Placental autotaxin expression is diminished in women with pre-eclampsia.

AIM: Lysophosphatidic acid (LPA) is a member of a new class of lipid mediators and exerts varied physiological and pathological functions. The secreted protein, autotaxin (ATX), is a key enzymatic determinant of local LPA production. The primary aim of this study was to investigate the potential involvement of the placental ATX-LPA system in pre-eclampsia (PE). MATERIAL AND METHODS: We compared human placental ATX mRNA expression in pregnancies complicated by severe PE with that in healthy placentas using real-time polymerase chain reaction. We further assessed whether these expression levels were associated with disease-onset patterns. RESULTS: Placental transcription of ATX increased progressively during normal pregnancy. In the analysis for pre-eclamptic placentas, the placental ATX expression in the early-onset group, but not in late-onset group, was significantly lower compared to normal controls. Multiple regression analysis revealed that occurrence of early-onset PE, but not late-onset PE, was a variable that was significantly associated with the placental ATX expression level. CONCLUSION: These findings support our previous work showing reduced ATX antigen levels in the peripheral blood of pre-eclamptic women. A disturbance in placental ATX production may be linked to poor placental development and systemic maternal symptoms in early-onset PE.

A possible coagulation-independent mechanism for pregnancy loss involving ß(2) glycoprotein 1-dependent antiphospholipid antibodies and CD1d.

PROBLEM ß(2) glycoprotein1 (ß(2) GP1)-dependent antiphospholipid antibodies (aPL) increase the risk for recurrent pregnancy loss. We address whether anti-ß(2) GP1 antibodies can interact with phosphatidylserine (PS)-bearing CD1d on trophoblast cells and induce local inflammation. METHODS CD1d-bearing choriocarcinoma cells were used in flow cytometry and immunoprecipitation experiments. CD1d-mediated cytokine induction was assessed using antibody cross-linking. Cytokine production during co-culture of decidual lymphocytes with CD1d-bearing cells was also examined. RESULTS Trophoblast surface-expressed CD1d forms a complex with PS-bound ß(2) GP1. Anti-ß(2) GP1 mAb cross-linking causes IL12p70 release from CD1d-bearing cells. IL12p70 release from CD1d-bearing trophoblast cells was also induced during co-culture with human decidual lymphocytes. The addition of anti-ß2GP1 mAb to co-cultures resulted in a three-fold increase in IL12p70 secretion. IFNγ secretion from decidual lymphocytes was also induced during co-culture with anti-ß2GP1 mAbs. CONCLUSIONS ß(2) GP1-dependent IL12 release from CD1d-bearing trophoblast in the presence of aPL may link the antiphospholipid syndrome to pregnancy loss via an inflammatory mechanism.

Serum autotaxin measurements in pregnant women: application for the differentiation of normal pregnancy and pregnancy-induced hypertension.

BACKGROUND: The bioactive lipid lysophosphatidic acid (LPA) exerts multiple effects in the female reproductive system. Serum/plasma LPA is mainly produced by the lysophospholipase D activity of autotaxin (ATX). Previous studies have suggested that ATX has critical roles in cancer, reproduction, and vascular development. In the present study, we evaluated the usefulness of serum ATX measurements in pregnant women. METHODS: We measured the serum ATX antigen levels in 32 normal pregnant women, 15 patients with pregnancy-induced hypertension (PIH), and 7 patients with preterm delivery using a recently developed automated enzyme immunoassay. RESULTS: The serum ATX antigen levels in normal pregnant women were significantly higher than those in non-pregnant women (P<0.001). The serum ATX antigen levels in normal pregnant women were significantly and positively correlated with the gestational week (r=0.809, P<0.001). During the third trimester, the serum ATX antigen levels of the patients with PIH (3.299 ± 1.720 mg/l) were significantly lower than those of the normal pregnant women (4.915 ± 2.323 mg/l) (P=0.04). CONCLUSIONS: The serum ATX antigen level increases with the progression of pregnancy. The serum ATX level may be a serological marker for the prediction of PIH.

CD1d, a sentinel molecule bridging innate and adaptive immunity, is downregulated by the human papillomavirus (HPV) E5 protein: a possible mechanism for immune evasion by HPV.

CD1d and CD1d-restricted natural killer T (NKT) cells serve as a natural bridge between innate and adaptive immune responses to microbes. CD1d downregulation is utilized by a variety of microbes to evade immune detection. We demonstrate here that CD1d is downregulated in human papillomavirus (HPV)-positive cells in vivo and in vitro. CD1d immunoreactivity was strong in HPV-negative normal cervical epithelium but absent in HPV16-positive CIN1 and HPV6-positive condyloma lesions. We used two cell lines for in vitro assay; one was stably CD1d-transfected cells established from an HPV-negative cervical cancer cell line, C33A (C33A/CD1d), and the other was normal human vaginal keratinocyte bearing endogenous CD1d (Vag). Flow cytometry revealed that cell surface CD1d was downregulated in both C33A/CD1d and Vag cells stably transfected with HPV6 E5 and HPV16 E5. Although the steady-state levels of CD1d protein decreased in both E5-expressing cell lines compared to empty retrovirus-infected cells, CD1d mRNA levels were not affected. Confocal microscopy demonstrated that residual CD1d was not trafficked to the E5-expressing cell surface but colocalized with E5 near the endoplasmic reticulum (ER). In the ER, E5 interacted with calnexin, an ER chaperone known to mediate folding of CD1d. CD1d protein levels were rescued by the proteasome inhibitor, MG132, indicating a role for proteasome-mediated degradation in HPV-associated CD1d downregulation. Taken together, our data suggest that E5 targets CD1d to the cytosolic proteolytic pathway by inhibiting calnexin-related CD1d trafficking. Finally, CD1d-mediated production of interleukin-12 from the C33A/CD1d cells was abrogated in both E5-expressing cell lines. Decreased CD1d expression in the presence of HPV E5 may help HPV-infected cells evade protective immunological surveillance.

Expression of autotaxin, an ectoenzyme that produces lysophosphatidic acid, in human placenta.

PROBLEM: Lysophosphatidic acid (LPA) is a bioactive lipid mediator and thought to play an important role in pregnancy. Plasma LPA is produced by autotaxin (ATX), and ATX activity in plasma increases during pregnancy paralleled with gestational weeks and decreases to near the non-pregnant level soon after delivery. However, the source of increased ATX during pregnancy is still uncertain. We hypothesized that the source of increased ATX might be placenta. METHOD OF STUDY: We investigated the protein and mRNA expression of ATX in human placenta using immunohistochemistry and RT-PCR, respectively. RESULTS: At all 3 gestational trimesters, immunohistochemical staining for placenta tissues revealed the most marked positive staining of ATX protein in trophoblasts. Real-time PCR revealed that mRNA amounts of ATX in placenta tissues paralleled with gestational weeks, i.e. ATX level in plasma. CONCLUSION: These findings suggest that trophoblasts might produce ATX and its bioactive resultant substance, LPA, paralleled with gestational weeks.

Perinatal findings of Seckel syndrome: a case report of a fetus showing primordial dwarfism and severe microcephaly.

OBJECTIVE/METHODS: Seckel syndrome is a rare form of primordial dwarfism and most of the previous reports have been limited to postnatal findings. We report on a fetus showing severe microcephaly, intrauterine growth restriction and a few gyri with shallow sulci on the fetal brain suggesting cortical dysplasia, followed by ultrasound and magnetic resonance imaging in the prenatal period. RESULTS: Cardiotocograph revealed a reassuring fetal status throughout the whole pregnancy period. A male infant weighing 1,556 g was delivered at 39 weeks' gestation, and a diagnosis of Seckel syndrome was made based on postnatal typical findings. Although previous reports on prenatal findings of Seckel syndrome are quite limited, we think that our case presents typical features of a fetus affected by this syndrome. CONCLUSIONS: When prenatal ultrasound shows severe microcephaly and intrauterine growth restriction, this rare syndrome should be included in the differential diagnosis. Moreover, magnetic resonance imaging of the affected fetal brain provides further diagnostic clues.

Fetus with prenatally diagnosed posterior mediastinal lymphangioma: characteristic ultrasound and magnetic resonance imaging findings.

Prenatal diagnosis of lymphangiomas located in the posterior mediastinum has been reported to be extremely rare. We present a fetus with a prenatally diagnosed posterior mediastinal lymphangioma found at 28 weeks' gestation. Fetal ultrasound and magnetic resonance imaging (MRI) revealed a 46 x 26 x 30 mm multicystic mass extending above the diaphragm, located in the posterior mediastinum. The mass was symmetrically shaped and surrounded the thoracic aorta. No remarkable change was noted in the size, shape and texture of the cyst by serial ultrasound and the fetus did not develop cardiac failure or hydrops in the antenatal period. Postnatal chest X-ray and MRI confirmed the prenatal findings. The infant was asymptomatic, so he was placed on close follow-up without any medical or surgical treatment.