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Do decidual cytokines play a role in the aetiology of spontaneous miscarriage
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Invited Presentations / Journal of Reproductive Immunology 111 (2015) 4–9
S15 Do decidual cytokines play a role in the aetiology of spontaneous miscarriage G.E. Lash Reproductive and Vascular Biology Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK The establishment of pregnancy requires the co-ordinated implantation of the embryo into the receptive decidua, placentation, trophoblast invasion of the maternal decidua and myometrium as well as remodelling of the uterine spiral arteries. Failure of any of these steps can lead to a range of pregnancy complications including miscarriage, pre-eclampsia, fetal growth restriction, placenta accreta and pre-term birth. Cytokines are small multifunctional proteins often derived from leucocytes and have primarily been described through their immunomodulatory actions. The maternal-fetal interface is considered to be immunosuppressed to allow development of the semi-allogeneic placental-fetal unit. However, cytokine profiles of the decidua and different decidual cell types suggests that the in vivo situation is more complex. Data suggests that decidual derived cytokines not only play roles in immunosuppression but also in other aspects of the establishment of pregnancy including regulation of trophoblast invasion and spiral artery remodelling. This review focuses on the potential role of decidual derived cytokines in the aetiology of unexplained spontaneous miscarriage. http://dx.doi.org/10.1016/j.jri.2015.06.066 S16 The complement system at the embryo implantation site C. Agostinis 1 , R. Bulla 2,∗ 1
Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy 2 Department of Life Sciences, University of Trieste, Trieste, Italy The Complement (C) system plays an important role in the control of infectious agents and in the removal of immune complexes and apoptotic cells. Like other components of innate immunity, C is able to recognize the targets through the early components and to attack them through the biologically active products released as a result of activation. While recognition is restricted to harmful agents, the effector phase associated with the activation products of the terminal components is not selective for foreign targets and may also attack host cells. Thus, C can be considered an effective defence system but also a potential danger that may differently affect various tissues and organs. The protective function of the C system is particularly important during pregnancy since the implanted embryo is vulnerable to attack by pathogens that colonize the cervico-vaginal cavity. Uncontrolled complement activation is prevented in successful pregnancy by the regulatory proteins positioned on the surface of several placental cells, however, unrestricted C activation induced by antibody-dependent and independent mechanisms may overcome the neutralizing effect of the C inhibitors and results in tissue damage and poor pregnancy outcome. C components produced at feto-maternal interface serve an important function in placental development. C1q synthesized by decidual endothelial cells and expressed on the cell surface is
particularly important in this regard because it acts as a molecular bridge between endovascular trophoblast and endothelial cells. C1q is also produced by trophoblast and is used to favour trophoblast migration through the decidua. Defective expression of C1q by trophoblast is associated with impaired trophoblast invasion of decidua and may have important implications in pregnancy disorders such as preeclampsia characterized by reduced vascular remodeling. In conclusion the C system behaves as a double-edged sword, exerting a protective function and inducing damage in pathological situations that may result in poor pregnancy outcome. http://dx.doi.org/10.1016/j.jri.2015.06.067 S17 Syncytiotrophoblast vesicles in normal pregnancy and preeclampsia D. Tannetta ∗ , R. Dragovic, G. Collett, C. Redman, I. Sargent Nuffield Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Hospital, Oxford, UK The release of extracellular vesicles (EV) by the syncytiotrophoblast (STB) is an important mechanism by which the placenta signals to the mother. STBEV are comprised of exosomes (50–150 nm in size) and microvesicles (100–1000 nm). They are released by the STB into the maternal circulation throughout gestation in normal pregnancy where they appear to have an immunoregulatory role, inhibiting T cell and NK cell responses. In pre-eclampsia (PE) these STBEV are released in significantly increased numbers and have pro-inflammatory, anti-angiogenic and procoagulant activity which could explain the maternal systemic inflammation, endothelial dysfunction and activation of the clotting system which characterises the disorder. We have sought to determine the repertoire of molecules carried by the microvesicles and exosomes and how they differ in normal pregnancy and PE. To obtain sufficient vesicles for analysis we have carried out placental perfusion on normal and PE placentas. We have characterised the vesicles by nanoparticle tracking analysis and flow cytometry and investigated the protein cargo by mass spectrometry and glycosylation of STBEV surface proteins by lectin binding. STBEV isolated from PE placentas are larger than those from normal placentas, suggesting an increase in the proportion of microvesicles released. More than 2,000 proteins have been identified in these vesicles, with some unique to PE and others unique to normal pregnancy. Glycosylation of surface proteins is also altered in STBEV derived from PE placentas. These changes are being investigated to better understand placental pathology in PE and the use of STBEV as potential biomarkers and therapeutic targets for PE. http://dx.doi.org/10.1016/j.jri.2015.06.068
Invited Presentations / Journal of Reproductive Immunology 111 (2015) 4–9
S15 Do decidual cytokines play a role in the aetiology of spontaneous miscarriage G.E. Lash Reproductive and Vascular Biology Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK The establishment of pregnancy requires the co-ordinated implantation of the embryo into the receptive decidua, placentation, trophoblast invasion of the maternal decidua and myometrium as well as remodelling of the uterine spiral arteries. Failure of any of these steps can lead to a range of pregnancy complications including miscarriage, pre-eclampsia, fetal growth restriction, placenta accreta and pre-term birth. Cytokines are small multifunctional proteins often derived from leucocytes and have primarily been described through their immunomodulatory actions. The maternal-fetal interface is considered to be immunosuppressed to allow development of the semi-allogeneic placental-fetal unit. However, cytokine profiles of the decidua and different decidual cell types suggests that the in vivo situation is more complex. Data suggests that decidual derived cytokines not only play roles in immunosuppression but also in other aspects of the establishment of pregnancy including regulation of trophoblast invasion and spiral artery remodelling. This review focuses on the potential role of decidual derived cytokines in the aetiology of unexplained spontaneous miscarriage. http://dx.doi.org/10.1016/j.jri.2015.06.066 S16 The complement system at the embryo implantation site C. Agostinis 1 , R. Bulla 2,∗ 1
Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy 2 Department of Life Sciences, University of Trieste, Trieste, Italy The Complement (C) system plays an important role in the control of infectious agents and in the removal of immune complexes and apoptotic cells. Like other components of innate immunity, C is able to recognize the targets through the early components and to attack them through the biologically active products released as a result of activation. While recognition is restricted to harmful agents, the effector phase associated with the activation products of the terminal components is not selective for foreign targets and may also attack host cells. Thus, C can be considered an effective defence system but also a potential danger that may differently affect various tissues and organs. The protective function of the C system is particularly important during pregnancy since the implanted embryo is vulnerable to attack by pathogens that colonize the cervico-vaginal cavity. Uncontrolled complement activation is prevented in successful pregnancy by the regulatory proteins positioned on the surface of several placental cells, however, unrestricted C activation induced by antibody-dependent and independent mechanisms may overcome the neutralizing effect of the C inhibitors and results in tissue damage and poor pregnancy outcome. C components produced at feto-maternal interface serve an important function in placental development. C1q synthesized by decidual endothelial cells and expressed on the cell surface is
particularly important in this regard because it acts as a molecular bridge between endovascular trophoblast and endothelial cells. C1q is also produced by trophoblast and is used to favour trophoblast migration through the decidua. Defective expression of C1q by trophoblast is associated with impaired trophoblast invasion of decidua and may have important implications in pregnancy disorders such as preeclampsia characterized by reduced vascular remodeling. In conclusion the C system behaves as a double-edged sword, exerting a protective function and inducing damage in pathological situations that may result in poor pregnancy outcome. http://dx.doi.org/10.1016/j.jri.2015.06.067 S17 Syncytiotrophoblast vesicles in normal pregnancy and preeclampsia D. Tannetta ∗ , R. Dragovic, G. Collett, C. Redman, I. Sargent Nuffield Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Hospital, Oxford, UK The release of extracellular vesicles (EV) by the syncytiotrophoblast (STB) is an important mechanism by which the placenta signals to the mother. STBEV are comprised of exosomes (50–150 nm in size) and microvesicles (100–1000 nm). They are released by the STB into the maternal circulation throughout gestation in normal pregnancy where they appear to have an immunoregulatory role, inhibiting T cell and NK cell responses. In pre-eclampsia (PE) these STBEV are released in significantly increased numbers and have pro-inflammatory, anti-angiogenic and procoagulant activity which could explain the maternal systemic inflammation, endothelial dysfunction and activation of the clotting system which characterises the disorder. We have sought to determine the repertoire of molecules carried by the microvesicles and exosomes and how they differ in normal pregnancy and PE. To obtain sufficient vesicles for analysis we have carried out placental perfusion on normal and PE placentas. We have characterised the vesicles by nanoparticle tracking analysis and flow cytometry and investigated the protein cargo by mass spectrometry and glycosylation of STBEV surface proteins by lectin binding. STBEV isolated from PE placentas are larger than those from normal placentas, suggesting an increase in the proportion of microvesicles released. More than 2,000 proteins have been identified in these vesicles, with some unique to PE and others unique to normal pregnancy. Glycosylation of surface proteins is also altered in STBEV derived from PE placentas. These changes are being investigated to better understand placental pathology in PE and the use of STBEV as potential biomarkers and therapeutic targets for PE. http://dx.doi.org/10.1016/j.jri.2015.06.068