Abnormal expression of HLA-DR antigen in the placenta of a patient with pemphigoid gestationis

The villous stroma and fetal endothelium in chorionic villi adjacent to maternal decidua in a placenta of a woman suffering from pemphigoid gestationis were found to have abnormal expression of HLA-DR antigen. This aberrant DR expression may be a reflection of an immune attack on the placenta.     

Concordant expression of tissue factor and class II MHC antigens in human placental endothelium

Villitis of unestablished etiology is a placental lesion frequently associated with high risk pregnancies: it is also found in placentae from normal term pregnancies. The etiology of the lesion is unknown. Vasculitis and thrombosis have been described in villitis areas of placentae from normal and high risk pregnancies. We asked if fetal stem vessel endothelium in villitis lesions expresses MHC class II antigens, and if this is associated with a thrombogenic activity of these vessels. We found that endothelium of fetal stem vessels in villitis areas was usually MHC class II (HLA-DR, DP and DQ) reactive. Reactivity of fetal stem vessel endothelium for MHC class II antigens was associated with the presence of tissue factor reactivity and the absence of thrombomodulin reactivity. These changes on endothelial plasma membranes can promote intravascular coagulation, ischemic necrosis, vasculitis and other histological changes characteristic of villitis.     

Common mechanisms govern the expression of p21ras and class II MHC antigens in the murine placenta.

It has been shown that there is an inverse as well as a direct correlation between class II MHC antigen expression and the p21ras protein, depending on the cell type. By using trophoblastic cells derived from the spongiotrophoblast and labyrinthine trophoblast, the two major components of the murine placenta, we have examined the p21ras expression in these populations and how this correlates with the induction of class II MHC antigens. It has been shown that although only a small number of cells express the p21ras and class II proteins, they can be induced to express higher levels of these markers by two different treatments. Thus, gamma-interferon (gamma-IFN) induces p21ras and class II protein expression in spongiotrophoblast-derived cells, whereas 5-Azacytidine (5-AzaC) induces expression of these antigens in labyrinthine trophoblast-derived populations. Furthermore, it has been demonstrated that there is a direct correlation between the two markers, as blocking antibody to p21ras cancels the ability of gamma-IFN and 5-AzaC to induce class II antigens. As previous work from this laboratory has shown that in vivo class II induction in the placenta leads to fetal abortion, the present results suggest that both proteins are involved in a common signal transduction pathway which may lead to disruption of fetal membranes and fetal loss.     

Differential diagnosis of bullous skin lesions in neonates: pemphigoid gestationis

The clinical relevance of bullous skin diseases in newborns varies widely. We present the case of a preterm, 35 weeks of gestation, infant who was admitted to our hospital with skin lesions on face, thorax and plantae. There were no other pathological findings on clinical and neurological examinations. During another pregnancy the mother of the child had already suffered from pemphigoid gestationis. In the blood of the newborn complement-fixing auto-antibodies against BP180, the common antigen of pemphigoid gestationis and bullous pemphigoid, were detected. The skin lesions disappeared after a few days of local antiseptic therapy. Pemphigoid gestations is a rare autoimmune dermatosis in pregnancy. The frequency of skin lesions in newborns of mothers with pemphigoid gestationis is estimated to about 5 -- 10 %.     

T cell infiltration and MHC I and II expression in the presence of tumor antigens: An immunohistochemical study in patients with serous epithelial ovarian cancer

OBJECTIVES: Ovarian cancer is a frequent cause of death among women with gynaecologic malignancies despite the introduction of combination chemotherapy. There is therefore a need for new therapeutic strategies for patients with ovarian cancer, such as cellular immunotherapy. In this immunohistochemical study we analysed the expression of three tumor antigens, p53, HER-2/neu and MUC-1 in relation to the expression of major histocompatibility complex (MHC) class I and II on tumor cells, and we searched for the presence of (activated) immune effector cells at the tumor site. STUDY DESIGN: The study was carried out retrospectively in tumor tissue from 29 patients with serous ovarian cancer. Material used had been formalin fixed and paraffin embedded. Material had been obtained from 15 patients at staging laparotomy and from 14 patients during second look or intervention laparotomy. RESULTS: A positive staining for p53 was found in 19/29 (66%) of the tumors, with a high positivity in 13/29 (45%). HER-2/neu and MUC-1 staining was positive in 8/29 (28%) and 21/28 (75%), respectively. Downregulation of MHC class I on tumor cells was found in a minority of the patients, beta-2-microglobin (beta2m) was expressed on tumor cells in all patients. High staining for CD45RO correlated with a high positive staining for granzyme-B (R=0.40, P=0.04) and TIA-1 (R=0.39, P=0.04). A statistically significant better survival in the group with lower stage of disease was found. CONCLUSIONS: As only three out of 29 patients were negative for the tumor antigens p53, HER-2/neu and MUC-1, immunotherapy aiming at all three could serve almost all patients with ovarian cancer. We found that granzyme-B, TIA-1 and CD45RO+ T cells are present in the tumor biopsies, increasing this number by immunotherapy may be beneficial. The immune escape mechanism by MHC class I and beta2m downregulation seems to be of minor importance. Our data support the view that immunotherapy may offer new possibilities with high specificity in ovarian cancer.     

The expression of major histocompatibility antigens in the chorionic villi of molar placentae

Frozen sections of chorionic villi from molar placentae, ranging in menstrual age from 9 to 19 weeks, were studied by an immunoperoxidase technique using the monoclonal antibody to HLA-A,-B,-C antigens W6/32. The distribution of class I HLA antigens in molar placentae was compared with that in normal placental tissue of comparable menstrual age. The results showed that the distribution of these antigens in molar placentae is similar to that seen in normal placentae. In both tissues, class I HLA antigens were absent from the syncytiotrophoblast and the cytotrophoblast cells of the chorionic villi. However, these antigens were found to be present on cells in the mesenchymal stroma of both normal and molar chorionic villi.     

The expression of human leukocyte antigens class I and II in women with endometriosis or adenomyosis

Objectives.?The human leukocyte antigen (HLA) system has been implicated in the aetiology of endometriosis. We aimed to compare the HLA class I and II expression in endometrial specimens from women with endometriosis or adenomyosis.

Methods.?We studied the HLA class I and II expression in endometrial specimens from 16 women with endometriosis and 15 with adenomyosis which were compared with 15 specimens from women without endometriosis or adenomyosis. Immunohistochemistry was performed using mouse antihuman IgG2a monoclonal antibody for HLA I and IgG1 for HLA II.

Results.?Women with endometriosis had significantly higher HLA I and II expression in stroma (100% and 87.5% vs. 66.7% and 40%, p?<?0.02 and p?=?0.007, respectively) and glands (87.5% and 56.3% vs. 46.7% and 20%, p?<?0.02 and p?=?0.04, respectively) compared to controls, while in the adenomyosis group the expression of HLA I was comparable with controls and the HLA II expression was increased in stromal cells (73.3% vs. 40%, p?=?0.03) and decreased in glands (6.6% vs. 20%, p?=?NS).

Conclusion.?Women with endometriosis had a significantly higher expression of HLA molecules whereas in adenomyosis there was a tendency of lower expression of these molecules. This could explain the suppression of cellular immunity in the peritoneal cavity.     

Immunofluorescence study of the placenta in a case of pemphigoid gestationis: Pathophysiological bases

IntroductionPemphigoid gestationis (PG) is one of the main dermatoses of pregnancy that must be recognized and treated promptly, since it is related to worsening of foetal prognosis. Although skin involvement has been investigated, there is a lack of morphological and functional studies of the placenta in this pathology.Main symptoms and/or clinical findingsErythematous vesicular rash at 32 + 1 weeks of gestation.Main diagnosesPG.Therapeutic interventions and resultsImmunogammaglobulin in severe cases refractory to oral corticosteroids with complete disappearance of the lesions.ConclusionTo our knowledge, this is the first case to report a detailed analysis of IgG and C3 deposits in the basement membrane of the placental villi by means of an immunofluorescence study. These findings could be related to a slight malfunction of the placenta that may explain the adverse neonatal effects.     

Human retroplacental sera inhibit the expression of class II major histocompatibility antigens

Since factor(s) present in human pregnancy sera may interfere with HLA-DR expression on antigen-presenting cells which could account for fetal immune tolerance, we decided to investigate HLA-DR expression on the human myeloid macrophage cell line U937 using the monoclonal antibody RF DR2 and flow cytometry. Following incubation of U937 cells with recombinant interferon gamma (rIFN gamma) and fetal calf serum, 76% of the cells were HLA-DR positive. In contrast, when U937 cells were incubated with retroplacental serum (RP) only 40% of them were positive for HLA-DR and the mean fluorescent intensity for the cell population was significantly diminished. By performing these experiments at 37 and at 4 degrees C we concluded that a factor or factors present in RP bind onto and mask class II major histocompatibility (MHC) antigen expression.     

Vascular endothelial growth factor expression is unaltered in placentae and myometrial resistance arteries from pre-eclamptic patients

BACKGROUND: The purpose of this study is to determine whether there is any difference for vascular endothelial growth factor expression in placentae and myometrial resistance arteries from control and pre-eclamptic patients to clarify the source of the increased total vascular endothelial growth factor in pre-eclampsia. METHODS: With placentae tissue samples and small pieces of myometrium from the controls (n=10) and pre-eclampsia patients (n=7), vascular endothelial growth factor immunohistochemistry and mRNA in situ hybridization were performed. We also measured the serum vascular endothelial growth factor levels by competitive enzyme immunoassay at the same time. RESULTS: Vascular endothelial growth factor was identified primarily in syncytiotrophoblast in placental tissue, and it was also identified in smooth muscle cells in the myometrium and perivascular smooth muscle in myometrial resistance arteries. However, there were no differences in vascular endothelial growth factor expression between the groups in the presence of elevated serum levels of total vascular endothelial growth factor in pre-eclamptic patients (median 18.2 ng/ml versus 4.9 ng/ml). CONCLUSION: This study suggests that the placenta and perivascular smooth muscle are not the origin of the increased total vascular endothelial growth factor in pre-eclampsia. To clearly understand the role of vascular endothelial growth factor in pre-eclampsia, further studies are required to determine the sites of increased vascular endothelial growth factor synthesis.     

Expression of HLA class I and class II antigens in human choriocarcinoma cell lines

Eight choriocarcinoma cell lines (6:gestational origin, 2:non-gestational origin) were studied by a radioimmune inhibition test using monoclonal antibodies for the expression of HLA class I and class II antigens. Levels of HLA class I antigens were very slight or nil. On the other hand, no HLA class II antigen was detected in any choriocarcinoma cell lines examined.     

Histopathological findings in placentae from patients with intra-uterine fetal death and anti-phospholipid antibodies

Anti-phospholipid antibodies are associated with first trimester abortions and late intra-uterine fetal death. The histopathology of 47 placentae from 45 women with intra-uterine fetal death, including 16 patients with anti-phospholipid antibodies, was studied in order to detect potential differences between placentae from women with and without these antibodies. Thirteen patients had systemic lupus erythematosus or lupus-like disease, including 6 women with anti-phospholipid antibodies. In placentae from patients with anti-phospholipid antibodies, a decrease in vasculo-syncytial membranes, fibrosis mainly in infarcted areas, hypovascular villi and thrombosis or infarction was seen significantly more often than in placentae from women without these antibodies. Of 17 placentae from 16 patients with anti-phospholipid antibodies, only 3 did not demonstrate signs of thrombosis or infarction. Thrombosis/infarction was significantly associated with a decrease in vasculo-syncytial membranes, fibrosis, hypovascular villi and an increase in syncytial knots. These findings are most likely to be the result of prolonged hypoxia due to thrombosis or infarction. It is concluded that thrombosis or infarctions are prominent features in placenta from patients with anti-phospholipid antibodies and intra-uterine fetal death. Consequently, antithrombotic treatment during pregnancy forms a rational approach in these patients.     

Local immunosuppression determined by class II HLA antigen expression in patients with preclinical cervical carcinoma.

Class II HLA antigen expression was investigated in biopsy material from patients with preclinical cervical carcinoma. Class II molecules were determined immunohistochemically by MoAb against HLA-DR antigens. A significant reduction of class II positive cells was established in the tumor tissue compared to the normal cervical epithelium. A correlation between the tumor progression and the inhibition of the class II antigen expression was found.     

Decreased expression of thioredoxin and glutaredoxin in placentae from pregnancies with pre-eclampsia and intrauterine growth restriction

Pre-eclampsia is one of the major contributors to perinatal morbidity. This study was performed to test a hypothesis which suggests that pre-eclampsia is associated with inadequate control by the thioredoxin system and other related reducing systems. Placental tissue from normal pregnancies (NC), severe pre-eclampsia with fetuses small for gestational age (SPE), mild pre-eclampsia with fetuses small for gestational age (MPE) and pregnancies with small fetuses for gestational age without any sign of pre-eclampsia (IUGR) was collected immediately after delivery. The mRNA levels for thioredoxin and glutaredoxin were determined using a solution hybridization method and the distribution of the proteins in a normal placenta was analysed by immunohistochemistry. Results showed that the thioredoxin mRNA level in the SPE group was decreased to one third of the level in the NC group. Also the IUGR group showed a significant decrease. The glutaredoxin mRNA level in the SPE group was one half of that seen in the NC group. There was significant correlation between the mRNA levels for thioredoxin and glutaredoxin, both in the normal and growth restricted pregnancies. We conclude that the thioredoxin and glutaredoxin reducing systems are affected in placenta from pregnancies with pre-eclampsia and/or growth restriction of fetuses, and that the decrease correlates to the severity of the condition.     

Analysis of HLA class I and II antigens composition in high-risk pregnancy

DESIGN: We have analyzed the frequency of HLA class I and II antigens in high-risk pregnancy. MATERIAL AND METHODS: Altogether, 22 gravida hospitalized at the Department of Pathology of Pregnancy and Labour, Pomeranian Medical University in Szczecin formed group I (PE) with 12 cases of preeclampsia and group II with 10 cases of the antiphospholipid syndrome (APS). The control group included 40 multigravida. Typing of HLA class I and II antigens was done using the two-stage microcytotoxic test (NIH) of Mittal. RESULTS: Antigen B35 was found more frequent in preeclampsia and antiphospholipid syndrome groups than in multigravida. Furthermore, a statistically significant difference in the frequency of homozygotes for the HLA-DR locus was noted between groups PE and APS on one hand, and controls on the other. CONCLUSIONS: Identical HLA-DR3, DR4 and DR5 antigens were found more frequently in preeclampsia, while identical DR4 and DR6 in the antiphospholipid syndrome.     

Dynamics of selected MHC class I and II molecule expression in the course of HPV positive CIN treatment with the use of human recombinant IFN-gamma

BACKGROUND: Studies consistently reveal downregulation of major histocompatibility complex (MHC)-I molecules or/and selective loss of individual MHC-I alleles and upregulation of MHC-II molecules in the areas of cervical intraepithelial neoplasia (CIN) and in cervical cancers. In vitro studies demonstrated the interferon-gamma (IFN-gamma) potential of MHC class I and II molecule upregulation followed by increased cytolytic response against some cervical cancer cell lines. AIM OF THE STUDY: In vivo assessment of the correlation between regression/persistence state of CIN and the IFN-gamma-induced changes in both class of selected MHC molecule expression. METHODS: Seventeen subjects with CIN I/CIN II associated with high-risk HPV infection underwent uniform IFN-gamma treatment (four intracervical injections over 2-day interval for a total dose of 6,000,000 IU). Immunohistochemical staining has been performed within cervical punch biopsy specimens with the use of monoclonal antibody reacting with HLA-DR, HLA-HC and HLA-Bw4, and the mean proportion of given molecules expressing keratinocytes was counted before, immediately after and 2 months after IFN-gamma treatment RESULTS: The analysis revealed a rapid and significant increase of the HLA-Bw4 proportion in response to IFN-gamma, persistent in the group of complete responders (with CIN clearance). No significant changes in the proportion of HLA-HC 10 positive cells in response to IFN-gamma administration was demonstrated, nor a significant increase in HLA-DR positivity; however, the transient trend towards increasing the proportion of HLA-DR immediately after treatment completion was observed. CONCLUSIONS: Upregulation of selected MHC class I allele expression, but not necessary MHC class II or heavy chain fragments of MHC-I, induced by IFN-gamma correlates with the resolution of cervical intraepithelial lesions and high-risk HPV DNA clearance in vivo.