illustrates the role of extravillous trophoblasts in interacting with maternal immune cells, promoting a tolerogenic environment critical for successful pregnancy. The extravillous trophoblast expresses HLA-G, a molecule that plays a pivotal role in modulating maternal immune responses. HLA-G interacts with receptors on decidual natural killer (dNK) cells, such as ILT2/LILRB1 and KIR2DL4, reducing dNK cell cytotoxicity and promoting a tolerogenic phenotype. These interactions support trophoblast invasion, spiral artery remodeling, and angiogenesis through the secretion of factors like VEGF, angiogenin, TNF-α, and IFN-γ via ILT4 and LILRB1 receptors, leading to reduced chemotaxis, decreased cytotoxicity, and the adoption of a tolerogenic phenotype. Naive CD4+ T cells are influenced by HLA-G through ILT2, driving their differentiation into regulatory T cells (Tregs), which are essential for maintaining immune tolerance and preventing the maternal immune rejection of the fetus. Together, these cellular interactions and immune modulations establish a supportive environment for implantation and pregnancy maintenance. dNK: decidual natural killer cell; HLA-G: human leukocyte antigen-G; ILT2/LILRB1: immunoglobulin-like transcript 2/leukocyte immunoglobulin-like receptor subfamily B1; ILT4: immunoglobulin-like transcript 4; KIR2DL4: killer immunoglobulin-like receptor 2DL4; Treg: regulatory T cells; VEGF: vascular endothelial growth factor; TNF-α: tumor necrosis factor-alpha; IFN-γ: interferon-gamma.

Figure 2

Immune recognition at the maternal–fetal interface: interactions between extravillous trophoblasts and maternal immune cells. This figure illustrates the immune interactions at the maternal–fetal interface during pregnancy, highlighting how maternal immune cells recognize fetal antigens. The extravillous trophoblasts (fetal cells) express both paternal and maternal HLA-C antigens that interact with dNK cells via KIR receptors, as well as non-classical MHC molecules like HLA-E, which engage with receptors on decidual natural killer (dNK) cells, including KIRDL1/2/3, CD94/NKG2A, and NKG2C receptors. These interactions modulate dNK cell activity, promoting a tolerogenic environment that supports implantation and placental development. The direct recognition of these HLA molecules by maternal CD8+ T cells, through T cell receptors (TCRs), represents a pathway of direct allorecognition, contributing to the immune system’s regulation at the maternal–fetal interface. Additionally, maternal antigen-presenting cells (APCs) process fetal antigens from EVTs, potentially through trogocytosis (the transfer of membrane components). These processed antigens are presented to maternal CD4+ T cells via HLA class II molecules, leading to indirect allorecognition. This interaction induces a regulatory immune response characterized by the production of tolerogenic cytokines, such as TGF-β, IL-4, and IL-10, which help suppress inflammation and protect the fetus from maternal immune rejection. In contrast, direct allorecognition occurs between maternal CD8+ T cells and fetal antigens. APC: antigen-presenting cell; TCR: T cell receptor; HLA-C: human leukocyte antigen-C (paternal and maternal); HLA-E: human leukocyte antigen-E; KIR: killer immunoglobulin-like receptors; dNK: decidual natural killer cells; CD8+ T cells: cytotoxic T cells involved in direct allorecognition; CD4+ T cells: helper T cells involved in indirect allorecognition; TGF-β: transforming growth factor-beta; IL-4, IL-10: interleukins.

Figure 3

Roles of T-helper cell subsets in immune regulation and recurrent pregnancy loss. This figure illustrates the roles of T-helper (Th) cell subsets—Th1, Th2, and Th17—in pregnancy, emphasizing their distinct cytokine production and contributions to maternal–fetal interactions. Th1 cells produce IFN-γ, TNF-α, and IL-2, supporting tissue remodeling during implantation, regulating trophoblast invasion, and activating decidual natural killer (dNK) cells. Th2 cells secrete IL-4, IL-5, IL-6, IL-10, and IL-13, promoting maternal–fetal tolerance and creating an anti-inflammatory environment crucial for sustaining pregnancy. Th17 cells produce IL-17, IL-21, and IL-22, contributing to dNK cell activation but potentially posing risks when dysregulated. The balance between these Th cell subsets is essential for successful implantation, placental development, and pregnancy maintenance. Th: T-helper cell; IFN-γ: interferon-gamma; TNF-α: tumor necrosis factor-alpha; IL: interleukin; dNK: decidual natural killer cells.