CBX786159 1..16


Review

Placental protein 13: An important
biological protein in preeclampsia

Ranjeeta Gadde1, Dayanand CD1, and SR Sheela2

Abstract
Placental protein 13 (PP13), a glycan binding protein predominantly expressed in syncytiotrophoblast, dimeric in nature,
lacks N-terminal signal peptide, bypasses the endoplasmic reticulum, and secretes into maternal circulation as exosomes
or microvesicles. PP13 has jelly roll fold conformation with conserved carbohydrate recognition domain which specifically
binds to b-galactosides of the glycan receptors during placentation. PP13 binds to glycosylated receptors on human
erythrocytes and brings about hemagglutination by the property of lectin activity; other functions are immunoregulation
and vasodilation during placentation and vascularization. The gene LGALS13 located on 19q13.2 comprising four exons
expresses a 32-kDa protein with 139 amino acid residues, PP13. Impaired expression due to mutation in the gene leads to
a nonfunctional truncated PP13. The low serum levels predict high risk for the onset of preeclampsia or obstetric
complications. Hence, PP13 turned to be an early marker for risk assessment of preeclampsia. The recombinant PP13 and
monoclonal antibodies availability help for replenishing PP13 in conditions with low serum levels and for detection and
prevention of preeclampsia, respectively.

Keywords
Placental protein 13, preeclampsia, eclampsia, jelly roll fold, syncytiotrophoblast

Date received: 30 December 2017; accepted: 28 May 2018

Introduction

Preeclampsia is a pregnancy-specific disorder character-

ized by hypertension and proteinuria after 20 weeks of

gestation.
1

Although the exact etiology of the disorder is

still not known, the impairment in the early placentation is

associated with onset of preeclampsia that complicates up

to 2–8% of all the pregnancies.2 Prediction, understanding
of underpinning mechanism and prevention of preeclamp-

sia, is still not clear. Hence, preeclampsia and eclampsia are

the leading causes of maternal, perinatal morbidity, and

mortality.
3,4

Placental protein 13 (PP13) is a carbohydrate

binding protein synthesized in the syncytiotrophoblast,

which is involved in early placentation process.
5,6

It is a

member of galectin family with a conserved carbohydrate

recognition domain (CRD).
7–9

The specificity of this site

for b-galactosides-containing glycoconjugates10–12 is
established and plays a significant role in biological events

such as implantation and embryogenesis.
13,14

The biologi-

cal specificity of the PP13 present in the apical membrane

of the syncytiotrophoblast to the glycans of the membrane

and extracellular matrix proteins such as annexin II is a

primary requisite for the placental implantation to the

endometrium.
15

PP13 also binds to b- and g-actin within trophoblasts,
which facilitates the migration of trophoblasts toward the

placental bed and also increases the release of prostacyclins

for vascular remodeling of maternal spiral arteries in early

placentation.
16

From the immunological point of view, for

an effective placentation, PP13 induces the apoptosis of

1 Department of Biochemistry, Sri Devaraj Urs Medical College, Kolar,

India
2
Department of Obstetrics and Gynecology, Sri Devaraj Urs Medical

College, Kolar, India

Corresponding Author:

Dayanand CD, Department of Biochemistry, Sri Devaraj Urs Medical

College, SDUAHER, Tamaka, Kolar, Karnataka 563101, India.

Email: cd8905@yahoo.co.in

Journal of Circulating Biomarkers
Volume 7: 1–16

ª The Author(s) 2018
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maternal T cells to progress the deepening of implanta-

tion.
17

The expression of PP13 is also important for differ-

entiation and syncytialization of the villous trophoblast

which is vital for the release of placental hormones and

immune proteins for embryo development and immune

tolerance.
14,18

During pregnancy, various factors are the

reason for the release of PP13 into the maternal circulation.

The available studies indicated the low levels of PP13 in

serum/plasma generally in first trimester of pregnancy.

However, the levels gradually increase as gestation pro-

gresses.
19–22

The exact reason for the decreased PP13 lev-

els in first trimester and increased levels in the third

trimester is not known which is in line with the etiology

of the preeclampsia. Preeclampsia is associated with

impaired placentation,
23,24

evidence of low serum levels

of PP13, and other heterogeneous causes, hence became a

major cause for morbidity and mortality of fetus and

mother.
25,26

Therefore, an attempt was made to summarize

the information on PP13 in this article.

Historical perspective

Hans Bohn (1928–2014) gets the credit for successful iso-

lation of factor XIII (fibrin stabilizing factor) of blood coa-

gulation system from human placenta. After discovery, he

developed a quantification method to demonstrate factor

XIII deficiency that affects fibrin cross-linkage and fibrin

stabilizing property and is associated with wound healing

after injury or surgery.
27

During isolation and purification

procedure of factor XIII, he noticed that a side fraction

yielded human placental lactogen. Throughout this period,

there was a rise in the research interest related to physio-

logical and pathological aspects of human placenta.
28

This

trend motivated him to explore the content of human pla-

centa from a biochemical perspective. The galectin gener-

ally is numbered sequentially and hence the names for

galectin 1–12 were assigned.
29

The new member of the galectin family PP13 has been

designated as galectin 13.
28

PP13 is one among the 56

proteins isolated from the placenta by Hans Bohn. Later

on, in 1983, a research contribution by his coworkers led to

the purification and characterization of placental tissue pro-

teins 13 and 17.
30

He characterized many PPs for their

physicochemical characteristics and also developed immu-

noassay to quantify these proteins of diagnostic signifi-

cance. Several PPs such as PP4 (annexin-V), PP5 (tissue

factor pathway inhibitor-2), PP10 (plasminogen activator

inhibitor-2), and PP13 (galectin 13) were studied for their

amino acid sequence and biological functions with respect

to biological regulators of pregnancy process.
31–33

Thereafter, he continued his research in collaboration

with other scientists to investigate sequencing, structural,

and molecular biological characterization of several PPs

including PP13. This research contribution significantly

improved the understanding of biological role and diagnos-

tic importance in pregnancy complication, malignancies,

and other placental and pregnancy-related protein research.

Subsequently, PP research continued to add more informa-

tion for further discoveries and improvements in clinical

diagnostics and patient care.

Biosynthesis, secretion, and physical and
chemical characteristics of PP13

Biosynthesis of PP13

Biosynthesis of PP13 occurs on free ribosomes in the cyto-

plasm of syncytiotrophoblast and is present in soluble form

in the brush border apical plasma membrane as evident by

staining techniques.
34,35

The placental gene LGALS13

located on the long arm of chromosome 19 at loci q13.2

encodes PP13 protein exclusively.
36

LGALS13 gene and its

transcribing unit codes for PP13 at 50 end that has promoter
region followed by comprising four exons designated as

E1–E4 (Figure 1). The full length of cDNA encoding

human placental PP13 from expression library (Gen bank;

acc. no: AF117383.1) predicted the molecular mass and the

amino acid composition of the cloned protein which corre-

sponds to 578 bp insert with a 417-bp open reading frame

encoding a 139-amino acid protein.
37,38

Secretion of PP13

Nascent PP13 lacks N-terminal signal sequence; hence, it

bypasses the translocation route to endoplasmic reticulum

and golgi bodies. Instead, PP13 utilizes the “non-classical”

secretory pathway or unconventional routes to reach the

maternal circulation either through vesicular shedding or

direct translocational system. Studies showed that in the

syncytiotrophoblast, PP13 is highly co-localized with

cytoskeletal protein actin, annexin II, placental alkaline

phosphatase, a glycosylphosphatidylinositol-anchored lipid

raft resident protein, and CD71, a non-raft plasma mem-

brane protein.
28

The actin cytoskeleton polymerization and

associated motor proteins are the driving force for variety

of cellular processes for transportation of galectins.
39,40

The various secretory routes utilized by galectins in the

syncytiotrophoblast are either direct translocational or

extra cellular vesicular transport in the form of microvesi-

cles (40–100 nm) and exosomes (0.1–1 mm).41–44 A lot has
been already published on the release of PP13 by shedding

syncytiotrophoblast microparticles.
28,35

A recent study has

indicated that the amount of PP13 released via the exo-

somes and microvesicles is actually decreased in pree-

clampsia. The process regulating the release of these

organelles has not been extensively investigated and is not

well known. Therefore, future studies must evaluate PP13

biomarker potential in association with syncytiotrophoblast

extracellular vesicles and exosomes.
45

Even though PP13 primarily originated from placenta, it

has been demonstrated that its expression was also noticed

in human healthy liver, spleen, kidney, and bladder tissues

2 Journal of Circulating Biomarkers



and also in few pathological conditions of liver adenocar-

cinoma, neurogenic tumor, and malignant melanoma.
46

Physical and chemical characteristics of PP13

Human PP13 is the member of the b-galactoside binding
soluble-type galectin super family and is a relatively small

protein with a molecular weight of 32 kDa consisting of

139 amino acid residues. It is a homodimer stabilized by

disulfide bonds. Each polypeptide chain molecular weight

is 16 kDa.
47

The primary structure of PP13 has 69% homol-
ogy to human eosinophil Charcot–Leyden crystal structure

(galectin 10).
48

The secondary structure is similar to pro-

totype galectins such as galectin 7 and galectin 10 or Char-

cot–Leyden crystal protein.
49,50

The C-terminal CRD is of

chimera-type galectin (galectin 3).
51

The typical structural alignment of these proteins

showed five-stranded (F1–F5) and six-stranded (S1–S6 a/

S6b) b-sheets stabilized by one or two alpha-helices at their
ends (Figure 3). The structural variation in sequence of

primary structure of PP13 and galectin 10 is evident but

the secondary structure is found to be identical except for

F1 beta-sheet which is longer by one residue in case of

PP13. From repository, the model was available from Broo-

khaven protein data bank source with account number

IF87.
46

The dimeric nature of PP13 consists of two struc-

turally similar disulfide bonds between four cysteine resi-

dues (Cys19, Cys92, Cys136, and Cys138) present on the

surface of PP13. The alignment of galectin CRD motif

showed highly conserved sequences of 13 residues, of

which 8 residues (arginine 53 (Arg53), asparagine 65

(Asn65), tryptophan 72 (Trp72), Glu75, arginine 55

(Arg55), His57, Val63, and Thr77) play an important role

in sugar binding. From these eight residues, four residues

are of identical type (Val63, Asn65, Trp72, and Glu75) and

three are conservatively substituted (Arg53, Arg55, and

His57) in PP13.
46

With respect to substrate automatic docking with CRD

region particularly on the concave face of S4–S6 b-sheets,
several carbohydrates as ligand to protein conformations

were analyzed. They are N-acetyllactosamine, lactose,

mannose, N-acetylgalactosamine, galactose, and so on,

from which N-acetyllactosamine has more binding energy

(�26.9 kcal/mole) due to high van der Waals forces and

Figure 1. Location, arrangement, and structure of LGALS13 gene.53

Gadde et al. 3



strong stacking interaction. This interaction has affinity to

highly conserved Trp72 residue and strong hydrogen bond

with conserved Arg55, Asn65, and glutamine 75 (Gln75)

residues in CRD of PP13. This results in PP13 specificity

for the sugar provides the cellular selection of binding

molecules and its orientation toward binding.

Figure 2. Expression, secretion, and functions of PP13. (1) Bio-synthesis: PP13 transcripts are translated on the free ribosomes in the
cytoplasm of syncytiotrophoblast and dimerized as prototype PP13 with formation of carbohydrate recognition domain. (2) Intra-
cellular protein–protein interactions: Actin cytoskeleton and motor proteins in the cytoplasm interaction drive the translocation of
PP13 to the apical membrane of the syncytiotrophoblast and extracellular space. (3) Interaction with cell surface glycans and lattice
formation: PP13 cross-links with glycoconjugates on cell surfaces and forms galectin–glycan lattice. (4) Cross-linking and signaling. (5)
Cell–cell interactions: The cross-linked dimeric PP13 and lattice lead to intracellular signaling cascade to promote cell–cell interactions.
(6) Cell–matrix interactions: Binding to b-galactoside residues of extracellular matrix proteins generates response to PP13 functions.
(7) Cytoplasm of syncytiotrophoblast. (8) Apical membrane of syncytiotrophoblast. (9) Extracellular matrix. (10) Decidual membrane.
PP13: placental protein 13.28

Figure 3. (a) PP13 “jelly-roll” fold structure indicating five- and six-stranded b-sheets linked by two alpha helices. (b) Eight amino acid
residues on the carbohydrate recognition domain of PP13. (c) Stereoscopic view of PP13 molecule with bound N-acetyllactosamine to
the residues in the carbohydrate recognition domain (A455, Asn65, and Gln75) and the tryptophan ring (Trp72) playing a key role in
stacking interactions46 PP13: placental protein 13; Asn65: asparagine 65; Gln75: glutamine 75; Trp72: tryptophan 72.

4 Journal of Circulating Biomarkers



Computational analysis indicated that the positions of

serine and tyrosine phosphorylation sites are serine 48,

tyrosine 41, and tyrosine 80 close to the highly conserved

CRD.
46

PP13 is a glycoprotein with a 0.6% carbohydrate content
and has the electrophoretic mobility same as that of albu-

min; isoelectric point (PI) is in the range of 4.7–4.8 and

sedimentation coefficient is 3.1 svedberg or S value. The

primary structure of PP13 has two linear polypeptide

chains. Each chain has methionine at the C-terminal and

asparagine at the amino terminal.
30

Annexin II and b/g-
actin were identified as ligands for PP13 by the mass spec-

trometry; hence, these proteins are considered to play a key

role in placentation and maternal artery remodeling,

respectively.
52

Structure of LGALS13 gene and its mutations

The LGALS13 gene encoding for PP13 is expressed by the

placental syncytiotrophoblast on chromosome 19

(19q13.1). LGALS13 gene and its transcribing unit codes

for PP13 at 50 end that has promoter region followed by
comprising four exons designated as E1–E4, which consist

of base pairs in E1(60 bp), E2 (72 bp), E3 (211 bp), and E4

(251 bp) spaced by introns. Intronic regions vary between

499 bp and 1834 bp in length. Exon 4 and part of exon 3 of

LGALS13 gene exclusively code for the entire CRD.
53

Many studies reported that downregulated placental

expression of LGALS13 is due to mutations in the gene,

characterized by single nucleotide polymorphism (SNP)

and single nucleotide deletion (delT221 mutation) in exon

3, mutations of the exon–intron boundaries (Dex-2 muta-

tion), and an SNP in promoter region. The DNA variants

result in the expression of truncated protein which cannot

bind carbohydrates. The implication of altered, misfolded,

and nonfunctional protein may be associated with a variety

of obstetrical syndromes such as preeclampsia where the

normal implantation and placentation are generally

disrupted.

In support of this genetic evidence, decreased PP13 lev-

els and its messenger RNA (mRNA) expression of

LGALS13 in the first trimester of pregnancy,
36,54–57

SNP

(221delT) with low PP13 level is seen in adverse pregnancy

conditions
58–60

and intronic polymorphisms are associated

with PP13 level and impaired of lysophospholipase activ-

ity.
52,59–61

The promoter variants with SNPs were found in

women with increased risk to develop preeclampsia.
62–64

Transcription factor activating enhancer binding protein 2

alpha (TFAP2A) is a protein encoded by human TFAP2A

gene. It binds to specific DNA sequence and recruits tran-

scription machinery. It specifically binds to G regions at

�98 position than to A in the promoter region and induces
promoter expression as revealed by PP13 promoter reporter

expression studies after transfecting BeWo cells with PP13

having “A” or “C” in the �98 promoter position.65

Decreased placental expression of glial cell missing-1

and estrogen-related receptor g genes, encoding transcrip-
tion factors, regulates LGALS13 expression in the syncytio-

trophoblast which is associated with trophoblast fusion and

syncytium formation.
18

According to the available litera-

ture, the following few studies clearly demonstrate that

decreased PP13 level or impairment in expression and its

possible genetic causes are seen in women with preterm

preeclampsia. Ongoing research to determine whether the

presence of polymorphic PP13 variants may serve to

improve our understanding of the underlying pathophysiol-

ogy is of paramount importance.

The mutation in the promoter region and the exons of

LGALS13 gene is responsible for lower expression of PP13

mRNA and the low levels of plasma PP13 in the first tri-

mester. Therefore, genetic analysis of LGALS13 and

plasma PP13 level is one among the several biomarkers

studied to understand preeclampsia and its complications

at early stage to facilitate antenatal checkup.

Quantification of PP13

The quantity of PP13 from serum, plasma, tissue fluids, and

placental tissue was carried out by employing immune-based

technique—enzyme-linked immunosorbent assay (ELISA)

which is currently widely employed procedure for PP13

assay from biological samples. The results published from

this assay method in several research studies generate varied

information in different trimesters of normotensive pregnan-

cies and subjects likely to develop preeclampsia and eclamp-

sia. Measurement of PP13 is not a routine investigation in

clinical medicine but gained much attention in pregnancy-

related research. In many studies, quantification of PP13 in

biological sample was done either by ELISA
19–22,66–76

or by

dissociation-enhanced lanthanide fluorescence immunoas-

say (DELFIA) methods.
77–86

The underlying principle of ELISA for the estimation of

PP13 is an enzyme-linked antibody sandwich method. The

test principle is that the microtiter plate is pre-coated with

an antibody specific to PP13. Standards or samples are then

added to the appropriate microtiter plate wells with a

biotin-conjugated antibody specific to PP13. Avidin con-

jugated to horseradish peroxidase is added to each micro-

plate well and incubated. After the addition of

tetramethylbenzidine substrate solution, only those wells

that contain PP13, biotin-conjugated antibody, and

enzyme-conjugated avidin will exhibit a change in color.

The enzyme–substrate reaction is terminated by the addi-

tion of sulfuric acid solution and the color change is mea-

sured at a wavelength of 450 nm. The concentration of

PP13 in the samples is then determined by comparing the

absorbance of the samples with the standard curve. DEL-

FIA technique is also used to estimate PP13 in many

research contexts. The unit for representing the quantifica-

tion is picogram per milliliter or nanogram per milligram of

tissue. It is reported that the normal term placenta yields

Gadde et al. 5



nearly 3.7 mg of PP13.
28

The advantage of ELISA method

over DELFIA is that the reducing agent dithiothreitol in the

sample dilution buffer of the ELISA keeps the PP13 in

monomer form which prevents its affinity to the sugar resi-

dues of various blood proteins especially of the erythrocytes.

Functions of PP13

Placental implantation

Placental implantation involves attachment of the blasto-

cyst to the endometrial epithelium and subsequent inva-

sion in order to form a functional placenta. It occurs

through the trophoblast, an outer layer of blastocyst, that

subsequently develops into syncytiotrophoblast, which is

involved in implantation and placentation.
87

It is known

that placentation also involves PP13, a member of group

of pregnancy-related proteins. It is highly expressed in

placenta at maternal–fetal interface and may play an

important role in the maintenance of pregnancy (e.g.

embryo implantation, maternal–fetal immune tolerance,

placentation, and vascular remodeling). The fact that

structural and functional characteristics of this protein and

its role are important in placental development and regu-

lation pathways is receiving increased interest in recent

times.
88

The carbohydrate binding specificities were

extensively studied by numerous extracellular methods

such as solid phase assays,
89,90

surface plasmon reso-

nance,
91

fluorescence polarization,
92

frontal affinity chro-

matography,
93

and isothermal calorimetry.
94

b-human chorionic gonadotropin induced trophinin is an
intrinsic membrane protein expressed on the apical mem-

brane of the trophectoderm cells which is involved in adhe-

sion of blastocyst to the endometrial epithelium during

implantation process.
95,96

In addition to this, binding of

PP13 to the glycosylated receptor is also important for

adhesion and signaling in placentation. Based on sugar

binding assay results, it has been found that PP13 has the

strongest binding affinity to the N-acetyllactosamine,

mannose, and N-acetylglucosamine residues of carbohy-

drate moiety in glycoproteins and glycolipids present on

placenta.
97

An automatic docking study done using FlexX

module of SYBYL determined that the carbohydrate

molecules such as N-acetyllactosamine, lactose, mannose,

N-acetylgalactosamine, and galactose are located at

different ligand positions at the CRD.
98–100

Another study

has also reported that all the carbohydrate conformations

were characterized by their binding energies
101

and PP13

has the highest van der Waals interaction with N-acetyllac-

tosamine (�26.9 kcal/mol).
A strong stacking interaction with the aromatic ring of

Trp72 and three strong hydrogen bond interactions (<2.5

Å) with Arg55, Asn65, and Gln75 residues in CRD of PP13

were detected. The conserved Arg53 and Arg55 in the CRD

play a critical role in the interactions between PP13 and the

lactose moiety. Mannose has the lowest van der Waal

interaction with the PP13 but no hydrogen bond interac-

tions were reported (Table 1).
46

Sugar binding assays to

determine the affinity property found that PP13 exists as

homodimer stabilized by disulfide, a bond linkage, which is

favorable for hemagglutination in terms of lectin activity.

Reducing agents diminish dimerization and reduce sugar

binding affinity and hemagglutination activity. This unique

property of PP13 affects its biological activity in the

placenta.
102

In vivo, placentally expressed purified PP13 was found

to be phosphorylated. Experiments done with placental

PP13/galectin 13 showed that it contains phosphorylation

sites. Computational analysis indicated sites for serine/tyr-

osine kinase phosphorylation at positioning Ser48 (44–57)

and Tyr41 (37–45) and Tyr80 (76–84) close to CRD

domain. The carbohydrate binding affinity was observed

to be the same in PP13-B (placentally expressed phos-

phorylated) and PP13-R (bacterially expressed non-phos-

phorylated). The only possible linkage of phosphorylation

is to lysophospholipase activity. Since limited information

is available on phosphorylation and functional properties of

PP13, it is necessary to establish the exact role of phos-

phorylated PP13.
103

Regarding the hemagglutination process, several

research reports (Table 2) showed that PP13 has the ten-

dency to bind to b-galactosides located on the terminal
positions of ABO blood group antigens. Immunoassay

staining intensity of placental tissue showed variable

PP13 binding to RBC antigens of respective blood groups

A, B, and O.
34

Research reports pertaining to relationship

between different blood groups and preeclampsia risk indi-

cated mixed results regarding the effect of blood groups on

preeclampsia severity. A review of a few studies looking at

this subject suggests higher risk of preeclampsia with A

blood group,
104,105

with O blood group,
106,107

and with

AB blood group.
34,105,108–113

Yet a few more studies sug-

gested no relationship between them.
114–118

A limited num-

ber of studies explored the association of different blood

groups with decreased bioavailability of PP13.
34,113,119

Further research and large cohort studies are required to

Table 1. Van der Waals energies of PP13-ligand complexes.

Ligand

van der
Waals energy

(kcal/mol)

Number of
hydrogen

bonds

Amino acid
residues involved

in hydrogen
bonding

N-acetyl-D-
lactose amine

�765.2 3 Arg55, Asn65,
Gln75

Lactose �759.4 2 Arg55(2)
N-acetyl-D-

galactosamine
�751.9 2 Arg55(2)

Galactose �751.4 3 Arg53(2), Asn65
Mannose �741.5 0 —

PP13: placental protein 13; Arg55: arginine 55; Asn65: asparagine 65;
Gln75: glutamine 75; Arg53: arginine 53.

6 Journal of Circulating Biomarkers



investigate the effect of blood groups on the availability of

PP13 and its association with preeclampsia.

Immunological function

Maternal immunological response is essential for the estab-

lishment, maintenance, and completion of a healthy suc-

cessful pregnancy. The human semi-allogeneic fetus is not

rejected by the maternal immune system, despite expres-

sing paternal antigens due to many fetal, maternal, and

placental mechanisms that have been implicated in aiding

fetal tissues in escaping maternal immune attacks. The

immunological barrier (placenta and maternal decidua)

plays a crucial role in acceptance of the fetus and making

the decidua more receptive for the invading fetus.

Of the numerous mechanisms involved, uterine natural

killer cells (regulate the trophoblast invasion through

secretion of angiogenic growth factors),
120

cytokines and

chemokines (interleukin-8 and interferon inducible protein-

10),
121

dendritic cells,
122

macrophages,
123

the complement

system,
124

Toll-like receptors,
125

decidualized endome-

trium secretion,
126

the trophoblast human leucocyte anti-

gen (HLA) expression pattern,
127

Fas ligand,
128

indoleamine 2,3-dioxygenase,
129

B7 family,
130

T helper

cells,
131

and T regulatory cells
132

are all implicated in

modulating immune responses for an effective implanta-

tion. The inadequate maternal–fetal immune tolerance is

one of the proposed mechanisms leading to preeclampsia.

Breakdown of maternal–fetal tolerance also leads to other

pregnancy-specific autoimmune diseases, bleeding compli-

cations during the first trimester, pregnancy-induced hyper-

tension, and preterm or recurrent miscarriages.
133

So apart from the abovementioned mechanisms, human

placenta-specific galectins expressed by the syncytiotro-

phoblast at the maternal–fetal interface are key regulator

proteins of the immune responses. They confer immune

tolerance to the semi-allogeneic fetus by bringing about the

apoptosis of maternal T lymphocytes to sustain placenta-

tion.
134,135

PP13 drains through the decidual veins in the

form of exosomes/microvesicles into the decidua where it

attracts and activates maternal immune cells, diverting

them away from maternal spiral arteries to facilitate unin-

terrupted spiral artery remodeling. PP13 plays a unique role

in early pregnancy by forming decidual crystal-like aggre-

gates within decidual zones of necrosis. These zones are

associated with necrotic and apoptotic immune cells which

are CD45RO memory T cells, CD68 þ macrophages, and
CD57 þ large granular lymphocytes. The decidual zones of
necrosis peak at 7–8 weeks of gestation when placental

circulation is not yet established and diminish after the

Table 2. Research studies showing association of blood groups A, B, and O with preeclampsia.

S.No. Author Year Study design Results

1 May 1973 Case control Association of blood group A with preeclampsia than O blood group
2 Scott and Beer 1976 Case control No association between ABO blood group and preeclampsia risk
3 Amin et al. 1989 Case control Blood group O as the risk factor for preeclampsia
4 Spinillo et al. 1995 Case control Maternal AB blood group associated with increased risk of severe preeclampsia
5 Witsenburg et al. 2005 Case control ABO blood group never observed as risk in pregnancy complications

(preeclampsia, HELLP syndrome, and PIH).
6 Clark and Wu 2008 Prospective

cohort
No effect of ABO blood type on the risk of preeclampsia

7 Hiltunen et al. 2009 Nested case
control

Preeclampsia risk associated with AB blood group

8 Than et al. 2011 Case control Maternal blood group AB contributes to less PP13 bioavailability and increased
risk of preeclampsia

9 Lee et al. 2012 Cohort AB blood group associated with high risk of developing preeclampsia than O
blood group

10 Phaloprakarn and
Tangjitgamol

2013 Case control Blood groups A and AB were associated with increased risk for preeclampsia

11 Hentschke et al. 2014 Case control No association between blood groups and preeclampsia
12 Seyfizadeh et al. 2015 Case control ABO blood group associated with unfavorable outcomes of pregnancy
13 Manjunatha and Anita 2015 Cross-

sectional
AB blood group has highest preeclampsia risk

14 Avci et al. 2016 Case control AB blood group with decreased availability of PP13 associated with higher risk of
preeclampsia

15 Elmugabil et al. 2016 Case control Blood group O with higher risk for preeclampsia
16 Reisig et al. 2016 Case control Blood group A with increased risk of preeclampsia
17 Mital et al. 2016 Case control AB blood group with higher risk of preeclampsia.
18 Aghasadeghi and

Saadat
2017 Case control No association between ABO blood groups and preeclampsia risk

19 Beyazit et al. 2017 Case control No association between blood groups and preeclampsia

PP13: placental protein 13. PIH: pregnancy induced hypertension.

Gadde et al. 7



completion of spiral artery remodeling at about 10–14

weeks of gestation. The diversion of these immune cells

facilitates uninterrupted trophoblast invasion and remodel-

ing of the maternal spiral arterioles.
17

As the demands of the growing fetus for oxygen and

nutrients increase as the pregnancy progresses, the trans-

formation of the maternal vasculature becomes critical.

Impaired spiral artery remodeling may be linked to an

immune maladaptation syndrome, preeclampsia followed

by failure of the fetus to reach its optimal growth, and

intrauterine growth retardation (IUGR).
136–139

Among the

studied recombinant galectins, the apoptotic effects of

PP13 on freshly isolated activated CD3 þ T cells were
stronger when compared to galectin 1. The PP13/galectin

13 functional role with respect to T cell apoptosis is similar

to that of the mechanism behind T cell apoptosis caused by

galectin 1.
28

However, the similar effect was not found with trun-

cated PP13 due to lack of CRD function and T cell apop-

totic activity. Hence, structural integrity of PP13 is crucial

in sugar binding and the regulation of cell–matrix interac-

tions for successful human placentation. Thus, inadequate

placental expression and structural derangement with

altered function of PP13 result in adverse conditions during

pregnancy and poor obstetric outcome.
36

The involvement

of PP13 as pro-inflammatory function demonstrated in in

vitro study where PP13 triggered the secretion of cytokines

and chemokines into the culture medium from mononuc-

lear cells isolated from peripheral blood of pregnant

women. Thus, varied action of PP13 with respect to apop-

totic and pro-inflammatory function studied in in vitro

experiments.
28

Regulation of blood pressure

The role of PP13 in embryo implantation in maternal–fetal

interface has been reported. But animal experiments and

studies in humans regarding the role of PP13 in blood

pressure regulation are lacking. Nonetheless, there are stud-

ies which suggest that PP13 contributes to vasodilation and

remodeling of uteroplacental vasculature and improves

pregnancy outcome.
140–142

The exact molecular mechan-

ism of vasodilation and the unidentified responsive element

that influences endothelial nitric oxide synthase and

cyclooxygenase enzymes in preeclampsia model are yet

to be elucidated even though prostaglandins do play an

important role in vascular remodeling during early

placentation.
142

Introduction of PP13 to cultured trophoblasts elicited

depolarization of the trophoblast membrane by calcium

ions leading to liberation of linoleic and arachidonic acids

from the trophoblast membrane lipids and this leads to

increased amount of prostacyclin and thromboxane synth-

esis.
50

The in vivo vasodilatory effects of PP13 in pree-

clamptic animal models and the levels of PP13 correlated

with nitric oxide and prostaglandin levels. This needs to be

further investigated in order to evaluate the potential ther-

apeutic use of PP13 in humans for improving blood flow

and pregnancy outcome in hypertensive disorders of preg-

nancy or preeclampsia.

Recombinant PP13

Recombinant PP13 (PP13-R) was genetically engineered

and produced by Hy-laboratories (Hylabs Rehovot, Israel).

The basis for PP13 sequence construct has been validated

by Sanger sequencing information published by National

Centre for Biotechnology Information, USA. The same

sequence constructs are expressed in transfected Escheri-

chia coli. The expressed protein was harvested and affinity

purified, verified by SDS PAGE, HPLC, and immunoblot

using PP13-specific monoclonal antibodies. Several in vivo

and in vitro extensive studies explored the functional

aspects of recombinant PP13 in biomedical research.

In a protein conformation study, PP13-R was reported as

a homodimer stabilized by disulfide bonds possessing bind-

ing strength to different sugars in nonreducing conditions.

However, the reducing conditions favorable for the mono-

meric form lack binding ability to sugars.
58

In vitro study on hemagglutination of human erythro-

cytes described the binding affinities of common recombi-

nant PP13 (PP13-R) and truncated recombinant PP13

(TrPP13). PP13-R has the strongest binding affinity to the

b-galactosides on the erythrocyte surface of the blood
group AB and weakest affinity to erythrocytes of blood

group B. However, this is not exhibited by TrPP13 due to

altered CRD. This provides evidence that conserved CRD

is crucial to exhibit lectin activity.
28

The major in vitro

study information is that the immune response of recombi-

nant galectin was studied and noted that among the galec-

tins, PP13-R had the strongest apoptosis-inducing effect on

the freshly isolated maternal T cells. This observation laid

the strong foundation to understand the central role of PP13

in maintaining immune tolerance at the maternal–fetal

interface.
36

In an experimental animal model, the role of CRD of

PP13 was elucidated in pregnancy by comparing the wild-

type recombinant PP13 and truncated variant on adminis-

tering both the variants to pregnant rats. The significance of

wild-type PP13 in regulating blood pressure and expanding

uteroplacental vasculature was noted. This suggests that

PP13 may have a potential therapeutic role during preg-

nancy risk.
65

Phosphorylation of the protein side chains of

PP13 expressed and purified from placenta indicated the

specific biological function and necessitates further

research in order to understand the role that the phosphory-

lated protein plays and its mechanism. The inherent biolo-

gical property restored on wild-type PP13 and PP13-R

studied and compared by phosphorus-31 nuclear magnetic

resonance analysis and found that both variants exhibited

weak endogenous lysophospholipase activity. The affinity

purified wild-type PP13 and PP13-R when incubating with

8 Journal of Circulating Biomarkers



protein extracts from human placenta or WRL-68 fetal

hepatic cell lines identified annexin-II and b/g-actin as spe-
cifically bound proteins for PP13.

101

The role of PP13-R on the cardiovascular system in

gravid and nongravid rodents showed, for the first time,

the influence of PP13 on vasodilation, uterine artery remo-

deling, and in improving uteroplacental blood flow as well

as adaptation of the maternal vasculature to pregnancy. The

same author also studied the role of PP13-R on pregnant

rats in lowering blood pressure, venous remodeling, and

improving fetal growth.
140

Administration of truncated

PP13 variant resulted only in a hypotensive effect with loss

of venous remodeling and increase in placenta and pup

weights.
79

In a recent animal study, the role of PP13-R in

endothelial signaling pathways of vasodilation of resis-

tance arteries from pregnant and nonpregnant rats was stud-

ied and concluded that PP13 may become useful

therapeutically in improving blood flow and pregnancy

outcomes in hypertensive pregnancies.
142

Screening performance

Preeclampsia is one of the most common and life-

threatening disorders of pregnancy affecting a total of 8.5

million women worldwide. Preeclampsia is responsible for

18% of maternal deaths and up to 40% of fetal mortality.
Despite extensive research, preeclampsia still lacks a safe,

cost-effective, reliable, early means of diagnosis, or predic-

tion. PP13/galectin 13 produced by the syncytiotrophoblast

during pregnancy is involved in normal placentation. In

normal pregnancies, serum levels of PP13 slowly rise with

gestational age. Several studies have reported that

decreased serum levels of PP13 in the first trimester

increase the risk of subsequently developing preeclampsia.

Measurement of PP13 levels as a first trimester screening

marker for preeclampsia may provide an opportunity for

identification of women destined to develop early-onset

preeclampsia.

Romero et al.
69

studied a cohort of 300 patients, of

which 50 developed preeclampsia. Serum PP13 concentra-

tion in the first trimester was significantly lower in patients

who developed preterm and early-onset preeclampsia than

in those with normal pregnancies; and at 80% specificity, a
cutoff of 0.39 multiples of median (MoMs) had a sensitivity

of 100% for early-onset preeclampsia and 85% for preterm
preeclampsia. Based on these results, it was concluded that

the first trimester maternal serum PP13 concentrations can

be used in the risk assessment for preeclampsia.

Gonen et al.
15

studied a cohort of 1366 pregnant women

and subsequently 20 were diagnosed with preeclampsia. At

6–10 gestational weeks, PP13 levels were significantly

lower among the preeclampsia group with a median of

0.28 MoM (95% confidence interval (CI) 0.15–0.39, p <
0.004). Using a cutoff of 0.40 MoM, the sensitivity was

80%, a false positive rate (FPR) was 20%, and odd ratio
was 16.0 (95% CI 18.2–169.2). This study reported that

PP13 in the first trimester alone or in combination with the

slope between the first and second trimesters may be a

promising marker for assessing the risk of preeclampsia.

Nicolaides et al.
66

studied PP13 as a biochemical marker

for the early onset of preeclampsia at 11 þ 0 to 13 þ 6
weeks of gestation. At an FPR of 10%, PP13 showed a
prediction rate of 80% as a single biochemical marker. In
combination with Doppler ultrasound PI, the prediction

rate increased to 90%.
Spencer et al.

68
conducted a nested case-control study to

evaluate whether the measurement of maternal serum PP13

and pregnancy associated plasma protein-A (PAPP-A) at

11 þ 0 to 13 þ 6 weeks of gestation alone or in combina-
tion with the second trimester uterine artery pulsatility

measured by Doppler velocimetry is useful in predicting

those women who will develop preeclampsia. There were

446 controls and 44 cases with early preeclampsia where

delivery was induced prior to 35 weeks. In addition, there

were 44 cases with preeclampsia in which delivery was not

induced before term. Median PP13 levels for controls, all

cases, and early preeclampsia cases were 176.9, 121.9, and

111.7 pg/mL, with MoMs of 1.00, 0.69, and 0.63, respec-

tively (p < 0.001). The first trimester PP13 levels may be

useful in predicting preeclampsia and early preeclampsia,

and the accuracy of the method increases when coupled

with the second trimester Doppler PI measurement. Further

studies are required to establish the real value of PP13 in

the first trimester screening for preeclampsia.

Plasma PP13 has also been used in combination with

urinary glycosaminoglycans/proteoglycans as early mar-

kers for preeclampsia by De Muro et al.
20

A total of 62

women were enrolled in the study, of which 24 presented

complications such as preeclampsia, proteinuria, and

hypertension during pregnancy. Plasma levels of PP13

were significantly reduced in the group of women who

went on to develop complications compared with controls

(p ¼ 0.022). The reduced plasma levels of PP13 and the
alteration of the relative content of urinary glycosamino-

glycans and proteoglycans observed in their study could be

a promising tool for the prediction of preeclampsia in an

early stage of pregnancy.

MoslemiZadeh et al.
75

conducted a prospective nested

case-control study that recruited 1500 pregnant women and

100 women developed preeclampsia and represented the

case group. Of 100 women with preeclampsia, 66 cases

have mild preeclampsia, while 34 cases have severe pre-

eclampsia. Serum PP13 levels along with PAPP-A were

measured in the first and second trimesters and were sig-

nificantly lowered in women who developed preeclampsia

(p < 0.001). The cumulative value of all the four variables

with cut-off points of 238.5 has sensitivity and specificity

of 91.0% and area under curve of 0.968. The study con-
cluded that measuring PP13 with PAPP-A in both trime-

sters of pregnancy is advantageous for the prediction of the

incidence of preeclampsia.

Gadde et al. 9



Wortelboer et al.
81

conducted a nested case-control

study to investigate the predictive value of PP13 along with

other biochemical markers such as Pregnancy associated

plasma protein A (PAPP-A), b-human chorionic gonado-
tropin (b-hCG) and Placental growth factor(PlGF) and
desintegrin ADAM 12 in the first trimester of pregnancy.

PP13 and PlGF were reduced in women with preeclampsia,

with median of 0.68 and 0.73 MoM, respectively (p <

0.0001 for both). This study demonstrates that PP13 and

PlGF in the first trimester might be promising markers in

risk assessment for early preeclampsia/HELLP syndrome.

Odibo et al.
73

conducted a prospective cohort study of

pregnant women followed from the first trimester to deliv-

ery as part of a first trimester screening study for adverse

pregnancy outcomes. This study was conducted on 477

women of whom 42 women were diagnosed with pree-

clampsia. For a fixed FPR of 20%, PP13, PAPP-A, and
mean uterine artery pulsatility index identified 49, 58, and

62%, respectively, of women who developed any form of
preeclampsia. PP13 was best in predicting early onset pre-

eclampsia with a sensitivity of 79% at an FPR of 20% and
can be considered as individual predictors of women at risk

to develop preeclampsia.

Svirsky et al.
76

conducted a cohort study to determine

the first trimester maternal serum PP13 in singleton versus

twins with and without severe preeclampsia. In twins, the

median was 1.74 MoM (n ¼ 76) versus 1.74 in unaffected
twins (p ¼ 0.10) and 2.26 (n ¼ 6) for mild preeclampsia (p
¼ 0.30). Among singletons with severe preeclampsia, the
median was 0.44 MoM (n ¼ 26, p < 0.0001), and for mild
preeclampsia 0.62 (n ¼ 17, p < 0.001). Based on the results,
they concluded that PP13 was higher in twins than single-

tons corresponding to larger placental mass.

Beljan et al.
22

conducted a prospective study to detect

whether the first trimester serum PP13 and copeptin can

predict preeclampsia in advanced age nulliparous women.

This study confirmed a significant contribution for the

combination of two biomarkers for the prediction of pre-

eclampsia (p ¼ 0.007). Decreased level of PP13 and an
increased level of copeptin can predict preeclampsia with

a sensitivity of 66.7% and a specificity of 97.3%, with an
FPR of 2.7%.

El Sherbiny et al.
74

conducted a cohort study on 100

women to assess the value of PP13 as an early marker for

screening of preeclampsia and to correlate with the PP13

mRNA. The maternal serum PP13 level in the preeclamp-

tic group was (157.9 + 45.5 pg/mL), which is signifi-
cantly lower than that of the control group (225 + 67.3
pg/mL), with a highly statistically significant difference

(p < 0.0001). The frequency of maternal PP13 was also

lower in the preeclamptic group (28%) compared to that in
the control group (76%), with a highly statistically signif-
icant difference (p < 0.0001). This study concluded that

serum PP13 assay and PP13 mRNA expression are reli-

able markers for early detection of preeclampsia and was

recommended doing it as a routine investigation during

the first trimester.

Khalil et al.
71

conducted a nested case-control study to

evaluate whether the first trimester maternal serum PP13

can predict preeclampsia in women with a priori high risk.

Women who developed preeclampsia had significantly

lower (p < 0.001) PP13 MoMs compared with controls.

PP13 MoMs for controls and preeclampsia cases were 1.0

(range 0.0–10.0) and 0.4 (range 0.0–7.0), respectively (p <

0.001). At an MoM cutoff of 0.53, for an FPR of 10%,
sensitivity was 50% for preeclampsia at term (>37 weeks),
62% for preterm preeclampsia (<37 weeks), and 71% for
early onset preeclampsia (< 34 weeks). Based on these

results, the first trimester PP13 can predict preeclampsia

in women at increased priori risk and predicts early-onset

better than late-onset disease.

Chafetz et al.
67

performed a prospective, nested case-

control study to evaluate the first trimester serum PP13 as a

screening test for preeclampsia and intrauterine growth

restriction. The median first trimester PP13 level was

132.5 pg/mL in the control subjects (n ¼ 290). Median
PP13 levels were significantly lower among women

who had preeclampsia (27.2 pg/mL; p < 0.001), IUGR

(86.6 pg/mL; p < 0.001), and preterm delivery (84.9 pg/mL;

p ¼ 0.007). When PP13 was expressed as multiples of the
gestational age-specific medians among the control sub-

jects, the MoMs were 0.2 for preeclampsia, 0.6 for IUGR,

and 0.6 for preterm delivery (p < 0.001 for each disorder

compared with subjects). Receiver operating characteristic

analysis yielded areas under curve of 0.91, 0.65, and 0.60

for preeclampsia, IUGR, and preterm delivery, respec-

tively. At a 90% specificity rate, the corresponding sensi-
tivities were 79, 33, and 28%, respectively. This study
concluded that maternal PP13 levels in the first trimester

are a promising diagnostic tool for the prediction of pre-

eclampsia with high sensitivity and specificity.

Huppertz et al.
70

conducted a prospective longitudinal

study with 41 normal pregnant women, 18 cases with pre-

term delivery or cervix insufficiency, and 4 with develop-

ing late-onset preeclampsia. Six hundred and sixty-six

blood samples were obtained every 2–4 weeks starting

from 5 weeks to 8 weeks of gestation (10–12 samples/

patient) and tested for serum PP13. In normal pregnant

women delivering at term, median maternal serum PP13

levels were increasing from 166 pg/mL to 202 pg/mL and

382 pg/mL in the first, second, and third trimesters, respec-

tively. Preeclamptic women had significantly reduced

PP13 levels in the first trimester (MoM of 0.14 at 7–8

weeks; p ¼ 0.005 compared to normal). PP13 in the third
trimester was significantly higher compared to normal at

35–36 weeks with PP13 MoM of 1.79. This preliminary

study indicates that low levels of PP13 in early pregnancy

indentify at risk pregnancies, whereas high levels precede

the syndrome in late pregnancy and suggest syncytiotro-

phoblast necrosis.

10 Journal of Circulating Biomarkers



A large number of cohort studies are required to deter-

mine the study replicability and to establish PP13 measure-

ments as an early screening indicator in larger population.

However, the exact reason for lower level of PP13 bioavail-

ability in the first trimester of the susceptible subjects likely

to develop preeclampsia is still unknown. Despite consid-

erable amount of research, development of sensitive, sta-

ble, reliable, and cost-effective biochemical analytes is of

great importance.

Future perspectives

Reliable early screening for preeclampsia is one of the most

important challenges in prenatal care, since preeclampsia is

a serious complication and an important cause of maternal

and perinatal morbidity and mortality with a prevalence of

2–8%2 resulting in about 50,000–60,000 deaths annually
worldwide.

143
It is responsible for 18% of maternal deaths

and up to 40% of fetal mortality.6 According to World
Health Organization, the mortality rate of preeclampsia in

developing countries is seven times higher than developed

countries.
144

PP13 is produced by the syncytiotrophoblast throughout

pregnancy. The significantly reduced levels in the first tri-

mester make it a promising tool for identifying women at

increased risk of preeclampsia and scope for research to

find the exact cause for low levels of PP13 at the first

trimester. However, whether it has a better predictive value

when used alone or should be included in the highly sen-

sitive panel of biomarkers needs to be determined by con-

ducting larger prospective studies in different populations.

Data generated in animal studies suggest that PP13 has a

beneficial effect in regulating blood pressure and the poten-

tial use of this galectin as a therapeutic drug. Administering

PP13 to patients at risk for preeclampsia may be helpful in

reducing the incidence of preeclampsia and in improving

obstetrical outcomes.

An extensive research is necessary to study the effect of

PP13 in arterial expansion and a thorough understanding of

the mechanistic pathway in preeclamptic animal or human

model. Hence, there is a scope to evaluate the efficacy of

recombinant PP13 supplementation in alleviating preg-

nancy complications at conception. Thus, the outcome

would gain momentum in advanced preeclampsia research

through clinical trials. The PP13 structure has additional

domains known to possess lysophospholipase activity and

phosphorylation sites. The role of these functional domains

in relation to normal pregnancy and in pregnancy compli-

cations still needs to be studied further.

Summary

The overall aim of this review article is to summarize the

properties and biological functions of PP13 in normal preg-

nancy and in preeclampsia. PP13 is a 32-kDa protein

localized in the brush border membrane of the

syncytiotrophoblast lining at the common fetal–maternal

blood spaces of the placenta. As a “prototype” galectin, it

has a single sugar binding domain or CRD which emerges

into the extracellular space and has lectin-like activity. The

dimerized phosphorylated protein functions as a regulator

of blood flow and blood pressure and has special immune

functions at the fetal–maternal interface. PP13 induces dif-

ferent levels of hemagglutination, which depend on the

type of blood group antigen, and it is involved in multistep

process in pregnancy that supports trophoblast invasion as

well as generation of maternal systemic endothelial effect.

Further data are needed to establish whether dysregulation

of PP13 levels in the maternal circulation in early preg-

nancy can serve as a reliable screening, predictive, and

prognostic biomarker for preeclampsia.

Animal experimental results which found beneficial

effects of PP13 in regulating blood pressure suggest the

potential use of this galectin 13 as a therapeutic drug in

preeclampsia. However, a large prospective and longitu-

dinal studies are needed to confirm this observation.

Although advanced research is focusing on molecular

and epigenetic changes in preeclampsia, future study

designs should first identify a highly sensitive and spe-

cific serum marker.

PP13 is known to be involved in different stages of

pregnancy ranging from trophoblast invasion to vasodila-

tion of the maternal vasculature needed for the increased

blood flow to the fetus. Administration of recombinant

PP13 in women with low serum levels may prevent

impaired placental development in preeclampsia. Further

research is required to completely understand the role of

PP13 in the development of preeclampsia. The diagnosis of

preeclampsia based on biomarkers might be useful in iden-

tifying patients at risk, monitoring disease progression to

provide effective and timely interventions.

Conclusion

PP13, a placental galectin protein, is a homodimeric, phos-

phorylated protein localized in syncytiotrophoblast. By its

CRD, it exerts erythrocytes agglutination or lectin activity

through sugar binding capabilities. It is an immune regula-

tory, vasodilatory protein with weak lysophospholipase

activity involved in placentation process. The low levels

of blood PP13 acts as a new biological protein for indivi-

dualized risk assessment and drug design target in manage-

ment of preeclampsia. Preparation of monoclonal

antibodies and recombinant PP13 helps in research for

detection and replenishing the PP13 level in preeclampsia

has attracted much attention.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with

respect to the research, authorship, and/or publication of this

article.

Gadde et al. 11



Funding

The author(s) received no financial support for the research,

authorship, and/or publication of this article.

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    /TileHeight 256
    /Quality 30
  >>
  /AntiAliasMonoImages false
  /CropMonoImages false
  /MonoImageMinResolution 900
  /MonoImageMinResolutionPolicy /OK
  /DownsampleMonoImages true
  /MonoImageDownsampleType /Average
  /MonoImageResolution 175
  /MonoImageDepth -1
  /MonoImageDownsampleThreshold 1.50286
  /EncodeMonoImages true
  /MonoImageFilter /CCITTFaxEncode
  /MonoImageDict <<
    /K -1
  >>
  /AllowPSXObjects false
  /CheckCompliance [
    /None
  ]
  /PDFX1aCheck false
  /PDFX3Check false
  /PDFXCompliantPDFOnly false
  /PDFXNoTrimBoxError true
  /PDFXTrimBoxToMediaBoxOffset [
    0.00000
    0.00000
    0.00000
    0.00000
  ]
  /PDFXSetBleedBoxToMediaBox false
  /PDFXBleedBoxToTrimBoxOffset [
    0.00000
    0.00000
    0.00000
    0.00000
  ]
  /PDFXOutputIntentProfile (U.S. Web Coated \050SWOP\051 v2)
  /PDFXOutputConditionIdentifier (CGATS TR 001)
  /PDFXOutputCondition ()
  /PDFXRegistryName (http://www.color.org)
  /PDFXTrapped /Unknown

  /CreateJDFFile false
  /Description <<
    /ENU <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>
  >>
  /Namespace [
    (Adobe)
    (Common)
    (1.0)
  ]
  /OtherNamespaces [
    <<
      /AsReaderSpreads false
      /CropImagesToFrames true
      /ErrorControl /WarnAndContinue
      /FlattenerIgnoreSpreadOverrides false
      /IncludeGuidesGrids false
      /IncludeNonPrinting false
      /IncludeSlug false
      /Namespace [
        (Adobe)
        (InDesign)
        (4.0)
      ]
      /OmitPlacedBitmaps false
      /OmitPlacedEPS false
      /OmitPlacedPDF false
      /SimulateOverprint /Legacy
    >>
    <<
      /AllowImageBreaks true
      /AllowTableBreaks true
      /ExpandPage false
      /HonorBaseURL true
      /HonorRolloverEffect false
      /IgnoreHTMLPageBreaks false
      /IncludeHeaderFooter false
      /MarginOffset [
        0
        0
        0
        0
      ]
      /MetadataAuthor ()
      /MetadataKeywords ()
      /MetadataSubject ()
      /MetadataTitle ()
      /MetricPageSize [
        0
        0
      ]
      /MetricUnit /inch
      /MobileCompatible 0
      /Namespace [
        (Adobe)
        (GoLive)
        (8.0)
      ]
      /OpenZoomToHTMLFontSize false
      /PageOrientation /Portrait
      /RemoveBackground false
      /ShrinkContent true
      /TreatColorsAs /MainMonitorColors
      /UseEmbeddedProfiles false
      /UseHTMLTitleAsMetadata true
    >>
    <<
      /AddBleedMarks false
      /AddColorBars false
      /AddCropMarks false
      /AddPageInfo false
      /AddRegMarks false
      /BleedOffset [
        9
        9
        9
        9
      ]
      /ConvertColors /ConvertToRGB
      /DestinationProfileName (sRGB IEC61966-2.1)
      /DestinationProfileSelector /UseName
      /Downsample16BitImages true
      /FlattenerPreset <<
        /ClipComplexRegions true
        /ConvertStrokesToOutlines false
        /ConvertTextToOutlines false
        /GradientResolution 300
        /LineArtTextResolution 1200
        /PresetName ([High Resolution])
        /PresetSelector /HighResolution
        /RasterVectorBalance 1
      >>
      /FormElements true
      /GenerateStructure false
      /IncludeBookmarks false
      /IncludeHyperlinks false
      /IncludeInteractive false
      /IncludeLayers false
      /IncludeProfiles true
      /MarksOffset 9
      /MarksWeight 0.125000
      /MultimediaHandling /UseObjectSettings
      /Namespace [
        (Adobe)
        (CreativeSuite)
        (2.0)
      ]
      /PDFXOutputIntentProfileSelector /DocumentCMYK
      /PageMarksFile /RomanDefault
      /PreserveEditing true
      /UntaggedCMYKHandling /UseDocumentProfile
      /UntaggedRGBHandling /UseDocumentProfile
      /UseDocumentBleed false
    >>
  ]
  /SyntheticBoldness 1.000000
>> setdistillerparams
<<
  /HWResolution [288 288]
  /PageSize [612.000 792.000]
>> setpagedevice