The protection of the trophoblast from a cytotoxic attack may be understood in terms of either a tolerance by the maternal immune system to allopresence or the evasion of the trophoblast from detection by a fully operational immune system. This question has occupied reproductive scientists for many years and true until present, no clear consensus has emerged with respect to the precise answer. Currently, there is evidence to suggest that both mechanisms may contribute to the success of pregnancy. Herein we will briefly review elements that support the validity of those two theories. Experimental models have examined the question of maternal tolerance of the conceptus. It was found that the conceptus itself, represented by amnion or chorion when transplanted into the rat skin, survived for up to 14 days compared to a heterologous skin graft which lasted only 7 days before being rejected. In addition, the decidua (of maternal origin) survived the longest and actually contributed to the survival of the amnion and chorion when transplanted together. This indicates that the conceptus has the ability to blunt, albeit temporarily, the immune system of the intact animal, and further, that the maternal system, represented by the decidua, has a significant role in the enhancing this immune auto-tolerance. Therefore, these observations point to the additive role of the mother and conceptus in allograft survival , What remains rather surprising is the lack of immunologic consequence due to trophoblastic cells migration to the lung, a condition apparently unique to human pregnancies. These cells in the peripheral circulation neither stimulate an inflammatory response nor cause cellular lymphoid infiltration, which in general indicate an immune response to alloantigens. On the other hand, as we will discuss, extravillous trophoblasts express MHC type I antigens.
It is important to determine whether the specialized immune environment created during pregnancy results from a quantitative change in the amount of circulating lymphocytes or from contributions of various immunomodulatory factors. Studies have shown that there are no significant alterations in the relative presence of T and B lymphocytes or in the ratio of T helper/ suppressor cells in the blood and peripheral tissues. However, in the placenta, the inverse may be seen, with relatively more CD8+ cells than CD4+ cells. The number and activity of NK cells in the periphery is decreased, but no changes in their function are seen in the decidua, where the activity is less than half of that seen in the periphery .
Because no major quantitative changes in the lymphocyte population are present during pregnancy when compared to non pregnant women, one must explore any qualitative changes in the immune system that may contribute to the unique immune status. It is logical to assume that the observed phenomena are a result of specific immunomodulatory products of fetal origin and intricate interactions within the maternal immune system. The basis for a cytotoxic attack depends upon the histocompatibility of the foreign agent and the response of the maternal host - whether the immune system recognizes it as self or nonself. This discrimination requires the recognition of glycoprotein transplantation antigens on the cell surface, in particular, major histocompatibility complex (MHC) antigens. These include both the monomorphic class I MHCs and the polymorphic class II MHCs which are expressed on B-cells, macrophages, and other gamma-interferon treated immunocompetent cells . Human placental villous trophoblasts do not express class I or class II histocompatibility antigens (HLA-A, B, and DR), B2 microglobulin, or H-Y antigens, whereas trophoblasts of the extravillous type may express certain class I MHC antigens. On the other hand, hCG is expressed by the villous trophoblast while it is not expressed by the extravillous trophoblast. These major differences in antigen expression between the two trophoblastic types and locations contribute to the limited trophoblast invasivity at the extravillous site as well as to the lack of immune recognition by maternal lymphocytes in the villous trophoblast, thereby creating the necessary balance between invasion and containment.
Studies of human syncitiotrophoblast plasma membranes indicate that monoclonal antibodies and heteroantisera do recognize trophoblast determinants. However, the trophoblast may also express viral antigens that go undetected by the immune system. The existence of a special HLA-G type, a truncated type MHC, may contribute to the recognition of the trophoblast as "self"  and protect against NK cells. Unlike the class II MHCs, HLA-G functions as a class I MHC antigen, exhibiting limited polymorphism. This characteristic protects the paternally-derived HLA-G genes from recognition by the immune system as foreign and may restrict the extent of peptide antigen presentation to maternal T cells , Trophoblast cells are also protected from NK mediated lysis by their lack of NK target structures on their surface . Another antigen present on sync-tiotrophoblasts is the trophoblast-lymphocyte cross-reactive antigen (TLX). There has been a lot of controversy regarding the exact nature and significance of this interaction. This unique trophoblast alloanti-genic system is similar but unrelated to HLA antigens. TLX appears to be a part of an allelic antigen system that differs from the previously defined histocompatibility systems. The detection of TLX antigens on the trophoblast cell surface by the maternal immune system may stimulate the production of protective factors such as blocking antibodies that may aid in successful implantation . A typical response in normal pregnancy is the production of blocking factors that inhibit mixed lymphocyte culture. Some of these blocking antibodies may be TLX specific, leading to the possibility that TLX antigens are functioning similarly to transplantation antigens and elicit a protective maternal immune response that protects the developing placenta. In this capacity, the CD46+ antigen may be involved in allowing the interaction of non-self disparate cells, thus allowing sperm egg interaction and implantation of the blastocyst to the endometrium
. Immune reactions may be created through raising of monoclonal antibodies (Mabs) against trophoblasts, suggesting that trophoblasts are not immunologically silent. Mabs have been raised against a variety of trophoblastic components in an effort to characterize the immunohistochemical nature of trophoblast populations and to search for trophoblast-specific molecules
Other research indicates that surface antigens on mouse trophoblasts may be masked by an inert sialo-mucin coating that is immunologically inert, however, this has not yet been proven . Trophoblast derived IFNs may also be a regulator of their own cell-surface antigen expression. IFNs cause an increase in both the expression and shedding of surface antigens . Trophoblast IFNs may also contribute to local immunosuppression by stimulating the secretion of suppresor cells that further aid in immunoregulation . This occurs at the feto-placental interface, resulting in the production of cytokines that enable the embryo to implant and protect the fetus. In vitro studies of IFN-b has shown the suppression of mitogen-induced proliferation on human T and B lymphocytes, lending evidence to the theory that trophoblast I FN induced immunosuppression causes fetal protection against cellular immune response. The maternal immune response and endocrine system cooperate in the maintenance of this cytokine system that protects both the trophoblast and prevents the rejection of the fetus.
The placenta secretes a variety of placenta-specific materials including both proteins and steroid hormones. The placental proteins have a qualitative effect as exhibited by the actions of hCG. hCG acts to inhibit phytohemaglutinin-induced lymphocyte transformation, inhibit mixed lymphocyte culture reaction, and stimulate immunoglobulin synthesis by pokeweed mitogen- activated blood mononuclear cells. In addition to hCG, other large proteins PAPP-A, SP-1, and human placental lactogen (HPL) have been shown to inhibit complement-induced hemolysis, inhibit PHA induced lymphocyte formation, and inhibit mixed lymphocyte culture reaction. The role of PP14 as inhibitor of interleukin 1 has also been suggested . PAPP-A may have a significant effect as an immunosuppressive factor. It has been shown to be produced by normal trophoblast cell cultures and to be greatly reduced in choriocarcinoma cell lines. Trophoblastic fluid from cell cultures of first-trimester human placentas generate suppressor lymphocytes and may contribute to the immunologic tolerance of the fetal allograft .
Early pregnancy factor (EPF) may also be an important immunosuppressant although it remains until present poorly defined. In a study by Clark , an immunosuppressive material, embryo-associated suppressor factor (EASF), was detected that may correlate with successful implantation. EASF appears to have a direct effect on both T and B cell proliferation, suppression stemming from binding to specific lymphocyte receptors after mitogenic stimulation . In another study, EPF was shown by the rosette-inhibition test to be directly involved in the maintenance of the fetal allograft. EPF may be produced either by the ovary or the placenta in response to a signal from the conceptus and circulating levels in the preimplantation period may indicate the presence of a viable embryo . Because EPF is present in both pregnant and nonpregnant states, its exact role in pregnancy remains elusive.
For the past few years we have explored a novel phenomenon, preimplantation factor (PIF) that is only present in pregnancy and which may have an important role in initiating alio- tolerance in mammals. This is a specific embryonal signal that reflects embryonal viability [21- 22], It is detected shortly after fertilization both in vivo and in embryo cultures and disappears from the circulation when pregnancy fails, weeks before hCG levels start declining , We have identified PIF as being, most likely, a novel oligopeptide. We believe that this factor is capable of modulating the immune system since it is currently detected by the lymphocyte- platelet binding assay (LPBA) using CD2 antibody which specifically binds T lymphocytes as well as NK cells . Currently, we are aiming to examine the role of this factor by generating antibodies against it and testing whether such antibodies are capable of interfering with pregnancy development, thus establishing its critical role in reproduction. PIF may be an embryonal signal that allows for the initiation of pregnancy. Therefore, a generalized embryo derived signal may be required to initiate the immunological activation that allows for implantation to take place and pregnancy to be successful. In this context, the uterus is a privileged site which however requires involvment of a viable embryo to create a truly accomodating environment.
There is also an immunosuppressive response from the effect of placental sex steriods and corticosteroids. Both estrogens and progesterone display evidence of this response. Progesterone is capable of inhibiting PHA-induced lymphocyte transformation or mixed lymphocyte culture reaction and may induce the expression of a lymphocyte blocking factor as well as inhibiting Concanavalin-A stimulated thymidine incorporation by lymphocytes. Progesterone's immunosuppressive properties have been demonstrated both in vivo and in vitro on cell-mediated immune responses, indicating that it may decrease IL-1 action, a stimulator of hCG release , and depress lymphocyte -monocyte interactions. Estrogens may also enhance the ability of monocytes to phagocytise IgG-coated red blood cells. Blood levels of free corticosteroids are increased in pregnancy and may contribute to the amelioration of several autoimmune conditions such as rheumatoid arthritis. These combined immunosuppressive effects may aid the success of joining the fetus as a homograft to the maternal host ,
The placenta also expresses regulatory molecules such as growth factors. Receptors for the growth factors, epidermal growth factor (EGF), insulin and insulin-like growth factors (IGF-I and IGF-II) exist on the syncitiotrophoblast surface of the placenta. A receptor for platelet-derived growth factor (PDGF) may also exist on cytotrophoblasts. The EGF receptor serves to bind both EGF and TGF-a. ,
Suppression of the immune response to the tro-phoblast surface antigens may be due in part to the production of anti-idiotypic antibodies during pregnancy that negate the effects of anti-HLA antibodies ,
Immunoglobulin receptors are present in the placenta and are critical for the passage of maternal IgG across the placenta. In addition, large immunoglobulins are not allowed to pass into the fetus, and antipaternal HLA antibodies are selectively removed in the placental sink. Anti-HLA antibodies injected into mice do not attach to the trophoblast, but they do attach to stromal cells and endothelium. Some other anti-HLA antibodies which are not directed against paternal antigens do not pass through the placental barrier, confirming its selectivity. However, leukocytes do pass the placenta in both directions, demonstrating that the placenta is not a true barrier for lymphocytes and, therefore, allowing in certain cases very large molecules passage ,
Overall, there is evidence that both tolerance, through maternal involvement in pregnancy maintenance and the minimization of the maternal immune response through masking, and evasion are operative throughout pregnancy in a carefully balanced fashion. The alteration of any of those, as seen in clinical situations, leads to the rejection of the conceptus. For instance, patients with autoimmune conditions but normal trophoblast will frequently have a pregnancy loss. Similarly, the presence of a normal maternal environment but defective trophoblast (like a chromosomal abnormality) will result in an equally unfavorable outcome.
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