Surrogacy

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Surrogacy 

Intended parents attend the birth of their child by a gestational surrogate.

Surrogacy is an arrangement, often supported by a legal agreement, whereby a woman agrees to delivery/labour on behalf of another couple or person, who will become the child's parent(s) after birth. People may seek a surrogacy arrangement when a couple do not wish to carry a pregnancy themselves, when pregnancy is medically impossible, when pregnancy risks are dangerous for the intended mother, or when a single man or a male couple wish to have a child.

In surrogacy arrangements, monetary compensation may or may not be involved. Receiving money for the arrangement is known as commercial surrogacy. The legality and cost of surrogacy varies widely between jurisdictions, sometimes resulting in problematic international or interstate surrogacy arrangements. Couples seeking a surrogacy arrangement in a country where it is banned sometimes travel to a jurisdiction that permits it. In some countries, surrogacy is legal only if money is not exchanged.

Where commercial surrogacy is legal, couples may use the help of third-party agencies to assist in the process of surrogacy by finding a surrogate and arranging a surrogacy contract with her. These agencies often screen surrogates' psychological and other medical tests to ensure the best chance of healthy gestation and delivery. They also usually facilitate all legal matters concerning the intended parents and the surrogate.

Methods

Surrogacy may be either traditional or gestational, which are differentiated by the genetic origin of the egg. Gestational surrogacy tends to be more common than traditional surrogacy and is considered less legally complex.

Traditional surrogacy

A traditional surrogacy (also known as partial, natural, or straight surrogacy) is one where the surrogate's egg is fertilised by the intended father's or a donor's sperm.

Insemination of the surrogate can be either through sex (natural insemination) or artificial insemination. Using the sperm of a donor results in a child who is not genetically related to the intended parent(s). If the intended father's sperm is used in the insemination, the resulting child is genetically related to both the intended father and the surrogate.

In some cases, insemination may be performed privately by the parties without the intervention of a doctor or physician. In some jurisdictions, the intended parents using donor sperm need to go through an adoption process to have legal parental rights of the resulting child. Many fertility centres that provide for surrogacy assist the parties through the legal process.

Gestational surrogacy

Gestational surrogacy (also known as host or full surrogacy) was first achieved in April 1986. It takes place when an embryo created by in vitro fertilization (IVF) technology is implanted in a surrogate, sometimes called a gestational carrier. Gestational surrogacy has several forms, and in each form, the resulting child is genetically unrelated to the surrogate:

• The embryo is created using the intended father's sperm and the intended mother's eggs;
• The embryo is created using the intended father's sperm and a donor egg;
• The embryo is created using the intended mother's egg and donor sperm;
• A donor embryo is transferred to a surrogate. Such an embryo may be available when others undergoing IVF have embryos left over, which they donate to others. The resulting child is genetically unrelated to the intended parent(s).

Risks

The embryo implanted in gestational surrogacy faces the same risks as anyone using IVF would. Preimplantation risks of the embryo include unintentional epigenetic effects, influence of media which the embryo is cultured on, and undesirable consequences of invasive manipulation of the embryo. Often, multiple embryos are transferred to increase the chance of implantation, and if multiple gestations occur, both the surrogate and the embryos face higher risks of complications.

Gestational surrogates have a smaller chance of having hypertensive disorder during pregnancy compared to mothers pregnant by oocyte donation. This is possibly because gestational carriers tend to be healthier and more fertile than women who use oocyte donation. Gestational carriers also have low rates of placenta previa / placental abruptions (1.1–7.9%).

Children born through singleton IVF surrogacy have been shown to have no physical or mental abnormalities compared to those children born through natural conception. However, children born through multiple gestation in gestational carriers often result in preterm labor and delivery, resulting in prematurity and physical and/or mental anomalies.

Outcomes

Among gestational surrogacy arrangements, between 19–33% of gestational surrogates will successfully become pregnant from an embryo transfer. Of these cases, 30–70% will successfully allow the intended parent(s) to become parent(s) of the resulting child.

For surrogate pregnancies where only one child is born, the preterm birth rate in surrogacy is marginally lower than babies born from standard IVF (11.5% vs 14%). Babies born from surrogacy also have similar average gestational age as infants born through in vitro fertilization and oocyte donation; approximately weeks. Preterm birth rate was higher for surrogate twin pregnancies compared to single births. There are fewer babies with low birth weight when born through surrogacy compared to those born through in vitro fertilization but both methods have similar rates of birth defects.

Indications for surrogacy

Opting for surrogacy is often a choice made when women are unable to carry children on their own. This can be for a number of reasons, including an abnormal uterus or a complete absence of a uterus either congenitally (also known as Mayer-Rokitansky-Kuster-Hauser syndrome) or post-hysterectomy. Women may have a hysterectomy due to complications in childbirth such as heavy bleeding or a ruptured uterus. Medical diseases such as cervical cancer or endometrial cancer can also lead to surgical removal of the uterus. Past implantation failures, history of multiple miscarriages, or concurrent severe heart or renal conditions that can make pregnancy harmful may also prompt women to consider surrogacy. The biological impossibility of single men and same-sex couples having a baby also may indicate surrogacy as an option.

Gestational surrogacy

In gestational surrogacy, the child is not biologically related to the surrogate, who is often referred to as a gestational carrier. Instead, the embryo is created via in vitro fertilization (IVF), using the eggs and sperm of the intended parents or donors, and is then transferred to the surrogate.

According to recommendations made by the European Society of Human Reproduction and Embryology and American Society for Reproductive Medicine, a gestational carrier is preferably between the ages of 21 and 45, has had one full-term, uncomplicated pregnancy where she successfully had at least one child, and has had no more than five deliveries or three Caesarean sections.  

The International Federation of Gynaecology and Obstetrics recommends that the surrogate's autonomy should be respected throughout the pregnancy even if her wishes conflict with what the intended parents want.

The most commonly reported motivation given by gestational surrogates is an altruistic desire to help a childless couple. Other less commonly given reasons include enjoying the experience of pregnancy, and financial compensation.

History

Having another woman bear a child for a couple to raise, usually with the male half of the couple as the genetic father, has been referenced since the ancient times. Babylonian law and custom allowed this practice, and a woman unable to give birth could use the practice to avoid a divorce, which would otherwise be inevitable.

Many developments in medicine, social customs, and legal proceedings around the world paved the way for modern surrogacy:

• 1936 – In the U.S., drug companies Schering-Kahlbaum and Parke-Davis started the pharmaceutical production of estrogen.
• 1944 – Harvard Medical School professor John Rock became the first person to fertilize human ovum outside the uterus.
• 1953 – Researchers successfully performed the first cryopreservation of sperm.
• 1976 – Michigan lawyer Noel Keane wrote the first surrogacy contract in the United States.
• 1978 – Louise Brown, the first "test-tube baby", was born in England, the product of the first successful IVF procedure.
• 1985–1986 – A woman carried the first successful gestational surrogate pregnancy.
• 1986 – Melissa Stern, otherwise known as "Baby M," was born in the U.S. The surrogate and biological mother, Mary Beth Whitehead, refused to give up custody of Melissa to the couple with whom she made the surrogacy agreement. The courts of New Jersey found that Whitehead was the child's legal mother and declared contracts for gestational carrierhood illegal and invalid. However, the court found it in the best interest of the infant to award custody of Melissa to the child's biological father, William Stern, and his wife Elizabeth Stern, rather than to Whitehead, the gestational carrier.
• 1990 – In California, gestational carrier Anna Johnson refused to give up the baby to intended parents Mark and Crispina Calvert. The couple sued her for custody (Calvert v. Johnson), and the court upheld their parental rights. In doing so, it legally defined the true mother as the woman who, according to the surrogacy agreement, intends to create and raise a child.
• 2009 – Ukraine, one of the most requested countries in Europe for this treatment, has its first Surrogacy Law approved.

Psychological concerns

Surrogate

Anthropological studies of surrogates have shown that surrogates engage in various distancing techniques throughout the surrogate pregnancy so as to ensure that they do not become emotionally attached to the baby. Many surrogates intentionally try to foster the development of emotional attachment between the intended mother and the surrogate child.

Some surrogates describe feeling empowered by the experience.

Although gestational surrogates generally report being satisfied with their experience as surrogates, there are cases in which they are not. Unmet expectations are associated with dissatisfaction. Some women did not feel a certain level of closeness with the couple and others did not feel respected by the couple. Some gestational surrogates report emotional distress during the process of surrogacy. There may be a lack of access to therapy and emotional support through the surrogate process.

Gestational surrogates may struggle with postpartum depression and issues with relinquishing the child to their intended parents. Immediate postpartum depression has been observed in gestational surrogates at a rate of 0-20%. Some surrogates report negative feelings with relinquishing rights to the child immediately after birth, but most negative feelings resolve after some time.

Child and parents

A systematic review of 55 studies examining the outcomes for surrogacy for gestational carriers and resulting families showed that there were no major psychological differences in children up to the age of 10 years old that were born from surrogacy compared to those children born from other assisted reproductive technology or those children conceived naturally.

Gay men who have become fathers using surrogacy have reported similar experiences to those of other couples who have used surrogacy, including their relationship with both their child and their surrogate.

A study has followed a cohort of 32 surrogacy, 32 egg donation, and 54 natural conception families through to age seven, reporting the impact of surrogacy on the families and children at ages one, two, and seven. At age one, parents through surrogacy showed greater psychological well-being and adaptation to parenthood than those who conceived naturally; there were no differences in infant temperament. At age two, parents through surrogacy showed more positive mother–child relationships and less parenting stress on the part of fathers than their natural conception counterparts; there were no differences in child development between these two groups. At age seven, the surrogacy and egg donation families showed less positive mother–child interaction than the natural conception families, but there were no differences in maternal positive or negative attitudes or child adjustment. The researchers concluded that the surrogacy families continued to function well.

Legal issues

Main article: Surrogacy laws by country

The legality of surrogacy varies around the world. Many countries do not have laws which specifically deal with surrogacy. Some countries ban surrogacy outright, while others ban commercial surrogacy but allow altruistic surrogacy (in which the surrogate is not financially compensated). Some countries allow commercial surrogacy, with few restrictions. Some jurisdictions extend a ban on surrogacy to international surrogacy. In some jurisdictions rules applicable to adoptions apply while others do not regulate the practice.

The US, Ukraine, Russia and Georgia have the most liberal laws in the world, allowing commercial surrogacy, including for foreigners. Several Asian countries used to have liberal laws, but the practice has since been restricted. In 2013, Thailand banned commercial surrogacy, and restricted altruistic surrogacy to Thai couples. In 2016, Cambodia also banned commercial surrogacy. Nepal, Mexico, and India have also recently banned foreign commercial surrogacy. Surrogacy is legal and common in Iran, and monetary remuneration is practiced and allowed by religious authorities.

Laws dealing with surrogacy must deal with:

• Enforceability of surrogacy agreements. In some jurisdictions, they are void or prohibited, and some jurisdictions distinguish between commercial and altruistic surrogacy.
• The different issues raised by traditional and gestational surrogacy.
• Mechanisms for the legal recognition of the intended parents as the legal parents, either by pre-birth orders or by post-birth adoption.

Although laws differ widely from one jurisdiction to another, some generalizations are possible:

The historical legal assumption has been that the woman giving birth to a child is that child's legal mother, and the only way for another woman to be recognized as the mother is through adoption (usually requiring the birth mother's formal abandonment of parental rights).

Even in jurisdictions that do not recognize surrogacy arrangements, if the potential adoptive parents and the birth mother proceed without any intervention from the government and do not change their mind along the way, they will likely be able to achieve the effects of surrogacy by having the gestational carrier give birth and then give the child up for private adoption to the intended parents.

If the jurisdiction specifically bans surrogacy, however, and authorities find out about the arrangement, there may be financial and legal consequences for the parties involved. One jurisdiction (Quebec) prevented the genetic mother's adoption of the child even though that left the child with no legal mother.

Some jurisdictions specifically prohibit only commercial and not altruistic surrogacy. Even jurisdictions that do not prohibit surrogacy may rule that surrogacy contracts (commercial, altruistic, or both) are void. If the contract is either prohibited or void, then there is no recourse if one party to the agreement has a change of heart: if a surrogate changes her mind and decides to keep the child, the intended mother has no claim to the child even if it is her genetic offspring, and the couple cannot get back any money they may have paid the surrogate; if the intended parents change their mind and do not want the child after all, the surrogate cannot get any money to make up for the expenses, or any promised payment, and she will be left with legal custody of the child.

Jurisdictions that permit surrogacy sometimes offer a way for the intended mother, especially if she is also the genetic mother, to be recognized as the legal mother without going through the process of abandonment and adoption. Often this is via a birth order in which a court rules on the legal parentage of a child. These orders usually require the consent of all parties involved, sometimes even including the husband of a married gestational surrogate. Most jurisdictions provide for only a post-birth order, often out of an unwillingness to force the gestational carrier to give up parental rights if she changes her mind after the birth.

A few jurisdictions do provide for pre-birth orders, generally only in cases when the gestational carrier is not genetically related to the expected child. Some jurisdictions impose other requirements in order to issue birth orders: for example, that the intended parents be heterosexual and married to one another. Jurisdictions that provide for pre-birth orders are also more likely to provide for some kind of enforcement of surrogacy contracts.

Citizenship

The citizenship and legal status of the children resulting from surrogacy arrangements can be problematic. The Hague Conference Permanent Bureau identified the question of citizenship of these children as a "pressing problem" in the Permanent Bureau 2014 Study (Hague Conference Permanent Bureau, 2014a: 84–94). According to U.S. Department of State, Bureau of Consular Affairs, for a child born abroad to be a U.S. citizen one or both of the child's genetic parents must be a U.S. citizen. In other words, the only way for a foreign born surrogate child to acquire U.S. citizenship automatically at birth is if they are the biological child of a U.S. citizen. Furthermore, in some countries, the child will not be a citizen of the country in which they are born because the gestational carrier is not legally the parent of said child. This could result in a child being born without citizenship.

Ethical issues

Numerous ethical questions have been raised with regards to surrogacy. They generally stem from concerns relating to social justice, women's rights, child welfare, and bioethics.

Gestational carrier

Those who view surrogacy as a social justice issue argue that it leads to the exploitation of women in developing countries whose wombs are commodified to meet the reproductive needs of the more affluent. While opponents of this stance argue that surrogacy provides a much-needed source of revenue for women facing poverty in developing countries, others purport that the lack of legislation in such countries often leads to much of the profit accruing to middlemen and commercial agencies rather than the gestational carriers themselves. It has been argued that under laws of countries where surrogacy falls under the umbrella of adoption, commercial surrogacy can be considered problematic as payment for adoption is unethical, but not paying a gestational carrier for her service is a form of exploitation. Both opponents and supporters of surrogacy have agreed that implementing international laws on surrogacy can limit the social justice issues that gestational carriers face in transnational surrogacy.

Other human rights activists express concern over the conditions under which gestational carriers are kept by surrogacy clinics which exercise much power and control over the process of surrogate pregnancy. Isolated from friends and family and required to live in separate surrogacy hostels on the pretext of ensuring consistent prenatal care, it is argued that gestational carriers may face psychological challenges that cannot be offset by the (limited) economic benefits of surrogacy. Other psychological issues are noted, such as the implications of gestational carriers emotionally detaching themselves from their babies in anticipation of birth departure.

The relevance of a woman's consent in judging the ethical acceptability of surrogacy is another point of controversy within human rights circles. While some hold that any consensual process is not a human rights violation, other human rights activists argue that human rights are not just about survival but about human dignity and respect. Thus, decisions cannot be defined as involving agency if they are driven by coercion, violence, or extreme poverty, which is often the case with women in developing countries who pursue surrogacy due to economic need or aggressive persuasion from their husbands. On the other end of the spectrum, it has been argued that bans on surrogacy are violations of human rights under the existing laws of the Inter-American Court of Human Rights reproductive rights landmark.^[52]

Some feminists have also argued that surrogacy is an assault to a woman's dignity and right to autonomy over her body. By degrading impoverished women to the mere status of “baby producers”, commercial surrogacy has been accused by feminists of commodifying women's bodies in a manner akin to prostitution. Some feminists also express concerns over links between surrogacy and patriarchal expressions of domination as numerous reports have been cited of women in developing countries coerced into commercial surrogacy by their husbands wanting to "earn money off of their wives' bodies".

Supporters of surrogacy have argued to mandate education of gestational carriers regarding their rights and risks through the process in order to both rectify the ethical issues that arise and to enhance their autonomy.

Child

Those concerned with the rights of the child in the context of surrogacy reference issues related to identity and parenthood, abandonment and abuse, and child trafficking.

It is argued that in commercial surrogacy, the rights of the child are often neglected as the baby becomes a mere commodity within an economic transaction of a good and a service. Such opponents of surrogacy argue that transferring the duties of parenthood from the birthing mother to a contracting couple denies the child any claim to its “gestational carrier” and to its biological parents if the egg and/or sperm is/are not that of the contracting parents. In addition, they claim that the child has no right to information about any siblings he or she may have in the latter instance. The relevance of disclosing the use of surrogacy as an assisted reproductive technique to the child has also been argued to be important for both health risks and the rights of the child.

Religious issues

See also: Religious response to assisted reproductive technology

Different religions take different approaches to surrogacy, often related to their stances on assisted reproductive technology in general.

Buddhism

Buddhist thought is inconclusive on the matter of surrogacy. The prominent belief is that Buddhism totally accepts surrogacy since there are no Buddhist teachings suggesting that infertility treatments or surrogacy are immoral. This stance is further supported by the common conception that serving as a gestational carrier is an expression of compassion and therefore automatically aligns with Buddhist values.

However, numerous Buddhist thinkers have expressed concerns with certain aspects of surrogacy, hence challenging the contention that surrogacy is always compatible with Buddhist tradition. One Buddhist perspective on surrogacy arises from the Buddhist belief in reincarnation as a manifestation of karma. According to this view, gestational carrierhood circumvents the workings of karma by interfering with the natural cycle of reincarnation.

Others reference the Buddha directly who purportedly taught that trade in sentient beings, including human beings, is not a righteous practice as it almost always involves exploitation that causes suffering. Susumu Shimazono, professor of Religious Studies at the University of Tokyo, contends in the magazine Dharma World that surrogacy places the childbearing surrogate in a position of subservience, in which her body becomes a "tool" for another. Simultaneously, other Buddhist thinkers argue that as long as the primary purpose of being a gestational carrier is out of compassion instead of profit, it is not exploitative and is therefore morally permissible. This further highlights the lack of consensus on surrogacy within the Buddhist community.

Christianity

Catholicism

The Catholic Church is opposed to surrogacy, which it views as immoral and incompatible with Biblical texts surrounding topics of birth, marriage, and life. Paragraph 2376 of the Catechism of the Catholic Church states that: "Techniques that entail the dissociation of husband and wife, by the intrusion of a person other than the couple (donation of sperm or ovum, surrogate uterus), are gravely immoral." Many proponents of this stance express concern that the sanctity of marriage may be compromised by the insertion of a third party into the marriage contract. Additionally, the practice of in vitro fertilisation involved in gestational surrogacy is generally viewed as morally impermissible due to its removal of human conception from the act of sexual intercourse. Anti-abortion Catholics also condemn in vitro fertilisation due to the killing of embryos that accompanies the frequent practice of discarding, freezing, or donating non-implanted eggs to stem cell research. As such, the Catholic Church deems all practices involving in vitro fertilisation, including gestational surrogacy, as morally problematic.

Hinduism

As India and other countries with large Hindu populations have become centers for fertility tourism, numerous questions have been raised regarding whether or not surrogacy conflicts with the Hindu religion. While Hindu scholars have not debated the issue extensively, T. C. Anand Kumar, an Indian reproductive biologist, argues that there is no conflict between Hinduism and assisted reproduction. Others have supported this stance with reference to Hindu mythology, including a story in the Bhagavata Purana which suggests the practice of gestational carrier-hood:

Kamsa, the wicked king of Mathura, had imprisoned his sister Devaki and her husband Vasudeva because oracles had informed him that her child would be his killer. Every time she delivered a child, he smashed its head on the floor. He killed six children. When the seventh child was conceived, the gods intervened. They summoned the goddess Yogamaya and had her transfer the fetus from the womb of Devaki to the womb of Rohini (Vasudeva's other wife who lived with her sister Yashoda across the river Yamuna, in the village of cowherds at Gokulam). Thus the child conceived in one womb was incubated in and delivered through another womb.

Additionally, infertility is often associated with karma in the Hindu tradition and consequently treated as a pathology to be treated. This has led to general acceptance of medical intervention for addressing infertility amongst Hindus. As such, surrogacy and other scientific methods of assisted reproduction are generally supported within the Hindu community. Nonetheless, Hindu women do not commonly use surrogacy as an option to treat infertility, despite often serving as surrogates for Western commissioning couples. When surrogacy is practiced by Hindus, it is more likely to be used within the family circle as opposed to involving anonymous donors.

Islam

For Muslims, the Qur'anic injunction that "their mothers are only those who conceived them and gave birth to them (waladna hum)" denies the distinction between genetic and gestational mothers, hence complicating notions of lineage within the context of surrogacy, which are central to the Muslim faith.

Jainism

Harinegameshin Transfers Mahavira's Embryo, from a Kalpasutra manuscript, c. 1300–1350, Philadelphia Museum of Art

Jain scholars have not debated the issue of surrogacy extensively. Nonetheless, the practice of surrogacy is referenced in the Śvētāmbara tradition of Jainism according to which the embryo of Lord Mahavira was transferred from a Brahmin woman Devananada to the womb of Trishala, the queen of Kshatriya ruler Siddharth, by a divinity named Harinegameshin. This account is not present in Digambara Jain texts, however.

Other sources state that surrogacy is not objectionable in the Jain view as it is seen as a physical operation akin to any other medical treatment used to treat a bodily deficiency. However, some religious concerns related to surrogacy have been raised within the Jain community including the loss of non-implanted embryos, destruction of traditional marriage relationships, and adulterous implications of gestational surrogacy.

Judaism

In general, there is a lack of consensus within the Jewish community on the matter of surrogacy. Jewish scholars and rabbis have long debated this topic, expressing conflicting views on both sides of the debate.

Those supportive of surrogacy within the Jewish religion generally view it as a morally permissible way for Jewish women who cannot conceive to fulfill their religious obligations of procreation. Rabbis who favour this stance often cite Genesis 9:1 which commands all Jews to "be fruitful and multiply". In 1988, the Committee on Jewish Law and Standards associated with the Conservative Jewish movement issued formal approval for surrogacy, concluding that "the mitzvah of parenthood is so great that ovum surrogacy is permissible".

Jewish scholars and rabbis which hold an anti-surrogacy stance often see it as a form of modern slavery wherein women's bodies are exploited and children are commodified. As Jews possess the religious obligation to "actively engage in the redemption of those who are enslaved", practices seen as involving human exploitation are morally condemned. This thinking aligns with concerns brought forth by other groups regarding the relation between surrogacy practices and forms of human trafficking in certain countries with large fertility tourism industries. Several Jewish scholars and rabbis also cite ethical concerns surrounding the "broken relationship" between the child and its surrogate birth mother. Rabbi Immanuel Jacovits, chief rabbi of the United Hebrew Congregation from 1976 to 1991, reported in his 1975 publication Jewish Medical Ethics that "to use another person as an incubator and then take from her the child that she carried and delivered for a fee is a revolting degradation of maternity and an affront to human dignity."

Another point of contention surrounding surrogacy within the Jewish community is the issue of defining motherhood. There are generally three conflicting views on this topic: 1) the ovum donor is the mother, 2) the gestational carrier is the mother, and 3) the child has two mothers--both the ovum donor and the gestational carrier. While most contend that parenthood is determined by the woman giving birth, a minority opt to consider the genetic parents the legal parents, citing the well-known passage in Sanhedrin 91b of the Talmud which states that life begins at conception. Also controversial is the issue of defining Judaism in the context of surrogacy. Jewish Law states that if a Jewish woman is the surrogate, then the child is Jewish. However, this often raises issues when the child is raised by a non-Jewish family and approaches for addressing this issue are also widely debated within the Jewish community.

Fertility tourism

Main article: Fertility tourism

Some countries, such as the United States, Canada, Greece, Ukraine, Georgia and Russia, are popular surrogacy destinations for foreign intended parents. Eligibility, processes and costs differ from country to country. Fertility tourism for surrogacy is driven by legal restrictions in the home country or the incentive of lower prices abroad. Previously popular destinations, India, Nepal, Thailand, and Mexico have all recently implemented bans on commercial surrogacy for non-residents.

Immune tolerance in pregnancy

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Immune_tolerance_in_pregnancy 

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. It is studied within the field of reproductive immunology.

Mechanisms

Placental mechanisms

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:

• It secretes neurokinin B containing phosphocholine molecules. This is the same mechanism used by parasitic nematodes to avoid detection by the immune system of their host.
• Also, there is the presence of small lymphocytic suppressor cells in the fetus that inhibit maternal cytotoxic T cells by inhibiting the response to interleukin 2.
• The placental trophoblast cells do not express the classical MHC class I isotypes HLA-A and HLA-B, unlike most other cells in the body, and this absence is assumed to prevent destruction by maternal cytotoxic T cells, 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 I isotypes HLA-E and HLA-G, which is assumed to prevent destruction by maternal natural killer cells, which otherwise destroy cells that do not express any MHC class I. However, trophoblast cells do express the rather typical HLA-C.
• It forms a syncytium 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 epithelium 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. 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 viviparous 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 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, 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.

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.

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).

Regulatory T cells also likely play a role.

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

Insufficient tolerance

Many cases of spontaneous abortion may be described in the same way as maternal transplant rejection, and a chronic insufficient tolerance may cause infertility. Other examples of insufficient immune tolerance in pregnancy are Rh disease and pre-eclampsia:

• Rh disease is caused by the mother producing antibodies (including IgG antibodies) against the Rhesus D antigen on their baby's red blood cells. 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 their produce IgG antibodies against the D antigen (Anti-D). Maternal IgG is able to pass through the placenta into the fetus and if the level of it is sufficient, it will cause destruction of D positive fetal red blood cells, leading to development of the anti-Rh type of hemolytic disease of the fetus and newborn (HDFN). Generally, HDFN becomes worse with each additional Rh incompatible pregnancy.
• One cause of pre-eclampsia 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 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 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. 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.

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. 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.

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

Main article: Susceptibility and severity of infections in pregnancy

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

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.

Immune tolerance

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Immune_tolerance 

Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissue that would otherwise have the capacity to elicit an immune response in a given organism. It is induced by prior exposure to that specific antigen and contrasts with conventional immune-mediated elimination of foreign antigens (see Immune response). Tolerance is classified into central tolerance or peripheral tolerance depending on where the state is originally induced—in the thymus and bone marrow (central) or in other tissues and lymph nodes (peripheral). The mechanisms by which these forms of tolerance are established are distinct, but the resulting effect is similar.

Immune tolerance is important for normal physiology. Central tolerance is the main way the immune system learns to discriminate self from non-self. Peripheral tolerance is key to preventing over-reactivity of the immune system to various environmental entities (allergens, gut microbes, etc.). Deficits in central or peripheral tolerance also cause autoimmune disease, resulting in syndromes such as systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, autoimmune polyendocrine syndrome type 1 (APS-1), and immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX), and potentially contribute to asthma, allergy, and inflammatory bowel disease. And immune tolerance in pregnancy is what allows a mother animal to gestate a genetically distinct offspring with an alloimmune response muted enough to prevent miscarriage.

Tolerance, however, also has its negative tradeoffs. It allows for some pathogenic microbes to successfully infect a host and avoid elimination. In addition, inducing peripheral tolerance in the local microenvironment is a common survival strategy for a number of tumors that prevents their elimination by the host immune system.

Historical background

The phenomenon of immune tolerance was first described by Ray D. Owen in 1945, who noted that dizygotic twin cattle sharing a common placenta also shared a stable mixture of each other's red blood cells (though not necessarily 50/50), and retained that mixture throughout life. Although Owen did not use the term immune tolerance, his study showed the body could be tolerant of these foreign tissues. This observation was experimentally validated by Leslie Brent, Rupert E. Billingham and Peter Medawar in 1953, who showed by injecting foreign cells into fetal or neonatal mice, they could become accepting of future grafts from the same foreign donor. However, they were not thinking of the immunological consequences of their work at the time: as Medawar explains:

"We did not set out with the idea in mind of studying the immunological consequences of the phenomenon described by Owen; on the contrary, we had been goaded by Dr. H.P. Donald into trying to devise a foolproof method of distinguishing monozygotic from dizygotic twins... ."

However, these discoveries, and the host of allograft experiments and observations of twin chimerism they inspired, were seminal for the theories of immune tolerance formulated by Sir Frank McFarlane Burnet and Frank Fenner, who were the first to propose the deletion of self-reactive lymphocytes to establish tolerance, now termed clonal deletion. Burnet and Medawar were ultimately credited for "the discovery of acquired immune tolerance" and shared the Nobel Prize in Physiology or Medicine in 1960.

Definitions and usage

In their Nobel Lecture, Medawar and Burnet define immune tolerance as "a state of indifference or non-reactivity towards a substance that would normally be expected to excite an immunological response." Other more recent definitions have remained more or less the same. The 8th edition of Janeway's Immunobiology defines tolerance as "immunologically unresponsive…to another's tissues.".

Immune tolerance encompasses the range of physiological mechanisms by which the body reduces or eliminates an immune response to particular agents. It is used to describe the phenomenon underlying discrimination of self from non-self, suppressing allergic responses, allowing chronic infection instead of rejection and elimination, and preventing attack of fetuses by the maternal immune system. Typically, a change in the host, not the antigen, is implied. Though some pathogens can evolve to become less virulent in host-pathogen coevolution, tolerance does not refer to the change in the pathogen but can be used to describe the changes in host physiology. Immune tolerance also does not usually refer to artificially induced immunosuppression by corticosteroids, lymphotoxic chemotherapy agents, sublethal irradiation, etc. Nor does it refer to other types of non-reactivity such as immunological paralysis. In the latter two cases, the host's physiology is handicapped but not fundamentally changed.

Immune tolerance is formally differentiated into central or peripheral; however, alternative terms such as "natural" or "acquired" tolerance have at times been used to refer to establishment of tolerance by physiological means or by artificial, experimental, or pharmacological means. These two methods of categorization are sometimes confused, but are not equivalent—central or peripheral tolerance may be present naturally or induced experimentally. This difference is important to keep in mind.

Central tolerance

Central tolerance refers to the tolerance established by deleting autoreactive lymphocyte clones before they develop into fully immunocompetent cells. It occurs during lymphocyte development in the thymus and bone marrow for T and B lymphocytes, respectively. In these tissues, maturing lymphocytes are exposed to self-antigens presented by medullary thymic epithelial cells and thymic dendritic cells, or bone marrow cells. Self-antigens are present due to endogenous expression, importation of antigen from peripheral sites via circulating blood, and in the case of thymic stromal cells, expression of proteins of other non-thymic tissues by the action of the transcription factor AIRE.

Those lymphocytes that have receptors that bind strongly to self-antigens are removed by induction of apoptosis of the autoreactive cells, or by induction of anergy, a state of non-activity. Weakly autoreactive B cells may also remain in a state of immunological ignorance where they simply do not respond to stimulation of their B cell receptor. Some weakly self-recognizing T cells are alternatively differentiated into natural regulatory T cells (nTreg cells), which act as sentinels in the periphery to calm down potential instances of T cell autoreactivity (see peripheral tolerance below).

The deletion threshold is much more stringent for T cells than for B cells since T cells alone can cause direct tissue damage. Furthermore, it is more advantageous for the organism to let its B cells recognize a wider variety of antigen so it can produce antibodies against a greater diversity of pathogens. Since the B cells can only be fully activated after confirmation by more self-restricted T cells that recognize the same antigen, autoreactivity is held in check.

This process of negative selection ensures that T and B cells that could initiate a potent immune response to the host's own tissues are eliminated while preserving the ability to recognize foreign antigens. It is the step in lymphocyte education that is key for preventing autoimmunity (entire process detailed here). Lymphocyte development and education is most active in fetal development but continues throughout life as immature lymphocytes are generated, slowing as the thymus degenerates and the bone marrow shrinks in adult life.

Peripheral tolerance

Peripheral tolerance develops after T and B cells mature and enter the peripheral tissues and lymph nodes. It is established by a number of partly overlapping mechanisms that mostly involve control at the level of T cells, especially CD4+ helper T cells, which orchestrate immune responses and give B cells the confirmatory signals they need in order to produce antibodies. Inappropriate reactivity toward normal self-antigen that was not eliminated in the thymus can occur, since the T cells that leave the thymus are relatively but not completely safe. Some will have receptors (TCRs) that can respond to self-antigens that:

• are present in such high concentration outside the thymus that they can bind to "weak" receptors.
• the T cell did not encounter in the thymus (such as, tissue-specific molecules like those in the islets of Langerhans, brain, or spinal cord not expressed by AIRE in thymic tissues).

Those self-reactive T cells that escape intrathymic negative selection in the thymus can inflict cell injury unless they are deleted or effectively muzzled in the peripheral tissue chiefly by nTreg cells (see central tolerance above).

Appropriate reactivity toward certain antigens can also be quieted by induction of tolerance after repeated exposure, or exposure in a certain context. In these cases, there is a differentiation of naïve CD4+ helper T cells into induced Treg cells (iTreg cells) in the peripheral tissue or nearby lymphoid tissue (lymph nodes, mucosal-associated lymphoid tissue, etc.). This differentiation is mediated by IL-2 produced upon T cell activation, and TGF-β from any of a variety of sources, including tolerizing dendritic cells (DCs), other antigen presenting cells, or in certain conditions surrounding tissue.

Treg cells are not the only cells that mediate peripheral tolerance. Other regulatory immune cells include T cell subsets similar to but phenotypically distinct from Treg cells, including TR1 cells that make IL-10 but do not express Foxp3, TGF-β-secreting TH3 cells, as well as other less well-characterized cells that help establish a local tolerogenic environment. B cells also express CD22, a non-specific inhibitor receptor that dampens B cell receptor activation. A subset of B regulatory cells that makes IL-10 and TGF-β also exists. Some DCs can make Indoleamine 2,3-dioxygenase (IDO) that depletes the amino acid tryptophan needed by T cells to proliferate and thus reduce responsiveness. DCs also have the capacity to directly induce anergy in T cells that recognize antigen expressed at high levels and thus presented at steady-state by DCs. In addition, FasL expression by immune privileged tissues can result in activation-induced cell death of T cells.

nTreg vs. iTreg cells

The involvement of T cells, later classified as Treg cells, in immune tolerance was recognized in 1995 when animal models showed that CD4+ CD25+ T cells were necessary and sufficient for the prevention of autoimmunity in mice and rats. Initial observations showed removal of the thymus of a newborn mouse resulted in autoimmunity, which could be rescued by transplantation of CD4+ T cells. A more specific depletion and reconstitution experiment established the phenotype of these cells as CD4+ and CD25+. Later in 2003, experiments showed that Treg cells were characterized by the expression of the Foxp3 transcription factor, which is responsible for the suppressive phenotype of these cells.

It was assumed that, since the presence of the Treg cells originally characterized was dependent on the neonatal thymus, these cells were thymically derived. By the mid-2000s, however, evidence was accruing of conversion of naïve CD4+ T cells to Treg cells outside of the thymus. These were later defined as induced or iTreg cells to contrast them with thymus-derived nTreg cells. Both types of Treg cells quieten autoreactive T cell signaling and proliferation by cell-contact-dependent and -independent mechanisms including:

• Contact-dependent:

• Granzyme or perforin secretion upon contact
• Upregulation of cAMP after contact, inducing anergy (reduced proliferation and IL-2 signaling)
• Interaction with B7 on T cells
• Downregulation of CD80/CD86 costimultory molecules on antigen presenting cells upon interaction with CTLA-4 or lymphocyte function-associated antigen 1 (LFA-1)

• Contact-independent

• Secretion of TGF-β, which sensitizes cells to suppression and promotes Treg-like cell differentiation
• Secretion of IL-10
• Cytokine absorption leading to cytokine deprivation-mediated apoptosis

nTreg cells and iTreg cells, however, have a few important distinguishing characteristics that suggest they have different physiological roles:

• nTreg cells develop in the thymus; iTreg cells develop outside the thymus in chronically inflamed tissue, lymph nodes, spleen, and gut-associated lymphoid tissue (GALT).
• nTreg cells develop from Foxp3- CD25+ CD4+ cells while iTreg cells develop from Foxp3+ CD25- CD4- cells (both become Foxp3+ CD25+CD4+).
• nTreg cells, when activated, require CD28 costimulation, while iTreg cells require CTLA-4 costimulation.
• nTreg cells are specific, modestly, for self-antigen while iTreg cells recognize allergens, commensal bacteria, tumor antigens, alloantigens, and self-antigens in inflamed tissue.

Tolerance in physiology and medicine

Allograft tolerance

Immune recognition of non-self-antigens typically complicates transplantation and engrafting of foreign tissue from an organism of the same species (allografts), resulting in graft reaction. However, there are two general cases in which an allograft may be accepted. One is when cells or tissue are grafted to an immune-privileged site that is sequestered from immune surveillance (like in the eye or testes) or has strong molecular signals in place to prevent dangerous inflammation (like in the brain). The second is when a state of tolerance has been induced, either by previous exposure to the antigen of the donor in a manner that causes immune tolerance rather than sensitization in the recipient, or after chronic rejection. Long-term exposure to a foreign antigen from fetal development or birth may result in establishment of central tolerance, as was observed in Medawar's mouse-allograft experiments. In usual transplant cases, however, such early prior exposure is not possible. Nonetheless, a few patients can still develop allograft tolerance upon cessation of all exogenous immunosuppressive therapy, a condition referred to as operational tolerance. CD4+ Foxp3+ Treg cells, as well as CD8+ CD28- regulatory T cells that dampen cytotoxic responses to grafted organs, are thought to play a role. In addition, genes involved in NK cell and γδT cell function associated with tolerance have been implicated for liver transplant patients. The unique gene signatures of these patients implies their physiology may be predisposed toward immune tolerance.

Fetal development

Main article: Immune tolerance in pregnancy

The fetus has a different genetic makeup than the mother, as it also translates its father's genes, and is thus perceived as foreign by the maternal immune system. Women who have borne multiple children by the same father typically have antibodies against the father's red blood cell and major histocompatibility complex (MHC) proteins. However, the fetus usually is not rejected by the mother, making it essentially a physiologically tolerated allograft. It is thought that the placental tissues which interface with maternal tissues not only try to escape immunological recognition by downregulating identifying MHC proteins but also actively induce a marked peripheral tolerance. Placental trophoblast cells express a unique Human Leukocyte Antigen (HLA-G) that inhibits attack by maternal NK cells. These cells also express IDO, which represses maternal T cell responses by amino acid starvation. Maternal T cells specific for paternal antigens are also suppressed by tolerogenic DCs and activated iTregs or cross-reacting nTregs. Some maternal Treg cells also release soluble fibrinogen-like proteins 2 (sFGL2), which suppresses the function of DCs and macrophages involved in inflammation and antigen presentation to reactive T cells^[24] These mechanisms altogether establish an immune-privileged state in the placenta that protects the fetus. A break in this peripheral tolerance results in miscarriage and fetal loss. (for more information, see Immune tolerance in pregnancy).

The microbiome

The skin and digestive tract of humans and many other organisms is colonized with an ecosystem of microorganisms that is referred to as the microbiome. Though in mammals a number of defenses exist to keep the microbiota at a safe distance, including a constant sampling and presentation of microbial antigens by local DCs, most organisms do not react against commensal microorganisms and tolerate their presence. Reactions are mounted, however, to pathogenic microbes and microbes that breach physiological barriers(epithelium barriers). Peripheral mucosal immune tolerance, in particular, mediated by iTreg cells and tolerogenic antigen-presenting cells, is thought to be responsible for this phenomenon. In particular, specialized gut CD103+ DCs that produce both TGF-β and retinoic acid efficiently promotes the differentiation of iTreg cells in the gut lymphoid tissue. Foxp3- TR1 cells that make IL-10 are also enriched in the intestinal lining. Break in this tolerance is thought to underlie the pathogenesis of inflammatory bowel diseases like Crohn's disease and ulcerative colitis.

Oral tolerance and hypersensitivity

See also: Goblet cell § Role in oral tolerance

Oral tolerance refers to a specific type of peripheral tolerance induced by antigens given by mouth and exposed to the gut mucosa and its associated lymphoid tissues. The hypo-responsiveness induced by oral exposure is systemic and can reduce hypersensitivity reactions in certain cases. Records from 1829 indicate that American Indians would reduce contact hypersensitivity from poison ivy by consuming leaves of related Rhus species; however, contemporary attempts to use oral tolerance to ameliorate autoimmune diseases like rheumatoid arthritis and other hypersensitivity reactions have been mixed. The systemic effects of oral tolerance may be explained by the extensive recirculation of immune cells primed in one mucosal tissue in another mucosal tissue, allowing extension of mucosal immunity. The same probably occurs for cells mediating mucosal immune tolerance.

Oral tolerance may depend on the same mechanisms of peripheral tolerance that limit inflammation to bacterial antigens in the microbiome since both involve the gut-associated lymphoid tissue. It may also have evolved to prevent hypersensitivity reactions to food proteins. It is of immense immunological importance, since it is a continuous natural immunologic event driven by exogenous antigen.

Allergy and hypersensitivity reactions in general are traditionally thought of as misguided or excessive reactions by the immune system, possibly due to broken or underdeveloped mechanisms of peripheral tolerance. Usually, Treg cells, TR1, and Th3 cells at mucosal surfaces suppress type 2 CD4 helper cells, mast cells, and eosinophils, which mediate allergic response. Deficits in Treg cells or their localization to mucosa have been implicated in asthma and atopic dermatitis. Attempts have been made to reduce hypersensitivity reactions by oral tolerance and other means of repeated exposure. Repeated administration of the allergen in slowly increasing doses, subcutaneously or sublingually appears to be effective for allergic rhinitis. Repeated administration of antibiotics, which can form haptens to cause allergic reactions, can also reduce antibiotic allergies in children.

The tumor microenvironment

Immune tolerance is an important means by which growing tumors, which have mutated proteins and altered antigen expression, prevent elimination by the host immune system. It is well recognized that tumors are a complex and dynamic population of cells composed of transformed cells as well as stromal cells, blood vessels, tissue macrophages, and other immune infiltrates. These cells and their interactions all contribute to the changing tumor microenvironment, which the tumor largely manipulates to be immunotolerant so as to avoid elimination. There is an accumulation of metabolic enzymes that suppress T cell proliferation and activation, including IDO and arginase, and high expression of tolerance-inducing ligands like FasL, PD-1, CTLA-4, and B7. Pharmacologic monoclonal antibodies targeted against some of these ligands has been effective in treating cancer. Tumor-derived vesicles known as exosomes have also been implicated promoting differentiation of iTreg cells and myeloid derived suppressor cells (MDSCs), which also induce peripheral tolerance. In addition to promoting immune tolerance, other aspects of the microenvironment aid in immune evasion and induction of tumor-promoting inflammation.

Evolution

Though the exact evolutionary rationale behind the development of immunological tolerance is not completely known, it is thought to allow organisms to adapt to antigenic stimuli that will consistently be present instead of expending considerable resources fighting it off repeatedly. Tolerance in general can be thought of as an alternative defense strategy that focuses on minimizing impact of an invader on host fitness, instead of on destroying and eliminating the invader. Such efforts may have a prohibitive cost on host fitness. In plants, where the concept was originally used, tolerance is defined as a reaction norm of host fitness over a range of parasite burdens, and can be measured from the slope of the line fitting these data. Immune tolerance may constitute one aspect of this defense strategy, though other types of tissue tolerance have been described.

Schematic of the reaction norm of tolerance. Organisms of genotype 2 are considered more tolerant to the pathogen than organisms of genotype 1.

The advantages of immune tolerance, in particular, may be seen in experiments with mice infected with malaria, in which more tolerant mice have higher fitness at greater pathogen burdens. In addition, development of immune tolerance would have allowed organisms to reap the benefits of having a robust commensal microbiome, such as increased nutrient absorption and decreased colonization by pathogenic bacteria.

Though it seems that the existence of tolerance is mostly adaptive, allowing an adjustment of the immune response to a level appropriate for the given stressor, it comes with important evolutionary disadvantages. Some infectious microbes take advantage of existing mechanisms of tolerance to avoid detection and/or elimination by the host immune system. Induction of regulatory T cells, for instance, has been noted in infections with Helicobacter pylori, Listeria monocytogenes, Brugia malayi, and other worms and parasites. Another important disadvantage of the existence of tolerance may be susceptibility to cancer progression. Treg cells inhibit anti-tumor NK cells. The injection of Treg cells specific for a tumor antigen also can reverse experimentally-mediated tumor rejection based on that same antigen. The prior existence of immune tolerance mechanisms due to selection for its fitness benefits facilitates its utilization in tumor growth.

Tradeoffs between immune tolerance and resistance

Immune tolerance contrasts with resistance. Upon exposure to a foreign antigen, either the antigen is eliminated by the standard immune response (resistance), or the immune system adapts to the pathogen, promoting immune tolerance instead.

Resistance typically protects the host at the expense of the parasite, while tolerance reduces harm to the host without having any direct negative effects on the parasite. Each strategy has its unique costs and benefits for host fitness:

	Costs	Benefits
Elimination (resistance)	Pain, swelling, and disruption of tissue function by inflammation. Tissue damage by inflammatory mediators (immunopathology) High energy cost Risk of autoimmunity, hypersensitivity, allergy	Reduces pathogen burden Neutralizes toxins and eliminates dangerous organisms Prevents parasitism
Tolerance	Direct damage by pathogen (toxins, digestion, etc.) Energy and resources lost to pathogen	Reduced tissue damage from immune response Less selection pressure on pathogens for resistance Promotes commensalism Lower energy cost

Evolution works to optimize host fitness, so whether elimination or tolerance occurs depends on which would benefit the organism most in a given scenario. If the antigen is from a rare, dangerous invader, the costs of tolerating its presence are high and it is more beneficial to the host to eliminate it. Conversely, if experience (of the organism or its ancestors) has shown that the antigen is innocuous, then it would be more beneficial to tolerate the presence of the antigen rather than pay the costs of inflammation.

Despite having mechanisms for both immune resistance and tolerance, any one organism may be overall more skewed toward a tolerant or resistant phenotype depending on individual variation in both traits due to genetic and environmental factors. In mice infected with malaria, different genetic strains of mice fall neatly along a spectrum of being more tolerant but less resistant or more resistant but less tolerant. Patients with autoimmune diseases also often have a unique gene signature and certain environmental risk factors that predispose them to disease. This may have implications for current efforts to identify why certain individuals may be disposed to or protected against autoimmunity, allergy, inflammatory bowel disease, and other such diseases.

Tumor antigen

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Tumor_antigen 

 

 

The spectrum of target antigens associated with tumor immunity and allo-immunity after allogeneic hematopoietic stem cell transplantation. Host-derived T and B cells can be induced to recognize tumor-associated antigens, whereas donor-derived B and T cells can recognize both tumor-associated antigens and alloantigens.

Tumor antigen is an antigenic substance produced in tumor cells, i.e., it triggers an immune response in the host. Tumor antigens are useful tumor markers in identifying tumor cells with diagnostic tests and are potential candidates for use in cancer therapy. The field of cancer immunology studies such topics.

Mechanism of tumor antigenesis

Processing of tumor antigens recognized by CD8+ T cells

Normal proteins in the body are not antigenic because of self-tolerance, a process in which self-reacting cytotoxic T lymphocytes (CTLs) and autoantibody-producing B lymphocytes are culled "centrally" in primary lymphatic tissue (BM) and "peripherally" in secondary lymphatic tissue (mostly thymus for T-cells and spleen/lymph nodes for B cells). Thus any protein that is not exposed to the immune system triggers an immune response. This may include normal proteins that are well sequestered from the immune system, proteins that are normally produced in extremely small quantities, proteins that are normally produced only in certain stages of development, or proteins whose structure is modified due to mutation.

Classification of tumor antigens

Classes of human tumor antigens recognized by T lymphocytes, with their genetic process

Initially tumor antigens were broadly classified into two categories based on their pattern of expression: Tumor-Specific Antigens (TSA), which are present only on tumor cells and not on any other cell and Tumor-Associated Antigens (TAA), which are present on some tumor cells and also some normal cells.

This classification, however, is imperfect because many antigens thought to be tumor-specific turned out to be expressed on some normal cells as well. The modern classification of tumor antigens is based on their molecular structure and source.

Accordingly, they can be classified as;

• Products of Mutated Oncogenes and Tumor Suppressor Genes
• Products of Other Mutated Genes
  • Overexpressed or Aberrantly Expressed Cellular Proteins
  • Tumor Antigens Produced by Oncogenic Viruses
  • Oncofetal Antigens
  • Altered Cell Surface Glycolipids and Glycoproteins
  • Cell Type-Specific Differentiation Antigens

Types

Any protein produced in a tumor cell that has an abnormal structure due to mutation can act as a tumor antigen. Such abnormal proteins are produced due to mutation of the concerned gene. Mutation of protooncogenes and tumor suppressors which lead to abnormal protein production are the cause of the tumor and thus such abnormal proteins are called tumor-specific antigens. Examples of tumor-specific antigens include the abnormal products of ras and p53 genes. In contrast, mutation of other genes unrelated to the tumor formation may lead to synthesis of abnormal proteins which are called tumor-associated antigens.

Other examples include tissue differentiation antigens, mutant protein antigens, oncogenic viral antigens, cancer-testis antigens and vascular or stromal specific antigens. Tissue differentiation antigens are those that are specific to a certain type of tissue. Mutant protein antigens are likely to be much more specific to cancer cells because normal cells shouldn't contain these proteins. Normal cells will display the normal protein antigen on their MHC molecules, whereas cancer cells will display the mutant version. Some viral proteins are implicated in forming cancer (oncogenesis), and some viral antigens are also cancer antigens. Cancer-testis antigens are antigens expressed primarily in the germ cells of the testes, but also in fetal ovaries and the trophoblast. Some cancer cells aberrantly express these proteins and therefore present these antigens, allowing attack by T-cells specific to these antigens. Example antigens of this type are CTAG1B and MAGEA1.

Proteins that are normally produced in very low quantities but whose production is dramatically increased in tumor cells, trigger an immune response. An example of such a protein is the enzyme tyrosinase, which is required for melanin production. Normally tyrosinase is produced in minute quantities but its levels are very much elevated in melanoma cells.

Oncofetal antigens are another important class of tumor antigens. Examples are alphafetoprotein (AFP) and carcinoembryonic antigen (CEA). These proteins are normally produced in the early stages of embryonic development and disappear by the time the immune system is fully developed. Thus self-tolerance does not develop against these antigens.

Abnormal proteins are also produced by cells infected with oncoviruses, e.g. EBV and HPV. Cells infected by these viruses contain latent viral DNA which is transcribed and the resulting protein produces an immune response.

In addition to proteins, other substances like cell surface glycolipids and glycoproteins may also have an abnormal structure in tumor cells and could thus be targets of the immune system.

Importance of tumor antigens

Tumor antigens, because of their relative abundance in tumor cells are useful in identifying specific tumor cells. Certain tumors have certain tumor antigens in abundance.

Tumor antigen	Tumor in which it is found	Remarks
Alphafetoprotein (AFP)	Germ cell tumors Hepatocellular carcinoma
Carcinoembryonic antigen (CEA)	Bowel cancers	Occasional lung or breast cancer
CA-125	Ovarian cancer
MUC-1	Breast cancer
Epithelial tumor antigen (ETA)	Breast cancer
Tyrosinase	Malignant melanoma	normally present in minute quantities; greatly elevated levels in melanoma
Melanoma-associated antigen (MAGE)	Malignant melanoma	Also normally present in the testis
abnormal products of ras, p53	Various tumors

Certain tumor antigens are thus used as tumor markers. More importantly, tumor antigens can be used in cancer therapy as tumor antigen vaccines.