MATERNAL IMMUNE TOLERANCE INDUCTION MECHANISMS
Maternal immune tolerance refers to the case where the fetus is contained safe in the mother’s body despite of immunological reactions that can occur as a result of the fetus having a different genetical composition from that of the mother which can lead to it being recognized as a foreign substance by the mother’s immune system there by triggering reactions that can eliminate the fetus. Immunological reactions occurs when the body senses presence of a foreign substance in the body system and these reactions involves activation of white blood cell (leukocytes) which in turn attack the detected foreign substance to destroy it. The immune system consists of different types of cells such as T lymphocytes and B lymphocytes and works in synergy with complement system that provides chemokines such as interleukins to regulate it activities during the process of eliminating the detected antigen (foreign substance). This paper looks at the various ways in which maternal immune tolerance to the fetus is induced in body of a mother carrying a fetus.
Specialized Fetal Tissue and Cells Role
The fetus tissue exhibits the major histocompatibity complexes (MHC) class I and II which are molecules capable of presenting the fetus as a foreign material to the immune system of the mother for it eliminated (Friedman, A.1988, 37). During pregnancy period, the placenta which is a group of similar tissues joining the developing fetus to the uterine wall of the mother acts as protective barrier against immune reactions from the mother’s body that can harm the fetus. There are several mechanisms that enable the fetus to avoid harmful immunological reactions from the mother body and the mechanism can either involve elimination of locally stimulated maternal white blood cells or blocking of pathways that can facilitate destruction of the fetus by white blood cells in the immune system of the mother.
The fetus possess some specialized tissues that synthesize, enzymes which prevents development of lymphocytes and an example of such enzyme is Indole-amine Pyrrole2, 3-dioxygenase. This has the function of eliminating and preventing synthesis of Tryptophan amino acid, which stimulates growth of effectors T cells, which can invade the fetus to eliminate it (Creasy, K. and Resnik, R. 2003, 31-33).
Human fetus cells also contains some lymphatic cells that suppresses production of a cell signaling protein called Interleukin-2 (IL-2) that has the function of controlling T cell activities and absence of this signaling protein results to the safety of the fetus since T cells will not be able to detect the fetus( Mosier, D.1975, 175) .
Crry and CD95L Protein Role
In mice, a compliment regulator protein called Crry (complement receptor-related gene Y) plays a significant role in preventing elimination of mice fetus since its presence inhibits stimulation of the immune system of the mouse and thus providing safety to the fetus. Crry protein regulator blocks synthesis of C3 which is a protein molecule responsible for stimulating the complement system of the immune system of the mother and therefore absence of C3 component serves as means of enabling the maternal body to tolerate the fetus ( Robertson, A. 2010, 35 ).
Another way in which human and mice fetus escapes destruction by the immune reactions in the maternal system is by manifesting a cluster of differentiation receptor (CD95L), also known as FAS receptor or apoptosis antigen. The CD95L occurs as a protein molecule on the surface of mice and human fetal cells and its presence causes automatic death of stimulated T cells that can kill the fetus (Mattson, R. 1998, 383).
Mattson, R. (1998, 383) explains that mice that lack functional CD95L due to natural mutation spontaneously aborts its fetus since the activated lymphocyte cells detect it as an antigen there by attacking and killing it.
Human Leukocytes Antigen A and B
Another way which prevents the fetus from being reacted upon by the immune reaction of the mother’s body is by it lacking major histocompatibility class 1 isotopes called Human Leukocyte Antigens A and B (HLA-and HLA B), which are molecules with the function of presenting protein chains of small length (antigen) to the immune system. Absence of these isotopes in the placenta tissue is very significant for the safety of the fetus in human maternal body since it protects it from being damaged by the cytotoxic T cells from the mother. Interestingly, the placenta tissue exhibits the human leukocyte antigen E and G which protects the fetus from being invaded by the Natural Killer cells of immune system from the mother (Sakaguchi, S. 2004, 531-536).
T helper 1 and T helper 2 Regulation
During pregnancy, the walls of uterus(and later placenta) releases a chemical factor called leukemia inhibitor which is said to help in initiating a suppressed localized immune environment for the safety of the fetus by maintaining a balance between T helper 1 and T helper 2 cells. He further states that pre-eclampsia which is a health disorder of pregnancy characterized by high blood pressure and high amounts of protein and which leads to natural induced elimination of the fetus from the mother’s is caused by imbalanced amounts of Th1 and Th2 cells where the Th2 prevails in large amounts than the Th1cells.Pre-eclasmpsia disorder reduces the amount of blood flowing to the uterus which in turn affects the growth of the fetus and also separation of placenta and uterus walls resulting to spontaneous expulsion of the uterus(Nelson,J.2012,426-427).
Uterine Natural Killer cells
The Natural Killer (uNK) cells of the inner lining of the uterus also play a role of maintaining safety of the fetus in the maternal body. Friedman explains that the walls of a uterus carrying a fetus is dominated by numerous Unk cells that are of non-cytotoxic CD56 and CD16- phenotype that prevent invasion of the human and mice fetus by the maternal immune reactions. He further states that lack of physiological change of the uterine spiral arteries by the uNK cells can cause preeclampsia in humans (Nelson, J.2012, 428).
Regulatory T cells
Regulatory T cells consist of several cells of immune system such as CD4+, CD25+ and foxp3+ cells. The T regulatory cells plays a significant role in maternal fetal immune tolerance both in human and mice .The T regulatory cells creates a safe maternal environment for the fetus by manifesting IL-10, TGF-β and haem oxygenase isoform 1 (HO-1) which acts as stimulated macrophages that release anti-inflammatory cytokines that prevents injuries that can result from inflammation reactions from several white blood such as CD4 and CD8 T cells, B cells, and NK cells (Nelson, J.2012, 421-423). The T regulatory cells number rises throughout the period of pregnancy and they also they ensure that the fetus is not destroyed by maternal effectors T cells by blocking them from reaching the fetus in the uterine.
The FOXP3 cell which is referred as scurfin is a protein molecule that has a role of regulating development and activities of T regulatory cells when they are performing their crucial role of stopping the immune reactions. Zhao, Z. (2007, 211-218) states that experiments have shown that lack of T regulatory cells in humans and in mice lead to spontaneous elimination of the fetus from maternal body since the immune reactions occurs uncontrollably which also results to body attacking its own tissues. Zhao also explains that T regulatory cell absence can cause preeclampsia since the number of suppressor cells such as CD4+ and CD 25+ are reduced in the blood flowing and also in the placental tissue and this can lead to active immune cells harming the fetus and causing it removal from the body. He states that women who have low levels of T regulatory cells in the peripheral blood flow usually experience premature birth of their fetus.
Role of Seminal fluid in synthesis of T regulatory cells
Seminal fluid is also known as semen and it refers to the fluid secreted by the human man male sexual gland and it consists of spermatozoa, fructose and proteolytic enzyme among other enzymes. Seminal fluid is a potential source of agents such as TGFβ and prostaglandin E which plays a significant role in activating development of T regulatory cells. Robertson states that in mice, the sexual activity initiates an order of actions in which female dendritic cells cross-present seminal fluid antigens and activates T cells which then flow through the blood to be available in the walls of the uterus. He argues that same actions can take place human genital tract during which seminal fluid initiates immune cell alterations that lead to generation of T regulatory cells (Robertson, A. 2010, 6).
Trowsdale, J. and Betz, A. (2006, 243) explains that studies have shown that there is increase in the number of CD4+CD25+ T cell population in the para-aortic lymph nodes (LNs) that drain the uterus during the period by which mating takes place and when the embryo attaches to the uterine wall and he adds that this is determined by the exposure of female to seminal fluid factors during ejaculation process. They also adds that seminal fluid activates generation of FOXP3+ which in turn control the activities of T regulatory cells which are important in maintenance of consistent attachment of fetus to the uterine wall.
T 17 cells Regulation
Results from various experiments indicate that T helper 17 cells are capable of detecting the fetus as an antigen thus initiating immune reactions in the mother’s body that can lead to elimination of the fetus from the body of the mother. The inflammatory effects caused by T helper 17 cells are removed by uterine natural killer cells which secrete IFN-γ CD56bright and CD27+ which neutralizes the inflammatory effects (Friedman, A. 1988, 35).
Preeclampsia is pregnancy disease that is seen in pregnant women and it is symbolized by presence of excess proteins in urine and rising of the blood pressure to abnormal levels. Women with this disorder usually have symptoms such as swelling of legs and hands. This disorder commonly manifests itself during the second trimester of pregnancy but it can occur earlier. Preeclampsia prevails in 3-5% of pregnancies and it can lead to spontaneous abortion of the fetus and it also causes slow growth of inner walls of uterus during pregnancy which results to unsuccessful implantation. Preeclampsia cannot be treated and can be a risk to mother and as Friedman explains it is caused by several factors which include abnormal formation and development, alteration in biology of the placenta, the systemic inflammatory reactions, presence of several hormones and other proteins that are in the mother’s circulation, changes in immune factors, improper cardiovascular adaptations to the pregnant state, underlying maternal risks for cardiovascular disease, associations with insulin resistance and diabetes, and deficiencies in essential nutrients, minerals, and vitamins(Starkey,P.1993, 367-368).
On the other hand, rhesus factor disease which is also known as the Hemolytic Disease of the Newborn occurs as a result of the mother generating antibodies that react against the rhesus D antigen on the surface of the baby’s red blood cells and this happens if the mother is Rhesus negative and the baby is Rhesus positive and if there exist traces of Rhesus positive antibodies in the blood of the mother from any previous pregnancy since these antibodies will be able to move from the mother’s circulation into the fetus circulation through placenta. Presence of these antibodies in the circulation system of the fetus will lead to the Rhesus D antigen on the surface the fetal red blood cell being detected as a foreign material whereby immunological reactions will take place destroying the fetal blood cells (Robertson, A. 2010, 4)
Several mechanisms of pregnancy immune tolerance are carried out by the placenta despite the truth that it is not the only barrier to immune reactions. Foreign fetal cells have the ability of moving through the placenta and are present in the mother’s circulatory system. As it have been discussed above, the fetus is able to evade dangerous immunological reactions occurring in the mother’s system using various ways such increased number of T regulatory cells which suppress stimulated effector T cells, presence of chemokines such as Indole-amine Pyrrole2, 3-dioxygenase and leukemia inhibitor which blocks development of immune cells and also by the fetal cells presenting protein molecule such as CD95L which causes programmed death of activated immune system cells to stop them from killing the fetus. Despite being a protective barrier from harmful reactions and antigens that may be present in the mother’s circulation system, the placenta also permits maternal IgG antibodies into the fetus to prevent it against infection (Creasy, K. and Resnik, R. 2003, 36). In the first three months of pregnancy, the gametes and the reproductive system exhibits cell surface and soluble glycoprotein’s that suppress any immune response that may come up and protects the fetus from being rejected. The above discussed mechanisms ensure that the mother’s immune reactions do not react to the fetus and these mechanisms are confined within the uterus ensuring that the mother is also not affected.
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