Expert Review ajog.

org

Progress in the understanding of the pathophysiology of

immunologic maladaptation related to early-onset
preeclampsia and metabolic syndrome related to
late-onset preeclampsia
Pierre-Yves Robillard, MD; Gustaaf Dekker, MD, PhD; Marco Scioscia, MD, PhD; Shigeru Saito, MD, PhD

Introduction
Although many theories have been pro- Among mammalian species, human reproduction has 2 outstanding features. The hu-
posed, it is now widely but not univer- man hemochorial placentation is characterized by a very deep endovascular trophoblast
sally accepted that syncytiotrophoblast invasion in the spiral arteries, reaching deep into the myometrium. This requires an
(STB) stress is the fundamental pathway agonistic direct cell-cell interaction between the maternal immune system and semi-
leading to maternal syndrome.1e3 In allogeneic trophoblast. The second feature is preeclampsia, a heterogeneous syndrome,
early-onset preeclampsia, shallow endo- a uniquely human condition. The human female is one of the few mammals exposed to
vascular trophoblast invasion in the her partner’s semen on multiple occasions before conception. Regulatory T cells,
spiral arteries, leading to ischemia or especially paternal antigen-specific regulatory T cells, play an important role in the
reperfusion and inflammatory injuries, maintenance of pregnancy. Sexual intercourse increases the number of dendritic cells in
seems to be the most important pathway the uterus that play an important role in the induction of paternal antigen-specific reg-
leading to STB stress.2e6 In late-onset ulatory T cells. Paternal antigen-specific regulatory T cells maintain pregnancy by
preeclampsia, the much more common inducing tolerance. In the decidua basalis of preeclamptic cases, clonal regulatory T cells
phenotype of the syndrome, STB stress are reduced; these would normally monoclonally expand to recognize fetal or paternal
seems to be primarily related to maternal antigens. Programmed cell death-1 expressed on T cells regulate cytotoxic T-cell activity
constitutional and lifestyle-related fac- and protect the fetus against maternal rejection. Programmed cell death-1 expression on
tors, such as cardiometabolic fitness.7 clonal cytotoxic T cells is reduced in preeclampsia especially in early-onset pre-
Many recent studies have demonstrated eclampsia, making the fetus and placenta vulnerable to attack by cytotoxic T cells. These
phenomena can explain the epidemiologic phenomenon that preeclampsia is more
common in couples using condom contraception, with shorter cohabitation periods, first
From the Service de Néonatologie, Centre
Hospitalier Universitaire Sud Réunion, Saint-
pregnancies, first pregnancies in multiparous women when they change partner, and
Pierre, La Réunion, France (Dr Robillard); Centre pregnancies after assisted reproduction using donated gametes.
d’Études Périnatales Océan Indien, Centre In contrast to its importance in early-onset preeclampsia, shallow trophoblast inva-
Hospitalier Universitaire Sud Réunion, Saint- sion does not play a role in the development of preeclampsia, that is, immune
Pierre, La Réunion, France (Dr Robillard);
maladaptation does not seem to be involved. Late-onset preeclampsia (>34 weeks’
Department of Obstetrics and Gynecology,
Robinson Institute, Lyell McEwin Hospital, gestation), representing 80% to 90% of preeclampsia in most developed countries
University of Adelaide, Adelaide, South Australia with a “Western lifestyle,” is strongly associated with maternal cardiometabolic
(Dr Dekker); Unit of Gynecological Surgery, variables (metabolic syndrome). Although the underlying pathophysiology might be
Department of Obstetrics and Gynecology, Mater quite different, syncytiotrophoblast stress is the final common pathway leading to the
Dei Hospital, Bari, Italy (Dr Scioscia); and
maternal syndrome among the subtypes of preeclampsia by causing an imbalance
Department of Obstetrics and Gynecology,
University of Toyama, Toyama, Japan (Dr Saito). between proangiogenic factors (placental growth factor and vascular endothelial
growth factor) and antiangiogenic factors (soluble fms-like tyrosine kinase-1 and
Received June 24, 2021; revised Oct. 19, 2021;
accepted Nov. 2, 2021. soluble endoglin). Low-dose aspirin, started before 16 week’s gestation, will prevent
The authors report no conflict of interest. up to 60% of early-onset preeclampsia but will not prevent late-onset preeclampsia.
This study did not receive any financial support.
Optimizing prepregnancy weight and controlling gestational weight gain may be the
most effective ways to prevent preeclampsia.
This paper is part of a supplement.
Corresponding author: Pierre-Yves Robillard, Key words: immunology, inositol phosphoglycan P-type, maternal-fetal graft paradox,
MD. [email protected] placental dysfunction, preeclampsia, primipaternity, regulatory T cells
0002-9378
ª 2021 The Author(s). Published by Elsevier Inc. This is
an open access article under the CC BY-NC-ND that imbalances between proangiogenic pivotal role in the pathophysiology of
license (http://creativecommons.org/licenses/by-nc- (vascular endothelial growth factor preeclampsia.6 The imbalance between
nd/4.0/).
https://doi.org/10.1016/j.ajog.2021.11.019
[VEGF] and placental growth factor these proangiogenic vs antiangiogenic
[PlGF]) and antiangiogenic(soluble fms- factors is detectable long before the
like tyrosine kinase-1 [sFlt-1] and solu- clinically detectable onset of pre-
ble endoglin [sEng]) factors play a eclampsia. The sFlt-1-to-PlGF ratio

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measurement is currently used in several are thought to interact with each other to restriction (FGR). Early-onset pre-
countries assisting clinicians in the develop preeclampsia. eclampsia is typically associated with
management of patients with We hope this review article improves FGR (Figure). Recognition of the role of
preeclampsia.6,8,9 our understanding of the pathophysi- immune maladaptation is relevant for
Women at the time of their first ology of preeclampsia. the practicing obstetrician as follows:
pregnancy are 10 to 15 years older than
at the start of even the 20th century and Preeclampsia—the immune 1. A more prolonged period of sperm
mostly had lengthy sexual relationships maladaptation hypothesis exposure provides a partial protec-
before conceiving. Currently, late-onset Although many studies are supporting tion against early-onset preeclamp-
preeclampsia (>34 weeks’ gestation) is the immune maladaptation hypothesis, sia. All women with changing
by far the most commonly encountered there are also epidemiologic studies that partners are strongly advised to use
phenotype of preeclampsia. Couple- question its validity. Nowadays, pre- condoms to prevent sexually trans-
specific immune maladaptation, one pregnancy maternal constitutional fac- mitted diseases. However, a certain
of the topics reviewed in this study, tors, particularly obesity, play major period of sperm exposure within a
plays only a very minimal role in late- roles in the pathophysiological pathways stable relation, when pregnancy is
onset preeclampsia. In late-onset pre- leading to late-onset preeclampsia, by far aimed for, is associated with a partial
eclampsia, the main drivers seem to be the most common preeclampsia protection against preeclampsia.14,15
increased maternal body mass index phenotype. It might be this type of pre- 2. According to the primipaternity
(BMI), increased gestational weight eclampsia that was primarily studied in concept, a multiparous woman with a
gain (GWG), and other clinical char- the published large Scandinavian and US new partner should be approached as
acteristics composed of metabolic syn- studies arguing against the immune being a primigravid women.14,15 All
drome and maternal age. The fact that maladaptation hypothesis.12In these primigravid pregnant women and
late-onset preeclampsia is by far the studies, the authors showed that the multiparous women with a new
most common phenotype led some re- incidence of preeclampsia in multipa- partner should be asked about the
searchers to conclude that preeclampsia rous women increased with the number length of their sexual relationship
is caused by a “poor” prepregnancy of years since the last delivery; after a with the father of the pregnancy.16,17
cardiovascular or metabolic status— birth interval of 10 years, the incidence 3. Artificial donor insemination, oocyte
and indeed for the term phenotype of of preeclampsia in multiparous women donation, and embryo donation are
the syndrome. This special issue has a was the same as in primigravid women. associated with an increased risk of
separate study on these conflicting The authors concluded that in women developing pregnancy-induced hy-
viewpoints—the placenta “villain or with a new partner, it was the more pertensive disorders.16,17
victim”7 with the ancestral discussion prolonged birth interval that explained
between the seed (trophoblastic im- the increased rate of preeclampsia and It should be noted that the role of a
plantation) and soil (maternal pre- not the primipaternity effect, that is, no “new father” (primipaternity) is associ-
dispositions to vascular diseases), the immune maladaptation. It could well be ated with not only an excess risk of pre-
cited contradictors even proposing that these authors studied primarily the eclampsia but also lower infant
the preceding “soil” to replace the term preeclampsia (gestational ages are birthweight. In addition, in this aspect,
“seed,”10,11 that is, they argue that it is not provided in these studies). However, multiparous women with a new partner
lack of cardiometabolic fitness that more recently, it was demonstrated that behave similarly to primigravid women.18
causes the disease.7 the effect of prolonged birth interval on It has been observed for 160 years,
In our opinion, these viewpoints are the preeclampsia risk could also be without proper explanations, that pri-
not mutually exclusive, so we proposed explained by immune maladaptation. miparous women gave birth to slightly
“the seed and the soil.” Research, Paternal antigen-specific regulatory T lighter babies than multiparous women.18
particularly more than the past 15 to 20 (PAS-Treg) cells remain in the body after We have recently shown that when
years, has taught us about the heteroge- delivery and have a life span. Therefore, comparing birthweights, primipaternity-
neity of this major obstetrical problem. the number of these Treg cells decreases multiparous women have 100- to 150-g
In this aspect, Redman’s papers deserve after 10 years from the last pregnancy.13 lighter babies on average than their
reevaluation.2,3 Late, researchers have Therefore, >10 years after delivery, the multiparous counterparts (after adjust-
learned to heed his message. We believe risk of developing preeclampsia is ment for preeclampsia, smoking, alcohol,
that understanding that immunomala- equivalent to that of primiparous and maternal BMI). Considering the hu-
daptation induces shallow placentation, women, even in multiparous women man pregnancy as a “maternal-fetal graft
which is a “seed” of preeclampsia, and (Figure). paradox,” it makes sense to assume that
metabolic syndrome, such as symptoms Immune maladaptation is involved in the first establishment of a “couple’s
during the late pregnancy period, which the causation of shallow trophoblast in- symbiosis” might be less successful in first
is a “soil” induce hypertension and vasion in the spiral arteries, resulting in pregnancies. In subsequent pregnancies,
proteinuria (Figure). The seed and soil placental dysfunction and fetal growth the tissue habituation (including some

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FIGURE
Pathogenesis of early and late-onset preeclampsia

When there was no or little semen exposure, PAS-Treg cell induction was insufficient, resulting in insufficient immune tolerance to the fetus and poor
placentation. In primiparous women, the number of PAS-Treg cells was lower than that in multiparous women and no pregnancy memory NK cells
resulting in poor placentation. In multiparous women with a new partner, the risk of poor placentation was increased because of inadequate induction of
the new partner’s PAS-Treg cells. In multiparous women >10 years after delivery, memory PAS-Treg cells were decreased year by year. Therefore, the
risk of preeclampsia in these cases were similar to that in primiparous women. In these cases, serum sFlt-1 was elevated, and PlGF was decreased
because of poor placentation. In addition, the pulsatility index levels in the uterine arteries were increased. The combination of these factors resulted in
vascular endothelial dysfunction, which led to hypertension, proteinuria, and FGR by 34 weeks’ gestation. In contrast, in late-onset preeclampsia,
placentation was normal in early pregnancy, but hypertension and proteinuria developed after 34 weeks’ gestation because of the addition of stressors
that trigger preeclampsia, such as obesity, much gestational weight gain, hyperlipidemia, metabolic syndrome, and aging.
NK cells, natural killer cell; PAS-Treg cell, paternal antigen-specific regulatory T-cell; PlGF, placental growth factor; sFlt-1, soluble fms-like tyrosine kinase-1.
Robillard et al. Understanding the pathophysiology of early-onset and late-onset preeclampsia. Am J Obstet Gynecol 2022.

permanent changes in uterine vascula- cohabitation and incidence of pre- reproductive disadvantage in humans
ture) has already been boosted by a eclampsia suggests that long-term sperm compared with other mammals. During
first pregnancy.18,19 In the discussion of exposure may be important for human all human history, in developing coun-
the immunology of preeclampsia work- implantation success19,20 This makes tries nowadays and until the 1950s in
shop 2018 paper20 (Tables 1 and 2), the physiological sense as the human female developed countries, eclampsia accoun-
current authors stated that “with the is one of the few mammals exposed to ted for at least 1% of human births.20
hemochorial placenta, women would her partner’s semen on multiple occa- Robillard et al20,21 postulated that the
have to face a potentially serious immu- sions before conception. From an existence of the clinical syndrome
nologic ‘attack’ at the fetomaternal inter- evolutionary perspective, it can be preeclampsia-eclampsia required
face.” To prevent rejection, mammals have argued that induction of PAS tolerance mankind to adapt to a tremendous
acquired an immunologic tolerance through repeated sperm exposure may reproductive burden. Considering sem-
mechanism. However, inadequate toler- have reproductive advantages, perhaps iallogenic trophoblastic implantation,
ance can lead to complications, such as by promoting the implantation and we are facing 2 specific human features:
preeclampsia and poor placentation- survival of embryos conceived in long- (1) preeclampsia or eclampsia is
induced FGR (Figure). term relationships (Figure). In terms of confined to humans and (2) the very
The observation of an inverse rela- evolution, the relatively high incidence deep trophoblastic invasion character-
tionship between the duration of sexual of preeclampsia represents a istic of normal human placentation. The

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The concept that preeclampsia may

TABLE 1
be an immunologic disorder dates back
Summary of major advances in immunology of reproduction these last 3
to the beginning of the 20th cen-
decades
tury.22,23 In the early 1950s, Medawar24
Major advances in immunology of reproduction proposed the concept of the “fetus as an

Lack of HLA-G in preeclampsia (1990s) Redman and Sargent,3 2009 allograft.” Since then, it has been

Role of cytokines (Th1 or Th2 paradigm) (1990s) assumed that implantation of the fetal

Immunologic role of seminal fluid (TGF-b) (Trem- placenta would be controlled by a
ellen, & S. Robertson (1998) maternal immune response mediated

Pivotal role of NK cells (implantation and angio- by T cells (adaptive immune system)
genesis) B.A. Croy, A. Moffett, S. Hiby (2000e2004)

Dysregulation of angiogenic factors by complement recognizing paternally derived alloanti-
activation (Girardi et al, 2006) gens expressed by the placenta,

Role of hyperglycosylated HCG (deepness of im- although initially missing the impor-
plantation) (Cole, 2007) tance of the innate immune system. The

Immunologic animal model for preeclampsia (Gir- focus of research in the remainder of the
ardi, 2008)

Pivotal role of T Reg cells (Saito, 2010) 20th century was focused on the adap-
tive immune system. The pivotal
Adapted from Robillard et al.17 Copy of the original Table with permission of the JRI. All references are found in reference 17.
involvement of the innate immune
HCG, human chorionic gonadotropin; HLA-G, human leukocyte antigen G; NK, natural killer; TGF-b, transforming growth
factor b. system in the immunology of repro-
Robillard et al. Understanding the pathophysiology of early-onset and late-onset preeclampsia. Am J Obstet duction was only recognized at the
Gynecol 2022.
beginning of the 20th century.

trophoblast normally invades the spiral the size of its brain requiring about 60% The innate immune system: the
arteries into the myometrium, with of total fetal nutritional needs during the role of natural killer cells
semiallogeneic endovascular trophoblast extraordinary phase of brain develop- In a landmark study in 2000, Croy et al25
cells physiologically replacing the ment in the second and third trimester of demonstrated that the natural killer
maternal endothelial cells in these spiral pregnancy and hypothesized that the (NK) cells were the key regulators of
arteries (hemochorial placenta) and large size of the human fetal brain would adequate implantation and the endo-
disrupting the vascular smooth muscle require the deep endovascular tropho- vascular trophoblast invasion were crit-
layer. This agonistic maternal cell- blast invasion, which increases the ically involved in the remodeling of
fetoplacental cell interaction necessi- maternal blood flow to intervillous spiral arteries in mice. The mouse find-
tated a high degree of active tolerance spaces. According to this hypothesis, ings were later confirmed in
toward the semiallogeneic placental tis- such a deep invasion of the trophoblast humans.26,27 NK cells represent the
sue, compared with other mammals. can only occur on the basis of major predominant population of lymphocytes
Robillard et al17,20,21 postulated that the immunogenetic compromises in terms in the decidua, and T and B cells are rare.
major difference between the human of maternal-paternal tissue tolerance NK cells express inhibitory and activa-
fetus and their mammal counterparts is (Table 1 and 2). tory killer cell immunoglobulinlike

TABLE 2
Biologic puzzle of human reproduction for mammalian zoologists and proposed explanation
Anthropological mysteries on human “extravagant” sexuality Evolutionary adaptation of human reproduction and “extravagant”
disconnected with reproduction (Diamond, 1997)70,71 sexuality

Incredibly low fertility rate (20%e25% at the youngest age)
“Necessity” in humans because of big fetal big brain

Loss of estrus
A deeper trophoblastic implantation (nutritional exchanges 2 per

Concealed ovulation body size)

No sperm competition at conception
Hominids have hemochorial placentas: intimate cohabitation be-

Society, nuclear families, “universality” of marriage tween maternal and paternal (trophoblast) tissues. No physical

Common parental care (birds and not mammals) barrier on the maternal side. Therefore, major immunologic issues

Testis size of human males (too big compared with other pri- of “compatibility tolerance”
mates without sperm competition)
Maternal habituation to specific paternal tissues through sperm

Menopause exposure of (1) big testes and (2) low fertility rate (impregnation)

Loss of estrus (impossible with a 25% fertility rate)

Concealed ovulation: to remain constantly “attractive”
The human “extravagant sexuality” might be an adaptation allowing a safe trophoblastic (very aggressive) implantation. Adapted from Robillard et al.21
Robillard et al. Understanding the pathophysiology of early-onset preeclampsia and late-onset preeclampsia. Am J Obstet Gynecol 2022.

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receptors (KIR) capable of recognizing that NK cells play an important role in tolerance in the uterus.35,39,40 These
human leukocyte antigen (HLA) class I placentation, and spiral arterial remod- immature type of DCs flows into the
molecules. Uterine NK cells influence eling but shallow placentation alone uterus from the lymph nodes or tissues
both extravillous trophoblast invasion cannot cause preeclampsia in mouse29 other than the uterus and peaks 3.5 days
and maternal placental bed vascular and human30 and cannot explain the after mating just before implantation in
remodeling by producing a series of cy- epidemiologic risk factors for pre- mice.39 In contrast, the mature type of
tokines involved in angiogenesis and eclampsia described previously. For DCs moves into uterine draining lymph
vascular stability, such as VEGF, PlGF, example, pregnancy memory NK cells nodes and is thought to induce the
and angiopoietin. Moffett-King et al26 can explain the successful placentation development of PAS-Treg cells.35 These
changed our understanding of the and reduce the risk of preeclampsia in Treg cells move to the uterus just before
importance of the HLA-CeNK cell re- the next pregnancy with the same part- the implantation, resulting in successful
ceptor interaction. HLA-C loci are ner but cannot explain the increased risk implantation and establishing the im-
dimorphic for residues 77 to 80, and of preeclampsia in the first pregnancy plantation by inducing tolerance to the
these 2 HLA-C groups interact with when the partner change in multiparous semiallograft fetus.37,38 The in vitro
different NK cell receptors. There is great women. study revealed that uterine DCs after
diversity of NK KIR haplotypes in Although the NKG2 expression re- mating induce PAS-Treg cells.35 No such
humans with variations in the number of flects NK cell memory of previous result was obtained for uterine DCs after
genes and polymorphisms at individual pregnancies, this “memory” is not part- mating with male mice lacking seminal
loci. All women express KIR on decidual ner specific and thus does not explain the plasma after seminal vesicle removal.35
NK cells for both groups of HLA-C al- epidemiologic studies supporting the Therefore, exposure to seminal plasma
leles, and as HLA-C is polymorphic, each immune maladaptation hypothesis. is important in the induction of PAS
pregnancy will involve different combi- tolerance. These results can explain the
nations of paternally derived fetal HLA- The paramount immunologic role risk of preeclampsia in women with
C expressed on extravillous trophoblast of semen for induction of paternal condom use and short cohabitation.14,15
and maternal KIRs. Mothers lacking antigen-specific regulatory T The critical seminal factor seems to be
most or all activating KIRs (AA geno- cells seminal vesicle-derived transforming
type) when the fetus had HLA-C2 ge- Treg cells play a central role in the growth factor beta 1 (TGF-b1). Seminal
notype, belonging to the HLA-C2 group, maintenance of allogenic pregnancy by vesicle-derived TGF-b1 is secreted pre-
are at a substantial risk of inducing PAS tolerance.31e33 Seminal dominantly in a latent form. Seminal
preeclampsia.27 plasma priming induces the PAS-Treg plasmin and uterine factors transform
The main problem in the discovery by cells.34,35 PAS-Treg cells clonally prolif- the latent form into bioactive TGF-b1.41
Croy et al25 and Moffett-King et al26 was erate after pregnancy.36 Indeed, clonally Intrauterine insemination of TGF-b1
that NK cells did not seem to have an expanded Treg cells, a surrogate marker in vivo results in an increase in
immunologic memory like T cells, and for PAS-Treg cells, are decreased at granulocyte-monocyte colony-stimu-
the epidemiologic studies indicated that decidua basalis of preeclamptic cases but lating factor (GM-CSF) production that
“pregnancy memory” must exist to not in miscarriages.37 Treg cells are a is sufficient to initiate an endometrial
explain that subsequent pregnancies specialized subpopulation of T cells that leukocytosis comparable with that seen
with the same male partner are protected act to suppress the immune response, following mating.42 The introduction of
against preeclampsia. More recently, it thereby maintaining homeostasis and TGF-b1 into the uterus in combination
was shown that even NK cells may have self-tolerance. Sperm exposure does with paternal ejaculate antigens favors
“memory.” Wohl et al28 demonstrated protect against developing preeclamp- the growth and survival of the semi-
that decidual NK cells “remember” a first sia.14,15 Actual partner-specific exposure allogenic fetus, as evidenced by increases
pregnancy. NKG2 is a key molecule that to the sperm cells seems to be important in fetal and placental weights in animal
recognizes HLA-E expressed on extra- for that matter. Deposition of semen in studies, in 2 ways. First, by initiating a
villous trophoblast. NKG2 expression on the female genital tract provokes a postmating inflammatory reaction,
uterine NK cells is overexpressed in cascade of cellular and molecular events TGF-b1 increases the ability for taking
multiparous women. This over- that resemble a classic inflammatory the paternal antigens contained within
expression is specific to decidual NK response. Dendric cells (DCs) are the ejaculate. Second, TGF-b1 and the
cells and independent of age (gestational antigen-presenting cells, and they pre- subsequent postcoital inflammatory
week). This activation leads to a higher sent antigens to T cells. The number of response initiate a strong type 2 (Th2)
expression of pregnancy supporting DCs increase in the uterus during im- immune deviation and suppress type 1
factors, such as VEGF-a. Furthermore, plantation, promote decidualization and (Th1) immune deviation that induces
these precursors of pregnancy memory angiogenesis, and are known to be fetal rejection. The processing of an an-
NK cells seem to be present in the essential for implantation.38 Seminal tigen by antigen-presenting cells in an
endometrium, especially “activated” by plasma priming induces the increased environment containing TGF-b1 is likely
pregnancy.28 These reports suggested number of immature DCs that induce to initiate a Th2 phenotype within these

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TABLE 3
Immunologic tolerance comparisons of the risk factors between preeclampsia and miscarriage
Preeclampsia
Variable Early onset Late onset Miscarriage
Impairment of paternal antigens-specific tolerance
First pregnancy in primigravida Yes Weak No
First pregnancy in multipara cases with new partner Yes Weak No
Impairment of seminal plasma priming
Use of condoms Yes Weak No
Short cohabitation Yes Weak No
Artificial insemination by donor Yes Weak No
Complete allografted fetus
Oocyte donation Yes Weak Yes
Robillard et al. Understanding the pathophysiology of early-onset and late-onset preeclampsia. Am J Obstet Gynecol 2022.

responding T cells.42 By initiating a Th2 epidemiologic risk factors are different expressed on cytotoxic T cells, reduce
immune response toward paternal ejac- between preeclampsia and miscarriage cytotoxic activity and are beneficial in
ulate antigens, seminal TGF-b1 may (Table 3). Because of 16,000 poly- maintaining pregnancy.47 When the
inhibit the induction of Th1 responses morphisms, the diversity of HLA antigens immunosuppressive PD-1 expression rate
against the semiallogenic conceptus that in humans, identification of PAS-Treg cells was examined in clonal cytotoxic T cells,
are thought to be associated with poor and cytotoxic T cells are extremely diffi- PD-1 was expressed on most cytotoxic T
placental development and fetal growth. cult. Therefore, researchers assumed that cells in normal pregnancy, but this rate
Decidual macrophages, present in an Treg cells and cytotoxic T cells that spe- was reduced in preeclampsia.48 These data
immunosuppressive phenotype from cifically recognize paternal or fetal anti- suggest that decreased PAS-Treg cells and
the moment of implantation,43 may gens have the same T-cell receptor decreased PD-1 expression on clonal
inhibit NK cell lytic activity through their repertoire sequence and are clonally cytotoxic T cells induce fetal rejection in
release of molecules, such as TGF-b1, increased. Tsuda et al37 and Morita et al46 preeclampsia. Indeed, increased cytotoxic
interleukin 10 (IL-10), and prostaglandin purified Treg cells and cytotoxic T cells T-cell response to paternal antigens is
E2 (PGE2). Under the influence of the into a single cell and analyzed the mRNA observed in preeclampsia.49
local cytokine environment, antigen- expression of T-cell receptors to identify PAS-Treg cells increase in second
presenting cells, such as macrophages clonal Treg cells and cytotoxic T cells. Treg pregnancy with the same partner, but
and DCs, may take up, process, and pre- cell volume was reduced in miscarriage this increase is not second pregnancy
sent ejaculate paternal antigen to T cells in cases with normal fetal karyotypes, with a “new partner” in mice.36 This
the draining lymph nodes.39 In addition, whereas clonal Treg cells in the decidua explains that a first pregnancy with a new
sperm assists in promoting female im- basalis were similar to those in normal partner is a risk of preeclampsia in
mune tolerance by eliciting uterine cyto- pregnancy. Importantly, clonal Treg cells humans (Figure).50,51
kine expression through a toll-like significantly reduced preeclampsia.37 As mentioned above, immunologic
receptor 4edependent signaling.44 Assuming that clonal Treg cells are PAS- maladaptation is deeply involved in the
Treg cells, the result explained that first pathogenesis of preeclampsia, but there
The involvement of the balance of pregnancy, that is, primigravida or mul- are still some issues that need to be
regulatory T cells and cytotoxic T tigravida with a new partner after a short resolved. Decreasing Treg cell levels in
cells in preeclampsia cohabitation period, is at risk of pre- mice increases the susceptibility to pre-
The establishment of pregnancy depends eclampsia but not miscarriage (Table 3). term birth and leads to FGR without an
on a balance between the induction of Clonal decidual cytotoxic T cells increased increase in the uterine artery pulsatility
tolerance by Treg cells and immunologic in the late pregnancy period, but there was index, which is a hallmark of pre-
rejection of the fetus by cytotoxic T no difference in clonal cytotoxic T-cell eclampsia. Interestingly, these mice did
cells.31e33 Treg cells play a central role in rates between preeclampsia and normal not develop preeclampsia.52,53 There-
the induction and maintenance of feto- pregnancies.46 Immunosuppression- fore, it is unclear whether the decrease in
maternal tolerance.31e33 Decreased Treg induced molecules, such as programmed PAS-Treg or PD-1 expression on PAS
cells are observed in both preeclampsia32 cell death-1 (PD-1) and lymphocyte acti- cytotoxic T cells is a direct cause of pre-
and miscarriage,33,45 whereas vation gene 3 (LAG-3), which are eclampsia. However, the trophoblast

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invades the uterus much more shallowly transferred from the fetal or placental Ocean)65,66 have described that late-
in mice than in humans, and the gesta- unit to the maternal circulation by a onset preeclampsia (and much less
tional period is only 20 days in mice. more permissive placental plasma early-onset preeclampsia) is largely and
Therefore, experimental results in mice membrane with a thinner glycocalyx and specifically linearly associated with rising
cannot be directly applied to human. In less tight junctions as a result of immu- maternal BMI (Figure). Further research
addition, as it is difficult to amplify PAS- nologic alterations. This lipidic form of is urgently required to properly under-
Treg cells in vitro for the treatment of IPGs, such as IPG P-type, may stand the main drivers and pathways on
preeclampsia, agonistic antibodies contribute to endothelial damage and how cardiometabolic syndrome lead to
against PD-1 may be a candidate for the atherosis.59 Inflammation and ischemia late-onset preeclampsia.59 Optimizing
therapy. and reperfusion injuries result in glyco- prepregnancy weight would probably
T helper (Th) cells play a central role calyx shedding that, along with dimin- represent an important primary pre-
in modulating systemic immune re- ished tight junctions, provide a vector ventative strategy. Recently, we demon-
sponses. Th cells are classified into Th1 mechanism for the leakage IPGs from strated that having a high BMI does not
cells, which activate cell mediators by the fetal or placental unit into the automatically translate into a high risk of
their effective cytokines, such as IL-2 and maternal circulation.59,61 Furthermore, term preeclampsia. In a large population
IFN-Y, and Th2 cells, which induce hu- the possibility for IPGs to be detected in cohort study, we demonstrated that pa-
moral immunity by their effective cyto- maternal urine during preeclampsia tients with obesity could decrease their
kines, such as IL-4, IL-5, IL-9, IL-10, IL- several weeks before the clinical onset of risks by optimizing their GWG.67e69
13, and IL-25. Th17 cells induce the disease in early- and late-onset types Large randomized control studies are
inflammation by IL-17. The balance of of the disease62,63 may represent, along required to evaluate if these observa-
Th1, Th2, and Th17 and Treg is impor- with other candidate urinary bio- tional data can be replicated in a pro-
tant for a successful pregnancy.48,54 markers, a valid cheap tool for early spective trial.
Predominant Th1 and Th17 cell immu- diagnosis and screening in particular in In summary, our understanding of the
nities and decreased Treg cells are low-income countries.63 Although the pathophysiology of preeclampsia has
observed in preeclampsia.48,54,55 These sFlt-1-to-PlGF ratio has been used to dramatically improved. Immune mal-
immune conditions induce excessive predict early-onset preeclampsia,8,9 uri- adaptation is involved in the develop-
inflammation, which may induce endo- nary IPGs are useful in predicting late- ment of early-onset preeclampsia. Low-
vascular dysfunction resulting in the onset preeclampsia. dose aspirin reduces the risk for early-
development of preeclampsia.56 Treg onset preeclampsia, but not the risk for
cells suppress the activation of Th1 and What about prevention of late-onset preeclampsia. In contrast,
Th17 cells.48 Therefore, a combination preeclampsia obesity and metabolic syndrome are
of Th1 and Th17 cells activation and a To date, we have strong evidence that associated with late-onset preeclampsia,
decrease in Treg cells may be responsible early-onset preeclampsia, the dangerous but this is not an established method for
for the development of preeclampsia. but relatively rare form of preeclampsia in its prevention. Broad and sustained
terms of maternal and fetal morbidities, public education toward healthy pre-
What is the interaction between can be prevented up to 62% of cases by pregnancy weight and possibly subse-
immunologic alterations and the aspirin 150 mg/d when started before 16 quently optimizing GWG may have the
placental metabolic syndrome in weeks’ gestation.64 Taking aspirin from potential to greatly reduce late-onset
preeclampsia? the early pregnancy period may reduce preeclampsia. n
Recently, the risk between preeclampsia the degree of shallow placentation (ie, a
and metabolic syndrome is becoming seed of preeclampsia) and prevent the References
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