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The main contact between the mother and her growing foetus is the placenta and it acts as the vertical transmission of immunity and infection.
During sexual intercourse, the sperm from the father and the ovum from a mother, which are haploid cells, fuse together to form a diploid zygote. This develops into a blastocyst, containing an inner mass, the embryoblast and an outer mass, the trophoplast, which goes on to form the placenta.
This is the stage at which the blastocyst is able to attach itself to the wall of the uterus. The blastocyst is only able to adhere to the uterus wall when in the appropriate stage of the menstrual cycle. This refers to when the endometrium has thickened sufficiently and a large number of blood vessels and capillaries are available for the blastocyst to stick to. The menstrual cycle also controls steroid hormones oestrogen and progesterone, secreted by the corpus luteum, which in turn determine the state of the endometrium.
The blastocyst then usually secretes a protein called human chronic gonadotrophin (hCG) once it is attached to the uterus wall. The purpose of this protein is to prevent the disintegration of the corpus luteum of the ovary and maintain the progesterone production which is critical for pregnancy. The protein hCG travels through the maternal blood circulation and further thickens the uterus wall, ensuring a large amount of oxygen and nutrients are available to the growing embryo.
After the blastocyst successfully implants into the uterus wall, the corpus luteum continues to secrete hormones until the placenta is fully formed, at approximately three months. The duration of pregnancy is broken down into three periods called trimesters. The corpus luteum stops secreting hormones at approximately the end of the first trimester and the foetus continues to develop into a fully formed organism through the second and third trimesters until birth.
The process by which the mother's ovum is fertilised and implanted into the uterus wall through to birth is countered by several important obstacles, the first one being the uptake of the semi-allergenic blastocyst. However, from an immunological aspect, the maternal immune system should be able to recognise this as being non-self and an immune response is normally triggered to ensure it is exterminated from the body.
The major histocompatibility complex (MHC) is a large genomic region found in most vertebrates. It happens to be the most gene-dense region of the mammalian genome and plays a pivotal role in the immune system, autoimmunity and reproduction. The proteins encoded by MHC are expressed on the surface of cells and presents both self and non-self antigens to a form of white blood cell, called a T cell. The MHC activates an immune response by encoding glycoprotein's that go on to bind to antigens and presenting them to these T-lymphocytes. These T cells have the ability to kill or to pathogens which are infected. MHC is split into two main groups: class I and class II. MHC class I genes are shown on the surface of all somatic cells which are nucleated. They function by binding viral and cancer infected peptides.
MHC class I genes can be separated into 'classical' and 'non-classical' types. The peptides are presented from the mammal's pathogens to the T-cells in the classical type and they operate as ligands for inhibitory receptors on NK cells (natural killer) and other leukocytes. MHC class I non-classical genes are less distinguishable on the cells. The functions of these products produced by these genes involve acting as a ligand for inhibitory leukocyte receptors.
MHC class II genes are expressed on antigen-presented cells such as B cells and macrophages. Their main function is to monitor the extracellular environment and present peptides, such as bacteria, to the T cells. The trophoblast cells present non-classical MHC class I proteins and it inhibits the activation of leukocytes in the uterus and helps protect the embryo and foetus from being rejected.
MHC class II genes are primarily expressed on antigen-presenting cells of the immune system such as B cells and macrophages. They are more involved in the monitoring of the extracellular environment by presenting peptides obtained from parasites to the T-cells e.g. bacteria. Expression of non-classical MHC class I proteins by trophoblast cells is believed to inhibit the activation of leukocytes in the uterus and help protect the foetus from rejection
The newly formed zygote would contain a region on the genome which would code the major histocompatibility complex and it would be derived from both the mother and the father. The antigens from the father will be displayed on the cell surface, which are immunologically different from the mothers and therefore the maternal immune system - more specifically the T cells - would recognise it as non-self or foreign. The T cells would activate, proliferate and act to eradicate the supposed threat if it is presented with what the body recognises as the semi-allogenic foetus and its corresponding cytokine, which would signal the to the T cell the site at which the infection was recognised, ultimately causing an immune response resulting in the elimination of the blastocyst and preventing its development.
Cytokines, which are regulatory protein molecules produced by nucleated cells in the body, constitute to the function of the autocrine and paracrine. Studies have shown that cytokines maintain the pregnancy by regulating the immune system and during early pregnancy, the placental tissues and the conceptus produce cytokines, such as interferon's (INF) and interleukins (IL). Cytokines main function in terms of pregnancy is to ensure the foetus is not rejected and counter-acted against by the mother's immune system.
T cells are specialised immune cells that can recognise foreign cells and subsequently eradicate them via cytotoxic means of activity. T cells are separated into subclasses with each having their own cytotoxic profiles, TH1 and TH2 cells. The TH1 cells are related to delayed-type hypersensitivity reactions and the TH2 cells involves antibody responses. The study also found that the maintenance of a TH2 cytokine environment, especially the production of IL-4, IL-5, IL-6, IL-10 and IL-13, appeared to be vital for successful pregnancy. Other studies have contradicted this and suggested that the TH1 cytokine environment is just as essential as a TH2 cytokine environment.
A histocompatibility antigen encoded in the foetal MHC, human leukocyte antigen-G (HLA-G), is defined as a non-classical class I antigen. This antigen prevents the blastocyst from being eliminated and is usually expressed on its cell surface.
The antigen HLA-G can also be associated with tumour and disease cells, due to its ability to mask cells from any form of immunological attack. The mechanism by which HLA-G performs its function is by binding to the inhibitory receptors on the T lymphocytes. This antigen aids the development of the blastocyst, after binding to these inhibitory receptors, as it would no longer be seen as non-self or a foreign body meaning that the maternal immune system would not act to eliminate it.
The placenta acts as an important part of the maternal immune system by protecting the mammalian foetus and embryo, including the transfer of antibody Immunoglobulin G (IgG). This antibody is a monomeric immunoglobulin, comprising of two heavy chains and two light chains. Each IgG molecule has two antigen-binding sites. These immunoglobulins can bind to various pathogens including viruses and bacteria. The purpose of transferring these antibodies from the mother to her foetus is to provide it with some form of immunity against pathogens while it develops its own immune system. There are four subclasses of IgG, named IgG1, IgG2, IgG3 and IgG4. Apart from IgG2, all other isotypes of Immunoglobulin G are able to cross the placenta into the foetus. The reason behind this refers to the fact that IgG2 has an extremely low affinity of binding to the Fc receptor on phagocytic cells. The structure of the IgG molecule is shown on the left (Figure 1.1).
Figure 1.1 - Structure of IgG molecule
This period of immunity which is "passed down" to the foetus occurs during approximately the first four months of pregnancy, prior to the foetus developing its own immune system. The "transfer period", which occurs around month four of pregnancy, is the point at which the IgG count in the foetus is at its lowest levels, as the maternal IgG are no longer being supplied and the foetal IgG are being created. This is the point at which the foetus is most susceptible and vulnerable to infection. IgG is the only immunoglobulin to cross the placenta due to its versatility in opposing infection by complement activation and by its long half-life in serum (approximately 23 days).
Figure 1.2 - Graph showing the varying levels of antibody classes in newborn before and after birth.
The placental syncytiotrophoblasts, multinucleated cells forming the outer syncytial layer of the trophoblasts, uses the Fc receptor molecules to assist the facilitation of the IgG antibodies. FcRn (a specific Fc receptor) is a class I MHC receptor and they must bind to an IgG molecule in the CH-2 and CH-3 region in order to facilitate the immunoglobulin molecule into the foetus. FcRn also prolongs the half-life of the IgG molecule, bind to it at pH 6 and releases it at ph 7.4.
Uterine natural killer (uNK) cells are found in the uterus and these cells undergo phenotypic transformation as gestation progresses. They characteristically present an absence of catalytic activity. These cells are proliferated and differentiated by Decidual stromal cell derived IL-15.
uNK cells make up the major lymphocyte population at implantation sites, constituting approximately 30-90% of the total number of cells during the first trimester. The numbers of cells decrease during the second trimester. These cells produce the necessary cytokines for the implantation of the trophoblast, in this case IFN-Î³.
After birth, mothers are also able to pass immunity on to the infant through the maternal colostrum. This is the milk produced by the mammary glands during late pregnancy and a few days after birth. Colostrum is a very-concentrated milk form which is rich in nutrients. It also contains transforming growth factor-Î² (TGF-Î²) which helps the newborn develop their individual immune system, in particular the development of IgA.
There are mechanisms which protect the embryo and foetus from the maternal immune system but as well as immunity being passed down from the mother, infections could also easily be transmitted. For example, HIV can be transmitted to an infant from a HIV-positive mother. It is usually transmitted during the latter stages of pregnancy, the labour period and breast feeding. The placenta has a role of a 'barrier', whereby it stops the mother's blood from entering the foetus during the first two trimesters. Labour contractions induce the micro-infusions of the mother's blood into the placenta making the foetus susceptible to the virus.
The foetus can receive other infections from the mother such as herpes simplex and gonorrhoea, which are a few types of sexually transmitted diseases the mother could have obtained.
Pregnancy on the whole is a very complex and unique process that occurs in mammals. A lot of studies and evidence has been collected both for and against the reason behind why the maternal immune system does not trigger a response to eradicate the foetus. These studies looked for mechanisms by the way in which the embryo and foetus inside a mother's womb is protected. Most of the studies studied the hormones involved and the mechanisms occurring in and around the foetus. Major histocompatibility complex (MHC) is a plays an important role in pregnancy as it expresses two different types of genes and experiences changes to ensure the maintenance of pregnancy.
HLA-G is an important gene which experiences some of the changes made by the MHC and mainly operates in sustaining the pregnancy by inhibiting the functions of the immune cells.
The placenta is a barrier between the foetus and the mother and ensures that the mother's blood cannot be infused into the growing foetus. Another function of the placenta is to facilitate the transfer of IgG molecules to support the foetuses immune system, especially during the first trimester before the transfer period. Cytokines are also vital in ensuring the well-being of the foetus as it modulates the immune system and the associated cells. Studies have shown that it main function is to regulate and balance the uterus' environment between TH1 and TH2 at certain stages, so that the foetus can continue to grow. uNK cells aid the way cytokines function by protecting the uterus and demonstrating its main method of action.
There are several mechanisms that protect a foetus and embryo from being eliminated or destroyed as a result of the maternal immune system. The mechanisms discussed give a reliable insight into the different stages by which the foetus is protected to ensure its survival in the mother's womb.