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An essay for the 2011 Undergraduate Awards Competition by Evanna Mills. Originally submitted for Junior sophister mini-review (Immunology) at Trinity College, Dublin, with lecturer Prof. Luke O'Neill in the category of Life Sciences
An essay for the 2011 Undergraduate Awards Competition by Evanna Mills. Originally submitted for Junior sophister mini-review (Immunology) at Trinity College, Dublin, with lecturer Prof. Luke O'Neill in the category of Life Sciences

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Published by: Undergraduate Awards on Aug 29, 2012
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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)-
α, IFN
β, interleukin (IL)
-12 and IL-15. IFN-
α, 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-
α (TNF
 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
class I molecules; healthy cells have a relatively high number of MHC I molecules but NK cellsinduce apoptosis in cells when MHC I expression is reduced. The activation threshold of NKcells is very specific for levels of MHC class I so they can respond quickly to viruses that block MHC1 expression on host cells. This quick response avoids activation of CD8 T cells which arecytotoxic and are involved in the adaptive immune response. Killing by NK cells is activated bybinding to receptors that are induced by cell damage or receptors that are encoded by invadingviruses. These receptors are normally glycoproteins present on the surface of infected cells.The main family of human NK receptor is the killer-cell immunoglobulin-like receptor(KIR) family. KIR are either inhibitory containing long cytoplasmic tails that containimmunoreceptor tyrosine based inhibitory motifs (ITIMs) or activating through shortcytoplasmic tails, that associate through their transmembrane domains with a molecule calledDAP12. Each NK cell expresses 1 to 5 different KIR receptors that bind a range of MHC 1variants. These polymorphisms become very important when considered with respect to uNKs.NK cells also express Fc receptors, the most common of which CD16. When Fc receptorson the cell surface are bound to the Fc region of an antibody, or to a soluble mediator, theystimulate the release of cytokines such as IFN-
γ and the NK cell cytotoxic granules which leads
to apoptosis of the target cell. The destruction of antibody-coated target cells by NK cells iscalled antibody-dependent cell-mediated cytotoxicity.
 NK subpopulations
One of the two NK subpopulations(Cooper
2001), CD56
NK cells aremore cytotoxic and comprise about 90% of the NK population, compared with the secondpopulation, CD56
NK cells, which are less cytotoxic and make up the remaining 10%.These less cytotoxic cells are primarily responsible for secreting many immunoregulatorycytokines, including IFN-
γ, TNF
β, IL
-10, IL-13 and granulocyte-macrophage colony-stimulating factor (GM-CSF)(Cooper et al. 2001). CD56
NK cells, which are abundant inthe deciduas(Hanna
2003), can migrate to secondary lymphoid organs and non-lymphoidorgans, such as the uterus. CD56
cells express low levels of CD16 and therefore cannotperform antibody-dependent cell-mediated cytotoxic function(Bryceson
2006)and areconsidered to be a regulatory subset of NK cells.
Properties of uNK cells
The majority of uNK cells are of the non-toxic or regulatory CD56
class and aresimilar to pbCD56
NK cells(Hanna et al. 2003)although their expression of KIRs ishigh and they also express an activating receptor, NKp44, that only activated pbNKs express;this suggests that uNKs might be activated in the decidual environment(El Costa
2008).uNKs also display inhibitory receptors that may play a role in reducing the cytotoxcity of thesecells via interactions with human leukocyte anitigen (HLA)-G, a member of the family of MHCclass I complexes, and HLA-E present on trophoblast cells(El Costa et al. 2008).  Inhibitory KIRs have a long cytoplasmic tails while activating receptors have short tails(Bashirova
2006). Each KIR locus has 2 alleles, resulting in three possible genotypes, AA,AB or BB(Hiby
). Six of the seven A haplotypes code for inhibitory KIRs, while Bhaplotypes have several additional activating KIR genes. So the maternal genotype could be AA(no activating KIR), AB or BB (both having 1-10 activating KIRs). Expression of 2DS1 gene,which codes for an activating KIR, on the B haplotype is crucial(Hiby et al.). These KIRsinteract with either HLA-C1 or HLA-C2 molecules, which are present on the invading EVTcells; the allotypes differ in an amino acid present at position 80 with C1 possessing an
asparagine and C2 a lysine(Sharkey
2008). This allows for a large range of possible KIR,HLA-C phenotypes which prove to be very important in the success of pregnancy.EVT display specific pattern of HLA molecules including HLA-G and HLA-E, which areinvariant, and HLA-C which is polymorphic(Moffett-King 2002)allowing it to function as analloantigen that requires allo-recognition by uNKs(Hiby et al.). Sharkey and colleagues (2008)have shown that mRNA and protein expression of KIRs that specifically recognize HLA-C ishigh in early pregnancy. It has been shown that both the number of uNK cells expressing KIRspecific for HLA-C, and the level of expression of these KIRs is increased compared with pbNKcells(Verma
 KIR repertoire is dynamic
Changes in the KIR repertoire occurs over the course of pregnancy, with the mostdramatic changes during the first few weeks of pregnancy(Sharkey et al. 2008). Expression of KIRs specific for HLA-C on uNK, compared with pbNK, cells, is high during the first weeks of pregnancy, corresponding major trophoblast invasion, and drops as pregnancy progresses; 40-90% of uNK cells expressed KIR2DL3/L2/S2 and 25-80% showed positive expression of KIR2DL1/S1. These declined with gestation but expression on pbNK cells was unchanged. EVTcells do not express KIRs specific for HLA-B allotypes and therefore low and constant levels of expression were observed during pregnancy. Further analysis revealed that inhibitory (2DL1,2DL2, 2DL3) and activating (2DS1, 2DS2) KIRs that recognize HLA-C were expressed to agreater extent in uNK, compared with pbNK, cells, in contrast with KIR2DL5 and KIR3DL1,which interact with HLA-B. These findings suggest that there is independent regulation of KIRsin blood and decidua(Sharkey et al. 2008).
Certain KIR-HLA-C interactions can be more beneficial than others
Polymorphism of both KIR and HLA-C molecules exist and experimentation indicatesthat certain combinations may be detrimental to pregnancy(Hiby et al.). The KIR haplotypes aredivided into two regions: centromeric and telomeric. HLA-C1 binds to the inhibitoryKIR2DL2/3, and HLA-C2 binds to the inhibitory KIR2DL1 and to the activating KIR2DS1.Increased activation can result in increased production of cytokines and angiogenic factors thatregulate placentation.Hiby and colleagues (2010) took a genetic approach to understanding how the differentKIR/HLA-C combinations affected the success of placentation and pregnancy. They showed thatEVT express both maternal and paternal HLA-C molecules and in equal proportion indicatingthat maternal KIRs are capable of allorecognition of paternal HLA-C as well as self recognitionand that both maternal and paternal HLA-C molecules contribute to reproductive success(Hibyet al.). Their work has confirmed that the KIRAA expression is significantly increased inpregnancies affected by preeclampsia, FGR and RM(Hiby
2004). As well as this, it wasshown that, in affected pregnancies, there were increased C2 carrier frequencies in both motherand fetus. The most dangerous combination was determined to be KIRAA and C2.There are 3 possible genotypes of the HLA-C: homozygous for C1 (C1/C1),heterozygous (C1/C2), and homozygous for C2 (C2/C2) and this applies to both the fetus and themother. It is likely that the uNKs are educated in some way and therefore have an estimate of thelevels of C2 present maternally. The fetus could have equal, less or greater numbers of C2 genesthan the mother and this can affect the uNK response.In all affected cases there is a greater number of KIRAA than in the control(Hiby et al.2004). It has also been shown that, in pregnancies where the fetus has more C2 genes than themother, the levels of KIRAA are significantly higher, so a greater number of fetal C2 genes

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