Tania Nevers

TLR-Mediated Preterm Birth in Response to Pathogenic Agents

The incidence of preterm birth in developed countries has risen in the past decades. Underlying causes for this enigmatic pregnancy complication are numerous, yet infectious agents that induce dysregualtion of immunity at the maternal-fetal interface pose one of the most probable causes of preterm birth. This paper highlights two factors regarding maternal infections that trigger unscheduled inflammatory sequences that are deleterious to the maternal-fetal balance necessary to maintain pregnancy. Firstly, we discuss the role of Toll-like receptors (TLRs) as sentinels of uterine immunity in the context of response to pathogens. We highlight the idea that particular TLR activations lead to differential immune cascades that induce preterm birth. Secondly, two alternative routes of pathogenic entry may prove to be critical for inducing preterm birth via a cytokine storm or a secondary and currently unknown cell-mediated mechanism of uterine inflammation. This paper summarizes pathways that underlie activation of adverse and diverse immune responses to foreign agents that may result in preterm birth.

Vascular IL-10: a protective role in preeclampsia

IL-10 is a pregnancy compatible cytokine that plays a vital role in maintaining the balance of anti-inflammatory and pro-inflammatory milieu at the maternal-fetal interface. Recent evidence now suggests that IL-10 is a potent vascular cytokine that can blunt hypertension and inflammation-mediated vascular dysfunction. Thus, a re-evaluation of IL-10 as a cytokine supporting endovascular interactions and angiogenesis as well as blunting hypoxic-injury and preeclampsia-like features is warranted. In this review, we highlight these novel functions of IL-10 and propose that its immune-modulating and vascular functions are mutually inclusive, particularly in the context of normal gestation.

Review: hCG, preeclampsia and regulatory T cells

Human chorionic gonadotropin (hCG) is crucial for successful pregnancy. Its many functions include angiogenesis and immune regulation. Despite years of research, the etiology of preeclampsia remains unknown. Marked by insufficient trophoblast invasion and poor spiral artery remodeling, preeclampsia has also been linked to immune dysregulation. Here we discuss the roles of hCG in the context of endovascular cross-talk between trophoblasts and endothelial cells and immune tolerance. We propose that functional and glycosylation modifications of hCG may contribute to the pathogenesis of preeclampsia.

Interfering with Gal-1–mediated angiogenesis contributes to the pathogenesis of preeclampsia

Preeclampsia (PE) is a pregnancy-specific disorder characterized by sudden onset of hypertension and proteinuria in the second half of pregnancy (>20 wk). PE is strongly associated with abnormal placentation and an excessive maternal inflammatory response. Galectin-1 (Gal-1), a member of a family of carbohydrate-binding proteins, has been shown to modulate several processes associated with placentation and to promote maternal tolerance toward fetal antigens. Here, we show that Gal-1 exhibits proangiogenic functions during early stages of pregnancy, promoting decidual vascular expansion through VEGF receptor 2 signaling. Blocking Gal-1–mediated angiogenesis or lectin, galactoside-binding, soluble, 1 deficiency results in a spontaneous PE-like syndrome in mice, mainly by deregulating processes associated with good placentation and maternal spiral artery remodeling. Consistent with these findings, we observed a down-regulation of Gal-1 in patients suffering from early onset PE. Collectively, these results strengthen the notion that Gal-1 is required for healthy gestation and highlight Gal-1 as a valuable biomarker for early PE diagnosis.

Uterine Regulatory T cells, IL-10 and Hypertension

Citation Nevers T, Kalkunte S, Sharma S. Uterine Regulatory T Cells, IL‐10 and hypertension. Am J Reprod Immunol 2011; 66 (Suppl. 1): 88–92

NKG2D Blockade Inhibits Poly(I:C)-Triggered Fetal Loss in Wild Type but Not in IL-10−/− Mice

Infection and inflammation can disturb immune tolerance at the maternal-fetal interface, resulting in adverse pregnancy outcomes. However, the underlying mechanisms for detrimental immune responses remain ill defined. In this study, we provide evidence for immune programming of fetal loss in response to polyinosinic:polycytidylic acid (polyI:C), a viral mimic and an inducer of inflammatory milieu. IL-10 and uterine NK (uNK) cells expressing the activating receptor NKG2D play a critical role in poly(I:C)-induced fetal demise. In wild type (WT) mice, poly(I:C) treatment induced expansion of NKG2D+ uNK cells and expression of Rae-1 (an NKG2D ligand) on uterine macrophages and led to fetal resorption. In IL-10−/− mice, NKG2D− T cells instead became the source of fetal resorption during the same gestation period. Interestingly, both uterine NK and T cells produced TNF-α as the key cytotoxic factor contributing to fetal loss. Treatment of WT mice with poly(I:C) resulted in excessive trophoblast migration into the decidua and increased TUNEL-positive signal. IL-10−/− mice supplemented with recombinant IL-10 induced fetal loss through NKG2D+ uNK cells, similar to the response in WT mice. Blockade of NKG2D in poly(I:C)-treated WT mice led to normal pregnancy outcome. Thus, we demonstrate that pregnancy-disrupting inflammatory events mimicked by poly(I:C) are regulated by IL-10 and depend on the effector function of uterine NKG2D+ NK cells in WT mice and NKG2D− T cells in IL-10 null mice.

New frontiers in reproductive immunology research: bringing bedside problems to the bench

The 31st Annual Meeting of the American Society for Reproductive Immunology provided an excellent platform for basic and clinical scientists to brainstorm on current reproductive health issues such as repeated implantation and pregnancy failure, preterm birth, preeclampsia and genital tract infections such as HIV. The goal of the meeting was to foster cross-pollination of ideas as well as to encourage participation of young investigators in the field. The conference was preceded by the 4th Annual Post-Graduate Workshop with the theme of bringing bedside problems to the bench and facilitating collaboration between clinicians and basic scientists. Christopher Davies and Richard Bronson chaired the conference, which hosted approximately 180 delegates representing more than 26 countries across Asia, Australia, Latin America, Europe and North America.