Immune tolerance in pregnancy

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Immune tolerance in pregnancy or maternal immune tolerance is the immune tolerance shown towards the fetus and placenta during pregnancy. This tolerance counters the immune response that would normally result in the rejection of something foreign in the body, as can happen in cases of spontaneous abortion. [1] [2] It is studied within the field of reproductive immunology.

Contents

Mechanisms

Placental mechanisms

The placenta functions as an immunological barrier between the mother and the fetus. Placenta.svg
The placenta functions as an immunological barrier between the mother and the fetus.

The placenta 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 immunoglobulin G (IgG) to pass 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 cells 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 immunoglobulin M type, [7] 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 sensitization of mothers (usually of blood type O) to antigens in foods or bacteria that are homologous to A and B antigens. [8]

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. [9]

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. [10] 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. [10] 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).

Regulatory T cells also likely play a role. [11]

Also, a shift from cell-mediated immunity toward humoral immunity is believed to occur. [12]

Insufficient tolerance

Many cases of spontaneous abortion may be described in the same way as maternal transplant rejection, [2] 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. [15] 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. [15]

Infertility and miscarriage

Immunological responses could be the cause in many cases of infertility and miscarriage. Some immunological factors that contribute to infertility are reproductive autoimmune failure syndrome, the presence of antiphospholipid antibodies, and antinuclear antibodies.

Antiphospholipid antibodies are targeted toward the phospholipids of the cell membrane. Studies have shown that antibodies against phosphatidylserine, phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol and phosphatidylethanolamine target the pre-embryo. Antibodies against phosphatidylserine and phosphatidylethanolamine are against the trophoblast. [16] These phospholipids are essential in enabling 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. [16]

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 cells 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. [16] Both the presence of antiphospholipids 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. [16]

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. [17]

Increased infectious susceptibility

The increased immune tolerance is believed to be a major contributing factor to an increased susceptibility and severity of infections in pregnancy. [18] Pregnant women are more severely affected by, for example, influenza, hepatitis E, herpes simplex and malaria. [18] The evidence is more limited for coccidioidomycosis, measles, smallpox, and varicella. [18] Pregnancy does not appear to alter the protective effects of vaccination. [18]

Interspecific pregnancy

If the mechanisms of rejection-immunity of the fetus could be understood, it might lead to interspecific pregnancy, having, for example, pigs carry human fetuses to term as an alternative to a human surrogate mother. [19]

Related Research Articles

<span class="mw-page-title-main">Placenta</span> Organ that connects the fetus to the uterine wall

The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate maternal and fetal circulations, and is an important endocrine organ, producing hormones that regulate both maternal and fetal physiology during pregnancy. The placenta connects to the fetus via the umbilical cord, and on the opposite aspect to the maternal uterus in a species-dependent manner. In humans, a thin layer of maternal decidual (endometrial) tissue comes away with the placenta when it is expelled from the uterus following birth. Placentas are a defining characteristic of placental mammals, but are also found in marsupials and some non-mammals with varying levels of development.

<span class="mw-page-title-main">Pre-eclampsia</span> Hypertension occurring during pregnancy

Pre-eclampsia is a multi-system disorder specific to pregnancy, characterized by the onset of high blood pressure and often a significant amount of protein in the urine. When it arises, the condition begins after 20 weeks of pregnancy. In severe cases of the disease there may be red blood cell breakdown, a low blood platelet count, impaired liver function, kidney dysfunction, swelling, shortness of breath due to fluid in the lungs, or visual disturbances. Pre-eclampsia increases the risk of undesirable as well as lethal outcomes for both the mother and the fetus including preterm labor. If left untreated, it may result in seizures at which point it is known as eclampsia.

Rh disease is a type of hemolytic disease of the fetus and newborn (HDFN). HDFN due to anti-D antibodies is the proper and currently used name for this disease as the Rh blood group system actually has more than 50 antigens and not only the D-antigen. The term "Rh Disease" is commonly used to refer to HDFN due to anti-D antibodies, and prior to the discovery of anti-Rho(D) immune globulin, it was the most common type of HDFN. The disease ranges from mild to severe, and occurs in the second or subsequent pregnancies of Rh-D negative women when the biologic father is Rh-D positive.

<span class="mw-page-title-main">Gestational hypertension</span> Medical condition

Gestational hypertension or pregnancy-induced hypertension (PIH) is the development of new hypertension in a pregnant woman after 20 weeks' gestation without the presence of protein in the urine or other signs of pre-eclampsia. Gestational hypertension is defined as having a blood pressure greater than 140/90 on two occasions at least 6 hours apart.

<span class="mw-page-title-main">Trophoblast</span> Early embryonic structure that gives rise to the placenta

The trophoblast is the outer layer of cells of the blastocyst. Trophoblasts are present four days after fertilization in humans. They provide nutrients to the embryo and develop into a large part of the placenta. They form during the first stage of pregnancy and are the first cells to differentiate from the fertilized egg to become extraembryonic structures that do not directly contribute to the embryo. After blastulation, the trophoblast is contiguous with the ectoderm of the embryo and is referred to as the trophectoderm. After the first differentiation, the cells in the human embryo lose their totipotency because they can no longer form a trophoblast. They become pluripotent stem cells.

<span class="mw-page-title-main">Hemolytic disease of the newborn</span> Fetal and neonatal alloimmune blood condition

Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis fetalis, is an alloimmune condition that develops in a fetus at or around birth, when the IgG molecules produced by the mother pass through the placenta. Among these antibodies are some which attack antigens on the red blood cells in the fetal circulation, breaking down and destroying the cells. The fetus can develop reticulocytosis and anemia. The intensity of this fetal disease ranges from mild to very severe, and fetal death from heart failure can occur. When the disease is moderate or severe, many erythroblasts are present in the fetal blood, earning these forms of the disease the name erythroblastosis fetalis.

<span class="mw-page-title-main">Placental abruption</span> Medical condition

Placental abruption is when the placenta separates early from the uterus, in other words separates before childbirth. It occurs most commonly around 25 weeks of pregnancy. Symptoms may include vaginal bleeding, lower abdominal pain, and dangerously low blood pressure. Complications for the mother can include disseminated intravascular coagulopathy and kidney failure. Complications for the baby can include fetal distress, low birthweight, preterm delivery, and stillbirth.

<span class="mw-page-title-main">Complications of pregnancy</span> Medical condition

Complications of pregnancy are health problems that are related to, or arise during pregnancy. Complications that occur primarily during childbirth are termed obstetric labor complications, and problems that occur primarily after childbirth are termed puerperal disorders. While some complications improve or are fully resolved after pregnancy, some may lead to lasting effects, morbidity, or in the most severe cases, maternal or fetal mortality.

Rho(D) immune globulin (RhIG) is a medication used to prevent RhD isoimmunization in mothers who are RhD negative and to treat idiopathic thrombocytopenic purpura (ITP) in people who are Rh positive. It is often given both during and following pregnancy. It may also be used when RhD-negative people are given RhD-positive blood. It is given by injection into muscle or a vein. A single dose lasts 12 weeks. It is made from human blood plasma.

<span class="mw-page-title-main">Syncytiotrophoblast</span> Embryonic cell of the placental surface

Syncytiotrophoblast is the epithelial covering of the highly vascular embryonic placental villi, which invades the wall of the uterus to establish nutrient circulation between the embryo and the mother. It is a multinucleate, terminally differentiated syncytium, extending to 13 cm.

In ABO hemolytic disease of the newborn maternal IgG antibodies with specificity for the ABO blood group system pass through the placenta to the fetal circulation where they can cause hemolysis of fetal red blood cells which can lead to fetal anemia and HDN. In contrast to Rh disease, about half of the cases of ABO HDN occur in a firstborn baby and ABO HDN does not become more severe after further pregnancies.

Hemolytic disease of the newborn (anti-Rhc) can range from a mild to a severe disease. It is the third most common cause of severe HDN. Rh disease is the most common and hemolytic disease of the newborn (anti-Kell) is the second most common cause of severe HDN. It occurs more commonly in women who are Rh D negative.

The Eutherian Fetoembryonic Defense System(eu-FEDS) is a hypothetical model describing a method by which immune systems are capable of recognizing additional states of relatedness like "own species" such as is observed in maternal immune tolerance in pregnancy. The model includes descriptions of the proposed signaling mechanism and several proposed examples of exploitation of this signaling in disease states.

<span class="mw-page-title-main">Minor histocompatibility antigen</span>

Minor histocompatibility antigen are peptides presented on the cellular surface of donated organs that are known to give an immunological response in some organ transplants. They cause problems of rejection less frequently than those of the major histocompatibility complex (MHC). Minor histocompatibility antigens (MiHAs) are diverse, short segments of proteins and are referred to as peptides. These peptides are normally around 9-12 amino acids in length and are bound to both the major histocompatibility complex (MHC) class I and class II proteins. Peptide sequences can differ among individuals and these differences arise from SNPs in the coding region of genes, gene deletions, frameshift mutations, or insertions. About a third of the characterized MiHAs come from the Y chromosome. Prior to becoming a short peptide sequence, the proteins expressed by these polymorphic or diverse genes need to be digested in the proteasome into shorter peptides. These endogenous or self peptides are then transported into the endoplasmic reticulum with a peptide transporter pump called TAP where they encounter and bind to the MHC class I molecule. This contrasts with MHC class II molecules's antigens which are peptides derived from phagocytosis/endocytosis and molecular degradation of non-self entities' proteins, usually by antigen-presenting cells. MiHA antigens are either ubiquitously expressed in most tissue like skin and intestines or restrictively expressed in the immune cells.

Interspecific pregnancy is the pregnancy involving an embryo or fetus belonging to another species than the carrier. Strictly, it excludes the situation where the fetus is a hybrid of the carrier and another species, thereby excluding the possibility that the carrier is the biological mother of the offspring. Strictly, interspecific pregnancy is also distinguished from endoparasitism, where parasite offspring grow inside the organism of another species, not necessarily in the womb.

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. The concept has been used by fertility clinics to explain fertility problems, recurrent miscarriages and pregnancy complications observed when this state of immunological tolerance is not successfully achieved. Immunological therapy is a method for treating many cases of previously "unexplained infertility" or recurrent miscarriage.

Ashley Moffett, is a Professor in the Department of Pathology at the University of Cambridge specialising in Reproductive Immunology, and a fellow of King's College, Cambridge. She became a fellow of the Royal College of Obstetricians and Gynaecologists in 2015, and a fellow of the Academy of Medical Sciences in 2019.

Rh factor testing, also known as Rhesus factor testing, is the procedure of determining the rhesus D status of an individual.

An Intrauterine transfusion (IUT) is a procedure that provides blood to a fetus, most commonly through the umbilical cord. It is used in cases of severe fetal anemia, such as when fetal red blood cells are being destroyed by maternal antibodies. IUTs are performed by perinatologists at hospitals or specialized centers.

Extravillous trophoblasts(EVTs), are one form of differentiated trophoblast cells of the placenta. They are invasive mesenchymal cells which function to establish critical tissue connection in the developing placental-uterine interface. EVTs derive from progenitor cytotrophoblasts (CYTs), as does the other main trophoblast subtype, syncytiotrophoblast (SYN). They are sometimes called intermediate trophoblast.

References

  1. ↑ Williams, Zev (20 Sep 2012). "Inducing Tolerance to Pregnancy". New England Journal of Medicine. 367 (12): 1159–1161. doi:10.1056/NEJMcibr1207279. PMC   3644969 . PMID   22992082.
  2. 1 2 3 Clark DA, Chaput A, Tutton D (March 1986). "Active suppression of host-vs-graft reaction in pregnant mice. VII. Spontaneous abortion of allogeneic CBA/J x DBA/2 fetuses in the uterus of CBA/J mice correlates with deficient non-T suppressor cell activity". J. Immunol. 136 (5): 1668–75. doi: 10.4049/jimmunol.136.5.1668 . PMID   2936806. S2CID   22815679.
  3. ↑ "Placenta 'fools body's defences'". BBC News. 2007-11-10.
  4. 1 2 Page 31 to 32 in: Maternal-Fetal Medicine : Principles and Practice. Editor: Robert K. Creasy, Robert Resnik, Jay D. Iams. ISBN   978-0-7216-0004-8 Published: September 2003
  5. ↑ Mi S, Lee X, Li X, et al. (Feb 2000). "Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis". Nature. 403 (6771): 785–9. Bibcode:2000Natur.403..785M. doi:10.1038/35001608. PMID   10693809. S2CID   4367889.
  6. ↑ Luis P. Villarreal (Sep 2004). "Can Viruses Make Us Human?" (PDF). Proceedings of the American Philosophical Society. 148 (3): 314. Archived from the original (PDF) on 2005-03-02.
  7. ↑ Magnetic immunodiagnostic method for the demonstration of antibody/antigen complexes especially of blood groups Archived 2012-02-29 at the Wayback Machine Yves Barbreau, Olivier Boulet, Arnaud Boulet, Alexis Delanoe, Laurence Fauconnier, Fabien Herbert, Jean-Marc Pelosin, Laurent Soufflet. October 2009
  8. ↑ MSD manuals > Perinatal Anemia Last full review/revision Oct 2020
  9. ↑ Williams Z, Zepf D, Longtine J, et al. (March 2008). "Foreign fetal cells persist in the maternal circulation". Fertil. Steril. 91 (6): 2593–5. doi: 10.1016/j.fertnstert.2008.02.008 . PMID   18384774.
  10. 1 2 Clark GF, Dell A, Morris HR, Patankar MS, Easton RL (2001). "The species recognition system: a new corollary for the human fetoembryonic defense system hypothesis". Cells Tissues Organs (Print). 168 (1–2): 113–21. doi:10.1159/000016812. PMID   11114593. S2CID   22626737.
  11. ↑ Trowsdale J, Betz AG (March 2006). "Mother's little helpers: mechanisms of maternal-fetal tolerance". Nat. Immunol. 7 (3): 241–6. doi:10.1038/ni1317. PMID   16482172. S2CID   33530468.
  12. ↑ Jamieson DJ, Theiler RN, Rasmussen SA. Emerging infections and pregnancy. Emerg Infect Dis. 2006 Nov. Available from https://www.cdc.gov/ncidod/EID/vol12no11/06-0152.htm
  13. ↑ Robertson, Sarah. "Research Goals --> Role of seminal fluid signalling in the female reproductive tract". Archived from the original on 2012-03-29.
  14. ↑ Sarah A. Robertson; John J. Bromfield; Kelton P. Tremellen (August 2003). "Seminal 'priming' for protection from pre-eclampsia—a unifying hypothesis". Journal of Reproductive Immunology. 59 (2): 253–265. doi:10.1016/S0165-0378(03)00052-4. PMID   12896827.
  15. 1 2 Van Der Hoorn, M. L. P.; Lashley, E. E. L. O.; Bianchi, D. W.; Claas, F. H. J.; Schonkeren, C. M. C.; Scherjon, S. A. (Nov–Dec 2010). "Clinical and immunologic aspects of egg donation pregnancies: a systematic review". Human Reproduction Update. 16 (6): 704–12. doi: 10.1093/humupd/dmq017 . PMID   20543201.
  16. 1 2 3 4 Gronowski, Ann M (2004), Handbook of Clinical Laboratory Testing During Pregnancy, Humana Press, ISBN   978-1-58829-270-4
  17. ↑ Kaandorp, S. P.; Goddijn, M. T.; Van Der Post, J. A. M.; Hutten, B. A.; Verhoeve, H. R.; Hamulyák, K.; Mol, B. W.; Folkeringa, N.; Nahuis, M.; Papatsonis, D. N. M.; Büller, H. R.; Van Der Veen, F.; Middeldorp, S. (29 April 2010). "Aspirin plus Heparin or Aspirin Alone in Women with Recurrent Miscarriage". New England Journal of Medicine. 362 (17): 1586–1596. doi: 10.1056/NEJMoa1000641 . PMID   20335572.
  18. 1 2 3 4 Kourtis, Athena P.; Read, Jennifer S.; Jamieson, Denise J. (5 June 2014). "Pregnancy and Infection". New England Journal of Medicine. 370 (23): 2211–2218. doi:10.1056/NEJMra1213566. ISSN   0028-4793. PMC   4459512 . PMID   24897084.
  19. ↑ Darwin's children LeVay, Simon. (1997, October 14). from The Free Library. (1997). Retrieved March 06, 2009
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