Inmunologia de Preeclampsia

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ulated by the release of necrotic and/or apoptotic syncytiotro-

phoblast cells into the maternal circulation [10]. As the first

stage of preeclampsia mostly accounts for its origins, this re-

view will discuss the second stage, as it is when the maternal-

inflammatory response takes place, and most pathophysiologi-

cal processes occur. The second stage of preeclampsia may

also involve poor fetal growth and can be associated indepen-dently 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 pre-

eclampsia [12].

Some components of the innate and adaptive immune sys-

tem that may participate in the physiopathology of preeclamp-

sia will be described here, as they produce certain cytokines,

they modulate immune responses, or they have shown a modi-

fied function that may lead to the symptoms of this disease.

The pathophysiology of preeclampsia also involves altered lev-

els of angiogenic factors, AT2-R autoantibodies [1315], and

the presence of different miRNAs [16, 17].

THE ROLE OF ANGIOGENIC/ANTIANGIOGENIC FACTORS AND THEIRINTERACTION WITH THE IMMUNESYSTEM IN PREECLAMPSIA

The persistence of low-oxygen tensions or altered oxygen-sens-

ing mechanisms in preeclampsia promotes placental overex-

pression of HIF-1[7, 18]. Later, an imbalance between pro-

and antiangiogenic factors can be observed in this syndrome.

Proangiogenic factors include the VEGF and PlGF, whereas

antiangiogenic factors that can be present in preeclamptic pa-

tients are the sENG [19] and the sVEGF-R1 [20, 21] and itsgeneric splice variant, known as sFlt1 [21]. sFlt1 inhibits VEGF

and PlGF by binding to these factors in the maternal circula-

tion 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 hy-

poxic villous trophoblast, participates in the clearing of free-

maternal VEGF [27]. Two isoforms of sVEGF-R1 have been

described: sFlt1, which is generic, and sFlt1-14, which is hu-

man specific [21]. sFlt1-14, the most common VEGF inhibitor

produced by the human placenta in preeclampsia, is a C-termi-nal 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 subse-

quent 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 differ-

ences in sFlt1 levels in women that develop the disease earlier

or later in pregnancy may be reflecting different oxygen con-

centrations 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 ofTGF-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 condi-

tions [31]. Likewise, the binding of AT1-AA, which will be

described later in the manuscript, can promote the secre-

tion of sENG and sFlt1 through TNF--mediated mecha-

nisms [32, 33].

THE ROLE OF miRNAs INPREECLAMPSIA

miRNAs are nonprotein-coding RNAs that regulate gene ex-

pression and may play a role in the pathogenesis of pre-eclampsia, also serving as possible biomarkers for this disease

[34]. Several miRNAs have been found elevated in placentas

with preeclampsia. For example, in severe preeclampsia, miR-

16, miR-29b, miR-195, miR-26b, miR-181a, miR-335, and miR-

222 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 acknowl-

edged as a regulator of the transcript variants 1 and 2 of the Bcell lymphoma 2-like gene [16]. On the other hand, miR-210

is a potent miRNA up-regulated by hypoxia [17] that can in-

hibit the migration and invasion ability of trophoblast cells

[39]. Another miRNA overexpressed in preeclampsia that may

contribute to its development by down-regulating the angio-

genic-regulating factor CYR61 is miR-155 [40]. miRNAs may

not only be key players in the pathophysiology of preeclamp-

sia, 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 circu-

lation may stimulate the production of several cytokines by

peripheral monocytes [41]. The recognition of STBMs by pe-

ripheral mononuclear leukocytes has been related to inhibi-

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

TNF-, and IL-12 [42]. STBMs bind predominantly to recep-

tors 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 pla-

centas exacerbate LPS responses in PBMCs [46]. This may

help to explain the increased production of cytokines in pre-

eclampsia, 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 areprobably secondary to the activation of endothelial cells by

STBMs and may be involved in the pathophysiology of pre-

eclampsia [47].

THE INNATE IMMUNE SYSTEM IN THEPATHOPHYSIOLOGY OF PREECLAMPSIA

TLRs in preeclampsiaAccording to the danger model [48], hypoxia can lead to a

persistent inflammatory response, and this may occur in pre-

eclamptic patients. A key inflammatory factor in preeclampsia

is the recognition of DAMPs that can result from endothelialcell 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 sys-

tem cells [51]. S100 and HMGB1 are proteins that behave as

DAMPs [51, 52]. High cytoplasmic expression of HMGB1 oc-

curs 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 poten-tial ability to respond to DAMPs, although the role of the pla-

centa 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 com-

pared with those of normal human pregnancies, and the acti-

vation of TLR3, -7, and -8 by dsRNAs and ssRNAs promotes

pregnancy-dependent, proteinuric hypertension and endothe-

lial dysfunction in mice [60]. Likewise, the binding of circulat-

ing fetal DNA to TLR9 in mice can activate an inflammatory

response, leading to IL-6 secretion [61]. This may be particu-

larly 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 peri-

odontal 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 inflamma-

tory processes. These mechanisms involve binding to TLRs,

making these receptors possible therapeutic targets for pre-

eclampsia.

Transcription factors, NF-B and TLRs, inpreeclampsia

It has been proposed that transcription factors may help usgain 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 dis-

eases [66]. In patients with preeclampsia, increased transloca-

tion of nuclear NF-B has been found in peripheral blood-

activated 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 pro-

moting an increase of NF-B in this syndrome, as all TLR sig-naling pathways culminate in the activation of this transcrip-

tion 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 preg-

nancy, as it may decrease IFN-and TNF- production

through inhibition of NF-B in PBMCs of pregnant

women [70].

Monocytes promoting inflammatory conditions inpreeclampsia

Leukocytes from the nonspecific or innate immune system areimportant in normal pregnancy, as they promote successful

implantation and participate in several events at the feto-ma-

ternal interface [71]. These cells may, however, also be in-

volved 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

Laresgoiti-Servitje The immune system in the pathophysiology of preeclampsia

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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 re-

ceptor) and CD16 (FCRIII). Classical monocytes are

CD14

CD16

, intermediate monocytes are CD14

CD16

,and nonclassical monocytes are CD14CD16 [76]. Women

with normal pregnancies have low percentages of classical

monocytes and higher percentages of nonclassical/intermedi-

ate monocytes compared with nonpregnant women [77]. Non-

classical and intermediate monocytes are even higher in pre-

eclampsia than in normal pregnancies [77, 78], and they show

up-regulated expression of TLR4 [78], reflecting the impor-

tance 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, inter-

mediate monocytes are predisposed toward antigen presenta-

tion. They secrete inflammatory cytokines and ROS and may

participate in angiogenesis [79]. In contrast, nonclassicalmonocytes 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, pro-

mote oxidative stress, and may lead to an increase in endothe-

lium-derived vascular contracting molecules to diminish the

bioavailability of vascular-relaxing factors derived from the en-

dothelium [81, 82]. Furthermore, elevated TNF- levels corre-

late 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 preeclampsiaNeutrophils are activated in the peripheral blood [83, 84] andin 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 infiltra-

tion 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 hy-

drogen peroxide [87]. Moreover, oxidants generated by acti-

vated neutrophil NADPH oxidase may react with different tar-gets to form toxic metabolites that are products of lipid per-

oxidation, 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, suggest-

ing that these patients are under persistent oxidative stress

that contributes to an inflammatory response [89]. Neutro-

phils may be carriers of cellular oxidative stress from the pla-

centa 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,

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 homog-

enized, the nuclear and granular membranes disintegrate, and

these components combine to create the NET. The NET isliberated 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 pathogen-

esis 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 ne-

crosis and apoptosis and depends on autophagy [96], genera-

tion of ROS, and NADPH oxidase [92], which is required toincrease neutrophil adhesion to the endothelium.

Besides oxidative stress-induced inflammation and endothe-

lial dysfunction, preeclamptic patients also have increased lev-

els of MPO. This enzyme is produced by activated monocytes

and neutrophils and may contribute to placental and endothe-

lial oxidative damage and the dysfunction of endothelial cells

reported in these patients [97].

NK cellsPlacental 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 theymay inhibit the invasion of the extravillous trophoblast [99]

and probably promote a CD4 Th1 cytokine profile in pre-

eclamptic 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 pro-

motes their activation, especially in the presence of IL-8 [101].

Components of STBMs are also ligands for the NK cell recep-

tor 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 dys-

regulation of the RAS [104], the presence of AT1-R and

AT2-R in NK cells could be relevant in this syndrome.

DCsBesides B cells and macrophages, DCs function as APCs dur-

ing pregnancy and can modulate immune responses [105].

DCs are the link between the innate and adaptive immune



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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 modu-

late immune responses, depending on their activation through

different TLRs or depending on the cytokine microenviron-

ments in which their activation occurs [107].

Decidual CD14

DC-SIGN

DCs may play an important rolein 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]. Consider-

ing 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 re-

sponses [112], the decreased number of lymphoid DCs inblood 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 ex-

press TLR16 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 pre-

eclampsia, it may be relevant to evaluate to what extent TLR9

ligands, such as oligodeoxynucleotides containing unmethyl-

ated 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 inflam-

matory 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 matu-

ration state but the inflammatory factors or cytokines presentduring 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 fac-

tors 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.

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 phe-

notype 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, includ-

ing 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 preeclamp-

tic pregnancy. The presence of low IL-10 levels in pre-

eclampsia 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 fe-

tal-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 partici-pating in the pathophysiology of this syndrome could be

oversimplifying the mechanisms involved, as patients with

preeclampsia can have changes in other T lymphocyte sub-

sets. 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 subsetsOne CD4 lymphocyte subset that may be involved in the

pathophysiology of preeclampsia is the CD4CD25FoxP3

Treg (FoxP3 is a Treg transcription factor) [125]. Some re-

searchers have found no differences in Treg numbers betweenhealthy and preeclamptic pregnancies [126]. Others have re-

ported 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 activ-

ity, they exhibit reduced regulatory capacity [125]. Thus,

Tregs and Treg subsets seem to play a role in the patho-

physiology of preeclampsia, but their role remains unclear.

The presence of increased levels of sENG, a protein

thought to impair TGF- binding to receptors, could beblocking TGF- signals required for Treg functions and may

participate in changes in this cell population in preeclamp-

sia [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 re-

lated 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 pres-

ent in preeclamptic women compared with healthy pregnant

women [132]. The predominance of Th17 cells in pre-




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eclampsia, accompanied by decreased Treg function and an

altered balance in the Th17:Treg ratio [129], may be a re-

sult 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 che-

motaxis of NK cells and T cells by binding to AT1-R, a RAS-

mediated inflammatory pathway may also be involved in pre-eclampsia [103].

The role of B lymphocytes and antibodies inpreeclampsiaA 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 phe-

notypic properties with murine B-1a lymphocytes [136]. In

mice, B-1a cells have been involved in the generation of auto-

antibodies [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

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

peripheral blood and spleen CD5 B cells may produce poly-

specific, autoreactive antibodies [140]. The identification of

CD19 CD5 B cells that can produce AT1-AAs [135] repre-

sents an important step in the understanding of the patho-

physiology of preeclampsia. However, the mechanisms promot-

ing 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 hu-

man trophoblast and vascular cells [143], and their bindinginduces sFlt1 and sENG production by human villous explants

through TNF-pathways [32, 33]. Binding of AT1-AA in-

creases TNF- signaling in human placental villous explants,

which then promotes IL-6 production that induces endothe-

lin-1 production [144]. AT1-AAs, by ligating to the AT1-R on

vascular smooth muscle cells, may also promote vasoconstric-

tion [145] and can mediate hypertension by promoting pla-

cental 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-

Figure 1. In normal pregnancy, low levels of STBMs contribute to the inhibition of IFN-production and a shift toward Th2 responses. In pre-eclampsia, however, persistent hypoxia, the presence of free fetal DNA, and the shedding of high amounts of STBMs into the maternal cir-culation promote inflammatory conditions, in which neutrophils (NTs), monocytes (MNs), NK cells, endothelial cells (ECs), and DCs arestimulated. Neutrophil stimulation results in the activation of elastases and the production of superoxides and hydrogen peroxide viaNADPH 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 re-sults in vascular damage and dysfunction. In contrast, the nonclassical and intermediate monocytes in the presence of up-regulated TLR4secrete cytokines and may contribute to the persistent inflammatory conditions. Plasmacytoid and myeloid DCs (pDCs and mDCs, respec-tively) also respond to TLR ligands and can modulate T cell responses. NK cells may play a role in the production of IFN- and the shifttoward Th1 responses and may also respond to TLR ligands.



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

intrauterine growth restriction in some patients with pre-

eclampsia, directly by activating AT1-R on the surface of fe-

tal 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 de-scribed in preeclamptic patients. The presence of autoantibod-

ies against1, 2, and 1 adrenoreceptors has been demon-

strated 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 pro-

duction 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 de-

scribed inFig. 2.

CONCLUSIONS

Persistent hypoxia, alterations in oxygen-sensing mecha-

nisms 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 shed-

ding of STBMs from the placenta during preeclampsia may

promote endothelial cell dysfunction and activation of ma-

ternal leukocytes, such as monocytes, neutrophils, NK cells,

and DCs. Whereas monocytes are involved in the secretion

of proinflammatory cytokines and may be promoting persis-

tent inflammatory conditions in the preeclamptic patient,

neutrophils play an important role in the vascular damage

seen in preeclampsia. Neutrophils can be activated by in-

flammatory conditions caused by STBMs and persistent hyp-oxia. They may harm the endothelium through NET forma-

tion, elastase activation, or superoxide-related damage, pro-

moting vascular dysfunction that results in increased

vascular resistance. On the other hand, changes in DC sub-

types 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 regu-

lated by TLR3 and TLR9 ligands.

As TLRs can act as receptors for STBMs, fetal DNA, andDAMPs, TLRs may play a key role in maintaining inflamma-

tory conditions in preeclampsia. Moreover, TLRs may repre-

sent important therapeutic targets in this syndrome. Further

research is needed regarding the role of TLRs in the recog-

nition of STBMs and DAMPs in preeclampsia and their pos-

sible 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 char-

acteristics. 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 sys-

tem cells and the possible participation of miRNAs in immune

system regulation in preeclampsia.

The immune system plays an important role in many patho-

physiological processes occurring in preeclamptic patients.

This review aimed to examine the participation of several com-

ponents of the immune system in the pathophysiology of pre-

eclampsia. However, it has its limitations, as because of the

great amount of cells and molecules that may be implicated, itis not possible to give a comprehensive overview of all of the

interactions involved in this syndrome.

Figure 2. Although changes in T cell subsets maybe present at the origin of preeclampsia, thepersistence of inflammatory conditions pro-moted by hypoxia, increased STBMs, or freefetal DNA via activation of the innate immunesystem cells may affect the generation of differ-ent T cell responses. Preeclamptic women havelower mRNA levels of FoxP3, increased numbersof Th17, increased RORc mRNA, and increasedTh1 T-bet mRNA. High IFN-concentrations maypromote the development of Th1 lymphocytes,whereas IL-1, IL-6, and IL-7 may promote the gen-eration of Th17 lymphocytes in preeclampticwomen. These changes can result in a reducedregulatory capacity of Tregs in preeclampsia and alow Treg:Th17 ratio. High levels of sENG could beaffecting TGF-signaling required for iTreg.CD19 CD5 B cells participate in the patho-physiology of preeclampsia by producing AT1-AAs.Factors promoting the development of these anti-bodies have not been described yet.




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DISCLOSURES

The author declares no conflicts of interest.

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KEY WORDS:

preeclampsia STBM neutrophil dendritic cell lymphocyte mono-cyte TLR B cell



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Inmunologia de Preeclampsia