IFN-γ Facilitates Release of Class II-Loaded Intracellular Pools in Trophoblast Cells: A Novel Property Independent of Protein Synthesis (original) (raw)
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Journal of Experimental Medicine
The acceptance of the fetal allograft in the face of a completely competent maternal immune system remains a perplexing and critical problem in transplantation immunology . Varieties of potential mechanisms by which the fetus could avoid rejection have been proposed by Medawar (1) and by Billingham , and these proposals set the stage for much of the work in this field. The mechanisms proposed to prevent immune destruction of the fetus by the mother have postulated roles for blocking antibodies, immunosuppressive antibody-antigen complexes, nonimmunoglobulin immunosuppressive molecules, suppressor cells, and selective maternal immunoincompetence (reviewed in references 3-8). Many of these arguments turn on the question of what type of transplantation antigens encoded by the MHC are present in the placenta. Class I antigens have been demonstrated in the placenta of the mouse (9-13), human (14-21), and rat (22-24) using alloantisera and mAbs. Other studies in the human showed that the placenta also carries unique class I, or class I-like, antigens, the TLX antigens (25, 26), and class I molecules that carry only broadly crossreactive public antigenic determinants . Class II antigens are absent from the placenta in both the mouse (9, 28) and the human 29) .
Analysis of the IFN-γ-induced signal transduction pathway in fetal rejection
Mediators of Inflammation, 1995
The placenta, one of the most important fetal tissues during gestation, ensures nutrition, development and protection of the fetus. Although placenta lacks expression of class II MHC antigens, they can be induced either by interferon-gamma (IFN-γ) on the spongiotrophoblast zone, or by 5-azacytidine (5-azaC) on the labyrinthine trophoblast zone, two agents actively participating in a plethora of immunological and inflammatory reactions. This induction is correlated with fetal abortion and fetal developmental abnormalities. In this work thein vitroandin vivosignal transduction pathways followed by IFN-γ or 5-azaC to induce class H antigen expression on placental cells by using specific pathway inhibitors has been studied. It is shown that at least three intracellular pathways are implicated in the Ia induction, p21rasis the first protein activated by the two agents while further signalling requires Ca2+mobilization and PKC activations. When thein vitroresults are transferred to live a...
MHC class II expression and antigen presentation by human endometrial cells
The Journal of Steroid Biochemistry and Molecular Biology, 2001
It has been demonstrated previously that mixed cell suspensions from the female reproductive tract consisting of human epithelial and stromal cells were capable of presenting foreign antigen to autologous T cells. There have been, however, no reported studies examining antigen presentation by isolated epithelial cells from the human female reproductive tract. It is now shown that freshly isolated epithelial cells from the uterine endometrium constitutively express MHC class II antigen and that class II was upregulated on cultured epithelium by interferon gamma (IFNg). Using a highly purified preparation, it was demonstrated that these epithelial cells were able to process and present tetanus toxoid recall antigen driving autologous T cell proliferation. Cells isolated from the basolateral sub-epithelium stroma were also potent antigen presenting cells in this model system. Thus, isolated endometrial epithelial cells were able to directly process and present antigen to T cells and may be responsible for the transcytosis and delivery of antigen to professional antigen presenting cells found in the sub-epithelial stroma.
Reproduction, 2001
The mammalian fetus is potentially at risk from maternal immune attack because it can express paternally inherited polymorphic antigens, including those encoded by the major histocompatibility complex (MHC). The aim of this study was to investigate in more detail MHC class I upregulation by binucleate trophoblast cells in the bovine placenta. A method was developed to isolate binucleate cells by enzymatic disaggregation and density gradient centrifugation of bovine placental cotyledons. In cytospin preparations, 25-30% of purified binucleate cells stained positively with antibodies that recognize bovine MHC class I. The same antibodies were used to immunoprecipitate radiolabelled class I molecules from lysates of binucleate cells and fetal peripheral blood mononuclear cells. The protein species isolated from the two types of cell were similar in size and degree of glycosylation. PCR amplification of cDNA generated from binucleate cells and subsequent sequence analysis demonstrated t...
Production of Embryotoxic IgG Antibodies During IFN-γ Treatment of Pregnant Mice
American Journal of Reproductive Immunology, 1996
bodies during IFN-y treatment of pregnant mice. AJRI 1996; 36:111-117 @ Munksgaard, Copenhagen PROBLEM: Administration of IFN-y during pregnancy in mice is deleterious not only to fetal survival but also to maternal physiology. Thus, injection of recombinant IFN-y from days 6-1 1 of gestation results in significant increase of fetal abortion, decrease of fetal weight accompanied by morphological defects of the embryo, and induction of class I1 MHC antigens on the spongiotrophoblast zone of the placenta. At the maternal level, this treatment causes splenomegaly, decrease of hematocrit levels, and increase of IgG production. In an attempt to dissect out the different phenomena observed, we examined the properties of polyclonal IgG antibodies contained in the animals' serum as to their ability to recognize antigenic determinants on IFN-y-induced placentae and isolated trophoblasts. METHOD: Serum from IFN-y-treated pregnant mice was tested in vitro for its ability to recognize specific structures on primary trophoblasts and placental sections induced by IFNy. In vivo this serum was injected in pregnant mice, and the outcome of pregnancy was evaluated. Monoclonal antibodies, resulting from the fusion of spleen cells from IFN-y-treated pregnant mice to a myeloma cell line, were used to certify the IgG-dependent embryotoxic effects observed with the polyclonal serum. RESULTS: It was demonstrated that both the polyclonal serum and the monoclonal antibodies recognize antigenic determinants only on the IFN-y-induced trophoblasts, placentae, and embryos, reduce fetal size, and cause splenomegaly in the mother, but do not affect the percentage of abortions as compared to controls. CONCLUSIONS: IFN-y induces specific protein(s) on trophoblasts, which are responsible for embryotoxic antibody production in the mother. Since human abortion has been correlated with the production of embryotoxic IgG antibodies, this animal model may prove to be a useful tool in the analysis of events leading to pregnancy loss.
Mouse oocytes and preimplantation embryos bear the two sub-units of interferon-gamma receptor
Molecular Reproduction and Development, 2001
Cytokines and growth factors play important roles in implantation and maintenance of pregnancy, but also during early development. Among them interferon-gamma (IFNg) is highly expressed by mammalian trophoblast cells during implantation and seems to be involved in some cases of pregnancy loss. In the present study we investigated the possible presence of IFNg receptors (IFNGR) on mouse oocytes and preimplantation embryos. The two receptor chains IFNgRa (IFNGR-1) and IFNgRb (IFNGR-2) have been detected by indirect immunofluorescence at the surface of mouse oocytes (in germinal vesicle and metaphase II stages), as well as at all stages of in vitro embryo development from the one-cell to blastocyst stage. IFNGR appeared to colocalize partly with ganglioside GM1 at the cell surface of oocytes and embryos, indicating a possible preferential localization of this receptor in``rafts'' microdomains. This was analyzed in more detail using software developed in the laboratory. IFNg was found to bind to its receptor at all stages analyzed. RT-PCR and Southern blot experiments confirmed the presence of the transcriptionally regulated IFNGR-2 chain mRNA, in mouse oocytes and preimplantation embryos. These results show, for the first time, that mouse oocytes and preimplantation embryos bear a complete and theoretically functional IFNGR, suggesting that this cytokine could play a role during early development.
American Journal of Reproductive Immunology, 1997
IFN-receptors in human first trimester and term placental tissues and on isolated trophoblast c~c~l l s. AJRl 1997; 37:443-448 0 Munksgaard, Copenhagen PROBLEM: Type-I interferon (IFN) is the protein recognizing pregnancy in ruminants. Although IFN is secreted in early pregnancy, its role is not still clear in other species. Like other cytokines, IFN exerts its biological functions through specific membrane receptors. We have investigated the potential action of IFN in human pregnancy by studying the distribution of the receptors in the human placenta. METHOD: Reactivity to monoclonal antibodies (mAbs) to the type-I IFN-receptor (R) was analyzed by immunohistochemistry in human placental tissues and in cytospins of first trimester trophoblast cells. RESULTS: Type-I IFN-R immunoreactivity was observed mostly in first trimester villous cytotrophoblasts and in the cytotrophoblast cell columns. Trophoblast in the decidua, the epithelium of the uterine glands, and most of the isolated trophoblast cells were also immunoreactive. CONCLUSION: The expression of type-I IFN-R in the highly proliferating and migrating trophoblast suggests that this cytokine has a role in trophoblast growth and invasion. The production of IFN by the trophoblast cells, although detectable throughout ges
American Journal of Reproductive Immunology, 1999
S. Monoclonal antibodies aguinst maternal rnajor histocompatibility coniplex class I molecules induce rupid abortion in mice. AJRI 1999; 41:217-223 0 Munksgaard, Copenhagen PROBLEM: The role of antibodies against fetal or maternal antigens in maintaining or losing pregnancy is not clear. METHOD OF STUDY: Term-pregnant mice were injected with monoclonal antibodies against only fetal or fetal and maternal major histocompatibility complex class I molecules. The development of pregnancy was then followed. RESULTS: Antibodies against maternal, but not fetal, major histocompatibility complex class I molecules induced abortion in mice. The abortion occurred 6-8 hr after the administration of autoreactive antibodies. The abortion could only be induced after the formation of placenta. Antibodies against tumor necrosis factor-a could not prevent or postpone the abortion. Extensive bleeding has been detected in the placenta of aborting mice 3 hr after the administration of the antibodies. CONCLUSIONS: This study indicates that autoreactive antibodies present risk for pregnancy and that the damage leading to abortion induced by such antibodies most likely occurs at the maternal side of placenta.