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Although some 70% of patients with rheumatoid arthritis remit during pregnancy, the mechanism for this is not known. A variety of mechanisms have been invoked but none appear to be sufficiently established as an explanation. The most likely explanation is that a factor, or factors, cause the inhibition of release of lymphokines which thereby have a suppressive effect on rheumatoid inflammation.
The interaction between the fertility alpha 2-microglobulin and steroid sex hormones (estrone, estriol, estradiol, progesterone, testosterone) was studied by the use of cross immunoelectrophoresis with intermediate gels. alpha 2-microglobulin was shown to bind to the above hormones, its affinity to testosterone being the highest. The ability of alpha 2-microglobulin to bind to steroid hormones can be used for its isolation by affinity chromatography with immobilized steroid hormones.
Extracts of cervical mucus contain measurable levels of placental protein 14 (PP14), a protein known to suppress proliferative responses of human peripheral blood lymphocytes. Such extracts have been shown to exert suppressive activities on allogeneically stimulated peripheral blood lymphocytes in a dose-dependent manner. However, there was no correlation between the PP14 content of cervical mucus samples and their suppressive activities. Such activity could not be removed from the extracts by dialysis, suggesting high molecular weight mediators. These results indicate that there may be an immunosuppressive factor in human cervical mucus which functions to protect inseminated sperm in a potentially immunologically hostile environment in the female reproductive tract.
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Crude human decidual extracts containing up to 15.0 mg/l PP14 were investigated for their effects on the release of interleukin-2 (IL-2) and of IL-2 receptor (IL-2R) from phytohaemagglutinin (PHA) stimulated lymphocytes. The crude decidual extract suppressed IL-2 production over the culture period investigated (0-90 h) with maximal suppression observed at around 66 h of culture. The suppression was dose dependent over the range of PP14 concentrations used (0-7.0 mg/l). Decidual extracts also inhibited the release of soluble IL-2R into the culture supernatants over the same period. In both cases, the specific reduction of the PP14 content of the extracts by a monoclonal anti-PP14 immunoadsorbent reduced the observed suppression. These results suggest that PP14 inhibits the production of IL-2 from mitogenically stimulated lymphocytes, and leads to a reduced IL-2R release. The mechanism for such an effect is as yet unknown; however, it may explain the previously reported immunosuppressive activity of PP14.
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Two human endometrial proteins, PP12 and PP14, are abundant in human amniotic fluid which is an excellent source for purification. In SDS-PAGE, purified PP12 migrates as several immunoreactive bands from 17,000 to 34,000, all having the same N-terminal amino acid sequence of Ala-Pro-Trp-Gln-Cys-Ala-, and all of them binding IFG-I. PP14 migrates at 28,000, and its N-terminal sequence is Met-Asp-Ile-Pro-Gln-Thr-Lys-Gln-Asp-Leu-Gln-Leu-Pro-Lys-Leu-Ala-Gly-Thr- Trp-His-Ser-Met-. There is a 59% identity between this sequence and that of horse beta-lactoglobulin, and also between PP14 and beta-lactoglobulins of various other species. PP14 and human retinol-binding protein show a 23% sequence identity, and the amino acid residues -Gly-Thr-Trp- at positions 17-19 of PP14 are identical with the corresponding residues of human retinol-binding protein. This site is assumed to play a part in the binding of retinol. An additional sequence identity (32%) is reported here for PP14 and protein BG, a 182 amino acid protein deduced from a 700-base pair cDNA clone isolated from the olfactory neuroepithelium of the frog. Sequence homology is also reported here between PP14 and insecticyanin, a camouflage-associated biliprotein in insects. The sequence of PP14 is therefore homologous to members of a family of proteins that bind and transport biologically active small molecules. Clinical studies have indicated an increase of PP12/IGF-bp and PP14 in the endometrium with advancing secretory changes. PP12/IGF-bp is also found in preovulatory follicular fluid. In hyperstimulated cycles of infertile women undergoing in-vitro fertilization, the serum PP12/IGF-bp concentration rises as multiple follicles mature, and luteinized granulosa cells contain this protein. In non-pregnant women, elevated values have been found in patients with advanced ovarian cancer and primary liver cancer. During pregnancy the serum PP12/IGF-bp concentration rises above the level in non-pregnant women around Week 8 of gestation. Abnormally high levels are seen in patients with pre-eclampsia and, in the third trimester, there is an inverse correlation between the maternal serum PP12/IGF-bp level and fetal weight. From these studies it is likely that a relationship exists between PP12/IGF-bp, the metabolism of IGFs and fetal growth. In non-pregnant women, serum PP14 concentrations appear to reflect endometrial secretory function. This is indicated by cyclic changes in the PP14 concentration in endometrial tissue and by the rising PP14 values in the late luteal phase.(ABSTRACT TRUNCATED AT 400 WORDS)
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We examined the proteins in serum and peritoneal fluid of women with endometriosis (and of healthy controls) for evidence of an autoimmune response that might account for their impaired fertility. No antibodies against endometrial glycoproteins or against "progestin dependent endometrial protein" (PEP) were found in any serum or peritoneal fluid sample. Levels of PEP were not different in serum from women with moderate to severe endometriosis (n = 6), with mild endometriosis (n = 21), or from disease-free cycling controls (n = 19). PEP levels in peritoneal fluid from mild endometriosis and from controls did not differ but were elevated ten times in fluid obtained in the secretory phase from women with moderate to severe disease. This suggests that PEP levels in peritoneal fluid reflect the extent of ectopic endometrial growth. The salient finding was a heretofore undescribed protein (mol wt 70,000) in secretory phase peritoneal fluid samples (18/20) and its absence during the proliferative phase (0/35).
Placental protein 14 (PP14), originally isolated from the human placenta and its adjacent membranes, was detected in the serum of nonpregnant women. The levels were measured by radioimmunoassay in 218 serum samples from 19 women throughout the menstrual cycle. In 13 women with a normal ovulatory cycle, the levels showed consistent variation. They were highest (up to 172 ng/ml) in the late secretory phase and remained high for the first days of the next cycle. Low concentrations were found from the midproliferative to the early luteal phase of the cycle. No similar variation was seen in anovulatory cycles of six other women. Compared with ovulatory cycles, anovulatory cycles exhibited lower PP14 levels in the latter part of the cycle (P less than 0.001) and in the beginning of the next cycle (P less than 0.01). In ovulatory cycles, the sustained elevation of serum PP14 concentration over the following period may be explained by the fairly long half-life (42 hours) of PP14 in serum: once the level has increased, it declines slowly. These results suggest that PP14 measurement may become a novel means to distinguish between ovulatory and anovulatory cycles even after the onset of the next period.
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The concentration of PP14 in seminal plasma was determined by radioimmunoassay. The levels were 13-362 mg/liter in normospermic specimens (n = 36), 10-252 mg/liter in samples from 46 infertile men (oligo-, astheno-, terato- or necrospermia), and 30-233 mg/liter in 7 vasectomized men. No significant difference was found in the PP14 levels in the groups examined. Low PP14 levels (13-25 micrograms/liter) were detected in male sera. In RIA, serial dilutions of seminal plasma and purified PP14 gave parallel dose-response curves. In tandem-crossed immunoelectrophoresis, seminal plasma PP14 showed a reaction of identity with PP14 purified from human term placenta. The isoelectric point of seminal plasma PP14 was 5.2-5.4 and that of early maternal serum PP14 was 4.8-4.9. In the normospermic group a moderate negative correlation (p less than 0.05) was found between the volume of seminal plasma and the PP14 level, whereas the correlation was positive (p less than 0.05) in the infertile group. There also was a negative correlation (p less than 0.05) between the percentage of motile spermatozoa and PP14 concentration. No correlation was observed between the sperm count or age of men and PP14 level in seminal plasma. The origin of seminal plasma PP14 is not from the testes, as the levels in vasectomized and nonvasectomized men were similar. By immunoperoxidase staining, PP14 was detected in the epithelium of seminal vesicles but not in the testis.
OBJECTIVE: To investigate changes in menstrual cycle hormones and endometrial maturation that may contribute to the decline in fertility with aging. DESIGN: Prospective controlled clinical study. SETTING: Normal human volunteers in an academic research institution. SUBJECTS: Women with regular menstrual cycles. INTERVENTIONS: Thirty-two women, aged 20 to 30 or 40 to 50 years, had daily blood drawing starting on cycle day 6 to 10 and continuing until 2 days after the onset of next menses. In addition, 60 women, aged 20 to 30 or 40 to 50 years, had a total of 93 endometrial biopsies performed on day 7 to 9 after the LH surge. MAIN OUTCOME MEASURES: Serum LH, FSH, E2, inhibin, P, and placental protein 14 (PP14) levels and histologic maturation of the endometrium. RESULTS: Serum FSH levels were increased whereas inhibin concentrations were reduced in the luteal-follicular transition of women > 40 years. No other hormonal changes were seen in this population, including P and PP14 secretion. Disruption of endometrial maturation occurred at a similar frequency in both age groups. CONCLUSIONS: Follicular recruitment, but not luteal function or endometrial maturation, is disturbed in cycling women > 40 years and may contribute to the decline in fertility with aging.
As biochemical markers for early diagnosis of disturbed pregnancies the placental proteins have been found special interest. It is suggested that measuring the serum concentration of placental proteins may have prognostic value in predicting the course of pregnancy. Furthermore, the activity of decidual tissue as well as the state of the menstrual cycle can be monitored. In this a review is given comprising the characteristics and possible clinical applications of these proteins, especially with respect to placental protein 12 (PP12), placental protein 14 (PP14) and the pregnancy associated plasma protein A (PAPP-A).
In a study it was investigated to what extent the early pregnancy factor, the placental proteins 12 and 14 and tumor necrosis factor alpha are suited to control and select patients with habitual abortions for immunotherapy. Immunotherapy shows good clinical results. Placental protein 12 ist not suited for selecting patients. Placental protein 14 shows typical changes after the application of polyvalent immunoglobulin and could be an important prognostic factor. Tumor necrosis factor alpha seems to be useful for selecting patients for immunotherapy, because in cases of habitual abortions this factor can be a sign for immunological causes. In the late phase of pregnancy, early pregnancy factor is also an indicator for disturbances of pregnancy.
Placental protein 14 (PP14), an immunosuppressive molecule previously known to be expressed in the female and male reproductive tracts only, was shown to be expressed by hematopoietic cells of the megakaryocytic lineage. Northern blot analysis confirmed the induction specificity of PP14 mRNA in phorbol ester-treated K562 cells. Potent immunosuppressive activity in conditioned medium from phorbol ester-treated K562 cells was attributed to hematopoietic PP14 by anti-PP14 antibody blocking. Immunoprecipitation with anti-PP14 antibodies from conditioned medium revealed two distinct PP14 protein isoforms, designated PP14.1 and PP14.2. Polymerase chain reaction cloning and analysis demonstrated the presence of distinct mRNA counterparts to PP14.1 and PP14.2 that had not been resolved by Northern blot analyses. Hematopoietic PP14.1 mRNA corresponds in size to endometrial PP14 mRNA, whereas the smaller hematopoietic PP14.2 mRNA displays an internal in-frame 66-nucleotide deletion that can be explained by alternative splicing and predicts a 22-amino-acid deletion in the encoded gene product. Both PP14 mRNA isoforms were additionally detected by reverse transcriptase polymerase chain reaction analyses in two human megakaryocytic cell lines and in normal human megakaryocytes and platelets. PP14 mRNA was not detected by reverse transcriptase polymerase chain reaction in a panel of nonhematopoietic, nonendometrial tissues examined. The finding of hematopoietic PP14 within the megakaryocytic lineage provides an additional regulatory link between the coagulation and immune systems in normal and pathological settings.
Progesterone-associated endometrial protein (PAEP/PP14) is a 28-kD glycoprotein with sequence homology to beta-lactoglobulins containing a retinol-binding motif. PAEP/PP14 is present at nanomolar concentrations in human serum. It is produced by secretory and decidualized endometrium in women and by seminal vesicle epithelium in men. We report here that PAEP mRNA is constitutively expressed in normal hematopoietic tissue. Western immunoblotting of bone marrow cells with rabbit antibodies to PAEP gave a band at 28 kD, and immunocytochemical staining with monoclonal antibodies localized PAEP into the cytoplasm of erythroid precursors representing different stages of the normoblast series. PAEP was not detected in mature red blood cells, platelets, or in cells of the myeloid lineage. Untreated K562 leukemia cells did not contain PAEP, whereas treatment of the cells with tetradecanoylphorbol acetate (TPA) induced strong expression of PAEP mRNA and synthesis of the intact protein that was found both in the cytoplasm of the differentiating cells and in the supernatant of TPA-treated cultures. These findings add a new member to the growing family of genes that are constitutively expressed both in the reproductive tract and in the hematopoietic system.