Regulation of the immunotolerance during the early stages of pregnancy

Einer der beeindruckensten Vorgänge hinsichtlich immunologischer Regulationsmechanismen ist die maternale Immuntoleranz gegenüber dem fetalen Semi-Allograft während der Schwangerschaft, auch tituliert als die „Schwangerschafts-Pause des Immunsystems“. Das Tolerieren des Fötus durch das mütterliche Immunsystem ergibt sich aus einem komplexen Zusammenspiel von Steroidhormonen, Zytokinen und weiteren Faktoren, die die Funktion der Immunzellen an der fetalen-maternalen Grenzzone regulieren. Beispielsweise werden niedrige Progesteron- und Th2- Zytokinspiegel und hohe Th1-Zytokinspiegel mit einer erhöhten Fehlgeburtenrate in Verbindung gebracht. Dieses Hormon- und Zytokinprofil kann durch psychosozialen Stress getriggert werden. Interessanterweise können die abortogenen Effekte, induziert durch Stress, mit Hilfe von Dydrogesteron aufgehoben werden. Es handelt sich hierbei um ein Progesteron-Derivat mit hoher Selektivität für den Progesteron- Rezeptor, das die Abnahme abortogen wirkender Zytokine wie TNF-α, IL-12 und IFN-γ bewirkt. Die Abstossung des Fötus wird unter anderem vom Zusammenspiel zwischen ICAM-1, das von Antigen-präsentierenden Zellen exprimiert wird, und seinem Liganden LFA-1 vermittelt: Die ICAM-1/ LFA-1-Interaktion führt zu einer interzellulärer Adhäsion, welche eine Rekrutierung von pro-inflammatorischer Zellen zur Implantationsstelle bewirkt sowie die Reifung von DZ in der Dezidua fördert. Schließlich wird durch die Reifung von DZ eine weitere Polarisierung des lokalen Zytokinprofils hin zum inflammatorischen Th1-Profil hervorgerufen. Die Blockade dieses Mechanismus resultiert in der Wiederherstellung von Immunakzeptanz in gestörten Schwangerschaften. Gezeigt werden konnte, dass Progesteron in Synergie mit Gal-1, einem immunmodulatorischen, Glykan- bindenden Protein, agiert: Bei reduzierter Gal- 1-Expression während der gestörten Schwangerschaft kann die Behandlung mit rekombinantem Gal-1 den Schwangerschaftsverlust verhindern. Die Immunakzeptanz wird über multiple Mechanismen wiederhergestellt, u. a. durch die Induktion toleranzbildender DZ, die wiederum in vivo die Expansion von IL- 10 produzierender regulatorischer T-Zellen vermitteln. An Schleimhautoberflächen wird die Immunantwort durch Antigenpräsentierende Zellen determiniert, hier findet der Erstkontakt mit dem fremden Antigen statt. In der Dezidua stellen die DC während der Schwangerschaft die entscheidende regulierende Population dar. Sie haben die Fähigkeit, mit anderen Komponenten des uterinen Signalnetzwerkes, z. B. den natürlichen Killerzellen, zu interagieren und die Immunantwort im Sinne einer stimulatorischen oder toleranzbildenden Art und Weise zu modulieren. Studien haben gezeigt, dass die DZ-NK-Interaktion in ein toleranzbildendes Spektrum resultieren kann. Dieses Spektrum ist charakterisiert durch herabregulierte Aktivierungsmarker auf uterinen NK-Zellen und DZ mit gleichzeitiger Dominanz Schwangerschafts-protektiver Th2-Zytokine. Die Interaktion von NK und DZ beeinflusst auch die uterine Zellproliferation. Dieser Prozess wird stark moduliert durch Signale die vom Trophoblasten ausgesendet werden. Die wichtige Rolle von DZ während der frühen Schwangerschaft wurde zudem in in vivo Studien untersucht, die zeigten, dass die transiente Depletion von CD11c positiven Zellen (z. B. durch die Gabe von Diphtherie-Toxin) den Implantationsprozess in Mäusen stört und in einer reduzierten Zucht-Fähigkeit resultiert. Die Reifung von uterinen NK-Zellen wird an DZ-depletierten Implantationsstellen unterbunden. Das spiegelte sich in einer reduzierten Perforin-Expression sowie einer verminderten Anzahl von PAS positiven Zellen wieder. Die Depletion von DZ in der Implantationsphase verursachte Anomalien in der Entwicklung der Plazenta (Hypozellularität von Spongiotrophoblast-Zellen und Labyrinth-Zellen, reduzierte Anzahl von Trophoblast-Riesenzellen). Zudem werden zwei charakteristische Marker der Trophoblast-Differenzierung (plazentare Laktogen-1 sowie Proliferin) herabreguliert. Zusammenfassend spielen die Funktionen der DZ und ihre Interaktionen mit dem dezidualen Mikromilieu eine wichtige Rolle um das Gelingen einer Schwangerschaft zu unterstützen.Successful mammalian pregnacy relies on the development of maternal immune tolerance towards the fetal semiallograft, which has been referred to as immunity's pregnant pause. Fetal tolerance results from a complex interplay involving steroid hormones, cytokines and other soluble factors that modulate leukocyte functions at the maternal fetal interface. For instance, low levels of progesterone and predominance of Th1 type cytokines have often been associated with increased abortion rates, which can also be boosted by psychoemotional stress. In mice, the abortogenic effects of stress can be counteracted by treatment with dydrogesterone (a progesterone derivative highly selective for the progesterone receptor), decreasing the frequency of abortogenic cytokines such as TNF-α, IL-12 and IFN-γ. Experiments in vivo have also shown that stress-triggered fetal rejection can be prevented by interfering with the molecular cross talk between ICAM-1, expressed on antigen presenting cells and its ligand, LFA-1, restoring immune acceptance mechanisms in challenged pregnancies. Intercellular adhesion events involving the ICAM-1/LFA-1 pathway mediate the recruitment of proinflammatory cells to the implantation site, promote dendritic cell (DC) maturation in the decidua, and subsequently induce additional local Th1 polarization via mature DCs. More recently, progesterone has been shown to act in synergy with Galectin (Gal)-1 (an immunoregulatory glycan-binding protein) to promote fetal tolerance. Consistently with a marked decrease in Gal-1 expression during failing pregnancies, treatment with recombinant Gal-1 restored fetal immune acceptance through multiple mechanisms, including the induction of tolerogenic DC, which in turn promoted the expansion of interleukin-10 (IL-10)-secreting regulatory T cells in vivo. Antigen presenting cells, mediating the first encounter with non-self antigens, are likely to be the core of immunoregulatory mechanisms acting on mucosal surfaces. Particularly in the decidua, DC have emerged as an important regulatory population given their ability to interact with other cellular components of the uterine milieu (i.e., natural killer cells) and modulate the nature of immune responses in stimulatory or tolerogenic fashion. Studies in vitro have shown that such DC-NK cell cross talk can result in the promotion of a tolerogenic microenvironment characterized by downregulation of the expression of activation markers on uterine NK cells and DC and dominance of pregnancy-protective Th2 cytokines. NK and DC interactions were also shown to influence uterine cell proliferation, providing the first clues into a role played by these cells during the process of endometrial decidualization. The important role played by DC during early pregnancy was further highlighted by studies in vivo showing that transient depletion of CD11c+ cells (i.e., through administration of diphtheria toxin) impairs the implantation process in mice, resulting in a reduced breeding efficiency. The analysis of DC- depleted implantation sites further revealed impairments in the maturation of uterine NK cell precursors, as demonstrated by decreased perforin expression and reduced numbers of periodic-acid-Schiff (PAS)-positive cells. Depletion of DC during the implantation process resulted in substantial anomalies in decidual and placental development, including defective vascular development as well as hypocellularity of the spongiotrophoblast and labyrinthine layers and impaired differentiation of trophoblast giant cells. In view of these findings, DC functions and their interactions within the decidualizing microenvironment are of critical importance to support a successful pregnancy outcome

Pregnancy Galectinology: Insights Into a Complex Network of Glycan Binding Proteins

Galectins are a phylogenetically conserved family of soluble β-galactoside binding proteins, consisting of 15 different types, each with a specific function. Galectins contribute to placentation by regulating trophoblast development, migration, and invasion during early pregnancy. In addition, galectins are critical players regulating maternal immune tolerance to the embedded embryo. Recently, the role of galectins in angiogenesis during decidualization and in placenta formation has gained attention. Altered expression of galectins is associated with abnormal pregnancies and infertility. This review focuses on the role of galectins in pregnancy-associated processes and discusses the relevance of galectin-glycan interactions as potential therapeutic targets in pregnancy disorders

Influence of relative NK-DC abundance on placentation and its relation to epigenetic programming in the offspring

Normal placentation relies on an efficient maternal adaptation to pregnancy. Within the decidua, natural killer (NK) cells and dendritic cells (DC) have a critical role in modulating angiogenesis and decidualization associated with pregnancy. However, the contribution of these immune cells to the placentation process and subsequently fetal development remains largely elusive. Using two different mouse models, we here show that optimal placentation and fetal development is sensitive to disturbances in NK cell relative abundance at the fetal–maternal interface. Depletion of NK cells during early gestation compromises the placentation process by causing alteration in placental function and structure. Embryos derived from NK-depleted dams suffer from intrauterine growth restriction (IUGR), a phenomenon that continued to be evident in the offspring on post-natal day 4. Further, we demonstrate that IUGR was accompanied by an overall reduction of global DNA methylation levels and epigenetic changes in the methylation of specific hepatic gene promoters. Thus, temporary changes within the NK cell pool during early gestation influence placental development and function, subsequently affecting hepatic gene methylation and fetal metabolism.Fil: Freitag, Nancy. Medicine University of Berlin; AlemaniaFil: Zwier, M. V.. University of Groningen; Países BajosFil: Barrientos, Gabriela Laura. Medicine University of Berlin; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Tirado González, Irene. Medicine University of Berlin; AlemaniaFil: Conrad, Melanie L.. Medicine University of Berlin; AlemaniaFil: Rose, Matthias. Medicine University of Berlin; AlemaniaFil: Scherjon, S. A.. University of Groningen; Países BajosFil: Plösch, T.. University of Groningen; Países BajosFil: Blois, Sandra M.. Medicine University of Berlin; Alemani

Role of galectin-glycan circuits in reproduction: from healthy pregnancy to preterm birth (PTB)

Growing evidence suggests that galectins, an evolutionarily conserved family of glycan-binding proteins, fulfill key roles in pregnancy including blastocyst implantation, maternal-fetal immune tolerance, placental development, and maternal vascular expansion, thereby establishing a healthy environment for the growing fetus. In this review, we comprehensively present the function of galectins in shaping cellular circuits that characterize a healthy pregnancy. We describe the current understanding of galectins in term and preterm labor and discuss how the galectin-glycan circuits contribute to key immunological pathways sustaining maternal tolerance and preventing microbial infections. A deeper understanding of the glycoimmune pathways regulating early events in preterm birth could offer the broader translational potential for the treatment of this devastating syndrome

Altered Glycosylation Contributes to Placental Dysfunction Upon Early Disruption of the NK Cell-DC Dynamics

Immune cells [e. g., dendritic cells (DC) and natural killer (NK) cells] are critical players during the pre-placentation stage for successful mammalian pregnancy. Proper placental and fetal development relies on balanced DC-NK cell interactions regulating immune cell homing, maternal vascular expansion, and trophoblast functions. Previously, we showed thatin vivodisruption of the uterine NK cell-DC balance interferes with the decidualization process, with subsequent impact on placental and fetal development leading to fetal growth restriction. Glycans are essential determinants of reproductive health and the glycocode expressed in a particular compartment (e.g., placenta) is highly dependent on the cell type and its developmental and pathological state. Here, we aimed to investigate the maternal and placental glycovariation during the pre- and post-placentation period associated with disruption of the NK cell-DC dynamics during early pregnancy. We observed that depletion of NK cells was associated with significant increases of O- and N-linked glycosylation and sialylation in the decidual vascular zone during the pre-placental period, followed by downregulation of core 1 and poly-LacNAc extended O-glycans and increased expression of branched N-glycans affecting mainly the placental giant cells and spongiotrophoblasts of the junctional zone. On the other hand, expansion of DC induced a milder increase of Tn antigen (truncated form of mucin-type O-glycans) and branched N-glycan expression in the vascular zone, with only modest changes in the glycosylation pattern during the post-placentation period. In both groups, this spatiotemporal variation in the glycosylation pattern of the implantation site was accompanied by corresponding changes in galectin-1 expression. Our results show that pre- and post- placentation implantation sites have a differential glycopattern upon disruption of the NK cell-DC dynamics, suggesting that immune imbalance early in gestation impacts placentation and fetal development by directly influencing the placental glycocode

Role of galectin-glycan circuits in reproduction: from healthy pregnancy to preterm birth (PTB)

Growing evidence suggests that galectins, an evolutionarily conserved family of glycan-binding proteins, fulfill key roles in pregnancy including blastocyst implantation, maternal-fetal immune tolerance, placental development, and maternal vascular expansion, thereby establishing a healthy environment for the growing fetus. In this review, we comprehensively present the function of galectins in shaping cellular circuits that characterize a healthy pregnancy. We describe the current understanding of galectins in term and preterm labor and discuss how the galectin-glycan circuits contribute to key immunological pathways sustaining maternal tolerance and preventing microbial infections. A deeper understanding of the glycoimmune pathways regulating early events in preterm birth could offer the broader translational potential for the treatment of this devastating syndrome.Fil: Blois, Sandra M.. Experimental and Clinical Research Center; Alemania. Charité-Universitätsmedizin Berlin; Alemania. University Medical Center Hamburg-Eppendorf; AlemaniaFil: Verlohren, Stefan. Charité-Universitätsmedizin Berlin; AlemaniaFil: Wu, Gang. Imperial College London; Reino UnidoFil: Clark, Gary. University of Missouri; Estados UnidosFil: Dell, Anne. Imperial College London; Reino UnidoFil: Haslam, Stuart M.. Imperial College London; Reino UnidoFil: Barrientos, Gabriela Laura. Hospital Aleman. Laboratorio de Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Medawar’s post era: Galectins emerged as key players during fetal-maternal glycoimmune adaptation

Lectin-glycan interactions, in particular those mediated by the galectin family, regulate many processes required for a successful pregnancy. Over the past decades, increasing evidence gathered from in vitro and in vivo experiments indicate that members of the galectin family specifically bind to both intracellular and membrane bound carbohydrate ligands regulating angiogenesis, immune-cell adaptations required to tolerate the fetal semi-allograft and mammalian embryogenesis. Therefore, galectins play important roles in fetal development and placentation contributing to maternal and fetal health. This review discusses the expression and role of galectins during the course of pregnancy, with an emphasis on maternal immune adaptions and galectin-glycan interactions uncovered in the recent years. In addition, we summarize the galectin fingerprints associated with pathological gestation with particular focus on preeclampsia

Uterine NK cells are critical in shaping DC immunogenic functions compatible with pregnancy progression.

Dendritic cell (DC) and natural killer (NK) cell interactions are important for the regulation of innate and adaptive immunity, but their relevance during early pregnancy remains elusive. Using two different strategies to manipulate the frequency of NK cells and DC during gestation, we investigated their relative impact on the decidualization process and on angiogenic responses that characterize murine implantation. Manipulation of the frequency of NK cells, DC or both lead to a defective decidual response characterized by decreased proliferation and differentiation of stromal cells. Whereas no detrimental effects were evident upon expansion of DC, NK cell ablation in such expanded DC mice severely compromised decidual development and led to early pregnancy loss. Pregnancy failure in these mice was associated with an unbalanced production of anti-angiogenic signals and most notably, with increased expression of genes related to inflammation and immunogenic activation of DC. Thus, NK cells appear to play an important role counteracting potential anomalies raised by DC expansion and overactivity in the decidua, becoming critical for normal pregnancy progression

NK cell-derived IL-10 is critical for DC-NK cell dialogue at the maternal- fetal interface

DC-NK cell interactions are thought to influence the development of maternal tolerance and de novo angiogenesis during early gestation. However, it is unclear which mechanism ensures the cooperative dialogue between DC and NK cells at the feto-maternal interface. In this article, we show that uterine NK cells are the key source of IL-10 that is required to regulate DC phenotype and pregnancy success. Upon in vivo expansion of DC during early gestation, NK cells expressed increased levels of IL-10. Exogenous administration of IL-10 was sufficient to overcome early pregnancy failure in dams treated to achieve simultaneous DC expansion and NK cell depletion. Remarkably, DC expansion in IL-10−/− dams provoked pregnancy loss, which could be abrogated by the adoptive transfer of IL-10+/+ NK cells and not by IL-10−/− NK cells. Furthermore, the IL-10 expressing NK cells markedly enhanced angiogenic responses and placental development in DC expanded IL-10−/− dams. Thus, the capacity of NK cells to secrete IL-10 plays a unique role facilitating the DC- NK cell dialogue during the establishment of a healthy gestation

Differential Spatiotemporal Patterns of Galectin Expression are a Hallmark of Endotheliochorial Placentation

Problem: Galectins influence the progress of pregnancy by regulating key processes associated with embryo-maternal cross talk, including angiogenesis and placentation. Galectin family members exert multiple roles in the context of hemochorial and epitheliochorial placentation; however, the galectin prolife in endotheliochorial placenta remains to be investigated. Method of study: Here, we used immunohistochemistry to analyze galectin (gal)-1, gal-3 and gal-9 expression during early and late endotheliochorial placentation in two different species (dogs and cats). Results: We found that during early feline gestation, all three galectin members were more strongly expressed on trophoblast and maternal vessels compared to the decidua. This was accompanied by an overall decrease of gal-1, gal-3 and gal-9 expressions in late feline gestation. In canine early pregnancy, we observed that gal-1 and gal-9 were expressed strongly in cytotrophoblast (CTB) cells compared to gal-3, and no galectin expression was observed in syncytiotrophoblast (STB) cells. Progression of canine gestation was accompanied by increased gal-1 and gal-3 expressions on STB cells, whereas gal-9 expression remained similar in CTB and STB. Conclusion: These data suggest that both the maternal and fetal compartments are characterized by a spatiotemporal regulation of galectin expression during endotheliochorial placentation. This strongly suggests the involvement of the galectin family in important developmental processes during gestation including immunemodulation, trophoblast invasion and angiogenesis. A conserved functional role for galectins during mammalian placental development emerges from these studies.Facultad de Ciencias Veterinaria