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PubMed1999

Glycosylation and rheumatic disease.

Rheumatoid arthritis (RA) and other rheumatic diseases are associated with a significant defect in the galactosyltransferase enzyme that results in a profound change in the galactosylation of immunoglobulin G. This change has been demonstrated to be integrally associated with pathogenic mechanisms associated with inflammation in RA. It is not thought that these changes are unique to RA, but it is thought that there may be subtle changes in the disruption of glycosylation homeostasis causing a unique sugar change to be associated with a number of other rheumatic diseases. This is referred to as 'sugar printing the rheumatic diseases' and may be a concept useful both diagnostically and therapeutically.

Arthritis, Rheumatoid↗
PubMed1993

Markers for endometriosis.

Screening for endometriosis is subject to general rules. The two most important conditions, i.e. the disorder should be well-defined and serious, and there must be an effective way to treat or prevent it through screening, are not satisfied for endometriosis. Given the lack of understanding of the pathogenesis of this disease and the disreputable evidence of treatment effectiveness, other criteria for worthwhile screening programmes, such as prevalence, cost effectiveness and screening test performance, cannot be evaluated. Markers may be applied in the diagnostic process in the individual patient, although it should be realized that the best results will be obtained in patients with advanced disease, in whom routine pelvic examination will establish the diagnosis on purely clinical grounds anyway. The development of appropriate tissue markers may in the future shed more light on the intricate mechanisms involved in the pathogenesis of endometriosis.

Antigens, Tumor-Associated, Carbohydrate↗
PubMed1989

Secretory proteins of the endometrium--potential markers for endometrial dysfunction.

In contrast to our detailed knowledge of endometrial structure, the study of endometrial function is still in its infancy. It seems likely that most of the changes that occur in the endometrium during the cycle are directed towards the promotion of implantation, and that the proteins secreted by the tissue have a role to play in the maintenance of pregnancy. One approach to the study of these proteins has been the incubation of endometrium in vitro with labelled amino acid precursors, and this method has revealed that in early pregnancy two proteins are quantitatively more important than the others synthesized and secreted by the endometrium. One of these proteins is a homologue of beta-lactoglobulin, also known as alpha 2-PEG, PP14 or PEP. It is synthesized by endometrial glands and no other source has been identified. Its synthesis is induced in the luteal phase of the menstrual cycle, rises to a peak in the early weeks of pregnancy and then rapidly declines as the decidua spongiosa is replaced by decidua compacta. The direction of its secretion appears to be into the amniotic fluid, and its function may be to transport a vitamin or other essential substance to the early conceptus: another possible function is immunosuppression. The protein can be measured in peripheral blood and may be useful as a marker of the effect of progesterone-or its lack of effect, as in the inadequate luteal phase. The other quantitatively important endometrial protein is IGF binding protein, which is produced mainly by stromal fibroblasts in the late luteal phase of the cycle. During the cycle the contribution of the endometrium to serum levels of IGF-BP is slight, but in pregnancy, as the amount of decidua compacta increases, levels in peripheral blood rise, with peaks at 18-24 weeks and at 36-40 weeks. The function of the protein may be to protect the mother by inhibiting IGF, or to enable IGF to stimulate the growth of endometrial stroma. Links between this protein and disorders of fetal growth have been suggested. The diversity of the possible functions of these proteins, and the continuing uncertainty over their roles, underline the complexity of endometrial functions.(ABSTRACT TRUNCATED AT 400 WORDS)

Biomarkers↗
PubMed2004

Placental protein 14 concentrations in circulation related to hormonal parameters and reproductive outcome in women undergoing IVF/ICSI.

Serum concentrations of placental protein 14 (PP14), steroids and gonadotrophins were related to the outcome of IVF/intracytoplasmic sperm injection in 195 normogonadotrophic women subjected to the long protocol gonadotrophin-releasing hormone agonist (GnRHa; buserelin) pituitary down-regulation protocol and gonadotrophin stimulation (HMG or rFSH). Pituitary down-regulation was initiated on cycle day 21 and the patients were randomized to either intranasal or s.c. administration of buserelin. After 14 days of down-regulation, the patients were randomized on stimulation day 1 (S1) to ovarian stimulation with 225 IU per day of either human menopausal gonadotrophin (HMG) or recombinant FSH (rFSH) for a fixed period of 7 days. The daily gonadotrophin dose was adjusted on the following day according to ovarian response. Patient's blood was sampled for PP14 and hormone analysis on cycle days 21, S1, S8 and on the day of oocyte retrieval. Mean concentrations of PP14 on day 21 of the cycle were significantly lower in conception than in non-conception cycles, whereas progesterone and oestradiol were similar in conception and non-conception cycles. PP14 concentrations on the first day of stimulation and at oocyte retrieval were significantly higher in conception than in non-conception cycles, whereas concentrations after 8 days of stimulation were similar. Neither mode of GnRHa administration nor type of gonadotrophin significantly influenced PP14 concentrations throughout ovarian stimulation. Circulating PP14 is thus an important physiological signal of the fertility status of the individual in the cycle antecedent to and during ovarian stimulation. Measuring mid-luteal serum PP14 may offer a clinical test helping to decide if infertility treatment should be initiated in the subsequent cycle.

Adult↗
PubMed2003

Changes in T-plastin expression with human trophoblast differentiation.

During the first trimester of pregnancy, the human placenta is an actively dividing and highly invasive tumour-like tissue, while near term, it represents a fully developed, non-invasive unit. In order to understand the molecular basis of this marked difference in the placental phenotypes, an approach based on a differential display-reverse transcription-polymerase chain reaction (DD-RT-PCR) was adopted to analyse changes in gene expression, using total RNA isolated from first-trimester and term placental villi. Using this approach, T-plastin was initially identified as being differentially expressed in the human first-trimester placenta. T-plastin is an actin-bundling protein and is known to be highly expressed in actively dividing cells and up-regulated in several carcinomas. Using a homogenous population of cytotrophoblasts and syncytiotrophoblasts isolated from human placentae, the present authors demonstrate the differential expression of T-plastin in cytotrophoblasts compared with the terminally differentiated syncytiotrophoblasts. The down-regulation of T-plastin expression is further demonstrated in human trophoblastic BeWo cells induced to differentiate using transforming growth factor (TGF)beta1, a growth factor known for its anti-proliferative and anti-invasive response in placental cells. These studies suggest that expression of T-plastin in the placental context may indeed be associated with the enhanced replicative potential of placental trophoblasts.

Blotting, Western↗
PubMed1994

Characterisation of the differential expression of marker antigens by normal and malignant endometrial epithelium.

In order to examine the production of marker proteins, a reproducible method has been established for culturing purified epithelial cells from normal and malignant endometrium. We have examined the differential expression of secretory proteins using immunohistochemistry in frozen tissue sections, immunocytochemistry in cell cultures derived from the same specimens and protein assays on the culture supernatants. Placental protein 14 (PP14) was produced by normal premenopausal epithelium but not by the post-menopausal or malignant endometrial epithelium. In contrast, placental alkaline phosphatase (PLAP) was produced by endometrial cancers and the endometrial adenocarcinoma-derived cell line Ishikawa, but not by the normal endometrial epithelium. Other markers such as CA-125, which was produced by both normal and malignant endometrium but not by the cell line, and human chorionic gonadotrophin (beta-hCG), which was produced by Ishikawa cells but not by any of the fresh tissues, were less cancer specific. Placental alkaline phosphatase is a direct product of endometrial cancers that can be readily assayed in serum using this two-site assay to test its clinical usefulness in monitoring patients at risk for endometrial cancer.

Adenocarcinoma↗
PubMed1988

Human endometrial proteins.

Human endometrium synthesizes a number of proteins. Two of the major proteins are the low molecular weight insulin-like growth factor-binding protein (IGF-bp25) and endometrial protein PP14 (placental protein 14). Both proteins have been cloned from human decidual cDNA library and their complete amino acid sequences have been deduced. IGF-bp25 is found in various tissues and body fluids including secretory and decidualized endometrium, amniotic fluid, liver, follicular fluid and luteinized granulosa cells of preovulatory ovarian follicles. Clinical studies have shown that there is no systematic variation in the circulating levels during normal menstrual cycle, whereas in hyperstimulated cycles the levels are higher when there are many preovulatory follicles and immediately after follicle aspiration for in vitro fertilization (IVF). Some women with polycystic ovarian disease have a subnormal level of IGF-bp25 in serum. The other protein, PP14, is synthesized by secretory and decidualized endometrium, and it is also abundant in amniotic fluid. PP14 is mainly released by secretory endometrial glands during the last week of ovulatory cycles. There is a consistent variation in serum PP14 levels during normal menstrual cycle. The levels are lowest at the time of ovulation and rise steeply during the last week of luteal phase and peak at the onset of menstruation. Administration of micronized oral progesterone to normally ovulating infertile women brings about elevation in their serum PP14 levels during late luteal phase. In postmenopausal women cyclical estrogen-progestogen replacement causes elevation of serum PP14 level, but this does not take place in hysterectomized postmenopausal women.(ABSTRACT TRUNCATED AT 250 WORDS)

Endometrium↗
PubMed2000

Endometrial receptivity and the window of implantation.

Implantation is a highly co-ordinated event that involves both embryonic and endometrial participation. The endometrium expresses a sophisticated repertoire of proteins during the menstrual cycle many of which help to define a period of receptivity collectively known as the 'window of implantation'. Many of these factors, which are temporally aligned with this window, are now seen as chemical messengers that are recognized by the embryo and facilitate embryonic growth and differentiation. The use of such proteins as biomarkers has also advanced our understanding of the implantation process and may identify women with implantation failure and infertility. While the study of endometrial receptivity is still evolving, the field is growing rapidly and will probably enhance our ability to diagnose and treat couples with infertility, especially in the arena of assisted reproductive technologies (ART).

Biomarkers↗
PubMed2001

Circulating plasma leptin and IGF-1 levels in girls with premature adrenarche: potential implications of a preliminary study.

Premature adrenarche is a condition characterized by precocious development of pubic and/or axillary hair, due to early onset of adrenal androgen secretion. Girls with premature adrenarche may later develop menstrual irregularities, hyperandrogenism, and the classic polycystic ovary syndrome. As leptin is thought to modulate the onset of pubertal development, we measured plasma leptin levels in 7 girls with premature adrenarche, and 8 age-matched comparison girls. Because leptin, the hypothalamic-pituitary-adrenal (HPA), the hypothalamic-pituitary-gonadal axes are functionally interrelated, we also determined salivary and plasma cortisol, dehydroepiandrosterone (DHEA), DHEA-sulfate, androstenedione, estradiol, and estrone. Finally, since IGF-I may play a role in adrenocortical function, we determined plasma levels of IGF-1, and IGF-BP1. Plasma was collected by an intravenous catheter at times 0, 20, and 40 min, starting at 1.30 p.m. Girls with premature adrenarche had a higher body mass index (BMI) and an over two-fold elevation of their plasma leptin than comparison girls. This group also had elevated levels of salivary and plasma cortisol, and increased levels of DHEA, DHEA-S, androstenedione, estradiol and estrone. Plasma IGF-1 and the ratio of IGF-1/IGF-BP1 were elevated. We propose that girls with premature adrenarche may represent an overlapping group characterized by both features of increased adiposity and HPA axis activity, which together, and depending on the genetic/constitutional background of the individual, may account for the development of adrenal hyperandrogenism, and, later, the polycystic ovary syndrome.

Adrenal Glands↗
PubMed1995

[Value of serum placental protein 14 determination in differential diagnosis of abnormal early pregnancy].

Single measurements of hCG and placental protein 14 were carried out in 32 patients with tubal pregnancies, in 38 patients with spontaneous abortion and 28 women with normal intrauterine pregnancies from the 5th to the 7th week of pregnancy. HCG-measurement could only show significant differences between normal and abnormal early pregnancies. PP 14-measurements showed significant differences between all groups. Low concentrations of serum PP 14 point to an ectopic pregnancy.

Abortion, Threatened↗
PubMed1989

Three pregnancy proteins (PP12, PP14, and PAPP-A): their biological and clinical relevance.

The three pregnancy proteins, PP12, PP14, and PAPP-A, reviewed here are all produced by the endometrium under the influence of progesterone. Their production is low during the secretory phase and increases dramatically after decidualization and pregnancy. PP12 and PP14 are synthesized by the epithelial cells and PAPP-A is synthesized by the stromal cells. Reflecting perhaps the relative abundance of stromal cells, PAPP-A concentrations increase progressively to term, whereas the levels of PP12 and PP14 level off and even decline after the 20th week of gestation. These proteins are also found in nonpregnant subjects in extrauterine sites: follicles, follicular fluid, luteal cells, and fallopian tubes, and in males, in seminal vesicles and seminal fluid. PP12 has been found in several forms of cancer, although not with sufficient frequency to make it a useful tumor marker. The biologic function of these proteins is still subject to speculation, but they do reflect the biosynthetic capacity of decidualized endometrium, and especially PP14 may find clinical application in the management of infertility patients.

Carrier Proteins↗
PubMed2002

Comparison of gene expression at the feto-maternal interface between normal and recurrent pregnancy loss patients.

Normal pregnancy requires a series of immunological, metabolic, vascular and endocrine regulating processes. However, the specific genes and proteins involved in these processes are not well defined. Aberration of these processes may lead to problems in pregnancy. One of these problems may be recurrent pregnancy loss (RPL). Little information is available on the level of expression of genes that may play a role in normal pregnancy. Therefore, this study determined whether different levels of gene expression at the feto-maternal interface could be associated with factors for RPL. The expression patterns of genes isolated from subtractive hybridization analysis performed with chorionic villi from normal and abnormal pregnancies were investigated. Eight genes classified into groups, including immunosuppression-related, embryo attachment-related and angiogenesis-related, were isolated.

Abortion, Habitual↗
PubMed1988

Complete amino acid sequence of human placental protein 14: a progesterone-regulated uterine protein homologous to beta-lactoglobulins.

Placental protein 14 (PP14), also known as progestagen-dependent endometrial protein and pregnancy-associated endometrial alpha 2-globulin, is synthesized by the human secretory endometrium and decidua. We have isolated from a human decidual cDNA library clones corresponding to PP14 and deduced its entire amino acid sequence. PP14 contains 180 amino acids, 18 of which correspond to a putative signal peptide. The predicted molecular weight of the pre-PP14 is 20,555 and that of the mature protein is 18,787. PP14 is encoded by a 1-kilobase-pair mRNA that is expressed in human secretory endometrium and decidua but not in postmenopausal endometrium, placenta, liver, kidney, and adrenals. The 162-residue-long sequence of PP14 is highly homologous to beta-lactoglobulins, with a 53.4% identity with the amino acid sequence of horse beta-lactoglobulin I. The four cysteinyl residues (positions 66, 106, 119, and 160) responsible for intramolecular disulfide bridges in beta-lactoglobulins are all conserved in PP14. Southern blot analysis of human DNA suggested that PP14 gene sequences encompass some 20 kilobase pairs of the human genomic DNA.

Amino Acid Sequence↗
PubMed2003

Negative regulation of T cell activation by placental protein 14 is mediated by the tyrosine phosphatase receptor CD45.

CD45 is the major protein tyrosine phosphatase receptor on T cell surfaces that functions as both a positive and a negative regulator of T cell receptor (TCR) signaling. Although CD45 is required for the activation of TCR-associated Src family kinases, it also dephosphorylates phosphoproteins involved in the TCR-signaling cascade. This study links CD45 to the inhibitory activity of placental protein 14 (PP14), a major soluble protein of pregnancy that is now known to be a direct modulator of T cells and to function by desensitizing TCR signaling. PP14 and CD45 co-capped with each other, pointing to a physical linkage between the two. Interestingly, however, the binding of PP14 to T cell surfaces was not restricted to CD45 alone, with evidence showing that PP14 binds to other surface molecules in a carbohydrate-dependent fashion. Notwithstanding the broader molecular binding potential of PP14, its interaction with CD45 appeared to have special functional significance. Using transfected derivatives of the HPB. ALL mutant T cell line that differ in CD45 expression, we established that the inhibitory effects of PP14 are dependent upon the expression of intact CD45 on T cell surfaces. Based upon these findings, we propose a new immunoregulatory model for PP14, wherein one of its surface molecular targets, CD45, mediates its T cell inhibitory activity, accounting for the intriguing capacity of PP14 to elevate TCR activation thresholds and thereby down-regulate T cell activation.

Calcium↗
PubMedDate not supplied

Serum placental protein 14: a novel marker of selective oestrogen receptor modulator action on the postmenopausal endometrium.

The primary objective of this study was to investigate whether changes in the serum level of an endometrial secretory protein, placental protein 14 (PP14), can reflect endometrial adverse events induced by selective oestrogen receptor modulators (SERMs). A randomized, double-blind, placebo-controlled trial was used. Participants were healthy postmenopausal women aged 45-65 years, who received either various doses of raloxifene (30, 60 or 150 mg day-1) or levormeloxifene (1.25, 5, 10 or 20 mg day-1) or placebo for 12 months. Serum PP14 and endometrial thickness (ET) were monitored by radio-immunoassay and transvaginal ultrasonography, respectively. In the levormeloxifene trial, endometrial status at 12 months was assessed by hysteroscopy. Raloxifene induced only slight increases in serum PP14 and ET. Levormeloxifene, however, induced marked increases in both study parameters at all the does tested. The 6 month changes in PP14 showed a positive correlation with both the 6 and 12 month changes in ET (P < 0.001). Marked stromal oedema, pseudocysticity with or without hypervascularity and endometrial proliferation were seen on hysteroscopy in those showing the largest increases in serum PP14. These results suggest that the PP14 assay used on a group basis may provide useful information on the endometrial effects of SERMs administered in a given dose range, and thereby could assist future clinical trials aiming to find the optimal dose range of new SERMs.

Adult↗
PubMed2004

High prevalence of human anti-bovine IgG antibodies as the major cause of false positive reactions in two-site immunoassays based on monoclonal antibodies.

A sandwich ELISA for quantification of the endometrial protein PP14 revealed false positive reactions in 81% of male sera (n = 54). The PP14 ELISA was based on two monoclonal antibodies (Mabs) with different epitope specificities--a catcher and a biotinylated indicator. The monoclonal antibodies were purified by protein G affinity chromatography from culture supernatant containing 10% (v/v) fetal calf serum (FCS). Human anti-animal IgG (bovine, mouse, horse, and swine) antibodies and human anti-bovine serum albumin antibodies were measured using an ELISA design, with direct bridging of the solid phase and biotinylated antigens. The false positive reactions were abolished by addition of 1% (v/v) bovine serum to the dilution buffer (DB). Human anti-bovine IgG antibodies (HABIA) were detected in 99 out of 104 sera from blood donors (50 females; 54 males). HABIA levels in male sera (n = 54) were positively correlated to the false positive signals in the PP14 ELISA (r = 0.923; p < 0.0001). Antibodies to IgG from other mammalian species (mouse, horse, and swine) were also detected in the donor sera, but levels and frequencies were lower compared to that of HABIA. Furthermore, HABIA were positively correlated to human anti-bovine serum albumin antibodies in the donor sera (r = 0.639; p < 0.0001; n = 103). HABIA (prevalence 95%) cause false positive reactions due to crossbinding of contaminating bovine IgG and/or crossreaction with mouse IgG in two-site immunoassays. The apparent presence of human anti-mouse IgG antibodies (HAMA), described to create false positive results, may be due to a crossreacting fraction of the polyclonal circulating antibodies against bovine IgG.

Adult↗