Pregnancy establishment implies the existence of a highly vascularized and transient organ, the placenta, which ensures oxygen supply to the fetus via haemoproteins. Haem metabolism, including its catabolism by haem oxygenase-1 (HO-1), should be of importance in maintaining the homeostasis of haemoproteins and controlling the deleterious effects associated with haem release from maternal or fetal haemoglobins, thus ensuring placental function and fetal development. We demonstrate that HO-1 expression is essential to promote placental function and fetal development, thus determining the success of pregnancy. Hmox1 deletion in mice has pathological consequences for pregnancy, namely suboptimal placentation followed by intrauterine fetal growth restriction (IUGR) and fetal lethality. These pathological effects can be mimicked by administration of exogenous haem in wild-type mice. Fetal and maternal HO-1 is required to prevent post-implantation fetal loss through a mechanism that acts independently of maternal adaptive immunity and hormones. The protective HO-1 effects on placentation and fetal growth can be mimicked by the exogenous administration of carbon monoxide (CO), a product of haem catabolism by HO-1 that restores placentation and fetal growth. In a clinical relevant model of IUGR, CO reduces the levels of free haem in circulation and prevents fetal death. We unravel a novel physiological role for HO-1/CO in sustaining pregnancy which aids in understanding the biology of pregnancy and reveals a promising therapeutic application in the treatment of pregnancy pathologies.

Regulatory T cells (Treg) play an important role in fetal protection. They expand during normal pregnancy and protect fetal antigens from maternal effector cells. Their effect is associated with the up-regulation of tolerance-associated molecules at the fetal-maternal interface. Among these, Heme Oxygenase-1 (HO-1, coded by Hmox1) is of special importance as its blockage correlates with increased abortion rates and its up-regulation positively affects pregnancy outcome. Here, we aimed to investigate whether the protective effect of Treg is mediated by HO-1 in a mouse model. HO-1 blockage by Zinc Protoporhyrin (ZnPPIX) abrogated the protective effect of Treg transfer. We found that HO-1 is important in maintaining maternal dendritic cells (DCs) in an immature state, which contributes to the expansion of the peripheral Treg population. This brings to light one essential pathway through which Treg mediates the semi-allogeneic fetus tolerance.

Abstract-Preeclampsia is a devastating pregnancy-associated disorder affecting 5% to 8% of pregnant women worldwide.It emerges as an autoimmune-driven disease, and, among others, the autoantibodies against angiotensin type 1 receptor II have been proposed to account for preeclampsia symptoms. Despite much attention focused on describing autoantibodies associated with preeclampsia, there is no clue concerning the cell population producing them. CD19 ϩ CD5 ϩ B-1a B cells constitute the main source of natural and polyreactive antibodies, which can be directed against own structures. Here, we aimed to identify the B-cell subpopulation responsible for autoantibody production during preeclampsia and to study their regulation, as well as their possible use as markers for the disease. The frequency of CD19 ϩ CD5 ϩ cells in peripheral blood of preeclamptic patients is dramatically increased compared with normal pregnant women as analyzed by flow cytometry. This seems to be driven by the high human chorionic gonadotropin levels present in the serum and placenta supernatant of preeclamptic patients versus normal pregnant women. Not only Ϸ95% of CD19 ϩ CD5 ϩ cells express the human chorionic gonadotropin receptor, but these cells also expand on human chorionic gonadotropin stimulation in a lymphocyte culture. Most importantly, isolated CD19 ϩ CD5 ϩ cells produce autoantibodies against angiotensin type 1 receptor II, and CD19 ϩ CD5 ϩ cells were further detected in the placenta of preeclamptic but not of normal pregnancies where barely B cells are present. Our results identify a B-cell population able to produce pregnancy-pathological autoantibodies as possible markers for preeclampsia, which opens vast diagnostic and therapeutic applications. P reeclampsia (PE) is a devastating human pregnancyassociated disorder characterized by the onset of hypertension, proteinuria, and edema after the 20th week of pregnancy. It represents one of the most frequent medical complications of pregnancy, affecting Ϸ5% to 8% of all pregnant women. 1 Limited progress has been achieved in identifying the causes, being the induction of delivery the only available treatment for the clinical symptoms. 2 Recently, the idea that PE may represent an autoimmune disease has emerged. 3 This is based on the fact that many autoantibodies were identified in PE patients and suspected to account for the symptoms of the disease. [4][5][6] Much attention was focused on autoantibodies against angiotensin type 1 receptor II (AT 1 -AAs), because they have been detected in the serum of PE patients. 7 These autoantibodies are able to bind to and to activate the AT 1 angiotensin receptor, leading to the release of antiangiogenic factors from the placenta, which are reportedly involved in the origin of the disease. [8][9][10] In spite of the efforts put on identifying autoantibodies related to PE, no attention has been so far focused on the cell population responsible for their production. This is a very important piece of information, because it may provide a novel tar...