The Immunogenetic Conundrum of Preeclampsia

Pregnancy is an immunological challenge to the mother. The fetal tissues including the placenta must be protected from activation of the maternal immune system. On the other hand, the placental tissue sheds into the maternal circulation and must be adequately identified and phagocytized by the maternal immune system. During a healthy pregnancy, numerous immunosuppressive processes take place that allow the allograft fetus to thrive under exposure to humoral and cellular components of the maternal immune system. Breakdown of immune tolerance may result in sterile inflammation and cause adverse pregnancy outcomes such as preeclampsia, a vascular disease of the pregnancy with unpredictable course and symptoms from several organs. Immunological incompatibility between mother and fetus is strongly indicated in preeclampsia. Recently, genetic factors linking immunological pathways to predisposition to preeclampsia have been identified. In this mini-review genetic variation in immunological factors are discussed in the context of preeclampsia. Specifically, we explore immunogenetic and immunomodulary mechanisms contributing to loss of tolerance, inflammation, and autoimmunity in preeclampsia

Estudio del rol de Galectina-1 en el establecimiento y desarrollo de la endometriosis

Endometriosis is characterized by the presence of endometrial tissue outside the uterus reassembled in well-vascularized endometriotic lesions. Galectin-1 (Gal-1) is an endogenous lectin upregulated in tumor and inflammatory microenvironments, where it plays essential roles in angiogenesis mechanisms. In this study, it was demonstrated that tissue expression of Gal-1 in endometriotic lesions and eutopic endometrium was restricted to stromal and endothelial cells and was absent in epithelial cells. Besides, Gal-1 protein expression levels were higher in the endometriotic lesions than eutopic endometrium from patients with minimal or mild degree of endometriosis, suggesting that Gal-1 could be playing a key role in the onset and development of this pathology at early stages. It was also found that the presence of Gal-1 is crucial for in vitro proliferation of endometrial stromal cells, for the vascular development and consequent growth of endometriotic lesions in vivo, and it was also demonstrated that the specific blockade of Gal-1 at peritoneal level restricts the growth of endometriotic lesions, suggesting that in the future this endogenous lectin could become potential therapeutic target that allows to develop new effective treatments to mitigate the progression of this disease. These results highlight the pivotal role of Gal-1 in endometriosis pathophysiology.Fil: Bastón, Juan Ignacio. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaLa endometriosis se caracteriza por la presencia de tejido endometrial fuera de la cavidad uterina formando lesiones que se desarrollan y vascularizan en sitios ectópicos. Galectina-1 (Gal-1) es una lectina endógena que desempeña importantes funciones pro-angiogénicas e inmunomoduladoras en la biología tumoral. El objetivo principal de esta tesis fue estudiar el rol de Gal-1 en la etiopatogenia de la endometriosis.\nDemostramos que Gal-1 se expresa en las células estromales y endoteliales pero no en las células epiteliales endometriales eutópicas y ectópicas. Además, los niveles de Gal-1 son mayores en las lesiones que en el endometrio eutópico de las pacientes con endometriosis grado I/II, lo cual podría indicar que Gal-1 juega un papel primordial en los estadios tempranos del establecimiento de esta patología. Observamos también que Gal-1 juega un papel significativo en la fisiopatología de la endometriosis, dado que promueve la proliferación in vitro de las células estromales endometriales, además del desarrollo vascular y el crecimiento de las lesiones endometriósicas in vivo. También se demostró que el bloqueo específico a nivel peritoneal de esta lectina limita el crecimiento de las lesiones, lo cual lleva a sugerir que Gal-1 podría convertirse un blanco terapéutico potencial para combatir la progresión de esta enfermedad

The Drosophila Receptor Tyrosine Kinase Tie Instructs Function of the bantam MicroRNA in the Response to Ionizing Radiation

Life or death choices of cells in Drosophila depend on the accumulation of critical levels of pro-apoptotic factors such as hid. Ionizing radiation (IR) causes lesions to macromolecules in cells that trigger damage responses and result in death of cells expressing critical amounts of hid. Cells are eliminated by apoptosis to prevent the transfer of damaged genetic material to daughter cells. However, some cells must be preserved in order for organisms to survive and regenerate. Therefore, genes that limit apoptosis can enhance organismal survival. The ban miRNA limits apoptosis after IR exposure by regulating the 3'UTR of hid. Though important for developmental apoptosis and proliferation, ban is also activated by radiation-induced apoptosis, and promotes organismal and cellular survival after IR exposure. To better understand how pro- and anti-apoptotic factors regulate survival after IR exposure I screened for genes that could modify ban function in a dose-dependent manner. I identified Tie, a receptor tyrosine kinase in the VGFR/PDGFR family, as an important regulator of IR-induced increases in ban activity and levels. Previously, the only known role for Tie in Drosophila was in long-range signaling in border cell migration. Although tie is not required for development, it is required for radiation survival. These suggest that tie instructs ban activity in radiation responses. Additionally, tie is required for protection from radiation-induced apoptosis conferred by death of neighboring cells. Although many questions remain to be answered, this work provides a further level of insight into how life and death decisions of cells are regulated following exposure to IR. Since IR is used in cancer therapies to induce apoptosis, I hope that this work could contribute to development of more effective cancer therapies

Cell-cell interactions in the gastrointestinal tumour-microenvironment

The tumour-microenvironment consists of malignant epithelial cells, surrounding cancer associated (myo-)fibroblasts, endothelial cells creating the tumours__ vasculature system and infiltrating inflammatory cells. In this thesis we have studied how interactions between these cell types contribute to the initiation, progression and metastasis formation in gastrointestinal cancers. We have focused on how the availability of two important growth factors (Transforming Growth Factor-_ and Vascular Endothelial Growth Factor) in tumour angiogenesis and myofibroblasts differentiation is regulated by interactions between different cell types. First we revealed that active TGF-_1 levels are strongly increased in gastric and colorectal carcinomas and that they are indicative for the survival of these patients. In premalignant lesions increased activation is not yet observed. In addition we show that active TGF-_ levels are correlated with the number of myofibroblasts in colorectal carcinomas. Furthermore we reveal that interaction between colon cancer cells and cancer associated fibroblasts leads to increased TGF-_ activation, subsequent myofibroblast trans-differentiation accompanied by upregulation of TGF-_ expression and increased matrix metalloproteinase (MMP) secretion. To further evaluate how MMPs regulate tumour progression we have investigated their role in tumour-angiogenesis. We show that MMP-9, derived from tumour-infiltrating neutrophils, contributes to the angiogenic switch, by releasing tumour cell derived VEGF from the extracellular matrix. Finally, we show that tumour-angiogenesis requires endothelial MMP-7 expression and is regulated by MMP-14 dependent cleavage of the TGF-_ co-receptor endoglin on angiogenic endothelial cells. In conclusion, these studies show that interaction between tumour cells, fibroblasts and endothelial cells are important for the generation of myofibroblasts by TGF-_ activation and for the initiation of angiogenesis by regulating VEGF release. These data further validate the tumour-microenvironment as an important therapeutic target.UBL - phd migration 201