A review of relevant literature linking adaptive and innate immunity with preeclampsia is provided below. Adaptive immune response (Immunological tolerance) A considerable amount of epidemiological evidence (Table 1) supports the view that increased exposure to paternal antigens present around the fetus or on sperm results in immunological tolerance to these paternal antigens and reduces the risk of H 89 2HCl preeclampsia[39C41]. Table 1 Immunological tolerance to paternal antigens reduces the risk of preeclampsia 1.Risk is reduced by repeated sexual exposure to paternal semen[63][44].2.Barrier contraception (e.g. individuals are directed to H 89 2HCl a common epitope provides obvious diagnostic and therapeutic opportunities. Research reviewed here raises the intriguing possibility that preeclampsia may be a pregnancy-induced autoimmune condition characterized by the presence of disease-causing angiotensin receptor activating autoantibodies Introduction Preeclampsia is usually a serious and common hypertensive complication of pregnancy that is a leading cause of maternal and neonatal mortality and morbidity. It is a multisystem disorder generally appearing after the 20th week of gestation and characterized by hypertension, proteinuria, vascular abnormalities, and often intrauterine growth retardation[1C3]. In severe cases preeclampsia is usually accompanied with the HELLP syndrome (Hemolysis, Elevated Liver enzymes and Low Platelets). Preeclampsia affects ~7% of first pregnancies and is a leading cause of maternal death and a major contributor to maternal and perinatal morbidity. The only effective treatment is usually delivery of the fetus and placenta, often resulting in severe complications of prematurity for the neonate. The producing preterm births and the associated increased infant morbidity and mortality are especially disheartening effects of preeclampsia. In fact, 15% of all preterm births are indicated early deliveries for preeclampsia. Preeclampsia also increases the risk of intrauterine growth restriction, resulting in low birth-weight babies at increased risk for long term disabilities. The underlying mechanisms responsible for the pathogenesis of preeclampsia remain poorly comprehended. Numerous recent studies have shown that women with preeclampsia possess angiotensin receptor agonistic autoantibodies that bind to and activate the AT1 angiotensin receptor[4C12]. The introduction of these autoantibodies into pregnant mice induces clinical features of preeclampsia via AT1 receptor activation[6]. These findings suggest that preeclampsia may be an autoimmune condition in which AT1 receptor agonistic autoantibodies, termed AT1-AAs, contribute to many features of the disease. These autoantibodies identify a common epitope around the AT1 receptor and their ability to activate AT1 receptors is usually blocked by a 7-amino acid (aa) peptide that corresponds to this epitope. Overall, the studies summarized here raise the intriguing possibility that preeclampsia is usually a pregnancy-induced autoimmune disease in which pathophysiological symptoms result from autoantibody-induced angiotensin receptor activation. AT1-AAs activate AT1 receptors on a variety of cell types and provoke biological responses relevant to the pathophysiology of preeclampsia A growing body evidence show that AT1-AA activate AT1 receptors on a variety of cells and provoke biological responses that are relevant to the pathophysiology of preeclampsia (Fig. 1). Open in a separate window Physique 1 Autoantibodies from women with preeclampsia are functional mimics of Ang II and activate AT1 receptors on many cell typesAutoantibody-induced AT1 receptor activation on cardiac myocytes prospects to increased contraction rates. The activation of AT1 receptors on mesangial cells and trophoblast cells results in increased synthesis and secretion of Rabbit Polyclonal to ETS1 (phospho-Thr38) soluble factors such as interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1), and soluble fms like tyrosine kinase-1 (sFlt-1, a soluble form of the vascular endothelial growth factor-1 receptor), all of which are elevated in women with preeclampsia. In addition, AT1-AAs stimulate the synthesis of NADPH oxidase in several cell types, resulting in increased production of reactive oxygen H 89 2HCl species (ROS) and oxidative damage. Increased production of tissue factor (TF) by vascular easy muscle mass cells and monocytes may contribute to hypercoagulation often associated with preeclampsia. We propose that AT1-AA activate AT1 receptors on many cell types and in this way contribute to pathophysiological changes associated with preeclampsia. Cardiomyocytes Angiotensin receptor agonistic autoantibodies (AT1-AAs) were originally detected by Wallukat [5] based on the ability of these autoantibodies to activate AT1 angiotensin receptors on cultured neonatal rat cardiac myocytes. Autoantibody-induced receptor activation stimulated an increase in the beating rate of cardiomyocytes, a feature that was blocked by losartan, an AT1 receptor antagonist. The autoantibody-induced chronotropic effect was also blocked by a seven amino acid (7-aa) peptide that corresponds to.