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Context: Although decidual natural killer (NK) cell accumulation and vascular remodeling are critical steps to ensure successful pregnancy, the molecular mechanisms controlling these events are poorly defined., Objective: Herein we analyzed whether chemerin, a recently identified chemoattractant involved in many pathophysiological processes, could be expressed in the uterine compartment and could regulate events relevant for the good outcome of pregnancy., Design: Chemerin expression in human primary culture of stromal (ST) cells, extravillous trophoblast cells, and decidual endothelial cells (DEC) was analyzed by RT-PCR, ELISA, and Western blot. Migration through ST or DEC of peripheral blood and decidual (d) NK cells from pregnant women was performed using a transwell assay. A DEC capillary-like tube formation assay was used to evaluate endothelial morphogenesis., Results: Chemerin is differentially expressed by decidual cells during early pregnancy being present at high levels in ST and extravillous trophoblast cells but not in DEC. Notably, ST cells from pregnant women exhibit and release higher levels of chemerin as compared with ST cells from menopausal or fertile nonpregnant women. Chemerin can support peripheral blood NK cell migration through both DEC and ST cells. Although dNK cells exhibit lower chemerin receptor (CMKLR1) expression than their blood counterpart, CMKLR1 engagement on dNK cells resulted in both ERK activation and migration through decidual ST cells. Interestingly, DEC also express CMKLR1 and undergo ERK activation and capillary-like tube structure formation upon exposure to chemerin., Conclusions: Our data indicate that chemerin is up-regulated during decidualization and might contribute to NK cell accumulation and vascular remodeling during early pregnancy.

The spiral arteries undergo physiologic changes during pregnancy, and the failure of this process may lead to a spectrum of pregnancy disorders, including pre-eclampsia. Our recent data indicate that decidual endothelial cells (DECs), covering the inner side of the spiral arteries, acquire the ability to synthesize C1q, which acts as a link between endovascular trophoblast and DECs favouring the process of vascular remodelling. In this study, we have shown that sera obtained from pre-eclamptic patients strongly inhibit the interaction between extravillous trophoblast (EVT) and DECs, preventing endovascular invasion of trophoblast cells. We further demonstrated that mannose-binding lectin (MBL), one of the factor increased in pre-eclamptic patient sera, strongly inhibits the interaction of EVT with C1q interfering with the process of EVT adhesion to and migration through DECs. These data suggest that the increased level of MBL in pre-eclampsia may contribute to the failure of the endovascular invasion of trophoblast cells.

In vitro studies have documented β2 glycoprotein I (β2GPI) binding to endothelial cells (ECs) and trophoblast using antiphospholipid antibodies. The in vivo binding of β2GPI to these cells and the conditions that favor their interaction have not been investigated. We analyzed the in vivo distribution of cyanine 5.5-labeled β2GPI in mice and evaluated the effect of pregnancy and circulating antibodies on its tissue localization. The signal was detected in the liver by whole body scan and ex vivo analysis. The β2GPI failed to bind to the vascular endothelium and reacted only with the ECs of uterine vessels. In pregnant mice the protein was localized on ECs and trophoblast at the embryo implantation sites. Immunized mice showed a similar β2GPI biodistribution to naive mice but the immunized pregnant animals exhibited a significant increase in fetal loss associated with C3 and C9 deposition at the implantation sites. Treatment of mice with LPS after β2GPI-Cy5.5 injection promoted protein localization on gut and brain ECs associated with IgG, C1q, and C9 deposition in immunized mice. These findings indicate that β2GPI binding to EC requires priming with pro-inflammatory factors which is not needed for uterine and placental localization probably dependent on hormonal changes.

Fetal trophoblast cells invading the decidua in the early phase of pregnancy establish complex interaction with the maternal extracellular matrix. We discovered that C1q was widely distributed in human decidual stroma in the absence of C4 and C3 and was actively synthesized by migrating extravillous trophoblasts. The cells expressed the messages for the three chains of C1q and secreted this complement component that interacted with the proteins of the decidual extracellular matrix. Solid phase-bound C1q promoted trophoblast adhesion and migration, and cell binding to C1q resulted in activation of ERK1/2 MAPKs. Ab inhibition experiments showed that the receptors for the globular head of C1q/p33 and α(4)β(1) integrin were both involved in this process and were colocalized on the cell surface following binding of C1q to trophoblasts. We also found that C1q(-/-) mice manifested increased frequency of fetal resorption, reduced fetal weight, and smaller litter sizes compared with wild-type mice. C1q deficiency was associated with impaired labyrinth development and decidual vessel remodeling. Collectively, these data suggest that C1q plays an important role in promoting trophoblast invasion of decidua and that defective local production of C1q may be involved in pregnancy disorders, such as pre-eclampsia, characterized by poor trophoblast invasion.

An important role played by trophoblast cells at the feto-maternal interface is to exert immunomodulatory functions, including recognition of bacterial and viral agents and recruitment of leucocytes to eradicate pathogens. In this study we present data showing that the trophoblast cell line HTR8/SVneo and freshly isolated human first trimester trophoblast cells (CTBs) synthesize complement molecules C4, C3 and the late complement components, as assessed by ELISA and RT-PCR. Both cell types secrete C4 and C3, and HTR8/SVneo trophoblast cells secrete C6 in a measurable amount. The expression of C4 by HTR8/SVneo trophoblast cells and of C3 and C4 by CTBs was up-regulated by IFNgamma, while IL-1alpha and TNFalpha had no effect on the expression of complement components. In conclusion, we show that trophoblast cells produce complement components, and that synthesis of these proteins may be regulated by the pro-inflammatory cytokine IFNgamma. Complement synthesis by trophoblast cells potentially contributes to placental immune defence from pathogen infection.

This study was prompted by the observation that decidual endothelial cells (DECs), unlike endothelial cells (ECs) of blood vessels in normal skin, kidney glomeruli and brain, express surface-bound C1q in physiologic pregnancy. This finding was unexpected, because deposits of C1q are usually observed in pathologic conditions and are associated with complement activation. In the case of DECs, we failed to detect immunoglobulins and C4 co-localized with C1q on the cell surface. Surprisingly, DECs expressed mRNA for the three chains of C1q and secreted detectable level of this component in serum-free medium. The ability to synthesize C1q is acquired by DECs during pregnancy and is not shared by ECs obtained from endometrium and from other sources. Cell-associated C1q has a molecular weight similar to that of secreted C1q and is released from DECs following treatment with heparinase or incubation at low pH. This suggests that C1q binds to DECs and it is not constitutively expressed on the cell surface. C1q is localized at contact sites between endovascular trophoblast and DECs and acts as an intercellular molecular bridge because adhesion of endovascular trophoblast to DECs was inhibited by antibodies to C1q and to a receptor recognizing its globular portion expressed on trophoblast.

Objective: Evaluate preoperative imaging in predicting operative stage. Describe the outcomes in surgically treated juvenile nasopharyngeal angiofibroma (JNA) with the influence of middle cranial fossa, carotid, or dural involvement on recurrence., Study Design: Retrospective cohort of surgically treated patients with JNA., Subjects and Methods: Eighty-five patients from a regional Italian referral center were assessed for recurrence, radiologic, and operative staging. High risk areas involved were recorded at surgery., Results: Recurrence for advanced disease (IIIb+) was 18.2% (6 of 33) and 15.3% (13 of 85) overall. Preoperative staging poorly correlated with operative stage (P = 0.15). No single high risk area was predictive for recurrence, but the absence of any risk factor was associated with a favorable outcome (P < 0.01)., Conclusion: Dural involvement by tumor is rare and imaging may overstage disease. Anterior access, endoscopic or open, is sufficient to address intracranial involvement. When an open approach is used, a midface degloving technique affords excellent exposure even for advanced disease. Lateral approaches with their associated morbidity can be reserved for selected recurrent disease.

During early pregnancy, uterine mucosa decidualization is accompanied by a drastic enrichment of CD56(high)CD16(-) natural killer (NK) cells. Decidual NK (dNK) cells differ from peripheral blood NK (pbNK) cells in several ways, but their origin is still unclear. Our results demonstrate that chemokines present in the uterus can support pbNK cell migration through human endothelial and stromal decidual cells. Notably, we observed that pregnant women's pbNK cells are endowed with higher migratory ability compared with nonpregnant women's or male donors' pbNK cells. Moreover, NK cell migration through decidual stromal cells was increased when progesterone-cultured stromal cells were used as substrate, and this correlated with the ability of progesterone to up-regulate stromal cell chemokine expression. Furthermore, we demonstrate that dNK cells migrate through stromal cells using a distinct pattern of chemokines. Finally, we found that pbNK cells acquire a chemokine receptor pattern similar to that of dNK cells when they contact decidual stromal cells. Collectively these results strongly suggest that pbNK cell recruitment to the uterus contributes to the accumulation of NK cells during early pregnancy; that progesterone plays a crucial role in this event; and that pbNK cells undergo reprogramming of their chemokine receptor profile once exposed to uterine microenvironment.

Fetal loss in animals and humans is frequently associated with inflammatory conditions. D6 is a promiscuous chemokine receptor with decoy function, expressed in lymphatic endothelium, that recognizes and targets to degradation most inflammatory CC chemokines. Here, we report that D6 is expressed in placenta on invading extravillous trophoblasts and on the apical side of syncytiotrophoblast cells, at the very interface between maternal blood and fetus. Exposure of D6-/- pregnant mice to LPS or antiphospholipid autoantibodies results in higher levels of inflammatory CC chemokines and increased leukocyte infiltrate in placenta, causing an increased rate of fetal loss, which is prevented by blocking inflammatory chemokines. Thus, the promiscuous decoy receptor for inflammatory CC chemokines D6 plays a nonredundant role in the protection against fetal loss caused by systemic inflammation and antiphospholipid antibodies.

Superficial siderosis is a rare condition characterized by deposition of hemosiderin in the leptomeninges and in the subpial layers of the brain and spinal cord. It is associated with cerebrospinal fluid abnormalities consistent with recurrent bleeding into the subarachnoid space. The usual symptoms are hearing loss, ataxia, spastic paraparesis, sensory and sphincter deficits, and mental deterioration. A case is presented of severe superficial siderosis of the central nervous system in a 51-year-old man who had suffered a brachial plexus injury at the age of 20 years. The diagnosis was made by means of magnetic resonance imaging 16 years after the initial symptoms, which comprised bilateral hearing loss and anosmia. Subarachnoid bleeding was due to traumatic pseudomeningocele of the brachial plexus, a very unusual cause of superficial siderosis. This case is interesting insofar as the surgical treatment prevented further bleeding and possibly progression of the disease.

Purpose: To report the clinical and neuroradiologic findings of superficial siderosis of the CNS, due to chronic subarachnoid bleeding of unknown origin., Materials and Methods: We observed seven cases. The main clinical manifestations were progressive deafness and ataxia. Four patients had had previous cranial or cervical trauma, with root avulsion in two, many years before onset of deafness and ataxia. Neuroradiologic studies included MR (0.5 T in four and 1.5 T in three) and angiography of the brain in all cases, CT in six cases, MR of the spine in six, and myelography in four., Results: MR demonstrated a rim of marked hypointensity in T2-weighted images, consistent with hemosiderin deposits, on the surface of cerebellum, brain stem, inferior part of cerebral hemispheres, and spinal cord. CT showed cerebellar atrophy in five cases, and a rim of mild hyperdensity around the brain stem in two. Angiographic studies were negative. Myelography showed cervical nerve root avulsion in two cases and a cervicodorsal extradural cyst in one. Cerebrospinal fluid contained RBCs in all the six examined cases., Conclusion: Although CT may occasionally suggest the diagnosis of superficial siderosis, MR demonstrates this abnormality to better advantage.