Journal of Human Reproductive Sciences

REVIEW ARTICLE
Year
: 2019  |  Volume : 12  |  Issue : 4  |  Page : 274--282

Female unexplained infertility: A disease with imbalanced adaptive immunity


Motahareh Ehsani1, Mousa Mohammadnia-Afrouzi2, Mohammad Mirzakhani1, Sedighe Esmaeilzadeh3, Mehdi Shahbazi2,  
1 Student Research Committee, School of Medicine, Babol University of Medical Science, Babol, Iran
2 Infertility and Health Reproductive Research Center; Immunoregulation Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
3 Infertility and Health Reproductive Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran

Correspondence Address:
Dr. Mehdi Shahbazi
Department of Immunology, School of Medicine, Babol University of Medical Sciences, Babol
Iran

Abstract

Unexplained infertility (UI) among women consists of only 10-17% of infertile females. Unexplained or idiopathic infertility is a condition, in which couples are not able to conceive without any definite causes. The presence of the decidual immune system (innate or adaptive) is essential for a successful pregnancy and fertility that is mediated by T helper (Th) 1, Th2, Th17, T follicular helper, CD8+ CD28− T, and regulatory T cells, as well as autoantibodies such as antiphospholipid antibody, antithyroid antibody, antiovarian antibody, cytokines, and chemokines. Therefore, altered proportions or levels of the mentioned compartments of the adaptive immune system may cause pregnancy failure and infertility, especially in UI. Consequently, a deep understanding of immunological compartments in females with UI may help us to define the causes of this disease with regard to immunology. This review will discuss immunological factors, including cellular, molecular components, and transcription factors that are involved in the etiology of UI.



How to cite this article:
Ehsani M, Mohammadnia-Afrouzi M, Mirzakhani M, Esmaeilzadeh S, Shahbazi M. Female unexplained infertility: A disease with imbalanced adaptive immunity.J Hum Reprod Sci 2019;12:274-282


How to cite this URL:
Ehsani M, Mohammadnia-Afrouzi M, Mirzakhani M, Esmaeilzadeh S, Shahbazi M. Female unexplained infertility: A disease with imbalanced adaptive immunity. J Hum Reprod Sci [serial online] 2019 [cited 2020 Jan 28 ];12:274-282
Available from: http://www.jhrsonline.org/text.asp?2019/12/4/274/273116


Full Text



 Introduction



The embryo implantation is vital for a successful pregnancy, in which molecular and cellular events (e.g, growth factors and cytokine expression) lead to the development of decidua, adhesion and invasion of trophoblast, and also formation of the placenta. This process takes place in the receptive endometrium during the midsecretory phase or from 19th to 23rd day of the menstrual cycle.[1] In fact, during pregnancy, the expression level of Vitamin D receptor (VDR) is changed. In more detail, VDR expression level in the decidua increases significantly in midstages.[2],[3] More than one in every six couples with implantation failure are not able to conceive and are known as infertile. Both genders, whether men or women, equally suffer from infertility.

Definite causes of female infertility range from endometriosis, ovulation, and fallopian tube disorders. In addition to these causes, there are some indefinite causes, which lead to unexplained or idiopathic infertility. Approximately 16% of infertility is reported as unexplained infertility (UI). In addition, women with UI consist of only 10%–17% of infertile females.[4] It was reported that the occurrence of UI depends on the age and selection criteria in the study population. The diagnosis of UI includes hysterosalpingography or laparoscopy to evaluate tubal patency and serum progesterone for detection of ovulation.[5] Many couples with a provisional UI might have spontaneous fertility in the future with the rate of 2%–4% per menstruation in couples.[6]

Aside from complex collaborations between the developing embryo and decidualized endometrium, recognition of the fetus as a semiallogeneic antigen is also crucial for the successful implantation, leading to the maternal immune tolerance against the fetus. The maternal immune tolerance needs alterations in cellular and humoral immune responses which is mediated via the immune cells, cytokines, and chemokine in the decidua.[1],[7] As the decidual immune system (innate or adaptive) is vital for acceptance (fertility) and rejection of the fetus (infertility), altered proportions or levels of immune compartments could break the maternal immune tolerance and result in infertility, and especially UI [Table 1] and [Figure 1].[8] The decidual adaptive immune system includes cellular and humoral immune systems. In more details, decidual cellular immune system includes T helper (Th) subsets such as Th1, Th2, Th17, T follicular helper (Tfh), CD8+ CD28− T, and regulatory T (Treg) cells and decidual humoral immune system includes autoantibodies and cytokines such as pro-inflammatory and anti-inflammatory cytokines which could play a key role in the female fertility and infertility. Thus, in this paper, we will discuss adaptive immunity and its role in the rejection of the fetus in females with UI.{Table 1}{Figure 1}

 Cellular Immunity



CD4+ T cells and CD8+ T cells as T-lymphocytes populations have a vital role in fertility and infertility, especially in UI.[9],[10] Naïve CD4+ T cells are activated and are differentiated following the interaction with antigen-major histocompatibility (MHC) expressed on dendritic cell (DC) as a professional antigen presenting cell (APC). The CD4+ T cells possess several functions, including stimulation of the innate immune cells, cytotoxic T cells, B-lymphocytes, and nonimmune cells.

Furthermore, these CD4+ T cells could play a potential role in the inhibition of the immune response like regulatory CD4+ T cells. There are different subsets of CD4+ T cells such as T helpers: Th1, Th2, Th17 and Treg cells, which have a distinct role in immune responses. The differentiation of these subsets of T cells from naive T cells to different mentioned subsets occurs after the engagement of T cell receptor, receiving DC signals, and an expression of distinct transcription factors, including T-box transcription Factor (T-bet), GATA Binding Protein 3 (GATA3), Retinoic acid receptor-related orphan-receptor-C (RORγt), and forkhead box protein P3 (Foxp3), respectively.[11]

T helper subsets

T helper 1/T helper 2 ratio

The Th1/Th2 ratio has a crucial role in the success of fertility and infertility. While in the pregnancy, Th1 cells inhibit the invasion of a trophoblastic cell, Th2 cells modulate a Th1 response, promote the trophoblast invasion, and maintain the fetus; so, the balance is strongly shifted toward Th2 response.[8] Th1 cells are responsible for the immune response against intracellular pathogens; also, they could trigger autoimmunity and inflammation in which mononuclear phagocytes, including M1 (Classical) macrophages, involve and produce toxic nitric oxide. On the other hand, Th2 cells are responsible for the immune response against extracellular pathogens in which M2 (Alternative) macrophage is involved and produces trophic polyamines. The second macrophage phenotypes (M2) are capable of decreasing the activation of the first macrophage phenotypes (M1) and play a significant role in terminating inflammation. In fact, Th1 cells suppress the development of other subsets of Th cells such as Th2 and Th17. T-bet, the main transcription factor could either promote the development of Th1 cells or suppress the development of Th2 cells by inhibiting the interleukin (IL)-4 gene expression and impairing the GATA3 function, as IL-4 and GATA3 are the essential differentiating cytokines and transcription factors of Th2 cells, respectively. T-bet also inhibits Th17 cells subset by binding to retinoid orphan nuclear receptor (RORC) promoter (encoding the Th17 transcription factor, RORγ t). On the other hand, GATA3 inhibits Th1 development by binding to T-bet.[11] With regard to importance of Th1/Th2 balance in pregnancy, inflammation and subsequent changes in the dominance of Th1 or Th2 population determine the chance of fetus survival.

Ozkan et al. demonstrated that the Th1/Th2 cell ratio increased in females with UI.[8] Wilczyński et al. studied the Th1 and Th2 status before and after immunization in these patients and concluded that the immunization makes changes in the balance of Th1 and Th2 cells causing Th2 dominance and subsequent pregnancy success.[12]

T helper 17

Due to the promotion of inflammatory response and secretion profile of cytokine (IL-17), these cells are named Th17. Because of the interaction with DCs and contribution of IL-6, IL-21, IL-23, and transcription growth factor (TGF-β), naive CD4+T cells are differentiated into the Th17 cells subset. This process is mediated via expression of RORγt that is the main Th17 cells transcription factor. This differentiation has three steps: stimulation step by TGF-β and IL-6, the self-amplification step by IL-21, and the stabilization step by IL-23. Th17 cells are responsible for the immune response against extracellular bacteria and fungi. Moreover, they play a critical role in the pathology of autoimmunity. Some studies suggest that Th17 cells have a fundamental role in the acceptance or rejection of the fetus. Hence, based on this fact that Th17 cells have a critical role in fertility and infertility, the high or low number of these cells may result in fetus rejection or fertility.[11],[13]

Some other studies also highlighted the role of Th17 cells in the fetus rejection. Ozkan ZS et al. also observed that the level of serum IL-17 increased in females with UI, which is an indicator of increased peripheral blood Th17 cells.[8]

Recent studies have reported that in addition to the vital role of Th17 cells in the occurrence of UI, these cells are vital in the occurrence of unexplained recurrent spontaneous abortion (URSA).

Saifi et al. showed that the proportion of Th17 cells in the peripheral blood and decidua was significantly higher in URSA patients compared to normal, early pregnant women. Meanwhile, there was an inverse relationship between Th17 cells and Treg cells in the peripheral blood lymphocytes (PBL) and decidua in URSA. The expression of Th17-related factors, IL-17, IL-23 as well as RORC, in PBL and decidua in URSA patients, was significantly higher than fertile group.[14] Wang et al. studied the expression of IL-27 and the role of the IL-27, secreted cytokine by tolerogenic DCs, in the regulation of Th17/Treg cells expression in URSA and found that the expression of IL-27 was lower in decidua of URSA patients compared to fertile females, which result in increased Th17/Treg cells ratio.[15]

Abdolmohammadi et al. with the aim of evaluating the frequency of Th17 cells and their regulating microRNAs (miRNAs) in RSA and control (fertile) women, realized that there is a significant increase in the number of Th17 cells in women with RSA, while there is no significant difference in the expression level of related miRNA, mir-326.[16]

T follicular helper/CD4+ T cell

Following CD4+ T cells-B cells interaction, C-X-C chemokine receptor type 5 (CXCR5−) and C-C chemokine receptor type 7 (CCR7+) naive T cells could differentiate to CXCR5+ CD4+ T cells in the presence of IL-6 and 21.[17],[18] These differentiated T cells subset are named Tfh cells and involved in the humoral immune system response. Actually, after losing the CCR7 and quitting T cell rich zone of lymph node as a secondary lymphoid organ, the Tfh cells enter the pre-germinal center to interact with antigen-activated B cells and leading to their differentiation into plasma cells. There are different types of Tfh cells based on the pattern of cytokine secretion, including Tfh1, Tfh2, and Tfh10. The Tfh1 is characterized by secreting interferon-gamma (IFN-γ), which triggers immunoglobulin G 2 alpha (IgG2α) production; Tfh2 by secreting IL-4, which triggers IgG 1/E (IgG1/E) production; and Tfh10 by secreting IL10, which triggers IgA production.[11] These antibodies could be named as potential autoantibodies that could induce the immune response to auto-antigen or semialloantigens such as the fetus, leading to the development of the inflammatory process during pregnancy and infertility. An et al. confirmed that an increased ratio of the Tfh/CD4+ T cell in peripheral blood could be a contradictory factor that indirectly induces the autoimmune response against the fetus in females with UI.[10]

CD8+CD28− T cell

CD8+ T cells might function as either stimulators or modulators of the immune system response. The modulatory effect is attributed to CD8+ CD28– cells as the suppressor T cells. After antigenic stimulation, CD8+ T cells downregulate CD28 expression and upregulate CD8 expression and are differentiated to CD8+ CD28− T cells. It was demonstrated that these MHC-I-restricted suppressor T cells in humans could be differentiated from primed CD8+ T cells with frequent in vitro stimulation mediated by APCs and Foxp3 expression. It is confirmed that CD8+ CD28− T cells suppress the activity of Th cell via IL-10 secretion or cell-to-cell contact pathways.[19] The latter pathway is mediated by acting on APCs and inducing them to express a high level of encoding Ig-like transcript (ILT) 3 and ILT4 genes, converting to tolerogenic ones. Expression of the ILT3 and ILT4 receptors (a family of the immunoglobulin-like inhibitory receptors) inhibit the CD40-CD40 L signaling pathway. As CD40 L (CD154) interacts with CD40 on APC and plays a significant role in inducing them to upregulate B7 molecules to interact with CD80 and CD86 costimulatory molecules and accelerate CD4+ T cell clonal expansion, blockage of this molecule might lead to modulating the action, expansion, and IFN-γ secretion in CD4+ T cells. These tolerogenic ILT3high ILT4high APCs interact with naive CD4+ T cells, which could have the following fates: undergoing anergy, apoptosis or gain constant CD25, FOXP3 expression, and acquire regulatory activity. Furthermore, these APCs are capable of interacting with naive CD8+ T cells, inducing FOXP3 expression, and converting their differentiation to suppressor T cells.[20] Several studies evaluated the role of the subsets of the T cell in the field of the reproductive immunity. The previous study discovered a notably high number of CD8+ CD28− T cell populations in decidual tissue during pregnancy, which is induced by trophoblast cells in the first trimester at the fetal-maternal interface. These cells are a unique subset of CD8+ T cells that might function in creating tolerogenic and modulatory condition through regulating self-reactive T and NK (natural killer) cells function.[21]

Moreover, a recent study showed that a decreased number of these CD8+ T cells in the maternal-fetal interface might cause the immune cells activity and inflammation, which may lead to infertility. Hill et al. reported that the suppressor CD8+ CD28− T cells/Cytotoxic T cells ratio and the percentage of CD8+ CD28− T cells decreased in females with UI.[9]

Treg cells and forkhead box protein P3 transcription factor

The CD4+ CD25+ natural thymus-derived Treg (nTreg) and the CD4+ CD25-peripheral-induced Treg (iTreg) are two Treg subsets. The former Treg subset expresses a high level of FOXP3, while the latter does not. The iTreg subset is divided into type 1 regulatory T (Tr1) cells and Th type 3 cells after antigen recognition with the help of cytokines.[11] CD4+ CD25+ FoxP3+ nTreg cells perform their suppressive function mainly through cell–cell contact-dependent mechanisms and largely independent from cytokine. These mechanisms include the transfer of cyclic adenosine monophosphate (cAMP) to target cells through gap junctions[22] as well as the expression of CD39 and CD73 facilitating the local generation of adenosine affecting target cells via adenosine receptors.[23] Both cAMP and adenosine lead to a metabolic disruption in target cells such as CD4+ T cells. It has been shown that regulatory CD4+ CD25high Foxp3 T cells consist of 14% of decidual T lymphocytes and play a critical role in suppressing the maternal immune system response against the fetus, induction of tolerance, and survival of the fetus during pregnancy. This function is mediated via inhibiting the proliferation of decidual CD4+ CD25– and CD8+ T cells (self-reactive T cells). As CD4+ CD25+ T cells induce expression and activation of indolamine 2, 3-dioxygenase (IDO) in DCs, they can affect tryptophan metabolism in DCs, which is mediated via the interaction of B7-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). The IDO catalyzes the tryptophan degradation that results in tryptophan deficiency. As tryptophan is known as a vital stimulus for effector T cells clonal expansion, these cells undergo apoptosis without tryptophan.[24]

Yamamoto et al. demonstrated that the expression of Foxp3 (Treg cells transcription factor) is reduced in females with UI. This finding represents that endometrial Treg cell population is decreased in females with UI.[25]

In addition to the critical role of Treg cells in etiology of UI, it is approved that this cell population has a critical role in etiology of RSA. Abdolmohammadi et al. assessed the frequency of Treg cells, expression of related transcription factors and their regulating miRNAs in RSA and control (fertile) women. The finding showed that the number of Treg cells decreased in these patients along with related transcription factors including GATA3 and glucocorticoid-induced TNFR family-related gene, while the expression level of the related miRNAs, miR-106b-25–93 in these patients is increased.[16]

Mei et al. evaluated the proportions of CD4+ CD25high T cells and FOXP3 expression in peripheral blood and decidua in patients with URSA and discovered that statistically significantly lower proportions of CD4+ CD25high T cells and FOXP3 expression were observed in the peripheral blood of URSA women compared to fertile females.[26]

Jafarzadeh et al. with regard to the fact that intravenous IgG (IVIG) treatment have a modulatory effect on immune system cells, particularly Treg cells, evaluated the treatment impact on the frequency of Treg cells in URSA women. He stated that IVIG treatment lead to the increase in the frequency of Treg cells subset and a successful pregnancy subsequently.[27]

As Inhibitor of DNA-binding protein 3 (Id3) and CTLA-4 (Cytotoxic T-Lymphocyte Associated Protein 4) is required for Treg-cell generation, Ding et al. identified the endometrial Id3 and CTLA-4 unexplained repeated implantation failure (RIF) and concluded that the presence of Id3+ and CTLA-4+ Treg cells in the pre-implantation endometrium is increased in women with RIF.[28]

 Humoral Immunity



Autoantibodies

As immunological factors could result in fetal loss, infertility, and autoimmunity; immunity against antigens expressed on the genital system and its secretion could play a possible role in the rejection of the semiallogeneic fetus and infertility in females. Basically, autoantibodies such as antiphospholipid antibodies (APAs), antithyroid antibodies (ATAs), and antiovarian antibodies (AOAs) also account for this autoimmunity and infertility, especially UI.[29],[30],[31] Production of these autoantibodies is positively correlated with the number of Tfh cells and its secreted cytokine, IL-21.[10]

Antiphospholipid antibodies

Based on researches, APAs could impact directly and indirectly on fertility and infertility. Two types of APAs, not particularly organ-specific antibodies, are APA lupus anticoagulant (LA) and anticardiolipin antibodies (ACA).[32] Aggregation of a heterogeneous population of named antibodies against phospholipids, particularly the antiphosphatidyl choline, anticardiolipin, antiphosphatidyl serine, LAs, and antinuclear antibodies could lead to the development of the antiphospholipid syndrome (APS). The APS is an autoimmune and hypercoagulable state caused by APAs. Increased levels of APAs are assumed to cause an unfavorable maternal immune response against implanting of the embryo and in turn pregnancy failure.[33] APAs have three targets: endothelial cells,[34] trophoblast,[35] and preimplantation embryos.[36] In the endothelial cells, APAs interrupt the generation of prostacyclin that assists vasodilatation and oppressing platelet accumulation, which result in thrombosis.[34] Thrombosis is the formation of an occlusive clot within a blood vessel that reduces blood flow to distal tissue and organs. Thrombosis also restricts the delivery of nutrients and oxygen, resulting in localized tissue and organ necrosis. Blood clot not only is formed under injured conditions but also under certain conditions, including APS. The efficient coagulation system of blood is so important during the development of the thrombosis. Large occlusive clots (thrombi) can break off and embolize to form secondary thrombi in distal locations.[37] Thrombosis in veins and arteries could be one of APS complication, which leads to pregnancy loss and infertility, but its occurrence is still unclear. Complement activation is also involved in the pathogenesis of the APS, this means that complement system (especially complement component 5a) and subsequent leukocyte activation could contribute to thrombotic APS and obstetric APS. Further, the latter one is considered as an activator of platelets, endothelial cells, and also mononuclear leukocytes especially neutrophil that is a leading factor of the fetal wound and pregnancy failure.[38]In vitro assessment also showed that APS prevents the extravillous trophoblast development and migration by binding to β2-glycoprotein I that is an indicator of pregnancy failure.[35]

Moreover, Radojcić et al. with the aim of measuring nonorgan-specific anticardiolipin level as one of APAs found that it is elevated in females with infertility, confirming the fact that these autoantibodies participate in the pathology of the UI and infertility.[39]

Sauer et al. measured the levels of APAs, including ACA, antiphosphatidylethanolamine, antiphosphatidylinositol, antiphosphatidic acid, antiphosphatidylglycerol, antiphosphatidylcholine, and antiphosphatidylserine and demonstrated that these antibodies increased in females with UI.[33] Patients with URSA also showed high levels of ACA (IgG and IgM) and LA compared to the normal subject.[40]

Antithyroid antibodies

Thyroid autoimmunity (TAI) is a condition in which autoantibodies against thyroid peroxidase (TPO) and / or thyroglobulin (TG) are secreted that affects 5%–20% of healthy pregnancies.[41] The cause of TAI disease is still unknown; it is assumed to be a bifactorial disease (genetic and environmental factors). Two types of TAI disease include autoimmune thyroiditis and autoimmune hyperthyroidism that are called Hashimoto's (lymphocytic) thyroiditis (HT) and Graves' disease (GD), respectively. The impaired CD4+ CD25+ T regulatory cell populations cause failure in the tolerance of the immune system response and imbalancement in cytokines network, which contribute to the stabilization of apoptosis. Induced apoptosis seems to have a key role in the etiology of the HT and GD. However, different mechanisms are involved in this process. In the HT, the induction of apoptosis leads to the damage of thyrocytes; whereas, in the GD, it leads to damage of thyroid-infiltrating lymphocytes. The differences in the apoptotic mechanisms produce two very different forms of thyroid autoimmune responses, eventually developing into HT and GD, respectively. With regard to the role of thyroid hormones in balancing of immune system, the Th1 cell populations and secreted tumor necrosis factor alpha (TNF-α) is higher than Th2 cells population and secreted IL-10 in women with TAI. So the correlation of TAI with impaired cellular and humoral immune responses along with the rejection of the fetus is evident.[42] Aside from this, as thyroid hormones are vital for the development of a fetus, especially its brain, somatic tissues, and also the progression of its metabolism in early gestation, the TAI disease could influence adversely on pregnancy that is accompanied with infertility, including UI.

Bellver et al. discovered that the prevalence of TAI with anti-TPO (aTPO), anti-TG (aTG), and aTPO plus aTG antibodies in females with UI was enhanced.[43] Geva et al. supported the Bellver J discoveries. They evaluated the presence of ATAs in females with UI and concluded that there is a high level of these antibodies in mentioned patients.[44] Habib Zade and Faghih confirmed the results of these previous studies represented that an increase in serum aTPO antibodies is related to the occurrence of UI.[31]

Antiovarian antibodies

AOAs are a heterogeneous group of antibodies and include antibodies against the zona pellucida, granulosa membrane, and theca interna that consist of follicle containing ovum.[45] There is little knowledge about the role of female genital tract-specific antibodies. In the past, AOAs were known to be correlated with premature menopause, adrenal defect, and polyglandular autoimmunity.[46],[47] Recently, it has been proved that these antibodies could be involved in either infertility or unsuccessful in vitro fertilization (IVF) treatment. Frequent IVF treatments make ovarian antigens to be released in a considerable amount. These antigens might be capable of stimulating the production of AOAs.[45] In more detail, antibodies against granulosa cells with the cooperation of the complement system have a cytotoxic effect. This effect is along with inhibiting the production of progesterone by these cells.[48] In addition, AOA prevents DNA synthesis and the growth of granulosa cells.[49] Thus, these antibodies play an essential role in reproductive functions of the human ovary, and they can influence it negatively which lead to infertility.

Luborsky et al. assessed the frequency of AOAs in order to compare these antibody levels in unexplained infertile women and control group (fertile females). The results indicated that the frequency of these antibodies was significantly enhanced in females with UI.[50] Shatavi et al. with regard to the fact that polyclonal anti-hormone antibodies such as gonadotropin antibodies aside from AOA are an important biomarker in UI realized that a high frequency of gonadotropin antibodies was observed in females with UI.[51]

Cytokine

Cytokine networks have a significant function in the reproductive system and pregnancy. Cytokines influence the uterine functions through menstruation, implantation, pregnancy, and parturition. The interactions among cytokines are a complicated and dynamic process that is regulated by pregnancy hormones.[52] In addition to their role in regulating biological processes, they possess an immunomodulatory, mitogenic, and proapoptotic role in nonimmune cells.[53] Cytokines also participate in regulating trophoblast invasiveness. The maternal hormones contribute to the modulatory effect of cytokines on maintaining the fetus. During pregnancy, these hormones could define the differentiation of naive CD4+ T cells into Th1 or Th2 cells. At the fetal-maternal interface, pregnancy hormones such as progesterone induce the IL-3, IL-4, IL-5, and IL-10 production, which suppress Th1 responses and help to create a tolerogenic environment in women, whereas relaxin, which is another hormone produced by the ovary and the placenta, promotes the production of IFN-γ by Th1 cells. Furthermore, Th1-secreted cytokines (such as IFN-γ, IL-2, and TNF) cause the failure in pregnancy, whereas Th2 secreted cytokines (such as IL-4, IL-5 and IL-10, which suppress Th1 responses) cause the tolerance to the fetus and pregnancy. The early pregnancy human decidua provides a pro-inflammatory environment to support placentation and paradoxically harboring anti-inflammatory cytokine. The anti-inflammatory cytokines could modulate the immune cells response. Moreover, IL-35 is capable of inhibiting the Th-17 cells development.[54] Thus, the imbalance in cytokine networks, pro-inflammatory, and anti-inflammatory cytokines may lead to impaired pregnancy and infertility, including UI.

Ozkan et al. demonstrated that unexplained infertile females had a high ratio of TNF-α/IL-10, IFN-γ/IL-10, and IFN-γ/IL-4 compared with fertile females, while IL-35/IL-17 was lower in comparison with fertile females, representing that the ratio of pro-inflammatory/anti-inflammatory cytokines is increased in former patients.[8] According to the previous study, the IL-4 level might increases in females with UI as well.[10] Wilczyński et al. evaluated the TNF-a, IL-10, IL-5, IL-4, IL-2, and IFN-γ levels in these patients after immunization and realized that only IFN-γ level is decreased.[12]

Wang et al. in order to assess the effect of adoptive transfer of trichostatin-induced CD4+ CD25+ FOXP3+ Treg cells on the prevention of RSA in CBA/J mice, injected trichostatin to the mice on first and 4th day of pregnancy and realized that TSA treatment lead to the successful pregnancy and high secretion of TGF-β and IL-10 indicating high number of CD4+ CD25+ FOXP3+ Treg cells in RSA prone mice.[55]

 Conclusion



Studies have demonstrated that prominent changes are made to create a maternal immune tolerance to the fetus during pregnancy, whereas imbalance in their status is involved in the initiation of inflammatory process and pathology of infertility, especially UI. How does this maternal immune system imbalance occur? Autoimmunity (the process in which self-reactive immune cells and autoantibodies involve), including APS, thyroid and ovarian autoimmunity preferentially could affect women, almost throughout their reproductive age. In fact, autoimmune conditions probably influence all steps of fertility from ovarian and testicular failures to implantation failure, representing as pregnancy failure and infertility. Based on these findings, more studies are needed to be carried out to recognize the different aspects of the adaptive immune system response and its disordering functions in females with UI.

Acknowledgment

We are grateful to Dr. Evangeline Foronda for the English editing and proofreading.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Guzeloglu-Kayisli O, Kayisli UA, Taylor HS. The role of growth factors and cytokines during implantation: Endocrine and paracrine interactions. Semin Reprod Med 2009;27:62-79.
2Shahbazi M, Zarnani AH, Salek-Moghaddam A, Karimi F, Ghasemi J, Kazemi Sefat GE, et al. Expression of Nuclear Receptor for 1, 25- Dihydroxy Vitamin D3 in Reproductive Organs of Cycling Mice. J Reprod Infertil 2008;8:307-18.
3Shahbazi M, Jeddi-Tehrani M, Zareie M, Salek-Moghaddam A, Akhondi MM, Bahmanpoor M, et al. Expression profiling of Vitamin D receptor in placenta, decidua and ovary of pregnant mice. Placenta 2011;32:657-64.
4Hull MG, Glazener CM, Kelly NJ, Conway DI, Foster PA, Hinton RA, et al. Population study of causes, treatment, and outcome of infertility. Br Med J (Clin Res Ed) 1985;291:1693-7.
5Aboulghar MA, Mansour RT, Serour GI, Al-Inany HG. Diagnosis and management of unexplained infertility: An update. Arch Gynecol Obstet 2003;267:177-88.
6Gelbaya TA, Potdar N, Jeve YB, Nardo LG. Definition and epidemiology of unexplained infertility. Obstet Gynecol Surv 2014;69:109-15.
7Erlebacher A. Immunology of the maternal-fetal interface. Annu Rev Immunol 2013;31:387-411.
8Ozkan ZS, Deveci D, Kumbak B, Simsek M, Ilhan F, Sekercioglu S, et al. What is the impact of Th1/Th2 ratio, SOCS3, IL17, and IL35 levels in unexplained infertility? J Reprod Immunol 2014;103:53-8.
9Hill JA, Faris HM, Schiff I, Anderson DJ. Characterization of leukocyte subpopulations in the peritoneal fluid of women with endometriosis. Fertil Steril 1988;50:216-22.
10An LF, Zhang XH, Sun XT, Zhao LH, Li S, Wang WH, et al. Unexplained infertility patients have increased serum IL-2, IL-4, IL-6, IL-8, IL-21, TNFα, IFNγ and increased Tfh/CD4 T cell ratio: Increased tfh and IL-21 strongly correlate with presence of autoantibodies. Immunol Invest 2015;44:164-73.
11Luckheeram RV, Zhou R, Verma AD, Xia B. CD4+ T cells: Differentiation and functions. Clin Dev Immunol 2012;2012:925135.
12Wilczyński JR, Radwan P, Tchórzewski H, Banasik M. Immunotherapy of patients with recurrent spontaneous miscarriage and idiopathic infertility: Does the immunization-dependent Th2 cytokine overbalance really matter? Arch Immunol Ther Exp (Warsz) 2012;60:151-60.
13Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006;24:179-89.
14Saifi B, Rezaee SA, Tajik N, Ahmadpour ME, Ashrafi M, Vakili R, et al. Th17 cells and related cytokines in unexplained recurrent spontaneous miscarriage at the implantation window. Reprod Biomed Online 2014;29:481-9.
15Wang WJ, Liu FJ, Qu HM, Hao CF, Qu QL, Xiong W, et al. Regulation of the expression of Th17 cells and regulatory T cells by IL-27 in patients with unexplained early recurrent miscarriage. J Reprod Immunol 2013;99:39-45.
16Abdolmohammadi Vahid S, Ghaebi M, Ahmadi M, Nouri M, Danaei S, Aghebati-Maleki L, et al. Altered T-cell subpopulations in recurrent pregnancy loss patients with cellular immune abnormalities. J Cell Physiol 2019;234:4924-33.
17Nurieva RI, Chung Y, Hwang D, Yang XO, Kang HS, Ma L, et al. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 2008;29:138-49.
18Vogelzang A, McGuire HM, Yu D, Sprent J, Mackay CR, King C, et al. A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity 2008;29:127-37.
19Colovai AI, Liu Z, Ciubotariu R, Lederman S, Cortesini R, Suciu-Foca N, et al. Induction of xenoreactive CD4+ T-cell anergy by suppressor CD8+CD28- T cells. Transplantation 2000;69:1304-10.
20Liu Z, Tugulea S, Cortesini R, Lederman S, Suciu-Foca N. Inhibition of CD40 signaling pathway in antigen presenting cells by T suppressor cells. Hum Immunol 1999;60:568-74.
21Shao L, Jacobs AR, Johnson VV, Mayer L. Activation of CD8+ regulatory T cells by human placental trophoblasts. J Immunol 2005;174:7539-47.
22Klein M, Vaeth M, Scheel T, Grabbe S, Baumgrass R, Berberich-Siebelt F, et al. Repression of cyclic adenosine monophosphate upregulation disarms and expands human regulatory T cells. J Immunol 2012;188:1091-7.
23Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A, Giometto R, et al. Expression of ectonucleotidase CD39 by foxp3+ treg cells: Hydrolysis of extracellular ATP and immune suppression. Blood 2007;110:1225-32.
24Heikkinen J, Möttönen M, Alanen A, Lassila O. Phenotypic characterization of regulatory T cells in the human decidua. Clin Exp Immunol 2004;136:373-8.
25Yamamoto H, Yamashita Y, Saito N, Hayashi A, Hayashi M, Terai Y, et al. Lower FOXO3 mRNA expression in granulosa cells is involved in unexplained infertility. J Obstet Gynaecol Res 2017;43:1021-8.
26Mei S, Tan J, Chen H, Chen Y, Zhang J. Changes of CD4+CD25high regulatory T cells and FOXP3 expression in unexplained recurrent spontaneous abortion patients. Fertil Steril 2010;94:2244-7.
27Jafarzadeh S, Ahmadi M, Dolati S, Aghebati-Maleki L, Eghbal-Fard S, Kamrani A, et al. Intravenous immunoglobulin G treatment increases live birth rate in women with recurrent miscarriage and modulates regulatory and exhausted regulatory T cells frequency and function. J Cell Biochem 2019;120:5424-34.
28Ding JL, Diao LH, Yin TL, Huang CY, Yin B, Chen C, et al. Aberrant expressions of endometrial Id3 and CTLA-4 are associated with unexplained repeated implantation failure and recurrent miscarriage. Am J Reprod Immunol 2017;78:1-7.
29Taylor PV, Campbell JM, Scott JS. Presence of autoantibodies in women with unexplained infertility. Am J Obstet Gynecol 1989;161:377-9.
30Edassery SL, Shatavi SV, Kunkel JP, Hauer C, Brucker C, Penumatsa K, et al. Autoantigens in ovarian autoimmunity associated with unexplained infertility and premature ovarian failure. Fertil Steril 2010;94:2636-41.
31Habib Zade V, Faghih N. Prevalence of anti-thyroid peroxidase (tpo) antibodies in euthyroid women with unexplained infertility referred to ivf center in Afzalipour hospital in 2013-2014. SSU J 2017;24:972-80.
32Rai RS, Regan L, Clifford K, Pickering W, Dave M, Mackie I, et al. Antiphospholipid antibodies and beta 2-glycoprotein-I in 500 women with recurrent miscarriage: Results of a comprehensive screening approach. Hum Reprod 1995;10:2001-5.
33Sauer R, Roussev R, Jeyendran RS, Coulam CB. Prevalence of antiphospholipid antibodies among women experiencing unexplained infertility and recurrent implantation failure. Fertil Steril 2010;93:2441-3.
34Rand JH, Wu XX, Andree HA, Lockwood CJ, Guller S, Scher J, et al. Pregnancy loss in the antiphospholipid-antibody syndrome – A possible thrombogenic mechanism. N Engl J Med 1997;337:154-60.
35Quenby S, Mountfield S, Cartwright JE, Whitley GS, Chamley L, Vince G, et al. Antiphospholipid antibodies prevent extravillous trophoblast differentiation. Fertil Steril 2005;83:691-8.
36Azem F, Geva E, Amit A, Lerner-Geva L, Shwartz T, Ben-Yosef D, et al. High levels of anticardiolipin antibodies in patients with abnormal embryo morphology who attended an in vitro fertilization program. Am J Reprod Immunol 1998;39:161-3.
37Yau JW, Teoh H, Verma S. Endothelial cell control of thrombosis. BMC Cardiovasc Disord 2015;15:130.
38Girardi G, Berman J, Redecha P, Spruce L, Thurman JM, Kraus D, et al. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J Clin Invest 2003;112:1644-54.
39Radojcić L, Marjanović S, Vićovac L, Kataranovski M. Anticardiolipin antibodies in women with unexplained infertility. Physiol Res 2004;53:91-6.
40Al Jameil N, Tyagi P, Al Shenefy A. Incidence of anticardiolipin antibodies and lupus anticoagulant factor among women experiencing unexplained recurrent abortion and intrauterine fetal death. Int J Clin Exp Pathol 2015;8:3204-9.
41Antonelli A, Ferrari SM, Corrado A, Di Domenicantonio A, Fallahi P. Autoimmune thyroid disorders. Autoimmun Rev 2015;14:174-80.
42Wang SH, Baker JR. The role of apoptosis in thyroid autoimmunity. Thyroid 2007;17:975-9.
43Bellver J, Soares SR, Alvarez C, Muñoz E, Ramírez A, Rubio C, et al. The role of thrombophilia and thyroid autoimmunity in unexplained infertility, implantation failure and recurrent spontaneous abortion. Hum Reprod 2008;23:278-84.
44Geva E, Lessing JB, Lerner-Geva L, Azem F, Yovel I, Amit A, et al. The presence of antithyroid antibodies in euthyroid patients with unexplained infertility and tubal obstruction. Am J Reprod Immunol 1997;37:184-6.
45Barbarino-Monnier P, Gobert B, Guillet-Rosso F, Béné MC, Landes P, Faure G, et al. Antiovary antibodies, repeated attempts, and outcome of in vitro fertilization. Fertil Steril 1991;56:928-32.
46Ahonen P, Miettinen A, Perheentupa J. Adrenal and steroidal cell antibodies in patients with autoimmune polyglandular disease type I and risk of adrenocortical and ovarian failure. J Clin Endocrinol Metab 1987;64:494-500.
47Luborsky JL, Visintin I, Boyers S, Asari T, Caldwell B, DeCherney A, et al. Ovarian antibodies detected by immobilized antigen immunoassay in patients with premature ovarian failure. J Clin Endocrinol Metab 1990;70:69-75.
48McNatty KP, Short RV, Barnes EW, Irvine WJ. The cytotoxic effect of serum from patients with addison's disease and autoimmune ovarian failure on human granulosa cells in culture. Clin Exp Immunol 1975;22:378-84.
49van Weissenbruch MM, Hoek A, van Vliet-Bleeker I, Schoemaker J, Drexhage H. Evidence for existence of immunoglobulins that block ovarian granulosa cell growth in vitro. A putative role in resistant ovary syndrome? J Clin Endocrinol Metab 1991;73:360-7.
50Luborsky J, Llanes B, Davies S, Binor Z, Radwanska E, Pong R, et al. Ovarian autoimmunity: Greater frequency of autoantibodies in premature menopause and unexplained infertility than in the general population. Clin Immunol 1999;90:368-74.
51Shatavi SV, Llanes B, Luborsky JL. Association of unexplained infertility with gonadotropin and ovarian antibodies. Am J Reprod Immunol 2006;56:286-91.
52Orsi NM, Tribe RM. Cytokine networks and the regulation of uterine function in pregnancy and parturition. J Neuroendocrinol 2008;20:462-9.
53Kawamura K, Kawamura N, Kumagai J, Fukuda J, Tanaka T. Tumor necrosis factor regulation of apoptosis in mouse preimplantation embryos and its antagonism by transforming growth factor alpha/phosphatidylionsitol 3-kinase signaling system. Biol Reprod 2007;76:611-8.
54Mao H, Gao W, Ma C, Sun J, Liu J, Shao Q, et al. Human placental trophoblasts express the immunosuppressive cytokine IL-35. Hum Immunol 2013;74:872-7.
55Wang J, Yang J, Yan Y, Zhu Z, Mu Y, Wang X, et al. Effect of adoptive transfer of CD4 CD25 Foxp3 treg induced by trichostatin A on the prevention of spontaneous abortion. J Reprod Immunol 2019;131:30-5.