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Saturday, June 17, 2023

Human-based computation

From Wikipedia, the free encyclopedia

Human-based computation (HBC), human-assisted computation, ubiquitous human computing or distributed thinking (by analogy to distributed computing) is a computer science technique in which a machine performs its function by outsourcing certain steps to humans, usually as microwork. This approach uses differences in abilities and alternative costs between humans and computer agents to achieve symbiotic human–computer interaction. For computationally difficult tasks such as image recognition, human-based computation plays a central role in training Deep Learning-based Artificial Intelligence systems. In this case, human-based computation has been referred to as human-aided artificial intelligence.

In traditional computation, a human employs a computer to solve a problem; a human provides a formalized problem description and an algorithm to a computer, and receives a solution to interpret. Human-based computation frequently reverses the roles; the computer asks a person or a large group of people to solve a problem, then collects, interprets, and integrates their solutions. This turns hybrid networks of humans and computers into "large scale distributed computing networks" where code is partially executed in human brains and on silicon based processors.

Early work

Human-based computation (apart from the historical meaning of "computer") research has its origins in the early work on interactive evolutionary computation (EC). The idea behind interactive evolutionary algorithms is due to Richard Dawkins. In the Biomorphs software accompanying his book The Blind Watchmaker (Dawkins, 1986) the preference of a human experimenter is used to guide the evolution of two-dimensional sets of line segments. In essence, this program asks a human to be the fitness function of an evolutionary algorithm, so that the algorithm can use human visual perception and aesthetic judgment to do something that a normal evolutionary algorithm cannot do. However, it is difficult to get enough evaluations from a single human if we want to evolve more complex shapes. Victor Johnston and Karl Sims[12] extended this concept by harnessing the power of many people for fitness evaluation (Caldwell and Johnston, 1991; Sims, 1991). As a result, their programs could evolve beautiful faces and pieces of art appealing to public. These programs effectively reversed the common interaction between computers and humans. In these programs, the computer is no longer an agent of its user, but instead, a coordinator aggregating efforts of many human evaluators. These and other similar research efforts became the topic of research in aesthetic selection or interactive evolutionary computation (Takagi, 2001), however the scope of this research was limited to outsourcing evaluation and, as a result, it was not fully exploring the full potential of the outsourcing.

A concept of the automatic Turing test pioneered by Moni Naor (1996) is another precursor of human-based computation. In Naor's test, the machine can control the access of humans and computers to a service by challenging them with a natural language processing (NLP) or computer vision (CV) problem to identify humans among them. The set of problems is chosen in a way that they have no algorithmic solution that is both effective and efficient at the moment. If it existed, such an algorithm could be easily performed by a computer, thus defeating the test. In fact, Moni Naor was modest by calling this an automated Turing test. The imitation game described by Alan Turing (1950) didn't propose using CV problems. It was only proposing a specific NLP task, while the Naor test identifies and explores a large class of problems, not necessarily from the domain of NLP, that could be used for the same purpose in both automated and non-automated versions of the test.

Finally, Human-based genetic algorithm (HBGA) encourages human participation in multiple different roles. Humans are not limited to the role of evaluator or some other predefined role, but can choose to perform a more diverse set of tasks. In particular, they can contribute their innovative solutions into the evolutionary process, make incremental changes to existing solutions, and perform intelligent recombination. In short, HBGA allows humans to participate in all operations of a typical genetic algorithm. As a result of this, HBGA can process solutions for which there are no computational innovation operators available, for example, natural languages. Thus, HBGA obviated the need for a fixed representational scheme that was a limiting factor of both standard and interactive EC. These algorithms can also be viewed as novel forms of social organization coordinated by a computer, according to Alex Kosorukoff and David Goldberg.

Classes of human-based computation

Human-based computation methods combine computers and humans in different roles. Kosorukoff (2000) proposed a way to describe division of labor in computation, that groups human-based methods into three classes. The following table uses the evolutionary computation model to describe four classes of computation, three of which rely on humans in some role. For each class, a representative example is shown. The classification is in terms of the roles (innovation or selection) performed in each case by humans and computational processes. This table is a slice of three-dimensional table. The third dimension defines if the organizational function is performed by humans or a computer. Here it is assumed to be performed by a computer.

Division of labor in computation

Innovation agent
Computer Human
Selection
agent
Computer Genetic algorithm Computerized tests
Human Interactive genetic algorithm Human-based genetic algorithm

Classes of human-based computation from this table can be referred by two-letter abbreviations: HC, CH, HH. Here the first letter identifies the type of agents performing innovation, the second letter specifies the type of selection agents. In some implementations (wiki is the most common example), human-based selection functionality might be limited, it can be shown with small h.

Methods of human-based computation

  • (HC) Darwin (Vyssotsky, Morris, McIlroy, 1961) and Core War (Jones, Dewdney 1984) These are games where several programs written by people compete in a tournament (computational simulation) in which fittest programs will survive. Authors of the programs copy, modify, and recombine successful strategies to improve their chances of winning.
  • (CH) Interactive EC (Dawkins, 1986; Caldwell and Johnston, 1991; Sims, 1991) IEC enables the user to create an abstract drawing only by selecting his/her favorite images, so human only performs fitness computation and software performs innovative role. [Unemi 1998] Simulated breeding style introduces no explicit fitness, just selection, which is easier for humans.
  • (HH2) Wiki (Cunningham, 1995) enabled editing the web content by multiple users, i.e. supported two types of human-based innovation (contributing new page and its incremental edits). However, the selection mechanism was absent until 2002, when wiki has been augmented with a revision history allowing for reversing of unhelpful changes. This provided means for selection among several versions of the same page and turned wiki into a tool supporting collaborative content evolution (would be classified as human-based evolution strategy in EC terms).
  • (HH3) Human-based genetic algorithm (Kosorukoff, 1998) uses both human-based selection and three types of human-based innovation (contributing new content, mutation, and recombination). Thus, all operators of a typical genetic algorithm are outsourced to humans (hence the origin of human-based). This idea is extended to integrating crowds with genetic algorithm to study creativity in 2011.
  • (HH1) Social search applications accept contributions from users and attempt to use human evaluation to select the fittest contributions that get to the top of the list. These use one type of human-based innovation. Early work was done in the context of HBGA. Digg and Reddit are recently popular examples. See also Collaborative filtering.
  • (HC) Computerized tests. A computer generates a problem and presents it to evaluate a user. For example, CAPTCHA tells human users from computer programs by presenting a problem that is supposedly easy for a human and difficult for a computer. While CAPTCHAs are effective security measures for preventing automated abuse of online services, the human effort spent solving them is otherwise wasted. The reCAPTCHA system makes use of these human cycles to help digitize books by presenting words from scanned old books that optical character recognition cannot decipher.
  • (HC) Interactive online games: These are programs that extract knowledge from people in an entertaining way.
  • (HC) "Human Swarming" or "Social Swarming". The UNU platform for human swarming establishes real-time closed-loop systems around groups of networked users molded after biological swarms, enabling human participants to behave as a unified collective intelligence.
  • (NHC) Natural Human Computation involves leveraging existing human behavior to extract computationally significant work without disturbing that behavior. NHC is distinguished from other forms of human-based computation in that rather than involving outsourcing computational work to human activity by asking humans to perform novel computational tasks, it involves taking advantage of previously unnoticed computational significance in existing behavior.

Incentives to participation

In different human-based computation projects people are motivated by one or more of the following.

  • Receiving a fair share of the result
  • Direct monetary compensation (e.g. in Amazon Mechanical Turk, ChaCha Search guide, Mahalo.com Answers members)
  • Opportunity to participate in the global information economy
  • Desire to diversify their activity (e.g. "people aren't asked in their daily lives to be creative")
  • Esthetic satisfaction
  • Curiosity, desire to test if it works
  • Volunteerism, desire to support a cause of the project
  • Reciprocity, exchange, mutual help
  • Desire to be entertained with the competitive or cooperative spirit of a game
  • Desire to communicate and share knowledge
  • Desire to share a user innovation to see if someone else can improve on it
  • Desire to game the system and influence the final result
  • Fun
  • Increasing online reputation/recognition

Many projects had explored various combinations of these incentives. See more information about motivation of participants in these projects in Kosorukoff,[36] and Von Hippel.[37]

Human-based computation as a form of social organization

Viewed as a form of social organization, human-based computation often surprisingly turns out to be more robust and productive than traditional organizations. The latter depend on obligations to maintain their more or less fixed structure, be functional and stable. Each of them is similar to a carefully designed mechanism with humans as its parts. However, this limits the freedom of their human employees and subjects them to various kinds of stresses. Most people, unlike mechanical parts, find it difficult to adapt to some fixed roles that best fit the organization. Evolutionary human-computation projects offer a natural solution to this problem. They adapt organizational structure to human spontaneity, accommodate human mistakes and creativity, and utilize both in a constructive way. This leaves their participants free from obligations without endangering the functionality of the whole, making people happier. There are still some challenging research problems that need to be solved before we can realize the full potential of this idea.

The algorithmic outsourcing techniques used in human-based computation are much more scalable than the manual or automated techniques used to manage outsourcing traditionally. It is this scalability that allows to easily distribute the effort among thousands of participants. It was suggested recently that this mass outsourcing is sufficiently different from traditional small-scale outsourcing to merit a new name crowdsourcing. However, others have argued that crowdsourcing ought to be distinguished from true human-based computation. Crowdsourcing does indeed involve the distribution of computation tasks across a number of human agents, but Michelucci argues that this is not sufficient for it to be considered human computation. Human computation requires not just that a task be distributed across different agents, but also that the set of agents across which the task is distributed be mixed: some of them must be humans, but others must be traditional computers. It is this mixture of different types of agents in a computational system that gives human-based computation its distinctive character. Some instances of crowdsourcing do indeed meet this criterion, but not all of them do.

Human Computation organizes workers through a task market with APIs, task prices, and software-as-a-service protocols that allow employers / requesters to receive data produced by workers directly in to IT systems. As a result, many employers attempt to manage worker automatically through algorithms rather than responding to workers on a case-by-case basis or addressing their concerns. Responding to workers is difficult to scale to the employment levels enabled by human computation microwork platforms. Workers in the system Mechanical Turk, for example, have reported that human computation employers can be unresponsive to their concerns and needs.

Applications

Human assistance can be helpful in solving any AI-complete problem, which by definition is a task which is infeasible for computers to do but feasible for humans. Specific practical applications include:

Criticism

Human-based computation has been criticized as exploitative and deceptive with the potential to undermine collective action.

In social philosophy it has been argued that human-based computation is an implicit form of online labour. The philosopher Rainer Mühlhoff distinguishes five different types of "machinic capture" of human microwork in "hybrid human-computer networks": (1) gamification, (2) "trapping and tracking" (e.g. CAPTCHAs or click-tracking in Google search), (3) social exploitation (e.g. tagging faces on Facebook), (4) information mining and (5) click-work (such as on Amazon Mechanical Turk). Mühlhoff argues that human-based computation often feeds into Deep Learning-based Artificial Intelligence systems, a phenomenon he analyzes as "human-aided artificial intelligence".

Microbial intelligence

From Wikipedia, the free encyclopedia

Microbial intelligence (known as bacterial intelligence) is the intelligence shown by microorganisms. The concept encompasses complex adaptive behavior shown by single cells, and altruistic or cooperative behavior in populations of like or unlike cells mediated by chemical signalling that induces physiological or behavioral changes in cells and influences colony structures.

Complex cells, like protozoa or algae, show remarkable abilities to organize themselves in changing circumstances. Shell-building by amoebae reveals complex discrimination and manipulative skills that are ordinarily thought to occur only in multicellular organisms.

Even bacteria can display more behavior as a population. These behaviors occur in single species populations, or mixed species populations. Examples are colonies or swarms of myxobacteria, quorum sensing, and biofilms.

It has been suggested that a bacterial colony loosely mimics a biological neural network. The bacteria can take inputs in form of chemical signals, process them and then produce output chemicals to signal other bacteria in the colony.

Bacteria communication and self-organization in the context of network theory has been investigated by Eshel Ben-Jacob research group at Tel Aviv University which developed a fractal model of bacterial colony and identified linguistic and social patterns in colony lifecycle.

Examples of microbial intelligence

Bacterial

  • Bacterial biofilms can emerge through the collective behavior of thousands or millions of cells
  • Biofilms formed by Bacillus subtilis can use electric signals (ion transmission) to synchronize growth so that the innermost cells of the biofilm do not starve.
  • Under nutritional stress bacterial colonies can organize themselves in such a way so as to maximize nutrient availability.
  • Bacteria reorganize themselves under antibiotic stress.
  • Bacteria can swap genes (such as genes coding antibiotic resistance) between members of mixed species colonies.
  • Individual cells of myxobacteria coordinate to produce complex structures or move as social entities. Myxobacteria move and feed cooperatively in predatory groups, known as swarms or wolf packs, with multiple forms of signalling and several polysaccharides play an important role.
  • Populations of bacteria use quorum sensing to judge their own densities and change their behaviors accordingly. This occurs in the formation of biofilms, infectious disease processes, and the light organs of bobtail squid.
  • For any bacterium to enter a host's cell, the cell must display receptors to which bacteria can adhere and be able to enter the cell. Some strains of E. coli are able to internalize themselves into a host's cell even without the presence of specific receptors as they bring their own receptor to which they then attach and enter the cell.
  • Under nutrient limitation, some bacteria transform into endospores to resist heat and dehydration.
  • A huge array of microorganisms have the ability to overcome being recognized by the immune system as they change their surface antigens so that any defense mechanisms directed against previously present antigens are now useless with the newly expressed ones.
  • In April 2020 it was reported that collectives of bacteria have a membrane potential-based form of working memory. When scientists shone light onto a biofilm of bacteria optical imprints lasted for hours after the initial stimulus as the light-exposed cells responded differently to oscillations in membrane potentials due to changes to their potassium channels.

Protists

  • Individual cells of cellular slime moulds coordinate to produce complex structures or move as multicellular entities. Biologist John Bonner pointed out that although slime molds are “no more than a bag of amoebae encased in a thin slime sheath, they manage to have various behaviors that are equal to those of animals who possess muscles and nerves with ganglia -- that is, simple brains.”
  • The single-celled ciliate Stentor roeselii expresses a sort of "behavioral hierarchy" and can 'change its mind' if its response to an irritant does not relieve the irritant, implying a very speculative sense of 'cognition'.
  • Paramecium, specifically P. caudatum, is capable of learning to associate intense light with stimulus such as electric shocks in its swimming medium; although it appears to be unable to associate darkness with electric shocks.
  • Protozoan ciliate Tetrahymena has the capacity to 'memorize' the geometry of its swimming area. Cells that were separated and confined in a droplet of water, recapitulated circular swimming trajectories upon release. This may result mainly from a rise in intracellular calcium.

Applications

Bacterial colony optimisation

Bacterial colony optimization is an algorithm used in evolutionary computing. The algorithm is based on a lifecycle model that simulates some typical behaviors of E. coli bacteria during their whole lifecycle, including chemotaxis, communication, elimination, reproduction, and migration.

Slime mold computing

Logical circuits can be built with slime moulds. Distributed systems experiments have used them to approximate motorway graphs. The slime mould Physarum polycephalum is able to solve the Traveling Salesman Problem, a combinatorial test with exponentially increasing complexity, in linear time.

Soil ecology

Microbial community intelligence is found in soil ecosystems in the form of interacting adaptive behaviors and metabolisms. According to Ferreira et al., "Soil microbiota has its own unique capacity to recover from change and to adapt to the present state[...] [This] capacity to recover from change and to adapt to the present state by altruistic, cooperative and co-occurring behavior is considered a key attribute of microbial community intelligence."

Many bacteria that exhibit complex behaviors or coordination are heavily present in soil in the form of biofilms. Micropredators that inhabit soil, including social predatory bacteria, have significant implications for its ecology. Soil biodiversity, managed in part by these micropredators, is of significant importance for carbon cycling and ecosystem functioning.

The complicated interaction of microbes in the soil has been proposed as a potential carbon sink. Bioaugmentation has been suggested as a method to increase the 'intelligence' of microbial communities, that is, adding the genomes of autotrophic, carbon-fixing or nitrogen-fixing bacteria to their metagenome.

Peripheral tolerance

From Wikipedia, the free encyclopedia

In immunology, peripheral tolerance is the second branch of immunological tolerance, after central tolerance. It takes place in the immune periphery (after T and B cells egress from primary lymphoid organs). Its main purpose is to ensure that self-reactive T and B cells which escaped central tolerance do not cause autoimmune disease. Peripheral tolerance prevents immune response to harmless food antigens and allergens, too.

Deletion of self-reactive T cells in the thymus is only 60-70% efficient, and naive T cell repertoire contains a significant portion of low-avidity self-reactive T cells. These cells can trigger an autoimmune response, and there are several mechanisms of peripheral tolerance to prevent their activation. Antigen-specific mechanisms of peripheral tolerance include persistent of T cell in quiescence, ignorance of antigen and direct inactivation of effector T cells by either clonal deletion, conversion to regulatory T cells (Tregs) or induction of anergy. Tregs, which are also generated during thymic T cell development, further suppress the effector functions of conventional lymphocytes in the periphery. Dendritic cells (DCs) participate in the negative selection of autoreactive T cells in the thymus, but they also mediate peripheral immune tolerance through several mechanisms.

Dependence of a particular antigen on either central or peripheral tolerance is determined by its abundance in the organism. B cell peripheral tolerance is much less studied and is largely mediated by B cell dependence on T cell help.

Cells mediating peripheral tolerance

Regulatory T cells

Tregs are the central mediators of immune suppression and they play a key role in maintaining peripheral tolerance. The master regulator of Treg phenotype and function is Foxp3. Natural Tregs (nTregs) are generated in the thymus during the negative selection. TCR of nTregs shows a high affinity for self-peptides, Induced Tregs (iTreg) develop from conventional naive helper T cells after antigen recognition in presence of TGF-β and IL-2. iTregs are enriched in the gut to establish tolerance to commensal microbiota and harmless food antigens. Regardless of their origin, once present Tregs use several different mechanisms to suppress autoimmune reactions. These include depletion of IL-2 from the environment, secretion of anti-inflammatory cytokines IL-10, TGF-β and IL-35 and induction of apoptosis of effector cells. CTLA-4 is a surface molecule present on Tregs which can prevent CD28 mediated costimulation of T cells after TCR antigen recognition.  

Tolerogenic DCs

DCs are a major cell population responsible for the initiation of the adaptive immune response. They present short peptides on MHCII, which are recognized by specific TCR. After encountering an antigen with recognition danger or pathogen-associated molecular patterns, DCs start the secretion of proinflammatory cytokines, express costimulatory molecules CD80 and CD86 and migrate to the lymph nodes to activate naive T cells.  However, immature DCs (iDCs) are able to induce both CD4 and CD8 tolerance. The immunogenic potential of iDCs is weak, because of the low expression of costimulatory molecules and a modest level of MHCII. iDCs perform endocytosis and phagocytosis of foreign antigens and apoptotic cells, which occurs physiologically in peripheral tissues. Antigen-loaded iDCs migrate to the lymph nodes, secrete IL-10, TGF-β and present antigen to the naive T cells without costimulation. If the T cell recognizes the antigen, it is turned into the anergic state, depleted or converted to Treg. iDCs are more potent Treg inducers than lymph node resident DCs. BTLA is a crucial molecule for DCs mediated Treg conversion. Tolerogenic DCs express FasL and TRAIL to directly induce apoptosis of responding T cells. They also produce indoleamine 2,3-dioxygenase (IDO) to prevent T cell proliferation. Retinoic acid is secreted to support iTreg differentiation, too. Nonetheless, upon maturation (for example during the infection) DCs largely lose their tolerogenic capabilities.

LNSCs

Aside from dendritic cells, additional cell populations were identified that are able to induce antigen-specific T cell tolerance. These are mainly the members of lymph node stromal cells (LNSCs). LNSCs are generally divided into several subpopulations based on the expression of gp38 (PDPN) and CD31 surface markers. Among those, only fibroblastic reticular cells and lymphatic endothelial cells (LECs) were shown to play a role in peripheral tolerance. Both of those populations are able to induce CD8 T cell tolerance by the presentation of the endogenous antigens on MHCI molecules. LNSCs lack expression of the autoimmune regulator, and the production of autoantigens depends on transcription factor Deaf1. LECs express PD-L1 to engage PD-1 on CD8 T cells to restrict self-reactivity. LNSCs can drive the CD4 T cell tolerance by the presentation of the peptide-MHCII complexes, which they acquired from the DCs. On the other hand, LECs can serve as a self-antigen reservoir and can transport self-antigens to DCs to direct self-peptide-MHCII presentation to CD4 T cells. In mesenteric lymph nodes(mLN), LNSCs can induce Tregs directly by secretion of TGF-β or indirectly by imprinting mLN-resident DCs.

Intrinsic mechanisms of T cell peripheral tolerance

Although the majority of self-reactive T cell clones are deleted in the thymus by the mechanisms of central tolerance, low affinity self-reactive T cells continuously escape to the immune periphery. Therefore, additional mechanisms exist to prevent self-reactive and unrestained T cells responses.

Quiescence

When naive T cells exit the thymus, they are in a quiescent state. That means they are in the G0 stage of the cell cycle and they have low metabolic, transcriptional and translational activities. Quiescence can prevent naive T cell activation after tonic signaling. After antigen exposure and costimulation, naive T cells start the process called quiescence exit, which results in proliferation and effector differentiation.

Ignorance

Self-reactive T cells can fail to initiate immune response after recognition of self-antigen. The intrinsic mechanism of ignorance is when the affinity of TCR to antigen is too low to elicit T cell activation. There is also an extrinsic mechanism. Antigens, which are present in generally low numbers, can´t stimulate T cells sufficiently. Specialized mechanisms ensuring ignorance by the immune system have developed in so-called immune privileged organs. The abundance of antigen and anatomical location is the most important factors in T cell ignorance. In the inflammatory context, T cells can override ignorance and induce autoimmune disease.

Anergy

Anergy is a state of functional unresponsiveness induced upon self antigen recognition. T-cells can be made non-responsive to antigens presented if the T-cell engages an MHC molecule on an antigen presenting cell (signal 1) without engagement of costimulatory molecules (signal 2). Co-stimulatory molecules are upregulated by cytokines (signal 3) in the context of acute inflammation. Without pro-inflammatory cytokines, co-stimulatory molecules will not be expressed on the surface of the antigen presenting cell, and so anergy will result if there is an MHC-TCR interaction between the T cell and the APC.  TCR stimulation leads to translocation of NFAT into the nucleus. In the absence of costimulation, there is no MAPK signaling in T cells and translocation of transcription factor AP-1 into the nucleus is impaired. This disbalance of transcription factors in T cells results in the expression of several genes involved in forming an anergic state.  Anergic T cells show long-lasting epigenetic programming that silences effector cytokine production. Anergy is reversible and T cells can recover their functional responsiveness in the absence of the antigen.  

Peripheral deletion

After T cell response to co-stimulation-deficient antigen, a minor population of T cells develop anergy and a large proportion of T cells are rapidly lost by apoptosis. This cell death can be mediated by intrinsic pro-apoptotic family member BIM. The balance between proapoptotic BIM and the antiapoptotic mediator BCL-2 determine the eventual fate of the tolerized T cell.  There are also extrinsic mechanisms of deletion mediated by the cytotoxic activity of Fas/FasL or TRAIL/TRAILR interaction.

Immunoprivileged organs

Potentially self-reactive T-cells are not activated at immunoprivileged sites, where antigens are expressed in non-surveillanced areas. This can occur in the testes, for instance. Anatomical barriers can separate the lymphocytes from the antigen, an example is the central nervous system (the blood-brain-barrier). Naive T-cells are not present in high numbers in peripheral tissue but stay mainly in the circulation and lymphoid tissue.

Some antigens are at a too low concentration to cause an immune response – a subthreshold stimulation will lead to apoptosis of a T cell.

These sites include the anterior chamber of the eye, the testes, the placenta and the fetus, and the central nervous system. These areas are protected by several mechanisms: Fas-ligand expression binds Fas on lymphocytes inducing apoptosis, anti-inflammatory cytokines (including TGF-beta and interleukin 10) and blood-tissue-barrier with tight junctions between endothelial cells.

In the placenta IDO breaks down tryptophan, creating a "tryptophan desert" micro environment which inhibits lymphocyte proliferation.

Split tolerance

Since many pathways of immunity are interdependent, they do not all need to be tolerised. For example, tolerised T cells will not activate autoreactive B cells. Without this help from CD4 T cells, the B cells will not be activated.

Surrogacy

From Wikipedia, the free encyclopedia

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

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

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

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

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

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.

Space travel in science fiction

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