Recurrent implantation failure: A comprehensive summary from etiology to treatment

Innate lymphoid cells (ILCs) are a growing family of immune cells that mirror the phenotypes and functions of T cells. However, in contrast to T cells, ILCs do not express acquired antigen receptors or undergo clonal selection and expansion when stimulated. Instead, ILCs react promptly to signals from infected or injured tissues and produce an array of secreted proteins termed cytokines that direct the developing immune response into one that is adapted to the original insult. The complex cross-talk between microenvironment, ILCs, and adaptive immunity remains to be fully deciphered. Only by understanding these complex regulatory networks can the power of ILCs be controlled or unleashed in order to regulate or enhance immune responses in disease prevention and therapy.

The microbiota plays a fundamental role in the induction, education and function of the host immune system. In return, the host immune system has evolved multiple means by which to maintain its symbiotic relationship with the microbiota. The maintenance of this dialogue allows the induction of protective responses to pathogens and the utilization of regulatory pathways involved in the sustained tolerance to innocuous antigens. The ability of microbes to set the immunological tone of tissues, both locally and systemically, requires tonic sensing of microbes and complex feedback loops between innate and adaptive components of the immune system. In this review, we will highlight the dominant cellular mediators of these interactions and discuss emerging themes associated with our current understanding of the homeostatic immunological dialogue between the host and its microbiota.

Uterine spiral arteries play a vital role in supplying nutrients to the placenta and fetus, and for this purpose they are remodelled into highly dilated vessels by the action of invading trophoblast (physiological change). Knowledge of the mechanisms of these changes is relevant for a better understanding of pre-eclampsia and other pregnancy complications which show incomplete spiral artery remodelling. Controversies still abound concerning different steps in these physiological changes, and several of these disagreements are highlighted in this review, thereby suggesting directions for further research. First, a better definition of the degree of decidua- versus trophoblast-associated remodelling may help to devise a more adequate terminology. Other contestable issues are the vascular plugging and its relation with oxygen, trophoblast invasion from the outside or the inside of the vessels (intravasation versus extravasation), the impact of haemodynamics on endovascular migration, the replacement of arterial components by trophoblast, maternal tissue repair mechanisms and the role of uterine natural killer (NK) cells. Several of these features may be disturbed in complicated pregnancies, including the early decidua-associated vascular remodelling, vascular plugging and haemodynamics. The hyperinflammatory condition of pre-eclampsia may be responsible for vasculopathies such as acute atherosis, although the overall impact of such lesions on placental function is far from clear. Several features of the human placental bed are mirrored by processes in other species with haemochorial placentation, and studying such models may help to illuminate poorly understood aspects of human placentation.