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1112603
Review
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
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
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].
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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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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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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
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.
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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-
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DISCLOSURES
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KEY WORDS:
preeclampsia STBM neutrophil dendritic cell lymphocyte monocyte TLR B cell