Uterine natural killer cells exert their function by production of high levels of cytokines such as granulocyte-macrophage colony stimulating factor (GM-CSF), colony stimulating factor-1 (CSF-1) and interleukin-2 (IL-2). Recurrent miscarriage (RM) is a stressful condition for both patients and clinicians. As uterine natural killer (uNK) cells share many similar properties with peripheral blood NK cells, their population in the blood has been reported to be associated with RM. Steroids are used as anti-inflammatory agents to try to improve success of implantation, as aside from the immunology of pregnancy, there could be other inflammatory processes in the practice of in-vitro fertilization (IVF) such as stimulation from the intrauterine catheter during embryo transfer. As with RM, immunomodulation therapies have been tried to suppress NK cell activity. A recent meta-analysis of three trials shows that IvIg treatment significantly increases the live-birth rate in patients who fail IVF.

At the site where the placenta implants there is intermingling of fetal trophoblast cells with maternal tissues. Uterine natural killer (uNK) cells are defined by the high expression of the surface marker CD56 so they are designated CD56superbright. NK cells are not a feature of the myometrium so the behavior of trophoblast in the deeper part of the uterus is independent of their influence. A further potential site where maternal immune cells can interact with endovascular trophoblast is in the spiral arteries in the decidua basalis. All uNK cells express high levels of the inhibitory receptor CD94/NKG2A whose ligand is HLA-E. HLA-G is a non-classical HLA class I molecule that was identified and found to be expressed by trophoblast cells nearly 20 years ago. The overall conclusion is that the local immunity in the human implantation site is an unusual one that is reflected in the cell types present.

Reproductive immunologists have always followed mainstream immunology and tried to fit the immunology of the maternal-fetal relationship into the paradigms of the day. Attachment of the blastocyst to the uterine lining is thought to trigger the differentiation of the trophectoderm into two layers: an inner cytotrophoblast layer and an outer syncytium of syncytiotrophoblast. Adults homozygous for a highly truncated 'null' allele of human leucocyte antigen G (HLA-G) have been identified. The birth of these individuals suggests that the expression of full-length, membrane-associated HLA-G in trophoblast is not an obligate requirement for pregnancy. The various trophoblast populations differ with respect to both their expression of major histocompatibility complex (MHC) and which maternal immune cells they encounter. In humans, uterine natural killer (uNK) cells are present before implantation and in nonpregnant cycles where the number of uNK cells changes during the course of the menstrual cycle.

This chapter focuses on the role of progestin-induced decidualisation in regulating endometrial haemostasis and vascular stability. Observations made by in situ hybridisation and immunohistochemistry of endometrial sections, together with in vitro studies of human endometrial stromal cells (HESCs), indicate that progest-ininduced decidualisation creates a pro-haemostatic, vascular-stabilising milieu that resists bleeding. During decidualisation of human endometrium, the interstitial-type extracellular matrix (ECM) of the follicular phase, which is enriched in fibronectin and collagen types I, III,V and VI, is converted to a mixture of residual interstitial proteins and new peridecidual basal laminar-type components. The resulting peridecidual cell ECM plays an integral role in implantation by modulating migration of the invading trophoblast and in counteracting the threat of local haemorrhage during endovascular trophoblast invasion by serving as a vascular support and stabilising scaffolding structure. Uterine natural killer (NK) cells have been implicated in maintaining decidualisation and in limiting trophoblast invasion.