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INTRODUCTION
In pregnant females, local adaptation of the maternal immune system allows for successful
coexistence between the mother and the semi-allograft that is the fetus/placenta expressing
both maternal (self) and paternal (nonself) genes [1-4]. Cytotoxic adaptive immune responses
are diminished, bypassed, or even abrogated, while regulatory adaptive immunity is enhanced
[5,6]. By contrast, innate (natural) immunity remains intact, serving two purposes: one, to
continue to provide host defense against infection, and two, to interact with fetal tissues to
promote successful placentation and pregnancy [4,7-10].
The placenta and fetal membranes are directly exposed to maternal blood and tissues. Thus,
unique features of the cells that comprise this interface must underlie the remarkable ability of
the genetically distinct fetal tissue to inhabit the maternal host.
Many immunologists studying reproduction agree that maternal immunity is not solely
antagonistic to trophoblast tissue [11,12]. Indeed, a maternal immune presence in the decidua
is essential for successful implantation [4]. Evidence of the opposite hypothesis (ie, that
trophoblasts have offensive mechanisms for actively killing maternal lymphocytes) is lacking. It
is clear, however, that the placenta is normally protected from the killing functions of maternal
cells through a number of immune-protective mechanisms [13].
Fetal trophoblast cells — Fetal trophoblast cells are the specific cell layer that protects the
embryo from those components of the maternal immune system dedicated to destroying
foreign tissues. The inner cell mass and resultant embryo are secluded and protected beneath a
layer of trophoblastic cells throughout pregnancy ( figure 1).
Trophoblast cells are derived from the external trophectoderm layer of the blastocyst and
develop into the placenta. Precursor trophoblast cells choose one of three developmental
pathways (see "Placental development and physiology" and "The placental pathology report"):
● They may remain quiescent in the villi as a pool of cells for future needs (villous
cytotrophoblast cells).
● They may proliferate and migrate/invade into the decidua, ultimately forming the chorion
membrane (extravillous cytotrophoblast cells). Extravillous trophoblast cells may also
interact with maternal decidual immune cells and invade into the maternal spiral arteries,
replacing the endothelial layer (endovascular trophoblast).
● They may merge into the developing syncytiotrophoblast through a process of cell fusion to
create a multinucleate cell layer. While this creates a barrier for the controlled movement
and transport of molecules, the placenta is not an impermeable barrier. There is evidence
for the bidirectional movement of maternal and fetal cells [14]. This may be explained, in
part, by the presence of gaps in the syncytiotrophoblast, particularly later in gestation [15].
Placental membranes — The placenta and its attached membranes can protect themselves
from maternal immune cell attack and modulate the local maternal immune system to promote
and maintain normal placentation and pregnancy. The mechanisms utilized vary with the state
of differentiation and anatomic location of the trophoblast cells. This cell type, which protects
the embryo itself as well as certain components of the extraembryonic membranes that are
derived from the inner cell mass, such as the amnion membrane, relies upon multiple
strategies to avoid detection by potentially cytotoxic maternal immune cells and antibody-
mediated cell destruction while influencing the local immune environment that is necessary for
successful pregnancy [4].
The placenta is not a typical transplant, since proteins derived from HLA genes are not
expressed codominantly on trophoblast cell membranes, unlike other cell types. (See "Human
leukocyte antigens (HLA): A roadmap" and "Transplantation immunobiology".)
● HLA class I – Strict regulation of the expression of specific HLA class I molecules in
subpopulations of trophoblasts is believed to protect the fetus against maternal immune
cells programmed to attack cells expressing foreign (paternal) HLA class I antigens. The
extravillous trophoblasts migrating into the decidua lack expression of HLA-A or HLA-B
class Ia antigens that are primary stimulators of classical graft rejection and instead display
a unique pattern of class Ia HLA-C and the nonclassical HLA class Ib molecules, HLA-E, HLA-
F, and HLA–G [1,17,18]. The genes encoding HLA-E, HLA-F, and HLA–G antigens have few
alleles in comparison with HLA-A and HLA-B. HLA-G, HLA-C, and HLA-F are expressed by first
trimester extravillous trophoblast, and, as gestation proceeds, their expression weakens
and becomes intracellular. HLA-E is expressed by the extravillous trophoblast only in the
first trimester [17].
HLA-C, HLA-E, HLA-G, and HLA-F may act to dampen or modulate maternal immune
responses by interacting with killer immunoglobulin-like receptors (KIRs) on decidual NK
(dNK) cells, macrophages, and a subset of T cells and with the T cell receptor on CD8+ T
cells [1,18-21]. The consequences of these interactions include activation of pathways in NK
cells and macrophages that interfere with the killer functions of these cells [22,23]. At the
same time, HLA-E and HLA-G may activate pathways in dNK cells, macrophages, and T cells
that promote trophoblast migration and placentation [18,24].
One mechanism by which HLA-G influences dNK cell and T cell function is through a
process of trogocytosis, in which a lymphocyte transfers plasma membrane fragments
containing cell surface molecules from an antigen-presenting cell to its own surface via the
immunologic synapse [18]. These acquired HLA-G+ NK and T cells are immunosuppressive
[25]. The HLA class Ia antigen, HLA-C, is expressed on extravillous trophoblast and may
have important interactions with leukocytes in some mothers [1,26]. As an example, certain
combinations of maternal KIRs and fetal HLA-C variants correlate with low birth weight and
preeclampsia [27,28]. HLA-C expression may be regulated by Nod-like receptor family pyrin
domain-containing 2 (NLRP2) [29].
HLA-G mRNA can be alternatively spliced to yield membrane-bound and soluble variants.
Soluble HLA-G is associated with immunomodulatory functions and promotion of
placentation [18,30]. Antigen-presenting cells expressing either a soluble or membrane-
bound form of HLA-G repress T cell alloproliferation via this pathway [31]. Soluble HLA-G
(HLA-G5) has been identified in maternal serum, is biochemically unique among the HLA-G
isoforms, and is associated with specific immune modulation and the promotion of a pro-
placentation environment [32-36].
● HLA class II – The genes that encode potentially dangerous paternally derived foreign HLA
class II HLA-D region molecules are entirely repressed in trophoblast cells. None of the
trophoblast subpopulations express HLA class II antigens either in vivo or in vitro. Control
over transcription of class II genes may be exerted by silencing of expression of the class II
transactivator (CIITA), a transacting factor that is essential for constitutive and interferon
(IFN) gamma-inducible MHC class II gene transcription [40].
● TNF superfamily – Apoptosis-inducing members of the TNF supergene family may also
have important roles in protecting the placenta and its membranes by inducing apoptosis
in potentially cytotoxic T cells. The ligands identified in and/or on human trophoblasts
include TNF-alpha, FasL, and TRAIL, as well as a number of less well-characterized TNF
superfamily members [46-49]. Some of these latter ligands, which include B cell-activating
factor (BAFF), may positively influence pregnancy host defenses by supporting maternal
and/or fetal antibody production [50].
All of these molecules, which are expressed as both membrane and soluble forms, can kill
activated immune cells targeting the trophoblast by transducing an apoptotic signal via
specific receptors on activated leukocytes. FasL may be of particular importance since FasL
prevents immune cell attack by interacting with leukocyte receptors (eg, Fas) in other
organs such as the eye and the testis.
Mothers routinely produce high titers of antibodies to paternally derived HLA and unique
trophoblast antigens, such as the unique placental isoform of alkaline phosphatase. Antibody
induction of complement-mediated lysis is prevented by high expression of CD46 and DAF in
various subpopulations of trophoblast cells.
Evidence supporting a role for complement proteins in placental immune protection is provided
by genetic deletion experiments. In mice, the absence of the complement regulatory protein
derived from Crry gene leads to placental disruption due to complement deposition in the
placenta and lysis of cells at the implantation site, followed by a massive inflammatory reaction
and fetal demise [68].
Dramatic changes take place in the uterus during pregnancy that also help contribute to
immune acceptance of and/or crosstalk with the fetus/placenta to promote a successful
pregnancy.
Similarly, the major roles of dNK cells may also be unique to pregnancy [86]. Although dNK cells
express a high level of cytotoxic factors, they are unable to form cytotoxic synapses to deliver
granule contents [87] and instead appear to play a role in trophoblast attraction and invasion,
decidual and placental angiogenesis and possibly fetal vasculogenesis, and vascular
modifications in the uterus [88-91]. A population of uNK cells that are found in repeated
pregnancies has been identified. These "memory-like" uNK cells may be involved in promoting
placentation [92]. One study proposed that uNK cells maintain endometrial homeostasis by
clearing senescent decidual cells [93]. As with macrophages, alterations in dNK cell numbers
and activation status may play a role in pregnancy complications, such as immunologic
infertility, recurrent spontaneous abortion, and preeclampsia [27,28,94-98]. Excessive dNK cell
recruitment and/or expansion, as well as elevated cytotoxic activity, have been associated with
pregnancy disorders such as implantation failure and miscarriage [97]. However, some studies
suggest the opposite that deficiencies in uNK numbers are associated with recurrent pregnancy
loss, highlighting the need to reassess approaches to NK cell profiling in patients with adverse
outcomes [99,100]. NK cell depletion compromises pregnancy in mice, further underscoring
their importance during pregnancy [101].
Innate lymphoid cells (ILCs) distinct from NK cells have been characterized in the human
decidua. During early pregnancy, group 3 ILCs (ILC3) are found. While their function is not fully
understood, ILC3s may establish functional interactions with stromal cells, regulate the
recruitment and function of other maternal immune cells, and contribute to vascular
remodeling [102,103]. At term, both ILC2s and ILC3s have been found in the decidua, and levels
may increase in preterm birth [104].
The role of decidual dendritic cells (dDCs) is less clear, although mouse studies have
demonstrated that these cells are critical for successful implantation and may also be involved
in remodeling of the maternal vasculature [6,105,106]. However, alternative views exist. One is
that dendritic cells may promote systemic immune tolerance during pregnancy [107]. Another
is that dendritic cells are trapped in the decidua to prevent the exposure of peripheral T cells to
fetal antigens [108]. Uterine dendritic cells are also thought to contribute to pregnancy success
by influencing NK cell function and the cytokine profile at the maternal-fetal interface [109].
Depletion of uterine dendritic cells in mice results in a severe impairment of implantation and
embryo resorptions, highlighting their importance [106]. Preeclampsia is also associated with
persistence of decidual basalis macrophages and recruitment of dendritic cells [110,111]. One
hindrance of our understanding of the presence and function of dendritic cells at the maternal-
fetal interface is that there are many subpopulations, and there is a lack of comprehensive
phenotyping. However, new immunophenotyping approaches are emerging [112].
CD4+CD25+ regulatory T cells (Tregs) are also present in the decidua of normal pregnant
females, and their presence and expansion during pregnancy are thought to be triggered in
both alloantigen-dependent and alloantigen–independent manners [5,120,121]. In human
cocultures of HLA-G+ extravillous trophoblast cells and CD4+ T cells, there is an increase in the
number of cells expressing a Treg phenotype [122]. These fetal-specific Tregs persist after
delivery and rapidly reaccumulate during subsequent pregnancies, indicating a memory
response [123]. In a mouse model, increased numbers of Tregs are seen in response to an
antigenic fetus [124]. Selective killing of these Tregs results in fewer antigenic offspring. There
are decreased numbers of peripheral blood and decidual Treg cells in females with
preeclampsia compared with normal pregnancy subjects. These findings suggest that Tregs
play a role in maternal tolerance to the fetus [121,125,126].
A subpopulation of CD4+ interleukin (IL) 17-producing T cells (T helper cell type 17 [Th17]) have
also been described in pregnancy. Their numbers are also expanded in the pregnant uterus,
although not as much as CD4+CD25+ Tregs. While they are inflammatory in nature, the presence
of Th17 cells may play a role in protecting the maternal-fetal interface from microbes, and the
Tregs present may serve to regulate their function. Thus, altered numbers of Th17 and/or ratio
of Th17 to Tregs are associated with pregnancy complications, such a spontaneous abortion,
preeclampsia, and preterm birth [121,127].
Mast cells are classically associated with allergic immune responses. However, in pregnancy,
their presence in the decidua may contribute to successful placentation. Uterine mast cells
expand in early pregnancy in the mouse [128] and are higher in human pregnancies compared
with nonpregnant females [129]. In the mouse, they have been shown to promote an
antiinflammatory state and contribute to tissue remodeling, angiogenesis, and spiral artery
transformation [128].
High concentrations of progesterone can suppress the maternal immune response [134]. As an
example, progesterone alters the T helper cell type 1 (Th1)/T helper cell type 2 (Th2) balance
and inhibits production of tumor necrosis factor (TNF) alpha in both mouse and human
macrophages [135,136].
Prostaglandin E2 — Prostaglandin E2 (PGE2) is produced by resident macrophages and
decidual cells. Lymphocytes proliferate poorly in the presence of this compound.
Cytokines — High levels of Th2-type cytokines are typical of mouse pregnancy [137,138] but
are less definitive in pregnant females. Nonetheless, many still consider human pregnancy to
be a Th2 antiinflammatory condition and that a shift towards Th1 cytokines will lead to abortion
or pregnancy complications. As an example, elevated levels of IL-6 in cervicovaginal and
amniotic fluid, but not plasma, was associated with spontaneous preterm birth [139]. Similarly
high levels of proinflammatory IL-1-beta and TNF-alpha in the amniotic fluids are associated
with preterm birth [140,141]. While disruption in cytokine profiles during pregnancy may be
detrimental, it is important to appreciate that human pregnancy is both proinflammatory and
antiinflammatory, depending upon the stage of gestation, rather than focusing on the murine
Th1/Th2 terminology [4,120,142]. What is clear is that the appropriate balance of cytokine and
chemokine expression at the maternal-fetal interface can govern the immune cell profile and
function within the decidua. For example, one study demonstrated in mice that effector T cells
cannot accumulate within the decidua, in part because of the epigenetic silencing of key
chemokine genes in decidual stromal cells [143]. In contrast, the expression of specific
cytokines and chemokines by the decidua and placenta are critical for recruitment and
maintenance of pro-pregnancy immune cells [144].
The pregnant immune system bears markers of both immune activation and dampening.
However, the consensus is that there is no generalized immunosuppression of maternal
immune responses in pregnancy. However, selective suppression or modulation may occur.
Studies have reported a decrease in proinflammatory capacity with dampening of the response
to microbial stimulation, while others have reported more monocyte-derived interleukin (IL) 12
in response to lipopolysaccharide (LPS) [145-149], for example. Thus, it appears that skewing
adjusts the maternal response to microbial challenge rather than effecting a global
suppression. In addition, the release of placental-derived microparticles may play a key role in
systemic maternal immune regulation [54-56].
Although multiparous females are excellent sources of antibodies to paternal human leukocyte
antigens (HLAs), maternal B lymphocytes specific for paternal HLA are partially deleted during
pregnancy. In addition, T lymphocytes specific for paternal HLA are difficult to demonstrate.
Results in transgenic mice suggest that pregnancy selectively depresses maternal T cells that
recognize paternal H-2 class I histocompatibility antigen [150]. (See "The adaptive humoral
immune response".)
There are at least two mechanisms for overcoming most immune reactions: One is active
suppression, and the other is enhanced tolerance. Enhanced tolerance has been clearly
demonstrated in normal pregnancy. Regulatory T cells (Tregs), which are critical mediators of
tolerance, become more numerous in pregnancy in response to the introduction of fetal
(paternal) antigens [151-154]. These Tregs produce IL-10, which appears to play a role in
maintaining pregnancy. In animals, IL-10 blockade increased the rate of abortions, although
successful pregnancy was still possible [155,156]. A population of IL-10 producing CD19+CD24hi
CD27+ regulatory B cells expands during normal pregnancy, and their role may be to suppress
undesired immune responses from maternal T cells [157].
IMMUNE FACTORS IN EARLY PREGNANCY LOSS
A high number of potential pregnancies are lost prior to or during implantation, based upon
the identification of chorionic gonadotropin (human growth hormone [hCG]) in females.
Spontaneous miscarriage before 20 weeks of gestation affects 15 to 20 percent of pregnant
females in the US [158]. While approximately 60 percent of miscarriages can be accounted for
by chromosomally abnormal embryos, the remainder are idiopathic [158] and, in many cases,
are thought to arise from implantation failure [159]. Whether any of these losses can be
accurately attributed to an immunologic cause (ie, based on maternal recognition and rejection
of normal embryos expressing paternal antigens) remains unclear despite research. In contrast,
recurrent embryonic losses due to genetic and endocrine abnormalities are well documented,
as are miscarriages due to infection and antiphospholipid antibodies. (See "Pregnancy loss
(miscarriage): Terminology, risk factors, and etiology" and "Causes of female infertility".)
Alternatively, some mothers with recurrent spontaneous abortions may lack essential
components of the described networks that provide immunologic protection to the embryos.
The most well-described immunologic dysregulation in females with infertility and recurrent
pregnancy losses (RPL) is related to natural killer (NK) cell numbers and function. In general,
excessive uterine NK (uNK) cell recruitment and/or expansion, as well as elevated cytotoxic
activity, are associated with implantation failure and RPL. Similarly, altered peripheral blood NK
(pNK) cells populations may also correlate with pregnancy losses and are a potential diagnostic
marker [97]. Consequently, there have been efforts targeting NK cells in an attempt to cure
infertility and miscarriage; however, well-controlled trials are lacking [161,162]. Alterations of
the T helper cell type 17 (Th17)/regulatory T cell (Treg) ratio both locally at the maternal-fetal
interface and systemically are also associated with RPL [97], as are elevated levels of peripheral
blood myeloid dendritic cells [163].
Contributions of the fetal immune system to maternal-fetal immunologic interactions are not
well understood. Some evidence suggests that the fetal immune system is unable to mount an
anti-maternal immune response until mid- to late pregnancy. As an example, placental
macrophages do not express human leukocyte antigen (HLA) class II antigens until the second
trimester. Therefore, they are incapable of acting as fully effective antigen-presenting cells until
this time [195]. In contrast, another study showed that fetal T cells were highly responsive to
stimulation but were biased towards developing into regulatory T cells (Tregs), which are
important in tolerance [196]. However, if fetal T cells are able to mount a response to maternal
antigens, these fetal T cells may play a role in preterm labor [197].
FUTURE DIRECTIONS
Although much is now known of the immunologic conditions that lead to successful pregnancy,
much remains to be learned. Promising areas of research include the involvement of human
leukocyte antigen (HLA) G in angiogenesis and autoimmune disorders and the effect of
complement activation on dysregulation of angiogenesis leading to intrauterine fetal growth
restriction [199-201]. Utilization of new genomics, proteomics, and immunophenotyping
techniques may assist [112,202]. Immunomodulators and/or manipulation of innate immune
processes may also provide new avenues for therapeutics [194,203].
SUMMARY
● Prevention of immune rejection of the fetus requires local immunologic adaptations within
the mother, resulting in a state in which cytotoxic adaptive immune responses are
diminished, bypassed, or even abrogated while regulatory adaptive immunity is enhanced.
In contrast, innate (natural) immunity remains intact, serving two purposes: one, to
continue to provide host defense against infection, and two, to interact with fetal tissues to
promote successful placentation and pregnancy. (See 'Introduction' above.)
● Trophoblast cells protect the embryo itself and certain components of the extraembryonic
membranes. Multiple strategies are used by these cells to avoid maternal immune cells and
antibody-mediated cell destruction, including altered human leukocyte antigen (HLA)
expression, synthesis of immunoregulatory molecules, and expression of high levels of
complement regulatory proteins that protect the extraembryonic tissues from maternal
anti-paternal cytotoxic antibodies. (See 'Immune defense mechanisms of the placenta and
extraplacental membranes' above.)
● Uterine changes during pregnancy also help contribute to maternal immune adaptation,
including alterations in the relative proportions, phenotype, and functions of leukocyte
subpopulations, induction of immunoregulatory molecules (progesterone, prostaglandins),
and changes in cytokine profiles across gestation. (See 'Local immune adaptation in the
pregnant uterus' above.)
ACKNOWLEDGMENT
The editorial staff at UpToDate would like to acknowledge E Richard Stiehm, MD, who
contributed as a Section Editor to an earlier version of this topic review.
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Topic 3966 Version 23.0
GRAPHICS
Embryo and the trophoblast at the end of the third week of development
Presomite embryo and the trophoblast at the end of the third week. Tertiary and secondary stem villi give the trophoblast
a characteristic radial appearance. Intervillous spaces, which are found throughout the trophoblast, are lined with
syncytium. Cytotrophoblastic cells surround the trophoblast entirely and are in direct contact with the endometrium. The
embryo is suspended in the chorionic cavity by means of the connecting stalk.
Reproduced with permission from: Sadler TW. Langman's Medical Embryology, 13th Edition, Lippincott Williams & Wilkins, Philadelphia
2015. Copyright © 2015 Lippincott Williams & Wilkins. www.lww.com.
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