Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The aim of this cohort study was to investigate immunophenotypic characteristics of natural killer (NK) cells by assessing specific molecules expressed in the decidua of sporadic miscarriages and induced abortions. The deciduae were obtained from 29 consecutively seen women whose pregnancies ended in first trimester miscarriages (MS), and the fetal chromosome karyotype of these MS was analysed. Additionally, 13 deciduae were obtained from induced abortion (IA) with informed consent. The expression of perforin, CD94, CD161, CD158a, CD158b, CD244 on CD3-CD56+NK cells, and perforin on CD3+CD8+ T cells was analysed by flow cytometry. The CD158a (mean+/-SD, 26.2+/-14.7%) and CD94 (50.2+/-25.7%) expressions in MS with normal chromosome karyotype (MSNK; n=11) were significantly decreased as compared with those (41.5+/-19.5%, 71.4+/-20.4%) in MS with abnormal karyotype (MSAK; n=18) and those (44.3+/-21.9%, 80.8+/-17.5%) in IA (n=13). Conversely, the perforin expression on CD3-CD8-CD56+NK cells (76.3+/-11.0%) and CD3+CD8+T cells (30.6+/-9.2%) in MSNK was significantly increased as compared with those (66.8+/-16.6%, 23.6+/-8.7%) in MSAK and those (62.9+/-11.6%, 19.7+/-8.1%) in IA. A positive correlation between CD94 and CD158a expressions on NK cells, negative correlations between CD94 on NK cells and perforin on NK cells/T cells, and between CD158a on NK cells and perforin on T cells were found in the decidua. A divergence of NK cell repertoire in the decidua might be related to aetiology of sporadic MSNK.
Mol Hum Reprod 2005 Jun
PMID:Divergence of natural killer cell receptor and related molecule in the decidua from sporadic miscarriage with normal chromosome karyotype. 1595 78

The purpose of this study was to analyze the placental and neonatal tissues in fatal cases for a wide variety of infectious agents and cytokine expression. Placentas and corresponding neonatal tissues in 21 consecutive cases of idiopathic spontaneous abortion or perinatal death, before or within 2 days of birth, were tested for an infectious agent. The controls included 10 consecutive cases of fetal and placental tissues from therapeutic abortions, 5 placentas from unremarkable childbirths, and 11 placentas from cases of spontaneous abortion or perinatal death of known cause (ruptured uterus, placenta abruption, prolapsed cord). An intrauterine infection was noted in 16 of 21 (76%) of the placentas associated with neonatal mortality; in each case, the same infectious agent was found in the neonatal tissues, primarily the spleen. The most common infectious agent was enterovirus/coxsackie virus (10 cases); the histologic findings in the placenta were nonspecific. There was strong expression of TNF-alpha in the placenta and spleen of each of the cases of intrauterine infection and in none of the 26 controls. It is concluded that in utero infection and the associated cytokine up-regulation are responsible for many cases of unexplained fetal and neonatal loss.
Diagn Mol Pathol 2005 Sep
PMID:Histologic, infectious, and molecular correlates of idiopathic spontaneous abortion and perinatal mortality. 1610 96

Low maternal folate or vitamin B12 status has been implicated in numerous pregnancy complications including spontaneous abortion. The primary aim of this study was to test a polymorphism within the trifunctional folate enzyme MTHFD1 (5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase, 10-formyltetrahydrofolate synthetase) for an association with a mother's risk of having an unexplained second trimester pregnancy loss. We genotyped 125 women who had at least one unexplained spontaneous abortion or intrauterine fetal death between 13 and 26 weeks gestation and 625 control women with no history of prior pregnancy loss. Our study is the first to identify an association between the MTHFD1 1958G-->A (R653Q) polymorphism and the maternal risk of having an unexplained second trimester pregnancy loss. Women who are MTHFD1 1958AA homozygous have a 1.64-fold increased risk of having an unexplained second trimester loss compared to women who are MTHFD1 1958AG or 1958GG [OR 1.64 (1.05-2.57), P = 0.03]. It has been reported that polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR), 677C-->T (A222V), transcobalamin II (TCII), 776C-->G (P259R), are associated with pregnancy loss. Both variants were tested in this study. Neither showed evidence of significantly affecting the maternal risk of having a second trimester pregnancy loss. In conclusion, the MTHFD1 1958AA genotype may be an important maternal risk factor to consider during pregnancy.
Mol Hum Reprod 2005 Jul
PMID:A polymorphism in the MTHFD1 gene increases a mother's risk of having an unexplained second trimester pregnancy loss. 1612 74

The published evidence regarding the administration of dydrogesterone in the treatment of habitual abortion is summarised in this review. Habitual abortion is defined as the loss of three or more consecutive pregnancies without known maternal or foetal pathology. The immunology of early pregnancy seems to determine the rejection or non-rejection of the allogenic embryo. When peripheral mononuclear cells from recurrent aborters are incubated with progesterone or dydrogesterone in vitro, T-helper (Th)2 cytokines such as interleukin (IL)-4 and IL-6 markedly increase whereas the Th1 cytokine interferon-gamma decreases. Additionally, both progesterone and dydrogesterone are thought to inhibit the activity of natural killer cells at the foeto-maternal interface in humans. Progesterone-induced blocking factor (PIBF) mediates the immunological effects of progesterone and dydrogesterone in pregnancy. It affects various phases of the maternal immune response involving both the cellular and humoral immune system, exerts anti-abortive effects and inhibits the release of arachidonic acid. It also favours the production of so-called asymmetric, pregnancy-protecting antibodies. In rodents, blockade of this factor results in the termination of pregnancy and in women considerably lower levels are found in those with threatened abortion or pre-term labour. In order to draw final conclusions as to the usefulness of dydrogesterone in women with a history of recurrent miscarriage, further controlled, blinded, randomised clinical trials are needed.
J Steroid Biochem Mol Biol 2005 Dec
PMID:The role of dydrogesterone in recurrent (habitual) abortion. 1618 36

HLA-G is a class Ib HLA gene with unique tissue expression pattern and immunomodulatory properties. Polymorphisms in the HLA-G promoter region have been associated with miscarriage and asthma, whereas expression levels have been associated with a wide range of pathologic conditions as well as survival of embryos after in vitro fertilization and of organs after transplantation. Here, we characterize the sequence variation and haplotype structure of the HLA-G promoter and flanking sequences in 44 African Americans, 47 European Americans and 43 Han Chinese by haplotype-specific PCR and sequencing. In all three populations, we observed high levels of nucleotide variation, an excess of intermediate-frequency alleles, and a genealogy with two common haplotypes separated by deep branches, features that are suggestive of balancing selection acting in this region. Comparisons to HLA-A and a pseudogene, HLA-J, suggested that the observed pattern of sequence variation in the HLA-G promoter region is not likely due to other selected HLA genes. We suggest that the mechanism for this selection is related to the highly regulated expression pattern of HLA-G and that high- and low-expressing promoters may be favored under temporally and/or spatially varying selective pressures.
Hum Mol Genet 2005 Dec 01
PMID:Evidence of balancing selection at the HLA-G promoter region. 1623 59

One hundred and eighty women with a history of recurrent, unexplained spontaneous abortion (mean 3.5 abortions) were randomised to receive oral dydrogesterone (10 mg b.i.d.), intramuscular human chorionic gonadotrophin (hCG; 5000 IU every 4 days) or no additional treatment (controls). Treatment was started as soon as possible after confirmation of pregnancy and continued until the 12th gestational week. All women received standard supportive care. Abortions were significantly (p < or = 0.05) less common in the dydrogesterone group (13.4%) than in the control group (29%); there were no statistically significant differences between the hCG group and the control group. There were no differences between the groups with respect to pregnancy complications or congenital abnormalities. In conclusion, hormonal support with dydrogesterone can increase the chances of a successful pregnancy in women with a history of recurrent spontaneous abortion.
J Steroid Biochem Mol Biol 2005 Dec
PMID:Dydrogesterone in the reduction of recurrent spontaneous abortion. 1625 4

HLA-G is thought to play a key role in implantation by modulating cytokine secretion to control trophoblast invasion and to maintain a local immunosuppressive state. It differs from other class I molecules in that the gene can be alternatively spliced to produce four membrane-bound (G1, G2, G3 and G4) and three soluble isoforms (G5, G6 and G7). The soluble isoforms have recently attracted attention as their levels may be diagnostic of poor trophoblast invasion in miscarriage or pre-eclampsia and the implantation potential of IVF embryos. Although the expression and function of HLA-G2, G3, G4 and G7 has previously been a matter of debate, until now it has been generally accepted that soluble HLA-G5 and HLA-G6 are both expressed and secreted by trophoblast. However, Blaschitz et al. (2005) have reinvestigated this question and come to the surprising conclusion that they are not. They have shown that trophoblast only expresses the membrane-bound HLA-G1 isoform and not soluble HLA-G5 and -G6. Furthermore, although soluble HLA-G could be found in trophoblast culture supernatants, it appears not to be derived by alternative splicing but by the cleavage of HLA-G1. The source of the soluble HLA-G may not matter from a diagnostic perspective, but these findings, if confirmed, have important implications for our understanding of the biology of HLA-G.
Mol Hum Reprod 2005 Oct
PMID:Does 'soluble' HLA-G really exist? Another twist to the tale. 1633 Apr 68

Listeria ivanovii differs from the human pathogen Listeria monocytogenes in that it specifically affects ruminants, causing septicaemia and abortion but not meningo-encephalitis. The genetic characterization of spontaneous L. ivanovii mutants lacking the virulence factor SmcL (sphingomyelinase) led us to identify LIPI-2, the first species-specific pathogenicity island from Listeria. Besides SmcL, this 22 kb chromosomal locus encodes 10 internalin (Inl) proteins: i-InlB1 and -B2 are large/surface-associated Inls similar to L. monocytogenes InlB; i-InlE to -L are small/excreted (SE)-Inls, i-InlG being a tandem fusion of two SE-Inls. Except i-inlB1, all LIPI-2 inl genes are controlled by the virulence regulator, PrfA. LIPI-2 is inserted into a tRNA locus and is unstable - half of it deleting at approximately 10(-4) frequency with a portion of contiguous DNA. The spontaneous mutants were attenuated in vivo in mice and lambs and showed impaired intracellular growth and apoptosis induction in bovine MDBK cells. Targeted knock-out mutations associated the virulence defect with LIPI-2 genes. The region between the core genome loci ysnB-tRNA(arg) and ydeI flanking LIPI-2 contained different gene complements in the different Listeria spp. and even serovars of L. monocytogenes, including remnants of the PSA bacteriophage int gene in serovar 4b, indicating it is a hot spot for horizontal genome diversification. LIPI-2 is conserved in L. ivanovii ssp. ivanovii and londoniensis, suggesting an early acquisition during the species' evolution. LIPI-2 is likely to play an important role in the pathogenic and host tropism of L. ivanovii.
Mol Microbiol 2006 Jan
PMID:A spontaneous genomic deletion in Listeria ivanovii identifies LIPI-2, a species-specific pathogenicity island encoding sphingomyelinase and numerous internalins. 1639 Apr 39

Recent data demonstrated that CD4+CD25+ regulatory T (Treg) cells and an enzyme called indoleamine 2,3-dioxygenase (IDO) mediate maternal tolerance to the fetus. Interestingly, Treg cells express the CTLA-4 molecule on their surface, and B7 (CD80/86) ligation by CTLA-4 enhanced IDO activity of dendritic cells (DCs) and monocytes by the induction of interferon gamma (IFN-gamma) production. In this study, we studied the IDO expression on peripheral blood monocytes and decidual monocytes or DCs after treatment with CTLA-4/Fc fusion protein or IFN-gamma using flow cytometry. IDO expressions on both peripheral blood DC and decidual DC and monocytes were up-regulated during normal pregnancy. On the other hand, both IDO expression on DC and monocytes after IFN-gamma treatment or CTLA-4 treatment were decreased in spontaneous abortion cases. The expression of CD86 on peripheral blood and decidual monocytes and DC in spontaneous abortion cases was lower compared with those in normal pregnancy subjects. Also, IFN-gamma production by decidual and peripheral blood mononuclear cells after CTLA-4/Fc treatment in spontaneous abortion cases was significantly lower than those in normal pregnancy subjects. These data suggest that CTLA-4 on Treg cells up-regulates IDO expression on decidual and peripheral blood DC and monocytes by the induction of IFN-gamma production.
Mol Hum Reprod 2005 Dec
PMID:IDO expression on decidual and peripheral blood dendritic cells and monocytes/macrophages after treatment with CTLA-4 or interferon-gamma increase in normal pregnancy but decrease in spontaneous abortion. 1642 Dec 20

Placental progesterone synthesis in humans prevents abortion of the fetus by maintaining uterine quiescence and low myometrial excitability. In rodents, a transient steroidogenic output is observed in the trophoblast giant cells during mid-pregnancy. Although the exact role of this locally produced progesterone is not clear, rodent trophoblast giant cells are an important cell model for studying the regulation of placental steroidogenesis. This chapter describes the methods we developed to analyze the regulation of genes involved in progesterone biosynthesis in miniature cultures of primary trophoblast cells from rodents. These genes include cholesterol side chain cleavage cytochrome P450 (P450scc) and its accessory proteins, steroidogenic acute regulatory protein (StAR) and 3beta-hydroxysteroid dehydrogenase/isomerase (3betaHSD). To obtain giant cells, uterine implantation sites are sliced in half, and the trophoblast giant cell layers are separated from the surrounding decidua by scraping. Cells can subsequently be separated by gentle enzymatic digestion with trypsin, or collagenase, and plated for further study in vitro. This chapter provides instructions, insights, and comments instrumental for performing in situ visualization of giant cell mRNA and proteins, analyzing enzyme activities, and conducting promoter analyses with a limited number of cells.
Methods Mol Med 2006
PMID:Analysis of trophoblast giant cell steroidogenesis in primary cultures. 1651 89


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