Melissa And Abbey Rough Draft

bold textThe Mystery of the Immunity at the Maternal-Fetal Interface
By Melissa Campbell and Abbey Bruns

The fetus is a growing organism living inside the maternal body. It depends on its mother for nutrients, oxygen, and other things necessary for life. Since the fetus is composed of foreign tissues, the mother should be killing it (why, with what? introduce the interaction with the IMMUNE SYSTEM here.) (Maybe think about using a different word than killing, such as rejecting, attacking, etc.) How she is going to kill him? Instead(,?) the mother provides the strength the fetus needs to grow and develop into a beautiful baby. The mystery remains that although the fetus is not destroyed by the maternal immune system, this same immune system provides protection for the women(use for women or for the woman) against other foreign material such as bacteria, viruses, and parasites. (The paper seems to go on a tangent here that does not progress towards a thesis statement or signposting the rest of the paper, either move or remove these randomesque facts.) Try to explain a little bit more about the mother-child interaction In 1956 the first major paper (study) was published on maternal-fetal interface immunology. This paper study described several possible explanations for this great mystery of life (1). In 1979, the use of antibodies with fluoresce (fluorescent?) tags for y-chromatin was used to determine the sex of the fetus (2)Doesnt seem to go with your paper. Today, several scientists have development ed experiments to further explore the ideas first presented in 1956. Among those experiments proposed the following with will be discussed here (instead of here, maybe use-in this paper) : roles of major histocompability complexes (MHC), interactions with natural killer cells (NK cells), responses to T1 and T2 helper cells, function(s) of HLA-Gdefine, and several other mirror ?components.
During fetal development* as cells divide, move comma they become a structure known (-or- referred to) as a blastula which is surrounded by a layer of cells called a trophoblast. These trophoblast cells line the placenta which is the membranous vascular organ that develops during pregnancy connecting the fetus to its mother. It is comprised of chorionic villi which contain villous stroma and fetal capillaries (3). The apical surface of the placenta is in contact with the maternal blood and the basolateral surface is connected into the fetal circulation (3)The apical surface is of the placenta is continuous with the maternal circulatory system, while the basolateral surface is connected into fetal circulation. Across these two epithelial layers the exchange of nutrient nutrients and wastes between the fetus and the mother occur. These epithelial cells contain tight junction(s) and become dented with blood vessels reducing diffusion between maternal and fetal circulatory systems (4)unclear sentence Try to reword, remember your reader. The efficiency of development of both circulatory systems is dependent on vascular endothelial growth factor (VEGF). This homodimeric growth factor is important for both vasculogenesis (de novo formation of embryonic blood vessels) and angiogenesis (growth of blood vessels from pre-existing vasculature (4). Surprisingly, one family member of VEGF is tumor necrosis factor alpha (TNFα) which purpose (I think it sounds better if you were to delete purpose here) will be discussed later (5). (What is surprising about this?) Angiogenesis is also important for neoplasia (formation of new tissue) (6). Neoplasia activates matrix metalloproteases and suppression of the immune function *which also occur* delete in the placenta (6). Not only is angiogenesis important for fetal development, but lymphangiogenesis (growth of lymph vessels) in the decidua maintains fetal fluid balance helping it survive (5). The network of capillaries enhanced by VEGF may create a barrier between maternal and fetal blood (,?) increasing the survival of the fetus.
One reason the fetus is not rejected may be due to the barrier or buffer zone between the fetus and the mother created by the trophoblast (7). The trophoblast contains proteins that the mother’s immune system should recognize as foreign, but these proteins never enter the maternal-fetal interface which may provide some immunity (8). Proteins from fetal allograft (to be described later) that do escape the trophoblast protection do not contain MHC class I or MHC class II molecules (9). MHC class I molecules are usually attached to every foreign cell every foreign cell?? (invading microbes?)and are recognized by CD8+ T-helper cells which lead to cell death. MHC Class II molecules are recognized by CD4+ T-helper cells which recruit other antigen presenting cell (APC) (Do the CD4+ T cells recruit APC's, or do the cytokines?) causing the engulfment of foreign molecules in the body (This does not make sense to me…the MHC class II molecules should be presented on the APC's (i.e. DC's), on the MHC II molecules are peptides from an invading microbe that have been engulfed already, the activated CD4+ t cells would then lead to antibody production). Another immune cell type, Natural Killer (NK) cells, which usually destroy foreign material in the absence of MHC molecules, should destroy the fetus. This attack is prevented by HLA-G expression (to be described later) which only occurs during pregnancy (9).
Allograft is a term used to describe foreign tissue usually when discussing tissue transplants, but has also been used to describe fetal tissue. The idea of fetal allograft was first presented with tissue donor complications and with studies of cell transfers into parts of the body such as the spleen (10). These results showed that the tolerance to such foreign tissue were systemic in nature and led to further research on why fetal allograft was not rejected by the mother (10). Macrophages are involved in cell-mediated immunity, such as allograft rejection. Mechanisms that block macrophage adhesion will help stop the rejection of placenta (11). Macrophage production increases premenstrually in the decidua (the lining of the uterus shed during menstruation) which may be caused by estrogen production. This means that high levels of macrophages will be present during fetal development. Also it has been proposed that these macrophages produce cytokines (tumor necrosis factor alpha (TNF-α) and transforming growth factor beta (TGF-β), which are important for a successful pregnancy (12). I dont think it sounds right to have "to be described later" in this paper Some statements in this paper lends the paper to being more informal. For example "this means that" at the beginning of a sentence sounds a little out of place in a paper with this much detail and good content. Try to use more formal writing when introducing research facts.
TNF-α kills trophoblast cells which helps reduce the outgrowth of the placenta possibly saving it from maternal immune rejection. TGF-β inhibits proliferation and differentiation of the trophoblasts which also protects the fetus from destruction. Any interruption of this delicate balance of cytokines can increase the rate of proinflammatory cytokines which can activate early birth (12). Interlekin-1 (interleukin) (present in the placenta) works with TGF- β regulating the immune response which mediates the maternal-fetal interface (13). T regulatory (Treg) cells (what are Tregs?) seem to be important for the stability *of the* and presence of fetal allograft. Abortion-prone mice were implanted with Treg cells from normal pregnant mice and were then able to reproduce normally (14). The inhibition of indoleamine 2,3-dioxygenase (IDO) may also be associated with fetal allograft rejection. IDO is an enzyme that catabolizes tryptophan which is recognized by interferon-gamma (IL-γ) on certain macrophages. Once tryptophan is catabolizetense, *then* delete it inhibits T cell proliferation (15).
One of the major mysteries is the expression of MHC molecules especially HLA-G by fetal tissue. Early studies have indicated that trophoblasts do not express polymorphic class I antigens HLA-A and –B, but they do express HLA-G (16). HLA-G is a non-classical MHC class I molecule (So, the HLA-G resides in the cytoplasm?, and I dont know, but can MHC class I molecules be non-classical?) derived from HLA class Ib gene which is a placenta-derived glycoprotein (17). It is cell type specific and regulated by development (18). Usually HLA-G is expressed early on during the first trimester and by the third trimester production greatly decreases (19) Why this happens?. During pregnancy, different isoforms of this molecule circulate throughout the mother (20). High levels of HLA-G are present during pregnancy and are responsible for activating MHC class I inhibitory receptors (21). Also HLA-G has been described to inhibit the activity of NK cells and decidual macrophages reducing cytokine production (22). This prevents maternal immune cells from binding to receptors such as those found on the placental surface. Also(,) HLA-G peptides favor cell surface expression which can recruit another HLA class Ib molecule, HLA-E which stops ligand binding of all NK cells and most T-cells (23).
The rhesus macaque has been used as a model organism to evaluate the importance of HLA-G for maternal-fetal immunology (24). These monkeys make great (The macaques are ideal model organisms..) model organisms because their gestation period is 5 months which is similar to a human’s gestation period. (Should redo the previous sentence, I cant think of a better way to put it right now)Studies with rhesus macaque used Mamu-AGdefine ( used Mamu-AG, a protein similar to HLA-G, to show non-polymorphic...) which is similar to HLA-G to show that non-polymorphic class I molecules are a common feature of fetal tissue and are important for the establishment of the microenvironment in which the fetus is housed until birth (25). Also, it (define "it") was found to blocking NK cells and MHC cell action providing immunity for the fetus which (is) consistent with the previous information (25)unclear sentence.
Specialized NK cells called CD1d-restricted natural killer T (iNKT) cells interactions with CD1d expressed on fetal cells has been linked to maternal-fetal immunology (26). iNKT cells may function at least partly by differential cytokine expression. The expression of three cytokines (GM-CSF, IFN-y, and IL-4) has been examined. The production of GM-CSF seemed to correlate with successful pregnancy. The more GM-CSF produced, the more likely a successful fetus was produced. Also smaller amounts of GM-CSF reduced the number of iNKT present (26). These specialized NK cells that interact with trophoblast proteins are often called decidual NK cells because they are different than peripheral NK cells. Decidual NK cells do not polarize their microtubule organizing center and perform-containing granules to the synapse, which may account for their cytotoxicity (27). IFN-γ interacts with T-lymphocytes and recognizes viral and other intracellular pathogens. IL-4 plays an important role in differentiation of naïve T-cells Explain what important role.
Different types of T-cell interactions may be related to the acceptance of the fetus. Responses from type 1 T helper (Th1) cells support the generation of cellular cytotoxicity whereas responses from type 2 T helper (Th2) cells support the production of non-cytotoxic antibodies and suppress the activity of Th1. During pregnancy Th2 are dominate (dominant)compared to Th1 (28). Th1 cytokines such as TNF-α and IFN-γ seems to be needed for an effective pregnancy (29). In the experiment with gram-positive intracellular bacterium Listeria monocytogenes the recruitment of these cytokines reduced the colonization of this bacterium (29). L. monocytogenes is one of the few bacteria that can crosses the maternal-fetal interface and directly encounter the fetus. Both the production and the response to these cytokines were observed to be maternal. This suggests that both Th1 and Th2 cytokines are important for a successful pregnancy (29). Both CD4+ and CD8+T-cells respond to fetal tissue through indirect antigen presentation which means that the maternal APC (such as macrophages and dendritic cells) must uptake the fetal tissue first before the T-cells can interact with it (30). This is considered a minor allorecognition pathway which stops the potential destruction of the fetus. Also CD8+ T-cells go through clonal deletion antigens without the recruitment of cytokines when they recognize fetal/placenta and are not able to destroy fetal/placenta antigens even when artificially activated (30).
For T-cell activity to affect pregnancy, progesterone is a key componentreword. Progesterone, a steroid hormone, is needed for the formation of uterine stromal cells (31). The cytoplasm of these stromal cells contains lipids, glycogen, and vimentin-type intermediate filaments which may enable it to influence the implantation of the embryo to the uterus wall (32). Also, the corpus luteum helps with the production of progestogens, which are capable of producing the same effects as progesterone (33). Progesterone increases the survival rate of fetal allograph, modulates antibody production, reduces the oxidation of macrophages, decrease(s) inflammatory cytokines produced by macrophages, and favors the production of IL-10(an anti-inflammatory cytokine) (34). Receptors for progesterone regulate thymocyte development. When thymic stromal cells interact with progesterone, they use a porcine mechanism to stop the production of early T-cells. Early or naïve T-cells are deficient in producing INF-γ which recognizes intracellular pathogens (35). With the absence of these T-cells (such as Th1 which was discussed earlier), fetal allograph would not be recognized by the maternal T-cells providing some fetal immunity (36).
Several other minor components are important for the fetal microenvironment including polyamine oxidase, interleukin-2, transcription factor gene AP-2γ, and a family of B7 immunomodulatory molecules.
Another protective mechanism for maternal -fetal interface immunity is the presence of polyamine oxidase. One of the main things (reasons)(I wouldnt use "things") that make the fetus “foreign” is the paternal genetic information. This parental material expression is what the maternal immune cells recognize as non-self. Spermine is a polyamine compound located in ribosomes and isolated from sperm which would be heavily present in the placenta (37). not sure but doesnt make sense that sperm are present in the placenta Polyamine oxidase activity in the placenta is 20-30 times higher than polyamine oxidase activity in peripheral blood serum. It has been used to reduce the proliferation of spermine, which prevents the rejection of the fetus. (37).
Interleukin-2 blocks factors produced in the uterus which may aid in maternal-fetal immunity (8). Fetal white blood cells from the father become less sensitive to IL-2. On the other hand, fetal white blood cells from the mother are unaffected because they are recognized as “self” Why is it call "self"?. This explains why the trophoblasts do not contain any paternal antigens. In women who have had several (20+) miscarriages the addition of white blood cells from the father resulted in successful pregnancies (8).
Researchers indicates that the transcription factor gene AP-2 is required during embryonic development (38). This gene regulates programs controlling proliferation and differentiation of extraembryonic trophectodermal cells and it also helps regulate the adenosine deaminase (ADA) gene (38).
A group of proteins (B7-Dc, B7-H3, and B7-H2) are also suggested to be expressed at the maternal-fetal interface. B7-Dc, B7-H3, and B7-H2 are all presented throughout the gestation period but are positioned differently (39). Both B7-Dc and B7-H3 inhibit antigen stimulated lymphocyte activation while B7-H2 maintains regulatory capacity. Although positioned differently, all help to steer maternal leukocytes away protecting the fetus from maternal immune rejection (39).
Several different mechanisms and molecules contribute to the fetal microenvironment that provides it with immunity from the maternal immune system. If something were to stop any of the above mechanisms discussed, inflammatory cytokines would be release(d) and anywhere from a miscarriage to death of the fetus would occur same thing right?(40). A lot of research has been done on the role of HLA-G expression during pregnancy, expression of cytokines in the placenta especially dealing with trophoblast cells, and the effect of progesterone. Some still say that the precise reason for maternal-fetal immunology is a mystery. Suggestions have been made, but no one knows if one or all of these mechanisms make it possible for a foreign tissue (the fetus) to survive inside the mother.
Melissa and Abbey- You have an interesting topic. There are some parts that need to be reworded. Among all that you have good information, just in some parts is lacking explanation =b

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