THE ROLE OF NATURAL KILLER CELLS IN PREGNANCYIntroduction
Less than half of clinically-established pregnancies end successfully withoutcomplication(Kwak-Kim
). Complications include preeclampsia, fetal growth restriction(FGR), recurrent miscarriage (RM), still birth and preterm labour. Adverse maternal immuneresponses to fetal cells may provide an explanation for the problems affecting pregnancy. Thisimmune response is initiated when maternal and fetal cells come into contact during placentation(Moffett & Loke 2006). The mechanism for placentation in humans is known as haemochorialplacentation. In this mode trophoblast cells, made up of cytotrophoblast and syncytiotrophoblastcells, are at the surface of the fetus and interact with maternal cellsExtravillous trophoblast (EVT) cells invade maternal spiral arteries and convert them intohigh conductance, low pressure vessels that can transport an adequate blood supply at anappropriate level of pressure to the fetus(Jauniaux
2006). While this is essential for thesurvival of the fetus is has a major drawback in that it exposes the fetus to a potential hazardousmaternal immune response(Moffett & Loke 2006). The uterus is a unique environment andcontains an array of immune cells including macrophages, T lymphocytes, regulatory T cells,NK T cells and dendritic cells.
Natural Killer Cells
NK cells are derived from the common lymphoid progenitor in the bone marrow, and arepresent in blood, spleen, liver, lungs and bone marrow, although they infiltate other organsduring an inflammatory response. They respond non-specifically to infection and are a keycomponent of the innate immune system, as opposed to the adaptive immune system in that theyrecognise non-self by identifying certain non-specific, conserved components of non-self microorganisms, they have no immunological memory and they become active immediately.This contrasts with the adaptive immune system that recognises specific molecules on foreigninvaders, that is activated later on in the immune response and that possess immunologicalmemory. NK cells recognise and kill infected cells in the body by releasing lytic granules whichcontain granzymes and perforin.
Activation and Recruitment of NK cells
NK cells are recruited activated by cytokines and chemokines which are secreted bystromal cells and macrophages. The most important of these activating molecules are interferon(IFN)-
β, interleukin (IL)
-12 and IL-15. IFN-
β are produced by cells that detect
intercellular viral replication and cells that recognise Toll-like receptors on the surface of a virus.Interferons stimulate NK cell activation, stimulate killing by cytotoxicity and stimulate furthercytokine production. IL-15 promotes maturation of NK cells and provides protection for matureNK cells. The combination of IL-15 and IL-12 stimulate NK cells to produce IFN-
γ, as does
tumour necrosis factor-
NK cell receptors
NK cells induce apoptosis by making direct contact with its target cell and therefore mustbe able to recognise self and non-self cells and healthy and non-healthy cells. NK cells areactivated by cells that have either lost an inhibitory receptor (such as downregulation of majorhistocompatibility complex (MHC) molecules) or gained an activating receptor. Interferon playsa key role as it induces the expression of MHC molecules and hence protects uninfected hostcells from degradation. Killing by NK cells is repressed by NK cell receptor binding to MHC