Endometrial Immune Dysfunction in Recurrent Pregnancy Loss

Abstract

Recurrent pregnancy loss (RPL) represents an unresolved problem for contemporary gynecology and obstetrics. In fact, it is not only a relevant complication of pregnancy, but is also a significant reproductive disorder affecting around 5% of couples desiring a child. The current knowledge on RPL is largely incomplete, since nearly 50% of RPL cases are still classified as unexplained. Emerging evidence indicates that the endometrium is a key tissue involved in the correct immunologic dialogue between the mother and the conceptus, which is a condition essential for the proper establishment and maintenance of a successful pregnancy. The immunologic events occurring at the maternal–fetal interface within the endometrium in early pregnancy are extremely complex and involve a large array of immune cells and molecules with immunoregulatory properties. A growing body of experimental studies suggests that endometrial immune dysregulation could be responsible for several, if not many, cases of RPL of unknown origin. The present article reviews the major immunologic pathways, cells, and molecular determinants involved in the endometrial dysfunction observed with specific application to RPL.

Maternal Obesity and the Uterine Immune Cell Landscape: The Shaping Role of Inflammation

“…Th1, Th2, and Th17 cells constitute the main subtypes of effector CD4 + T cells [65]. Th1 secrete IFN-γ and IL-2 as their signature cytokines and these factors in part orchestrate the complex interactions and cross-talk between decidual immune and endometrial cells with the fetal semiallograft, which contribute to pregnancy pathologies such as recurrent spontaneous abortion [66][67][68][69].…”

“…Furthermore, HLA-G binding to LILRB2 expressed on decidual APCs promotes a tolerogenic phenotype within decidual Mφ and DCs via secretion of IL-10 and TGF-β; these factors induce Treg expansion and limit T cell effector functions [211][212][213][214]. Alterations in immune function resulting from pro-inflammatory environmental cues could translate into impaired maternal-fetal tolerance resulting in impaired placentation, chronic inflammation, and poor pregnancy outcome [69,213].…”

Molecular Signaling Regulating Endometrium–Blastocyst Crosstalk

“…[5][6][7][8][9][10][11][12][13][14][15][16].7% in developed countries and 6.9-9.3% in developing countries [12,13] and may be a consequence of low embryo quality, male problems, or female dysfunctions. Female fertility problems account for 20-35% of infertility cases and may derive from a wide variety of causes such as age, anatomical, endocrine and immunological problems, and several pathological conditions affecting the endometrium [14][15][16][17][18][19]. These conditions may lead to defects in blastocyst implantation in the maternal uterus, resulting in implantation failure, a common cause of impaired fertility [20].…”

The potential therapeutic effects of curcumin on pregnancy complications: Novel insights into reproductive medicine

“…Regulated inflammation is necessary for the successful pregnancy in any phase of reproduction, from the menstrual cycle to early or late pregnancy, and the control of this process is maintained by local immune cells that enable maternal tolerance of fetal antigens 12 . Specific conditions such as immune responses to infectious agents (e.g., lipopolysaccharide [LPS]) or autoimmunity diseases may lead to uncontrolled maternal inflammatory reactions that are found both systemically (in circulation) and locally at the placenta during pregnancy 13,14 .…”

“…[6][7][8][9][10][11] Regulated inflammation is necessary for the successful pregnancy in any phase of reproduction, from the menstrual cycle to early or late pregnancy, and the control of this process is maintained by local immune cells that enable maternal tolerance of fetal antigens. 12 Specific conditions such as immune responses to infectious agents (e.g., lipopolysaccharide [LPS]) or autoimmunity diseases may lead to uncontrolled maternal inflammatory reactions that are found both systemically (in circulation) and locally at the placenta during pregnancy. 13,14 Inflammatory conditions are characterized by increased levels of cytokines and chemokines, such as tumor necrosis factor (TNF-α), interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, interferon-gamma (INF-γ), monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein (MIP), in pregnancy disorders, including preeclampsia, intra uterine growth restriction (IUGR), gestational diabetes (GD), fetal growth restriction (FGR), and preterm birth.…”