Immune tolerance in pregnancy
Encyclopedia
Immune tolerance
in pregnancy
or gestational/maternal immune tolerance is the absence of a maternal immune response against the fetus
and placenta
, which thus may be viewed as unusually successful allografts, since they genetically differ from the mother. In the same way, many cases of spontaneous abortion may be described in the same way as maternal transplant rejection
. It is studied within the field of reproductive immunology
.
functions as an immunological barrier between the mother and the fetus, creating an immunologically privileged site
. For this purpose, it uses several mechanisms:
Still, the placenta does allow maternal IgG antibodies to pass from to the fetus to protect it against infections. However, these antibodies do not target fetal cells, unless any fetal material has escaped across the placenta where it can come in contact with maternal B cell
s and make those B cells start to produce antibodies against fetal targets. The mother does produce antibodies against foreign ABO blood types, where the fetal blood cells are possible targets, but these preformed antibodies are usually of the IgM type, and therefore usually do not cross the placenta. Still, rarely, ABO incompatibility can give rise to IgG antibodies that cross the placenta, and are caused by sentitization of mothers (usually of blood type 0) to antigens in foods or bacteria.
In any case, the placenta does not block maternal IgG antibodies, which thereby may pass through the human placenta, providing immune protection to the fetus against infectious diseases.
One model for the induction of tolerance during the very early stages of pregnancy is the Eutherian Fetoembryonic Defense System (eu-FEDS) hypothesis. The basic premise of the eu-FEDS hypothesis is that both soluble and cell surface associated glycoproteins, present in the reproductive system and expressed on gametes, suppress any potential immune responses, and inhibit rejection of the fetus. The eu-FEDS model further suggests that specific carbohydrate
sequences (oligosaccharides) are covalently linked to these immunosuppressive glycoproteins and act as “functional groups” that suppress the immune response. The major uterine and fetal glycoproteins that are associated with the eu-FEDS model in the human include alpha-fetoprotein
, CA125, and glycodelin-A (also known as placental protein 14 (PP14)).
Regulatory T cell
s also likely play a role.
Also, a shift from cell-mediated immunity
toward humoral immunity
is believed to occur.
, and a chronic insufficient tolerance may cause infertility
. Other examples of insufficient immune tolerance in pregnancy are Rh disease
and pre-eclampsia
:
Pregnancies resulting from egg donation, where the carrier is less genetically similar to the fetus than a biological mother, are associated with a higher incidence of pregnancy-induced hypertension
and placental pathology. The local and systemic immunologic changes are also more pronounced than in normal pregnancies, so it has been suggested that the higher frequency of some conditions in egg donation may be caused by reduced immune tolerance from the mother.
Anti-phospholipid antibodies are targeted toward the phospholipids of the cell membrane. Studies have shown that antibodies against phosphatidylserine, phoshphatidylcholine, phosphatidylglycerol, phosphatidylinositol and phosphatidylethanolamine target the pre-embryo. Antibodies against phosphatidylserine and phosphatidylethanolamine are against the trophoblast. These phospholipids are essential in the aiding the cells of the fetus to remain attached to the cells of the uterus with implantation. If a female has antibodies against these phospholipids, they will be destroyed through the immune response and ultimately the fetus will not be able to remain bound to the uterus. These antibodies also jeopardize the health of the uterus by altering the blood flow
to the uterus.
Antinuclear antibodies cause an inflammation in the uterus that does not allow it to be a suitable host for implantation of the embryo. Natural killer cell
s misinterpret the fetal cells as cancer cells
and attack them. An individual that presents with reproductive autoimmune failure syndrome has unexplained infertility, endometriosis
, and repetitive miscarriages due to elevated levels of antinuclear antibodies circulating. Both the presence of anti-phospholipids antibodies and antinuclear antibodies have toxic effects on the implantation of embryos. This does not apply to anti-thyroid antibodies. Elevated levels do not have a toxic effect
, but they are indicative of a risk of miscarriage. Elevated anti-thyroid antibodies act as a marker for females who have T-lymphocyte dysfunction because these levels indicate T cells that are secreting high levels of cytokines that induce inflammation in the uterine wall.
Still, there is currently no drug that has evidence of preventing miscarriage by inhibition of maternal immune responses; aspirin has no effect in this case.
and listeriosis and may increase severity of illness and increase mortality rates from influenza
and varicella.
Immune tolerance
Immune tolerance or immunological tolerance is the process by which the immune system does not attack an antigen. It can be either 'natural' or 'self tolerance', in which the body does not mount an immune response to self antigens, or 'induced tolerance', in which tolerance to external antigens can...
in pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
or gestational/maternal immune tolerance is the absence of a maternal immune response against the fetus
Fetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
and placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
, which thus may be viewed as unusually successful allografts, since they genetically differ from the mother. In the same way, many cases of spontaneous abortion may be described in the same way as maternal transplant rejection
Transplant rejection
Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after...
. It is studied within the field of reproductive immunology
Reproductive immunology
Reproductive immunology refers to a field of medicine that studies interactions between the immune system and components related to the reproductive system, such as maternal immune tolerance towards the fetus, or immunological interactions across the blood-testis barrier...
.
Placental mechanisms
The placentaPlacenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
functions as an immunological barrier between the mother and the fetus, creating an immunologically privileged site
Immune privilege
Immune privilege is a term used to describe certain sites in the body which are able to tolerate the introduction of antigen without eliciting an inflammatory immune response. Tissue grafts are normally recognised as foreign antigen by the body and attacked by the immune system...
. For this purpose, it uses several mechanisms:
- It secretes Neurokinin BNeurokinin BNeurokinin B is a tachykinin peptide.It is found in higher concentration in pregnant women suffering pre-eclampsia and can bind the immune-cloaking molecule phosphocholine....
containing phosphocholinePhosphocholinePhosphocholine is an intermediate in the synthesis of phosphatidylcholine in tissues. Phosphocholine is made in a reaction, catalyzed by choline kinase, that converts ATP + Choline into Phosphocholine and ADP...
molecules. This is the same mechanism used by parasitic nematodeNematodeThe nematodes or roundworms are the most diverse phylum of pseudocoelomates, and one of the most diverse of all animals. Nematode species are very difficult to distinguish; over 28,000 have been described, of which over 16,000 are parasitic. It has been estimated that the total number of nematode...
s to avoid detection by the immune system of their hostHost (biology)In biology, a host is an organism that harbors a parasite, or a mutual or commensal symbiont, typically providing nourishment and shelter. In botany, a host plant is one that supplies food resources and substrate for certain insects or other fauna...
. - Also, there is presence of small lymphocytic suppressor cells in the fetus that inhibit maternal cytotoxic T cellCytotoxic T cellA cytotoxic T cell belongs to a sub-group of T lymphocytes that are capable of inducing the death of infected somatic or tumor cells; they kill cells that are infected with viruses , or are otherwise damaged or...
s by inhibiting the response to interleukin 2Interleukin 2Interleukin-2 is an interleukin, a type of cytokine immune system signaling molecule, which is a leukocytotrophic hormone that is instrumental in the body's natural response to microbial infection and in discriminating between foreign and self...
. - The placental trophoblast cells do not express the classical MHC class IMHC class IMHC class I molecules are one of two primary classes of major histocompatibility complex molecules and are found on every nucleated cell of the body...
isotypes HLA-AHLA-AHLA-A are a group of human leukocyte antigens that are encoded by the HLA-A locus on human chromosome 6p. The HLA genes constitute a large subset of the Major histocompatibility complex of humans. HLA-A is a component of certain MHC class I cell surface receptor isoforms that resides on the...
and HLA-BHLA-BHLA-B is a human gene that provides instructions for making a protein that plays a critical role in the immune system. HLA-B is part of a family of genes called the human leukocyte antigen complex...
, unlike most other cells in the body, and this absence is assumed to prevent destruction by maternal cytotoxic T cellCytotoxic T cellA cytotoxic T cell belongs to a sub-group of T lymphocytes that are capable of inducing the death of infected somatic or tumor cells; they kill cells that are infected with viruses , or are otherwise damaged or...
s, which otherwise would recognize the fetal HLA-A and HLA-B molecules as foreign. On the other hand, they do express the atypical MHC class IMHC class IMHC class I molecules are one of two primary classes of major histocompatibility complex molecules and are found on every nucleated cell of the body...
isotypes HLA-E and HLA-GHLA-GHLA-G histocompatibility antigen, class I, G, also known as human leukocyte antigen G , is a protein that in humans is encoded by the HLA-G gene....
, which is assumed to prevent destruction by maternal NK cells, which otherwise destruct cells that do not express any MHC class IMHC class IMHC class I molecules are one of two primary classes of major histocompatibility complex molecules and are found on every nucleated cell of the body...
. However, trophoblast cells do express the rather typical HLA-CHLA-CHLA-C belongs to the MHC class I heavy chain receptors. The C receptor is a heterodimer consisting of a HLA-C mature gene product and β2-microglobulin. The mature C chain is anchored in the membrane...
. - It forms a syncytiumSyncytiumIn biology, a syncytium is a large cell-like structure; filled with cytoplasm and containing many nuclei. Most cells in eukaryotic organisms have a single nucleus; syncytia are specialized forms used by various organisms.The term may also refer to cells that are connected by specialized membrane...
without any extracellular spaces between cells in order to limit the exchange of migratory immune cells between the developing embryo and the body of the mother (something an epitheliumEpitheliumEpithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
will not do sufficiently, as certain blood cells are specialized to be able to insert themselves between adjacent epithelial cells). The fusion of the cells is apparently caused by viral fusion proteins from endosymbiotic endogenous retrovirus (ERV). An immunoevasive action was the initial normal behavior of the viral protein, in order to avail for the virus to spread to other cells by simply merging them with the infected one. It is believed that the ancestors of modern viviparousViviparyVivipary has two different meanings. In animals, it means development of the embryo inside the body of the mother, eventually leading to live birth, as opposed to laying eggs...
mammals evolved after an infection by this virus, enabling the fetus to better resist the immune system of the mother.
Still, the placenta does allow maternal IgG antibodies to pass from to the fetus to protect it against infections. However, these antibodies do not target fetal cells, unless any fetal material has escaped across the placenta where it can come in contact with maternal B cell
B cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
s and make those B cells start to produce antibodies against fetal targets. The mother does produce antibodies against foreign ABO blood types, where the fetal blood cells are possible targets, but these preformed antibodies are usually of the IgM type, and therefore usually do not cross the placenta. Still, rarely, ABO incompatibility can give rise to IgG antibodies that cross the placenta, and are caused by sentitization of mothers (usually of blood type 0) to antigens in foods or bacteria.
Other mechanisms
Still, the placental barrier is not the sole means to evade the immune system, as foreign fetal cells also persist in the maternal circulation, on the other side of the placental barrier.In any case, the placenta does not block maternal IgG antibodies, which thereby may pass through the human placenta, providing immune protection to the fetus against infectious diseases.
One model for the induction of tolerance during the very early stages of pregnancy is the Eutherian Fetoembryonic Defense System (eu-FEDS) hypothesis. The basic premise of the eu-FEDS hypothesis is that both soluble and cell surface associated glycoproteins, present in the reproductive system and expressed on gametes, suppress any potential immune responses, and inhibit rejection of the fetus. The eu-FEDS model further suggests that specific carbohydrate
Carbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...
sequences (oligosaccharides) are covalently linked to these immunosuppressive glycoproteins and act as “functional groups” that suppress the immune response. The major uterine and fetal glycoproteins that are associated with the eu-FEDS model in the human include alpha-fetoprotein
Alpha-fetoprotein
Alpha-fetoprotein is a protein that in humans is encoded by the AFP gene....
, CA125, and glycodelin-A (also known as placental protein 14 (PP14)).
Regulatory T cell
Regulatory T cell
Regulatory T cells , sometimes known as suppressor T cells, are a specialized subpopulation of T cells which suppresses activation of the immune system and thereby maintains tolerance to self-antigens. The existence of regulatory T cells was the subject of significant controversy among...
s also likely play a role.
Also, a shift from cell-mediated immunity
Cell-mediated immunity
Cell-mediated immunity is an immune response that does not involve antibodies but rather involves the activation of macrophages, natural killer cells , antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen...
toward humoral immunity
Humoral immunity
The Humoral Immune Response is the aspect of immunity that is mediated by secreted antibodies produced in the cells of the B lymphocyte lineage . B Cells transform into plasma cells which secrete antibodies...
is believed to occur.
Insufficient tolerance
Many cases of spontaneous abortion may be described in the same way as maternal transplant rejectionTransplant rejection
Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after...
, and a chronic insufficient tolerance may cause infertility
Infertility
Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...
. Other examples of insufficient immune tolerance in pregnancy are Rh disease
Rh disease
Rh disease is one of the causes of hemolytic disease of the newborn...
and pre-eclampsia
Pre-eclampsia
Pre-eclampsia or preeclampsia is a medical condition in which hypertension arises in pregnancy in association with significant amounts of protein in the urine....
:
- Rh diseaseRh diseaseRh disease is one of the causes of hemolytic disease of the newborn...
is caused by the mother producing antibodiesAntibodyAn antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
(including IgG antibodies) against the Rhesus DRhesus blood group systemThe Rh blood group system is one of thirty current human blood group systems. Clinically, it is the most important blood group system after ABO. At Present, the Rh blood group system consists of 50 defined blood-group antigens, among which the 5 antigens D, C, c, E, and e are the most important...
antigenAntigenAn antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
on her baby's red blood cellRed blood cellRed blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
s. It occurs if the mother is Rh negative and the baby is Rh positive, and a small amount of Rh positive blood from any previous pregnancy has entered the mother's circulation to make her produce IgG antibodies against the D antigen (Anti-D). Maternal IgG is able to pass through the placentaPlacentaThe placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
into the fetusFetusA fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
and if the level of it is sufficient, it will cause destruction of D positive fetal red blood cells leading to development of Hemolytic Disease of the Fetal-Newborn (HDFN) Rh disease. Generally HDFN becomes worse with each additional Rh incompatible pregnancy.
- One cause of pre-eclampsiaPre-eclampsiaPre-eclampsia or preeclampsia is a medical condition in which hypertension arises in pregnancy in association with significant amounts of protein in the urine....
is an abnormal immune response towards the placenta. There is substantial evidence for exposure to partner's semen as prevention for pre-eclampsia, largely due to the absorption of several immune modulating factors present in seminal fluid.
Pregnancies resulting from egg donation, where the carrier is less genetically similar to the fetus than a biological mother, are associated with a higher incidence of pregnancy-induced hypertension
Pregnancy-induced hypertension
Gestational hypertension or pregnancy-induced hypertension is defined as the development of new arterial hypertension in a pregnant woman after 20 weeks gestation without the presence of protein in the urine.-Conditions:...
and placental pathology. The local and systemic immunologic changes are also more pronounced than in normal pregnancies, so it has been suggested that the higher frequency of some conditions in egg donation may be caused by reduced immune tolerance from the mother.
Infertility and miscarriage
Immunological responses could be the cause in many cases of infertility and miscarriage. Some immunological reasons that contribute to infertility are reproductive autoimmune failure syndrome, the presence of anti-phospholipid antibodies, and antinuclear antibodies.Anti-phospholipid antibodies are targeted toward the phospholipids of the cell membrane. Studies have shown that antibodies against phosphatidylserine, phoshphatidylcholine, phosphatidylglycerol, phosphatidylinositol and phosphatidylethanolamine target the pre-embryo. Antibodies against phosphatidylserine and phosphatidylethanolamine are against the trophoblast. These phospholipids are essential in the aiding the cells of the fetus to remain attached to the cells of the uterus with implantation. If a female has antibodies against these phospholipids, they will be destroyed through the immune response and ultimately the fetus will not be able to remain bound to the uterus. These antibodies also jeopardize the health of the uterus by altering the blood flow
Blood flow
Blood flow is the continuous running of blood in the cardiovascular system.The human body is made up of several processes all carrying out various functions. We have the gastrointestinal system which aids the digestion and the absorption of food...
to the uterus.
Antinuclear antibodies cause an inflammation in the uterus that does not allow it to be a suitable host for implantation of the embryo. Natural killer cell
Natural killer cell
Natural killer cells are a type of cytotoxic lymphocyte that constitute a major component of the innate immune system. NK cells play a major role in the rejection of tumors and cells infected by viruses...
s misinterpret the fetal cells as cancer cells
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
and attack them. An individual that presents with reproductive autoimmune failure syndrome has unexplained infertility, endometriosis
Endometriosis
Endometriosis is a gynecological medical condition in which cells from the lining of the uterus appear and flourish outside the uterine cavity, most commonly on the ovaries. The uterine cavity is lined by endometrial cells, which are under the influence of female hormones...
, and repetitive miscarriages due to elevated levels of antinuclear antibodies circulating. Both the presence of anti-phospholipids antibodies and antinuclear antibodies have toxic effects on the implantation of embryos. This does not apply to anti-thyroid antibodies. Elevated levels do not have a toxic effect
Toxicity
Toxicity is the degree to which a substance can damage a living or non-living organisms. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver...
, but they are indicative of a risk of miscarriage. Elevated anti-thyroid antibodies act as a marker for females who have T-lymphocyte dysfunction because these levels indicate T cells that are secreting high levels of cytokines that induce inflammation in the uterine wall.
Still, there is currently no drug that has evidence of preventing miscarriage by inhibition of maternal immune responses; aspirin has no effect in this case.
Increased infectious susceptibility
The immunologic changes in pregnancy alters the susceptibility to and severity of infectious diseases. For example, pregnancy may increase susceptibility to toxoplasmosisToxoplasmosis
Toxoplasmosis is a parasitic disease caused by the protozoan Toxoplasma gondii. The parasite infects most genera of warm-blooded animals, including humans, but the primary host is the felid family. Animals are infected by eating infected meat, by ingestion of feces of a cat that has itself...
and listeriosis and may increase severity of illness and increase mortality rates from influenza
Influenza
Influenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals...
and varicella.