Pregnancy-associated Alpha 2-glycoprotein Research Articles

Role of proteins of the macroglobulin family in regulation of tumor growth

Proteins of the macroglobulin family are an ancient and evolutionarily conservative link of the immune system, which is actively involved in both inhibition of tumor growth cells and proliferation of tumor cells. Two basically different binding sites and a great conformational plasticity of all representatives of the macroglobulin family, as well as the presence of two to four representatives of the family in the blood of most species allow them to transport diverse substances and exert various regulatory influences on both the tumor and the entire organism. For example, the capacity of macroglobulins for binding hydrolases makes it possible to inhibit enzyme mediated tumor invasion. At the same time, an excess of macroglobulin/hydrolase complexes can activate apoptosis. The tumor is able of using macroglobulins, especially pregnancy-associated proteins, for its own protection. Specifically, pregnancy-associated alpha2-glycoprotein, which is actively produced by human tumor cells, blocks the histocompatibility complex antigens. On the contrary, the capacity of binding zinc stimulates the thymulin-dependent activation of natural killer cells. Nevertheless, the actively growing tumor expresses many receptors to macroglobulins, which are the main carriers of some cytokines and growth factors essential for proliferation.

Changes in levels of IgM RF and alpha 2 PAG correlate with increased disease activity in rheumatoid arthritis during the puerperium.

In this prospective study of 24 pregnant patients with rheumatoid arthritis, quiescent disease activity in 21 patients (88%) during gestation was followed by more active disease in the puerperium in 19 patients (79%). Increased disease activity was reflected in a deterioration in manual dexterity and this was found to correlate with a post-partum rise in IgM rheumatoid factor (IgM RF) (r = 0.86) and a post-partum decline in pregnancy associated alpha-2 glycoprotein (PAG) (r = 0.44). The increase in IgM RF also correlated with increased disease activity measured by a visual analogue scale (r = 0.44). Changes in IgA RF were not observed. These results suggest that PAG and IgM RF could contribute to the modulation and pathogenesis of rheumatoid arthritis during pregnancy.

Detection of Immunoregulatory Factors in Retroplacental Serum in Human Pregnancy

Retroplacental serum (RPS) obtained from pregnant women at term deliveries was studied for regulatory effects on T-lymphocyte proliferation and for pregnancy-associated substances and compared with peripheral serum (PS) of the same donor. Proliferative response to phytohemagglutinin and alloantigens in RPS was lower than that in PS. RPS contained higher levels of human placental lactogen, progesterone, estradiol, and prostaglandin E2 than of PS. However, there were no differences in concentrations of pregnancy-associated alpha 2-glycoprotein, pregnancy-specific beta 1-glycoprotein, prostaglandin F2 alpha, alpha-fetoprotein, human chorionic gonadotropin, cortisol, carcinoembryonic antigen, and immunoglobulins between RPS and PS. The amounts of human placental lactogen, progesterone, or prostaglandin E2 seen in RPS did not inhibit T-cell proliferation. Mixtures of various doses of these three substances were still not inhibitory. Thus, the suppressive activity of RPS could not be explained by these pregnancy-associated substances, but a possible involvement of unknown immunoregulatory factors at fetomaternal interface might be suggested.

Serum pregnancy‐associated α2‐glycoprotein levels in the evolution of Hepatitis B virus infection

Serum pregnancy-associated alpha 2-glycoprotein (alpha 2-PAG) levels were evaluated in a follow-up study of patients with hepatitis B virus (HBV) infection and compared with biochemical and virological parameters. In a study of 25 patients with acute hepatitis, an association was found between high alpha 2-PAG values, ALT levels, and HBsAg in 20 patients (80%) (P less than 0.05), 18 recovered completely, and 2 had a protracted course. In five patients serum alpha 2-PAG levels were similar to those in the control group. On the other hand, eight (100%) chronic persistent HBV patients showed high levels of alpha 2-PAG (P less than 0.05) during the study period, and these levels correlated well with inflammatory activity and failure of HBsAg elimination. There were no significant differences in alpha 2-PAG values between asymptomatic HBsAg carriers and controls. Serial analysis of alpha 2-PAG, in correlation with viral markers, biochemical parameters, and histological data, would contribute to the ability to predict the final outcome of HBV infection.

Immunohistochemical definition of antigenic determinants of pregnancy‐associated α2‐glycoprotein (α2‐PAG) using monoclonal antibodies

Human pregnancy-associated alpha 2-glycoprotein (alpha 2-PAG) is a high molecular weight glycoprotein in normal sera. The protein is present in high concentration in the sera of pregnant females and in abnormally low concentration in association with conditions connected with abnormalities of mucosal immunity. Indirect immunoperoxidase techniques using poly- and monoclonal antibodies were employed to identify pregnancy-associated alpha 2-PAG in different tissues. Four monoclonal antibodies were selected from a battery of antibodies with defined specificities in order to ascertain reactivity with various epitopes of the antigen. The antibodies were applied to paraffin sections of breast, colon, salivary gland, and tonsil, and different fixation regimes were used in the preparation of the tissues. The polyclonal antibodies were found to stain plasma cells and epithelial lumina evenly in all the tissues included whereas the monoclonal antibodies were shown to stain certain components selectively. In breast and salivary glands, all four monoclonal antibodies could identify alpha 2-PAG, but in tonsil and colon, only two were reactive. This difference in epitope expression might reflect the internal processing of alpha 2-PAG, and lack of availability of certain epitopes may be indicative of functional blocking of certain domains.

Pregancy-specific and pregnancy-associated proteins in threatened abortion

Pregnancy sera (390) were taken between the 5th and 16th weeks of gestation, from subjects whose pregnancies were uneventful throughout the entire gestation period. In-house curves of first-trimester normal values (10th, 50th, 90th percentile) were established for human chorionic gonadotropin (hCG), human placental lactogen (hPL), pregnancy-specific beta 1-glycoprotein (SP-1), pregnancy-associated plasma protein A (PAPP-A), and pregnancy-associated alpha 2-glycoprotein (alpha 2-PAG) after the measurement of these proteins in the sera by immunoassay. Eighty sera from patients with threatened abortion were also obtained and the placental proteins mentioned above were determined. Values falling below the 10th percentile of the normal population were classified as positive (i.e., pathological) results; the others were considered negative. Based on the outcome of the pregnancy, the results were grouped into true positives (low value and lost pregnancy), false positives (low value and ongoing pregnancy), true negatives, and false negatives. The sensitivity, specificity, and the positive predictive value of each protein as an indicator for abortion were calculated. In terms of specificity hCG and SP-1 were good, whilst PAPP-A and hCG showed the highest sensitivity. The best predictive values were obtained from SP-1 and hCG. The results show that PAPP-A and SP-1 perform satisfactorily but that none of these proteins significantly improves on hCG.

Pregnancy-associated alpha 2-glycoprotein ( α2-PAG): development of a sensitive enzyme-linked immunoassay and comparison of serum concentrations in adults and children

Using a newly-developed and very sensitive enzyme-linked immunoassay technique, we have measured circulating α 2-PAG concentrations in 270 adults and 181 children. In adults, levels increased with age in both sexes and were significantly higher in women in each age category studied. In contrast, there were no significant differences between the sexes in children and no changes with age between 1 and 14 years. At puberty, α 2-PAG concentrations increased in girls and decreased in boys. The increase in girls is consistent with the known stimulatory effects of oestrogen on α 2-PAG production. We discuss the possibility that androgens may have an analogous inhibitory effect in males.

Interaction of pregnancy proteins with phytohemagglutinin P and concanavalin A

It has been established that trophoblast-specific beta-glycoprotein and pregnancy-associated alpha 2-glycoprotein specifically react with non-fixed PHA and Con A. Affinity to the former protein is significantly higher than to the latter one. alpha-Fetoprotein has a low affinity to Con A alone. Affinity to this lectin is in an agreement with the content of carbohydrates contained by pregnancy proteins. A considerable part of human serum proteins bind with Con A; receptors for PHA possess only some serum proteins. As the above-mentioned lectins are often used for stimulation of lymphocyte blast transformation, in is recommended that the constituent parts of the culture medium should be preliminarily tested to specify more accurately their affinity to PHA and Con A.

Influence of orchidectomy or oestrogen treatment on serum levels of pregnancy associated alpha 2-glycoprotein and sex hormone binding globulin in patients with prostatic cancer.

Peripheral serum levels of testosterone, immunoreactive oestrogens (E2), FSH, LH, prolactin and growth hormone (hGH) and two steroid-sensitive proteins, 'pregnancy-associated alpha 2-glycoprotein' (alpha 2-PAG) and sex hormone binding globulin (SHBG), were measured in patients with prostatic cancer before treatment and after orchidectomy or during combined oral and intramuscular oestrogen treatment. Following orchidectomy, the serum levels of testosterone and E2 decreased whilst the levels of FSH and LH increased significantly. No changes were noted in the serum levels of alpha 2-PAG, SHBG or prolactin. Oestrogen treatment significantly decreased the serum levels of testosterone, FSH and LH whilst levels of alpha 2-PAG, SHBG and prolactin were increased significantly. Serum levels of hGH during oestrogen treatment were significantly higher than in patients subjected to orchidectomy. These data are at variance with the established dogma of the oestrogen/androgen balance as a physiological regulator or liver protein synthesis, and indicate that factors other than the endogenous steroids may be operative. hGH may play an important role in this respect.

Pregnancy-associated alpha 2-glycoprotein (alpha 2-PAG) and IgA: their parallel distribution in the human gastrointestinal tract.

Using a combined immunoperoxidase (PAP)/direct immunofluorescence (IF) staining technique, pregnancy-associated alpha 2-glycoprotein (alpha 2-PAG) has been shown to be present in the majority of IgA-producing plasma cells in the lamina propria of both the jejunum and the colon. Both proteins have also been detected on the apical surface of columnar epithelial cells, particularly in the colon, and it is suggested that alpha 2-PAG, like IgA, may be secreted into the lumen of the gastrointestinal (GI) tract by an active transport mechanism. The concentration of alpha 2-PAG in the jejunal fluid of most subjects was found to be less than 20 micrograms/liter, although a number of subjects showed substantially elevated levels. The significance of the association between IgA and alpha 2-PAG, which is known to have immunosuppressive properties, is discussed in relation to the requirement for an efficient immunologic barrier within the GI tract.

Disease activity and pregnancy associated alpha 2-glycoprotein in rheumatoid arthritis during pregnancy.

Fourteen patients with rheumatoid arthritis were studied during pregnancy and clinical disease activity and serum concentrations of pregnancy associated alpha 2-glycoprotein (PAG) measured at monthly intervals until parturition. Disease activity diminished during pregnancy in 10 patients (group 1) and increased or remained unchanged in four (group 2). The mean PAG concentration produced by group 1 was 1250 +/- 737 mg/1, which was significantly higher than the mean of 470 +/- 304 mg/1 produced by group 2. Furthermore, there was a highly significant negative correlation coefficient (r = -0.41; p less than 0.001) between disease activity and PAG concentrations during gestation. Since there was no significant difference between the two groups of patients in any of the other serum factors measured, and since PAG has immunosuppressive properties in vitro, the results suggest that this protein may play an important part in inducing the remissions of rheumatoid arthritis which frequently occur during pregnancy.

In vitro monocyte maturation in squamous-cell carcinoma of the lung: influence of humoral factors.

A previously described defect of in vitro monocyte maturation in patients with squamous-cell carcinoma of the lung (SCC) has been investigated further. The maturation of patients' monocytes in pooled normal human serum was significantly better than in autologous serum. Conversely, the maturation of normal control monocytes was significantly depressed in patients' serum. The defect has been shown to be due to the presence of an inhibitory factor, rather than the lack of a necessary component in the patients' serum. Artificially aggregated gamma-globulin inhibited monocyte maturation in vitro, but the presence of immune complexes in the serum of many patients with SCC did not correlate well with the depression of in vitro maturation of monocytes from the same patient. Similarly, pregnancy-associated alpha 2-glycoprotein, in increased amounts in the serum of patients with SCC, showed no correlation with monocyte maturation. The addition of soluble extracts of tumour, but not of surrounding normal lung tissue significantly inhibited monocyte maturation. The results suggest that the defective monocyte maturation in patients with SCC is at least in part due to serum inhibitory factors, which are likely to be a heterogeneous group.

Limitations of using pregnancy-associated alpha-2 glycoprotein as a tumour marker

The development of a new enzyme-linked immunoassay for pregnancy-associated alpha-2 glycoprotein ( α 2-PAG) has provided an opportunity to reassess the value of this protein as a tumour marker. Serum samples from 800 healthy individuals and patients with various benign and malignant diseases were assayed. There was a very wide range of α 2-PAG levels in normal females (1- > 100 mg/l), and although the levels found in normal males were lower and better defined, this intrinsic variation between individuals makes a single determination in a tumour-bearing patient meaningless. Also, the levels of α 1-PAG in patients with advanced cancer were not significantly different from levels in localized cancer, benign disease or even healthy controls, and furthermore, levels before and after successful cancer treatment did not show a significant change. Our results therefore indicate that α 2-PAG is unsuitable for use as a tumour marker as there was no apparent relationship between the levels of α 2-PAG and either tumour burden or response to treatment.

Biochemical evaluation of patients with breast cancer.

Peripheral blood specimens were obtained from 50 patients with various stages of breast cancer (I-II = 7, III = 6, IV = 24, treated and NED = 13), and 20 biochemical tests were performed. There are significant differences of hemoglobin, LDH, SGPT, serum protein, albumin, and alpha globulin values between patients with early (I, II, NED) and late (III, IV) lesions. Among patients with stage IV diseases, those patients with bony metastases had significantly higher values of alkaline phosphatase, alpha-1 globulin, IgA, and C-reactive protein than those with nonosseous lesions. Neither CEA nor pregnancy-associated alpha-2 glycoprotein showed any correlation with different stages or sites of breast cancer in these small series of patients.

Tumor markers in inclusion cysts of the ovary.

The immunoperoxidase method was used to determine whether carcinoembryonic antigen, beta subunit of HCG placental lactogen, pregnancy-associated alpha-2 glycoprotein, and pregnancy-specific beta-1 glycoprotein could be found in inclusion cysts of the ovary. These tumor markers are found in the serum of patients with common epithelial carcinomas of the ovary and inclusion cysts are considered to be the origin of these tumors. Placental lactogen was found in 56 of 118 inclusion cysts, beta subunit of HCG in four of 141 cysts, alpha-2 glycoprotein in five of 141, and beta-1 glycoprotein in two of 118. it was concluded that primitive cells in inclusion cysts elaborate the same tumor markers found in serous cystadenoma and cystadenocarcinoma of the ovary. This observation, although not proving origin of tumor from the inclusion cyst, demonstrates a significant characteristic shared in common by all three.

Placental proteins (SP1, hCG, PP5) and alpha 2-PAG in trophoblastic diseases.

455 serial serum samples from 41 patients with trophoblastic tumour were analysed. Pregnancy-specific beta-1 glycoprotein (SP1), human chorionic gonadotropin (hCG), and placental protein 5 (PP5) were measured by specific radioimmunoassay. Pregnancy-associated alpha 2-glycoprotein (alpha 2-PAG) was measured by electroimmunoassay. SP1 and hCG levels were high in 36 and 35 patients respectively; alpha 2-PAG concentration was also high in 29 patients. PP5 was found only in patients with a hydatidiform mole and it disappeared from serum within a few hours of evacuation. SP1 and hCG levels decreased during the course of the treatment but seronegativity was reached only after some months: hCG was still detectable after that and disappeared from the serum more slowly. Both parameters were sensitive indicators of residual tumour activity and indicated the need more effective treatment some months before clinical manifestations of recurrence became evident. In some patients only one of the tumour markers was present during follow-up, indicating the importance of careful monitoring including the measurement of serum SP1 and hCG levels. A positive correlation between alpha 2-PAG and hCG, SP1 and the clinical course was found only in 80% of patients a finding which demonstrates the limited value of alpha 2-PAG measurements.

Plasma concentrations of pregnancy-associated alpha-2-glycoprotein in patients with leukaemia.

Plasma concentrations of pregnancy-associated alpha 2-glycoprotein (alpha 2-PAG) were estimated by electroimmunoassay in 64 patients with various leukaemias. 7% (2/30) of male patients and 28% (9/32) of female patients had alpha 2-PAG levels above the established upper limit for age- and sex-matched controls. There was no indication that these elevated alpha 2-PAG concentrations were related to type of leukaemia ana no correlation between the circulating levels of alpha 2-PAG and the absolute lymphocyte or monocyte counts was found.

Pregnancy-associated alpha-2-glycoprotein in recurrent oral ulceration and Behçet's syndrome.

Estimation of the serum concentration of pregnancy-associated alpha 2-glycoprotein (alpha 2-PAG) in male patients with recurrent oral ulcers (ROU) and Behçet's syndrome (BS) revealed significant increases in both groups of patients. The concentrations of alpha 2-PAG in 24 control subjects were less than 10 micrograms/ml, whereas 11/26 (42%; p less than 0.001) of patients with ROU and 20/33 (61%; p less than 0.0005) with BS had concentrations greater than 10 micrograms/ml. Indirect immunofluorescence staining for alpha 2-PAG on the surface membrane of blood mononuclear cells suggests that there is an increase in the number of alpha 2-PAG-positive cells in BS. It is not clear at present whether the increased concentrations of alpha 2-PAG might exert an inhibitory effect on the immune response. No correlation was observed between the levels of alpha 2-PAG in ROU and BS and concentrations of alpha 1-acid glycoprotein, C9, factor B or lysozyme. It is therefore unlikely that the increase in alpha 2-PAG is a manifestation of an increase in acute phase protein.

Immunochemical investigations on the problem of the pregnancy zone protein. XII. Serum concentrations of pregnancy-associated alpha-2-glycoprotein in diabetic pregnancy.

The concentration in serum of the pregnancy zone protein (PZ), a high molecular pregnancy-associated alpha 2-glycoprotein, increases during pregnancy, when oral contraceptives are taken and under certain pathological conditions. PZ is probably part of a multifactorial immunological defence system which prevents the premature rejection of the fetus and placenta which together may be regarded as an allograft. Normally, the PZ serum concentration begins to rise during the 6th-12th week of pregnancy and reaches its peak at about the 24th week. The mean values then remain stable and afterwards diminish slightly toward the end of the pregnancy. In contrast, the mean values in mothers with insulin-dependent diabetes mellitus continue to rise. Excessively high serum PZ concentrations are significantly more frequent among pregnant diabetic patients, especially where there is also rhesus D antigen incompatibility. No correlation was found between excessively high values and the risk features used for the Priscilla White classification. A few patients with progressive proliferative retinopathy even had unusually low values.

Significance of tumor markers in the diagnosis and treatment of bronchial carcinoma

In bronchogenic carcinoma a variety of tumor markers have been described in the last few years. These markers are oncofetal proteins like the carcinoembryonic antigen (CEA), pregnancy-associated antigens like the pregnancy-associated alpha 2-glycoprotein (alpha 2-PAG), and the beta-chorionic gonadotropin (beta-HCG), or normal proteins like isoferritin, coeruloplasmin and hormones. In addition, many attempts have been made to isolate tumor-specific antigens and proteins from lung tumor tissues. The clinical application of the different tumor markers for early diagnosis, staging and therapy control of lung cancer patients is described.