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8/10/2019 Placental Apoptosis in Recurrent Pregnancy Loss
that is epressed on %oth immune and nonimmune cell types 1=I0 Fas .hen %ound %y Fas7 activates a signal
transduction path.ay that eventually results in cell apoptosis0
Fas 5D@=8 is a cell surface protein %elonging to the CF receptor family0 ross-lin/ing of Fas .ith its
natural ligand 5Fas7; D@=78 induces apoptosis of Fas-%earing cells 5Cagata and *oldstein, 1@@=80 Fas and
Fas7 m4CAs are .idely epressed in several immune and non-immune tissues 5French et al., 1@@>80 and
$ lymphocytes %ecome activated .hen their receptors %ind foreign antigens0 his activation induces Fas
epression .hich delivers an apoptotic signal to the cell .hen %ound %y its ligand, allo.s disposal of
lymphocytes and suppresses the immune response 5Jau, 1@@=; #cott et al.,1@@>80 Fas7 epression in the
immune-privileged tissues has %een proposed as inducing apoptosis of the target cells, the activated Fas-
epressing lymphocytes, providing a po.erful mechanism to do.n-regulate a deleterious immune response
5#treilein, 1@@=; Jau, 1@@=80 Ee postulate that a similar mechanism mediated %y FasKFas7 interaction may
play a role in the protection of the semi-allogeneic fetus from maternal immune attac/ and may ma/e a
critical contri%ution to the immune-privileged environment of the placenta0
p53, a negative cell cycle regulator, is important in numerous biological processes, such as the cell cycle, DNA repair,
differentiation and apoptosis (7). p53 has been observed to be expressed abnormally in the chorionic villi and decidua
of females with hydropic, spontaneous or missed abortions; however, the expression of p53 in the chorionic villi from
patients with URSA has, to the best of our knowledge, yet to be investigated (8-10).
As cells undergo apoptosis, macrophages present at the maternal-fetal interface uic/ly remove apoptotic
cells %y phagocytosis to promote tropho%last survival and facilitate invasion and transformation of the spiral
arteries0 n placentas from complicated pregnancies, shallo. tropho%last invasion and inefficient spiral artery
transformation have %een o%served, .hich may %e partly due to the distri%ution and activation state of
infiltrating macrophages0
10 #hang E, #hu MM, 7iu M, Eang AM, 7v 7$, Lhao , 7i M, an 70 !levated epressions of p=', D&CA1,
and $a in placental villi from patients .ith recurrent spontaneous a%ortion0 !ur 4ev Med 6harmacol
#ci0 "91';15"+8''>-290
"0 #un , Lhang , ang 7, Eang #, 6iao H7, ao , Lhu 4, Du M4 , 7i DN0 hemo/ine 7"2
induces apoptosis of decidual stromal cells via %inding 4':419 in human spontaneous a%ortion0 Mol
Hum 4eprod0 "91';1@5198>>-2>0'0 4ull &, om%erg &, &O/s #, MPnni/ N, MQls M, #irot/ina M, JPrv #, 7aan M0 ncreased placental epression
and maternal serum levels of apoptosis-inducing 4A7 in recurrent miscarriage0 6lacenta0 "91';'+5"81+1-20+0 inar (, &ara F, an A0 6otential role of decidual apoptosis in the pathogenesis of miscarriages0 *ynecol
!valuation of FA# and caspase-' in the endometrial tissue of patients .ith idiopathic infertility and recurrent
pregnancy loss0 !ur N (%stet *ynecol 4eprod $iol0 "91';1>518+-="0>0 Eei D, Eu R, #hi H0 Apoptosis and p=' epression in the placental villi of females .ith
uneplained recurrent spontaneous a%ortion0 !p her Med0 "91+;5181@1-1@+0
0 Mayhe. M0 Jillous tropho%last of human placenta a coherent vie. of its turnover, repair and contri%utions
to villous development and maturation0 Histol Histopathol0 "991; 1>1"1'K1""+0
20 Uc/an D, #teele A, herry, Eang $, hamizo E, &outsoni/olis A, *il%ert-$arness !, *ood 4A0ropho%lasts epress Fas ligand a proposed mechanism for immune privilege in placenta and maternal
syncytiotropho%last in human term placentas complicated %y either preeclampsia or intrauterine gro.th
retardation0 Am J Obstet Gynecol 0 "99"; 12>1=2K1>>
110 roc/er 6, ooper #, (ng # , $a/er 6 C0 Differences in apoptotic suscepti%ility of cytotropho%lasts and
syncytiotropho%lasts in normal pregnancy to those complicated .ith preeclampsia and intrauterine gro.th
restriction0 Am J Pathol 0 "99'; 1>">'K>+'1"0 #chimmer A D, Hedley D E, 6enn 7 L, Minden M D0 4eceptor- and mitochondrial-mediated apoptosis in
acute leu/emia a translational vie.0 $lood0 "991; @2 '=+1-'=='1'0 Mer/is , ristofolini A, #anchis !, &oncurat M0 !pression of death cellular receptors FA#:D@= and D4+
during porcine placentation0 nt0 N0 Morphol0, "919; "25'82"@-2'+01+0 $rQ/er 7 !, &ruyt F A !, *iaccone *0 ell Death ndependent of aspases A 4evie.0 Clin Cancer Res.
"99=;11'1==-'1>"0
1=0 #trasze.s/i-havez # 7, A%rahams J M J, and Mor *0 he 4ole of Apoptosis in the 4egulation of
ropho%last #urvival and Differentiation during 6regnancy0 !ndocrine 4evie.s, "99=;">582K 2@
1>0 #harp AC, Heazell A!6, roc/er 6, and Mor *0 6lacental Apoptosis in Health and Disease0 Am N 4eprod
mmunol0 "919; >+5'8 1=@K1>@
10 Atia A and Mohamed A%d !lzaher M0 Catural /iller cells, Macrophages and nflammatory hemo/ines in
Decidual macrophages 5DM8 are the second most prominent cells in the maternal-fetal interfaceafter the C& cells0 hey produce more cyto/ines as part of their primary role as antigen presenting
cells1+71*0 Macrophages are involved in mediating %oth normal and a%normal placentation as .ell as
in modulating the placental response to infection via regulating -cell activities0 Additionally,
macrophages accumulate near the etravillous tropho%lasts, phagocytose the apoptotic decidual
cells and enhance the etravillous tropho%lasts invasion0 Ho.ever, increased num%er of
macrophages and the associated a%errant apoptosis could adverse the pregnancy outcomes1371,71)0
t is currently %elieved that many adverse pregnancy outcomes are referred to several
pathological conditions0 ndeed, placental:decidual apoptosis has the potential to illuminate many
aspects of these conditions0 #o, .e aim to study the apoptotic changes of these cells in relation to
4670
!aterials and !ethods
Patients
his prospective study .as conducted on +9 .omen .ith 467 5study group8 and another '9
.omen .ith spontaneous miscarriage 5control group80 #amples have %een collected from the
(%stetrics and *ynecology departments, at #alman %in A%dulaziz University Hospital and &ing
&halid Hospital, Al-&harS, &#A0 he study protocol .as approved %y the Hospital !thics
ommittee0 Eritten informed consent .as o%tained from all .omen prior to enrollment in the
study0
Placental specimens 8rom medically terminated normal pregnancies at ,9( 6eeks7 6ith noconcurrent medical illness7 history o8 a"ortions or smoking/alcohol ha"its 6ere included as
age-matched controls n ; %+2' Patient data included gestational age7 gra0idity7 parity as 6ell
as a"ortion and o"stetrics history
his prospective study .as conducted %et.een Nune "911 to August "91', at the (%stetrics and
*ynecology department, at the #alman $in A%dulaziz University Hospital and &ing &halid Hospital, Al-
&harS, &#A0 he study protocol .as approved %y Hospital !thics ommittee0 Eritten informed consent .as
o%tained from all .omen prior to enrollment in the study0 Five hundred .omen presented .ith spontaneous
miscarriage admitted to our hospital during this period, only =9 .omen .ith 467 .ere eligi%le for study
5study group8, another =9 .omen .ith sporadic miscarriages and matched for age for those .ith 467
recruited in the study as control group0
Decidual:placental samples have %een ta/en from all cases %y dilatation and evacuation .ithout any prior
pharmaceutical induction, .ithin the first "+ hours after diagnosis0 All enrolled .omen of the study the
follo.ing data .ere collected motherTs age, parity, %ody mass inde, maternal previous diseases, and family
history0 After that a thorough clinical eamination .as performed, aiming to eclude apart from common
disorders already /no.n as aggravating factors for increased ris/ for miscarriages0 Follo.ing evacuation,
specimens from %oth groups .ere formalin-fied and paraffin-em%edded for further staining0
Tissue Samples
Decidual:placental samples have %een ta/en from all cases %y dilatation and evacuation .ithout
any prior pharmaceutical induction, .ithin the first "+ hours after diagnosis0 All .omen enrolled in
this study the follo.ing data .ere collected motherTs age, parity, %ody mass inde, maternal
previous diseases, and family history0 After that a thorough clinical eamination .as performed,
aiming to eclude apart from common disorders already /no.n as aggravating factors for increased
ris/ for miscarriages0 Follo.ing evacuation, specimens from %oth groups .ere formalin-fied and
paraffin-em%edded for further staining0
8/10/2019 Placental Apoptosis in Recurrent Pregnancy Loss
Macrophages have a .ide dynamic plasticity; their response to eternal stimuli is varia%le and
can produce M1 or M" phenotypes0 M1-phenotype is proinflammatory and activated %y interferon-_; .hile M"-phenotypeis anti-inflammatory alternatively activated %y 71' or 7+%*0 M1 and M"
activated macrophages perform different functions; M" phenotype can %e anticipated during
normally developing pregnancy; .hile, the M1-su%type could %e a part of mechanism causing
pregnancy failure%30
hemo/ines and chemo/ine receptors are involved in materno-fetal immune regulations,
macrophage migration and angiogenesis%,0 (ur result noticed an epression of chemo/ines
X71" and 7' in decidual tissues of %oth study groups0 Ehere, the cell population and the
optical density of the immunopositive cells sho.ed no significant difference among %oth groups0
his result .as indicated %y 6ar/ et al1, as he had noticed that the immunopositive cell populations
and the intensity of X71" and 7' reactivity in decidual tissues .ere not correlated to the
num%er of dC& D=>B cells0 Ho.ever, other investigators indicated that invasive tropho%last cells
have the a%ility to produce the chemo/ines 7', 71+, and X71"%); .here their
corresponding receptors are found on the decidual macrophages and C&-cells0 his in turn
indicated that the epression of these chemo/ines %y tropho%last cells plays an important role in the
recruitment of specific leu/ocytes to the decidua&(7&10 herefore, from this result and others& .e
have speculated that epression of these chemo/ines regulate leu/ocytes migration to the site of
implantation regardless the pregnancy complications0
In conclusion, decidual C& cell and macrophages play a crucial role in normal pregnancy
continuation, .hile increasing level of these cells could affect the pregnancy outcome0 n contrast
the decidual chemo/ines epression seems to %e correlated directly to recruitment of leu/ocytes to
the site of implantation regardless the pregnancy outcome or the pathophysiology of the pregnancy
itself0 Additionally, further studies are needed to investigate other possi%le causes of 467 such as
chromosomal aneuploidy as .ell as epression of apoptotic mar/ers in decidual tissues0
8/10/2019 Placental Apoptosis in Recurrent Pregnancy Loss