Introduction
The premature pregnancy failure is acknowledged to affect approximately
15% of all the pregnancies recognized clinically. Recurrent pregnancy
loss (RPL) is defined as ≥2 successive pregnancy failures affecting less
than 5% of human female that belong to the reproductive age category
[1, 2]. Even though the precise cause of nearly 50% of recurrent
pregnancy losses remains unclear, nevertheless maternal immunological
dismissal may perhaps justify the majority of these unexplained cases of
pregnancy loss [2, 3]. Healthy human females having normal
functioning immune system may complete a half-allogenic conceptus to
full tenure without clear refusal by modifying the immune system so as
to accept and tolerate the embryo [4]. Acceptance and tolerance of a
half-allogenic conceptus recommends the role of whole body regulatory
processes in normal pregnant women [5, 6]. The exact devices that
shield the embryo from the maternal immune assault and dismissal are
poorly implicit. However, the genetically incompatible embryo escapes
maternal immune rejection perhaps as a result of communication among
several vital cytokines exuded by maternal and embryonic cells at
embryo-maternal interface [2, 7]. Human female endometrium develops
into decidua receptive for implantation [7] via the hormone and
growth factor driven process known as decidualization wherein
endometrial stromal cells are differentiated into decidual cells that
support growing embryo [8]. The decidual cells facilitate the early
development of blastocyst [8], shields the embryo from maternal
immune cell attack [9], gives dietetic support to the budding embryo
before the formation of the placenta [8, 9] and assist in
parturition[8]. Endometrial decidualization is essential for the
establishment of pregnancy [10]. The process of decidualization
involves the endometrial stromal cell reprogramming which includes the
production of diverse mediators such as cytokines and chemokines, and
selective recruitment of immune cells. This physiologic process involves
alteration in endometrial stromal cell secretome that leads to the
formation of immunomodulatory factors [11]. The trophoblastic cell
stimulation is also vital for the differentiation of endometrial tissue
[7].
The endometrium of human female synthesizes a broad array of cytokines
during the follicular phase and luteal phase of menstrual cycle [12,
13]. These cytokines are assumed crucial for modulating the uterine
atmosphere and making the uterus ready for implantation of the growing
conceptus as well as formation of working placenta during pregnancy. The
embryo-maternal interface and uterine tissues primarily provide a
regulated atmosphere required for avoiding the maternal dismissal of the
embryo. Typically, the naïve CD4+ T cells are the main cytokine
manufacturers and can be classified into various subsets such as Th1,
Th2, Th17 and T regulatory cells. The cytokines produced by T helper
cells are additionally manufactured in excess by various cell types
including trophoblast cells, stromal cells, epithelial cells, maternal T
lymphocytes, macrophages, natural killer (NK) cells and other maternal
leucocytes at the maternal-embryonic interface [12, 14] which
indicates that the development and continuation of the
embryonic-placental module depends on these cytokines (Table 1 & 2).
The cytokines that are present at the interface of maternal-embryonic
unit could have an effect on uterus milieu via the regulation of embryo
implantation, growth of placenta, cytotrophoblast production, blood
vessel formation, extra-villous trophoblast cell invasion, refashioning
of spiral arteries, cell development and apoptosis as well as induction
of embryonic tolerance [12, 64-68]. The success of pregnancy
essentially depends on reciprocal signaling between the mother and
developing blastocyst and decidual receptiveness all through the
implantation window [12, 69].
Cytokines along with cell surface receptors are believed to act as
communication mediators between trophoblastic and decidual cells
[70]. The communication among the cells at maternal-embryonic
interface modifies the expression of the variety and amount of
cytokines. The immune tolerance or immune stimulation may be linked to
the variations in the pattern of T cell cytokines [7]. Earlier the
CD4+ T cells of human beings were categorized into Th1 and Th2 cell
types depending upon their pattern of cytokine production [71].
Later a new subpopulation of CD4+ T cells termed as Th17 cells was
reported that manufacture IL17 [7]. The Th1 type of cells
participate in cellular immunity via producing IL2 and IFNγ whereas Th2
type of cells discharge IL4, IL5 and IL13 and participate in humoral
immunity [22]. Th1 cytokines have been attributed the fatal role as
they are believed fundamental in the rejection of acute allograft via
Th1 dependent effector mechanisms [72, 73]. Conversely, Th2 category
of cytokines appears essential for inducing and upholding the allograft
tolerance [7, 74-76]. Th1 cytokines as well have been reported
necessary for the continuance of pregnancy e.g. IFNγ is known as a key
cytokine involved in remodeling of spiral blood arteries and productive
outcome of pregnancy [12, 77-79]. Moreover, a study on various Th2
type of knockout mouse like IL4, IL5, IL6 and IL13 has shown normal
product of reproduction [12, 80, 81] even if dissimilar systems may
be associated with upholding of the pregnancies in mouse and human
suggesting the insignificance of predominant Th2 immunity in
accomplishment of the pregnancy. In case of abortion, supremacy of Th1
immunity has been reported, however, dominance of Th2 immunity is too
observed in RPL [25, 81-85]. Consequently, an ample equilibrium for
Th1/Th2 immunity with a little inclination toward Th2 kind of immunity
maybe appropriate in maintaining the pregnancy. Hyper stimulation of
either type of immunity i.e., Th1 or Th2 is thought to be destructive
for normal pregnancy [81]. In addition to Th1 and Th2 type of
cytokines, IL15 and IL18 have been observed at the maternal-embryonic
interface [64, 86]. The expansion of the T helper subpopulation to
incorporate Th17 and Treg cells, in fact, defied the Th1/Th2 paradigm
and added to its complexity [12]. Th17 cells that produce a potent
pro-inflammatory IL17 cytokine are essential players in the induction of
inflammation and rejection. The IL17 cells are reported to interact with
Th1 type of cells and associated with pathogenicity of allergy,
autoimmune disorders, transplant dismissal, pregnancy disorders and RPL
[87-92]. Treg cells are recognized as participants in mediating the
maternal tolerance towards the embryo [93-95].
The materno-embryonic tolerance prevents the rejection of embryonic
tissues and causes successful establishment of pregnancy [96-101].
The proliferation in Treg cells is with associated normal pregnancy,
whereas the diminished number of Treg cells brings about the failure of
pregnancy due to immune rejection of the embryo [95, 102]. Recent
research reports have shown elevated number of Th17 type of cells in the
decidua and peripheral blood of the patients that have a history of
spontaneous idiopathic RPL [81, 102, 103]. The decidual tissue in
RPL women has shown over-expression of RORγ (master transcription
factor) for Th17 cells and increased concentration of IL23, that
participates as a vital factor in the expansion of Th17 cells [81,
102]. In recent times, the occurrence of stromal cell derived IL17 has
been reported in the first trimester of human pregnancy that performs a
constructive function in supporting the pregnancy via the recruitment of
Th17 cells and promotion of trophoblast invasion, in addition to, the
inhibition of trophoblast apoptosis [104]. On the other hand, the
Th17 cells have been discovered to be infrequent and outnumbered by the
intensification of Treg cells [12]. The number of Treg cells and
associated functions significantly decrease both in decidual tissue and
peripheral blood of RPL women either pregnant or non-pregnant suggesting
the important role of Treg cells in RPL pathogenesis [94]. The
balance between Treg and Th17 cells as well as the Th17/Treg ratio has
been reported shifting towards Th17 cells during pregnancy-related
disorders that produce an inflammatory micro milieu at the
materno-embryonic interface [91,105]. A most recent study also
reported that the frequency of Treg cell decreases while as that of Th17
cells increases in RPL patients [106]. This suggests that pregnancy
success needs a tightly regulated Th1, Th2, Th17, and Treg balance and
any deviation may collapse the pregnancy (Table 3). The change in the
decidual cytokine expression has been made known to be allied with
spontaneous pregnancy loss [12]. Therefore, aberrant production of
certain cytokines might be a potential factor leading to RPL. However,
the exact mechanistic mode employed by aberrant immunological factors
for causing RPL is undecided, but may involve modulation or imbalance
between different immune cells specifically the T cell subsets.