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Review
Interplay of immune components and their association with recurrent
pregnancy loss
Raazia Tasadduq
a,
⇑
, Laiba Ajmal
a
, Farhat Batool
a
, Tehniyat Zafar
a
, Aleena Babar
a
, Amna Riasat
a
,
Abdul-Rauf Shakoori
b
a
Department of Biochemistry, Kinnaird College for Women, 93 Jail Road, G.O.R-1, Lahore, Pakistan
b
School of Biological Sciences, University of the Punjab, Lahore, Pakistan
article info
Article history:
Received 2 September 2020
Revised 18 January 2021
Accepted 21 January 2021
Available online 10 February 2021
Keywords:
Miscarriage
Antibodies
Immune System
Recurrent Pregnancy Loss
abstract
Maintenance and progression of pregnancy is an intricate process governed by a variety of developmental
cues. Recurrent pregnancy loss (RPL) is a complication experienced by expecting mothers that is defined
as three or more consecutive pregnancy losses. This review focuses on the dysfunctions of the immune
system as one of the key contributors towards RPL. The current data suggests that the alloimmune and
autoimmune factors contribute to the loss of fetus. Such causes despite being recognized as a definitive
reason for recurrent pregnancy loss, are still under extensive investigation with new parameters being
discovered and scrutinized for their association with RPLs. More in-depth and high throughput studies
are required for devising better diagnostic tools and management strategies for the affected female so
that they can carry their pregnancy to term.
Ó2021 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights
reserved.
Contents
1. Introduction . . . ...................................................................................................... 163
2. Discussion. . . . . ...................................................................................................... 163
2.1. Antiphospholipid syndrome and its association with RPL . . . . . . . . . ................................... ................... 163
2.2. Anticardiolipin antibody and recurrent pregnancy loss . . . . . . . . . . . ................................................ ...... 163
2.2.1. Thrombosis in uteroplacental interface. . . . . . . . . . . . ........................................................... 163
2.2.2. Raised ACA may lead to maternal acute atherosis . . . ........................................................... 164
2.3. Association of antinuclear antibodies and recurrent pregnancy loss . ...................................................... 164
2.3.1. ANA halts implantation by cross reacting with laminins. . . . . . . . . . . . . . . . . ........................................ 164
2.4. Anti-thyroid antibodies. . .......................................... ............................................... 164
2.4.1. Thyroid dependent mechanism . . . . . . . . . . . . . . . . . . ........................................................... 164
2.4.2. Thyroid independent mechanism . . . . . . . . . . . . . . . . ........................................................... 165
2.5. The role of natural killer cells in RPL . . . . . . . .... ..................................................................... 165
2.5.1. Activation of natural killer cells due to allorecognition patterns of HLA-C and killer immunoglobin like receptors (KIR) ..... 165
2.6. Cell mediated immunity and RPL . . . . . . . . . . ....................... .................................................. 166
2.6.1. Role of CD8
+
T cells in RPL. . . .............................................................................. 166
2.7. Male specific minor histocompatibility antigens and recurrent pregnancy loss . . . . . . . . . . . ................................... 166
https://doi.org/10.1016/j.humimm.2021.01.013
0198-8859/Ó2021 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.
Abbreviations: ACA, Anticardiolipin Antibodies; ANA, Antinuclear Antibodies; APA, Antiphospholipid Antibodies; APS, Antiphospholipid Syndrome; CTL-4, Cytotoxic T-
Lymphocyte Associated Protein 4; ECM, Extracellular Matrix; hCG, Human Chorionic Gonadotropin; HLA, Human Leukocyte Antigen; LAC, Lupus Anticoagulant; PB NK,
Peripheral Blood Natural Killer; PD-1, Programmed Death-1; RPL, Recurrent Pregnancy Loss; SLE, Systemic Lupus Erythematosus; SRM, Secondary RM; TAI, Thyroid
autoimmunity; TCTL, Cytotoxic T Lymphocyte; Tg, Thyroglobulin; TgAb, Thyroglobulin Antibody; Tim-3, T cell immunoglobulin and mucin domain 3; TPO, Thyroperoxidase;
TPOAb, Thyroid Peroxidase Antibody; TRAbs, Thyroid Receptor Antibody; TSH, Thyroid Stimulating Hormone; uNK, Uterine Natural Killer.
⇑
Corresponding author.
E-mail address: raazia.tasadduq@kinnaird.edu.pk (R. Tasadduq).
Human Immunology 82 (2021) 162–169
Contents lists available at ScienceDirect
www.ashi-hla.org
journal homepage: www.elsevier.com/locate/humimm
3. Conclusion . . . . ...................................................................................................... 167
Declaration of Competing Interest . . . . ................................................................................... 167
Acknowledgement . . . . . . . . . . . . . . . . . ................................................................................... 167
References . . . . ...................................................................................................... 167
1. Introduction
Miscarriages are one of the most significant complications
experienced by pregnant women and are associated with psycho-
logical and physical repercussions. It has been reported that about
10–20% of clinically confirmed pregnancies result in miscarriages
[1-3]. Recurrent pregnancy loss (RPL) is described as a condition
characterized by minimum of three failed pregnancies in a succes-
sion prior to 20 weeks of pregnancy.
Women with a history of 2 miscarriages have a 30% greater risk
of suffering from another miscarriage and this risk additionally
increases to 33% after 3 consecutive pregnancy losses. Despite this
number, studies have reported that only 1%2% of expecting
women suffer from three or more repetitive pregnancy losses
while 5% of expecting couples can experience two losses consecu-
tively [1,4]. After repetitive miscarriages, the chances further
increase, and the prognosis worsens with increasing age of the
mother [5]. Several possible etiologies exist for spontaneous loss
of pregnancies including untreated hypothyroidism, parental chro-
mosomal abnormalities, uterine anatomic abnormalities, and cer-
tain autoimmune disorders. Moreover, endocrine abnormalities,
thrombophilia, infections, immunologic abnormalities, and certain
environmental factors have also been linked with RPL. Among
these, genetic factors are reported to be the main contributing fac-
tor towards RPL, accounting for 2 to 5% of all the recurrent preg-
nancy losses [1]. In some couples, the RPL can be managed,
however, about 50% of RPL couples have no clinically defined clear
etiology [6].
Since the fetus is not genetically identical to the mother, certain
immunologic events must occur that allow the mother to carry the
fetus to full term resulting in successful pregnancies. Considering
pregnancy from this perspective, perturbations of the immunolog-
ical mechanisms could lead to RPL. Decreased maternal immune
tolerance towards the fetus may lead to such recurrent pregnancy
losses. Alloimmune and autoimmune factors have been reported to
contribute towards the immune related etiology of the RPL [2].
Hence, in this review we have highlighted the paradigms by which
the immune system may potentiate the occurrence of RPL. Further
exploration of the alloimmune and autoimmune mechanisms may
provide a way for better management of pregnancy for couples
experiencing RPL.
2. Discussion
2.1. Antiphospholipid syndrome and its association with RPL
The presence of high levels of plasma IgM or IgG class anticar-
diolipin antibodies (ACA), antib2glycoprotein 1 antibodies or lupus
anticoagulant (LAC) in women has been associated with RPL and
arterial/venous thrombosis. This clinical condition has been
described as antiphospholipid syndrome (APS), the clinical mark-
ers for which are antiphospholipid antibodies (APA), ACA and
LAC [7,8]. APA has been reported to be present in about 15% of
women with RPL and target negatively charged phospholipids
[9]. Women with APS have decreased platelet count and increased
chances of developing preeclampsia [10]. APS is thought to be trig-
gered by surgery, oxidative stress, trauma, infections and tissue
damage. APS may also occur due to other secondary autoimmune
disorder most commonly the systemic lupus erythematosus (SLE)
It can also be acquired due to RPL in women who do not have his-
tory of APS. The women who have been clinically diagnosed with
APS experience recurrent blood clots, thrombosis, and other APS
manifestations [11-13].
The APS antibodies cause trophoblastic apoptosis, uncontrolled
immunomodulatory responses, restricted intrauterine growth,
proinflammatory reactions, abnormal spiral arteries formation,
strokes, thrombocytopenia and targeting of vascular endothelium.
Women diagnosed with APS have diverse pregnancy outcomes
depending upon the clinical APS phenotype i.e., either thrombotic
or obstetric, with thrombotic APS resulting in severe complications
such as preeclampsia [11-13].
The presence of APS related antibodies such as APA, ACA, and
LAC, causes placental thrombosis and infarction and as a result,
leads to fetal loss during pregnancy. The autoantibodies interact
with phosphatidylserine exposed during trophoblast formation
affecting the placental structures (Fig. 1). Moreover, these are
linked with an increased cyclooxygenase activity in platelets that
synthesize thromboxane A2, causing thrombosis of placental vas-
culature and neonatal thrombotic complications such as hyper
coagulant state through platelet aggregation that results in fetal
death [7-9,11,14]. Studies have also shown that the affected
patients have low levels of prostacyclins, an inhibitor of platelet
activation and protein C that inactivates clotting process [7-
9,11,14]. Women with RPL are known to have increased throm-
boembolism [15]. Fetal death in APS also occurs due to inference
in spiral artery modeling during trophoblast formation [8].
2.2. Anticardiolipin antibody and recurrent pregnancy loss
Cardiolipin is a membrane-bound lipid that functions as an
anticoagulant in the body by prolonging clotting time of the blood.
However, autoimmune diseases like APS and SLE may lead to
abnormal production of antibodies against body’s own cardiolipin.
SLE is also an autoimmune disorder and it may lead to RPL and
other pregnancy complications by raised serum antibodies [16].
In patients suffering from SLE, increased LAC also causes blood
coagulation in arteries and blood vessels. Studies have been
attempted to identify the correlation between increased ACA and
LAC that causes thrombosis in placental tissues causing fetal loss
(Fig. 1). According to these studies, 12%–30% of females with RPL
have ACA and 15%–34% have LAC. In patients with SLE having
APA, 38% have both ACA and LAC [16,17]. This correlation is signif-
icant because ACA and LAC are the overlapping subsets of
antiphospholipid antibodies.
2.2.1. Thrombosis in uteroplacental interface
The increased rate of RPL in APS is significantly associated with
higher amounts of IgG anticardiolipin antibody whereas IgA and
IgM does not play much role [18]. Contrary to this, some studies
showed that elevated levels of both ACA IgG and IgM are positively
associated with RPL [19] while others confer that only IgM and not
IgG is associated with RPL [20]. Increased IgG initiates an autoim-
mune response in the uteroplacental interface leading to necrosis
in placental tissues by placental infarction. ACA causes membranes
to rupture and start coagulative necrosis. As a result, the fetus does
not get adequate blood supply through the placental vessels, and
pregnancy aborts [18,21].
R. Tasadduq, L. Ajmal, F. Batool et al. Human Immunology 82 (2021) 162–169
163
2.2.2. Raised ACA may lead to maternal acute atherosis
Acute atherosis of the maternal uteroplacental surface is char-
acterized by formation of lesions in the spiral arteries leading to
infarction of placental parenchyma. The lesions formed in such a
condition resemble early-stage atherosclerosis [22]. A study con-
ducted by Staff et al., devised quantitative methods for diagnosing
decidual acute atherosis in pregnant females and predicted that
such females are at a higher risk of developing atherosclerotic arte-
rial diseases in later stages of life [22]. In another study, it was pro-
posed that immunological incompatibility between mother and
fetus, such as fetal HLA-C antigen and maternal NK cells, may also
induce acute atherosis [23].
This is similar to acute tissue rejection in patients with trans-
planted organs. Generally, in APS patients, ACA targets renal, car-
diac, hepatic and other membranes of body. However, in females
suffering from APS during pregnancy, increased levels of ACA can
target placental villi during first trimester. This may eventually
result in decidual vasculopathy by acute atherosis (placental tissue
rejection). This vasculopathy is characterized by fibrinoid necrosis
of the vessel wall, an immune mediated uncontrolled cell death
where antigen–antibody complexes get deposited in blood vessels
along with fibrin. Additionally, granular deposition of antibodies
against cardiolipin, mainly IgG within the vessel walls may be a
histopathological hallmark of a maternal immunological reaction
against fetal tissues [24,25].
2.3. Association of antinuclear antibodies and recurrent pregnancy loss
Antinuclear antibodies (ANA) belong to a set of autoimmune
antibodies that target the cytoplasmic and nuclear antigens pre-
sent in all nucleated cells. Presence of ANA is a prominent feature
of various autoimmune disorders and is widely used as diagnostic
serologic markers to detect immunological diseases including
autoimmune RPL especially in women who are asymptomatic for
any other autoimmune disease [26,27].
2.3.1. ANA halts implantation by cross reacting with laminins
Uterus undergoes several morphological changes throughout
pregnancy during which laminins (LN), collagen and other pro-
teins, play an essential role in implantation of fertilized ovum into
the extracellular matrix (ECM) of uterus. After fertilization, the
decidual cells of endometrium initiate synthesis of laminins. As
the trophoblast stage of embryo approaches, these laminins are
deposited in ECM [28]. The most common laminin found in attach-
ment process is LN1. Migration and attachment of ovum to ECM is
aided by laminins, collagens (I, II, III, IV), entacins and fibronectins.
However, higher levels of ANA hinder the formation of trophoblast
cells by cross reacting with laminins. As a result, the fertilized egg
is not properly implanted and pregnancy aborts (Fig. 2)[29].
This condition is common in pregnant females suffering from
SLE as is associated with reduced fetal survival, recurrent fetal loss,
and other pregnancy complications. It was reported that tro-
phoblast cells migrated from cultured chorionic villous explants
of 6–7 weeks old placenta when levels of LN1 were increased.
However, this migration was abolished on exposing the explants
to anti DNA antibodies [29]. Major differences in ANA serum pos-
itivity, titer, and pattern have been observed among women with
and without RPL. The amount of ANA was found be threefold
higher in the RPL group than in the control group [27].
2.4. Anti-thyroid antibodies
Thyroid autoimmunity (TAI) is a condition characterized by
presence of autoantibodies, thyroid peroxidase antibody (TPOAb),
thyroglobulin antibody (TgAb) and thyroid receptors antibodies
(TRAbs). Various studies have reported the increased incidence of
RPL among females who were positive for anti-thyroid antibodies
[30-34]. Loss of fetus due to the presence of thyroid antibodies
can be explained by two mechanisms: thyroid-dependent manner
or thyroid independent mechanism.
2.4.1. Thyroid dependent mechanism
For progression and maintenance of pregnancy, an increase in
the production of thyroid hormone is required. Females who expe-
rience TAI cannot usually achieve heightened thyroid hormonal
levels owing to the presence of these antibodies. This condition,
if left untreated, may ultimately lead to pregnancy loss [35,36].
TPOAb has been found to exert cytotoxic effect on the thyroid
gland and causes hypothyroidism, thyroid destruction, and infiltra-
tion. TPO-Ab is associated with increased rate of complications
such as miscarriage, placental abruption, and pregnancy-induced
hypertension [37]. Abnormal elevation of TRAbs effects functioning
of thyroid in both the mother and fetus because these antibodies
can freely cross the placental barrier [37].
Fig. 1. Association of APS and ACA with RPL.
R. Tasadduq, L. Ajmal, F. Batool et al. Human Immunology 82 (2021) 162–169
164
2.4.2. Thyroid independent mechanism
Anti-thyroid antibodies may influence the outcome of preg-
nancy without the involvement of thyroid gland. Some tissues dis-
play antigens having similarity to the thyroid tissue including zona
pellucida, human chorionic gonadotropin receptors and placenta
[38]. Anti-thyroid antibodies can target extra-thyroid tissues
exhibiting cross-reactive antigens and thus affect fertility and
pregnancy outcomes [38].
hCG and TSH exhibit cross-reactivity with each other’s recep-
tors. Autoantibodies to TSH receptors have been reported to target
hCG receptors present on corpus luteum resulting in a decline of
activity of corpus luteum. Corpus luteum produce estrogen and
progesterone that are required for progression of pregnancy in first
12 weeks. Without an active corpus luteum, progesterone and
estrogen level could not be maintained at required level, thus
affecting the maintenance of pregnancy [39,40].
TSH levels are elevated in the presence of thyroid autoantibod-
ies. TSH exert stimulatory effect on the activity of NK cells (PB NK)
thus increasing their proliferation and cytotoxic activity [42,43].
Thyroid autoantibodies have been reported to cause dysfunction
of T cells of endometrium influencing the cytokines that negatively
affect the outcome of pregnancy [41]. Moreover, increased activa-
tion of polyclonal B cells has been documented in females experi-
encing thyroid autoimmunity. This is associated with an increase
in titer of no-organ specific antibodies that may affect placental
function and hence, pregnancy outcome [32,44].
2.5. The role of natural killer cells in RPL
Natural killer cells (NK cells) have been described as granular
lymphocytes with cytotoxicity against tumor cells [45]. These were
originally identified as having the ability to lyse target cells with-
out priming and were not restricted by target cell expression of
MHC 1 molecules [46]. However, it has been now established that
NK cells can engage MHC class 1, MHC class 1 like molecules and
molecules not related to MHC via its various receptors. Hence,
NK cells are not restricted to the type of target cells that they rec-
ognize [47]. NK cells have been identified by various cell surface
markers such as CD16 and CD56 [48]. In women suffering from
RPL, the expression of CD69 has been found to be significantly
higher on NK cells and the expression of CD94/NKG2 inhibitory
receptor is decreased [49].
NK cells are found in the peripheral blood (PB NK cells) and are
also found to be associated with the human endometrium (uNK
cells) during implantation and play key role in placental develop-
ment and implantation [50]. NK cells increase during late secretory
phase and the first trimester of pregnancy [51]. In non-pregnant
females, the NK cells reside in the uterine lining under hormonal
influence. During placental formation, these cells dominate the
uterine wall. uNK cells assemble at the implantation site in close
contact with the trophoblast cells, aiding in transformation of spi-
ral arteries into conductance vessels required for blood supply to
the fetus. These cells also aid in implantation by promoting tro-
phoblast incursion [52]. It is well established that PB NK cells have
potent cytotoxic activity and have been associated with improper
implantation and subsequent miscarriage [53].
Overproduction and increased cellular activity of NK cells has
been documented in women with unexplained RPL [54]. In cer-
tain situations, like RPL, the pelvic region becomes inflamed or
the endometrial lining is damaged. This triggers the immune sys-
tem that acts by deploying PB NK cells to the site of inflammation.
The uNK cells fail to protect the subsequent pregnancy as PB NK
cells mount the immune response. This results in maternal
immune rejection of the conceptus [55]. In a study, murine
embryos were treated with supernatants prepared from the differ-
ent type of white cell populations which were trophoblast acti-
vated. It was found that the cellular preparation enriched for T
cells or NK cell inhibited murine blastocyst development. Thus,
in females experiencing RPL, the production of cytokines by PB
NK cells and T cells may adversely affect blastocyst [56].
2.5.1. Activation of natural killer cells due to allorecognition patterns
of HLA-C and killer immunoglobin like receptors (KIR)
Uterine natural killer cells have been implicated in develop-
mental roles at the maternal-fetus interface. KIR of NK cells inter-
act with HLA class I gene products that might result in varied NK
cell mediated immunity against pathogens and hence this relation
is believed to be an important aspect of RPL. An increased existence
Fig. 2. Antinuclear Antibodies Cross React with Laminins leading to fetal loss.
R. Tasadduq, L. Ajmal, F. Batool et al. Human Immunology 82 (2021) 162–169
165
of HLA-C with 2DS2, (KIR gene haplotype) has been seen in North
Indian RPL patients that is considered as a top-end of activation
spectrum of NK cells. The RPL patients have been found to have a
decreased content of inhibiting KIR2DL1-HLA-C2 combination. It
is believed that KIR-HLA compound genotype can result in overac-
tivation of NK cells contributing to the generation of cytokine
milieu against fetal trophoblast cells. As a result, the occurrence
of HLA-C2 in the presence of maternal KIR2DL1 is closely associ-
ated with inhibition of NK cell towards the fetal trophoblast. The
occurrence of 2DS2 in combination with HLA-C1 in RPL is strongly
associated with NK cell activation and as result has been hypothe-
sized to be a significant element of the pathogenesis of RPL [57].
2.6. Cell mediated immunity and RPL
During pregnancy, cell mediated immune response against the
trophoblast cells is suppressed and failure of this normal suppres-
sion can lead towards unexplained RPL. Peripheral blood mononu-
clear cells (PBMC) of women having RPL respond to trophoblast by
proliferating and releasing embryotoxic factors that adversely
affect the embryo. In addition, the PBMC of such women has been
observed to release TNFs and INFs against the trophoblast cells
[56,58].
2.6.1. Role of CD8
+
T cells in RPL
Pregnancy loss in women with a history of RPL have been asso-
ciated with increased expression of CD16 that is responsible for
antibody dependent cytotoxicity against the fetus. CD8 suppressor
T cells are responsible for suppression of maternal immune
response against the fetus whereas B lymphocytes secrete antibod-
ies at the fetoplacental interface. Decidual CD8
+
T cells are consid-
ered to be the largest proportion of the decidual T cells [59].
Decreased population of CD8 (suppressor) T cells and increased
population of B lymphocytes has been observed in women with
RPL leading to a dysfunctional pregnancy state [60]. Decreased pro-
portion of CD8 cells suggests that suppressor T cells might possibly
play a role in acceptance of the fetus by preventing the maternal
immune system from rejecting it [60]. Depletion of CD8 cells
increased both spontaneous pregnancy loss and revoked protection
by cytokines. These findings indicate that the lymphocytes gener-
ate ‘suppressor’ cytokines in presence of trophoblast and that have
been found to be decreased and linked to embryotoxicity in recur-
rent aborters. Moreover, murine decidual CD8 + lymphocytes are
associated directly and indirectly with prevention of spontaneous
fetal loss even though the precise nature of such cells in humans
still remain unclear [60].
Decidual CD8
+
T cells increase extravillous trophoblast cells’
invasive capacity and the secretory products of the CD8
+
T cells
might affect the regulation of trophoblast invasion. However, no
specific mediators have yet been recognized [61]. It has been
believed for many years that CD8
+
memory cells exist in the
decidua [62]. Mounting evidence on the involvement of CD8
+
effec-
tor memory cells (EM) in immune tolerance towards the fetus has
been documented and although the proportion of the cells in blood
of pregnant woman was not different from non-pregnant females,
higher proportion of EM cells has been recorded in the peripheral
blood of postpartum women in comparison to women who have
never carried [63-66]. In addition to the quantitative variations,
alterations in functions of the CD8
+
EM cells in the decidua and
the peripheral blood have been reported. These include the
increased expression of the inhibitory checkpoint receptors pro-
grammed death-1 (PD-1) and T cell immunoglobulin and mucin
domain 3 (Tim-3) [64,67]. The increased expression of these pro-
teins on the decidual CD8
+
T cells might be the effect of interaction
with the trophoblast. This has been supported by the study in
which CD8
+
T cells that were co-cultured with trophoblast were
observed to have upregulate PD-1 and Tim-3 [68]. In addition,
genes involved in inhibitory receptors, chemotaxis and T regula-
tory cell differentiation were found higher in the CD8
+
EM cells
in the decidua than the peripheral blood [64]. These different char-
acteristic of the decidual and peripheral blood in relation to the
CD8
+
EM cells might be a contributing factor towards immune tol-
erance at the fetal maternal interface.
Tim-3 and cytotoxic T-lymphocyte associated protein 4 (CTL-4)
are two specific co-inhibitory molecules that regulate the CD8
+
T
cells response during tumor and infections. The expression of
Tim-3 and CTL-4 on CD8
+
T cells is found to be higher during preg-
nancy in response to trophoblasts. This co-expression of the inhibi-
tory molecules produced increased milieu of anti-inflammatory
cytokines. Moreover, the decreased expression of Tim-3 and CTL-
4 on the CD8
+
T cells was corelated to the increased incidence of
miscarriages irrespective of the number of CD8
+
T cells. Similarly,
blocking of these two resulted in decreased production of anti-
inflammatory cytokines having adverse effect on pregnancy lead-
ing to fetal loss. Hence this suggests the CD8
+
T cells having the
Tim-3 and CTL-4 expression prevent immune rejection of the fetus.
In addition, the women with decreased expression of Tim-3 and
CTL-4 pathways have more production of TNF-
a
and INF-
c
(pro-
inflammatory) but decreased amount of IL-10, IL-4 (anti-
inflammatory) and TGF-b1[69].
2.6.1.1. Role of T helper (Th) cells in RPL. Normally, the decidual T
cells produces T helper type 2 (Th2) that mediate the pregnancy
progression. Simultaneously, INF
c
acts on CD
4
+
cells and induce
these to differentiate into Th1 cells. The survival of the fetus is at
risk when there is excessive Th1 response, and this is associated
with pathological conditions such as preeclampsia and RPL. It has
been reported that the women who experience implantation fail-
ure or RPL possess predominantly high levels of Th1 in peripheral
blood compared to the normal females [5]. Increased in level of
Th1 related cytokine response is induced not only by trophoblast
antigens but also by the production of antigen-non-specific cytoki-
nes/chemokines [70,71].
IFN
c
mediated activation of decidual macrophages results in
the production of TNF-
a
and NO along with neopterin. Substantial
amount of TNF
a
is also produced by Th1, NK cells and several types
of trophoblasts cells. These signaling mediators induces the apop-
tosis, suppresses the trophoblast growth rate and inhibit the secre-
tion of Granulocyte Macrophage Colony Stimulating Factors, from
the epithelium of the uterus. Thus, leading to pregnancy termina-
tion and toxicity [72,73].
Neopterin acts as a marker of proinflammatory immune
response and is synthesized by macrophages upon stimulation
with IFN
c
. The elevated levels of neopterin in body fluids such as
cerebrospinal food, urine and blood serum activates T helper type
I cells (Th1). Thus, it leads to immunogenic stimulation during
pregnancy that is induced by the fetus as well as the placenta.
The presence of high levels of neopterin is associated with an
increased production of reactive oxygen species which may con-
tribute to RPL [74,75].
During RPL, paternal lymphocytes immunotherapy is suggested
to have a beneficial effect on the provision of nonspecific as well as
specific T cell suppression. The ELISA technique is rarely used for
monitoring the neopterin levels in clinical practice. However, rou-
tine clinical testing for the evaluation of neopterin levels during
pregnancy can contribute to the better prognosis [5].
2.7. Male specific minor histocompatibility antigens and recurrent
pregnancy loss
Male specific minor histocompatibility (HY) antigens also
result in RPL especially secondary recurrent miscarriages (SRM)
R. Tasadduq, L. Ajmal, F. Batool et al. Human Immunology 82 (2021) 162–169
166
that is at least three of the consecutive miscarriages after a still-
birth or live birth. In such condition a female pregnant with a
male fetus usually generates a cellular or humoral immune
response against the HY antigens. Epidemiologic studies on recur-
rent fetal loss showed that birth of a baby boy as compared to a
baby girl prior to miscarriages reduces the chance of the subse-
quent live birth [76,77].
HY antigens in males, encoded by the Y chromosome genes are
expressed in fetal cells including trophoblast fetal cells. Priming of
the immune system of mother against HY antigens harm the sub-
sequent embryos and fetus. The fetal cells cross the placenta and
DNA of the male fetus is detectable in mother’s circulation both
during and after pregnancy and they can persist in the circulation
for about 27 years postpartum. Studies showed that in females HY
specific cytotoxic T lymphocytes (TCTL) were identified in whom
pregnancy was only possible after exposure to male specific minor
histocompatibility HY antigens [78].
The HY antigens, after crossing the placenta, are presented to
the CD8 + TCTL by MHC class I and result in the destruction of cell
to which it is bound. These HY antigens are also presented to T
helper lymphocytes (CD4 + ) by MHC class II on antigen presenting
cells that result in T cell secreting cytokines followed by antibody
formation and the activation of TCTL (Fig. 3).
During pregnancies, the presentation of fetal peptides results in
noninflammatory reactions that result in T lymphocytes to become
tolerant to the fetal peptides [79]. A number of pregnancies that
involve a male fetus prior to the secondary recurrent miscarriage
(SRM) are linked with neonatal and obstetric complications that
are associated with an increased transfer of fetal cells in mother’s
circulatory system and the production of the inflammatory cytoki-
nes that result in SRM [76,79].
3. Conclusion
Existing studies indicate that immune system plays a pivotal
role in maintenance of a healthy and successful pregnancy. It is
crucial to have an in-depth understanding of feto-maternal
immune regulatory mechanisms whose dysfunction may lead to
loss of pregnancy. Current data regarding the interactions of the
cellular and molecular players at the feto-maternal interface can
be translated into diagnostic and therapeutic advances which ulti-
mately lead to better prognosis for the affected female. Immuno-
logical testing in case of females with autoimmune diseases has
been proven to be beneficial and has led to the better management
of pregnancy.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgement
We would like to acknowledge Bio Render that aided in the cre-
ation of the illustrations presented in this review.
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