In addition to its role in calcium homeostasis and bone formation, a modulatory role of the active form of vitamin D on cells of the immune system, particularly T lymphocytes, has been described. The ...effects of vitamin D on the production and action of several cytokines has been intensively investigated in recent years. In this connection, deficiency of vitamin D has been associated with several autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), Hashimoto Thyroiditis (HT), and multiple sclerosis (MS). In a successful pregnancy, the maternal immune response needs to adapt to accommodate the semiallogeneic fetus. Disturbances in maternal tolerance are implicated in infertility and pregnancy complications such as miscarriages (RM) and preeclampsia (PE). It is well-known that a subset of T lymphocytes, regulatory T cells (Tregs) exhibit potent suppressive activity, and have a crucial role in curtailing the destructive response of the immune system during pregnancy, and preventing autoimmune diseases. Interestingly, vitamin D deficiency is common in pregnant women, despite the widespread use of prenatal vitamins, and adverse pregnancy outcomes such as RM, PE, intrauterine growth restriction have been linked to hypovitaminosis D during pregnancy. Research has shown that autoimmune diseases have a significant prevalence within the female population, and women with autoimmune disorders are at higher risk for adverse pregnancy outcomes. Provocatively, dysregulation of T cells plays a crucial role in the pathogenesis of autoimmunity, and adverse pregnancy outcomes where these pathologies are also associated with vitamin D deficiency. This article reviews the immunomodulatory role of vitamin D in autoimmune diseases and pregnancy. In particular, we will describe the role of vitamin D from conception until delivery, including the health of the offspring. This review highlights an observational study where hypovitaminosis D was correlated with decreased fertility, increased disease activity, placental insufficiency, and preeclampsia in women with APS.
Preeclampsia (PE) is a life-threatening, pregnancy-induced disease and a leading cause of maternal and fetal morbidity and mortality. Despite considerable research, the causes of PE remain unclear, ...and there is no effective treatment. Studies in animal models that resemble this complex pregnancy-related disorder may help to identify possible therapies for PE. Complement component C1q has an important role in trophoblast migration, spiral arteries remodeling, and normal placentation. Here we show that pregnant C1q-deficient (C1q) mice recapitulate the key features of human PEhypertension, albuminuria, endotheliosis, decreased placental vascular endothelial growth factor (VEGF) and elevated levels of soluble VEGF receptor 1 (sFlt-1) that correlate with increased fetal death. In addition, decreased blood flow and increased oxidative stress are observed in placentas from C1q mice. Treatment of C1q mice with pravastatin restored trophoblast invasiveness, placental blood flow, and angiogenic balance and, thus, prevented the onset of PE. Serum-soluble receptors for VEGF-1 levels were reduced and placental VEGF levels were significantly increased in C1q mice treated with pravastatin compared with untreated C1q mice (VEGF1067±171 versus 419±194 pg/mL; P<0.01). Pravastatin treatment reduced hypertension (change in mean arterial pressure1±1 versus 18±3 mm Hg in C1q untreated mice), and albuminuria (of creatinine) was reduced from 820±175 to 117±45 μg/mg (both P<0.01). Renal damage and endothelial dysfunction were significantly attenuated with pravastatin. This model that highlights the causative role of impaired trophoblast invasion in the pathogenesis of PE allowed us to identify pravastatin as a good therapeutic option to prevent PE.
Recurrent fetal loss affects 1-5% of women of childbearing age. Immunological mechanisms may account for 40% of recurrent miscarriages, and in particular, the antiphospholipid syndrome (APS) appears ...to be implicated in 7-25% of the cases. Because antiphospholipid (aPL) antibodies have thrombogenic properties, fetal loss in patients with APS has been ascribed to thrombosis of placental vessels. However, we have shown that inflammation, specifically activation of complement with generation of the anaphylotoxin C5a, is an essential trigger of fetal injury. Thrombosis and inflammation are linked in many clinical conditions. Tissue factor (TF), the major cellular initiator of the coagulation protease cascade, plays important roles in both thrombosis and inflammation, and its expression is increased in patients with APS. Here we describe how TF, acting as a proinflammatory molecule, induces trophoblast injury and fetal death in a mouse model of APS. Importantly, we will discuss how TF contributes to C5a-induced oxidative burst in neutrophils leading to trophoblasts and fetal injury in APS. The finding that TF is an important effector in aPL-induced inflammation may allow the development of new therapies to abrogate the inflammatory loop caused by tissue factor and improve pregnancy outcomes in patients with aPL antibodies. Statins downregulate TF-induced inflammation and rescued the pregnancies in aPL-treated mice, suggesting they may be a good treatment for women with aPL-induced pregnancy complications.
Abstract Bad pregnancy outcomes have been associated with increased activation of the coagulation cascade and inflammation, in particular the activation of the complement cascade. Recent studies have ...suggested that inflammatory processes modulate thrombogenic pathways and vice versa. We studied the cross-talk between the coagulation and the complement cascade in the pathogenesis of recurrent miscarriages and preeclampsia in mice. We identified tissue factor (TF) as a crucial mediator of fetal and placental damage in mouse models of recurrent miscarriages and preeclampsia. Increased TF expression increases the release of reactive oxygen species and antiangiogenic molecules from inflammatory cells inducing trophoblast damage and bad pregnancy outcomes. We also demonstrated that pravastatin, by downregulating TF expression, prevents miscarriages and the onset of preeclampsia in mice.
The complement cascade was identified over 100 years ago, yet investigation of its role in pregnancy remains an area of intense research. Complement inhibitors at the maternal-fetal interface prevent ...inappropriate complement activation to protect the fetus. However, this versatile proteolytic cascade also favorably influences numerous stages of pregnancy, including implantation, fetal development, and labor. Inappropriate complement activation in pregnancy can have adverse lifelong sequelae for both mother and child. This review summarizes the current understanding of complement activation during all stages of pregnancy. In addition, consequences of complement dysregulation during adverse pregnancy outcomes from miscarriage, preeclampsia, and pre-term birth are examined. Finally, future research directions into complement activation during pregnancy are considered.
Inflammation is frequently linked to preterm delivery (PTD). Here, we tested the hypothesis that complement activation plays a role in cervical remodeling and PTD. We studied two mouse models of ...inflammation-induced PTD. The first model was induced by vaginal administration of lipopolysaccharide (LPS) and the second one by administration of progesterone antagonist RU486. Increased cervical C3 deposition and macrophages infiltration and increased serum C3adesArg and C5adesArg levels were observed in both models when compared to gestational age matched controls. A significant increase in collagen degradation, matrix metalloproteinase 9 (MMP-9) activity and tissue distensibility was observed in the cervix in both models. Mice deficient in complement receptor C5a did not show increased MMP-9 activity and cervical remodeling and did not deliver preterm in response to LPS or RU486, suggesting a role for C5aR in the cervical changes that precede PTD. In vitro studies show that macrophages release MMP-9 in response to C5a. Progesterone diminished the amount of C5aR on the macrophages surface, inhibited the release of MMP-9 and prevented PTD. In addition, macrophages depletion also prevented cervical remodeling and PTD in LPS-treated mice. Our studies show that C5a-C5aR interaction is required for MMP-9 release from macrophages, and the cervical remodeling that leads to PTD. Complement inhibition and supplementation with progesterone may be good therapeutic options to prevent this serious pregnancy complication.
Pregnancy poses a challenge for the immune systems of placental mammals. As fetal tissues are semi-allogeneic and alloantibodies that commonly develop in the mother, the fetus and the placenta might ...be subject to complement-mediated immune attack with the potential risk of adverse pregnancy outcomes. Here, I describe how the use of animal models was pivotal in demonstrating that complement inhibition at the fetomaternal interface is essential for a successful pregnancy. Studies in animals also helped the identification of uncontrolled complement activation as a crucial effector in the pathogenesis of recurrent miscarriages, intrauterine growth restriction, preeclampsia, and preterm birth. Clinical studies employing complement biomarkers in plasma and urine showed an association between dysregulation of the complement system and adverse pregnancy outcomes. A better understanding of the role of the complement system in pregnancy complications will allow a rational approach to manipulate its activation as a potential therapeutic strategy with the goal of protecting pregnancies and improving long-term outcomes for mother and child.
Women with antiphospholipid syndrome (APS), a condition characterized by the presence of antiphospholipid antibodies (aPL), often suffer pregnancy-related complications, including miscarriage. We ...have previously shown that C5a induction of tissue factor (TF) expression in neutrophils contributes to respiratory burst, trophoblast injury, and pregnancy loss in mice treated with aPL. Here we analyzed how TF contributes to neutrophil activation and trophoblast injury in this model. Neutrophils from aPL-treated mice expressed protease-activated receptor 2 (PAR2), and stimulation of this receptor led to neutrophil activation, trophoblast injury, and fetal death. An antibody specific for human TF that has little impact on coagulation, but potently inhibits TF/Factor VIIa (FVIIa) signaling through PAR2, inhibited aPL-induced neutrophil activation in mice that expressed human TF. Genetic deletion of the TF cytoplasmic domain, which allows interaction between TF and PAR2, reduced aPL-induced neutrophil activation in aPL-treated mice. Par2-/- mice treated with aPL exhibited reduced neutrophil activation and normal pregnancies, which indicates that PAR2 plays an important role in the pathogenesis of aPL-induced fetal injury. We also demonstrated that simvastatin and pravastatin decreased TF and PAR2 expression on neutrophils and prevented pregnancy loss. Our results suggest that TF/FVIIa/PAR2 signaling mediates neutrophil activation and fetal death in APS and that statins may be a good treatment for women with aPL-induced pregnancy complications.
Abstract
Women represent the cornerstone of a family’s overall health. Therefore, supporting women’s health, particularly in pregnancy, is important to promote public health. Emerging data highlight ...the contribution of social determinants of health (SDOH) on pregnancy outcomes in understudied, underrepresented, and underreported (U3) populations. Importantly, women are uniquely affected by and more vulnerable to adverse outcomes associated with SDOH. The maternal mortality rate has also increased significantly in the United States, especially among U3 individuals. Factors such as access to safe food, housing and environment, access to education and emergency/health services, and stressors such as interpersonal racism, poverty, unemployment, residential segregation, and domestic violence may make women from U3 populations more vulnerable to adverse reproductive health outcomes. Despite progress in promoting women’s health, eliminating social and health disparities in pregnant individuals remains an elusive goal in U3 populations. Moreover, chronic exposure to excessive social/cultural stressors may have a physiologic cost leading to pregnancy complications such as miscarriages, preterm birth, and preeclampsia. Thus, the identification of SDOH-related factors that drive differences in pregnancy-related complications and deaths and the implementation of prevention strategies to address them could reduce disparities in pregnancy-related mortality in U3 populations.
The antiphospholipid syndrome (APS) is defined by thrombosis and recurrent pregnancy loss in the presence of antiphospholipid (aPL) antibodies and is generally treated with anticoagulation therapy. ...Because complement activation is essential and causative in aPL antibody-induced fetal injury, we hypothesized that heparin protects pregnant APS patients from complications through inhibition of complement. Treatment with heparin (unfractionated or low molecular weight) prevented complement activation in vivo and in vitro and protected mice from pregnancy complications induced by aPL antibodies. Neither fondaparinux nor hirudin, other anticoagulants, inhibited the generation of complement split products or prevented pregnancy loss, demonstrating that anticoagulation therapy is insufficient protection against APS-associated miscarriage. Our data indicate that heparins prevent obstetrical complications in women with APS because they block activation of complement induced by aPL antibodies targeted to decidual tissues, rather than by their anticoagulant effects.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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