Autoimmune Activation toward Embryo Implantation is Rare in Immune-Privileged Human Endometrium

Abstract

Human embryo implantation represents embryo apposition, adhesion to the endometrial epithelium, and invasion into the stromal extracellular matrix within 1 to 2 days during days 6 to 9 after ovulation. The major molecular mechanisms mediating implantation include adhesion molecules, including mucins, selectins, integrins, and cadherins; extracellular matrix components, such as laminins and collagens and their degrading enzymes; phospholipids and immune regulatory molecules, including prostaglandins, cytokines; and immunosuppressive molecules expressed by invasive trophoblasts and endometrial cells. Many of these molecules are the targets for autoimmune reactions in autoimmune diseases and cancer; however, the relevance of those in immune-mediated implantation failure has not been defined. In this review, we will describe the molecules involved in 2-day event of human embryo implantation, which may also be involved in immune system activation and subsequently cause immune-mediated implantation failure. We speculate that the data in the literature are limited concerning antiendometrial antibodies because the endometrium might be taken as an immune-privileged site that avoids autoimmune activation that might harm the implantation process. Antibodies affecting human fertility in ways other than impairing implantation are outside the scope of the current article and will not be discussed.

Meta-signature of human endometrial receptivity: a meta-analysis and validation study of transcriptomic biomarkers

“…Our meta-signature of mid-secretory endometrium highlights the importance of defence responses, specifically the inflammatory response (now recognized as a type of non-specific immune response), immunoglobulin-mediated immune responses (humoral immunity) and the complement (major mediator of innate immunity), and coagulation cascade pathway in receptive-phase endometrium. Immune responses, including the inflammatory response, play important roles in the pre- and peri-implantation period, and the up-regulation of genes involved in immune responses during the mid-secretory phase was corroborated in our meta-analysis and has also been highlighted in several previous studies 20 , 31 , 47 – 49 . In order to provide a hospitable environment for the embryo, the balance should be established between the maternal immune tolerance toward a semi-allogeneic implanting embryo and the protective anti-infectious mechanisms in the receptive-phase uterus 47 , 49 .…”

Endometrial receptivity revisited: endometrial transcriptome adjusted for tissue cellular heterogeneity

“…To understand and characterize the recep-86 tive phenotype of endometrium, initially a histological dating method was developed (Noyes 87 et al, 1975). With 'omics' technologies, the understanding of molecular processes behind en-88 dometrial receptivity has evolved rapidly (Altmäe et al, 2014). Based on this knowledge, the 89 first gene expression-based clinical endometrial receptivity test was introduced in 2011 (Díaz-90…”

Immunogenetic contributions to recurrent pregnancy loss

“…While the fetus does exist in a relatively immune-privileged state, there are inflammatory responses that must occur at the appropriate time and strength for human implantation to occur. There are components of the immune system that can either promote or suppress trophoblastic implantation [34,35]. The entire state of pregnancy is in fact a proinflammatory state with most markers being elevated for the duration of pregnancy, including TNF-α, IL-1, IL-6, and IL-10, along with reduced levels of IL-2 and IFN-γ [36].…”