changes of nk cells in preeclampsia

Changes of NK Cells in PreeclampsiaAtsushi Fukui, Megumi Yokota, Ayano Funamizu, Rika Nakamua, Rie Fukuhara, Kenichi Yamada,Hidetaka Kimura, Asami Fukuyama, Mai Kamoi, Kanji Tanaka, Hideki Mizunuma

Department of Obstetrics and Gynecology, Hirosaki University Graduate School of Medicine, Aomori, Japan

Keywords

Angiogenesis, cytokine, natural cytotoxicity

receptor, NK cell, NKp46, preeclampsia

Correspondence

Atsushi Fukui, Department of Obstetrics and

Gynecology, Hirosaki University Graduate

School of Medicine, 5 Zaifu-cho, Hirosaki,

Aomori 036-8562, Japan.

E-mail: [email protected]

Submission December 30, 2011;

accepted February 5, 2012.

Citation

Fukui A, Yokota M, Funamizu A, Nakamua R,

Fukuhara R, Yamada K, Kimura H, Fukuyama

A, Kamoi M, Tanaka K, Mizunuma H. Changes

of NK cells in preeclampsia. Am J Reprod

Immunol 2012; 67: 278–286

doi:10.1111/j.1600-0897.2012.01120.x

The regulation of uterine and circulating peripheral blood natural killer

(NK) cells has been associated with reproductive immunology such as

recurrent pregnancy losses, implantation failures, or preeclampsia. Pre-

eclampsia is a hypertensive disorder of pregnancy characterized by

increased blood pressure accompanied by proteinuria and is a major

cause of maternal and fetal mortality. Natural cytotoxicity receptors

(NCRs) are unique markers, which regulate NK cell cytotoxicity and

cytokine production. The relation of NCRs to reproduction is not fully

characterized yet. The different profile of NCRs expression may suggest

presence of abnormal regulation of NK cell in women with reproductive

failures. Pregnant women with preeclampsia carry immunological

abnormalities of NCRs on peripheral blood NK cells during pregnancy.

The lower expression of NKp46+ NK cells in women with preeclampsia

may account for the higher production of NK1 cytokine that is known

as NK1 shift in pregnant women with preeclampsia. Evaluation of

NKp46 on peripheral blood NK cells may be applicable to find the onset

of preeclampsia. In this review, various expressions of NK cell surface

markers including NCRs on NK cells, NK cell cytotoxicity, and produc-

tion of cytokines and angiogenic factors by NK cells were reviewed in

relation to preeclampsia.

Introduction

Natural killer (NK) cells play an important role in

human pregnancy and systemic regulation of NK

cells contribute to reproductive success. Generally,

NK cells can attack the target cells without sensitiza-

tion. The roles of NK cells are known as elimination

of cancer cells or foreign substances and secretion of

a variety of cytokines. NK cells compose 5–10%of peripheral blood lymphocytes (PBL), and 70–90%of uterine lymphocytes are distinguished from other

cell types by the expression of NK-specific surface

markers, that is, CD56 positive cells. Human NK cell

subsets exist as either as CD56bright or CD56dim NK

cells. In addition, CD56bright cells are mainly in the

decidua. In peripheral blood, the main population of

NK cell is CD56dim cell. The regulation of uterine

and circulating peripheral blood NK cell may have

an association with reproductive immunology such

as recurrent pregnancy losses (RPL), implantation

failures, or preeclampsia.

Preeclampsia is a hypertensive disorder of preg-

nancy characterized by increased blood pressure

accompanied by proteinuria, both occurring after

20 weeks of gestation. Preeclampsia is identified in

3.9% of all pregnancies. In developed countries, 16%

of maternal deaths were because of hypertensive dis-

orders. On the other hand, those as a result of hemor-

rhage are 13%, abortion are 8%, and sepsis are 2%.1

So, preeclampsia is one of the leading causes of mater-

nal and perinatal morbidity and mortality. Preeclamp-

sia has pre-clinical (symptomless) and clinical

(symptomatic) stages. Until recently, only symptom-

atic final stage could be detected by clinical screening.

Two-stage disorder theory is well accepted for pre-

eclampsia. Stage 1 is poor placentation at early stage

of pregnancy, and stage 2 is placental oxidative stress

at late stage of pregnancy. Stage 1 is pre-clinical and

American Journal of Reproductive Immunology 67 (2012) 278-286

278 ª 2012 John Wiley & Sons A/S

REVIEW ARTICLE

characterized by faulty trophoblastic vascular remod-

eling of uterine arteries that causes failure to remodel

spiral arteries supplying uteroplacental circulation

and placental hypoxia. NK cell is known to produce

angiogenic cytokines and proteins and failure to

remodel spiral arteries downstream causes the stage 2

clinical syndrome. Then, stage 2 fetal growth restric-

tion and preeclampsia develop2 (Fig. 1). Moreover,

circulating T and NK cells are known to be activated

in preeclampsia.3 Besides, it is considered that uterine

NK cells could contribute to the development of pre-

eclampsia by inducing the lysis of trophoblast cells

lacking HLA-G.4 And loss of trophoblast cells that

should invade the developing spiral arteries would

result in the lack of a sufficient supply of oxygen and

nutrients to the developing placenta.5,6 Interestingly,

it is reported that at least one of etiologies for sponta-

neous abortion or infertility may in fact be essentially

the same as the one leads to preeclampsia in those

pregnancies that survive 20 weeks.4 Therefore, NK

cell seems to be important for the development of pre-

eclampsia. In this review, various surface markers

including natural cytotoxicity receptors (NCRs) on NK

cells and intracellular cytokines and angiogenic fac-

tors were reviewed in relation to preeclampsia.

Angiogenesis of NK cells and preeclampsia

Transforming growth factor (TGF)-b has an impor-

tant role in angiogenesis.7 Endometraial or decidual

CD16�/CD56bright NK cells produce not only TGF-bbut also other angiogenic factors such as angiopoie-

tin (Ang) 1, Ang 2, vascular endothelial growth fac-

tor (VEGF), and placental growth factor (PlGF).8,9

These results indicate that NK cell in uterus has an

important role in angiogenesis. That is, angiogenic

factors such as VEGF and PlGF and cytokines such

as IL-8 and IFN-inducible protein 10 induce and

support the invasion of the extravillous trophoblasts

into the maternal spiral arteries to achieve the

remodeling of the spiral arteries required for ade-

quate placental perfusion later in normal preg-

nancy.4 Recently, abnormal productions of some

angiogenic factors by peripheral blood NK cells were

reported. Molvarec et al.10 reported that the percent-

age of VEGF-producing peripheral blood NK cells

were significantly lower in women with preeclamp-

sia compared with healthy pregnant women. VEGF

(VEGF-A) is an effective angiogenic protein with

essential roles in angiogenesis. VEGF acts via binding

to VEGF receptors such as VEGF receptors 1 [soluble

fms-like tyrosine kinase-1 (sFlt1)]. And excess sFlt1

in preeclamptic serum impaired angiogenesis that is

restored by exogenous VEGF and PlGF.11 T cells and

NK cells can produce VEGF. Experimental data

showed that placental hypoxia because of abnormal

angiogenesis is the result of higher sFlt1.12,13 There

are five types of VEGF (VEGF-A, VEGF-B, VEGF-C,

VEGF-D, and VEGF-E) and two types of PlGF in

VEGF family. VEGF-C is shown to peak during the

Clinical

Stage 1Poor placentation

(early, 8~18weeks of pregnancy)

Stage 2Placental oxidative stress

(late)

Fetal-growth restrictionSystemic release of placental

factors

Systemic inflammatory response, endothelial activation

PREECLAMPSIASyndrome

Angiogenic cytokines

PreclinicalFailure to remodel spiralarteries supplying utero-placental circulation and

placental hypoxia

NKcell

Fig. 1 Two-stage disorder of preeclampsia. Stage 1 is poor placentation at early stage of pregnancy and stage 2 is placental oxidative stress at

late stage of pregnancy. Stage 1 is pre-clinical and characterized by faulty trophoblastic vascular remodeling of uterine arteries that causes failure

to remodel spiral arteries supplying uteroplacental circulation and placental hypoxia. Natural killer cell is known to produce angiogenic cytokines

and proteins and failure to remodel spiral arteries downstream causes the stage 2 clinical syndrome. Then, stage 2 fetal growth restriction and

preeclampsia develop.2


ª 2012 John Wiley & Sons A/S 279

CHANGES OF NK CELLS IN PREECLAMPSIA

early and midsecretory phase of the menstrual

cycle.14 Kalkunte et al.15 reported that a proangio-

genic factor, VEGF-C-producing uterine NK cell is a

non-cytotoxic phenotype. VEGF-C production is

hallmark property of non-cytotoxic uterine NK cells.

They also showed that VEGF-C could protect target

endothelial and trophoblast cells from killing by

cytotoxic peripheral blood NK cells.15 Dysregulation

of VEGF-C production by NK cell at feto-maternal

interface causes poor angiogenesis and pregnancy

complications. In fact, lower expression of VEGF-C is

reported in women with preeclampsia or intrauter-

ine growth restriction.16 Molvarec et al.17 also

reported that the percentage of galectin-1 expressing

NK cells in women with preeclampsia was signifi-

cantly decreased compared with that in normal preg-

nant women. The expressions of galection-1 of

circulating T cells and NK cells are significantly

higher in healthy pregnant women than in non-

pregnant women. Activated T cells, B cells, NK cells,

and macrophages express galectin-1. So, the decrease

in galectin-1 in women with preeclampsia may have

a relation to the development of the pro-inflamma-

tory Th1 or Th17 immune responses characteristics

of the maternal syndrome of disease.

Type 1 shift of NK cells in preeclampsia

Pregnancy has been reported to be associated with a

shift away from Th1 type and bias toward Th2 type

immune responses.18–20 The Th1/Th2 concept has

been extended by demonstrating that NK cells can

also show comparable polarities in their cytokine

secretion profiles.21,22 It is reported that predomi-

nant Th1-type immunity is present in preeclampsia

and this is similar to non-pregnant women.23,24 A

later study demonstrated that the production of Th1-

type cytokine, IFN-c, is also enhanced in NK

cells.25,26 Namely, type 1 shift of NK cells has been

reported in Preeclampsia.27 Interestingly, Borzy-

chowski et al. reported that there were no changes

in the Th1/Th2 or Tc1/Tc2 cell ratios in preeclamptic

women. However, the NK1/NK2 cell ratios were sig-

nificantly decreased in normal pregnancy compared

with non-pregnant and preeclamptic women.27

Although many studies used stimulated peripheral

blood mononuclear cells (PBMC) before evaluating

type1/type2 ratio and the majority of these studies

only investigated helper T cells and not NK cells,

they used pan type 1 (IL-18) and pan type 2 (ST2L)

lymphocyte function markers in flow cytometry

without stimulation of PBMC to characterize PBL

populations. Therefore, their data may show the true

cytokines ratio in vivo. At least higher NK1/NK2 ratio

may exist in women with preeclampsia. Further-

more, it was reported that increased IFN-c level in

peripheral blood in women with preeclampsia com-

pared with normal pregnancy in NK cells. However,

there was no significant difference in helper T cells

and cytotoxic T cells.28 Their results similarly show

that the shift away from type 2 to type 1 in pre-

eclamptic women was predominantly in NK cells

and not T cells. Moreover, Sargent et al.29 reported

that aberrant NK cell activation both locally in the

decidua and systemically in the maternal blood

might be the cause of preeclampsia.

Natural cytotoxicity receptors

For the NK cell surface markers, NCRs are unique

markers, which regulate NK cell cytotoxicity and

cytokine production. NCRs, which include NKp30,

NKp44 and NKp46, are expressed exclusively on NK

cells. The NKp46 receptor is a 46-kDa type I mem-

brane glycoprotein characterized by two C2-type

Ig-like domains in the extracellular portion and is

associated with CD3ζ and FceRIc that become

tyrosine phosphorylated. The NKp44 receptor is a

44-kDa type I membrane glycoprotein characterized

by a single V-type Ig-like domain in the extracellular

portion and is associated with KARAP/CAP12 mole-

cules. The NKp30 receptor is a 30-kDa type I mem-

brane glycoprotein characterized by a single V-type

Ig-like domain in the extracellular portion and asso-

ciated with CD3ζ polypeptides.30 NKp46 and NKp30

are constitutively expressed on NK cells, but NKp44

expression is induced after NK cell activation. We

previously reported that the three fourth of periph-

eral blood NK cells are NKp46+ NK cells and the half

of peripheral blood NK cells are NKp30+ NK cells.31

NCRs are the major receptors involved in NK cyto-

toxicity and have a function of the recognition and

lysis of tumor cells by NK cells. Signal cascade of

NCRs is as follows. First, cellular ligands, for which

recognition by NCRs are not fully elucidated, bind to

each NCR. Then, protein tyrosine kinases are acti-

vated. Protein tyrosine kinases phophorylate immu-

noreceptor tyrosine-based activation motifs. Then,

protein tyrosine kinases of zeta-chain associated pro-

tein of 70 kDa (Zap-70) or SYK are recruited and

activated. Then, SLP76, p85-PI3K, LAT, PLC-g1,

PLC-g2, and so on are phosphorylated and activated.



FUKUI ET AL.

Finally, the intracellular release of calcium induces

NK cell cytotoxicity and cytokines’ release.30

NKp46 and NKp44, but not NKp30, recognize

viral proteins such as the hemagglutinin of influ-

enza, or the hemagglutinin-neuraminidase of parain-

fluenza virus.32,33 The endogenous cellular ligands

recognized by NCRs are not known. Recently, NCR

ligands were found to be expressed by murine lym-

phoma and myeloma cell lines34 and in human pri-

mary nevi and melanomas.35,36 The NKp30 and

NKp46 receptors are expressed on the surface of

activated and non-activated NK cells. However, the

NKp44 receptor is expressed on the surface of acti-

vated NK cells only. In addition, the NKp30 and

NKp46 receptors have a function in cytotoxic activ-

ity and cytokine production of NK cells.

In uterus, it is reported that endometrial NK cells

have a unique receptor repertoire, or specifically,

they are positive for NKp46, and negative or positive

at low levels for NKp30 and NKp44, respectively, for

both proliferative and secretory phase endome-

trium.37 However, our data showed that endometrial

NK cells are positive for not only NKp46 but also

NKp30 and NKp44 in secretory phase endome-

trium.38 Zhang et al.39 reported higher expression of

NKp44 and NKp46, and we reported higher expres-

sion of NKp44 and NKp3038 on decidual NK cells in

women’s spontaneous abortion. NCR+ cells have

higher cytotoxicity and there may be a higher cyto-

toxicity in reproductive failures. On the other hand,

in peripheral blood, we reported lower expression of

NKp46 on circulating peripheral blood NK cells in

women with RPL and implantation failures,31 and

abnormal correlation between NCRs expression on

peripheral blood NK cells and cytokines production

by peripheral blood NK cells in women with RPL

and implantation failures.40 However, these patients

with abnormal expressions of NCRs, especially

NKp46 or NKp44, do not always fall into spontane-

ous abortion. Further study is needed to clarify the

participation of NCRs of endometrial and peripheral

blood NK cells in reproduction.

HLA-C and killer immunoglobulin-like receptor in

preeclampsia

Decidual NK cells can recognize HLA-C expressed by

extravillous trophoblast (paternal HLA-C). These NK

cells express killer immunoglobulin-like receptors

(KIR), and dominant ligand of KIR is HLA-C. There

are two types of KIR, one is an inhibitory receptor

and the other is an activating receptor. There are

hundreds of HLA-C variants. HLA-C can divide into

two functional groups by the presence of asparagine

and lysine at position 80 in the protein sequence.41

The former is HLA-C1 and the latter is HLA-C2.

HLA-C2 is recognized by inhibitory KIR2DL1

(CD158a) and activating KIR2DS1 (CD158h), and

C1 is recognized by inhibitory KIR2DL2 (CD158b1)

and KIR2DL3 (CD158b2). C1 is not recognized by

KIR-activating receptor. And HLA-C2 interacts more

strongly than HLA-C1.42 KIR can divide into two

functional groups KIR A and KIR B by the presence

and absence of particular subsets of KIR genes. Uter-

ine NK cell can produce angiogenic factors and cyto-

kines that induce trophoblast invasion. This is

enhanced by ligation of stimulatory KIR B and

reduced by KIR A.43 Maternal KIR genotypes could

be AA (no activating receptor) or AB/BB (one or

more activating receptor).44 So, fetal HLA-C2 with

maternal KIR B/B is the adequate placentation and

avoiding preeclampsia. On the other hand, fetal

HLA-C2 with maternal KIR A/A is the high risk of

preeclampsia.45

NCRs and preeclampsia

We have investigated the expression of NCRs on

peripheral blood NK cells in women with pre-

eclampsia. Pregnant women with preeclampsia

showed a significantly decreased percentage in

CD56+/NKp46+ cells and CD56bright/NKp46+ cells

compared with that in pregnant women without

preeclampsia.46,47 Interestingly, lower expression of

CD56+/NKp46+ cells in pregnant women with pre-

eclampsia was observed 3–4 months before the

onset of preeclampsia and it continued until deliv-

ery. Moreover, from the vantage of the gestational

week, lower expression of CD56+/NKp46+ cells in

pregnant women with preeclampsia was observed

at 20 weeks of gestation and it continued until

delivery. Onset of preeclampsia in our study was at

34 ± 6 weeks of gestation. Until recently, only

symptomatic final stage of preeclampsia could be

detected by clinical screening. However, there are

two stages of preeclampsia, that is to say pre-clini-

cal and clinical stage. Many researchers have tried

to predict preeclampsia before onset pre-clinical

stage. If we are able to know the development of

preeclampsia before onset of preeclampsia in pre-

clinical stage, NKp46 may have a potential to

become a useful marker for prediction of pre-




eclampsia like other factors such as sFlt1 and

PlGF.48,49 Besides, pregnant women with pre-

eclampsia showed a significantly higher percentage

in CD56+/NK44+ cells, CD56dim/NKp44+ cells and

CD56bright/NKp44+ cells compared with that in

pregnant women without preeclampsia. Moreover,

higher expression of CD56+/NKp44+ cells in preg-

nant women with preeclampsia was observed at 12

and 20 weeks of pregnancy. So, this means that

women with preeclampsia have a higher NK cell

cytotoxicity before onset of preeclampsia at stage 1

asymptomatic stage of preeclampsia. This may be

one of the reasons of abnormal placentation in pre-

eclampsia.

For NK cell cytokines production, NKp46+ NK cells

in pregnant women were negatively correlated with

tumour necrosis factor (TNF)-a+-producingCD56bright NK cells. However, there were no correla-

tions between the expression of NCRs and type 2

cytokines (IL-4 and IL-10) production by NK cells.

The expression of NKp46+ NK cells in pregnant

women with preeclampsia was lower than that in

normal pregnant controls. So, the lower expression

of NKp46+ NK cells in women with preeclampsia

may account for the higher production of NK1

(TNF-a) cytokine that is known as NK1 shift in preg-

nant women with preeclampsia (Fig. 2). These data

were presented at first clinical reproductive immu-

nology symposium that has been held at Providence,

RI, USA in 2011.

NK cell cytotoxicity and preeclampsia

There are various kinds of activating and inhibitory

receptors on the surface of NK cells (Table I). NK cell

cytotoxicity is decided by the balance of its activating

and inhibitory receptors. Not only NCRs but also

inhibitory NKG2A and activating NKG2C and NKG2D

are included as these receptors. Recently, some evi-

dences of the expressions of NCRs and NKG2D and

NK cell cytotoxicity were provided. Forte et al.50

reported that NKp44 and NKG2D function as trigger-

ing receptors involved in direct human NK cytotoxic-

ity against porcine endothelial cells, whereas NKp30

and NKp46 do not play a role. They concluded that

inhibition of interaction between NKp44 and NKG2D

on human NK cells might prevent direct NK

responses. Decreased expression of NKp46 and

NKG2D in patients with post-transplantation lympho-

proliferative disorders was also reported.51 This result

indicated that these patients have potential regulatory

mechanisms responsible for the NK cell functional

abnormalities. So, these receptors are associated with

NK cell cytotoxicity. Why then, it is reported that

stimulating the activating receptors on decidual NK

cells in a redirected activation assay increased produc-

tion of growth factors and angiogenic factors such as

VEGF and PlGF.9 On the other hand, Bachmayer

et al.52 reported that the levels of inhibitory NKG2A

and activating NKG2C on peripheral blood NK cell in

women with preeclampsia was significantly higher

than that in healthy pregnant women or healthy

donor. They concluded that the peripheral NK cell

pool is altered in women with preeclampsia with

enhanced NKG2A and NKG2C levels on NK cells.

Thus, the function and the expression of surface

markers on decidual (uterine) NK cell and peripheral

blood NK cell are different. How about NCRs? There

are some reports about the correlation between endo-

metrial/decidual NK cell and peripheral blood NK cell.

It is reported that peripheral blood NK cell levels

reflect changes in decidual NK cell levels.53 We can

easily have access to the peripheral blood, so it is often

used for diagnostic purpose to detect reproductive fail-

ures.54,55 We have previously reported that the per-

centages of CD16+/CD56dim NK cells in peripheral

blood and endometrium in IVF-ET cycle were signifi-

cantly higher and that of CD16�/CD56btight NK cells

was markedly lower in reproductive failures com-

pared with successful group.56 Others reported that

examination of peripheral blood NK cells would not

Fig. 2 Mechanism of NK1 shift in preeclampsia. NKp46+ NK cells were

significantly lower in women with preeclampsia compared with normal

pregnant women, and NKp46+ NK cells were negatively correlated

with type 1 cytokine-producing NK cells significantly. The lower

expression of NKp46+ NK cells in women with preeclampsia may

account for the higher production of NK1 cytokine that is known as

NK1 shift in pregnant women with preeclampsia. NK, natural killer.



FUKUI ET AL.

Table I NK Cell Receptors

NK cell inhibitory receptors NK cell activating receptors

Receptors Ligands Receptors Ligands

MHC class I specific MHC class I specific

KIR KIR

KIR2DL1 (CD158a) HLA-C KIR2DS1, KIR2DS2 HLA-C

KIR2DL2/3 HLA-C KIR2DL4 HLA-G

KIR2DL5 Unknown KIR2DS4, KIR2DS5, KIR3DS1 Unknown

KIR3DL1 HLA-Bw4 C-type lectin receptors

KIR3DL2 HLA-A3, -A11 CD94/NKG2C HLA-E

KIR3DL7 Unknown CD94/NKG2E/H Unknown

C-type lectin receptors Non MHC class I specific

CD94/NKG2A HLA-E Natural cytotoxicity receptors

CD161 Unknown NKp46 Unknown

Immunoglobulin like transcripts NKp44 Unknown

ILT-2 Unknown NKp30 Unknown

Others C-type lectin receptors

P75/AIRM Unknown NKG2D MICA, MICB, ULBP-1, 2, 3

IRp60 Unknown Others

LAIR-1 Ep-CAM CD16, CD2, LFA1, 2B4, NKp80, CD69, CD40 ligand

KIR, killer immunoglobulin-like receptors; MFC, major histocompatibility complex; NK, natural killer.

a2V-ATPase

Activating Receptor Inhibitory ReceptorNKG2CNKG2D NKG2A

KIRNCR

Type 1 (NK1) cytokines Type 2 (NK2) cytokines

Cytokines production

Cytotoxicity (+) Cytotoxicity (–)

NCR(NKp46)

Dual functions

Achievement and

maintenance of pregnancy

REPRODUCTIVE FAILURES

such asPreeclampsia

Amphibiousness of Natural Cytotoxicity Receptor (NCR)

KIR

NKp44, NKp46)NCR (NKp30,

NK cell

Fig. 3 Participation of natural killer (NK) cells in normal pregnancy and preeclampsia. NK cells express various kinds of their surface markers and

can produce various kinds of cytokines and angiogenic factors. Natural cytotoxicity receptors, especially NKp46, has dual functions. One is

cytotoxicity and the other is cytokines production. NK cell cytotoxicity is decided by the balance of the expression of its activating and inhibitory

receptor. NK1/NK2 balance is decided by its production of cytokines. Abnormal balance of the expression of NK cell surface activating and

inhibitory receptors and abnormal balance of NK1 and NK2 cytokines production lead to reproductive failure such as preeclampsia.




tell us what is happening in the uterus.57,58 It is evi-

dent that uterine NK cells are important for achieve-

ment and maintenance of pregnancy. However, it is

controversial for the function and usefulness of

peripheral blood NK cells. Often the interaction

between peripheral blood NK cells and trophoblast

are not well understood, and researchers are investi-

gating this with various roles of peripheral and decid-

ual NK cells.58,59 NK cells preferentially kill targets

with lower expression of major histocompatibility

complex class I proteins, because fewer inhibitory

receptors are engaging ligands. As a consequence,

syncytiotrophoblasts are not free from peripheral

blood NK cell cytotoxicity. We measured the correla-

tion between NCRs+ NK cells of peripheral blood and

midsecretory endometrium. There were significant

positive correlations between the percentage of

CD56+/NKp46+ and the CD56bright/NKp46+ NK cells

in peripheral blood and midsecretory endome-

trium.46,47 There was also significant positive correla-

tion between the percentage of CD56dim/NKp44+ NK

cells in peripheral blood and midsecretory endome-

trium. So for the expression of NKp46 and NKp44 on

NK cells, it may be possible to gain an understanding

of the uterine NKp46+ NK cells by evaluating periph-

eral blood NKp46+ and NKp44+ NK cells.

Conclusion

Appropriate expression of NK cells is important for

the successful achievement and maintenance preg-

nancy. There are abnormal expressions of NK cell

surface antigens and dysregulation of NK cell cyto-

toxicity and cytokines or angiogenic factors produc-

tion in women with reproductive failures such as

preeclampsia. The expression of NCRs, especially

NKp46 and NKp44 on NK cell, may be one of the

useful marker for prediction of preeclampsia (Fig. 3).

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changes of nk cells in preeclampsia

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