Uterine NK cells: Active regulators at the maternal-fetal interface

The Journal of clinical investigation (Impact Factor: 13.22). 05/2014; 124(5):1872-1879. DOI: 10.1172/JCI68107
Source: PubMed


Pregnancy presents an immunological conundrum because two genetically different individuals coexist. The maternal lymphocytes at the uterine maternal-fetal interface that can recognize mismatched placental cells are T cells and abundant distinctive uterine NK (uNK) cells. Multiple mechanisms exist that avoid damaging T cell responses to the fetus, whereas activation of uNK cells is probably physiological. Indeed, genetic epidemiological data suggest that the variability of NK cell receptors and their MHC ligands define pregnancy success; however, exactly how uNK cells function in normal and pathological pregnancy is still unclear, and any therapies aimed at suppressing NK cells must be viewed with caution. Allorecognition of fetal placental cells by uNK cells is emerging as the key maternal-fetal immune mechanism that regulates placentation.

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Available from: Francesco Colucci, Dec 11, 2014
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    • "23 [18–37] ns Systolic blood pressure (mmHg) 12 [10] [11] [12] [13] 14 [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] 12 [10] [11] [12] [13] í µí±ƒ < 0.001 * Diastolic blood pressure (mmHg) 7 [5–8.3] 8.7 [6] [7] [8] [9] [10] [11] [12] 7 [5.5–8.5] í µí±ƒ < 0.001 * Uterine height (cm) 32 [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] 26 [15–36] 26 [15–36] í µí±ƒ < 0.001 § Term at sampling (weeks of gestation) 31.7 [15.3–41] 30 [17–41] 30 [17–41] ns Term at delivery (weeks of gestation) 40.3 [35] [36] [37] [38] [39] [40] [41] [42] 32.3 [17–41.1] "
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    ABSTRACT: The major histocompatibility complex class I related chain (MIC) is a stress-inducible protein modulating the function of immune natural killer (NK) cells, a major leukocyte subset involved in proper trophoblast invasion and spiral artery remodeling. Aim of the study was to evaluate whether upregulation of soluble MIC (sMIC) may reflect immune disorders associated to vascular pregnancy diseases (VPD). sMIC was more frequently detected in the plasma of women with a diagnostic of VPD (32%) than in normal term-matched pregnancies (1.6%, P < 0.0001), with highest prevalence in intrauterine fetal death (IUDF, 44%) and vascular intrauterine growth restriction (IUGR, 39%). sMIC levels were higher in preeclampsia (PE) than in IUFD (P < 0.01) and vascular IUGR (P < 0.05). sMIC detection was associated with bilateral early diastolic uterine notches (P = 0.037), thrombocytopenia (P = 0.03), and high proteinuria (P = 0.03) in PE and with the vascular etiology of IUGR (P = 0.0038). Incubation of sMIC-positive PE plasma resulted in downregulation of NKG2D expression and NK cell-mediated IFN-γ production in vitro. Our work thus suggests that detection of sMIC molecule in maternal plasma may constitute a hallmark of altered maternal immune functions that contributes to vascular disorders that complicate pregnancy, notably by impairing NK-cell mediated production of IFN-γ, an essential cytokine favoring vascular modeling.
    BioMed Research International 08/2014; 2014:653161. DOI:10.1155/2014/653161 · 2.71 Impact Factor
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    • "The immunomodulatory properties of hCG are multiple and extremely important. First, hCG has a positive impact on uNK cells, the predominant leukocyte subtype of the gravid uterus that acts on establishment and maintenance of pregnancy, in humans and mice (2, 3, 118). Particularly, uNK cells contribute to essential vascular changes by regulating the remodeling of decidual spiral arterioles (119, 120) and by secreting angiogenic factors as members of VEGF family (121). "
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    ABSTRACT: Acceptance of the fetal semi-allograft by the mother's immune system has become the focus of intensive research. CD4+ T cells are important actors in the establishment of pregnancy. Th1/Th2 paradigm has been expanded to include CD4+ regulatory T (Treg) and T helper 17 (Th17) cells. Pregnancy hormones exert very significant modulatory properties on the maternal immune system. In this review, we describe mechanisms by which the endocrine milieu modulates CD4 T cell polarization during pregnancy. We first focused on Treg and Th17 cells and on their importance for pregnancy. Secondly, we review the effects of pregnancy hormones [progesterone (P4) and estradiol (E2)] on immune cells previously described, with a particular attention to human chorionic gonadotropin (hCG). The importance of Treg cells for pregnancy is evidenced. They are recruited before implantation and are essential for pregnancy maintenance. Decreased number or less efficient Treg cells are implicated in fertility disorders. As for Th17 cells, the few available studies suggest that they have a negative impact on fertility. Th17 frequency is increased in infertile patients. With the combination of its pro-effects on Th2 and Treg cells and anti-effects on Th1 and Th17 cells, P4 contributes to establishment of a favorable environment for pregnancy. E2 effects are more dependent on the context but it seems that E2 promotes Treg and Th2 cells while it inhibits Th1 cells. hCG positively influences activities of Treg and uterine natural killer cells. This embryo signal is an essential actor for the success of pregnancy, both as the endocrine factor regulating P4 secretion by the ovarian corpus luteum, but also as a paracrine agent during implantation as well as an angiogenic and immunologic mediator during the course of gestation. Luteinizing hormone (LH) immune properties begin to be studied but its positive impact on Treg cells suggests that LH could be a considerable immunomodulator in the mouse.
    Frontiers in Endocrinology 07/2014; 5:106. DOI:10.3389/fendo.2014.00106
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    ABSTRACT: Up to 5% of couples at reproductive age suffer from at least two consecutive miscarriages, and around 1% experience three or more consecutive gestational losses, most of them during the first ten weeks of pregnancy, resulting in a significant personal, social and economic public health burden. The pregnancy losses occurring after the twentieth gestational week, namely foetal death or stillbirth, are even more emotionally and psychologically devastating for the couple. In almost half of these cases there is not any known cause of foetal death. In the last years, significant progress in the identification and treatment of the risk factors associated to foetal death has been made: advanced maternal age, obesity, pre-existing maternal diseases or acquired infections during pregnancy; and associated immunological disorders. Among the latter, the most common cause is the obstetric antiphospholipid syndrome, autoimmune disease that can present with placental infarction, thrombosis in the utero-placental circulation and foetal loss. Here we review the evidence of other immunological disorders that have been associated with intrauterine foetal death: non-diagnosed celiac disease, peripheral expansion of natural killer cells and diverse autoimmune or inflammatory abnormalities. The detection and control of such abnormalities in women with history of prior foetal death may lead to a successful subsequent pregnancy.
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