Immunological Modes of Pregnancy Loss

Reproductive Medicine Program, Department of Obstetrics and Gynecology, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, Vernon Hills, IL, USA.
American Journal Of Reproductive Immunology (Impact Factor: 2.44). 03/2010; 63(6):611-23. DOI: 10.1111/j.1600-0897.2010.00847.x
Source: PubMed


During the implantation period, a significant portion of embryos are lost and eventually less than half of clinically established pregnancies end as full-term pregnancies without obstetrical complications. A significant portion of these pregnancy losses is associated with immune etiologies, including autoimmune and cellular immune abnormalities. Although an autoimmune etiology such as anti-phospholipid antibodies (APAs) has been reported to induce placental infarct and thrombosis at maternal-fetal interface, APAs induce inflammatory immune responses as well. Inflammatory immune responses, such as increased proportions of NK cells and Th1/Th2 cell ratios in peripheral blood are related to recurrent pregnancy losses and multiple implantation failures. Systemic and local inflammatory immune responses seem to be induced by activation of Toll-like receptors with infectious agents, fetal cell debris, or gonadotropin-releasing hormone agonist, etc. Cellular activation of T and NK cells leads to pro-inflammatory cytokine storm and consequently, placental infarction and thrombosis. Potential application of anti-inflammatory therapeutic agents for the prevention of pregnancy losses should be explored further.

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Available from: Alice Gilman-Sachs, Oct 07, 2014
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    • "The maternal immune system has to tolerate the semiallogeneic fetus in naturally conceived (NC) and in vitro fertilization (IVF) pregnancies to allow favorable pregnancy outcome [1] [2]. In fact a shift toward peripheral Th1/Th2 augmentation [11] and Th17/Treg cells imbalance has been reported in women with recurrent pregnancy losses [10] and in pregnancy-specific diseases such as preeclampsia [2]. As the fetus is fully allogeneic to the mother in egg donation (ED) pregnancies, the maternal immune response should be more tolerogenic in these particular pregnancies [2] [12]. "
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    ABSTRACT: This prospective longitudinal study aimed at comparing maternal immune response among naturally conceived (NC; n = 25), in vitro fertilization (IVF; n = 25), and egg donation (ED; n = 25) pregnancies. The main outcome measures were, firstly, to follow up plasma levels of interleukin (IL) 1beta, IL2, IL4, IL5, IL6, IL8, IL10, IL17, interferon gamma, tumor necrosis factor-alpha (TNFα), transforming growth factor-beta (TGFβ), regulated upon activation normal T-cell expressed and secreted (RANTES), stromal cell-derived factor 1 alpha (SDF1α), and decidual granulocyte-macrophage colony-stimulating factor (GM-CSF) during the three trimesters of pregnancy during the three trimesters of pregnancy; secondly, to evaluate if the cytokine and chemokine pattern of ED pregnant women differs from that of those with autologous oocytes and, thirdly, to assess if women with preeclampsia show different cytokine and chemokine profile throughout pregnancy versus women with uneventful pregnancies. Pregnant women in the three study groups displayed similar cytokine and chemokine pattern throughout pregnancy. The levels of all quantified cytokines and chemokines, except RANTES, TNFα, IL8, TGFβ, and SDF1α, rose in the second trimester compared with the first, and these higher values remained in the third trimester. ED pregnancies showed lower SDF1α levels in the third trimester compared with NC and IVF pregnancies. Patients who developed preeclampsia displayed higher SDF1α plasma levels in the third trimester.
    Full-text · Article · Sep 2015 · Journal of Immunology Research
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    • "Successful embryo implantation occurs followed by a local physiological and sterile inflammatory response, subsequently redirected towards a tolerogenic predominant profile. Consistently, a deregulated persistent inflammatory response during early placentation has been associated with pregnancy complications such as spontaneous recurrent abortion and pre-eclampsia (Girardi et al. 2006, Dekel et al. 2010, Kwak-Kim et al. 2010, Redman & Sargent 2010). By means of co-cultures of a human first-trimester trophoblast cell line with monocytes or DC from fertile women, here, we present evidence to support that non-neuronal ACh from trophoblast cells can modulate the migration and condition the activation of CD14+ cells and DC profile. "
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    ABSTRACT: Maternal antigen presenting cells attracted to the pregnant uterus interact with trophoblast cells and modulate their functional profile to favor immunosuppressant responses. Non neuronal cholinergic system is expressed in human cytotrophoblast cells and in immune cells with homeostatic regulatory functions.AimThe aim of this work was to evaluate whether non neuronal acetylcholine conditions maternal monocyte and DC migration and activation profiles.Methods We used an in vitro model resembling maternal-placental interface represented by the co-culture of human trophoblast cells (Swan-71 cell line) and monocytes or DC cells.ResultsWhen cytotrophoblast cells were treated with neostigmine (Neo) to concentrate endogenous acetylcholine levels, monocyte migration was increased. In parallel, high levels of IL-10 and decreased levels of TNF-α were observed upon interaction of maternal monocytes with trophoblast cells. This effect was synergized by Neo and was prevented by atropine, a muscarinic acetylcholine receptor antagonist. Similarly, trophoblast cells increased the migration of DC independently of Neo treatment, however enhanced IL-10 and MCP-1 synthesis in trophoblast-DC co-cultures with no changes in TNF-α and IL-6 was observed. In fact, there were no changes in HLA-DR, CD86 or CD83 expression. Finally, trophoblast cells treated with Neo increased the expression of two antigen presenting cell-attracting chemokines, MCP-1, MIP-1α and RANTES through muscarinic receptors and it was prevented by atropine.Conclusions Our present results support a novel role of acetylcholine synthesized by trophoblast cells to modulate antigen presenting cell migration and activation favoring an immunosuppressant profile that contributes to immune homeostasis maintenance at the maternal-fetal interface.This article is protected by copyright. All rights reserved.
    Full-text · Article · Mar 2015 · Acta Physiologica
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    • "However, the exact pathogenic mechanism behind the role of NK cells in human reproduction is unclear. Pathogenic autoantibodies such as antiphospholipid antibodies (APAs), antithyroid antibodies (ATAs), and other autoimmune antibodies have been reported to induce not only impaired blood circulation at the maternal-fetal interface, but also an inflammatory immune response which is related to RSA [7,8]. Moreover, women with RSA had significantly more positive test results for one or both thyroid antibodies (peroxidase and thyroglobulin) than fertile controls [9,10]. "
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    ABSTRACT: Objective To investigate whether natural killer (NK) cell and autoimmune antibody acts synergistically, by the action of autoantibodies to increase NK cell number and cytotoxicity, to decrease uterine blood flow during early pregnancy in pregnant women with a history of recurrent spontaneous abortion (RSA). Methods Seventy-five pregnant women (between 5 and 7 weeks gestation) with a history of unexplained RSA were included in the study group. Forty-one pregnant women without a history of RSA were included as controls. All women with a history of RSA were tested for autoantibodies and number of peripheral blood natural killer (pbNK) cell by flow cytometry. Study populations were stratified into four groups by existence of autoantibody and degree of increase of pbNK cells. The uterine radial artery resistance index (RI) was measured by color-pulsed Doppler transvaginal ultrasound. Results The mean RI of the autoimmune antibody-positive (AA+) group (0.63±0.09) was significantly higher than that of the normal control group (0.53±0.10, P=0.001). The mean RI of the AA+/only-NK elevated (eNK) group (0.63±0.09) was significantly higher than those of the only-AA+ group (0.55±0.07, P=0.019) and the only-eNK group (0.57±0.07, P=0.021). Conclusion Concurrent elevation in NK cells and autoimmunity results in decreased uterine blood flow during early pregnancy. However, the majority of cases of RSA remain unexplained and larger scale studies are needed to confirm our conclusion and to develop diagnostic and therapeutic plans for women with a history of RSA.
    Full-text · Article · May 2014
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