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.