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Frontiers in Immunology 2020Growth/differentiation factor-15 (GDF-15), also named macrophage inhibitory cytokine-1, is a divergent member of the transforming growth factor β superfamily. While... (Review)
Review
Growth/differentiation factor-15 (GDF-15), also named macrophage inhibitory cytokine-1, is a divergent member of the transforming growth factor β superfamily. While physiological expression is barely detectable in most somatic tissues in humans, GDF-15 is abundant in placenta. Elsewhere, GDF-15 is often induced under stress conditions, seemingly to maintain cell and tissue homeostasis; however, a moderate increase in GDF-15 blood levels is observed with age. Highly elevated GDF-15 levels are mostly linked to pathological conditions including inflammation, myocardial ischemia, and notably cancer. GDF-15 has thus been widely explored as a biomarker for disease prognosis. Mechanistically, induction of anorexia via the brainstem-restricted GDF-15 receptor GFRAL (glial cell-derived neurotrophic factor [GDNF] family receptor α-like) is well-documented. GDF-15 and GFRAL have thus become attractive targets for metabolic intervention. Still, several GDF-15 mediated effects (including its physiological role in pregnancy) are difficult to explain via the described pathway. Hence, there is a clear need to better understand non-metabolic effects of GDF-15. With particular emphasis on its immunomodulatory potential this review discusses the roles of GDF-15 in pregnancy and in pathological conditions including myocardial infarction, autoimmune disease, and specifically cancer. Importantly, the strong predictive value of GDF-15 as biomarker may plausibly be linked to its immune-regulatory function. The described associations and mechanistic data support the hypothesis that GDF-15 acts as immune checkpoint and is thus an emerging target for cancer immunotherapy.
Topics: Animals; Autoimmune Diseases; Biomarkers; Female; Growth Differentiation Factor 15; Homeostasis; Humans; Immune Checkpoint Inhibitors; Immunomodulation; Mice; Myocardial Infarction; Neoplasms; Placenta; Pregnancy
PubMed: 32508832
DOI: 10.3389/fimmu.2020.00951 -
Cell Stem Cell Jul 2015Clinical investigations using stem cell products in regenerative medicine are addressing a wide spectrum of conditions using a variety of stem cell types. To date, there... (Review)
Review
Clinical investigations using stem cell products in regenerative medicine are addressing a wide spectrum of conditions using a variety of stem cell types. To date, there have been few reports of safety issues arising from autologous or allogeneic transplants. Many cells administered show transient presence for a few days with trophic influences on immune or inflammatory responses. Limbal stem cells have been registered as a product for eye burns in Europe and mesenchymal stem cells have been approved for pediatric graft versus host disease in Canada and New Zealand. Many other applications are progressing in trials, some with early benefits to patients.
Topics: Clinical Trials as Topic; Endothelial Cells; Female; Humans; Immunosuppression Therapy; Limbus Corneae; Liver Diseases; Mesenchymal Stem Cell Transplantation; Myocardial Infarction; Neural Stem Cells; Osteoarthritis; Placenta; Pluripotent Stem Cells; Pregnancy; Regenerative Medicine; Stem Cell Transplantation; Stroke; Treatment Failure
PubMed: 26140604
DOI: 10.1016/j.stem.2015.06.007 -
American Journal of Obstetrics and... Oct 2015Chronic inflammatory lesions of the placenta are characterized by the infiltration of the organ by lymphocytes, plasma cells, and/or macrophages and may result from... (Review)
Review
Chronic inflammatory lesions of the placenta are characterized by the infiltration of the organ by lymphocytes, plasma cells, and/or macrophages and may result from infections (viral, bacterial, parasitic) or be of immune origin (maternal anti-fetal rejection). The 3 major lesions are villitis (when the inflammatory process affects the villous tree), chronic chorioamnionitis (which affects the chorioamniotic membranes), and chronic deciduitis (which involves the decidua basalis). Maternal cellular infiltration is a common feature of the lesions. Villitis of unknown etiology (VUE) is a destructive villous inflammatory lesion that is characterized by the infiltration of maternal T cells (CD8+ cytotoxic T cells) into chorionic villi. Migration of maternal T cells into the villi is driven by the production of T-cell chemokines in the affected villi. Activation of macrophages in the villi has been implicated in the destruction of the villous architecture. VUE has been reported in association with preterm and term fetal growth restriction, preeclampsia, fetal death, and preterm labor. Infants whose placentas have VUE are at risk for death and abnormal neurodevelopmental outcome at the age of 2 years. Chronic chorioamnionitis is the most common lesion in late spontaneous preterm birth and is characterized by the infiltration of maternal CD8+ T cells into the chorioamniotic membranes. These cytotoxic T cells can induce trophoblast apoptosis and damage the fetal membranes. The lesion frequently is accompanied by VUE. Chronic deciduitis consists of the presence of lymphocytes or plasma cells in the basal plate of the placenta. This lesion is more common in pregnancies that result from egg donation and has been reported in a subset of patients with premature labor. Chronic placental inflammatory lesions can be due to maternal anti-fetal rejection, a process associated with the development of a novel form of fetal systemic inflammatory response. The syndrome is characterized by an elevation of the fetal plasma T-cell chemokine. The evidence that maternal anti-fetal rejection underlies the pathogenesis of many chronic inflammatory lesions of the placenta is reviewed. This article includes figures and histologic examples of all chronic inflammatory lesions of the placenta.
Topics: CD8-Positive T-Lymphocytes; Chemokines; Chorioamnionitis; Chorionic Villi; Chronic Disease; Decidua; Female; Histocompatibility, Maternal-Fetal; Humans; Inflammation; Macrophages; Plasma Cells; Pregnancy
PubMed: 26428503
DOI: 10.1016/j.ajog.2015.08.041 -
BMJ Case Reports Jan 2018Thrombotic thrombocytopenic purpura (TTP) is a potentially reversible, life-threatening medical emergency. We present a case of a 21-year-old female with evidence of...
Thrombotic thrombocytopenic purpura (TTP) is a potentially reversible, life-threatening medical emergency. We present a case of a 21-year-old female with evidence of haemolytic anaemia based on the presence of positive markers of haemolysis. Negative Coomb's test, thrombocytopenia and placental infarcts raised suspicion for a thrombotic microangiopathy. She was diagnosed with TTP and managed with emergency plasma exchange. Her recovery was immediate.A presumptive diagnosis of TTP should be based on the presence of microangiopathic haemolytic anaemia with thrombocytopenia and plasma exchange should be initiated while complete work up is pending. Using the regular pentad solely for diagnosis of TTP will lead to underdiagnosis of many cases and should be avoided.Several microangiopathies can be seen during pregnancy including TTP/atypical haemolytic uraemic syndrome, HELLP syndrome, pre-eclampsia, disseminated intravascular coagulopathy and antiphospholipid antibody syndrome. Distinction between each type will be the focus of our discussion as treatment decisions differ accordingly.
Topics: Female; Humans; Plasma Exchange; Pregnancy; Pregnancy Complications, Hematologic; Purpura, Thrombotic Thrombocytopenic; Young Adult
PubMed: 29348275
DOI: 10.1136/bcr-2017-221648 -
Ultrasound in Obstetrics & Gynecology :... Jul 2022Doppler techniques are needed for the evaluation of the intraplacental circulation and can be of great value in the diagnosis of placental anomalies. Highly sensitive... (Review)
Review
Doppler techniques are needed for the evaluation of the intraplacental circulation and can be of great value in the diagnosis of placental anomalies. Highly sensitive Doppler techniques can differentiate between the maternal (spiral arteries) and fetal (intraplacental branches of the umbilical artery) components of the placental circulation and assist in the evaluation of the placental functional units. A reduced number of placental functional units can be associated with obstetric complications, such as fetal growth restriction. Doppler techniques can also provide information on decidual vessels and blood movement. Abnormal decidual circulation increases the risk of placenta accreta. Doppler evaluation of the placenta greatly contributes to the diagnosis and clinical management of placenta accreta, vasa previa, placental infarcts, placental infarction hematoma, maternal floor infarction, massive perivillous fibrin deposition and placental tumors. However, it has a limited role in the diagnosis and clinical management of placental abruption, placental hematomas, placental mesenchymal dysplasia and mapping of placental anastomoses in monochorionic twin pregnancies. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.
Topics: Female; Fetal Growth Retardation; Humans; Infarction; Placenta; Placenta Accreta; Placenta Diseases; Pregnancy; Ultrasonography, Doppler; Ultrasonography, Prenatal
PubMed: 34806234
DOI: 10.1002/uog.24816 -
PloS One 2022Trophoblast inclusions-cross sections of abnormal trophoblast bilayer infoldings-have previously been associated with aneuploidy, placenta accreta, and prematurity. This...
OBJECTIVE
Trophoblast inclusions-cross sections of abnormal trophoblast bilayer infoldings-have previously been associated with aneuploidy, placenta accreta, and prematurity. This study was conducted to establish the relationship between trophoblast inclusions and a range of placental, pregnancy, and birth outcomes in a patient population with high smoking and alcohol exposure. Specifically, we sought to evaluate the association between the presence of trophoblast inclusions and 1) three primary birth outcomes: full-term birth, preterm birth, and stillbirth; 2) gestational age at delivery; and 3) specific placental pathologies.
METHODS
Two slides containing chorionic villi were evaluated from 589 placentas that were collected from Stellenbosch University in Cape Town, South Africa as part of the prospective, multicenter cohort Safe Passage Study of the Prenatal Alcohol and SIDS and Stillbirth Network. The subsample included 307 full-term live births, 212 preterm live births, and 70 stillbirths.
RESULTS
We found that the odds of identifying at least one trophoblast inclusion across two slides of chorionic villi was significantly higher for placentas from preterm compared to term liveborn deliveries (OR = 1.74; 95% CI: 1.22, 2.49, p = 0.002), with an even greater odds ratio for placentas from stillborn compared to term liveborn deliveries (OR = 4.95; 95% CI: 2.78, 8.80, p < 0.001). Gestational age at delivery was inversely associated with trophoblast inclusion frequency. Trophoblast inclusions were significantly associated with small for gestational age birthweight, induction of labor, villous edema, placental infarction, and inflammation of the chorionic plate.
CONCLUSIONS
The novel associations that we report warrant further investigation in order to understand the complex network of biological mechanisms through which the factors that lead to trophoblast inclusions may influence or reflect the trajectory and health of a pregnancy. Ultimately, this line of research may provide critical insights that could inform both clinical and research applications.
Topics: Female; Gestational Age; Humans; Infant, Newborn; Placenta; Pregnancy; Pregnancy Complications; Premature Birth; Prospective Studies; South Africa; Stillbirth; Trophoblasts
PubMed: 35231069
DOI: 10.1371/journal.pone.0264733 -
Der Pathologe Nov 2021From the very beginning, special attention regarding severe acute respiratory syndrome-coronavirus‑2 (SARS-CoV-2) and the resulting coronavirus disease-2019 (COVID-19)... (Review)
Review
From the very beginning, special attention regarding severe acute respiratory syndrome-coronavirus‑2 (SARS-CoV-2) and the resulting coronavirus disease-2019 (COVID-19) has been paid to pregnant women.In this review, after a short introduction into the immunodefensive role of the placenta and viral infections in general, we describe the morphological changes of the placenta in SARS-CoV-2-infected pregnant women based on our own and other published studies, draw comparisons to the SARS epidemic, and discuss the question of vertical transmission of SARS-CoV‑2 from the mother to the neonate.The most common pathological findings of the placenta in SARS-CoV‑2 infection are signs of maternal and fetal malperfusion as well as potentially immunologically and/or thromboinflammation-mediated findings. These manifest as infarcts and decidual vasculopathy as well as thrombi in the fetal circulation and avascular villi. In some cases, there is also an inflammatory reaction with villitis, intervillositis, and fetal vasculitis. In addition, it has been shown that SARS-CoV‑2 can directly infect the placenta, so vertical transmission is possible.There is no COVID-19 specific pattern of placental alterations, although the detection of fetal thrombovasculitis, villitis, and intervillositis as well as fetal and maternal malperfusion could be best interpreted as the signature of SARS-CoV‑2 infection - considering the known pathophysiology of COVID-19 regarding other organs (inflammatory reaction and [micro]angiopathy). Detection of viral RNA in the fetal placental tissue and the umbilical cord indicates SARS-CoV‑2 vertical transmission.
Topics: COVID-19; Female; Humans; Infant, Newborn; Inflammation; Placenta; Pregnancy; Pregnancy Complications, Infectious; SARS-CoV-2; Thrombosis
PubMed: 34115179
DOI: 10.1007/s00292-021-00952-7 -
Archives of Gynecology and Obstetrics Dec 2021
Topics: Adult; COVID-19; Female; Fetal Growth Retardation; Humans; Infarction; Infectious Disease Transmission, Vertical; Male; Placenta; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Outcome; SARS-CoV-2; Ultrasonography, Doppler
PubMed: 34406458
DOI: 10.1007/s00404-021-06176-7 -
The Journal of Maternal-fetal &... Dec 2023To evaluate the risk of recurrence of severe placenta-mediated pregnancy complications and compare the efficacy of two different anti-thrombotic regimens in women with a... (Observational Study)
Observational Study
Placenta-mediated pregnancy complications in women with a history of late fetal loss and placental infarction without thrombophilia: risk of recurrence and efficacy of pharmacological prophylactic interventions. A 10-year retrospective study.
PURPOSE
To evaluate the risk of recurrence of severe placenta-mediated pregnancy complications and compare the efficacy of two different anti-thrombotic regimens in women with a history of late fetal loss without thrombophilia.
PATIENTS AND METHODS
We performed a 10-year retrospective observational study (2008-2018) analyzing a cohort of 128 women who suffered from pregnancy fetal loss (>20 weeks of gestational age) with histological evidence of placental infarction. All the women tested negative for congenital and/or acquired thrombophilia. In their subsequent pregnancies, 55 received prophylaxis with acetylsalicylic acid (ASA) only and 73 received ASA plus low molecular weight heparin (LMWH).
RESULTS
Overall, one-third of all pregnancies (31%) had adverse outcomes related to placental dysfunction: pre-term births (25% <37 weeks, 5.6% <34 weeks), newborns with birth weight <2500 g (17%), and newborns small for gestational age (5%). The prevalence of placental abruption, early and/or severe preeclampsia, and fetal loss >20 weeks were 6%, 5%, and 4% respectively. We found a risk reduction for combination therapy (ASA plus LMWH) compared with ASA alone for delivery <34 weeks (RR 0.11, 95% CI: 0.01-0.95 = 0.045) and a trend for the prevention of early/severe preeclampsia (RR 0.14, 95% CI: 0.01-1.18, = 0.0715), while no statistically significant difference was observed for composite outcomes (RR 0.51, 95%CI: 0.22-1.19, = 0.1242). An absolute risk reduction of 5.31% was observed for the ASA plus LMWH group. Multivariate analysis confirmed a risk reduction for delivery <34 weeks (RR 0.32, 95% CI 0.16-0.96 = 0.041).
CONCLUSION
In our study population, the risk of recurrence of placenta-mediated pregnancy complications is substantial, even in the absence of maternal thrombophilic conditions. A reduction of the risk of delivery <34 weeks was detected in the ASA plus LMWH group.
Topics: Infant, Newborn; Pregnancy; Female; Humans; Placenta; Retrospective Studies; Pre-Eclampsia; Heparin, Low-Molecular-Weight; Placenta Diseases; Thrombophilia; Abortion, Spontaneous; Aspirin; Infarction
PubMed: 36860098
DOI: 10.1080/14767058.2023.2183748