Why isn’t
the foetus rejected ?
A study of
the changes that occur in the mammalian immune system to allow for a successful
pregnancy
Recognition
of Self and Non-self
Physical Separation
Immune System Suppression Mechanisms
· Cytokines and TH1/TH2 Environments
· Natural Killer Cells and Macrophages
· HLA-G
Recurrent Spontaneous Abortion
Introduction
The paradoxical nature of pregnancy has intrigued immunologists since the beginning of the 20th century. Little’s 1924 paper reviewed the tolerance of the foetus and postulated that this must be due to the foetus having “no definite physiological characteristics which are individual enough to be recognised as foreign by the mother…” (Billington, 2003). The medical establishment continued to ponder the mechanisms of pregnancy until Medawar released his influential paper in 1953. In this he proposed that the “reasons why the foetus does not habitually provoke an immunological reaction from its mother may be classified under three headings: (a) the anatomical separation of foetus from mother; (b) the antigenic immaturity of the foetus; and (c) the immunological indolence or inertness of the mother” (Medawar, 1953). While these theories have been somewhat refined in recent years, Medawar’s papers and theories remain central to this particular area of research.
A foetus, the mating product of two histoincompatible individuals in an outbred population, is essentially an allograft. It is composed of 50% paternal genes and, therefore, produces paternal antigens that should be targeted for destruction by the maternal immune system due to recognition of them as foreign or non-self (Mellor, 2000). Transplantation of paternal tissues or organs into the maternal environment would, unless the immune system were suppressed, elicit a cascade of immune responses resulting in the rapid clearance of the transplant from the maternal body. In the vast majority of pregnancies, however, the foetal allograft is not rejected. Indeed, in successful pregnancies resulting in the birth of a viable foetus, the maternal immune system appears to be down-regulated or suppressed in some manner allowing for the development of an essentially non-self tissue within a fully immunologically competent maternal environment. While the foetus is not rejected, it does appear that the immune system is still able to function to protect the mother from a wide range of external pathogens for the term of her pregnancy, indicating that parts of her immune system must remain active to a greater or lesser degree.
This project intends to examine the mechanisms of, and immunological responses to, pregnancy in humans in an attempt to determine why the foetus is not rejected. It will also examine what happens when tolerance mechanisms breakdown and if there is any evidence to suggest that such a breakdown may be responsible for recurrent spontaneous abortion, a problem affecting an estimated 2% of couples who try to have children (Souza, 2002).
Recognition of Self and Non-self
During foetal development, the cells of the immune system are exposed to the majority of antigens present in an individual. These cells become tolerant to these antigens and do not mount an immune response to them. Any antigens not encountered during this period are considered foreign or non-self and the detection of these antigens within the body elicits an immune response that culminates in the clearance of the foreign antigen. A number of mechanisms, cell types and mediators interact during this immune response to achieve the elimination of any non-self antigens. The immune response to non-self antigens is the basis for transplantation rejection and vaccination. In instances when these mechanisms are directed against self-antigens, potentially fatal autoimmune conditions can develop. Thus, the immune system must be tightly regulated and controlled.
Physical Separation
The foetus is physically separated from the mother by the placenta across which nutrients, gases and wastes are exchanged (Ain, 2003). The blood of the mother and foetus come into close proximity but do not mix. In this way oxygen is able to diffuse into the embryo’s circulation from the mother and carbon dioxide is able to diffuse in the opposite direction (Raven, 2002). The outer layer of the placenta comprises trophoblast cells that form an unbroken barrier of protection (Billington, 2003) and implant into the endometrial lining of the uterus. As well as the transfer of beneficial molecules, the placenta can also allow harmful substances to reach the foetus. For instance, alcohol and drugs are able to cross the placenta and enter the foetal circulation resulting in potentially disastrous consequences (Raven, 2002).
Fig. 1. Cross-section of human
placenta. I: chorion plate, II: layer of villi, III: basal plate.
Arrows indicate blood flow from the
basal plate to the chorion plate and back (taken from Schäfer-Somi,
2003)
Immune
System Suppression Mechanisms
The maternal immune system is aware of the placenta and of the foetus (Erlebacher, 2001) as demonstrated by alloantigen specific alterations in maternal T- and B-cell phenotypes during pregnancy.
Although the conceptus possesses immunogenic qualities, the placenta itself is a site of active tolerance (Thellin, 2000) and could be described as immunologically privileged during pregnancy (Jerzak, 2002) due to the presence of the layer of trophoblast cells (Billington, 2003). A number of mechanisms have been proposed to account for the protection of trophoblast cells from immune destruction mediated by activated T- and natural killer cells.
Tolerance mechanisms ensure maintenance of the foeto-placental graft and act at a distance on the maternal immune system and at the placental level. The systemic effects are due to hormones, foetal antigens and cells in the maternal blood vessels (Thellin, 2000). The mechanisms by which this state of tolerance is achieved are numerous and research continues to determine whether factors other than those described below are involved. These mechanisms work synergistically with an array of cytokines acting centrally to control the actions of cells, hormones and specialised immune system recognition and effector molecules.
· Cytokines and TH1/TH2 Environments
Virtually every nucleated
cell in the body produces regulatory protein molecules called cytokines (Saito, 2000). Cytokines generally
act locally and exhibit autocrine and paracrine
actions, however, some enter the circulation and exert endocrine
changes. The attributes of pleitrophy
(different biological effects on different cell types), redundancy (different
cytokines mediate similar functions), synergy (combined effect of two cytokines
is greater than the additive effect of the individual cytokines) and antagonism
(one cytokine inhibits or counteracts another) allow cytokines to elicit a
number of biological changes (Kuby, 1994)
Evidence exists to support the view that cytokines play a key role in the maintenance of pregnancy via modulation of the immune system and associated cells (Saito, 2000). During the early stages of pregnancy, the conceptus and placental tissues produce a wide variety of cytokines, including interferons (IFN), interleukins (IL), tumour necrosis factor and granulocyte macrophage colony-stimulating factors (GM-CSF) (Schäfer-Somi, 2003). These cytokines are believed to modulate the immune system in order that the foetus is not rejected, however, the mechanisms by which each of the cytokines achieves this has not yet been fully elucidated.
T cells are specialised
immune cells that recognise foreign antigen and subsequently destroy them via
their own cytotoxic activities and via the activation of other cell types and
molecules. They can differentiate into
two distinct subsets each able to produce particular cytokine profiles and lead
to specific immune responses. TH1 cells
are involved in delayed-type hypersensitivity reactions and associated with cytotoxic T cell functions, whereas TH2 cells are
involved in antibody responses (Saito, 2000).
It is generally accepted
that the maintenance of an essentially TH2 cytokine environment,
namely production of IL-4, IL-5, IL-6, IL-10 and IL-13 (Saito,
2000), appears to be essential for successful pregnancy (Saito,
2000, Guilbert, 1996, Das, 2002, Vince, 1996 and Thellin, 2000). This shift away from the production of TH1
cytokines explains why clinical reports of ameliorated symptoms of rheumatoid
arthritis, MS and autoimmune thyroiditis, which are regarded as inflammatory
diseases mediated by TH1 cells and cytokines, have been made in
pregnant individuals (Matthieson, 2003 and Reinhard,
1998). However, TH1
responses may still be necessary to protect mother and foetus from pathogens,
suggesting a systemic shift towards a TH2 environment but not a
complete suppression of TH1 responses (Guilbert, 1996). Chaouat et al have challenged this
view of an essentially TH2 environment and suggested that other
cytokines, that do not fit neatly into a TH1 or TH2 environment,
may also be essential in the maintenance of pregnancy. They have examined interleukins 11 through 18
and determined that each is present at specific times during pregnancy
suggesting regulatory functions (Chaouat, 2002).
Decidual leukocytes and the preimplantaion embryo secrete IL-10, a cytokine that inhibits the proliferation and secretion of TH1 lymphocytes (Schäfer-Somi, 2003). During implantation of the blastocyst, the maternal endometrium response to the invading foetus graft has characteristics of an acute inflammatory response, however, once implanted, the blastocyst suppresses this response via secretion of IL-6 and prevents rejection (Makrigiannakis, 2003).
Many studies have reported
on the specific importance of IL-4 in the maintenance of pregnancy. IL-4 acts to suppress the TH1
response by inhibiting the production of IL-12 by macrophages and dendritic
cells (Bonney, 2001) and constitutive
IL-4 expression has been reported in human amniotic and decidual tissues (Vince, 1996).
· Leukaemia Inhibitory Factor
Leukaemia inhibitory factor (LIF), synthesised and secreted by maternal endometrial and stromal cells, and its receptor are necessary for the implantation, differentiation and growth of trophoblast cells (Thellin, 2000). LIF mRNA has also been demonstrated in decidual natural killer (NK) cells and T-cells (mainly of the TH2 subset) (Piccinni, 2001). Progesterone, IL-4 and IL-1 have been shown to up-regulate LIF production (Schäfer-Somi, 2003) by endometrial cells while down-regulation is achieved via the actions of both IL-12 and IFN-γ (cytokines that induce TH1 cells) (Jenkins, 2000).
· Natural Killer (NK) Cells and Macrophages
While antigen-specific T and B cells are almost absent from the pregnant uterus, a specialised group of NK cells, which exhibit only the CD56 NK cell marker, and macrophages participate in the maintenance of pregnancy (Saito, 2000).
Uterine natural killer (uNK) cells are found only in the uterus and exhibit very limited killing mechanisms (Ain, 2003). These cells undergo phenotypic transformation as gestation progresses. Midway through the gestation period, they characteristically display an absence of cytolytic activity and an increased production of effector molecules (Hunt, 2000a). Differentiation and proliferation of these cells is regulated by decidual stromal cell derived IL-15 (Ain, 2003).
Uterine NK cells comprise the major lymphocyte population at implantation sites accounting for 30 – 90 % of the total number of cells during the first trimester (Hunt, 2000a, Luppi, 2003). Once pregnancy progresses into the second trimester, the numbers of these cells greatly decrease. These cells produce cytokines necessary for the implantation of trophoblast cells early on in pregnancy, namely IFN-γ (Croy, 2002). After implantation has taken place, these cells are thought to contribute to the modification of the uterine vasculature although the mechanism by which this occurs is unknown (Ain, 2003).
Uterine NK cells also act at the maternal-foetal interface to provide protection against attack from microorganisms that, if allowed to cross the placenta, would risk the viability of the foetus (Luppi, 2003).
Macrophages that exhibit anti-inflammatory effects, have also been reported to be present in the placenta and comprise 10 – 15 % of the total cell population throughout the term of the pregnancy (Hunt, 2000a). These cells, termed Hofbauer cells (Vince, 1996) once activated, produce anti-inflammatory cytokines such as IL-10 and the level of cytotoxic free-oxygen species produced is greatly reduced (in some situations the levels are barely detectable) when compared to the amounts produced by “normal” macrophages (Thellin, 2000). Once again, these cells produce cytokines that drive the TH2 environment necessary for successful pregnancy.
· HLA-G
Antigenic recognition by
T-cells can only be achieved if the antigen is presented as a complex with
either a major histocompatibility (MHC) I or II molecule. These molecules are coded for by the human leukocyte
antigen (HLA) complex (individual antigens are designated A, B, C etc.). While all nucleated cells express MHC class I
molecules, syncytiotrophoblast cells do not express HLA-A or
B and only weakly express HLA-C. HLA-G
is a specialised antigen expressed only by these cells (Hunt,
2000b). It exhibits greatly
decreased polymorphism when compared to other HLA (Le Bouteiller, 2003) and specifically binds natural killer cells
via their killer-cell immunoglobulin-like receptors thus blocking their
cytotoxity (Furman, 2000).
Studies have shown that IL-10 produced by TH2 cells increases
HLA-G production (Thellin, 2000), thus protecting the foetus
via the inhibition of NK cell medicated lysis (Piccinni, 2001).
Some groups have also reported the presence of an additional MHC antigen, namely HLA-E. This antigen is believed to have similar properties to HLA-G (Billington, 2003).
· Progesterone
Progesterone is liberated by corpus luteum, due to the actions of IL-4 and IL-6 from TH2 cells (Saito, 2001), after ovulation and acts on the endometrium to prepare it for implantation (Saito, 2000). Throughout pregnancy, progesterone produced by the placental cells inhibits T-cell mediated graft rejection in the uterus (Hansen, 1998). This is achieved by the shift in balance from a TH1 to a TH2 cytokine environment (Thellin, 2000) and the inhibition of lymphocyte activation and proliferation (Szekeres-Bartho, 1990).
Lymphocytes of pregnant women have been shown to be particularly sensitive to the effects of progesterone compared to those of non-pregnant women (Szekeres-Bartho, 1990). The state of pregnancy itself causes an increase in the number of progesterone receptors that are displayed on peripheral blood lymphocytes (PBL) making them more susceptible to progesterone’s inhibitory mechanisms (Hansen, 1998).
It has been reported that in the presence of progesterone, lymphocytes secrete a 34 KDa protein blocking factor that has a direct inhibitory effect on the cytolytic effects of NK cells and PBL (Szekeres-Bartho, 1990). Thus the presence of progesterone is necessary for the state of immunosuppression that must be achieved in order for the maintenance of pregnancy.
This immunosuppression is
only required in the uterus while peripheral immune mechanisms must be
maintained at normal levels. This is
achieved due to progesterone levels only being high enough to inhibit
lymphocytes in the uterine environment due to production by cells within the
placenta. Additionally, other
peripherally produced molecules regulate the actions of progesterone so as not
to effect lymphocytes in an unwanted way (Hansen, 1998).
Progesterone also acts on syncytiotrophoblast cells driving them to produce cytokines that favour the TH2 environment necessary for successful pregnancy (Thellin, 2000).
· Apoptosis
Apoptosis, from Greek meaning “shedding of leaves”, is the mechanism of cell suicide that occurs when a death signal is activated. This is necessary throughout our lives from foetal development, when cells between fingers and toes die to leave individual digits rather than webbed hands and feet, to the death of cells once they have undergone a specific number of divisions, a mechanism that if not correctly regulated leads to uncontrolled cell division and cancers. Many pathways and genes regulate apoptosis, and it can be initiated as a result of internal factors as well as via the union of externally expressed ligands and molecules.
Apoptosis induction in immune cells has been proposed as a mechanism by which trophoblast cells are protected from anti-foetus immune cell destruction (Coumans, 1999). Studies have suggested that, during the first trimester of pregnancy, Fas ligand (FasL) molecules are expressed on the inner cytotrophoblast and outer syncytiotrophoblast cells of the placenta as well as the maternal decidual cells of the placenta (Makrigiannakis, 2003). Apoptosis is thus initiated in the maternal immune lymphocytes when Fas expressed on their surface contacts FasL on placental cells (Hoshimoto, 2002). Once Fas/FasL interaction occurs, a series of caspases (intracellular cysteine proteases) are activated that cleave specific substrates and, via the action of nucleases, degrade cellular DNA resulting in cell “suicide” (Jerzak, 2002).
· Complement
The complement system is a
complex cascade of mediators whose activation results in clearance of non-self
antigens via a number of interconnecting pathways. These pathways are regulated
by molecules such as decay-accelerating factor, which increases the rate at
which complement components are degraded, and membrane cofactor protein, which blocks
the antibody-binding site on complement molecules (Thellin, 2000). The presence of paternal antigens on the
surface of placental cells would almost certainly initiate complement-mediated
destruction of the placenta and foetus were these inhibitory mechanisms not in
place (Thellin, 2003).
· Blocking Antibodies
Relatively few groups have reported the presence of circulating antipaternal antibodies in the sera of pregnant women (Eblen, 2000). It has been suggested that such antibodies would bind to foetal antigens expressed by the syncytiotrophoblast, thereby camouflaging them and reducing recognition by the maternal immune system (Thellin, 2000). This hypothesis is, however, speculative and still to be proven through research.
· Tolerance
It has been reported that foetal cells migrate across the maternal-foetal interface and enter into the maternal circulation and induce short-term tolerance to foetal antigens (Bonney, 1997). This particular mechanism poses a number of problems. Firstly, the cells carrying foetal antigens may also be carrying infection but as they are not deleted, the mother may succumb to infection. Secondly, the cells may become tumourogenic. For this reason, many groups report that, rather than inducing tolerance, any foetal cells that do enter into the maternal circulation are deleted (Mellor, 2000).
Recurrent Spontaneous Abortion
Recurrent spontaneous abortion is defined as three or more consecutive, unexplained foetal losses before the foetus has reached 500g in weight or before the 20th week of pregnancy (Souza, 2002). Such pregnancy losses are distinct from those that can be attributed to genetic defects, chromosomal abnormalities or autoimmune disorders. These foetuses are viable and healthy and abort due to a breakdown in maternal immune tolerance. As each of the tolerance mechanisms discussed previously work synergistically to ensure a successful pregnancy, the failure of any one would likely result in abortion.
Mechanisms exist to reject the conceptus via rupture of one or more of the tolerance mechanisms. This allows the spontaneous abortion of the foetus in situations where the continuation of pregnancy would endanger the mother (Thellin, 2003) such as injury or infection. In the case of recurrent abortions, however, there does not appear to be any underlying cause for tolerance breakdown and the subsequent death and expulsion of the foetus.
The hypothesis that tolerance breakdown is responsible for immune mediated abortions was postulated many years ago, however, proving such a link has not been easy. Even so, some of the mechanisms by which tolerance breaks down have been elucidated.
Soluble Fas (sFas), a form lacking the anchoring transmembrane domain, has been shown to be present in decreased amounts in the sera of pregnant women, during the first trimester, compared to that observed in non-pregnant women. In those women who experience spontaneous abortion, however, the levels are elevated when compared to those measured during a “normal” pregnancy. Soluble Fas is thought to have a protective, anti-apoptotic effect on lymphocytes due to preferential binding to placental bound FasL (Hoshimoto, 1999). In a normal pregnancy, therefore, sFas in its decreased amount does not exhibit anti-apoptosis effects and does not override the tolerance mechanism abrogated by placental FasL. In those women who experience spontaneous abortion, sFas blocks bound FasL and leaves anti-foetal specific T-cells free to bind to foetal cells and initiate immune killing mechanisms leading to abortion. The precise mechanism to explain this increase in sFas remains unclear. One group has suggested that it is shed from injured vascular endothelial cells (Hoshimoto, 1999) that may explain why spontaneous abortion generally follows maternal trauma.
With regards to the cytokine environment in spontaneous abortors, it has been shown that all have a greater proportion of TH1, rather than TH2, cytokines present in sera taken from the vicinity of the conceptus whole peripheral blood levels are equivalent to those seen in a normal pregnancy (Piccinni, 2001). Specifically, it has been reported that such women have reduced IL-10, IL-4 and LIF levels and increased levels of IFN-γ. This IFN-γ is released from macrophages as a result of the actions of IL-12 (Jenkins, 2000). Such TH1-type cytokines cause inflammatory immune reactions and graft rejection mechanisms leading to abortion of the conceptus.
For many years now, it has been known that the administration of certain cytokines can prevent immune mediated abortion. Such cytokines include GM-CSF and IL-3, however, the results were obtained in mice and no comparable human studies have yet been successful (Wegmann, 1990).
Finally, although HLG-A is generally monomorphic, mutations in this gene may render it less effective at blocking the cytotoxic actions of NK cells. These cells could then participate in the destruction of the foetus (Redman, 1990). Although no literature exists at present to confirm or discount this hypothesis, several groups have reported that such a mechanism of tolerance breakdown may occur in cases of immune abortion.
Conclusion
Difficulties surrounding research in this area are enhanced by the ethical constraints of experimental design using human volunteers. Consequently, much of the research into pregnancy maintenance is conducted in animal species that may or may not have a direct correlation with the intimate workings of the human immune and reproductive systems.
Even so, the paradox of pregnancy is slowly being unravelled. From the information presented in this study, it is obvious that numerous mechanisms are involved with the maintenance of a successful pregnancy and that the breakdown of any one has the potential to lead to immune-mediated abortion.
Glossary
A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
Alloantigen – antigen that would initiate an immune response in a different member of the same species
Allogeneic – with different genetic constitution but of the same species
Allograft – graft between allogeneic individuals
Autocrine action- mediator having an effect on the same cell/tissue that produced it
Blastocyst – cellular mass in early pregnancy that implants into the uterine wall
Conceptus – synonym for foetus
Constitutive – continuously produced without need for stimulation
Corpus luteum – progesterone-producing structure that develops from a Graafian follicle during human reproductive cycle
Cytolytic – causes destruction of cell membrane causing cell to rupture (lyse)
Cytotoxic – poisonous to cells
Cytotrophoblast – upper layer of trophoblast
Decidual – derived from the decidua, a highly vascularised membrane of the uterus
Dendritic cell – antigen presenting cells that reside in tissues
Endocrine action – acts on targets in distant parts of the body
Endometrium – mucous membrane lining of the uterus
Fas/Fas ligand – complex that leads to an apoptotic signal via activation of caspases and DNA degradation
Immunogenic – capable of initiating an immune response
Immunologically privileged site – site where no immune system activity can take place, e.g. testes, eye
KDa
– Kilo
Leukocytes – white blood cells
Lymphocytes – specialised white blood cells called T (matured in the thymus) and B (matured in the bone marrow) cells
mRNA – messenger ribonucleic acid – transforms genetic information into proteins
Outbred population – one where all individuals are different allogeneic profile as opposed to inbred populations where all members are genetically identical due to repeated breeding between brothers and sisters.
Paracrine action- mediator having an effect on a cell /tissue other than the one that produced it
Phenotype – physical appearance of an individual/cell based on its genetic make-up and environment
Polymorphism (genetic) – variation in the genes caused by various different recombinations, mutations, deletions, inversions and substitutions.
Proteases – an enzyme that digests proteins
Syncytiotrophoblast – lower layer of trophoblast
Synergism – cooperative interaction of two of more entities (e.g. cytokines, cells, people) whose combined effect is greater than or equal to the effects of the individual entities
Trophoblast – epithelium surrounding the blastocyst that becomes part of the placenta
Tumourogenic – able to cause tumours
Viable – capable of maintaining life
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Created
by Amy Lewis BSc (Hons.)
Faculty
of Health and Biosciences, UEL,
Last updated 13 January 2004
Opening image taken from
www.standupgirl.com