Preeclampsia is a relatively common pregnancy disorder that originates in the placenta and causes variable maternal and fetal problems. In the worst cases, it may threaten the survival of both mother and baby. We summarize recent work on the causes of preeclampsia, which reveals a new mode of maternal immune recognition of the fetus, relevant to the condition. The circulating factors derived from the placenta, which contributes to the clinical syndrome, are now better understood. This brief review on preeclampsia does not cover all aspects of this intriguing condition but focuses on some new and interesting findings.

https://science.sciencemag.org/content/sci/308/5728/1592.full.pdf

Latest advances in understanding preeclampsia.

Natural killer (NK) cells were originally defined as effector lymphocytes of innate immunity endowed with constitutive cytolytic functions. More recently, a more nuanced view of NK cells has emerged. NK cells are now recognized to express a repertoire of activating and inhibitory receptors that is calibrated to ensure self-tolerance while allowing efficacy against assaults such as viral infection and tumor development. Moreover, NK cells do not react in an invariant manner but rather adapt to their environment. Finally, recent studies have unveiled that NK cells can also mount a form of antigen-specific immunologic memory. NK cells thus exert sophisticated biological functions that are attributes of both innate and adaptive immunity, blurring the functional borders between these two arms of the immune response.

/pdf/innate-or-adaptive-immunity-the-example-of-natural-killer-4ruyb8oaa3.pdf

Innate or Adaptive Immunity? The Example of Natural Killer Cells

Human CD56(bright) NK cells accumulate in the maternal decidua during pregnancy and are found in direct contact with fetal trophoblasts. Several mechanisms have been proposed to explain the inability of NK cells to kill the semiallogeneic fetal cells. However, the actual functions of decidual NK (dNK) cells during pregnancy are mostly unknown. Here we show that dNK cells, but not peripheral blood-derived NK subsets, regulate trophoblast invasion both in vitro and in vivo by production of the interleukin-8 and interferon-inducible protein-10 chemokines. Furthermore, dNK cells are potent secretors of an array of angiogenic factors and induce vascular growth in the decidua. Notably, such functions are regulated by specific interactions between dNK-activating and dNK-inhibitory receptors and their ligands, uniquely expressed at the fetal-maternal interface. The overall results support a 'peaceful' model for reproductive immunology, in which elements of innate immunity have been incorporated in a constructive manner to support reproductive tissue development.

Decidual NK cells regulate key developmental processes at the human fetal-maternal interface

MHC class I molecules are ligands for the killer-cell immunoglobulin-like receptors (KIRs), which are expressed by natural killer cells and T cells. The interactions between these molecules contribute to both innate and adaptive immunity. KIRs and MHC class I molecules are encoded by unlinked polymorphic gene families that distinguish all but the most related individuals. Combinations of MHC class I and KIR variants influence resistance to infections, susceptibility to autoimmune diseases and complications of pregnancy, as well as outcome after haematopoietic stem-cell transplantation. Such correlations raise the possibility that interplay between KIR and MHC class I polymorphisms has facilitated human survival in the presence of epidemic infections and has influenced both reproduction and population growth.

MHC class I molecules and kirs in human history, health and survival

Preeclampsia is a serious complication of pregnancy in which the fetus receives an inadequate supply of blood due to failure of trophoblast invasion. There is evidence that the condition has an immunological basis. The only known polymorphic histocompatibility antigens on the fetal trophoblast are HLA-C molecules. We tested the idea that recognition of these molecules by killer immunoglobulin receptors (KIRs) on maternal decidual NK cells is a key factor in the development of preeclampsia. Striking differences were observed when these polymorphic ligand: receptor pairs were considered in combination. Mothers lacking most or all activating KIR (AA genotype) when the fetus possessed HLA-C belonging to the HLA-C2 group were at a greatly increased risk of preeclampsia. This was true even if the mother herself also had HLA-C2, indicating that neither nonself nor missing-self discrimination was operative. Thus, this interaction between maternal KIR and trophoblast appears not to have an immune function, but instead plays a physiological role related to placental development. Different human populations have a reciprocal relationship between AA frequency and HLA-C2 frequency, suggesting selection against this combination. In light of our findings, reproductive success may have been a factor in the evolution and maintenance of human HLA-C and KIR polymorphisms.

/pdf/combinations-of-maternal-kir-and-fetal-hla-c-genes-influence-274ubx9hk3.pdf

Combinations of Maternal KIR and Fetal HLA-C Genes Influence the Risk of Preeclampsia and Reproductive Success

The fetus is considered to be an allograft that, paradoxically, survives pregnancy despite the laws of classical transplantation immunology. There is no direct contact of the mother with the embryo, only with the extraembryonic placenta as it implants in the uterus. No convincing evidence of uterine maternal T-cell recognition of placental trophoblast cells has been found, but instead, there might be maternal allorecognition mediated by uterine natural killer cells that recognize unusual fetal trophoblast MHC ligands.

Natural killer cells and pregnancy.

Nature Reviews Immunology 2, 656–663 (2002) On page 657 of this article, three items in the figure in Box 1 are labelled incorrectly: •the adaptor protein of NKG2D binding to MICA/B is labelled 'DAP12'. The correct label is 'DAP10'; •the adaptor protein of NKp30 is labelled 'CB33'. The correct labelis 'CD3ζ'; •the adaptor protein of NKp46 is labelled 'FcRγ/CD33'.

/pdf/erratum-natural-killer-cells-and-pregnancy-5bc55z8fqg.pdf

Erratum: Natural killer cells and pregnancy

The endometrium contains a unique subset of uterine-specific natural killer (uNK) cells, the proposed functions of which include a role in decidualization, menstruation, and implantation. These cells increase in number during the mid-late secretory phase of the menstrual cycle and are also present in large numbers in early pregnancy. The cyclical nature of uNK cell appearance suggests hormonal regulation of these cells. To date, it has not been possible to localize either estrogen receptors (ERs) or progesterone receptors (PRs) to uNK cells. In the present study, we have investigated the steroid receptor expression of uNK cells, including not only ER alpha and PR but also wild-type ER beta 1, its variant form ER beta cx/beta 2, and glucocorticoid receptor (GR) using specific monoclonal antibodies and real-time quantitative RT-PCR. mRNA encoding ER alpha, PR, ER beta cx/beta 2, ER beta 1, and GR were identified in extracts of human endometrium across the menstrual cycle and in decidua. Quantitative real-time RT-PCR demonstrated an absence of ER alpha and PR mRNA in purified uNK cells. In contrast, mRNA for ER beta cx/beta 2, ER beta 1, and GR was present in uNK cells. ER alpha, PR, ER beta cx/beta 2, ER beta 1, and GR proteins were identified in endometrial and decidual biopsies. Colocalization using specific monoclonal antibodies confirmed that uNK cells were immunonegative for ER alpha and PR protein. These cells were also immunonegative for ER beta cx/beta 2 but did express ER beta 1 and GR proteins. These results raise the possibility that estrogens and glucocorticoids could be acting directly on uNK cells through ER beta and GR, respectively, to influence gene transcription in the endometrium and decidua.

/pdf/steroid-receptor-expression-in-uterine-natural-killer-cells-2salccmlhq.pdf

Steroid receptor expression in uterine natural killer cells.

https://www.cell.com/trends/immunology/pdf/S1471-4906(02)02261-5.pdf

Natural killer cells and reproduction.

that these archaic cells took on a verycontemporary role in the prolongedintrauterine support of the foetus.However, the contribution of NK cells tomammalian pregnancy does not appear tobe uniform between species. Of all theorgans in the mammalian body, theplacenta probably differs the mostbetween species [5], and this variation isparalleled by differences in thecontribution of NK cells to pregnancy.However, common inter-species themes doemerge. For example, in mice, rats andhamsters, uNK cells congregate aroundthe uterine arteries, even thoughinfiltration of trophoblast into thesevessels differs markedly between thespecies (Robert Pijnenborg,Leuven,Belgium)In this context, it is interesting to notethat in some species, such as hoofedmammals, where there is littletrophoblast invasion into maternal tissue,uNK cells are notably sparse. Thus,NKcells are clearly not essential forpregnancy in all mammals, especiallythose with non-invasive placentation.Remarkably, however, even in thosespecies in which uNK cells are prominent,they might not be an obligate requirementfor successful gestation. For example, in mice with no uNK cells the arteries in the pregnant uterus retain theirnon-pregnant appearance, but this doesnot have an adverse effect on pregnancyoutcome (Anne Croy, Guelph, Canada).Thus, a major challenge to reproductiveimmunologists will be to determineexactly how ‘essential’NK cells are tooutbred pregnancies in different species.

https://www.cell.com/trends/immunology/pdf/S1471-4906(02)02228-7.pdf

Ashley Moffett-King

Papers

Natural killer cells and pregnancy.

Erratum: Natural killer cells and pregnancy

Steroid receptor expression in uterine natural killer cells.

Natural killer cells and reproduction.

Immunology of the lacrimal gland and ocular tear film