Novel approaches for mechanistic understanding and predicting preeclampsia

Department of Pediatrics, Women and Infants Hospital-Warren Alpert Medical School of Brown University, Providence, RI, USA.
Journal of Reproductive Immunology (Impact Factor: 2.82). 10/2009; 83(1-2):134-8. DOI: 10.1016/j.jri.2009.08.006
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Despite intense investigation, preeclampsia (PE) remains largely enigmatic. Relatively late onset of diagnostic signs and heterogeneous nature of the disease further contribute to poor understanding of its etiology and clinical management. There exist no concrete animal models that can provide mechanistic underpinnings for evaluating targeted therapeutic intervention. Poor cross-sectional findings with potential biochemical markers reported so far have proved counterintuitive and suggest a need for novel approaches to predict the early onset of disease. Because of the co-onset of local placental anomalies and systemic manifestation of symptoms, it is highly likely that serum from PE patients can provide a "blueprint" of causative factors. Proteomic and/or functional analysis of maternal serum are expected to predict the onset of disease ahead of manifestation of clinical symptoms. A serum-based predictive assay should overcome complexities resulting from the heterogeneous etiology of PE. This review attempts to address some of these issues and discuss the signature biochemical serum factors and propose new and better ways to predict PE.

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    • "and adaptive immune system that may have an influence on the onset of this disorder. It was suggested that activation of cell-mediated immunity might play a key role in the aetiology of pre-eclampsia (Darmochwal-Kolarz et al., 2007; Kalkunte et al., 2009; Saito and Sakai, 2003; Santner- Nanan et al., 2009; Sasaki et al., 2007). Dendritic cells (DCs) are antigen-presenting cells with the unique ability to induce primary immune responses. "
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    ABSTRACT: The aim of our study was to estimate the expression of B7-H1 and B7-H4 molecules on myeloid and plasmacytoid dendritic cells (DCs) in the peripheral blood of patients with pre-eclampsia, normal pregnant women and healthy non-pregnant women. Thirty-three patients with pre-eclampsia, 26 normal pregnant women, and 12 healthy non-pregnant women were included in the study. Dendritic cells were isolated from peripheral blood, stained with monoclonal antibodies against blood dendritic cell antigens and B7-H1 and B7-H4 molecules and estimated using flow cytometry. The expression of B7-H1 and B7-H4 molecules was significantly higher on CD1c(+) myeloid and CD303(+) plasmacytoid DCs in the first trimester of pregnancy than in the luteal phase of the ovarian cycle (CD1c(+)B7-H1(+): 19.19±10.55% vs. 11.99±6.79%; p<0.05; CD1c(+)B7-H4(+): 12.01±9.15% vs. 3.98±1.97%, p<0.001; CD303(+)B7-H1(+): 4.15±2.38% vs. 1.70±0.87%, p<0.05; CD303(+)B7-H4(+): 5.44±2.93% vs. 2.33±1.54%, p<0.01). Moreover, the expression of the B7-H1 molecule on CD1c(+) DCs in the second trimester of normal pregnancy was significantly higher than in the first trimester, but in the third trimester they decreased compared with the second trimester (II vs. I trimester: 32.23±11.30% vs. 19.19±10.55%, p<0.01; III vs. II trimester: 32.23±11.30% vs. 22.39±8.19%, p<0.01). The expression of B7-H1 molecule on CD1c(+) myeloid and CD303(+) plasmacytoid DCs was significantly lower in pre-eclampsia than in healthy third-trimester pregnant women (CD1c(+)B7-H1(+): 13.78±6.26% vs. 22.39±8.19%, p<0.05; CD303(+)B7-H1(+): 3.66±2.46% vs. 8.65±3.15%, p<0.01). Higher expressions of B7-H1 and B7-H4 molecules on CD1c(+) myeloid and CD303(+) plasmacytoid DCs in the first trimester of pregnancy suggest the role they play in the immunomodulation during early pregnancy.
    Journal of Reproductive Immunology 06/2013; 99(1-2). DOI:10.1016/j.jri.2013.04.004 · 2.82 Impact Factor
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    • "PE is a systemic disorder resulting from poor placentation. Although the pathogenesis of PE remains poorly understood, improper trophoblast invasion and poor spiral artery remodeling resulting in placental ischemia/hypoxia are the major pre-clinical events at the maternal-fetal interface (Brosens, et al., 1977; Meekins et al., 1994; Redman and Sargent 2009; Kalkunte, et al., 2009b). As a consequence, placenta-derived flux of inflammatory molecules and anti-angiogenic factors are observed in maternal systemic circulation resulting in endothelial dysfunction and symptoms of hypertension, proteinuria and kidney pathology (Levine, et al., 2004, Parikh and Karumanchi, 2008). "
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    ABSTRACT: 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.
    Journal of Reproductive Immunology 02/2011; 88(2):165-9. DOI:10.1016/j.jri.2011.01.009 · 2.82 Impact Factor
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    ABSTRACT: Citation Thaxton JE, Sharma S. Interleukin-10: a multi-faceted agent of pregnancy. Am J Reprod Immunol 2010 It is widely accepted that pregnancy constitutes a unique developmental event. Unprecedented intrauterine actions of angiogenesis, immunity, and neuroendocrine regulation are juxtaposed to mechanisms of senescence that enable fetal growth and protection. The suppressive and regulatory factors that facilitate healthy pregnancy are under investigation. In non-pregnant systems of infection and inflammation, the cytokine interleukin-10 (IL-10) has been widely investigated because of its potential as a key immunosuppressant in response to a multitude of inflammatory events. In the context of pregnancy, IL-10 levels increase markedly in women during early pregnancy and remain elevated well into the third trimester immediately prior to onset of labor. The role of IL-10 during pregnancy as a suppressor of active maternal immunity to allow acceptance of the fetal allograft has been a point of study. Moreover, secretion of IL-10 by a diverse set of maternal and fetal cells has proven to aid in the orchestration of normal processes of pregnancy. Interestingly, some of the more profound findings regarding the actions of IL-10 during pregnancy have manifested from research that focuses on aberrant pregnancy outcomes as a result of inflammation, hormonal imbalances, or gene–environment interactions. This review focuses on the role of IL-10 as a facilitator of successful pregnancy both as an immune suppressive agent and a mediator of cross talk between the placenta and the decidua. Importantly, we discuss investigations on adverse pregnancy conditions to further elucidate the multifarious role of IL-10 at the maternal–fetal interface.
    American Journal Of Reproductive Immunology 02/2010; 63(6):482-91. DOI:10.1111/j.1600-0897.2010.00810.x · 2.44 Impact Factor
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