The Neglected Uterine NK Cells/Hamperl Cells/Endometrial Stromal Granular Cell, or K Cells: A Narrative Review from History through Histology and to Medical Education.

Reproductive immunology is at the forefront of research interests, aiming to better understand the mechanisms of immune regulation during gestation. The relationship between the immune system and the implanting embryo is profound because the embryo is semi-allogenic but not targeted by the maternal immune system, as expected in graft-versus-host reactions. The most prominent cell population at the maternal-fetal interface is the population of uterine natural killer (uNK) cells. Uterine NK cells are two-faced immunologically active cells, bearing comparison with Janus, the ancient Roman god of beginnings and endings. Their first face can be seen as natural killer cells, namely lymphocytes, which are critical for host defense against viruses and tumors. Even though uNK cells contain cytolytic molecules, their cytotoxic effect is not applied to classical target cells in vivo, playing a permissive rather than a defensive role. Their second face is crucial in maintaining physiological gestation-uNK cells show critical immunomodulatory functions with the potential to control embryo implantation and trophoblast invasion, regulate placental vascular remodeling, and promote embryonic/fetal growth. Therefore, we believe that their current designation "natural killer cells" (the first "cytotoxic" Janus's face) is misleading and inappropriate, considering their principal function is supporting and maintaining pregnancy. In this narrative review, we will focus on three lesser-known areas of knowledge about uNK cells. First, from the point of view of histology, we will comprehensively map the history of the discovery of these cells, as well as the current histological possibilities of their identification within the endometrium. To be brief, the discovery of uNK cells is generally attributed to Herwig Hamperl, one of the most influential and prominent representatives of German pathology in the 20th century, and his co-worker, Gisela Hellweg. Secondly, we will discuss the interesting aspect of terminology, since uNK cells are probably one of the human cells with the highest number of synonymous names, leading to significant discrepancies in their descriptions in scientific literature. From the first description of this cell type, they were referred to as endometrial granulocytes, granular endometrial stromal cells, or large granular lymphocytes until the end of the 1980s and the beginning of the 1990s of the last century, when the first publications appeared where the name "uterine NK cells" was used. The third area of present review is medical teaching of histology and clinical embryology. We can confirm that uNK cells are, in most textbooks, overlooked and almost forgotten cells despite their enormous importance. In the present narrative review, we summarize the lesser-known historical and terminological facts about uNK cells. We can state that within the textbooks of histology and embryology, this important cell population is still "overlooked and neglected" and is not given the same importance as in fields of clinical research and clinical practice.

Morphology of the immune cells in the wall of the human uterine tube and their possible impact on reproduction-uterine tube as a possible immune privileged organ.

The uterine tube, as well as other parts of the upper female reproductive system, is immunologically unique in its requirements for tolerance to allogenic sperm and semi-allogenic embryos, yet responds to an array of sexually transmitted pathogens. To understand this dichotomy, there is a need to understand the functional morphology of immune cells in the wall of the uterine tube. Thus, we reviewed scientific literature regarding immune cells and the human uterine tube by using the scientific databases. The human uterine tube has a diverse population of immunocompetent cells representing both the innate and adaptive immune systems. We describe in detail the possible roles of cells of the mononuclear phagocyte system (macrophages and dendritic cells), T and B lymphocytes, natural killer cells, neutrophils and mast cells in association with the reproductive functions of uterine tubes. We are also discussing about the possible "immune privilege" of the uterine tube, as another mechanism to tolerate sperm and embryo without eliciting an inflammatory immune response. In uterine tube is not present an anatomical blood-tissue barrier between antigens and circulation. However, the immune cells of the uterine tube probably represent a type of "immunological barrier," which probably includes the uterine tube among the immunologically privileged organs. Understanding how immune cells in the female reproductive tract play roles in reproduction is essential to understand not only the mechanisms of gamete transport and fertilization as well as embryo transport through the uterine tube, but also in improving results from assisted reproduction.