Dendritic cells (DCs) are professional antigen-presenting cells with both immune stimulatory and regulatory functions. DCs are critical players in pregnancy, whose dysregulation is associated with multiple pregnancy-related complications. According to recently reported findings, this review aimed to elaborate the effects of subsets of DCs on gestation, including plasmacytoid DCs (pDCs), conventional DCs (cDCs), immature DCs (iDCs), and mature DCs (mDCs). The present review clearly illustrate that the subsets of DCs, the spatial-temporal regulation of DCs during pregnancy, the balance of pDCs/cDCs ratio influenced the pregnancy outcomes, and the balance of iDCs/mDCs ratio influenced the pregnancy outcomes. The possibility of targeting DC subsets for the treatment of pregnancy-related complications and eliminating the remaining gaps were discussed. A deeper understanding of DC subsets regulation during pregnancy can significantly contribute to the clinical application of these cells.
In 1973, Steinman and Cohn separated a new type of cells from the mouse spleen. These novel cells have a stellate morphology and are named dendritic cells (DCs)[1]. DCs were defined as professional antigen-presenting cells (APCs), promoting effective T-cell responses against pathogens and danger signals[2]. Besides, DCs are heterogenous cells that could also promote immune tolerance by delivering regulatory co-stimulatory signals and cytokines[3]. Although DCs can be constructively ablated without breaking the central and peripheral tolerance[4], they are indispensable for healthy pregnancy[5].
Reproduction is one of the most intriguing physiological processes. The balances of maternal-fetal immunity, and metabolism, are essential for the health of both mother and fetus. Multiple immune cells act coordinately to provide tolerance to avoid semi-allogeneic fetal rejection. Meanwhile, their cooperation also improves immune surveillance to fight against pathogens[6].
DCs, with divergent subsets, are important in the symphony. Their dysregulation is associated with multiple pregnancy-related complications, such as recurrent spontaneous abortion (RSA), repeated implantation failure (RIF), preeclampsia, intrauterine growth restriction (IUGR), and preterm birth[7]. Depletion of uterine DCs resulted in a severe impairment of the implantation process, leading to the embryonic resorption of mice[5]. Upregulation of DCs was supposed to contribute to the increase of implantation rate in vitro fertilization (IVF) patients[8]. However, there are still great gaps in understanding the role of DCs in pregnancy. In this review, recent achievements related to the balance of subtypes of DCs during gestation were discussed. We sincerely apologize to the researchers that those important works could not be included due to the limited topical of the review.
1.
Subsets of DCs
DCs are critical for the activation of naïve CD4+T cells and are considered professional antigen-presenting cells (APCs), are a set of well-charactered antigen-present-cells (APCs), which efficiently capture, process, and present antigens to T cells, and they are the most important sentinel cells for immune surveillance in the tumor microenvironment. DCs are classified into three main subsets: conventional DCs (cDCs), plasmacytoid DCs (pDCs), and Langerhans cells (LCs). Importantly, cDCs could be further divided to cDC1, mainly inducing activation of Th1 immunity, and cDC2, mainly inducing activation of Th2 immunity[2]. pDCs have a spherical morphology and express a profound level of type 1 interferon in response to viruses. pDCs, which have a weaker antigen-presenting ability compared with cDCs, mediate immune reactions mainly by cytokines. LCs are skin-residual DCs, which capture pathogen-associated antigens, migrate to nearby lymph nodes, and have active adaptive immune reactions.
pDCs and cDCs share common progenitors from both lymphoid and myeloid origin. Two essential transcriptional factors, ID2 and E2-2, control the differentiation of DC progenitors. The balance between E2-2 and ID2 determines the choice between cDC and pDC fates (Fig. 1).
Figure
1.
Differentiation of different subtypes of DCs.
Furthermore, both pDCs and cDCs have immunoregulatory responses or subtypes[9]. The maturation of DCs is supposed to be controlled or delayed in the presence of self-antigens. These immature DCs (iDCs) are typical tolerance subsets and fundamental for peripheral tolerance[10]. iDCs specifically induce the differentiation of tolerance T cells, such as regulatory T cells (Tregs)[11] and type 1 regulatory T cells (Tr1s)[12]. In contrast, mature cDCs (mDCs) initiate or prime T-cell responses against infection and tumors in the presence of danger signals. Costimulatory factors, such as major histocompatibility complex class II (MHC-II), CD80, CD83, and CD86 are referred to as “mature markers” for DCs (Table 1). The levels of these surface markers and proinflammatory cytokines are downregulated in iDCs. In contrast, high levels of markers and cytokines were detected in mature DCs (mDCs). Moreover, iDCs have a stronger phagocytic and a weaker immigratory activity compared with mDCs[9]. A special DC tolerant subset, DC-10, is characterized by the ability to secrete high levels of IL-10[13,14]. IL-10 is regarded as a strong immunoregulatory cytokine and a potent inhibitor of activated monocytes and macrophages[15]. These subsets of DCs have shown important influences on different physiological and pathological procedures, including normal pregnancy and pregnancy-related complications. Thus, it is essential to further concentrate on their roles in gestation.
2.
The spatial-temporal regulation of DCs during pregnancy
DCs have been detected in all components of the female reproductive system by immunohistochemistry and flow cytometry, including the uterus, ovary[25], fallopian tube[26] and vagina[27], mediating local immune surveillance. Especially, uterine DCs are critical for endometrial decidualization and fetal tolerance. The spatial-temporal changes of DCs in the endometrium during the whole pregnancy have been studied in mouse and human models.
In non-decidual endometrium, there are only CD83+ mDCs, whereas decidua retains mature and immature DCs (CD209+). The number of decidual iDCs is significantly higher than that of mDCs[16], indicating an immunoregulatory environment. Decidual iDCs can closely interact with decidual natural killer (NK) cells, suggesting interactions between these immune cells[17,28]. Intriguingly, these cells had a remarkable proliferation rate of 9.2% to 9.8%[16] and an apoptosis rate of 40.2%[17], suggesting a precise regulation of the decidua immune environment. The regulation mechanism remains to be further clarified.
As expected, decidual iDCs have a robust tolerance function and cannot prime naïve T cells[16]. The role of circulatory DCs in gestation followed a similar immune-regulatory nature, accompanied by downregulation of the expression levels of maturation markers[22,29]. Besides, decidual iDCs are indispensable for angiogenesis, which is essential for decidualization and fetal implantation. The DC depletion results in a reduction of uterine sFlt1 and TGF-β1, which can consequentially impair angiogenesis, as well as the proliferation and differentiation of decidual DC[5]. Pencovich et al. also confirmed the angiogenetic function of DCs in the pathology of endometriosis[30]. Other studies on endometriosis confirmed that tolerant IL10+ pDCs are responsible for decidual angiogenesis and lesion growth[31,32], which is consistent with the angiogenetic potential of decidual DCs.
The changes in DCs through human pregnancy have not been fully clarified. Bartmann et al. reported that the proportion of iDCs (CD209+) in decidual CD45+ cells slightly increased from early to late pregnancy[33]. Meanwhile, the proportions of circulating cDCs and pDCs fell in middle pregnancy and increased in late pregnancy subsequently[29,34]. The rise in the number of cDCs is associated with increased levels of costimulatory markers and inflammatory cytokines[22,29].
Murine models allowed a more efficient and precise assessment of decidual DCs. In early pregnancy of mice, the number of cDCs significantly increased in decidua[35], which could support embryonic implantation. In contrast, pDCs were excluded from decidua in early gestational age. After that, the number of decidual cDCs gradually declined until delivery. Zarnani et al. also reported a significant increase in the number of decidual DCs at early gestation. Besides, the average density of decidual DCs was significantly higher than endometrium of non-pregnant mice[36], indicating tissue-specific regulation. Yasuda et al. further elicited detailed changes of DC subsets. mDCs expanded rapidly at day 0.5 pc (post-coitus), and declined to non-pregnancy levels at day 1.5 to 2.5 pc. Adversely, iDCs expanded and reached a peak on day 3.5 pc just before embryo implantation, with the enhanced immunoregulatory phenotypes (characterized by PD-L2 expression). The expansion of iDCs happened only in allogeneic mating, indicating the immune tolerance-promoting function of semen plasma[37].
For the placenta and embryo, cDCs were entirely excluded from middle gestation. However, there is no research on the regulatory role of DCs in placenta and embryo during early gestation. The number of pDCs slightly increased in middle gestation, and declined again later[35].
The proliferation- and apoptosis-related markers of decidual DCs indicated in situ adjustments, and the further study revealed a fine-tuned migratory regulatory mechanism. Murine models showed that DCs continuously migrated from circulation into decidua after coitus[37]. The one-way migration has shown a dominance. Collins et al. reported that DCs lost reactions to lipopolysaccharide (LPS) or chemokines and were entrapped in decidua[38], which might minimize fetal immunogenetics. The mechanism of DC immigration and entrapment has remained elusive, although colony-stimulating factor 1 (CSF-1) might play a role in controlling uterine pre-DC extravasation[39].
Collectively, these results highlighted the delicate regulation of different DC subsets during pregnancy, although the modulation details largely remained unknown. This condition suggests the clinical significance of DCs, and further research needs to be conducted to clarify the underlying mechanisms.
3.
The balance of pDCs/cDCs ratio influenced the pregnancy outcomes
The balance of pDC/cDC ratio could influence the outcomes of pregnancy for several reasons: i) both pDCs and cDCs share a common progenitor; ii) the development of pDCs or cDCs is controlled by two mutually inhibitory transcription factors (ID2 and E2-2); iii) there is a correlation between the quantity of cDCs and embryo loss rate, which will be assessed in section 4 in the present review. The study of IUGR[40] showed that the absolute number of circulating pDCs significantly decreased in the late pregnancy of IUGR patients. The costimulatory factors (CD80, CD83, and CD86) were less expressed in IUGR pDCs[40], although the function of pDCs has remained elusive. In line with these results, the proportion of circulating pDCs or cDCs, and the pDC/cDC ratio showed to have a significant difference between RSA patients and healthy controls in early pregnancy[24]. The RSA group showed a significantly lower pDC proportion and a higher cDC proportion. Therefore, the robustly decreased pDC/cDC ratio helped discriminate RSA from a healthy pregnancy. Murine models reproduced these phenomena, in which cDC proportion significantly increased in decidual tissues of RSA mice, which was positively correlated with embryo loss[24]; in contrast, the pDC proportion and pDC/cDC ratio were negatively correlated[24]. The inadequate number of pDCs was in line with the significantly lower expression level of E2-2, which is the lineage-determining transcript factor for pDCs. Baicalin could correct E2-2 expression level that could partially restore pDC/cDC ratio[24]. In line with the murine model, RSA patients showed to have higher levels of miR-6875-5p, negatively regulating the E2-2 mRNA expression level[41]. Overall, pDC/cDC ratio plays an important role in the entire pregnancy process.
Moreover, the influences of pDCs were not only limited to the downregulation of the differentiation of cDCs. During pregnancy, the differentiation of pDCs and cDCs was specifically regulated in para-aortic lymph nodes (LNs)[42]. The proportion of pDCs in para-aortic LNs significantly increases during normal mouse pregnancy with a reduction of cDCs the number correspondingly. These pDCs have a higher potential in expanding Treg cells than cDCs, and are positively correlated with the number of Treg cells in LNs, rather than in decidua. Upregulation of interferon-γ (IFN-γ) could induce abortion in mice[43,44] and human[45], partly by breaking the balance of pDC/cDC ratio in para-aortic LNs. Consequentially, this process reduces the number of Treg cells in para-aortic LNs and decidua[42].
The balance of pDCs/cDCs ratio could critically influence pregnancy outcomes. Increasing the number of pDCs throughout pregnancy could play a role in maternal-fetal tolerance as follows: i) inhibiting the quantity of cDCs systematically; and ii) upregulating Treg cells in para-aortic LNs. Breaking of the balance is correlated with multiple pregnancy disorders and may be a target for RSA and pre-eclampsia.
4.
The balance of iDCs/mDCs ratio influenced the pregnancy outcomes
The balance of iDC/mDC ratio throughout the gestation was found critical for healthy pregnancy outcomes. The imbalance could lead to a variety of complications, including RSA, IUGR, preeclampsia, and preterm birth. Thus, the body makes a great effort to ensure a proper proportion of DC subtypes during pregnancy.
Sex hormones, increasing during pregnancy, influence DC differentiation and function via assuring tolerance phonotypes of decidual DCs[6]. Besides, tumor-associated glycoprotein-72 (TAG-72), a highly glycosylated protein specifically presented in secretory phase tubal mucosa, was reported to bind with mannose receptor or CD209 of iDCs. TAG-72-treated iDCs decreased the expression levels of CD83, interleukin-15 (IL-15), and IFN-γ, contributing to the tolerant environment of fallopian tube[46]. Seminal plasma could inhibit DC maturation, and the efficiency was related to mouse blastocyst implantation rate[47]. In decidua, the mixture of cell secretory molecules could enhance the ability of DCs to induce proliferation of Treg cells[48]. Another in vitro study of decidualized cells confirmed their ability in promoting IL-10 secreting differentiation of DCs from peripheral blood mononuclear cells (PBMCs)[14]. Consistently, Croxatto et al. revealed that decidual stromal cells could inhibit DC-mediated T cell proliferation by modulating the expression levels of indoleamine 2,3-dioxygenase (IDO) and prostaglandin E2 (PGE2)[49]. Moreover, extravillous trophoblasts (EVTs) were found to induce an immature phenotype of monocyte-derived DCs. These conditioned DCs had a tolerant cytokine profile, poorly responded to LPS, and induced proliferation of Treg cells rather than allogeneic T cells[50]. Collectively, multiple mechanisms should be developed to retain DCs in immature and anti-inflammatory phenotypes, and to sustain the tolerant maternal-fetal interfaces.
Furthermore, the decidual iDCs could be unfavorable during infections by tolerant placental pathogens with placental tropism[20], as well as the fetus. Placental DCs from healthy pregnant women do not respond to Coxiella burnetii Nine Mile 1 and Brucella abortus, which confirmed their immunoregulatory role.
As mentioned earlier, the imbalance would cause some consequences. Several studies have identified the increase of mDCs in serum and decidua associated with RSA[21,51–53]. The first systematic study of mDCs in RSA revealed significantly upregulated expression levels of CD83+ mDCs in decidua at gestational age of 8 weeks[21]. However, when the groups were compared as a whole by gestational age, there was no significant difference between RSA and healthy pregnancy groups[21]. Another study showed opposite results, which compared the expression levels of CD83+ mDCs and CD1a+ iDCs in gestational age of 0-14 weeks between RSA and healthy pregnancy groups[51]. There were significantly higher mDCs and lower iDCs in RSA group. The discrepancies could be attributed to different research objects. Qian et al. excluded RSA patients with unknown etiology[51], whose immune properties significantly differed compared with RSA patients[54].
Such differences were found between IVF/intracytoplasmic sperm injection (ICSI) patients, as well as RSA patients. Diao et al. retrospectively analyzed the endometrial immunological factors of pregnant and implantation failure patients at their first IVF/ICSI attempt. Patients in the failure group had a significantly higher number of CD83+ mDCs, CD68+ macrophages, CD 57+ NK and T cells, which all had a “mature” phenotype[52]. Consistent with this study, Lai et al. also reported that DCs from RSA patients and mice were all polarized to mDCs, with significantly upregulated expression levels of MHC-II, CD80, and CD86[24]. Eskandarian and Moazzeni also demonstrated the significant decrease of uterus DCs and increased expression levels of CD40, CD86, and MHC-II in RSA mice. Applying mesenchymal stem cells at implantation window significantly decreased the DC maturation markers, restored the frequency of uterus DCs and pregnancy rate of RSA mice[55], indicating the essential role of DCs in pregnancy.
In addition to RSA, breaking of the balance of mDC/iDC ratio was frequently found in other pregnancy-related complications. Against normal pregnancy, the number of decidual mDCs significantly increased, and the number of iDCs decreased in IUGR patients. These mDCs were clustered around vessels and apoptotic EVTs with T cells, indicating a strong restriction of fetal growth[53]. mDCs and corresponding cytokines were found in the decidua of preeclampsia patients and mice[56]. Depletion of iDCs during late pregnancy of mice was associated with the fetal absorption[57].
The mature phenotype of DCs and other immune cells indicated a proinflammatory internal environment of RSA patients. APCs are activated by damage-associated molecular patterns (DAMPs) and pathogen-associated patterns (PAMPs). They could promote inflammatory reactions against pathogens or sterile injury[58], and contribute to a variety of pregnancy-related complications. Toxoplasma gondii infection could increase the expression levels of “mature signatures” (CD80, CD86, MHC-II, and IL-12) and decrease the expression levels of “immature signatures” (IL-10 and IDO) in decidual DCs[59]. The dysfunction of decidual DCs and other immune cells[60,61] caused the failure of maternal-fetal tolerance and substantially serious abnormal pregnancy.
The increased expression level of extracellular high mobility group box 1 (HMGB1), a classical DAMP and proinflammatory factor, was found in preterm births without chorioamnionitis[62]. HMGB1 was supposed to decline around implantation in uterine fluid, otherwise leading to the accumulation of inflammatory cytokines and pregnancy failure[63]. A higher expression level of 70-kDa heat shock protein (HSP70) was identified in intra-amniotic infections[64], which could be related to preterm birth[64]. Redzovic et al. reported that exocellular HSP70 could promote the maturation of decidual iDCs by upregulating the expression levels of CD80, CD83, CD86, and MHC-II[65].
Alternative inflammatory molecules associated with pregnancy-related complications could also promote the maturation of decidual iDCs. St. Louis et al. demonstrated that α-GalCer induced late preterm birth in mice by upregulating the expression levels of inflammatory genes and promoting infiltration of mDCs to decidual tissues[66]. A similar result was also found in human. Lnc-DC, a long non-coding RNA specifically expressed in DCs, was significantly upregulated in decidua of preeclampsia patients[67]. The overexpression of lnc-DC promoted the maturation of DCs and significantly increased the proportion of T helper type-1 (Th1) cells, suggesting an inflammatory maternal-fetal interface[67].
The balance of mDCs/iDCs ratio indicates the uterus's immune responses to the fetus and the maternal-fetal tolerance consequentially. Healthy pregnancy shows a profound upregulation of decidual iDCs, contributing to the fetal tolerance. The immune-regulatory iDCs are strong enough to tolerate harmful pathogens with placental tropism. On the other side, high levels of mDCs present a pro-inflammatory environment, thereby leading to enhanced fetal antigen representation and multiple pregnancy-related complications. Correcting the imbalance of iDCs/mDCs ratio could restore mice reproduction, which might become a target for RSA patients.
Future Prospects
Based on the above-mentioned studies, several phenomena were reviewed in association with the role of DCs in pregnancy that could be summarized as follows: i) the changes of DC subsets during gestation; ii) the relationship between the imbalance of pDCs/cDCs ratio and pregnancy outcomes; iii) the causes and consequences of imbalance of iDCs/mDCs ratio, making DC subsets as an attractive therapeutic target for pregnancy-related complications. However, there are still major concerns that should be eliminated. For instancedoes the imbalance of DC subsets cause RSA? Retrospective research of RSA patients’ immune state before the first abortion will be of great significance. The molecular mechanism behind the regulation of DC subsets should be clear and correct the balance. The pathology of RSA and other pregnancy-related complications is heterogenetic, and the portion that is caused by DC imbalance should be profiled. The elimination of these concerns will promote the application of DC subsets as therapeutic targets.
The authors declare that there is no conflict of interest.
Authors’ contributions
NZ made key contributions to the article ideas and outlines. NZ and LRC participated in the data collection and original draft writing. YLY is responsible for reviewing and editing.
Steinman RM, Cohn, ZA. IDENTIFICATION OF A NOVEL CELL TYPE IN PERIPHERAL LYMPHOID ORGANS OF MICE. J Exp Med, 1973, 137(5): 1142-1162. DOI: 10.1084/jem.137.5.1142
[2]
Murphy TL, Murphy KM. Dendritic cells in cancer immunology. Cell Mol Immunol, 2022, 19(1): 3-13. DOI: 10.1038/s41423-021-00741-5
[3]
Waisman A, Lukas D, Clausen BE, et al. Dendritic cells as gatekeepers of tolerance. Semin Immunopathol, 2017, 39(2): 153-163. DOI: 10.1007/s00281-016-0583-z
[4]
Birnberg T, Bar-On L, Sapoznikov A, et al. Lack of Conventional Dendritic Cells Is Compatible with Normal Development and T Cell Homeostasis, but Causes Myeloid Proliferative Syndrome. Immunity, 2008, 29(6): 986-997. DOI: 10.1016/j.immuni.2008.10.012
[5]
Plaks V, Birnberg T, Berkutzki T, et al. Uterine DCs are crucial for decidua formation during embryo implantation in mice. J Clin Invest, 2008, 118(12): 3954-3965. DOI: 10.1172/JCI36682
[6]
Segerer SE, Staib C, Kaemmerer U, et al. Dendritic Cells: Elegant Arbiters in Human Reproduction. Curr Pharm Biotechnol, 2012, 13(8): 1378-1384. DOI: 10.2174/138920112800784916
[7]
Negishi Y, Takahashi H, Kuwabara Y, et al. Innate immune cells in reproduction. J Obstet Gynaecol Res, 2018, 44(11): 2025-2036. DOI: 10.1111/jog.13759
[8]
Gnainsky Y, Granot I, Aldo PB, et al. Local injury of the endometrium induces an inflammatory response that promotes successful implantation. Fertil Steril, 2010, 94(6): 2030-2036. DOI: 10.1016/j.fertnstert.2010.02.022
[9]
Kim MK, Kim J. Properties of immature and mature dendritic cells: phenotype, morphology, phagocytosis, and migration. RSC Adv, 2019, 9(20): 11230-11238. DOI: 10.1039/C9RA00818G
[10]
Roncarolo MG, Levings MK, Traversari C. Commentary Differentiation of T Regulatory Cells by Immature Dendritic Cells. J Exp Med, 2001, 193(2): F5-F10. DOI: 10.1084/jem.193.2.F5
[11]
Mahnke K, Johnson TS, Ring S, et al. Tolerogenic dendritic cells and regulatory T cells: A two-way relationship. J Dermatol Sci, 2007, 46(3): 159-167. DOI: 10.1016/j.jdermsci.2007.03.002
[12]
Levings MK, Gregori S, Tresoldi E, et al. Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25 + CD4 + Tr cells. Blood, 2005, 105(3): 1162-1169. DOI: 10.1182/blood-2004-03-1211
[13]
Liu S, Wei H, Li Y, et al. Characterization of dendritic cell (DC)-10 in recurrent miscarriage and recurrent implantation failure. Reproduction, 2019, 158(3): 247-255. DOI: 10.1530/REP
[14]
Gori S, Soczewski E, Fernández L, et al. Decidualization Process Induces Maternal Monocytes to Tolerogenic IL-10-Producing Dendritic Cells (DC-10). Front Immunol, 2020, 11: 1571. DOI: 10.3389/fimmu.2020.01571
[15]
Amodio G, Mugione A, Sanchez AM, et al. HLA-G expressing DC-10 and CD4 + T cells accumulate in human decidua during pregnancy. Hum Immunol, 2013, 74(4): 406-411. DOI: 10.1016/j.humimm.2012.11.031
[16]
Kämmerer U, Eggert AO, Kapp M, et al. Unique Appearance of Proliferating Antigen-Presenting Cells Expressing DC-SIGN (CD209) in the Decidua of Early Human Pregnancy. Am J Pathol, 2003, 162(3): 887-896. DOI: 10.1016/S0002-9440(10)63884-9
[17]
Tirado-González I, Muñoz-Fernández R, Prados A, et al. Apoptotic DC-SIGN + cells in normal human decidua. Placenta, 2012, 33(4): 257-263. DOI: 10.1016/j.placenta.2012.01.003
[18]
Schwede S, Alfer J, Von Rango U. Differences in regulatory T-cell and dendritic cell pattern in decidual tissue of placenta accreta/increta cases. Placenta, 2014, 35(6): 378-385. DOI: 10.1016/j.placenta.2014.03.004
[19]
Huang C, Zhang H, Chen X, et al. Association of peripheral blood dendritic cells with recurrent pregnancy loss: a case-controlled study. Am J Reprod. Immunol, 2016, 76(4): 326-332. DOI: 10.1111/aji.12550
[20]
Zarza SM, Mezouar S, Mege JL. From coxiella burnetii infection to pregnancy complications: Key role of the immune response of placental cells. Pathogens, 2021, 10(5): 627. DOI: 10.3390/pathogens10050627
[21]
Askelund K, Liddell HS, Zanderigo AM, et al. CD83 + dendritic cells in the decidua of women with recurrent miscarriage and normal pregnancy. Placenta, 2004, 25(2-3): 140-145. DOI: 10.1016/S0143-4004(03)00182-6
[22]
Bachy V, Williams DJ, Ibrahim MAA. Ibrahim, Altered dendritic cell function in normal pregnancy. J Reprod Immunol, 2008, 78(1): 11-21. DOI: 10.1016/j.jri.2007.09.004
[23]
Gorvel L, Ben Amara A, Ka MB, et al. Myeloid decidual dendritic cells and immunoregulation of pregnancy: Defective responsiveness to Coxiella burnetii and Brucella abortus. Front Cell Infect Microbiol, 2014, 4: 179. DOI: 10.3389/fcimb.2014.00179
[24]
Lai N, Fu X, Hei G, et al. The Role of Dendritic Cell Subsets in Recurrent Spontaneous Abortion and the Regulatory Effect of Baicalin on It. J Immunol Res, 2022: 2022. DOI: 10.1155/2022/9693064
[25]
Yang X, Gilman-Sachs A, Kwak-Kim J. Ovarian and endometrial immunity during the ovarian cycle. J Reprod Immunol, 2019, 133: 7-14. DOI: 10.1016/j.jri.2019.04.001
[26]
Rigby CH, Aljassim F, Powell SG, et al. The immune cell profile of human fallopian tubes in health and benign pathology: a systematic review. J Reprod Immunol, 2022, 152: 103646. DOI: 10.1016/j.jri.2022.103646
[27]
Lee SK, Kim CJ, Kim DJ, et al. Immune Cells in the Female Reproductive Tract. Immune Netw, 2015, 15(1): 16-26. DOI: 10.4110/in.2015.15.1.16
[28]
Leno-Durán E, Munoz-Fernández R, Garcia Olivares E, et al. Liaison between natural killer cells and dendritic cells in human gestation. Cell Mol Immunol, 2014, 11(5): 449-455. DOI: 10.1038/cmi.2014.36
[29]
Della Bella S, Giannelli S, Cozzi V, et al. Incomplete activation of peripheral blood dendritic cells during healthy human pregnancy. Clin Exp Immunol, 2011, 164(2): 180-192. DOI: 10.1111/j.1365-2249.2011.04330.x
[30]
Pencovich N, Luk J, Hantisteanu S, et al. The development of endometriosis in a murine model is dependent on the presence of dendritic cells. Reprod Biomed Online, 2014, 28(4): 515-521. DOI: 10.1016/j.rbmo.2013.12.011
[31]
Suen JL, Chang Y, Shiu YS, et al. IL-10 from plasmacytoid dendritic cells promotes angiogenesis in the early stage of endometriosis. J Pathol, 2019, 249(4): 485-497. DOI: 10.1002/path.5339
[32]
Suen JL, Chang Y, Chiu PR, et al. Serum level of IL-10 is increased in patients with endometriosis, and IL-10 promotes the growth of lesions in a murine model. Am J Pathol, 2014, 184(2): 464-471. DOI: 10.1016/j.ajpath.2013.10.023
[33]
Bartmann C, Segerer SE, Rieger L, et al. Quantification of the Predominant Immune Cell Populations in Decidua Throughout Human Pregnancy. Am J Reprod Immunol, 2014, 71(2): 109-119. DOI: 10.1111/aji.12185
[34]
Shah NM, Herasimtschuk AA, Boasso A, et al. Changes in T cell and dendritic cell phenotype from mid to late pregnancy are indicative of a shift from immune tolerance to immune activation. Front Immunol, 2017, 8: 1138. DOI: 10.3389/fimmu.2017.01138
[35]
Li Y, Lopez GE, Vazquez J, et al. Decidual-placental immune landscape during syngeneic murine pregnancy. Front Immunol, 2018, 9: 2087. DOI: 10.3389/fimmu.2018.02087
[36]
Zarnani AH, Moazzeni SM, Shokri F, et al. Kinetics of murine decidual dendritic cells. Reproduction, 2007, 133(1): 275-283. DOI: 10.1530/rep.1.01232
[37]
Yasuda I, Shima T, Moriya T, et al. Dynamic Changes in the Phenotype of Dendritic Cells in the Uterus and Uterine Draining Lymph Nodes After Coitus. Front Immunol, 2020, 11: 557720. DOI: 10.3389/fimmu.2020.557720
[38]
Collins MK, Tay CS, Erlebacher A. Dendritic cell entrapment within the pregnant uterus inhibits immune surveillance of the maternal/fetal interface in mice. J Clin Investig, 2009, 119(7): 2062-2073. DOI: 10.1172/JCI38714
[39]
Tagliani E, Shi C, Nancy P, et al. Coordinate regulation of tissue macrophage and dendritic cell population dynamics by CSF-1. J Exp Med, 2011, 208(9): 1901-1916. DOI: 10.1084/jem.20110866
[40]
Cappelletti M, Giannelli S, Martinelli A, et al. Lack of activation of peripheral blood dendritic cells in human pregnancies complicated by intrauterine growth restriction. Placenta, 2013, 34(1): 35-41. DOI: 10.1016/j.placenta.2012.10.016
[41]
Zhu XX, Yin XQ, Hei GZ, et al. Increased miR-6875-5p inhibits plasmacytoid dendritic cell differentiation via the STAT3/E2-2 pathway in recurrent spontaneous abortion. Mol Hum Reprod, 2021, 27(8): gaab044. DOI: 10.1093/molehr/gaab044
[42]
Fang W, Shi M, Meng C, et al. The Balance between Conventional DCs and Plasmacytoid DCs Is Pivotal for Immunological Tolerance during Pregnancy in the Mouse. Sci Rep, 2016, 6(1): 1-11. DOI: 10.1038/srep26984
[43]
Li ZY, Chao HH, Liu HY, et al. IFN-γ induces aberrant CD49b + NK cell recruitment through regulating CX3CL1: A novel mechanism by which IFN-γ provokes pregnancy failure. Cell Death Dis, 2014, 5(11): e1512-e1512. DOI: 10.1038/cddis.2014.470
[44]
Chen Y, Wu Q, Wei J, et al. Effects of aspirin, vitamin D3, and progesterone on pregnancy outcomes in an autoimmune recurrent spontaneous abortion model. Braz J Med Biol Res, 2021: 54. DOI: 10.1590/1414-431X2020E9570
[45]
Yang Y, Su X, Xu W, et al. Interleukin-18 and Interferon Gamma Levels in Preeclampsia: A Systematic Review and Meta-analysis. Am J Reprod Immunol, 2014, 72(5): 504-514. DOI: 10.1111/aji.12298
[46]
Laskarin G, Redzovic A, Vlastelic I, et al. Tumor-associated glycoprotein (TAG-72) is a natural ligand for the C-type lectin-like domain that induces anti-inflammatory orientation of early pregnancy decidual CD1a + dendritic cells. J Reprod Immunol, 2011, 88(1): 12-23. DOI: 10.1016/j.jri.2010.10.001
[47]
Wang D, Jueraitetibaike K, Tang T, et al. Seminal Plasma and Seminal Plasma Exosomes of Aged Male Mice Affect Early Embryo Implantation via Immunomodulation. Front Immunol, 2021, 12: 723409. DOI: 10.3389/fimmu.2021.723409
[48]
Ahmadabad HN, Salehnia M, Saito S, et al. Decidual soluble factors, through modulation of dendritic cells functions, determine the immune response patterns at the feto-maternal interface. J Reprod Immunol, 2016, 114: 10-17. DOI: 10.1016/j.jri.2016.01.001
[49]
Croxatto D, Vacca P, Canegallo F, et al. Stromal cells from human decidua exert a strong inhibitory effect on NK cell function and dendritic cell differentiation. PLoS One, 2014, 9(2): e89006. DOI: 10.1371/journal.pone.0089006
[50]
Zhao L, Shao Q, Zhang Y, et al. Human monocytes undergo functional re-programming during differentiation to dendritic cell mediated by human extravillous trophoblasts. Sci Rep, 2016, 6(1): 1-12. DOI: 10.1038/srep20409
[51]
Qian ZD, Huang LL, Zhu XM. An immunohistochemical study of CD83- and CD1a-positive dendritic cells in the decidua of women with recurrent spontaneous abortion. Eur J Med Res, 2015, 20(1): 1-7. DOI: 10.1186/s40001-014-0076-2
[52]
Diao L, Cai S, Huang C, et al. New endometrial immune cell-based score (EI-score) for the prediction of implantation success for patients undergoing IVF/ICSI. Placenta, 2020, 99: 180-188. DOI: 10.1016/j.placenta.2020.07.025
[53]
Dunk C, Kwan M, Hazan A, et al. Failure of decidualization and maternal immune tolerance underlies uterovascular resistance in intra uterine growth restriction. Front Endocrinol, 2019, 10: 160. DOI: 10.3389/fendo.2019.00160
[54]
Li D, Zheng L, Zhao D, et al. The Role of Immune Cells in Recurrent Spontaneous Abortion. Reprod Sci, 2021, 28(12): 3303-3315. DOI: 10.1007/s43032-021-00599-y
[55]
Eskandarian M, Moazzeni SM. Uterine dendritic cells modulation by mesenchymal stem cells provides a protective microenvironment at the feto-maternal interface: Improved pregnancy outcome in abortion-prone mice. Cell J, 2019, 21(3): 274. DOI: 10.22074/cellj.2019.6239
[56]
Huang SJ, Zenclussen AC, Chen CP, et al. The implication of aberrant GM-CSF expression in decidual cells in the pathogenesis of preeclampsia. Am J Pathol, 2010, 177(5): 2472-2482. DOI: 10.2353/ajpath.2010.091247
[57]
Negishi Y, Wakabayashi A, Shimizu M, et al. Disruption of maternal immune balance maintained by innate DC subsets results in spontaneous pregnancy loss in mice. Immunobiology, 2012, 217(10): 951-961. DOI: 10.1016/j.imbio.2012.01.011
Sun X, Xie H, Zhang H, et al. B7-H4 reduction induced by Toxoplasma gondii infection results in dysfunction of decidual dendritic cells by regulating the JAK2/STAT3 pathway. Parasit Vectors, 2022, 15(1): 1-17. DOI: 10.1186/s13071-022-05263-1
[60]
Liu X, Jiang M, Ren L, et al. Decidual macrophage M1 polarization contributes to adverse pregnancy induced by Toxoplasma gondii PRU strain infection. Microb Pathog, 2018, 124: 183-190. DOI: 10.1016/j.micpath.2018.08.043
[61]
Zhang H, Cui L, Ren L, et al. The Role of Decidual PD-1 + Treg Cells in Adverse Pregnancy Outcomes due to Toxoplasma gondii Infection. Inflammation, 2019, 42(6): 2119-2128. DOI: 10.1007/s10753-019-01075-1
[62]
Kato M, Negishi Y, Shima Y, et al. Inappropriate activation of invariant natural killer T cells and antigen-presenting cells with the elevation of HMGB1 in preterm births without acute chorioamnionitis. Am J Reprod Immunol, 2021, 85(1): e13330. DOI: 10.1111/aji.13330
[63]
Bhutada S, Basak T, Savardekar L, et al. High mobility group box 1 (HMGB1) protein in human uterine fluid and its relevance in implantation. Hum Reprod, 2014, 29(4): 763-780. DOI: 10.1093/humrep/det461
[64]
Chaiworapongsa T, Erez O, Kusanovic JP, et al. AMNIOTIC FLUID HEAT SHOCK PROTEIN 70 CONCENTRATION IN HISTOLOGIC CHORIOAMNIONITIS, TERM AND PRETERM PARTURITION NIH Public Access. J Matern-Fetal Neonatal Med, 2008, 21(7): 449-461. DOI: 10.1080/14767050802054550
[65]
Redzovic A, Gulic T, Laskarin G, et al. Heat-Shock Proteins 70 Induce Pro-Inflammatory Maturation Program in Decidual CD1a + Dendritic Cells. Am J Reprod Immunol, 2015, 74(1): 38-53. DOI: 10.1111/aji.12374
[66]
Louis DS, Romero R, Plazyo O, et al. Invariant NKT Cell Activation Induces Late Preterm Birth That Is Attenuated by Rosiglitazone. J Immunol, 2016, 196(3): 1044-1059. DOI: 10.4049/jimmunol.1501962
[67]
Zhang W, Zhou Y, Ding YL. Lnc-DC mediates the over-maturation of decidual dendritic cells and induces the increase in Th1 cells in preeclampsia. Am J Reprod Immunol, 2017, 77(6): e12647. DOI: 10.1111/aji.12647
DownLoad:
