Decidual Killer Immunoglobulin-Like Receptor (KIR)2DL1

Expression and the Onset of Preeclampsia, Birth Weight and

Placental Weight in Early and Late Onset Preeclampsia

Khairunnisa Abd Rauf

, Erry Gumilar Dachlan

and Ariyanto Harsono

Master Student of Immunology, Postgraduate School Universitas Airlangga, Surabaya, Indonesia

Department of Obstetrics and Gynaecology, RS DR Soetomo, Surabaya, Indonesia

Department of Pediatrics, RS Dr Soetomo, Surabaya, Indonesia

Keywords: decidual, immunohistochemistry, KIR2DL1, placenta

Abstract: A

successful spiral artery remodelling ensures adequate uteroplacental perfusion and sufficient nutrient

supply to fetus. HLA-C interaction with maternal KIR determines the outcome of spiral artery remodelling.

Strong KIR2DL1 inhibitory lowers cytokine expression and angiogenic factors that affect uteroplacental

perfusion and nutrient supply. We analysed the decidual expression of KIR2DL1 in early-onset

preeclampsia (EO-PE) and late-onset preeclampsia (LO-PE) groups. We found a significant difference

between KIR2DL1 expression and EO-PE and LO-PE groups (p <0.001), with a strong negative correlation

between decidual expression of KIR2DL1 and EO-PE (p <0.001, r=-0.723), birth weight (p <0.001, r=-

0,.70) and placental weight (p <0.001, r=-0.770).

1 INTRODUCTION

Preeclampsia is a complication of pregnancy

characterised by high blood pressure, with or

without proteinuria. Preeclampsia is the third cause

of maternal mortality after postpartum haemorrhage

and infection. Preeclampsia has a prevalence of 5-

8%. (Say et al., 2014)

In 2004, the main cause of maternal mortality is

preeclampsia (29.9%) and postpartum haemorrhage

(26.12%). These two have become the main causes

of maternal mortality for a long time. In 2014, there

were 567 maternal deaths in East Java, and most

cases occurred in Surabaya. (Dachlan et al., 2016)

The early pathology of preeclampsia is the

failure of spiral artery remodelling. This causes

abnormal placentation and triggers the release of

pro-inflammatory mediators. Spiral artery

remodelling begins with the invasion of vascular

smooth muscle cells and replacement of

endothelium by trophoblasts. (Moffett and Colucci,

2014) The process leads to activation of endothelial

system, causes high blood pressure and increases

protein level in urine. (Kopcow, 2007)

Spiral artery remodelling is related to immune

system of the mother and the fetus. This process is

mediated by extravillous trophoblast (EVT) that

expresses HLA-C molecule. The process will be

recognized by Killer Immunoglobulin-like Receptor

(KIR) of the uterine natural killer (uNK) cells that

produces cytokines and angiogenic factors for

placentation and spiral artery remodelling. (Alicia,

2014)

In preeclampsia, KIR-AA inhibitory receptors

(one of them is KIR2DL1) from uNK cells will

recognize HLA-C molecules from EVT. This lowers

cytokine expression and angiogenic factors and

increases anti-angiogenic factors, such as soluble

endoglin (sENG) dan soluble fms-like tyrosine

kinase-1 (sFLT1) (Alicia, 2014)

In addition to NK cells, CD4, CD8 and γδ T cells

express Killer Immunoglobulin-like receptors (KIR).

Inhibitory KIR on CD8 T cells may modulate the

function of the cell and lessen CD8 respons. During

the activation process, KIR enhances CD8 function.

There is limited information available on how HLA

class I molecules affect T cells as they do on NK

cells (Björkström et al., 2012). KIR expression on T

cells has advantages that T cell may differentiate

self-maternal cells from allogeneic fetal cells and

modulate decidual immune response during

pregnancy. (Tamara et al., 2009)

Rauf, K., Dachlan, E. and Harsono, A.

Decidual Killer Immunoglobulin-Like Receptor (KIR)2DL1 Expression and the Onset of Preeclampsia, Birth Weight and Placental Weight in Early and Late Onset Preeclampsia.

DOI: 10.5220/0007542103210324

In Proceedings of the 2nd International Conference Postgraduate School (ICPS 2018), pages 321-324

ISBN: 978-989-758-348-3

321

This paper analysed decidual expression of

inhibitory KIR2DL1 expression and its effect on the

onset of preeclampsia, birth weight and placental

weight.

2 MATERIALS AND METHODS

2.1 Study design

This study was designed to analyse the distribution

and trend of placental KIR2DL1 expression in early

and late preeclampsia group, as well as its effect on

pregnancy outcome, which is the onset of

preeclampsia, birth weight and placental weight.

2.2 Subjects

We examined 35 patients aged 18-40 years old with

preeclampsia, in which 14 patients were diagnosed

with early preeclampsia (onset <34 weeks) and 21

patients with late preeclampsia (onset ≥34 weeks).

Immediately after delivery, placental biopsy with the

measurement of 2x2 cm was performed after written

informed consent, and samples were preserved in

Normal Buffer Formalin. Within 48 hours, paraffin

block was made. Baby’s birth weight was

immediately measured using a standard medical

scale.

Ethical approval was obtained from Ethical

Committee of Dr Soetomo Hospital

(371/Panke.KKE/V/2017) and Dr Soewandhie

Hospital (070/16284/436.8.6/2017), Surabaya,

Indonesia.

2.3 Immunohistochemistry of

KIR2DL1

Immunohistochemistry was performed based on IHC

protocol supplied from LifeSpan BioSciences, Inc.

This study used Primary polyclonal Anti-

KIR2DL1/CD 158a LS-C192811 antibody and

immunohistochemistry kit from ScyTek laboratories.

For interpretation of immunohistochemistry,

manual counting was performed in 10 field of views.

We obtain a mean of positive cells in one field view.

2.4 Statistical Analysis

The obtained data were analysed using unpaired

(two samples) t-test and Pearson and Spearman

correlation test. p-value of ≤0.05 was considered

statistically significant.

3 RESULTS

Placental KIR2DL1 expressions were found in both

early and late preeclampsia groups. KIR2DL1

expression was higher in early preeclampsia group

(4.42 ± 0.84 positive cells/field view) compared to

late preeclampsia group (1.24 ± 0.23 positive

cells/field view). We found that KIR2DL1

expressions were not only found on uterine NK

cells, but also on T cells in decidual. High

expression of KIR2DL1 was not only contributed by

NK cells, but also T cells.

Figure 1: Placental expression of KIR2DL1 in EO-PE and

LO-PE group. A significantly higher expression of

KIR2DL1 was found in early preeclampsia group (p

<0.001)

For the onset of preeclampsia, the mean value for

the onset in EO-PE group was 28 ± 3.84 weeks, and

33.37 ± 5.19 weeks for LO-PE group. Spearman test

showed a significant strong negative correlation

between KIR2DL1 expression and onset of

preeclampsia (p <0.001, r=-0.723).

ICPS 2018 - 2nd International Conference Postgraduate School

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Figure 2: Strong negative correlation between KIR2DL1

expression and the onset of PE (p <0.001, r = -0.723).

A higher birth weight was obtained by LO-PE

with (2726.90 ± 542.45 gram) compared to EO-PE

(1553.57 ± 701.23 gram). There was a strong

negative correlation between KIR2DL1 expression

and birth weight (p <0.001, r=-0.770)

Figure 3: Birth weight is inversely related to KIR2DL1

expression in preeclampsia.

The mean value of placental weight for the

whole 35 samples was 427.14 ± 94.11 gram. A

higher placental weight was found in LO-PE group.

There was a strong negative correlation between

KIR2DL1 expression and placental weight (p

<0.001, r=-0.628)

Figure 4: Strong negative correlation between KIR2DL

expression and placental weight (p <0.001, r=-0.628).

4 DISCUSSION

The main pathological features of EO-PE are

incomplete transformation of spiral artery, which

impairs placental perfusion that results in inadequate

nutrition supply to the fetus. While in LO-PE, there

is a minimal or no failure in spiral artery

remodelling. (Gathiram and Moodley, 2016)

Difference in the main pathology is the cause of

different expression of KIR2DL1 in both early and

late preeclampsia group. KIR2DL1 expression is

also found in T cells, and this might contribute to

high expression of KIR2DL1.

During day 6-7 after fertilization, embryo will be

implanted at the wall of uterus. There are three steps

of implantation, which are apposition, adhesion and

invasion. Invasion of cytotrophoblast into the

vascular system is an important step in spiral artery

remodelling. Failure of spiral artery remodelling is

not a ‘yes’ or ‘no’ phenomenon. Severe failure leads

to preeclampsia with an earlier onset. If moderate or

minimal remodelling happens, the pregnancy will

continue until term, and it is manifested as late

preeclampsia. (Redman, Sargent and Staff, 2014)

Spiral artery remodelling involves invasion of

spiral artery endothelium and smooth muscle by

fetal trophoblast cells. (Whitley and Cartwright,

2010) Uterine NK Cells produces cytokines and

angiogenic factors that facilitate trophoblast

invasion. Secretion of these factors are lowered in

the presence of inhibitory AA haplotype KIR such

as KIR2DL1 (Redman, Sargent and Staff, 2014). We

found that inhibitory KIR2DL1 will lower the birth

weight.

Decidual Killer Immunoglobulin-Like Receptor (KIR)2DL1 Expression and the Onset of Preeclampsia, Birth Weight and Placental Weight

in Early and Late Onset Preeclampsia

323

Spiral artery provides nutrition and oxygenation

that is essential for fetal growth. Failure in spiral

artery remodelling damages uteroplacental perfusion

and thus effecting fetal growth.

One of the angiogenic factors secreted by uNK

cells are the Placental Growth Factor (PlGF), which

is a member of Vascular Endothelial Growth Factor

(VEGF). The function of PlGF is to aggravate the

growth and maturation of placental vascular system,

and also increase trophoblast proloferation. But in

the condition where inhibition signal is dominant,

PlGF production will be low and this will affect

placental growth. (Chau, Hennessy and Makris,

2017)

5 CONCLUSION

Higher expression of decidual KIR2DL1, earlier

onset of preeclampsia, low birth weight and low

placental weight found in EO-PE is consistent with

current concept of different pathophysiologic

pathway, leading to these different PE phenotypes.

ACKNOWLEDGEMENTS

We would like to thank the laboratory staff from

Anatomic Pathology Laboratory of Faculty of

Medicine Universitas Airlangga and Physiology

Laboratory of Brawijaya University Malang for their

assistance in completing this study.

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