Vikki M Abrahams

Yale-New Haven Hospital, New Haven, Connecticut, United States

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Publications (87)294.13 Total impact

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    ABSTRACT: ProblemWomen with antiphospholipid syndrome (APS) are at increased risk of recurrent pregnancy loss (RPL) and preeclampsia. Antiphospholipid antibodies (aPL) directly alter trophoblast function. Treatment with low molecular weight heparin (LMWH) reduces the risk of RPL but not preeclampsia. Moreover, LMWH stimulates trophoblast sFlt-1 release, an anti-angiogenic factor associated with preeclampsia. Since vitamin D deficiency is associated with APS and preeclampsia, this study sought to determine the effect of vitamin D on trophoblast function in the setting of aPL and LMWH.Method of studyA human first trimester trophoblast cell line (HTR8) and primary trophoblast cultures were treated with or without aPL in the presence and absence of vitamin D, LMWH or both. Trophoblast secretion of inflammatory cytokines and angiogenic factors were measured by ELISA.ResultsVitamin D alone or in combination with LMWH attenuated the aPL-induced trophoblast inflammatory response in the HTR8 cells and primary cultures. While vitamin D did not have any impact on aPL-mediated modulation of angiogenic factors in the primary trophoblast, it significantly inhibited LMWH-induced sFlt-1 release.ConclusionLMWH in combination with vitamin D may be more beneficial than single-agent therapy by preventing aPL-induced trophoblast inflammation and reversing LMWH-induced sFlt-1 secretion.
    American Journal Of Reproductive Immunology 07/2014; · 3.32 Impact Factor
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    ABSTRACT: Inflammation during pregnancy has devastating consequences for the placenta and fetus. These events are incompletely understood, thereby hampering screening and treatment.
    American journal of reproductive immunology (New York, N.Y.: 1989) 05/2014; · 3.32 Impact Factor
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    ABSTRACT: There has been growing interest in the role of viral infections and their association with adverse pregnancy outcomes. However, little is known about the impact viral infections have on the fetal membranes (FM). Toll-like receptors (TLR) are thought to play a role in infection-associated inflammation at the maternal-fetal interface. Therefore, the objective of this study was to characterize the cytokine profile and antiviral response in human FMs exposed to viral dsRNA, which activates TLR3, and viral ssRNA, which activates TLR8; and to determine the mechanisms involved. The viral dsRNA analog, Poly(I:C), induced upregulated secretion of MIP-1α, MIP-1β, RANTES and TNF-α, and downregulated IL-2 and VEGF secretion. In contrast, viral ssRNA induced a broader panel of cytokines in the FMs by upregulating the secretion of IL-1β, IL-2, IL-6, G-CSF, MCP-1, MIP-1α, MIP-1β, RANTES, TNF-α and GRO-α. Using inhibitory peptides against TLR adapter proteins, FM secretion of MIP-1β and RANTES in response to Poly(I:C) was MyD88-dependent; MIP-1α secretion was dependent on MyD88 and TRIF; and TNF-α production was independent of MyD88 and TRIF. Viral ssRNA-induced FM secretion of IL-1β, IL-2, IL-6, G-CSF, MIP-1α, RANTES and GRO-α was dependent on MyD88 and TRIF; MIP-1β was dependent upon TRIF, but not MyD88; and TNF-α and MCP-1 secretion was dependent on neither. Poly(I:C), but not ssRNA, induced a FM antiviral response by upregulating the expression of inflammasome components, IFNβ, MxA, OAS and APOBEC3G. These findings demonstrate that human FMs respond to two viral signatures by generating distinct inflammatory cytokine/chemokine profiles and antiviral responses through different mechanisms.
    Molecular Human Reproduction 04/2014; · 4.54 Impact Factor
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    ABSTRACT: Bacterial infection-associated inflammation is thought to be a major cause of preterm premature rupture of membranes (PPROM). Pro-inflammatory cytokines, such as IL1B, can weaken the fetal membranes (FM) by upregulating matrix metalloproteinases and inducing apoptosis. The mechanism by which infection leads to inflammation at the maternal-fetal interface and subsequent preterm birth is thought to involve innate immune pattern recognition receptors (PRR), such as the Toll-like receptors (TLR) and Nod-like receptors (NLR) which recognize pathogen-associated molecular patterns (PAMPs). The objective of this study was to determine the cytokine profile generated by FMs in response to the following bacterial TLR and NLR agonists: peptidoglycan (PDG; TLR2); lipopolysaccharide (LPS; TLR4); flagellin (TLR5); CpG ODN (TLR9); iE-DAP (Nod1) and MDP (Nod2). PDG, LPS, Flagellin, iE-DAP and MDP triggered FMs to generate an inflammatory response, however, the cytokine profiles were distinct for each TLR and NLR agonist; and only IL1B and RANTES were commonly upregulated in response to all five PAMPs. CpG ODN, in contrast, had a mild stimulatory effect only on MCP-1, and primarily downregulated basal FM cytokine production. IL1B secretion induced by PDG, LPS, flagellin, iE-DAP and MDP was associated with its processing. Furthermore, FM IL1B secretion in response to TLR2, TLR4 and TLR5 activation was caspase-1 dependent, while Nod1 and Nod2 induced IL1B secretion independent of caspase-1. These findings demonstrate that FMs respond to different bacterial TLR and NLR PAMPs by generating distinct inflammatory cytokine profiles through distinct mechanisms that are specific to the innate immune PRR activated.
    Biology of Reproduction 01/2014; · 4.03 Impact Factor
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    ABSTRACT: Women with antiphospholipid syndrome (APS) are at risk for pregnancy complications. Antiphospholipid antibodies (aPL) alter trophoblast function by triggering an inflammatory cytokine response; modulating angiogenic factor secretion; and inhibiting migration. While patients with APS are often treated with hydroxychloroquine (HCQ), its effect on trophoblast function is poorly understood. A human first trimester trophoblast cell line was treated with or without antihuman β2 GPI mAbs in the presence or absence of HCQ. Supernatants were analyzed by ELISA. Cell migration was measured using a colormetric assay. Antiphospholipid antibodies-induced trophoblast IL-8, IL-1 β, PlGF, and sEndoglin secretion were not altered by HCQ. aPL-induced inhibition of trophoblast migration was partially reversed by HCQ, even though HCQ significantly increased secretion of pro-migratory IL-6 to greater than baseline. aPL-induced upregulation of TIMP2 appears to inhibit trophoblast migration; the inability of HCQ to prevent aPL-induced TIMP2 may explain why migration was only partially restored. Hydroxychloroquine reversed the aPL-inhibition of trophoblast IL-6 secretion and partially limited aPL-inhibition of cell migration. Thus, some form of combination therapy that includes HCQ may be beneficial to pregnant APS patients.
    American Journal Of Reproductive Immunology 12/2013; · 3.32 Impact Factor
  • Graciela Krikun, Julie A Potter, Vikki M Abrahams
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    ABSTRACT: PROBLEM: Human endometrial endothelial cell (HEEC) innate immunity remains poorly characterized. Based on their direct contact with the circulation, HEECs are uniquely positioned to be exposed to viral infections. This study evaluated the innate immune response generated by HEECs after exposure to the TLR3 agonist, Poly(I:C) and the TLR8 agonist, viral ssRNA. METHOD OF STUDY: HEECs were treated with or without Poly(I:C) or ssRNA. Culture supernatants were measured for cytokines by multiplex analysis. RNA was analyzed by qRT-PCR for type I interferons and antiviral factors. RESULTS: Treatment of HEECs with Poly(I:C) rapidly upregulated the secretion of IL-2, IL-6, IL-8, IFN-γ, G-CSF, GM-CSF, MCP-1, MIP-1β, RANTES, and GRO-α after 12 hr, while ssRNA treatment induced the slower secretion of IL-6, IL-8, IFN-γ, G-CSF, VEGF, and GRO-α after 24 hr. Both viral components induced HEEC IFN-α and IFN-β expression. While treatment with Poly(I:C) induced APOBEC3G and OAS expression, treatment with ssRNA upregulated APOBEC3G and M×A mRNA. CONCLUSION: Our findings demonstrate that HEECs can differentially sense and respond to viral components by generating distinct inflammatory and antiviral immune responses, indicating that these cells likely play an active role in the immune protection of the uterus toward viral infections.
    American Journal Of Reproductive Immunology 04/2013; · 3.32 Impact Factor
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    ABSTRACT: Women with antiphospholipid syndrome (APS) are at risk of recurrent pregnancy loss and obstetrical disorders, such as preeclampsia and intrauterine growth restriction (IUGR). Antiphospholipid antibodies (aPL) directly target the placenta by binding beta2-glycoprotein I (β2GPI) expressed on the trophoblast. We recently demonstrated in human first trimester trophoblast cells that anti-β2GPI antibodies (Abs) induce the secretion of IL-1β in a Toll-like receptor 4 (TLR4)-dependent manner. IL-1β secretion requires processing of pro-IL-1β and this is mediated by the inflammasome, a complex of Nalp3, apoptosis-associated speck-like protein containing a CARD (ASC) and caspase-1. The objective of this study was to determine if aPL induce IL-1β production in trophoblast via the inflammasome. Using a human first trimester trophoblast cell line, we demonstrated that a mouse anti-β2GPI mAb and human polyclonal aPL-IgG induce IL-1β processing and secretion, which was partially blocked upon caspase-1 inhibition. Nalp3 and ASC knockdown also attenuated anti-β2GPI Ab-induced IL-1β secretion. Furthermore, aPL stimulated the production of uric acid in a TLR4-dependent manner; and inhibition of uric acid prevented aPL-induced IL-1β production by the trophoblast. These findings demonstrate that aPL, via TLR4 activation, induce a uric acid response in human trophoblast, which in turn activates the Nalp3/ASC inflammasome leading to IL-1β processing and secretion. This novel mechanism may account for the inflammation at the maternal-fetal interface, which causes placental dysfunction and increases the risk of adverse pregnancy outcome in patients with APS.
    PLoS ONE 01/2013; 8(6):e65237. · 3.73 Impact Factor
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    Manish Garg, Julie A Potter, Vikki M Abrahams
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    ABSTRACT: While infection-induced placental inflammation is a common mechanism of adverse pregnancy outcome, some pathogens can also trigger placental apoptosis, and Toll-like receptors (TLRs) mediate this response. Treatment of human first trimester trophoblast cells with bacterial peptidoglycan (PDG) reduces their constitutive secretion of IL-6 protein and induces apoptosis. This apoptotic response is dependent upon the cell's expression of TLR1, TLR2 and TLR10, and their lack of TLR6, such that ectopic expression of TLR6 prevents PDG-induced apoptosis and restores IL-6 production. In this current study we have identified three microRNAs (miRs) that regulate TLR2-mediated responses in the human trophoblast. Herein we report that miR-329 plays a pivotal role in mediating PDG-induced trophoblast apoptosis and inhibition of IL-6 mRNA expression by targeting the NF-κB subunit, p65. TLR2 activation by PDG upregulates miR-329 expression and inhibits NF-κB p65 and IL-6 mRNA, and this is reversed by the presence of TLR6. Moreover, inhibition of miR-329 prevents PDG-induced inhibition of NF-κB p65 and IL-6 mRNA expression, and restores cell survival. In addition, we have found miR-23a and let-7c to directly regulate PDG-mediated inhibition of IL-6 mRNA. TLR2 activation by PDG upregulates miR23a and let-7c expression and this is reversed by the presence of TLR6. Furthermore, inhibition of both miR23a and let-7c prevents PDG-inhibition of trophoblast IL-6 mRNA expression. Together, our findings suggest that multiple miRs are involved in the molecular regulation of TLR2-mediated responses in the trophoblast towards gram-positive bacterial components.
    PLoS ONE 01/2013; 8(10):e77249. · 3.73 Impact Factor
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    ABSTRACT: PROBLEM: There is a strong correlation between intrauterine bacterial infection and preterm labor. While inflammation is a common mechanism, certain pathogens may trigger placental apoptosis. TLR2 activation by gram-positive bacterial peptidoglycan (PDG) induces first-trimester trophoblast apoptosis and decreased IL-6 secretion. This is dependent upon the presence of TLR1 and the absence of TLR6 and both TLR2 coreceptors. As TLR10 is also a TLR2 coreceptor, the objective of this study was to determine its expression and function in the trophoblast. METHOD OF STUDY: First-and third-trimester human placental tissue and isolated trophoblast were evaluated for TLR10 expression. A first-trimester human trophoblast cell line stably transfected with a TLR10 dominant negative (TLR10-DN) or vector control was treated with or without PDG and analyzed for apoptosis and IL-6. RESULTS: TLR10 was expressed by trophoblasts during the first and third trimesters of pregnancy. PDG-induced trophoblast caspase-3 activity was inhibited by the presence of the TLR10-DN. The presence of the TLR10-DN had no effect on PDG reduction in trophoblast IL-6 secretion. CONCLUSION: This study demonstrates that trophoblast TLR10 plays a role in promoting apoptosis triggered by gram-positive bacterial components and suggests that TLR10 may regulate the balance between trophoblast survival and cell death.
    American Journal Of Reproductive Immunology 12/2012; · 3.32 Impact Factor
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    ABSTRACT: PROBLEM: Preterm premature rupture of fetal membranes (pPROM) occurs in 30-40% of spontaneous preterm births (PTB) and is associated with intra-amniotic infection and inflammation. The membranes may sense and respond to microbes via Toll-like receptors (TLRs); however, little is known about their expression and regulation in this tissue. The objective of this study was to evaluate the expression of TLRs 1-10 in fetal membranes after exposure to pathogens associated with intra-amniotic infection and PTB. METHOD OF STUDY: Normal human term fetal membrane explants were exposed to various bacteria. After 24 hrs, RNA was extracted and quantitative RT-PCR performed for TLRs1-10. RESULTS: Treatment of fetal membranes with Mycoplasma hominis increased expression of TLR4, TLR6, and TLR8 mRNA. Ureaplasma parvum upregulated TLR8 mRNA, and Porphyromonas gingivalis significantly increased fetal membrane TLR7 expression. In contrast, treatment with Gram-negative Escherichia coli (and its cell wall component lipopolysaccharide) downregulated TLR10 mRNA. No effect was detected for Ureaplasma urealyticum, Gardnerella vaginalis, or Group B Streptococcus. CONCLUSION: These findings demonstrate that different types of bacteria have distinct effects on fetal membrane TLR expression patterns. Moreover, these findings highlight the disparity of fetal membrane responses to infection and thus suggest heterogeneity in the mechanisms by which infection-associated pregnancy complications, such as pPROM and PTB, arise.
    American Journal Of Reproductive Immunology 09/2012; · 3.32 Impact Factor
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    ABSTRACT: STUDY QUESTION: What is the effect of pravastatin on antiphospholipid antibody (aPL) modulation of human first trimester trophoblast function? SUMMARY ANSWER: Pravastatin does not prevent the effects of aPL on human first trimester trophoblast cell function. WHAT IS KNOWN ALREADY: Antiphospholipid syndrome (APS) is associated with recurrent pregnancy loss and late pregnancy complications, such as pre-eclampsia, owing to direct targeting of the placenta by aPL. While treatment with heparin reduces the rate of pregnancy loss, the risk for severe pre-eclampsia remains high. Thus, there is a need to find alternative treatments for the prenatal management of patients with APS. Statins have recently been shown to prevent aPL-mediated fetal loss in mice but their effects on a human pregnancy model of APS have not yet been studied. DESIGN, DATA COLLECTION, METHODS: The human first trimester trophoblast cell line, HTR8, and human first trimester trophoblast primary cultures were incubated with or without a mouse anti-human beta 2 glycoprotein I (β(2)GPI) monoclonal antibody in the presence or absence of pravastatin. Cytokine and angiogenic factor secretion were measured by enzyme-linked immunosorbent assay and multiplex analysis. Cell migration was measured using a colorimetric two-chamber migration assay. MAIN FINDINGS: Using the human first trimester trophoblast cell line, HTR8, pravastatin significantly augmented, compared with no treatment, aPL-dependent secretion of interleukin (IL)-8 (P< 0.05), IL-1β (P< 0.05) and soluble endoglin (P< 0.01) but had no effect on aPL-induced up-regulation of vascular endothelial growth factor, placenta growth factor or growth-related oncogene alpha secretion. Furthermore, pravastatin alone limited basal HTR8 cell migration (P< 0.01), and did not mitigate the adverse effect of aPL on trophoblast migration. Pravastatin also had no impact on the secretion of pro-inflammatory cytokines and angiogenic factors by primary human first trimester trophoblast cells exposed to aPL. LIMITATIONS AND WIDER IMPLICATIONS OF THE FINDINGS: While our in vitro findings suggest that pravastatin may not be effective in preventing pregnancy complications in patients with APS, the in vivo condition may be more complex, and thus, more studies are needed to determine the effectiveness of pravastatin in the prevention of aPL-associated pregnancy complications in humans. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the American Heart Association.
    Human Reproduction 08/2012; 27(10):2933-40. · 4.67 Impact Factor
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    ABSTRACT: Chlamydia trachomatis (Ct) is an obligate intracellular bacterial pathogen. Previously, we showed that infection of human trophoblast cells by Ct triggers the secretion of the pro-inflammatory cytokine, interleukin (IL)-1β. The aim of this study was to understand the innate immune pathways involved in trophoblast production of IL-1β after Ct infection. The approach we took was to inhibit the expression or function of the key Toll-like receptors (TLRs), Nod-like receptors, and inflammasome components that have been associated with chlamydia infection. In this study, we report that Ct-induced trophoblast IL-1β secretion is associated with the transcription of IL-1β mRNA, the translation and processing of pro-IL-1β, and the activation of caspase-1. In addition, we demonstrate that Ct-induced IL-1β production and secretion by the trophoblast is independent of TLR2, TLR4, MyD88, and the Nalp3/ASC inflammasome. Instead we report, for the first time, the importance of Nod1 for mediating trophoblast IL-1β secretion in response to a Ct infection.Mucosal Immunology advance online publication 4 July 2012. doi:10.1038/mi.2012.63.
    Mucosal Immunology 07/2012; · 7.54 Impact Factor
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    ABSTRACT: Uterine innate immunity remains poorly characterized, and while endometrial endothelial cells are known to express Toll-like receptors (TLRs), little is known about their function in these cells. The present study evaluated the effect of Gram-negative bacterial lipopolysaccharide (LPS) on human endometrial endothelial cell (HEECs) cytokine secretion and tissue factor expression, and the role of TLR-4 in these responses. Human endometrial endothelial cells were treated with or without LPS ± LPS-RS, a TLR-4 antagonist, via the binding of MD-2. After 24 hr, cell-free supernatants were evaluated for cytokines by multiplex analysis and cell lysates were analyzed for tissue factor expression by Western blot. Treatment of HEECs with LPS significantly upregulated the secretion of IL-6, IL-8, and G-CSF, and this was prevented by LPS-RS. LPS also induced tissue factor expression by the HEECs; however, this was unaffected by LPS-RS. These findings suggest that TLR-4 is functional in HEECs and its activation by bacterial LPS induces a specific cytokine/chemokine response. However, bacterial LPS also induced tissue factor expression in what seemed to be a TLR-4-independent fashion, suggesting that this bacterial component can act on the HEECs through TLR-4-dependent and TLR-4-independent pathways. These findings indicate that endometrial endothelial cells may play an active role in uterine innate immunity.
    American Journal Of Reproductive Immunology 06/2012; 68(3):233-7. · 3.32 Impact Factor
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    ABSTRACT: Toll-like receptor-4 (TLR-4) protects against Gram-negative bacteria expressed lipopolysaccharide and 'danger signals' from injured or dying cells. Although decidual cells (DCs) and interstitial trophoblasts (ITs) are in close contact, TLR-4 has been studied extensively only in ITs. Formalin-fixed, paraffin-embedded serial sections of endometrium in follicular and luteal phases and deciduas from first and second trimester elective terminations and third trimester normal deliveries were immunostained for TLR-4, trophoblast-specific cytokeratin, and DC-specific vimentin. HSCORE assessed TLR-4 immunostaining in DCs versus ITs. TLR-4 HSCORES were significantly higher in: (i) first trimester DCs than luteal phase pre-decidual stromal cells; (ii) first and third versus second trimester DCs, but similar between third trimester deciduas parietalis and basalis; (iii) first versus second trimester ITs; (iv) DCs versus ITs across gestation. Higher TLR-4 in DCs than ITs suggests DCs as primary targets for Gram-negative bacteria and/or inflammation-related danger signals.
    American Journal Of Reproductive Immunology 05/2012; 68(2):146-53. · 3.32 Impact Factor
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    ABSTRACT: Toll-like receptors (TLRs) are central components of the innate immune system that recognize both microbial ligands and host products released during tissue damage. Data from epidemiologic studies and animal models suggest that inappropriate activation of the immune system plays a critical role in the development of preeclampsia. This study evaluates in a systematic fashion the expression and function of TLRs in the circulation of patients with preeclampsia compared to healthy pregnant controls. We evaluated TLR expression and function in primary dendritic cells (DCs) of 30 patients with preeclampsia and 30 gestational age-matched healthy pregnant controls. DCs were stimulated with the different TLR ligands engaging TLR1/2, TLR2/6, TLR3, TLR4, TLR5, TLR7, TLR8 and TLR9. The expression of TLR-induced production of TNF-α, IFN-α, IL-6, and IL-12 were measured by multicolor flow cytometry. Basal expression of TLR3, TLR4 and TLR9 was significantly increased in DCs isolated from women with preeclampsia. Preeclamptic DCs also expressed significantly higher basal levels of cytokines. In contrast, preeclamptic DCs demonstrated a less robust response to stimulation with various TLR ligands as compared with healthy pregnant controls. Under basal conditions, DCs from preeclamptic individuals express higher levels of select TLRs and produce more pro-inflammatory cytokines as compared with healthy controls. As such, the ability of these cells to mount an inflammatory reaction in response to a TLR ligand is limited. These data demonstrate a dysregulated pattern of TLR expression and cytokine production in DCs from PE patients that may limit further activation by TLR engagement.
    Journal of Reproductive Immunology 03/2012; 94(2):210-5. · 2.34 Impact Factor
  • B S Holder, C L Tower, V M Abrahams, J D Aplin
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    ABSTRACT: This study characterises HERV-W (syncytin 1) expression in normal and pathologic placenta and in BeWo cells. HERV-W mRNA levels were higher in the first trimester than at term, and similar patterns were observed with another retrovirally-derived mRNA species, ERV-3. N-glycosylated syncytin 1 precursor (73 kDa) is cleaved to surface-associated (SU) and transmembrane (TM) subunits. Both were evident in villous trophoblast, where perinuclear and punctate cytoplasmic deposits were observed, and linear TM subunit immunoreactivity was seen at the syncytial microvillous membrane. Punctate immunoreactivity was seen in BeWo cells with antibodies to SU and TM, and the two were co-localised. SU immunoreactivity was observed in association with fetal endothelium, and this effect was increased in tissue from pre-eclamptic placentas, which also showed a higher level of total SU protein. Absence of the TM subunit from endothelium suggests it is not a biosynthetic source. We suggest that SU is released from trophoblast into fetal circulation where it may bind vascular endothelium.
    Placenta 02/2012; 33(6):460-6. · 3.12 Impact Factor
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    ABSTRACT: Envelope glycoproteins of human endogenous retrovirus (HERV), such as syncytin 1 (HERV-W), are highly expressed in the placenta and some family members have immunomodulatory properties. Placental microvesicles (MV), which are shed into the maternal circulation during pregnancy, have been demonstrated to induce immune cell activation. Therefore, the aim of this study was to investigate the immunological properties of the highly expressed placental HERV-W protein, syncytin 1, and its potential involvement in placental MV modulation of immune cell activity. The MV shed from first trimester, normal term and pre-eclamptic term placentas, and from the BeWo trophoblast cell line, all contain syncytin 1. Recombinant syncytin 1 and syncytin 1-positive BeWo trophoblast MV both induced peripheral blood mononuclear cell (PBMC) activation, indicated through production of cytokines and chemokines. Reducing syncytin 1 content in BeWo MV inhibited PBMC activation. Recombinant syncytin 1 and syncytin-1-positive BeWo MV dampened PBMC responses to lipopolysaccharide challenge. Our findings suggest that syncytin 1 is shed from the placenta into the maternal circulation in association with MV, and modulates immune cell activation and the responses of immune cells to subsequent lipopolysaccharide stimulation. These studies implicate placental MV-associated HERV in fetal regulation of the maternal immune system.
    Immunology 02/2012; 136(2):184-91. · 3.71 Impact Factor
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    ABSTRACT: Normal pregnancy is associated with the presence of circulating placental microvesicles (MVs). Increased MV shedding and altered immune activation are seen in patients with preeclampsia, suggesting that placental MVs may play a role in the pathophysiology of this disease. Therefore, the aim of this study was to investigate the activation of peripheral blood mononuclear cells (PBMCs) by MVs shed by first-trimester, normal term, and preeclamptic term placenta. First-trimester and preeclamptic term, but not normal term, placental-derived MVs activated PBMCs, as evidenced by elevated IL1B. Significant changes were also seen with several other cytokines and chemokines, and in general when compared to normal term MVs, preeclamptic MVs induced a greater pro-inflammatory response in PBMCs. Pretreatment of PBMCs with first-trimester or normal term placental MVs resulted in a dampened IL1B response to a subsequent lipopolysaccharide (LPS) challenge. In contrast, treatment of PBMCs with preeclamptic term placental MVs exacerbated the LPS response. This was also the case for several other cytokines and chemokines. These studies suggest that placental MVs can modulate basal peripheral immune cell activation and responsiveness to LPS during normal pregnancy, and that in preeclampsia this effect is exacerbated.
    Biology of Reproduction 12/2011; 86(4):103. · 4.03 Impact Factor
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    ABSTRACT: Low molecular weight (LMW) heparin, with or without aspirin (acetylsalicylic acid [ASA]), is used to prevent complications in antiphospholipid syndrome in pregnancy. Our objective was to elucidate the actions of low-dose LMW heparin and ASA on basal and antiphospholipid antibody-induced modulation of trophoblast function. The human first-trimester trophoblast cell line (HTR-8) was treated with or without antiphospholipid antibody in the presence of no medication, low-dose LMW heparin, low-dose ASA, or combination therapy. Interleukin (IL)-6, IL-8, IL-1β, growth-regulated oncogene-α, vascular endothelial growth factor (VEGF), placental growth factor, soluble FMS-like tyrosine kinase-1, and soluble endoglin were measured in the supernatant. Cell migration was performed using a two-chamber assay. Low molecular weight heparin improved basal trophoblast migration and induced potent increases in growth-regulated oncogene-α and soluble FMS-like tyrosine kinase-1. Aspirin did not affect basal function. Combined therapy promoted migration but did not reverse the LMW heparin-induced soluble FMS-like tyrosine kinase-1 effect. Antiphospholipid antibody increased IL-8, IL-1β, growth-regulated oncogene-alpha, VEGF, placental growth factor, and soluble endoglin secretion, while decreasing cell migration and IL-6 and soluble FMS-like tyrosine kinase-1 secretion. The antiphospholipid antibody-induced cytokine changes were best reversed with LMW heparin, with partial reversal of IL-8 and IL-1β upregulation. The antiphospholipid antibody-induced angiogenic changes were worsened by LMW heparin, with increased soluble FMS-like tyrosine kinase-1 secretion. The therapies did not reverse antiphospholipid antibody-induced decrease in migration. In the absence of antiphospholipid antibodies, LMW heparin induces potentially detrimental proinflammatory and antiangiogenic profile in the trophoblast. In the presence of antiphospholipid antibodies, single-agent LMW heparin may be the optimal therapy to counter trophoblast inflammation, but also induces an antiangiogenic response. These findings may explain the inability of current therapies to consistently prevent adverse outcomes.
    Obstetrics and Gynecology 11/2011; 118(5):1021-8. · 4.80 Impact Factor

Publication Stats

2k Citations
294.13 Total Impact Points


  • 2002–2014
    • Yale-New Haven Hospital
      • • Department of Pathology
      • • Department of Laboratory Medicine
      New Haven, Connecticut, United States
  • 1970–2013
    • Yale University
      • Department of Obstetrics, Gynecology and Reproductive Sciences
      New Haven, Connecticut, United States
  • 2012
    • The University of Manchester
      • Manchester Maternal and Fetal Health Research Centre
      Manchester, ENG, United Kingdom
  • 2010
    • Università degli Studi di Siena
      Siena, Tuscany, Italy
  • 2004
    • Wayne State University
      • Department of Obstetrics and Gynecology
      Detroit, Michigan, United States
    • National Institute of Child Health and Human Development
      Maryland, United States
    • Dartmouth Medical School
      • Department of Microbiology and Immunology
      Hanover, NH, United States