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Research and Reports in Biology 2015:6 171–189
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The maternal immune system during pregnancy
and its inuence on fetal development
Sara S Morelli1
Mili Mandal2
Laura T Goldsmith1
Banafsheh N Kashani1
Nicholas M Ponzio3,4
1Department of Obstetrics,
Gynecology and Women’s Health,
New Jersey Medical School, Rutgers
University, Newark, 2Department of
Pha rma col ogy and Toxicology, Ern est
Mario School of Pharmacy, Rutgers
University, Piscataway, 3Department of
Pathology and Laboratory Medicine,
New Jersey Medical School, Rutgers
University, Newark, 4Graduate School
of Biomedical Sciences, Rutgers
University, Newark, NJ, USA
Correspondence: Sara S Morelli
Department of Obstetrics, Gynecology
and Women’s Health, New Jersey
Medical School, Rutgers University,
MSB E-506, 185 South Orange
Avenue, Newark, NJ 07103, USA
Tel +1 973 972 4127
Fax +1 973 972 4574
Email morellsa@njms.rutgers.edu
Abstract: The maternal immune system plays a critical role in the establishment, maintenance,
and completion of a healthy pregnancy. However, the specific mechanisms utilized to achieve
these goals are not well understood. Various cells and molecules of the immune system are key
players in the development and function of the placenta and the fetus. Effector cells of the immune
system act to promote and yet limit placental development. The T helper 1 (Th1)/T helper 2 (Th2)
immune shift during pregnancy is well established. A fine balance between proinflammatory
and anti-inflammatory influences is required. We herein review the evidence regarding maternal
tolerance of fetal tissues and the underlying cell-mediated immune and humoral (hormones and
cytokines) mechanisms. We also note the many unanswered questions in our understanding of
these mechanisms. In addition, we summarize the clinical manifestations of an altered mater-
nal immune system during pregnancy related to susceptibility to common viral, bacterial, and
parasitic infections, as well as to autoimmune diseases.
Keywords: maternal–fetal interface, immune system, fetal tolerance, lymphocyte subsets,
decidua, pregnancy
Introduction
The relationship between mother and fetus has fascinated immunologists for decades.
Survival of the semiallogeneic fetus was used by Billingham et al1 in 1953 as an
example of immune tolerance to the fetus by the maternal immune system. Numerous
hypotheses related to placental protection of the fetus, including expression (or lack
of expression) of histocompatibility antigens on fetal tissues, maternal immune toler-
ance to fetal antigens, and inhibition and/or regulation of maternal antifetal immune
responses have been put forth to explain the survival of the “immunogenic” fetus. Yet,
the mechanisms still remain to be totally clarified.
Part of the difficulty in studying these mechanisms is due to the variation among
species in which such investigations are conducted. Mice are used for many of these
investigations because of their short gestational time, relatively lower cost, well-defined
genetics (including mutant, transgenic, and knockout strains), and availability of a
wide spectrum of antibodies and reagents to perform immunologic and molecular
studies. However, differences in the reproductive system in general, and the feto–
materno–placental unit in particular, as well as differences in the development and
function of immune elements, often preclude direct extension of results observed in
mice to humans. In contrast, studies designed to investigate such questions in humans
are unethical, and studies incorporating nonhuman primates for these investigations
raise similar moral issues and are also prohibitively expensive.
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Morelli et al
Therefore, our review is not designed to address all the
unanswered questions surrounding the significance of the
maternal immune system during pregnancy and its influence
on fetal development. Rather, our goals are to identify the
gaps in the knowledge and understanding about the topic
from the published literature about various species and to
acknowledge contexts wherein differences preclude a direct
comparison with humans. Notwithstanding these differences
however, investigations conducted in other species, such
as rodents, do serve to identify possible strategies to address
some of these unanswered questions.
Additionally, we take an interdisciplinary approach as
coauthors who bring clinical and basic science perspectives
and expertise in reproductive and immunological disciplines.
Thus, we address topics related to definition of the maternal–
fetal interface, as well as the significance of maternal immune
responses in regulating key early events during both preg-
nancy (eg, implantation, angiogenesis, and vascular remodel-
ing) and in development of the fetal immune system. We then
review current understanding about maternal tolerance of
fetal tissues and the underlying cellular and humoral immune
mechanisms. Finally, we examine clinical manifestations of
an altered maternal immune system during pregnancy related
to susceptibility to certain viral, bacterial, and parasitic infec-
tions, as well as to autoimmune disorders.
Description and denition of the
maternal–fetal interface
Maternal: decidua
In women, invasion by the trophoblast is extensive,
encompassing the endometrium as well as the inner third
of the myometrium.2 To accommodate this, a pronounced
remodeling process must occur, involving multiple cellular
compartments of the uterus in preparation for implantation
and establishment and support of pregnancy. This process,
decidualization, occurs in humans on a cyclic basis beginning
in the midluteal phase of the menstrual cycle, independently
of pregnancy. In contrast, in rodents and most other species,
decidualization requires the presence of a blastocyst. The
term maternal decidua thus refers to the uterine mucosal
layer (endometrium) after it has undergone decidualization,
the requisite and complex differentiation process involving
the multiple cellular compartments of the endometrium in
preparation for embryo implantation.
The parenchymal cellular compartments of the maternal
decidua include the glandular epithelial compartment, the
luminal epithelial compartment, the endothelium of the spiral
arteries, and the decidualized stromal cells, all of which
undergo dramatic transformation in preparation for pregnancy.
The glandular epithelium acquires increased secretory activ-
ity under the influence of maternal progesterone.3 Dramatic
remodeling of spiral arteries occurs during decidualization,
discussed in greater detail later in this review. The endome-
trial stromal fibroblasts that undergo dramatic morphologic
and biochemical differentiation in preparation for implanta-
tion and support of pregnancy become known as decidual
cells, or decidualized stromal cells. Decidualized stromal
cells no longer have the characteristic spindle shape of the
endometrial stromal fibroblast and, instead, have acquired
an epithelioid phenotype, characterized by progressive cell
enlargement, rounding of the nucleus, and expansion of the
rough endoplasmic reticulum and Golgi complex, all con-
sistent with the transformation into a secretory cell.3 Major
secretory products of decidualized stromal cells include
prolactin and insulin-like growth-factor-binding protein-1,
the hallmark proteins widely used as phenotypic markers of
decidualization.4 These cells also secrete a number of cytok-
ines and growth factors (eg, interleukin [IL]-11, epidermal
growth factor [EGF], heparin-binding EGF-like growth
factor), which further regulate the process of decidualization
in an autocrine and/or paracrine manner.5
In addition to the parenchymal cellular compartments
making up the maternal decidua, various populations of
immune cells exist in the human endometrium throughout
the menstrual cycle. In early pregnancy, leukocytes are
abundant, comprising 30%–40% of all human decidual
stromal compartment cells.6 The basalis layer of the human
endometrium contains lymphoid aggregates composed of
T-cells and a small number of B-cells. In the functionalis layer
of the proliferative phase, few uterine natural killer (uNK)
cells, T-cells, and macrophages are scattered throughout the
stromal compartment.7 Although the numbers of T-cells and
macrophages remain largely unchanged throughout the luteal
phase and during the process of decidualization,7 there is a
dramatic increase in the number of uNK cells postovulation,
playing a critical role in preparation of the endometrium for
pregnancy. With regard to decidual immune cell popula-
tions during early pregnancy, studies using flow cytometry
and immunostaining of human tissues demonstrate that the
majority of first-trimester human decidual leukocytes are
uNK cells (∼70%), followed by macrophages (∼20%).8 T-cells
make up approximately 10%–20% of decidual leukocytes,
and dendritic cells (DCs) and B-cells are rare.8 As in humans,
uNK cells are the predominant leukocyte population in the
decidua of the rhesus macaque and the mouse, but studies to
determine relative numbers of other leukocyte populations in
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Maternal immune system and fetal development
murine decidua are lacking. The functions of each immune
cell type at the maternal–fetal interface are discussed in more
detail in this review, with a particular focus on uNK cells.
Fetal: placenta, fetal membranes
(amnion and chorion)
Structurally, the interface between the uterine mucosa
and the extraembryonic tissues is commonly referred
to as the maternal–fetal interface. This is represented in
Figure 1, which depicts the maternal immune cells and the
fetal trophoblast.9
Extraembryonic cells in direct contact with maternal
cells are the trophoblast cells, derived from the trophecto-
derm layer surrounding the blastocyst. In women, invasion
by the trophoblast into maternal spiral arteries substantially
increases uterine blood flow, puts maternal blood in direct
contact with fetal trophoblast cells, and ensures sufficient
delivery of maternal nutrients and oxygen to the placenta.10
However, the maternal and fetal circulations do not mix.
After attachment of the blastocyst to the endometrial luminal
epithelium, trophoblast cells invade the decidua as depicted
in Figure 1. The trophoblast, composed of an inner cell layer
(cytotrophoblast) and outer cell layer (syncytiotrophoblast),
does not give rise to the fetus itself, but rather to the placenta
and fetal membranes (amnion and chorion). As the blastocyst
and surrounding trophoblast invade the decidua, one pole
of the blastocyst remains oriented toward the endometrial
lumen, and the other remains buried in the decidua, which will
develop into the anchoring cytotrophoblasts and villous tro-
phoblasts, contributing to formation of the placenta, chorion,
and amnion. Of note are the species differences in the degree
of invasion by trophoblast cells, which have been documented
in detail elsewhere.11 In distinct contrast to the process in
women, trophoblast invasion is minimal in rodents.11,12
Signicance of maternal immune
responses during pregnancy
Immune cell subtypes and their
functional signicance
Immune cells accumulating in the human endometrium at
the time of decidualization play critical and diverse roles
at the maternal–fetal interface, including functions in
implantation, placental development, and immunity against
infectious diseases. Of all decidual leukocyte populations,
the most abundant are the phenotypically unique uNK
cells. These cells dramatically increase in number in the
human endometrium 3–5 days postovulation, accounting for
25%–40% of endometrial leukocytes prior to implantation
Mother
(decidua)
Fetus
(placenta)
Trophoblast
Luminal epithelium
Macrophage
B-cell
Dendritic cell
Th cell
Tc cell
uNK cell
Decidual
stromal cell
Figure 1 Schematic depiction of the human maternal–fetal interface including maternal immune cells such as uterine natural killer (uNK) cells, macrophages, (the predominant
immune cell types) and T helper (Th) cells, T-cytotoxic (Tc) cells, dendritic cells, as well as invading trophoblast cells.
Notes: Copyright © 2009 by SAGE Publications. Modied from: Weiss G, Goldsmith LT, Taylor RN, Bellet D, Taylor HS. Inammation in reproductive disorders. Reproductive
Sciences. 2009;16(2):216–229; by permission of SAGE Publications.9
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Morelli et al
and accounting for ∼70% of decidual leukocytes in the first
trimester.7,8 It is critical to note that uNK cells are both
phenotypically and functionally distinct from peripheral
NK cells. Phenotypically, they are identified by expression
of the NK cell marker CD56, expressed at high concentra-
tions (CD56bright), but they lack expression of CD16, found
on most peripheral NK cells (CD56dimCD16+).7 In terms
of function, peripheral CD56dimCD16+ NK cells are highly
cytotoxic, mediating both natural and antibody-dependent
killing, whereas uNK cells are only weakly cytotoxic and
do not normally kill trophoblast cells.13 In addition, uNK
cells are a potent source of immunoregulatory cytokines,14
matrix metalloproteinases (MMPs),15 and angiogenic fac-
tors.16 These various factors mediate extracellular matrix
remodeling, trophoblast invasion, and angiogenesis, which
are key processes in placentation and establishment of early
pregnancy at the maternal-fetal interface.17
In addition to uNK cells, decidual macrophages are rela-
tively abundant, comprising ∼20% of the human decidual leu-
kocyte population in the first trimester.8 In normal pregnancy,
most of the macrophages at the maternal–fetal interface are
of the M2 (immunomodulatory) phenotype.18 Present in
decidua prior to the presence of extravillous trophoblast,19
macrophages play a role in early spiral artery remodeling
by producing factors associated with tissue remodeling
(MMP-9) and angiogenesis (vascular endothelial growth fac-
tor [VEGF]).18 Apoptosis is an important event during spiral
artery remodeling and trophoblast invasion, and decidual
macrophages phagocytose apoptotic cells in remodeled vas-
cular wall and apoptotic trophoblast cells, thereby preventing
the release of proinflammatory substances from the apoptotic
cells into the decidua.20 First-trimester decidual macrophages
may also be responsible for inhibition of human uNK cell–
mediated lysis of invasive cytotrophoblast, mediated by
decidual secretion of transforming growth factor-beta-1
(TGF-β1), as demonstrated in human in vitro studies.21 In
distinct contrast to human uNK cells, which peak in number
at 20 weeks gestation and are nearly absent in the decidua at
term,12 decidual macrophages are present throughout preg-
nancy, but the precise role of decidual macrophages at the
end of pregnancy remains unknown.18
T-cells are also fairly abundant in human decidua,
comprising ∼10%–20% of the human decidual leukocyte
population,22,23 of which 30%–45% are CD4+ T-cells and
45%–75% are CD8+ T-cells.23 The main function of T-cells
in the decidua, particularly of CD4+ T-regulatory (Treg) cells,
is generally thought to be the promotion of tolerance to the
fetus24 (discussed in detail later in this review). However,
because a variety of different T-cell subsets are present, the
complex interactions of T-cells in the decidua have not been
completely defined.25 Human in vitro studies of CD8+ T-cells
isolated from first-trimester decidua demonstrate that these
cells exhibit cytotoxic activity as well as cytokine produc-
tion (predominantly interferon-gamma [IFN-γ] and IL-8).26
Since decidual CD8+ T-cell supernatants increase the in vitro
invasive capacity of extravillous trophoblast cells, secreted
products of CD8+ T-cells may play a role in regulation of
trophoblast invasion, but precise mediators have not yet
been identified.26
DCs, which are antigen-presenting cells that play a critical
role in regulation of the adaptive immune response, make up
a very small portion of human decidual leukocytes. However,
no single specific marker for DCs exists and their phenotypic
definition is therefore controversial, thereby limiting the
existing studies of decidual DCs.27 Using lineage-negative
and human leukocyte antigen-DR-positive (HLA-DR+) status
as a combination marker for DCs, Gardner and Moffett28
demonstrated that decidual DCs comprised ∼1% of first-
trimester human decidual leukocytes. Due to the rarity of
this cell population, functional studies of human decidual
DCs are scarce. Human in vitro studies have demonstrated
that decidual DCs, isolated from early-pregnancy decidua,
are more likely than peripheral DCs to prime naïve CD4+
T-cells into a Th2 phenotype, suggesting a potential role
for decidual DCs in averting Th1-mediated rejection of
the fetus.29 Decidual DCs also appear to regulate uNK cell
function, since coculture of decidual DCs with uNK cells
stimulated uNK cell proliferation and activation.30 In vivo
functional studies of decidual DCs exist only in mice and
are more definitive. Decidual DC–depleted mice exhibit
severely impaired implantation, impaired decidual prolif-
eration and differentiation, impaired angiogenesis, impaired
differentiation of uNK cells, and resorption of embryos.31,32
Therefore, at least in mice, decidual DCs play an important
role in decidualization and establishment and maintenance
of early pregnancy.
Mechanisms by which immune cells
(focus: uNK cells) regulate key early
events in establishment of pregnancy:
implantation, angiogenesis, and vascular
remodeling
uNK cells regulate trophoblast invasion
Studies performed by Hanna et al33 provided strong evi-
dence that human uNK cells play a role in regulation of
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Maternal immune system and fetal development
trophoblast invasion. These investigators demonstrated
that uNK cells isolated from first-trimester human decidua
express the chemokines IL-8 and IFN-inducible protein (IP)-
10, and that purified human invasive trophoblasts express
the chemokine receptors for these ligands: CXCR1 (IL-8
receptor) and CXCR3 (IP-10 receptor). The ability of uNK
cells, but not peripheral blood NK cells, to induce trophoblast
migration in an in vitro trophoblast migration assay was
significantly reduced in the presence of neutralizing anti-
bodies to IL-8 and IP-10. These investigators subsequently
performed in vivo studies in which NK cell subsets embed-
ded in Matrigel were injected into the subcutaneous tissues
of nude mice, and human trophoblast cells were injected
around the Matrigel plug. These in vivo experiments further
demonstrated that uterine, but not peripheral, NK cells pro-
moted trophoblast invasion, and that migration of tropho-
blast cells into the Matrigel plug was significantly reduced
in the presence of IL-8- and IP-10-neutralizing antibodies.
Overall, these studies demonstrated the ability of uNK cells
to positively regulate invasion of trophoblast, mediated by
the uNK-derived cytokines IL-8 and IP-10.33 However, tro-
phoblast invasiveness into maternal decidua must be tightly
regulated. The balance of factors involved in regulation of
invasion is not yet precisely determined. Excessive invasion
predisposes to placenta accreta, a potentially life-threatening
obstetrical condition in which the placenta attaches abnor-
mally to the uterine myometrium.34 Interestingly, human uNK
cells also have the ability to inhibit trophoblast invasion, as
demonstrated by Lash et al35 using in vitro Matrigel inva-
sion assays. These investigators demonstrated that human
uNK cells isolated from early human pregnancy decidua
are a source of IFN-γ, which inhibits trophoblast invasion
by increasing apoptosis of extravillous trophoblast cells and
decreasing trophoblast secretion of MMP-2.35 Thus, the fine
balance required to avoid either underinvasion or overinva-
sion of trophoblast in early human pregnancy is regulated, at
least in part, by the various cytokines derived from human
uNK cells present in decidua.
Role of uNK cells in angiogenesis and vascular
remodeling in early pregnancy
In humans, extensive vascular remodeling must occur to
allow for placentation and establishment of early pregnancy,
as well as to support the demands of a growing fetus. The
decidual spiral arteries must be transformed into larger-
diameter vessels with low resistance and high flow, capable of
transporting nutrients and oxygen to the fetus.22 In addition,
the endothelium of these vessels is replaced by extravillous
trophoblast cells that have migrated from the placenta,
allowing for diversion of blood flow into the space surround-
ing the placental villous tree and thereby permitting nutrient
and gas exchange between mother and fetus.36 Not only is
adequate vascular remodeling critical for the establishment
of a normal pregnancy, but abnormalities in these early events
are associated with later complications of pregnancy such as
preeclampsia and intrauterine growth restriction, which can
have a major impact on fetal and neonatal health.34
A critical role for uNK cells in vascular remodeling has
been demonstrated in both murine in vivo and human in
vitro studies. However, it is important to note significant
differences among species in terms of strategies to increase
blood flow to the site of maternal–placental exchange. In
humans, extensive invasion and destruction of preexisting
arteries by trophoblast occurs. In nonhuman primates such
as rhesus macaques, trophoblastic invasion and modification
of uterine arteries occurs, but unlike in humans, invasion of
decidual stroma by trophoblast in the rhesus monkey occurs
only to a minimal extent.12 In mice, the extent to which the
trophoblast invades both the decidual stroma and uterine
arteries is even more limited.12 Rodent models thus have
limited value in advancing our understanding of mechanisms
of vascular remodeling that facilitate human pregnancy.
Nevertheless, there are in vivo studies performed in mice
that cannot be performed in humans, and the availability
of nonhuman primates for such in vivo studies in early
pregnancy is limited. Therefore, much of the existing data
on uNK cell functions in vascular remodeling are derived
from murine studies.
Multiple murine in vivo studies demonstrate that uNK
cells play a critical role in the remodeling of endometrial
spiral arteries both prior to and during pregnancy. The
earliest studies demonstrating a critical role for uNK cells
in vascular remodeling in pregnancy were those conducted
by Guimond et al,37 who demonstrated several reproductive
abnormalities in the TgΕ26 mouse strain, which is deficient
in NK cells. Multiple vascular abnormalities associated
with implantation sites, including thickening of the media
and adventitia, endothelial damage, reduction in placental
size, and onset of fetal loss at Day 10 of gestation, were
demonstrated in NK-cell-deficient mice. Subsequent studies
from the same laboratory38 demonstrated that bone marrow
transplantation from severe combined immunodeficient
mice (which lack T- and B- lymphocytes but not NK cells)
to NK-cell-deficient mice led to restoration of the uNK cell
population in recipients, reduced anomalies in decidual
blood vessels, increased placental size, and restored fetal
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Morelli et al
viability. Overall, these studies provide strong support
for a critical role of murine uNK cells in decidualiza-
tion, placentation, and the appropriate vascularization of
implantation sites.
The role of murine uNK cells in vascular remodeling
and decidualization appears to be mediated via IFN-γ, since
transgenic mice that lack IFN-γ or its receptor fail to initi-
ate modification of decidual arteries and exhibit necrosis
of decidual cells, and treatment of NK-deficient mice with
recombinant IFN-γ rescues decidual morphology and initiates
decidual vessel modification.39,40 However, whether human
uNK cells regulate decidual vascular remodeling via IFN-γ
is yet to be definitively determined. The data regarding IFN-γ
expression by human uNK cells are conflicting, likely due to
differences in methodology between studies and the status of
cytokine stimulation of the uNK cells being studied. Evidence
for production of IFN-γ in unstimulated human uNK cells
is limited, but after exposure to stimulatory cytokines such
as IL-2, IL-12, or IL-15, human uNK cells isolated from
first-trimester decidua exhibit significantly increased IFN-γ
secretion.41,42 In addition, because IFN-γ is rapidly secreted
once produced, and expression of IFN-γ mRNA and protein
by human uNK cells rapidly decreases after 24–48 hours
in culture,35 conflicting data regarding IFN-γ expression by
human uNK cells may be attributable to length of time in
culture before measurement. In a nonhuman primate model
of early pregnancy, the major population of CD56bright uNK
cells isolated from early-pregnancy rhesus monkey decidua
is not a source of IFN-γ.43 Therefore, while compelling evi-
dence exists to support the role of IFN-γ in decidual vascular
remodeling in rodents, whether uNK cell-derived IFN-γ plays
an equally important role in vascular remodeling in humans
and in nonhuman primates remains unclear.
Rather, the finding that human uNK cells isolated from
first-trimester decidua are a potent source of the angiogenic
factors angiopoietin (Ang)1, Ang2, VEGF, and PLGF16,33 sup-
ports an important role for these cells in the vascular remod-
eling required for successful human pregnancy. Functional
studies by Hanna et al33 demonstrated that human uNK cells
isolated from first-trimester decidua are potent secretors of
angiogenic factors such as VEGF and placental growth factor
(PLGF). Supernatants derived from human uterine (but not
peripheral) NK cells promoted in vitro angiogenesis, as dem-
onstrated by an increased ability of human umbilical vascular
endothelial cells to form network-like structures, a process
inhibited in the presence of VEGF- and PLGF-neutralizing
proteins. In addition, these investigators33 demonstrated the
in vivo ability of human uNK cells to promote angiogenesis
and growth of human trophoblast choriocarcinoma (JEG-3)
tumor cells when injected subcutaneously into nude mice.
In vivo angiogenic properties of uNK cells were inhibited
in the presence of a VEGF- and PLGF-neutralizing protein.
These studies provide strong evidence that the angiogenic
properties of human uNK cells are mediated, at least in part,
by their secretion of VEGF and PLGF.
Inuence of maternal immune
response on development of
the fetal immune system
Compelling clinical data demonstrate that children of mothers
exposed to certain infectious organisms during pregnancy
have significantly higher frequencies of neurological dis-
orders,44–53 including schizophrenia and autism spectrum
disorders. In such scenarios, the etiology of these disorders
has been linked to activation of the maternal inflammatory/
immune responses (reviewed by Jonakait54 and Patterson55).
Rodent studies in which the maternal immune system is acti-
vated during pregnancy replicate these clinical findings and
provide validated mouse models of these disorders.46,47,51,56–66
Thus, maternal immune stimulation during pregnancy acts
as an environmental risk factor that affects development of
the brain and the immune system in the offspring.
The underlying mechanisms of these phenomena have
been studied primarily in prenatal rodent models, in which
pregnant dams are injected with either infectious pathogens
or synthetic agents that mimic viral or bacterial infections
(namely, lipopolysaccharides and polyinosinic:polycytidylic
acid [poly(I:C)]). Offspring of such immunostimulated
pregnant dams exhibit immune dysregulation and behavioral
abnormalities, as well as chemical and structural anomalies of
the brain, which are similar to those seen in individuals with
schizophrenia and autism spectrum disorders.63,67–72
There is a transient increase of cytokines (IL-1, IL-6,
IL-12, tumor necrosis factor-alpha [TNF-α], granulocyte-
macrophage colony stimulating factor) in the blood and
amniotic fluid of immunostimulated pregnant dams,73,74
which appears to influence development of the fetal immune
system, a concept known as “fetal programming”.75–79 Mandal
et al73,74,80 have also shown that offspring of immunostimu-
lated pregnant dams exhibit accelerated development and
heightened responsiveness of Th1, Th17, and cytotoxic effec-
tor T-cell subsets, indicating a proinflammatory phenotype
in these offspring.
We hypothesized that in utero exposure of the fetus to
cytokines elicited by maternal immune stimulation acts as
a “first hit” to influence fetal programming of the immune
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Maternal immune system and fetal development
system, which persists postnatally and into adulthood.
Such alterations of normal fetal programming results in
development of a “proinflammatory” phenotype, and upon
subsequent postnatal exposure to an immune stimulus (ie,
second hit), the offspring of the immunostimulated pregnant
dams exhibit exacerbated responses in comparison to off-
spring of phosphate-buffered saline (PBS)-injected dams.
Such a scenario is also consistent with the “multiple hit”
concept of mental disorders.81,82 In the context of neurode-
velopmental disorders, this would mean that abnormalities
of behavior and immune dysregulation observed in some
affected children could reflect such altered fetal programming
that is manifested postnatally upon encounter with a second
hit (eg, infection) to their immune system. We tested this
hypothesis in adult offspring of immunostimulated pregnant
dams using well-documented in vivo experimental models
that involve activation of the innate and/or adaptive immune
systems. In each of these models, the adult offspring of
immunostimulated dams mounted a more robust inflamma-
tory response than adult offspring of control dams injected
with PBS.73,83 Thus, offspring from immunostimulated dams
exhibit behavioral anomalies reminiscent of those seen in
individuals with some neurodevelopmental disorders, such
as schizophrenia and autism. In addition to their behavioral
abnormalities, our studies show that as a result of in utero
exposure to products of maternal immune stimulation, these
adult offspring also exhibit a “proinflammatory” phenotype
that confers a vulnerability to develop immune-mediated
pathology after birth and into adulthood.73,74,80
In this regard, the results obtained from our investigations
in mouse models have provided the scientific rationale for an
ongoing translational research project to determine whether
similar molecular pathogenic mechanisms are involved in a
cohort of autistic children who also exhibit diagnostic evi-
dence of immune dysregulation.84 Using DNA obtained from
the Autism Genetic Resource Exchange database, we initiated
a study to determine whether polymorphisms in selected
maternal cytokine genes occurred more frequently in moth-
ers of these autistic children. Our results show that mothers
of autistic children in this cohort have significantly higher
frequencies of proinflammatory cytokine gene polymor-
phisms, thereby conferring the genetic capability to respond
more vigorously to immune stimulation by producing the
types and amounts of cytokines that promote inflammatory
reactions. Moreover, analysis of preliminary data from the
offspring indicates that the autistic children of these mothers
inherit the maternal genotype. Thus, results obtained from
our investigation of the experimental prenatal mouse model
of maternal immune stimulation during pregnancy73 appear
to have biological relevance to humans.
Maternal–fetal tolerance
Billingham et al1 in 1953 were the first to propose the con-
cept of immune tolerance during pregnancy. They hypoth-
esized that the semiallogeneic fetus is able to survive due to
regulation of the immunologic interactions between mother
and fetus. Such regulation can be caused by a lack of fetal
antigen expression and/or functional suppression of maternal
immune response.1
HLAs that are expressed in the fetal membranes are
tolerogenic rather than immunogenic,85 and expression
of major histocompatibility complex (MHC) proteins at
the maternal–fetal interface is tightly regulated during
pregnancy.86 The MHC class I genes are subdivided into
classes Ia and Ib. The MHC class Ia is further subdivided
into HLA-A, B, and C and class Ib is subdivided into
HLA-E, F, and G. HLA class II (HLA-D) genes are not
translated in human trophoblast cells.87 Human trophoblast
cells express one MHC class Ia (HLA-C) and all MHC class
Ib molecules. In human placenta, fetal trophoblast cells do
not express MHC class Ia (HLA-A and B) molecules that
are responsible for the rejection of allografts in humans.88,89
Interactions between HLA-C and decidual NK cells may
also cause infiltration of trophoblast into maternal tissue.
Pregnancies with mismatched fetal HLA-C exhibit a greater
number of activated T-cells and functional Tregs in decidual
tissues compared to HLA-C-matched pregnancies.90 This
suggests that in uncomplicated pregnancies, decidual T-cells
recognize fetal HLA-C at the maternal–fetal interface
but are prevented from inducing a destructive immune
response.91
Regarding pregnancy, one of the most important ques-
tions is how the fetal–placental unit escapes maternal
rejection. Although there is a continuous interaction
between the fetus and maternal cells throughout pregnancy,
the fetus acts as a privileged site that is protected from
immune rejection.91 Expression of MHC molecules on
trophoblast cells is repressed in most of the species as a
strategy to avoid recognition and destruction by the mater-
nal immune cells.92 Peripheral blood lymphocytes from
pregnant mares demonstrate reduced capacity to develop
into effector cytotoxic T lymphocytes.93 This reduction
in T-cell-mediated alloreactivity returns to normal after
termination of pregnancy and is not observed in nonpreg-
nant mares. In addition, extracts from Day 80 placentas
from mares have been shown to inhibit proliferation of
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Morelli et al
maternal lymphocytes, and coculture of trophoblast cells
with maternal lymphocytes caused reduction in prolifera-
tion and cytokine production.94
Cell-mediated immunity:
mechanisms promoting
maternal–fetal tolerance
The Th1–Th2 shift in pregnancy
Pregnancy is a complex immunological state, wherein the
mother must tolerate the “foreign” fetus, and thus requires
a degree of immunosuppression. On the other hand, the
mother must maintain sufficient immune function to fight off
infection. One mechanism that plays a role in maintenance
of successful pregnancy is a switch from the Th1 cytokine
profile to the Th2 profile. This switch is more prominent
at the maternal–fetal interface. Th2 cells accumulate in
decidua, and uterine DCs can drive naïve T-cells to become
Th2 cells.95,96 Therefore, the switch to a Th2 phenotype is due
to both migration of Th2 cells and induction of Th2 cells at
the maternal–fetal interface, but there is little change in the
systemic immune system.96 The hypothesis of Th2 predomi-
nance and downregulation of Th1 response during pregnancy
was proposed by Wegmann et al,97 which is supported by
both murine and human studies. In mice, the proinflamma-
tory cytokines IFN-γ and TNF-α, or stimulation of toll-like
receptors, induce miscarriage, which can be reversed by
inhibitors of Th1 cytokines or by administration of anti-
inflammatory IL-10 (Th2 cytokine).98 However, IFN-γ also
plays an important role in vascular remodeling in early
murine pregnancy. Therefore, Th1-type immunity appears
to be controlled to avoid overstimulation during pregnancy.
Progesterone, estradiol, prostaglandin D2 (PGD2), and leu-
kemic inhibitory factor generated during pregnancy promote
the Th2 profile and are, in part, responsible for the Th2 bias
associated with normal pregnancy.96 However, transgenic
Th2 cytokine single-knockout mice such as IL-4-/-, IL-10-
/-99 and mice with single, double, triple, and quadruple gene
deletions of IL-4, IL-5, IL-9, and IL-13 have normal preg-
nancies, suggesting that a predominant Th2-type immunity
might not be essential for successful pregnancy.100
An increase of Th2 cytokines IL-4, IL-10, and mono-
cyte-colony stimulating factor in the peripheral blood and
the maternal–fetal interface is associated with successful
pregnancy. Trophoblast, decidua, and amnion contribute to
the Th2 cytokine-biased environment by production of IL-13,
IL-10, IL-4, and IL-6.101–103 Human placental cytotrophoblasts
have been shown to produce the immunosuppressive cytokine
IL-10.101 In addition, macrophages and Tregs present within
decidua during pregnancy also produce IL-10 and are involved
in maintenance of immune tolerance toward allogeneic fetal
antigens.91 The placenta also produces PGD2, which can
act as a chemoattractant for Th2 cells to the maternal–fetal
interface via the Th2 receptor CRTH2 (a chemoattractant
receptor-homologous molecule expressed on Th2 cells).
Women suffering recurrent pregnancy loss have reduced
expression of CRTH2+ cells than women undergoing elective
termination of pregnancy.104 Anti-inflammatory cytokines
IL-4 and IL-10 inhibit Th1 cells and macrophages, which
in turn prevent fetal allograft rejection. In addition, these
cytokines also inhibit TNF-α, cyclooxygenase-2 (COX-2),
and prostaglandin E2 in amnion-derived cells, which prevent
the onset of labor.24,105–107
Labor is often associated with a proinflammatory state
with reversal back to Th1 rather than Th2. Studies indicate
increases in Th1 proinflammatory cytokines and reduction in
Th2 cytokines in women who are in active labor. Fetal mem-
branes, myometrium, amnion, amniotic fluid, and decidua
produce proinflammatory cytokines IL-1β and TNF-α at
term and can induce nuclear factor kappa B. This transcrip-
tion factor regulates the expression of labor-associated genes
such as COX-2, IL-8, and MMP-9 and triggers a cascade of
labor-inducing events. Despite the proinflammatory nature
of Th1 cytokines, they are essential for successful pregnancy,
contributing to timely labor.108–110
Role of Tregs in pregnancy
CD4+CD25+ Tregs are a subpopulation of T-cells respon-
sible for the maintenance of immunological self-tolerance
by suppressing self-reactive lymphocytes in a cell contact-
dependent manner by production of TGF-β and IL-10.111,112
Tregs express transcription factor forkhead box transcrip-
tion factor (FoxP3), which acts as a major regulator in
their development and function.113 There are two main Treg
subsets: naturally occurring or thymic Tregs (tTregs) and
induced or extrathymic/peripheral Tregs (pTregs). tTregs are
CD4+CD25+Foxp3+ and express cytotoxic T lymphocyte-
associated antigen 4. pTregs develop from naïve T-cells after
exposure to antigens in the periphery and exposure to either
IL-10 or TGF-β and can be either Foxp3- or Foxp3+.114,115
Owing to their immunosuppressive function, Tregs also play
a key role during pregnancy by maintaining maternal–fetal
tolerance.
Several studies have confirmed an increase in Tregs dur-
ing pregnancy in blood, lymph nodes, and thymus, followed
by decrease from midgestation onward until they reach
nonpregnant levels at term or shortly thereafter. They play a
critical role in embryo implantation and in the maintenance
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Maternal immune system and fetal development
of the maternal immune tolerance against semiallogeneic
fetal antigens.116,117 Evidence suggests that Tregs during
pregnancy are specific to paternal alloantigens, which
protects the fetus from rejection by the mother’s immune
system.118 Expansion of Tregs in decidua from normal preg-
nant women suppresses maternal Th1/Th17 activity on the
semiallogeneic fetus.119
Murine experiments have shown increased levels of
Tregs in both syngeneic and allogeneic matings, suggesting
alloantigen-independent Treg expansion.120 Treg expansion
appears to be regulated by estradiol. This is supported by
in vitro studies, which show that physiological levels of
estradiol not only expand Tregs but also stimulate conver-
sion of CD4+CD25- T-cells into CD4+CD25+ T-cells.121
On the other hand, Zhao et al122 observed no increase in
Tregs in ovariectomized mice. Moreover, they detected
higher number of Tregs in pregnant mice from allogeneic
versus syngeneic matings, suggesting an involvement of
paternal antigens in Treg expansion.122 Recently, Robertson
et al123 showed that seminal fluid can drive Treg expan-
sion. Therefore, both antigen-dependent and antigen-
independent mechanisms are likely to be involved in Treg
expansion.
Tregs express various chemokine receptors whose
ligands are expressed at the maternal–fetal interface, which
might contribute to chemokine-mediated migration of
Tregs to the decidua.120 Furthermore, other immune cells
produce large amounts of CCL17, CCL4, and CCL1,124–126
which might attract Tregs specifically expressing CCR4
and CCR8.127,128 Besides chemokine-mediated migration of
Tregs, integrins, similar to CD62L, seem to play an impor-
tant role in Treg migration, as neutralizing CD62L-specific
antibody blocks expansion of Tregs in draining lymph nodes
and results in allograft rejection. Schumacher et al129 have
shown the importance of human chorionic gonadotropin as
one of the main attractants of Tregs to the maternal–fetal
interface.
Aluvihare et al117 first noted that Tregs increased in all
lymphoid organs in allogeneic matings of C57BL/6 female
mice with CBA males. They also adoptively transferred
lymphocytes from BALB/c females, either allopregnant
from C57BL/6 males or synpregnant from BALB/c males,
into T-cell-deficient BALB/c females, which were then
mated with C57BL/6 males. Pregnancy proceeded normally
when whole lymphocyte populations were transferred. In
contrast, lymphocytes depleted of Tregs resulted in fetal
resorptions, and there was a massive infiltration of T-cells
into the implantation sites.117 Zenclussen130 and Zenclussen
et al131 have shown complete prevention of abortion in the
CBA × DBA/2J model of naturally occurring spontaneous
abortions by transferring Tregs from alloimmunized mice,
and they also reported that no abortions occurred in the CBA
× BALB/c and CBA × CBA control matings. Finally, Chen
et al116 demonstrated that stimulation of Tregs, either directly
by low dose of IL-2 or indirectly by Fms-related tyrosine
kinase 3 ligand, led to normal pregnancy rates in CBA ×
DBA/2J abortion-prone mice. The results of these experi-
ments all demonstrate that in allogenic matings, Tregs are nec-
essary for prevention of a maternal immune response against
the fetus.
Clinical manifestations of an altered
immune system in pregnancy
The notion of pregnancy as an altered state of immune
suppression is well documented.132–136 Pregnancy is a time
period that poses a risk of increased susceptibility to infec-
tious diseases, and the maternal immune system is solely
responsible for defending against infectious microorgan-
isms and protecting the fetus because both the fetal and the
placental responses are limited.132,136 The Th1/Th2 immune
shifts in pregnancy are well established and have provided
a platform to further study the immune system.136 This
has led to refining our understanding about the immune
system and the development of a new paradigm regard-
ing pregnancy and immune function. This newer theory
proposes that the immune system during pregnancy is a
functional and active system, wherein not only a maternal
immune response exists but also a fetal–placental immune
response, which in combination is powerful in defending
both the mother and the fetus.133,136 With this notion, the
immune system is not suppressed, but rather in a modulated
state, and therefore, this explains why pregnant women have
differential responses to various pathogens.133 During this
altered response, signals are generated in the placenta, which
modulate the maternal immune system to behave uniquely
to different microorganisms.133 Although these old and new
paradigms surrounding the immunology of pregnancy dif-
fer, it is clear that the immune system’s goal in pregnancy
is to ensure that a pregnancy progresses successfully, while
still providing protection for both mother and fetus from
external pathogens.
Endocrine regulation of immune cells
Hormone concentrations vary with the initiation
of pregnancy, and there are specific fluctuations in
hormone levels throughout each trimester of preg-
nancy. In general, pregnancy hormones are thought
to suppress maternal alloresponses, while promoting
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Table 1 Endocrine regulation of immune cells and immune function
Hormone Th1 (proinammatory)
pathway
Th2 (anti-inammatory)
pathway
Effects on immune cells References
Estradiol (E2) Inhibits pathway via TNF-α,
IL-1β, and IL-6
Stimulates pathway via IL-4,
IL-10, TGF-β, and IFN-γ
Modulates lymphocyte
development and function
134,148
E2 Treg proliferation
E2 enhances Treg’s
suppressive function
Progesterone (P4) Inhibits pathway via TNF-α
and IL-6
Stimulates pathway via IL-4,
IL-10 (from T-cells)
P4 Treg proliferation 134,148–151
P4 enhances Treg’s
suppressive function
P4 favors development
of Th2 CD4 T-cells (may
be responsible for Th2
predominance during
pregnancy)
P4 suppresses T-cell activation
Wide distribution of P4
receptors in immune cells
(Dendritic, T, and B-cells)
uNK cells do not express
steroid receptors, P4 actions
likely mediated through
glucocorticoid receptors
Human chorionic
gonadotropin (hCG)
Inhibits pathway via TNF-αStimulates pathway via
TGFβ, IL-8, and IL-10
(from B-cells)
hCG attracts Tregs 134,148,152
hCG induces uNK cell
proliferation through mannose
receptor (uNK cells do not
express LH/CG receptor)
hCG promotes dendritic cell
and monocyte proliferation
and function
Abbreviations: CD, cluster of differentiation; IL, interleukin; IFN, interferon; LH/CG, luteinizing hormone/chorionic gonadotropin; TGF, transforming growth factor; Th, T
helper cell; TNF, tumor necrosis factor; Treg, T-regulatory cell; uNK, uterine natural killer; , decreased; , increased.
pathways of tolerance.137 Hormonal shifts are thought
to reduce the number of DCs and monocytes, decrease
macrophage activity, while blocking NK cells, T-cells, and
B-cells.137 Each of the major pregnancy-associated hor-
mones is thought to directly and indirectly affect the func-
tion of the major immune cells and thus impacts the immune
milieu during pregnancy. These alterations are discussed
in Table 1.
Evidence of altered immune function
in pregnancy: effects of infectious
organisms on pregnancy
The alterations in the immune system during pregnancy are
well established, and subsequently, these changes result in
increased susceptibility to certain viral, bacterial, and para-
sitic infections.132 This increased susceptibility is believed
to result from the suppression of cell-mediated immunity,
as pregnancy promotes a shift away from the Th1 to the
Th2 immune environment.132,134 Additionally, infection with
certain pathogens has been documented to result in severe
symptoms in pregnant patients because of these immune
changes.133,138 However, it is important to note that, in certain
infectious diseases among gravid patients, the morbidity
and mortality vary between developed and nondeveloped
countries. For example, pregnant women with varicella
in the US or Canada fare better than those diagnosed in
underdeveloped countries, where resources are limited.139
Thus, some bias may result when evaluating the severity of
disease states in pregnant women depending on geographi-
cal distribution.
Table 2 summarizes the more commonly recognized and
studied pathogens related to pregnancy. As seen in Table 2,
infectious diseases during pregnancy are associated with
not only maternal risks but fetal risks as well. These fetal
effects result from infections that cross the placenta, which
can cause miscarriage, congenital anomalies, or even fetal
death.133 As a result, the American Congress of Obstetricians
and Gynecologists and the US Centers for Disease Control
and Prevention recommend that all women be vaccinated
for influenza and tetanus, diphtheria, and pertussis (Tdap)
during pregnancy.140–142 Both these vaccines appear to be
safe when administered during pregnancy, with few maternal
and fetal adverse events.142,143 In contrast, live vaccines, such
as measles–mumps–rubella (MMR) and varicella, are not
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Maternal immune system and fetal development
Table 2 Common infectious organisms in pregnancy
Infectious
organisms
Type Risks Transmission Immune cells Other Fetal effects References
Cytomegalovirus
(CMV)
Viral Incidence in US: 1%–3% of
pregnant women
Transmission: 30% in
the rst trimester; up
to 72% in the third
trimester
uNK cells at level of
placenta
Most common cause of
intrauterine viral infection
Leading cause of congenital
infection (IUGR, seizures,
microcephaly, petechial rash,
hepatosplenomegaly), hearing
and visual impairments, mental
retardation, fetal death
36,153
Low risk for healthy pregnant
women
Infection progresses
from decidua
placenta
uNK and T-cells control
CMV infection and spread
during pregnancy
Inuenza virus Viral Risk of infection increases
with GA
Infection can spread
from maternal
bloodstream to
decidua (preferred
environment for viral
infections), where the
virus replicates, and
then it infects fetal
chorion and amnion
Innate response: involves
PRRs that recognize viral
components
Virus can induce apoptosis
in chorion cells (direct
cytopathic effect)
Maternal inuenza infection,
during any trimester, confers
fourfold increased risk of
bipolar disorder in offspring
145,154–156
Pregnant women seven
times more likely to be
hospitalized, twice as likely
to die from inuenza as
nonpregnant women
Pregnancy decreases
adiponectin levels (an
adipokine) a more pronounced
innate immune response
when infected with H1N1
Cell types: neutrophils,
macrophages and DCs
IAV increases gene
expression of cytokines
IL-1b, IL-6, TNF-α; may
lead to premature rupture
of membranes
Rhesus monkey model:
maternal inuenza affects fetal
neural development with
reduction in gray matter and
decreased white matter in
parietal cortex
In humans, IL-8 and serologic
evidence of maternal inuenza
infection associated with
schizophrenia in offspring
Pregnancy may enhance
systemic inammatory
response to inuenza
( TNF-α, G-CSF;
IFN-γ, MCP-1
Varicella zoster
virus (VZV)
Viral Primary varicella infection
in pregnant patients leads to
more severe disease than
reactivation
Infection may be
primary, or reactivation
in utero
Prodromal symptoms:
headache, fever, malaise
Fetal effects worse if infection
occurs early in pregnancy
132,139,157,158
Incidence: 0.7–3.0/1,000
pregnancies
Vertical transmission
occurs transplacentally
∼2.5% of varicella
infections in pregnancy
complicated by varicella
pneumonia
Congenital varicella syndrome:
cerebral abnormalities, cataracts,
microphthalmia, chorioretinitis,
mental retardation, skin lesions,
limb hypoplasia, IUGR, and low
birth weight
Varicella pneumonia more
common in pregnant women
than in nonpregnant women,
and presence of pneumonia
confers increased risk of
maternal mortality
Greater risk of fetal
transmission when
infection occurs in
third trimester
Other fetal risks: miscarriage,
stillbirth
(Continued)
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Table 2 (Continued)
Infectious
organisms
Type Risks Transmission Immune cells Other Fetal effects References
Listeriosis (Listeria
monocytogenes)
Bacterial Infections more common
during pregnancy (25%–33%
of all cases occur in pregnant
women)
Transmission: mostly
foodborne
Innate immune response:
macrophages produce IL-1,
IL-6, and TNF-α; this sets
stage for adaptive immune
response to Listeria; CD8+
T-cells peak 7–10 days after
infection
Symptoms: may be
asymptomatic or
nonspecic inuenza-like,
fever, back pain, and rarely
gastroenteritis
Fetal effects depend on the
timing of exposure to Listeria,
with most infections in the
third trimester
36,132,159–163
Pregnant women have
20-fold increased incidence
of infection
Listeria crosses mucosal
barrier in stomach,
hematogenous
spread to extravillous
trophoblasts and
chorionic villi to access
placenta (decidua
and placenta become
major reservoirs of the
organism)
In pregnancy, Th17
cells, causing IL-17a
and IL-22, potentiating the
inammatory response
Murine studies: Listeria blunts
maternal Treg suppression
which may lead to immune-
mediated fetal wastage
Infection can lead to miscarriage,
preterm labor, stillbirth, or
neonatal death (due to
granulomatosis infantiseptica,
causing microabscesses and
granulomas)
Guinea pig studies indicate that
fetus may be infected as early
as 2 days postinoculation
Tuberculosis (TB)
(Mycobacterium
tuberculosis)
Bacterial Difcult to diagnose, due to
nonspecic symptoms related
to physiologic response to
pregnancy (eg, fatigue,
shortness of breath, sweating,
cough, and mild fever)
Transmission via
respiratory tract
droplets
T-cells release IFN-γ in
response to specic
antigens presented by
M. tuberculosis
Screening high-risk
patients is imperative
for early diagnosis and
treatment
Without treatment, two
times increased risk of
preterm birth, IUGR, low
birth weight, prematurity,
and six times increased risk
of perinatal death
164–168
Without treatment, four
times increased risk of
maternal morbidity (higher
rates of abortion, postpartum
hemorrhage, labor difculties,
and preeclampsia)
Altered immunity
increases susceptibility
to infection and
reactivation of latent
TB, and risks are higher
in HIV-positive women
Higher risks in patients
coinfected with HIV
Congenital TB: neonates born
to mothers with active TB have
high mortality rate (20%–44%);
can be subclinical or associated
with birth defects
Vertical transmission
can occur via the
placenta and amniotic
uid (congenital TB)
or respiratory droplets
(neonatal TB)
Prevalence of active TB in
pregnant patients: 0.06%–
0.25% in low-prevalence
countries, and 0.07%–0.5%
in high-burden countries
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Maternal immune system and fetal development
Malaria
(Plasmodium
falciparum)
Parasitic Pregnant women more
susceptible than nonpregnant
women, with higher
susceptibility during rst half
of pregnancy
Pathogenesis:
infected erythrocytes
accumulate in IVS
(higher density than
peripheral circulation)
and maternal
phagocytes, deposition
of hemozoin (malaria
pigment) seen in IVS
Placental parasites express
surface ligands and antigens
that differ from those of
other P. falciparum variants,
facilitating evasion of immune
response
Maternal risks: anemia Pregnancy-associated malaria
causes up to 200,000 infant
deaths/year
46,133,147,169,170
Fetal risks: low birth weight
and IUGR
125 million pregnant women
worldwide are at risk of
malaria each year
Chronic infection associated
with low birth weight and
preterm delivery
Highly susceptible during
rst and second pregnancies
(despite acquired immunity
after years of exposure)
Toxoplasmosis
(Toxoplasma
gondii)
Parasitic Seronegative pregnant
women .2× as likely as
nonpregnant women to
seroconvert
Primary infection: ∼20%
vertical transmission
rate to fetus, and
highest transmission in
third trimester (∼32%)
uNK cells play important
role in defending against
T. gondii at maternal–fetal
interface, however, parasite
can evade uNK cells and
continue to replicate,
especially during
early pregnancy
Second most common
cause of fetal intrauterine
infection
Primary infection can result in
miscarriage, stillbirth, preterm
delivery, or fetal malformations
132,170–172
Transmission occurs
via ingestion of raw
meat or exposure to
cat feces
Often asymptomatic
(in mother), but treatment
aimed at preventing
congenital infection
Congenital toxoplasmosis:
hydrocephalus, seizures,
IUGR, mental retardation,
microphthalmia, eye disease,
intracranial calcications
Abbreviations: CD, cluster of differentiation; DC, dendritic cell; GA, gestational age; G-CSF, granulocyte-colony stimulating factor; IAV, inuenza A virus; H1N1, inuenza A virus subtype H1N1; IFN, interferon; IL, interleukin; IUGR,
intrauterine growth restriction; IVS, intervillous space; MCP-1, monocyte chemotactic protein-1; PRR, pattern recognition receptor; Th, T helper cell; TNF, tumor necrosis factor; Treg, T-regulatory cell; uNK, uterine natural killer;
, decreased; , increased.
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Morelli et al
recommended during pregnancy due to the theoretical risks
to the fetus.141,142
The risk of infection during pregnancy is a serious
matter, not only for concerns of maternal well-being but
also the potential fetal risks, which may have long-term
consequences. Animal studies have elucidated that the pla-
centa may trigger fetal inflammatory response syndrome
(FIRS), which is the diagnosis of a placental infection
without the growth of an organism, from the microbiology
standpoint.133,136 FIRS is serious and results in increased
circulating levels of cytokines, such as IL-1, IL-6, IL-8,
and TNF-α.133 These inflammatory shifts have been
demonstrated to increase the risk of fetal abnormalities, such
as ventriculomegaly or hemorrhages. Furthermore, human
studies have demonstrated an association between FIRS and
the development of autism, schizophrenia, neurosensorial
deficits, and psychosis.133,136 These observations further
validate the experimental mouse models described earlier in
which immunostimulation induces high levels of proinflam-
matory cytokines in blood and amniotic fluid of pregnant
dams, which are likely involved in the etiology of neurode-
velopmental disorders exhibited in their offspring.63,72–74 In
contrast, bacterial infections that reach the decidua trigger
a proinflammatory response that leads to the development
Table 3 Autoimmune disease in pregnancy
Autoimmune
disease
Improvement (remission of
symptoms)
Worsens (exacerbation of
symptoms)
Other References
Multiple sclerosis Mediated via suppression of
cell-mediated immunity
148,173
Reduced relapse rate mostly seen
in second and third trimesters
Flares common postpartum
Myasthenia gravis Symptoms may worsen, improve, or
remain unchanged
148
Symptoms vary among women and
between pregnancies in the same
woman
Psoriasis Improvement correlated with
higher levels of E2
148,174
E2 causes further shift from Th1
to Th2 type of immunity
Rheumatoid
arthritis
Mediated via suppression of
cell-mediated immunity
Flares may occur postpartum
Expansion of Tregs in pregnancy may
account for improvement of symptoms
during pregnancy
148,175
Decrease in Tregs postpartum may
account for postpartum disease ares
Systemic lupus
erythematosus
Increase in Th2-mediated
response worsens this humoral-
mediated autoimmune disease
Fetal effects: congenital heart block,
due to passive transplacental transfer
of anti-Ro (SS-A) and anti-La (SS-B)
Abs from mother to fetus
148,176
Causes irreversible damage to fetal
cardiac conduction system
Abs also cause neonatal lupus (skin
rashes, liver abnormalities, hematologic
cytopenias); effects are transient
(months) and improve once maternal
Abs are cleared from infant’s circulation
Autoimmune
hyperthyroidism
(Grave’s disease)
Autoimmune thyrotoxicosis may
improve because of a degree
of immunosuppression during
pregnancy
Fetal effects: TSH-R Abs can cross
placenta, causing fetal hyperthyroidism
that may lead to fetal tachycardia,
hydrops, fetal goiter, or IUGR
177
Flare may occur postpartum Untreated fetal hyperthyroidism has
∼15% mortality
Infant will continue to have maternal
TSH-R Abs for ∼3 months (transient
effects)
Abbreviations: Abs, antibodies; CD, cluster of differentiation; E2, estradiol; IUGR, intrauterine growth restriction; Th, T helper cell; Treg, T-regulatory cell; TSH-R, thyroid
stimulating hormone-receptor.
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Maternal immune system and fetal development
of intrauterine infections.144 This is through the activation of
pattern recognition receptors (PRRs) and increased secretion
of cytokines, such as IL-1 and TNF-α.145 Combined, these
contribute to poor pregnancy outcomes, disruption in fetal
development, or preterm births with resultant low-birth-
weight infants.146,147 Thus, it is important to recognize that
pregnancy can cause increased disease susceptibility, which
not only affects maternal morbidity but contributes to detri-
mental long-term fetal and neonatal outcomes.
Evidence of altered immune function in
pregnancy: effects of pregnancy on
autoimmune disease
As discussed, pregnancy confers a shift from Th1- to Th2-
mediated immunity, and this shift affects disease status in
women with known autoimmune diseases. In general, the
hormonal milieu induced by pregnancy shifts the cytokine
profile away from cell-mediated immunity (Th1 type of
immunity) and, therefore, improves inflammatory-type
autoimmune diseases.132 In contrast, autoimmune diseases
that are humorally (or antibody) mediated are exacerbated,
as pregnancy favors increased Th2-related activities, as
well as a Th2 cytokine profile.132,148 For details, please view
Table 3.
Conclusion and future outlook
Pregnancy in women is a dynamic state, with different
mechanisms used during different trimesters to enable and
ensure successful establishment, maintenance, and timely
termination of the pregnancy. Mechanisms operative in early
pregnancy to establish the pregnancy may differ from those
needed to maintain the pregnancy and from those required to
ensure successful and timely labor and delivery. Recent data
challenge the notion that pregnancy is simply an immunosup-
pressed state protecting the allogeneic fetus from attack by the
maternal immune system. The evidence suggests that rather,
pregnancy may be a state of upregulated innate immune
response and decreased cell-mediated response. Unique
decidual lymphoid cell populations actively contribute to
placental development and to tolerance of the fetus. Although
substantial progress in the understanding of the function of
immune cells during pregnancy, especially early pregnancy,
has been achieved, many unanswered questions regarding
regulation of their proliferation and function by endocrine
and other factors still remain. The published results from
human studies and animal models clearly indicate that a fine
balance between proinflammatory and anti-inflammatory
influences is critical for successful pregnancy. Thus, the
future challenge for translational research in reproductive
immunology will be to define more completely those factors
that favor optimal immunological environments that promote
fetal health and development at specific stages of pregnancy,
so that evidence-based regulatory therapeutic strategies can
then be designed.
Acknowledgments
The authors thank Yingting Zhang for her assistance with the
manuscript. Mili Mandal is currently affiliated with Oncol-
ogy, R&D, GlaxoSmithKline, Collegeville, PA, US.
Disclosure
The authors report no conflicts of interest in this work.
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