Epub ahead of print April 30, 2013 - doi:10.1189/jlb.

1112603

Review

A leading role for the immune system in the

pathophysiology of preeclampsia
Estibalitz Laresgoiti-Servitje1
American British Cowdray Medical Center, Mexico City, Mexico; and Department of Immunology, School of Medicine,
Universidad Panamericana, Mexico City, Mexico
RECEIVED NOVEMBER 28, 2012; REVISED APRIL 8, 2013; ACCEPTED APRIL 9, 2013. DOI: 10.1189/jlb.1112603

ABSTRACT
Preeclampsia syndrome is characterized by inadequate
placentation, because of deficient trophoblastic invasion of the uterine spiral arteries, leading to placental
hypoxia, secretion of proinflammatory cytokines, the
release of angiogenic and antiangiogenic factors and
miRNAs. Although immune-system alterations are associated with the origin of preeclampsia, other factors,
including proinflammatory cytokines, neutrophil activation, and endothelial dysfunction, are also related to the
pathophysiology of this syndrome. The pathophysiology
of preeclampsia may involve several factors, including
persistent hypoxia at the placental level and the release of high amounts of STBMs. DAMP molecules released under hypoxic conditions and STBMs, which
bind TLRs, may activate monocytes, DCs, NK cells, and
neutrophils, promoting persistent inflammatory conditions in this syndrome. The development of hypertension in preeclamptic women is also associated with endothelial dysfunction, which may be mediated by various mechanisms, including neutrophil activation and
NET formation. Furthermore, preeclamptic women
have higher levels of nonclassic and intermediate
monocytes and lower levels of lymphoid BDCA-2 DCs.
The cytokines secreted by these cells may contribute to the
inflammatory process and to changes in adaptive-immune
system cells, which are also modulated in preeclampsia.
The changes in T cell subsets that may be seen in preeclampsia include low Treg activity, a shift toward Th1 responses, and the presence of Th17 lymphocytes. B cells
can participate in the pathophysiology of preeclampsia by
producing autoantibodies against adrenoreceptors and au-

Abbreviations: AT2angiotensin-2, AT1-AA, angiotensin-1 receptor autoantibody, AT1/2-Rangiotensin-1/2 receptor, BDCA-2blood DC antigen 2,
DAMPdamage-associated molecular pattern, DC-SIGNDC-specific
ICAM-3-grabbing nonintegrin, ENGendoglin, Flt1Fms-like tyrosine kinase 1, FoxP3forkhead box P3, HIF-1hypoxia-inducible factor 1-,
HMGB1high-mobility group box-1, IP-10IFN--inducible protein-10,
iTreginduced regulatory T cell, miRNAmicroRNA, NETneutrophil extracellular trap, PlGFplacental growth factor, RAGEreceptor for advance
glycation end products, RASrenin angiotensin system, RORcretinoidrelated orphan receptor C, ssoluble, SGAsmall for gestational age,
STBMsyncytiotrophoblast microparticle, Tregregulatory T cell,
uNKuterine NK

0741-5400/13/0094-0001 Society for Leukocyte Biology

toantibodies that bind the AT1-R. J. Leukoc. Biol. 94:

000 000; 2013.

Introduction
Preeclampsia, a pregnancy disorder, in which hypertension
and proteinuria are present after the 20th week of gestation
[1], affects 4 6% of all pregnancies [2]. In the first weeks of
pregnancy, normal spiral artery remodeling is achieved by the
migration of differentiated cytotrophoblasts into the uterine
spiral arteries [3]. However, in preeclampsia, vascular changes
may not occur in the spiral arteries that provide blood to the
intervillous space, leading to decreased placental perfusion [4]
and the maintenance of high uteroplacental intravascular resistance [5]. As preeclampsia has multiple origins, the precise
etiology has not been defined clearly [6]. Researchers have
suggested that an association exists among impaired angiogenesis, changes in local oxygen tension [4], or oxygen-sensing
mechanisms [7] and immunological alterations in the early
placental microenvironment, which may all participate in the
origins of preeclampsia [8]. Later in the pregnancy, the considerably reduced uteroplacental flow that may be associated
with long-term uteroplacental hypoxia promotes the release of
chemokines and induces inflammation by activating monocytes
and neutrophils [9]. Although it is believed that placental hypoxia plays a relevant role in preeclampsia, recent studies suggest that the presence of hypoxic conditions may not be the
key feature in all preeclamptic patients, as a disruption of oxygen-sensing mechanisms that promote overexpression of
HIF-1 can be present in some women with this syndrome. As
high levels of HIF-1 and alterations in oxygen-sensing pathways are more common in early-onset preeclampsia, differences in these mechanisms may help differentiate early- and
late-onset preeclampsia [7].
Two stages of the preeclampsia syndrome have been proposed: (1) poor trophoblastic invasion, as a result of altered
production of immunoregulatory cytokines and angiogenic
factors and (2) a systemic, maternal-inflammatory response,
primarily involving the endothelium, which is apparently stim-

1. Correspondence: ABC Medical Center, Sur 136 No. 116 1-A, Mexico City,
01120, Mexico. E-mail: elaresgoiti@up.edu.mx; Twitter: @PNImmunology

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Journal of Leukocyte Biology 1

Copyright 2013 by The Society for Leukocyte Biology.

ulated by the release of necrotic and/or apoptotic syncytiotrophoblast cells into the maternal circulation [10]. As the first
stage of preeclampsia mostly accounts for its origins, this review will discuss the second stage, as it is when the maternalinflammatory response takes place, and most pathophysiological processes occur. The second stage of preeclampsia may
also involve poor fetal growth and can be associated independently with the development of intrauterine growth restriction
[11]. However, not all babies from preeclamptic mothers are
born SGA, and intrauterine growth restriction may be more
frequent in early-onset preeclampsia than in late-onset preeclampsia [12].
Some components of the innate and adaptive immune system that may participate in the physiopathology of preeclampsia will be described here, as they produce certain cytokines,
they modulate immune responses, or they have shown a modified function that may lead to the symptoms of this disease.
The pathophysiology of preeclampsia also involves altered levels of angiogenic factors, AT2-R autoantibodies [1315], and
the presence of different miRNAs [16, 17].

THE ROLE OF ANGIOGENIC/

ANTIANGIOGENIC FACTORS AND THEIR
INTERACTION WITH THE IMMUNE
SYSTEM IN PREECLAMPSIA
The persistence of low-oxygen tensions or altered oxygen-sensing mechanisms in preeclampsia promotes placental overexpression of HIF-1 [7, 18]. Later, an imbalance between proand antiangiogenic factors can be observed in this syndrome.
Proangiogenic factors include the VEGF and PlGF, whereas
antiangiogenic factors that can be present in preeclamptic patients are the sENG [19] and the sVEGF-R1 [20, 21] and its
generic splice variant, known as sFlt1 [21]. sFlt1 inhibits VEGF
and PlGF by binding to these factors in the maternal circulation and blocking their angiogenic effects [22]. Whereas sFlt1
levels are relatively low early in normal pregnancy [23], in the
presence of hypoxic conditions, sENG and sFlt1 are released
by the placenta [18, 24]. HIF-1 increases VEGF, ENG [25],
and sFlt1 expression [18]. sFlt1, which may be produced by
different cells, including endothelial cells [26] and the hypoxic villous trophoblast, participates in the clearing of freematernal VEGF [27]. Two isoforms of sVEGF-R1 have been
described: sFlt1, which is generic, and sFlt1-14, which is human specific [21]. sFlt1-14, the most common VEGF inhibitor
produced by the human placenta in preeclampsia, is a C-terminal variant isoform of sFlt1, and it is also known as sFlt1-e15a
[28]. Under hypoxic conditions, sFlt1-14 can accumulate in
the maternal circulation, neutralizing VEGF in distant organs
and extending the consequences of preeclampsia [15]. High
levels of sFlt1 and low levels of PlGF may predict the subsequent development of preeclampsia, as it may be detected 5
weeks before its onset [29].
sFlt1 levels differ in early- and late-onset preeclampsia. sFlt1
levels are higher in early-onset preeclampsia, making sFlt1 a
possible biomarker for the early-onset form of this syndrome
[30]. As sFlt1 is secreted under hypoxic conditions, the differences in sFlt1 levels in women that develop the disease earlier
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or later in pregnancy may be reflecting different oxygen concentrations in preeclamptic patients.

Components of the immune system, especially cytokines,
may be interacting with angiogenic and antiangiogenic factors
in preeclampsia. As sENG is increased in preeclampsia, and it
binds TGF-, compromising its function and/or bioavailability
[23], it may be possible that sENG could affect the levels of
TGF- required for iTreg. On the other hand, the levels of
TNF- present in preeclamptic patients can also promote the
release of sFlt1 [13], especially under chronic hypoxic conditions [31]. Likewise, the binding of AT1-AA, which will be
described later in the manuscript, can promote the secretion of sENG and sFlt1 through TNF--mediated mechanisms [32, 33].

THE ROLE OF miRNAs IN

PREECLAMPSIA
miRNAs are nonprotein-coding RNAs that regulate gene expression and may play a role in the pathogenesis of preeclampsia, also serving as possible biomarkers for this disease
[34]. Several miRNAs have been found elevated in placentas
with preeclampsia. For example, in severe preeclampsia, miR16, miR-29b, miR-195, miR-26b, miR-181a, miR-335, and miR222 are increased significantly in the placenta [35]. Placentas
with preeclampsia and preeclampsia complicated with SGA
newborns express miR-182 and miR-210, which are not present
in placentas related to SGA alone, SGA hypertension, or in
normal placentas [36]. miR-182 has been related T cell clonal
expansion [37], to cell cycle, and to apoptosis pathways [38].
miR-182 is present in placentas with severe preeclampsia, it
may regulate angiogenesis via VEGF, and it is also acknowledged as a regulator of the transcript variants 1 and 2 of the B
cell lymphoma 2-like gene [16]. On the other hand, miR-210
is a potent miRNA up-regulated by hypoxia [17] that can inhibit the migration and invasion ability of trophoblast cells
[39]. Another miRNA overexpressed in preeclampsia that may
contribute to its development by down-regulating the angiogenic-regulating factor CYR61 is miR-155 [40]. miRNAs may
not only be key players in the pathophysiology of preeclampsia, but they may also help differentiate pathologic aspects in
placentas affected by preeclampsia, preeclampsia complicated
with SGA, and SGA alone.

IMMUNE SYSTEM CELLS AND STBMs

In normal pregnancies, STBMs present in the maternal circulation may stimulate the production of several cytokines by
peripheral monocytes [41]. The recognition of STBMs by peripheral mononuclear leukocytes has been related to inhibition of IFN- production and to decreased levels of IP-10 in
the first trimester of normal pregnancies [42]. These changes
promote a shift toward type 2 T cell responses that is essential
for gestation [43]. In preeclampsia, however, significantly
higher levels of sSTBMs are present compared with normal
pregnancies [44]; suppression of IFN- production by NK cells
and other lymphocytes that were stimulated with STBMs does

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Laresgoiti-Servitje The immune system in the pathophysiology of preeclampsia

not occur; and these cells continue to secrete IFN-, IL-18,

TNF-, and IL-12 [42]. STBMs bind predominantly to receptors on monocytes and some B cells, inducing phagocytosis
[43]. The receptors that participate in STBM recognition have
not been identified clearly but may include RAGE and TLRs
[41]. Higher amounts of STBMs released by the placenta may
play a role in promoting a more robust inflammatory response
[41] in pregnant women. However, the conditions under
which the trophoblast microparticles are released may also be
relevant, as microparticles derived from a hypoxic trophoblast
induce higher concentrations of IL-6 and TNF- from PBMCs
that recognize STBMs than do particles derived from a normal
trophoblast [45]. Furthermore, STBMs from preeclamptic placentas exacerbate LPS responses in PBMCs [46]. This may
help to explain the increased production of cytokines in preeclampsia, in which the placenta can be hypoxic, and may also
be related to the generation of DAMPs under these hypoxic
environments.
In addition to cytokines derived from activated peripheral
granulocytes and monocytes, lymphocyte-derived cytokines are
probably secondary to the activation of endothelial cells by
STBMs and may be involved in the pathophysiology of preeclampsia [47].

THE INNATE IMMUNE SYSTEM IN THE

PATHOPHYSIOLOGY OF PREECLAMPSIA

TLRs in preeclampsia
According to the danger model [48], hypoxia can lead to a
persistent inflammatory response, and this may occur in preeclamptic patients. A key inflammatory factor in preeclampsia
is the recognition of DAMPs that can result from endothelial
cell dysfunction, changes in glucose metabolism, hypoxia, or
oxidative stress [49]. In hypoxic microenvironments, DAMPs
may not be oxidized and denatured and thus, may promote
inflammation [50] through ligation of receptors, such as
RAGE, TLR2, and TLR4, which are expressed in immune system cells [51]. S100 and HMGB1 are proteins that behave as
DAMPs [51, 52]. High cytoplasmic expression of HMGB1 occurs in decidual cells of preeclamptic patients [53], and S100B
is increased in amniotic fluid during preeclamptic pregnancies
[54] in direct relation to oxidative stress [55]. Furthermore,
expression of TLR4 [56], TLR2, TLR3, and TLR9 is increased
in trophoblasts of preeclamptic patients [57]. The expression
of TLRs and RAGE receptors by the placenta shows its potential ability to respond to DAMPs, although the role of the placenta in this matter remains unknown [53]. In mice, TLR3
activation can increase systolic blood pressure and endothelial
dysfunction, especially in the absence of IL-10 [58]. Although
this alteration has not been proven in humans, the findings
may be relevant, as preeclamptic women have decreased levels
of IL-10 [59]. Moreover, placentas of preeclamptic women
have increased expression of TLR3, TLR7, and TLR8 compared with those of normal human pregnancies, and the activation of TLR3, -7, and -8 by dsRNAs and ssRNAs promotes
pregnancy-dependent, proteinuric hypertension and endothelial dysfunction in mice [60]. Likewise, the binding of circulat-

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ing fetal DNA to TLR9 in mice can activate an inflammatory

response, leading to IL-6 secretion [61]. This may be particularly crucial in human preeclampsia, in which high levels of
circulating fetal DNA may be present [62]. Fetal DNA can
bind TLR9 promoting inflammation, and TLR9 signaling may
represent a potential therapeutic pathway, as it may be
blocked by pharmacological agents, such as chloroquine [61].
Maternal infections, especially urinary infections and periodontal disease, have been associated with an increased risk of
preeclampsia [63]. As many pathogens are recognized by TLRs
[64], pathogens may also be increasing TLR activation in this
syndrome. Thus, in preeclampsia, STBMs, pathogens, and
DAMPs may participate as important activators of inflammatory processes. These mechanisms involve binding to TLRs,
making these receptors possible therapeutic targets for preeclampsia.

Transcription factors, NF-B and TLRs, in

preeclampsia
It has been proposed that transcription factors may help us
gain insight into the pathophysiology of preeclampsia. On this
matter, microarray studies have shown a higher prevalence of
E-47, sterol regulatory element-binding protein, and NF-Bp50
transcription factor-binding sites in placentas complicated with
preeclampsia [65]. NF-B is a regulator of inflammatory gene
expression, it promotes the production of proinflammatory
cytokines, and is highly activated in some inflammatory diseases [66]. In patients with preeclampsia, increased translocation of nuclear NF-B has been found in peripheral bloodactivated leukocytes [67]. Whereas the activation of NF-B may
be associated to the presence of increased oxidative stress in
preeclampsia [68], it is possible that TLRs may also be promoting an increase of NF-B in this syndrome, as all TLR signaling pathways culminate in the activation of this transcription factor [69].
Regarding possible therapeutic strategies affecting NF-B
pathways, 5-deoxy-(12,14)-PGJ(2) has been proposed as a
therapeutic alternative to modulate NF-B signaling in pregnancy, as it may decrease IFN- and TNF- production
through inhibition of NF-B in PBMCs of pregnant
women [70].

Monocytes promoting inflammatory conditions in

preeclampsia
Leukocytes from the nonspecific or innate immune system are
important in normal pregnancy, as they promote successful
implantation and participate in several events at the feto-maternal interface [71]. These cells may, however, also be involved in the pathophysiology of pregnancy disorders [72].
Activated monocytes and neutrophils are present in the fetal
and placental circulation under hypoxic conditions and may
contribute to the increased vascular resistance and morbidity
of the fetus observed in preeclampsia [9].
Trophoblast cells under hypoxic conditions, such as those in
preeclampsia, produce high concentrations of IL-6 and IL-8
and low IL-10 levels [73]. Nevertheless, the placenta is not the
only contributor to the production of inflammatory cytokines
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Journal of Leukocyte Biology 3

in preeclampsia [74]. Monocytes may represent an important

source of proinflammatory cytokines in preeclampsia, as
monocytes from preeclamptic patients secrete high levels of
IL-1, IL-6, and IL-8 [75]. These cells have been classified into
three subsets, according to their expression of CD14 (LPS receptor) and CD16 (FCRIII). Classical monocytes are
CD14CD16, intermediate monocytes are CD14CD16,
and nonclassical monocytes are CD14CD16 [76]. Women
with normal pregnancies have low percentages of classical
monocytes and higher percentages of nonclassical/intermediate monocytes compared with nonpregnant women [77]. Nonclassical and intermediate monocytes are even higher in preeclampsia than in normal pregnancies [77, 78], and they show
up-regulated expression of TLR4 [78], reflecting the importance of TLRs and TLR ligands in this syndrome. The exact
function of the different subsets of monocytes in pregnancy
and preeclampsia is unknown. In nonpregnant humans, intermediate monocytes are predisposed toward antigen presentation. They secrete inflammatory cytokines and ROS and may
participate in angiogenesis [79]. In contrast, nonclassical
monocytes may exhibit DC characteristics and produce IL-12
and IL-8 [80].
During pregnancy, TNF-, IL-6, and other proinflammatory
cytokines derived from monocytes can activate the RAS, promote oxidative stress, and may lead to an increase in endothelium-derived vascular contracting molecules to diminish the
bioavailability of vascular-relaxing factors derived from the endothelium [81, 82]. Furthermore, elevated TNF- levels correlate with the activity of AT1-R autoantibodies and an increase
in sFLT-1 and sENG levels through AT1-R-mediated TNF-
induction [33].

Neutrophils and oxidative stress in preeclampsia

Neutrophils are activated in the peripheral blood [83, 84] and
in the decidua of preeclamptic patients, and elastase produced
by these cells may contribute to vascular damage [85]. In fact,
neutrophils are strongly associated with vascular dysfunction in
preeclamptic women, as they adhere to the endothelium in
high densities [86]. Increased expression of IL-8 and ICAM-1
in vessels of preeclamptic women contributes to the infiltration of neutrophils into the maternal systemic vasculature
[86]. Later, neutrophil adhesion to endothelial cells is linked
to increased expression of CD11b, and neutrophil adhesion
may be promoted by overproduction of superoxides and hydrogen peroxide [87]. Moreover, oxidants generated by activated neutrophil NADPH oxidase may react with different targets to form toxic metabolites that are products of lipid peroxidation, such as 4-hydroxynonenal, which contributes to
microbial death and the damage induced by neutrophils [88].
Lipid peroxidation is elevated before and after childbirth (and
delivery of the placenta) in women with preeclampsia, suggesting that these patients are under persistent oxidative stress
that contributes to an inflammatory response [89]. Neutrophils may be carriers of cellular oxidative stress from the placenta to the vascular environment of the mother [90].
Neutrophil activation results from exposure to hypoxic or
inflammatory conditions [89]. Placental microparticles, such as
STBMs, may act as inflammatory agents, as in preeclampsia,
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Volume 94, July 2013

the release of STBMs can activate neutrophils and promote

formation of NETs [91]. NETs are extracellular structures
composed of chromatin and granular proteins released during
the death process, which occurs upon neutrophil stimulation.
In this process, euchromatin and heterochromatin are homogenized, the nuclear and granular membranes disintegrate, and
these components combine to create the NET. The NET is
liberated when the cellular membrane breaks; it then binds to
and kills microorganisms [92]. In the preeclamptic placenta,
many NETs are induced in the intervillous space as a result of
stimulation of neutrophils by STBMs and IL-8 [91]. As NETs
participate in the pathogenesis of inflammatory disorders and
autoimmunity [93], they may also contribute to the pathogenesis of preeclampsia, playing a role in the deficient placental
perfusion associated with this disease [94]. In epithelial and
endothelial cells, NETs can induce cytotoxicity, which is mostly
mediated by histones and MPO [95]. The death process that
initiates NET formation, called NETosis, is different from necrosis and apoptosis and depends on autophagy [96], generation of ROS, and NADPH oxidase [92], which is required to
increase neutrophil adhesion to the endothelium.
Besides oxidative stress-induced inflammation and endothelial dysfunction, preeclamptic patients also have increased levels of MPO. This enzyme is produced by activated monocytes
and neutrophils and may contribute to placental and endothelial oxidative damage and the dysfunction of endothelial cells
reported in these patients [97].

NK cells
Placental NK cells, designated as uNK cells, play an important
role in the acceptance and rejection of the fetus, as they are in
direct contact with the trophoblasts [98]. uNK cells produce
decidual IFN- in early human pregnancy, during which they
may inhibit the invasion of the extravillous trophoblast [99]
and probably promote a CD4 Th1 cytokine profile in preeclamptic women. Their participation may be more relevant
during the origins of preeclampsia. Peripheral NK cells from
preeclamptic women express lower intracellular VEGF levels
than those from normal pregnant women [100], a finding that
may link these cells with the endothelial dysfunction seen in
this syndrome. Moreover, as NK cells express functional TLR3
and TLR9, they can recognize RNA and CpG DNA, which promotes their activation, especially in the presence of IL-8 [101].
Components of STBMs are also ligands for the NK cell receptor NKG2D [102]. Thus, STBMs or fetal DNA may interact
with NK cells in patients with preeclampsia.
NK cells also express several components of the RAS, such
as renin, angiotensinogen, angiotensin-converting enzyme, and
AT1-R and AT2-R, making NK cells responsive to AT2 levels
[103]. Considering that preeclampsia may be related to dysregulation of the RAS [104], the presence of AT1-R and
AT2-R in NK cells could be relevant in this syndrome.

DCs
Besides B cells and macrophages, DCs function as APCs during pregnancy and can modulate immune responses [105].
DCs are the link between the innate and adaptive immune

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Laresgoiti-Servitje The immune system in the pathophysiology of preeclampsia

system, as they can respond to a variety of stimuli, such as TLR

ligands, cytokines, and immune complexes [106]. These cells
are particularly relevant during pregnancy, as they may modulate immune responses, depending on their activation through
different TLRs or depending on the cytokine microenvironments in which their activation occurs [107].
Decidual CD14DC-SIGN DCs may play an important role
in iTreg induction, and in preeclampsia, CD14DC-SIGN
and CD14DC-SIGN decidual DCs induce iTreg cells poorly
[108]. Regarding peripheral blood DCs, human myeloid DCs
(DC-1) are CD4CD11chighCD123lowCD45ROBDCA-1,
and plasmacytoid (lymphoid) DCs (DC-2) in peripheral blood
are CD4CD11cCD123highCD45RABDCA-2 [109]. The
percentage of BDCA-2 lymphoid DCs is significantly lower in
the blood of preeclamptic patients compared with women in
the third trimester with normal pregnancies [110]. Considering that CD11c (BDCA-1) myeloid DCs produce IL-12 and
may modulate toward Th1 responses [111] and that lymphoid
CD303 (BDCA-2) DCs can promote a shift toward Th2 responses [112], the decreased number of lymphoid DCs in
blood of preeclamptic women is noteworthy. Furthermore,
suppression of Th1 responses by DCs may be associated with
expression of serpin in myeloid APCs, which is a plasminogen
activator inhibitor [113] that is decreased in preeclamptic
women [114]. Myeloid and plasmacytoid DCs respond to TLR
ligands, depending on their TLR expression. Myeloid DCs express TLR1 6 and TLR8, whereas plasmacytoid DCs strongly
express TLR7 and TLR9 and have a low expression of TLR4
and TLR2 [115]. TLRs may represent a possible therapeutic
target in this syndrome, as DCs in women with preeclampsia
also show increased expression of basal TLR3, TLR4, and
TLR9 and secrete higher levels of IFN-, TNF-, IL-1, and
IL-12 [116].
Because of changes in expression of TLRs in DCs in preeclampsia, it may be relevant to evaluate to what extent TLR9
ligands, such as oligodeoxynucleotides containing unmethylated CpG motifs, or TLR7 ligands, such as RNA [117], may
participate in the overproduction of IFNs and the modulation
of the immune response in preeclamptic patients.
Until recently, the stage of DC maturation was considered to
be essential for their ability to induce Tregs or activate inflammatory T cell responses, but the developmental stage is no
longer considered a key factor that differentiates between
tolerogenic versus immunogenic DCs [118]. It is not the maturation state but the inflammatory factors or cytokines present
during DC maturation that may influence the ability of DCs to
induce different T cell responses [119]. The role of DCs in
preeclampsia requires further investigation. Factors promoting
the polarization of lymphoid versus myeloid DCs and the factors present during their maturation in preeclampsia remain
unclear. The participation of TLRs and their ligands in DCs
may help broaden our perspective regarding the role of these
cells in the pathophysiology of preeclampsia.
Figure 1 shows possible ligands for TLRs and their roles in
preeclampsia. The activation of innate immune system cells
that participate in the pathophysiology of preeclampsia is also
described.

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THE ADAPTIVE IMMUNE SYSTEM

In preeclampsia, the Th1/Th2 paradigm has been used to
explain T cell behavior, as a shift from a Th1 to a Th2 phenotype at the fetal-maternal interface may not occur in this
syndrome. Whereas Th1 cytokines, including IL-1, IL-2, and
IFN-, are predominant in preeclampsia, the production of
Th2 cytokines, including IL-10 and IL-5, can be decreased
[120]. The changes in cytokine microenvironments, including elevated IFN- levels [121123], occur during the first
weeks of pregnancy and promote a CD4 Th1 lymphocyte
cytokine profile that can persist further into the preeclamptic pregnancy. The presence of low IL-10 levels in preeclampsia is also relevant [59], as IL-10 protects the fetus
from rejection during normal pregnancy via activation of
HLA-G expression in trophoblasts and monocytes at the fetal-maternal interface [124]. Although many women with
preeclampsia present a shift toward Th1 cytokines, the
Th1/Th2 paradigm does not respond to all of the questions
regarding immune regulation in preeclampsia. The sole use
of this paradigm to explain immunological aspects participating in the pathophysiology of this syndrome could be
oversimplifying the mechanisms involved, as patients with
preeclampsia can have changes in other T lymphocyte subsets. The alterations in numbers and function of Th17 cells
and Tregs may help us understand more clearly the role of
lymphocytes in the pathophysiology of preeclampsia.

T lymphocyte subsets
One CD4 lymphocyte subset that may be involved in the
pathophysiology of preeclampsia is the CD4CD25FoxP3
Treg (FoxP3 is a Treg transcription factor) [125]. Some researchers have found no differences in Treg numbers between
healthy and preeclamptic pregnancies [126]. Others have reported reduced numbers of Tregs in preeclampsia compared
with normal pregnancies [127, 128]. CD4CD25FoxP3 Treg
function is reduced in preeclampsia, which may be related to
the presence of inflammatory conditions [129]. Moreover, the
Treg pool in preeclamptic patients consists mostly of
CD4CD25FoxP3HLA-DRCD45RA cells. Although these
cells express HLA-DR, which is related to suppression activity, they exhibit reduced regulatory capacity [125]. Thus,
Tregs and Treg subsets seem to play a role in the pathophysiology of preeclampsia, but their role remains unclear.
The presence of increased levels of sENG, a protein
thought to impair TGF- binding to receptors, could be
blocking TGF- signals required for Treg functions and may
participate in changes in this cell population in preeclampsia [130].
In addition to Tregs, CD4 IL-17-producing T cells (Th17)
may participate in preeclampsia. Preeclamptic patients have a
lower ratio of Tregs:Th17 cells [131]. T cell polarization is related to an imbalance of T cell transcription factors in PBMCs
and in the decidua of preeclamptic patients. Decreased mRNA
levels of FoxP3 and increased levels of the Th17 transcription
factor RORc and the Th1 transcription factor T-bet are present in preeclamptic women compared with healthy pregnant
women [132]. The predominance of Th17 cells in preVolume 94, July 2013

Journal of Leukocyte Biology 5

Figure 1. In normal pregnancy, low levels of STBMs contribute to the inhibition of IFN- production and a shift toward Th2 responses. In preeclampsia, however, persistent hypoxia, the presence of free fetal DNA, and the shedding of high amounts of STBMs into the maternal circulation promote inflammatory conditions, in which neutrophils (NTs), monocytes (MNs), NK cells, endothelial cells (ECs), and DCs are
stimulated. Neutrophil stimulation results in the activation of elastases and the production of superoxides and hydrogen peroxide via
NADPH and MPO activation, respectively. Direct stimulation of neutrophils by STBMs may also result in damage through NET formation.
Superoxides also promote neutrophil adhesion to the endothelium and NET formation at this level. Consequently, neutrophil activation results in vascular damage and dysfunction. In contrast, the nonclassical and intermediate monocytes in the presence of up-regulated TLR4
secrete cytokines and may contribute to the persistent inflammatory conditions. Plasmacytoid and myeloid DCs (pDCs and mDCs, respectively) also respond to TLR ligands and can modulate T cell responses. NK cells may play a role in the production of IFN- and the shift
toward Th1 responses and may also respond to TLR ligands.

eclampsia, accompanied by decreased Treg function and an

altered balance in the Th17:Treg ratio [129], may be a result of altered levels of cytokines, including IL-6 and IL-1,
that promote differentiation of these cells from progenitor
cells [133]. However, CD8 lymphocytes and NK cells also
secrete IL-17 and may contribute to inflammation in this
syndrome [134].
T lymphocytes also possess functional RAS elements, able to
produce AT2 at inflammatory sites. As AT2 can promote chemotaxis of NK cells and T cells by binding to AT1-R, a RASmediated inflammatory pathway may also be involved in preeclampsia [103].

The role of B lymphocytes and antibodies in

preeclampsia
A CD19 CD5 B cell population, which is able to produce
AT1-AAs, has been identified in the placenta of preeclamptic
patients [135]. These human CD19 CD5 B cells share phenotypic properties with murine B-1a lymphocytes [136]. In
mice, B-1a cells have been involved in the generation of autoantibodies [137]. Likewise, human CD19 CD5 B cells may
become autoreactive [138], as they are able to activate somatic
hypermutation mechanisms that can promote mutations in the
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Volume 94, July 2013

variable regions of the BCR [139]. This is a reason why human

peripheral blood and spleen CD5 B cells may produce polyspecific, autoreactive antibodies [140]. The identification of
CD19 CD5 B cells that can produce AT1-AAs [135] represents an important step in the understanding of the pathophysiology of preeclampsia. However, the mechanisms promoting the development of AT1-R autoantibodies have not been
described yet.
AT1-AAs of the IgG isotype [141] are present in 70 95% of
preeclamptic patients [30, 142], they bind to receptors in human trophoblast and vascular cells [143], and their binding
induces sFlt1 and sENG production by human villous explants
through TNF- pathways [32, 33]. Binding of AT1-AA increases TNF- signaling in human placental villous explants,
which then promotes IL-6 production that induces endothelin-1 production [144]. AT1-AAs, by ligating to the AT1-R on
vascular smooth muscle cells, may also promote vasoconstriction [145] and can mediate hypertension by promoting placental oxidative stress [14, 146]. High levels of AT1-AAs are
associated with the presence of hypertension, proteinuria, and
sFlt1 and may correlate with the severity of the disease
[142]. Moreover, AT1-AAs may be a possible biomarker for
late-onset preeclampsia [30]. As AT1-AAs can cross the pla-

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Laresgoiti-Servitje The immune system in the pathophysiology of preeclampsia

cental barrier [104], these antibodies may also contribute to

intrauterine growth restriction in some patients with preeclampsia, directly by activating AT1-R on the surface of fetal organs and indirectly by induction of apoptosis in the
placenta [147]. AT1-AAs do not disappear completely after
childbirth [148].
AT1-AAs are not the only autoantibodies that have been described in preeclamptic patients. The presence of autoantibodies against 1, 2, and 1 adrenoreceptors has been demonstrated in patients with severe preeclampsia and may increase
the risk of neonatal morbidity and mortality [149]. Further
studies are needed to identify the factors triggering their production and plausible mechanisms by which these antibodies
may promote severe preeclampsia.
The participation of B cells and different T cell subsets and
the possible mechanisms that modulate their activity are described in Fig. 2.

CONCLUSIONS
Persistent hypoxia, alterations in oxygen-sensing mechanisms at the placental level, and increased levels of sSTBMs
from the placenta are important factors that can contribute
to the pathophysiology of preeclampsia. The increased shedding of STBMs from the placenta during preeclampsia may
promote endothelial cell dysfunction and activation of maternal leukocytes, such as monocytes, neutrophils, NK cells,
and DCs. Whereas monocytes are involved in the secretion
of proinflammatory cytokines and may be promoting persistent inflammatory conditions in the preeclamptic patient,
neutrophils play an important role in the vascular damage
seen in preeclampsia. Neutrophils can be activated by inflammatory conditions caused by STBMs and persistent hypoxia. They may harm the endothelium through NET formation, elastase activation, or superoxide-related damage, pro-

moting vascular dysfunction that results in increased

vascular resistance. On the other hand, changes in DC subtypes may also participate in preeclampsia. Lower levels of
lymphoid BDCA-2 DCs in preeclampsia could promote
Th1-type responses in this syndrome, and they may be regulated by TLR3 and TLR9 ligands.
As TLRs can act as receptors for STBMs, fetal DNA, and
DAMPs, TLRs may play a key role in maintaining inflammatory conditions in preeclampsia. Moreover, TLRs may represent important therapeutic targets in this syndrome. Further
research is needed regarding the role of TLRs in the recognition of STBMs and DAMPs in preeclampsia and their possible relationship with the modulation of DCs and T cell
subsets.
CD19CD5 B cells, by producing AT1-AAs, are important
contributors to the pathophysiology of preeclampsia and have
rendered preeclampsia as a syndrome with autoimmune characteristics. This concept is also supported by the presence of
autoantibodies against adrenoreceptors in patients with severe
preeclampsia. However, the factors promoting the production
of adrenoreceptor autoantibodies and the mechanisms by
which these antibodies participate in preeclampsia still need to
be explored. Many questions remain regarding the interaction
between angiogenic/antiangiogenic factors with immune system cells and the possible participation of miRNAs in immune
system regulation in preeclampsia.
The immune system plays an important role in many pathophysiological processes occurring in preeclamptic patients.
This review aimed to examine the participation of several components of the immune system in the pathophysiology of preeclampsia. However, it has its limitations, as because of the
great amount of cells and molecules that may be implicated, it
is not possible to give a comprehensive overview of all of the
interactions involved in this syndrome.

Figure 2. Although changes in T cell subsets may

be present at the origin of preeclampsia, the
persistence of inflammatory conditions promoted by hypoxia, increased STBMs, or free
fetal DNA via activation of the innate immune
system cells may affect the generation of different T cell responses. Preeclamptic women have
lower mRNA levels of FoxP3, increased numbers
of Th17, increased RORc mRNA, and increased
Th1 T-bet mRNA. High IFN- concentrations may
promote the development of Th1 lymphocytes,
whereas IL-1, IL-6, and IL-7 may promote the generation of Th17 lymphocytes in preeclamptic
women. These changes can result in a reduced
regulatory capacity of Tregs in preeclampsia and a
low Treg:Th17 ratio. High levels of sENG could be
affecting TGF- signaling required for iTreg.
CD19 CD5 B cells participate in the pathophysiology of preeclampsia by producing AT1-AAs.
Factors promoting the development of these antibodies have not been described yet.

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Volume 94, July 2013

Journal of Leukocyte Biology 7

DISCLOSURES

The author declares no conflicts of interest.

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KEY WORDS:
preeclampsia STBM neutrophil dendritic cell lymphocyte monocyte TLR B cell

Volume 94, July 2013

Journal of Leukocyte Biology 11