Enhanced cytotoxic phenotype, all of the events entailed in regular embryo implantation are dysregulated. On account of their increased cytotoxic phenotype, this abnormal uNK cells subpopulation fails to appropriately interact with EVT cells, and as an alternative they attack and destroy EVTs. Moreover, secretion of development hormones and cytokines by abnormal uNK cells is compromised, lowering EVTs invasion in to the decidua. In the end, abnormal uNK cells fail to promote spiral arteries remodeling. These events bring about implantation failure or to impaired pregnancy maintenance, sooner or later resulting in miscarriage. RIF: recurrent implantation failure; RM: recurrent miscarriage; uNK: uterine organic killer cells; EVT: extravillous trophoblast; HLA-G: human leukocyte antigen G; KIR: killer cell immunoglobulin-like receptor; MMPs: matrix metalloproteinases; VEGF: vascular endothelial development factor.Biomedicines 2021, 9,12 ofPrior to advocating the prospective clinical application of uNK cells in diagnosis, prognosis, and therapy of sufferers with RIF and RM, a step forward should be taken with regards to introducing a standardized methodology for assessing the density of uNK cells, as described above. Buttressing the truth that the discrepancies might constitute valid grounds for such contradicting proof amongst studies, it has been reported that, in ladies with RIF, unique subpopulations of lymphocytes could or might not be detected because of the methodology employed [59,64]. Flow cytometry or immunocytochemistry enable identification of uNK cells. Nonetheless, both present with confounders. As an illustration, in flow cytometry, agents in the peripheral blood could compromise the outcomes, contrary to immunocytochemistry, exactly where cells inside the blood vessels could be quickly distinguished [59]. This fact becomes relevant when we contemplate that the lack of a standardized technique of evaluation is regarded a hindrance for researchers when publishing uNK information. Resolving this lack of consensus with regards to what is a regular or excessive uNK cell numbers is an crucial prerequisite that may ascertain publication of useful data by unique sources. This will, in turn, allow a comparison among studies and protected conclusions to be drawn. Another limitation that published studies are posing refers to the selection of stimulation protocols to which females undergoing IVF have already been subjected. NK cell subpopulations could undergo alterations connected with all the stimulation protocols employed. Hence, comparing studies that are carried out in IVF cycles employing distinct stimulation approaches raises a bias [69]. Research investigating the efficiency from the aforementioned therapies and pharmaceutical protocols present with extreme confounders stemming from the process of endometrial biopsy employed. Performing endometrial biopsy to Didesmethylrocaglamide Autophagy evaluate a treatment’s impact on uNK cells’ levels might compromise assessment in the therapeutic impact itself [77]. It is crucial, (-)-Bicuculline methochloride In Vivo albeit difficult, for studies to record uNK cells in peripheral blood simultaneously with all the biopsy in an effort to elaborate on a potential systemic or neighborhood effect [74]. A summary with the part of uNK cells on the events entailed through embryo implantation as well as around the pathophysiological mechanisms involved in RIF and RM is presented in Figure 1. 4. Immunotherapy Choices for uNK Connected RIF and RM There are several therapy protocols proposed in literature serving as tools for the management of individuals diagnosed with RIF and RM tha.