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. Author manuscript; available in PMC: 2017 Dec 1.
Published in final edited form as: Obstet Gynecol Clin North Am. 2016 Oct 14;43(4):679–698. doi: 10.1016/j.ogc.2016.07.004

Immune regulation in pregnancy: a matter of perspective?

Elizabeth A Bonney 1
PMCID: PMC5527289  NIHMSID: NIHMS823470  PMID: 27816154

Synopsis

The maternal immune system is complex and governed by multiple hormonal and metabolic factors, including those provided to her via the fetus. Understanding of the balance between maternal tolerance and protection of the fetus may require thinking from multiple theoretical approaches to general problem of immune activation and tolerance. The basics for this process are discussed here and may suggest both specific experiments in human and animal models and specific interventions in pregnant patients with immune system-related disease.

Keywords: Immune regulation, pregnancy, maternal tolerance

Why is understanding of the immune system in pregnancy clinically relevant?

The immune system matters. Several areas of clinical relevance should come to mind. First, regulation of the immune system is thought to play a role in both male and female fertility1 and dysregulation of the immune system is still thought to play a role in recurrent miscarriage2. Women with asthma, autoimmune disease, immune deficiency and other derangements of the immune system are at risk for poor pregnancy outcomes3 and it is clear that interactions between pregnancy and the immune system influence the woman post-partum and beyond4. Recent emergence of viruses such as pandemic influenza 5 Ebola6 and Zika7, 8 also underline the utility of focus on the immune system, particularly with regard to vaccine development for pregnant women. Finally, the implications of the interaction between the pregnant mother’s immune system and infectious agents spill not only into the health of the woman but also the health of the embryo, fetus and neonate. Next is a brief overview of the immune system as relates to pregnancy.

Host defense

The importance of inherent protective mechanisms present in the reproductive track, including both barrier and antimicrobial actions, has been recognized9. Balance within the microbiome of various tissues can mean the difference between health and autoimmune disease10. The more than 1 billion organisms living in the vagina- are now thought to mediate both immune protective11 and immune modulatory functions12. Moreover, alterations in the vaginal microbiome may be associated with increased risk of preterm birth13. While the association between altered vaginal microbiome and adverse pregnancy has been observed14, 15, the interaction between pregnancy, the microbiome and subsequent disease or health has not been formally tested. In addition to bacteria existing in the vagina, there are viruses which interact with bacteria and the local immune system to support health or generate disease16. The microorganisms present in the vagina, in addition to other immune factors, are likely influenced by endogenously produced vaginal fluid and those agents such as lubricants and foreign objects (e.g. pessaries). While the cyclic nature of vaginal fluid in the non-pregnant state and the overall composition of the vaginal fluid and cervical mucous present during pregnancy has been evaluated, specific antimicrobial and immune modulating mechanisms are still under examination. For example, antimicrobial peptides such as defensins, reviewed elsewhere17, are players in the composition of the cervico-vaginal fluid and are protectors against ascending infection.

Another important element of host defense during pregnancy is trophoblast. This is true in that these cells may present a physical barrier to prevent transmission of infection to the fetus18, 19. In addition, trophoblast expresses molecules that help to limit or prevent persistent infection2023. However, persistent involvement of the placenta may be seen in several viral infections24. In this light it is interesting that it has been postulated that fetal cells are thought to be the source of persistent maternal infection with Zika virus25.

Innate immunity

Inherent immune-protective/modulating properties of cells and products of the vagina and cervix are often spoken of differently from specific cells of the innate immune system. Characteristics attributed to the innate immune system are lack of specificity, rapidity, and lack of memory. The last of these three characteristics has come into question, however, since it is apparent that some innate immune cells, particularly NK cells are capable of being “educated” 26, possibly by interaction with trophoblast or decidual cells27. It is said that a hallmark of pregnancy is increased activation in systemic innate immunity28, 29. However, local innate immunity is said to be modified during gestation to be functionally active early in pregnancy in order to assist in implantation, down-regulated through most of gestation and then increased with parturition and labor.

Mast cells30 play a sentinel role in tissues. Stimulation of mast cells by bacteria or other agents via surface-expressed pattern recognition receptors, generates mediators that enhanced blood flow, smooth muscle contraction and trafficking of neutrophils, basophils and eosinophils. Mast cell granules are packed with proteins, including interleukin (IL) IL-6, tumor necrosis factor (TNF), leukotrienes, and histamine 31. Histamine exerts its actions through four G protein-coupled receptors (H1-4R). H1R and H4R are regulators of inflammatory, allergic and autoimmune disease32, 33,32, 3437, and recent evidence suggests that H2R and H4R support the generation of regulatory T cells (Treg) that modulate immune responses3840.

Mast cells are present in the uterus and cervix41. Interactions between mast cells and other cells at the maternal-fetal interface mediate implantation(H2R) 42 support angiogenesis43, 44, and preserves quiescence 45 until-term when histamine from mast cells binds to H1R and fosters uterine contractions 46, 47,48. Type I sensitivity induces premature labor in humans49 and in n animals50 via histamine binding to H1R in the uterus51.

Neutrophils52 are critical to the innate response through phagocytosis of bacteria and production of reactive oxygen species, lytic enzymes, and peptides that lead to activation of the inflammatory cascade. Activated neutrophils can pass from the blood through endothelial cells by the use of metalloproteinases that disrupt cellular membranes. Some organisms and stimuli induce neutrophils to undergo a unique form of death, “NETosis” which involves extrusion of chromatin and cytoplasmic contents which in turn can bind up and help immobilize bacteria. This process also generates tissue damage and more inflammation53. There exist phenotypic subsets of neutrophils, and some of these may have particular relevance to pregnancy. In the first trimester of human pregnancies, a unique sub population of neutrophils, so called “N2” becomes prominent54. This population may be supported by local expression of TGF-β and expresses proteins important to angiogenesis, including vascular endothelial growth factor (VEGF)-A. At term and in the context of preterm birth, inflammatory, or “N1” neutrophils traffic to the uterus in response to molecules such as IL-8, where they may express matrix metalloproteinases that help to dissolve fetal membranes. After delivery, neutrophils traffic to the cervix to participate in tissue repair55.

Dendritic cells typically reside in a quiescent state in tissues. When activated, these cells mature and initiate protein antigen processing and traffic to the lymph nodes draining the tissue. Activated dendritic cells are considered to be the most proficient at processing antigenic protein and placing peptides from that protein into the cleft of major histocompatibility molecules and shunting the MHC-plus-peptide complexes to the surface for presentation to T cells. Presentation involves the binding of the MHC-peptide complex to the T cell receptor, binding of other surface molecules on dendritic cells to their receptors on T cells, and elaboration of soluble factors that can modify the T cell response. The result of this interaction can result in activation and proliferation of T cells specific for the protein whose peptide is in the MHC molecule. The dendritic cell population is likely to be slightly different depending on the tissue of residence, and this is true with regard to the placenta, uterus, uterine draining node and spleen56. It is possible that tissue-specific differences in the dendritic cell population are developmentally regulated. It has been observed that dendritic cells in the uterus are limited in their ability to traffic to the uterine draining lymph nodes during pregnancy57 and that this supports tolerance of the fetus. Other possibilities of control of dendritic cell function may occur at the level of maturation58, 59, as it has been proposed that “immature” dendritic cells support immune tolerance of tissue grafts60 and cancers61. However, inflammation can override these mechanisms and produce activation of dendritic cells from the uterus56.

Macrophages62, 63

Members of the mononuclear phagocyte family includes monocytes and macrophages. In general, monocytes are generated in the bone marrow and circulate as diverse populations31 until they traffic to tissues in response to specific developmental or environmental signals such as infection or inflammation62. Trafficking to tissues induces differentiation to macrophages. Inflammation or infection, including phagocytosis of bacteria and necrotic cells, causes activation and maturation of tissue-resident macrophages to full effector function31. Depending on the tissue type and local signals expressed, macrophages may form distinct phenotypes. One, the “M1” phenotype is considered to be the “inflammatory phenotype” and is marked by expression of inflammatory cytokines such as IL-1β, IL-6, IL-23 and IL-17 31, 62. The development of this phenotypic subset is driven by the local expression of gamma interferon (γIFN) produced by Th1 cells and NK cells and also by TNF expressed by activated dendritic cells62. Local expression of βIFN by trophoblast can also support generation of this phenotype62. A second group of phenotypes, “M2” includes M2a. These are generated by interaction with Th2-cell elaborated cytokines such as IL-4 and IL-13, and primarily participate in wound healing. Another M2 phenotypic subset, sometimes termed “regulatory” or “M2c can be activated in certain tissues by ligation of their toll-like receptors. Their development can be supported by the action of IL-10 expressed by Treg and can in turn secrete IL-10 themselves and further support Treg development 62. Another suppressive offshoot of the monocyte lineage is terms the monocytic myeloid-derived suppressor cells, similar to tumor-associated macrophages that are said to suppress immune response in tumors and other tissues64.

During pregnancy, hormonal changes can alter the presence and phenotype of circulating monocytes63. In the decidua, macrophages are present and assist with implantation65. Through gestation, they are present at relatively constant numbers in the uterus. The presence of macrophages increases in the cervix at term66 and in preterm labor67, 68. Macrophage subsets63 may contribute to the mechanisms leading to disruption of the fetal membranes, due to expression of matrix metalloproteinases69, uterine contractions due to expression of prostaglandins70, and softening and dilation of the cervix due to expression of collagenases71.

Given the capacity and complexity of macrophage subsets, it is easy to imagine that macrophages also assist with healing and remodeling of the epithelium over the implantation site, and with cervical and uterine remodeling in the post partum72. Further, data suggests that T cells can modify the phenotype of macrophages or monocytes in secondary lymphoid organs draining the uterus73. This suggests that macrophages may play a part in regulatory circuits that modify inflammation-induced poor pregnancy outcomes.

NK cells are grouped within the ILC1 subset of innate lymphoid cells, and represent a population of cells that can augment inflammation in many sites. While initially thought to be mostly involved in killing of abnormal cells including virally infected74 and cancer75 cells, over time it has been recognized that distinct subpopulations of NK cells exist. These subpopulations express decreased ability to kill but increased ability to provide factors that modify the growth or differentiation of other cells. Adding complexity to the evolving picture of NK cells are the observations that NK cells can “learn” from exposure to cells and factors from their environment. The complexity of NK cells is highlighted by their presence and function at the maternal-fetal interface where they can collaborate with trophoblast and endothelial cells to remodel decidual vessels and increase blood flow through the placenta. In other sites lack of or alteration in MHC tends to cause NK cell killing. However, it appears that at the maternal-fetal interface, NK cells may “learn” and retain the ability to limit trophoblast killing despite the relative lack of MHC expression in the placenta. NK cell function is regulated by an array of inhibitory receptors, including killer Ig-like receptors (KIRs), and activating receptors76 Thus relative expression of inhibitory versus activating receptors might regulate the level of cytotoxicity expressed by these cells. The ILC2 innate lymphoid subset express cytokines such as IL-477, but little is known about their presence in decidua or placenta78. Within the ILC3 group are the lymphoid tissue inducer (LTi), and NK22 cells. In human decidua, LTi produce γ–interferon and IL-17 both thought to be important in the response to infection, and NK22 cells- those that are phenotypically similar to NK cells, but also secrete the cytokine IL-22, which can be a growth factor for trophoblast79.

NK T cells have limited specificity but several of the effector functions of classical T cells. NKT cells were originally shown to be inherently capable of producing cytokines such as IL-480. Invariant NKT cells recognize lipid ligands bound to the “MHC-like” molecule CD1 81. Within the reproductive track, activated NK T cells have been shown to mediate pregnancy loss and preterm birth in mouse models82. In contrast, the tumor environment can generate NKT cells that down-regulate immune responses83 which may occur at the maternal-fetal interface 84.

γδ T cells

During development a proportion of T cell lineage cells generate T cell receptor chains gamma (γ) and delta (δ), instead of alpha (α) and beta (β). These cells develop and populate tissues earlier than their αβ counterparts, have a limited repertoire and in addition tend to populate mucosal surfaces85. This places them in a unique position to sample the environment in which the animal exists and be a first line of defense. The exact nature of the antigens recognized by γδ cells is unknown, but it has been suggested that they, like NKT cells, respond to certain lipids in the context of CD185. In addition, this cell type plays a potential regulatory role as they express the capacity to kill activated T cells 86. These cells are present in the reproductive tract, where they may modify local immunity87. Sex steroids influence the development of these cells88. They expand during pregnancy and are found in placental villi in humans89 and in mice90. Although genetic deficiency in γδ T cells does not inhibit successful pregnancy it may be that pregnancies deficient in γδ T cells are more susceptible to infection91.

Adaptive immunity

T cells

T cells bearing αβ T cell receptor chains comprise the primary regulation of the adaptive immune response. T cells express either the CD4 or CD8 Co-receptor that restricts its ability to recognize peptide bound to MHC class II or class I, respectively. Naïve T cells of either type leave the thymus to circulate between blood and lymph node draining various organs. When a naïve T cell interacts productively with an activated dendritic cell that presents the MHC-plus-peptide complex recognized by the T cells’ receptor, the T cell begins to change its developmental status. If the correct mix of other signals is also received by the T cell it can begin to divide and produce daughter cells. The “other signals” include signaling through molecules such as CD28 and T cell-generated cytokines such as IL-2. Further, the cells that present antigen to T cells can produce cytokines and other factors that can modify the T cell subset that is generated by activation. Finally, T cells can directly or indirectly provide signals that support or suppress the kind of effector function in other T cells.

For CD4 T cells, the many possibilities for effector function have not been clearly delineated. Expression of cytokines such as IL-4, IL-5, and IL-13 constitute a population of CD4 T cells, “Th2”, important in the production of antibody and protection against some parasites. Over-activity of such cells is a hallmark of allergy and asthma. In contrast, expression of cytokines such as γINF and TNF constitute a population, Th1, which supports cytotoxic immune responses. The Th2-Th1 paradigm has been the focus of interest with regard to maternal tolerance of the fetus, as many observations suggested that pregnancy caused a shift in the maternal immune system towards Th2 versus Th1 responses92. However, the idea that pregnancy is critically dependent on this shift waned because deficiency in critical Th2 cytokines results in grossly normal pregnancies in animal models (for example93).

With regard to the conundrum defined by the competing needs of maternal tolerance of the fetus and maternal and fetal immune protection, a newer paradigm has arisen. This one is focused on the presence and function of two other CD4 T cell subsets: Treg on the one hand and Th17 cells on the other. The hallmark cytokines of the Treg subset are TGF-β and IL-10, both produced by cells of the placenta. It is now said that Treg are the primary suppressors of immune responses. Treg lineages include those that are thymus-derived (tTreg) and developmentally inhabit tissues, in contrast to those that arise after activation by antigen in the periphery (pTreg). This later group, it is said, prevents over activation and supports the re-establishment of a quiescent state. In mouse pregnancy, even when mother, father and offspring are all the same genotype (“syngeneic”) there is evidence that the hormonal milieu of pregnancy supports the expansion of Treg capable of suppressing local immunity94. In addition, exposure to semen can cause the induction of fetal/paternal antigen specific Treg95. Further exposure to fetal antigens during the course of pregnancy expands this population, thus creating a regulatory pool bearing immunologic memory to fetal antigens which can then support maternal tolerance in subsequent pregnancies. However, exposure of Treg to inflammatory signals such as ligands for the Toll-like receptor and IL-6 can shift Treg to a potent and highly inflammatory subset, Th17, known for its expression of IL-17. Th17 are induced during the inflammatory response to agents such as listeria96 and influenza97 and a potential mediator of infection-related abortion and premature labor98. Other CD4 T cell subsets invoked in regulation of immunity in the maternal-fetal interface include the Th9 subset, which may be important in the local inflammatory response that supports parturition99.

CD8 T cells also can express varying classes of responsiveness, depending on innately expressed genes and exposure to particular signals and cytokines from other T cells100 or antigen presenting cells101. CD8 T cells produce molecules, such as granzyme and perforin that assist in killing virally infected cells102. They also can assist in the disruption of transplanted organs103. CD8 T cells are present at the maternal-fetal interface104, particularly during viral infection24. While CD8 T cells and be modified by pregnancy, they still can attack fetal cells in the maternal blood and lymphoid organs105, 106. In contrast, and adding to the paradigm that Treg support maternal tolerance, is the observation that pregnancy can support the generation of CD8 Treg99, 107, which may modify CD8 T cell cytotoxicity during pregnancy.

Memory

At some point after immune activation in response to antigen, the proliferative response ends, and a significant proportion of the population of antigen specific effector cells generated die. The result of this process is a pool of memory T cells. On a population level, memory T cells arise from a linearly differentiated subset of antigen specific T cells108. Pregnancy generates a pool of memory T cells that are specific for fetal antigen4, 105. Moreover, evidence suggests that vaccination or infection during pregnancy does not impair immunologic memory24, 109.

Recent observations have focused on a new class of “tissue resident’ T cells that are thought to be critical in the rapid response of mucosal surfaces to viral or other pathogens. Infection in mucosa generates this pool which can rapidly circulate back to the index tissue with subsequent infections. Both CD4 and CD8 tissue resident T cells have been observed in the vagina110, 111 and in uterine112,113, 114 tissues.

B cells give rise to antibody producing plasma cells. They develop in the bone marrow and circulate to the periphery where they occupy specialized areas within lymph nodes. There, they can be exposed to antigen migrating from tissues into draining lymph nodes or present on lymph node-resident follicular dendritic cells115. For a subset of antigens with a particular structure, exposure to B cells may cause direct activation, proliferation and differentiation. For another set of antigens, binding to antigen specific B cell receptors causes antigen uptake, processing and presentation to T cells. This later process generates T cell production of soluble and cell-surface molecules that can bind to B cells and mediate immunoglobulin production, class switch, and differentiation to plasma cells116. Lineages of B cells include regulatory B cells that express IL- 10, down modulate the B cell response and thus repress autoimmune disease117. The B cell compartment undergoes homeostatic changes during pregnancy118, 119, that may increase serum immunoglobulins during this time, as well as support distribution of immunoglobulins, including IgA and IgG, through tissues into their respective lumen (for example120). It also has been observed that pregnancy expands regulatory B cells121 and the strength and specificity of these Breg may modify both maternal tolerance and protection against infection.

Do gonadal steroids affect immune function?

Gonadal steroids comprise the environment generated by the X and Y chromosomes by which gene-by-environment interaction produces health or disease122. The view that one hormone, estrogen is pro-inflammatory and the other, progesterone, is anti-inflammatory is too simplistic. For example, estrogen can support antiviral immunity in the reproductive tract123, and this is thought to be dependent on an inflammatory cytokine. In contrast, estrogen can modulate immunity by supporting the presence of Treg124, and is used to treat autoimmune disease. For another example, progesterone, long held to be critical to the apparent immune suppression of pregnancy, supports the expression of cytokines, such as IL-15, that enhance the homeostatic proliferation of immune cells125,126, 127. The role of gonadal steroids in immune regulation is likely to be complex. The in vitro and in vivo effects of these molecules on immune cells have anchored the experimental evidence used to support idea that successful pregnancy requires immune modulation. What about the theoretical constructs addressing the immunology of pregnancy?

Theories and models of immune tolerance in the context of pregnancy

Tolerance is an active process by which the immune system does not respond to a given antigen

Despite the differences in placentation amongst mammalian species, the “problem of viviparity” is essentially one wherein the developing fetus is in intimate contact with the mother. In humans and rodents, there are at least four potential venues for such contact. The hemachorial placenta of these species, as the name implies, is such that blood from the mother directly bathes trophoblast which arises from the fetus and comprises the placenta. In addition, extra-villous trophoblast both anchors the placenta and replaces the endothelium of vessels in order to accommodate maternal blood flow into the intervillous space. Fetal cells migrate to the systemic circulation of the mother, and vice versa. This accounts for long-term micro-chimerism in both directions and may carry immunological consequences.

Self-non-self models of immunity128

Classically, recognition of that which is “non- self” initiates T cell activation129,130. In these models regulation of the immune response, including tolerance of self-antigens, includes reliance on specific methods of suppression. By these models, another way to generate functional tolerance is to limit the specific class or brand of immune response possible. Thus, a harmful immune response that is mediated by cytotoxic T cells is “suppressed” by the shifting of this immune response to one that produces non-cytotoxic antibody. Further, classical models of immunity suggest that a final phase of immune tolerance is the limitation of trafficking or function of T cells generated in the course of activation by antigen.

With respect to pregnancy, classical models have, through interpretation of existing data, morphed over time to include highly complex underlying mechanisms. For example, early models suggested that maternal tolerance was simply a matter of failure of maternal T cells to be exposed to fetal antigen128. As an extension of this idea, it has been proposed that there is specific limitation of the trafficking of dendritic cells from the uterus to the uterine draining nodes and that this limits presentation of fetal antigens to maternal T cells during pregnancy57. However, as previously mentioned, fetal and maternal cells can traffic in both directions131, 132, and pregnancy produces systemic immunity to fetal antigens.

Many mechanisms have been put forth to provide the local become activated. The list of molecules thought to provide both global and local suppression of immunity includes molecules such as indoleamine 2,3-deoxygenase IDO133, 134. These molecules have been used to support the idea that the whole of pregnancy is a state of relative immune suppression, and thus susceptibility to infectious disease. Further, the presence of alternatively activated macrophages and NK cells begin the list of cells with immune- suppressive properties that exist within the uterus and placenta during pregnancy. This list of cells recruited into the immune suppression paradigm culminated with the regulatory T cell, both in its CD4 and possibly CD8 formats.

The ‘Danger’ model 135, 136

This model is the major alternative to classical models of maternal tolerance of the fetus. This model has been discussed in detail in the context of adverse pregnancy outcomes137. The critical pieces of this model state that T cell, and therefore immune system activation, is not reliant on recognition of “non-self” but on recognition of “Danger”. Although this may appear to some as a matter of semantics, it does represent a major shift in how one might think about diseases, including infectious diseases, which occur during pregnancy. According to the Danger model, the expression of paternal or unique fetal antigens during pregnancy does not necessarily generate T cell activation if Danger is not present. Danger is expressed in fetal tissues and in the decidua through dysregulation of critical metabolic processes, necrosis, and similar mechanisms which produces a signal that activates dendritic cells and possibly alters the processing of locally expressed antigens. Danger is tied to the activation of dendritic cells and their expression of the co-stimulatory signals needed for T cell activation. According to the model, recognition of fetal antigen in the absence of co-stimulation leads to T cell death. Even if a population of T cells is generated against fetal antigens, they do not necessarily generate fetal loss and this is dependent on the structural integrity, growth and lack of continued expression of Danger in fetal tissues. Like the liver, the remaining placenta and related tissues, if healthy simply out runs or out grows any insult by potential attacking T cells. In this context, the expansion of antigen nonspecific or fetal antigen specific regulatory T cells may represent a “bystander effect” that supports the placenta’s normal growth or the ability to “out run” potentially harmful T cells. The fact that disruption of this population of T cells leads to loss of “semi-allogeneic” fetuses neither proves nor disproves the validity of self- non-self- recognition as the basis for immune activation. Through this model, the expression of molecules or the expansion of cells with immune-suppressing characteristics are non-critical to successful fetal antigen-specific maternal immune tolerance. What is critical is metabolic or physiologic health of fetal cells. This model is also consistent with the idea that some diseases of pregnancy carry a maternal component. For example, in pregnancies marked by pre-eclampsia, if maternal decidual or endothelial cells are rendered dysfunctional by some insult, this may lead to local or systemic maternal dendritic cell activation and processing of local (e.g., source is placental) or systemic (e.g., source is trafficking fetal cells) fetal antigens and presentation of the relevant peptides to maternal T cells. This may lead to specific anti-fetal immunity. In other pregnancies, trafficking of T cells into the decidua can occur in the context of infection and not lead to abortion24. Regulation of trafficking to this tissue by effector cells is a complex issue, and possibly not a default mechanism of tolerance.

With regard to the relationship between class of immune response and tolerance of the maternal-fetal unit, the Danger model suggests that every tissue has a specific tendency towards the type of immune response generated in that tissue138. The presence therefore of “foreign” or in the case of pregnancy, fetal/paternal antigen, as opposed to “self” antigen does not drive the class of the response. It may be that placental or intrauterine responses are geared towards certain classes as a result of early developmental programing. This may explain the observation of a tendency toward Th2-type immune responses in decidua or the systemic circulation during pregnancy. Moreover this model would support the idea that the pleotropic nature of cytokines and growth factors is such that pregnancy loss due to lack of expression of certain “Th2 cytokines, such as IL-10 may have more to do with the poor health of trophoblast than the failure of a class switch in maternal immunity. Further, the Danger model’s likely interpretation of the fact that lack of expression of the “pro-inflammatory” cytokine IL-6 leads to increased gestational length139 is that IL-6 is an important metabolic regulator of the time clock(s) leading to parturition, not that inherent mid-gestation suppression of inflammation is the primary goal of pregnancy-associated tissues.

“Evolutionary non-self“ model140

Although not intended to deal with pregnancy transplantation, or allo-immune recognition in general, it might be useful to speculate, given current data, what evolutionary non-self and related models might say about maternal tolerance of the fetus. In this offshoot of classical immune models, the focus is on activation of the innate immune response as the critical mechanism for overall immune activation.

By this model, T cell receptor recognition of self-peptides in the context of MHC underlines the basis for development in the thymus and survival and initial activation in the periphery. However, full activation is reliant on a costimulatory signal delivered by an activated antigen presenting cell. The signal for activation of the antigen presenting cell constitutes the point at which self is discriminated from non self. Three strategies for immune recognition are envisioned141:

  • The first is recognition of “microbial non-self” which occurs through binding of innate immune cell receptors expressed by dendritic cells or macrophages to pathogen associated molecular patterns (PAMPS) on infecting agents.

  • The second is recognition of “missing self”, that is recognition of molecules that are evolutionarily expressed on cells of the body or immune cells, but not bacteria, for example.

  • The third is recognition of “altered self” which is said to occur when there is expression of new cellular markers or abnormalities in cellular markers in the wake of viral or other pathological infection.

“Tolerance” in this model is an indirect process that occurs because microbial non self is segregated from cells that could recognize it, by inhibitory signals expressed on the tissue of interest, by increased expression of unique “self” antigens and by pathogen-associated mechanisms to decrease expression of “altered self” after infection. Later versions of this model also rely on the activity of “suppressor cells” to limit the function of autoreactive T cells142. We could guess, according to this model, that the presence of fetal antigens at the maternal-fetal interface does not necessarily activate the immune system. However, when infection occurs, the pattern receptor mediated immune system occurs in order to protect the mother. This thinking supports interpretation obtained through experimental models of infection or inflammation-induced preterm birth73, 143. The fact that parasitic infection within the placenta leads to dire consequences144 also fits within this model.

There are observations related to maternal tolerance that would be in line with the model’s focus on innate immune privilege. For example, the expression on the human zona pelucida of Sialyl-Lewisx motifis which bind immune-suppressive ligands such as sieglec-9, expression of the immune modulating glycoprotein Glycodelin-A (reviewed in9) and expression of the mucinous glycoprotein MUC 16 (also known as CA 125) by the endometrium9 are thought to suppress local activity of immune cells to protect the implanting embryo. For another example, the placenta expresses a number of small lectin molecules, the galectins, which are thought to be immune modulatory. The role of other unusual glycoproteins and their role in immune modulation in the reproductive track are being examined.

In the context of this model, the relatively low level of immune cell activation to the organisms present in the reproductive tract and uterus145, 146 might be explained by reproductive tract cell modulation of sialic acid residues147, or segregation of these organisms from the immune response by their retention intracellularly145, 146. Viral infection is common at the maternal-fetal interface, but the loss of pregnancy and other adverse outcomes occurs only in a portion of cases, and this may be related to a second “hit” that induces innate immune system activation148. An explanation consistent with this model is that certain viruses adapt to trophoblast in such a way that viral infection in trophoblast down regulates the expression of altered self and thus prevents immune system activation. Support for the idea of viral adaptation comes from the fact that evolutionary time has produced a placenta whose critical functions depend on genes taken from endogenous retroviruses149.

Is the post-partum immune system important?

Pregnancy is a time of rapid shifting in physiology. Resolution and new adaptation occurs globally during the postpartum state. For example, some degree of pregnancy-induced vascular adaptation continues for weeks to months after delivery150153. Elements of the physiology of pregnancy continue well into the woman’s post pregnancy life. Normal pregnancies are generally associated with very low long-term cardiovascular risks while complicated pregnancies, including preeclampsia154156, preterm birth157159, gestational diabetes160 and high multiparity161, are associated with cardiovascular risk. The post-partum state is likely an important time to ask questions about what happens to the maternal immune system. For example, how does one explain fetal cell micro-chimerism after delivery? Classical models suggest that through micro-chimerism, the fetus becomes an extension of maternal “self”162, 163 and that long-lived Treg, impair reactivity to fetal cells. By the Danger model, there is another perspective on these cells. If the trafficking of these cells was not caused by necrosis or dysregulation of tissues within the uterus, and further if the trafficking cells settle in their new homes without causing damage or disruption, then no immune response would be expected, and this might lead to the long term micro-chimerism that has been reported. Another question is how to explain evidence of new-onset autoimmune disease, such as thyroiditis164 or peri-partum cardio myopathy165, overshoots over baseline in severity of autoimmune disease in the postpartum period? While classical models would suggest these findings are related to release from immune suppression in the post-partum state, the evolutionary-non-self and Danger models might suggest persistent underlying infection or dysregulation, respectively, of maternal tissues as driving long term disease risk. There may be other models however, based on what we know about immune cell homeostasis166170, and these will have to be explored.

Key points.

  • Elements of host defense, innate and adaptive immunity alter during pregnancy.

  • The maternal immune system meets the needs for both tolerance and protection through complex regulation but not suppression.

  • Classical as well as non-classical models of immune system activation and tolerance can explain elements of maternal tolerance.

Footnotes

Disclosure: Nothing to disclose

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