Immunologic aspects of preeclampsia.

Preeclampsia is a syndrome with multiple etiologies. The diagnosis can be made without proteinuria in the presence of dysfunction of at least 1 organ associated with hypertension. The common pathophysiological pathway includes endothelial cell activation, intravascular inflammation, and syncytiotrophoblast stress. There is evidence to support, among others, immunologic causes of preeclampsia. Unlike defense immunology, reproductive immunology is not based on immunologic recognition systems of self/non-self and missing-self but on immunotolerance and maternal-fetal cellular interactions. The main mechanisms of immune escape from fetal to maternal immunity at the maternal-fetal interface are a reduction in the expression of major histocompatibility complex molecules by trophoblast cells, the presence of complement regulators, increased production of indoleamine 2,3-dioxygenase, activation of regulatory T cells, and an increase in immune checkpoints. These immune protections are more similar to the immune responses observed in tumor biology than in allograft biology. The role of immune and nonimmune decidual cells is critical for the regulation of trophoblast invasion and vascular remodeling of the uterine spiral arteries. Regulatory T cells have been found to play an important role in suppressing the effectiveness of other T cells and contributing to local immunotolerance. Decidual natural killer cells have a cytokine profile that is favored by the presence of HLA-G and HLA-E and contributes to vascular remodeling. Studies on the evolution of mammals show that HLA-E, HLA-G, and HLA-C1/C2, which are expressed by trophoblasts and their cognate receptors on decidual natural killer cells, are necessary for the development of a hemochorial placenta with vascular remodeling. The activation or inhibition of decidual natural killer cells depends on the different possible combinations between killer cell immunoglobulin-like receptors, expressed by uterine natural killer cells, and the HLA-C1/C2 antigens, expressed by trophoblasts. Polarization of decidual macrophages in phenotype 2 and decidualization of stromal cells are also essential for high-quality vascular remodeling. Knowledge of the various immunologic mechanisms required for adequate vascular remodeling and their dysfunction in case of preeclampsia opens new avenues of research to identify novel biological markers or therapeutic targets to predict or prevent the onset of preeclampsia.

Two waves of evolution in the rodent pregnancy-specific glycoprotein (Psg) gene family lead to structurally diverse PSGs.

BACKGROUND: The evolution of pregnancy-specific glycoprotein (PSG) genes within the CEA gene family of primates correlates with the evolution of hemochorial placentation about 45 Myr ago. Thus, we hypothesized that hemochorial placentation with intimate contact between fetal cells and maternal immune cells favors the evolution and expansion of PSGs. With only a few exceptions, all rodents have hemochorial placentas thus the question arises whether Psgs evolved in all rodent genera. RESULTS: In the analysis of 94 rodent species from 4 suborders, we identified Psg genes only in the suborder Myomorpha in three families (characteristic species in brackets), namely Muridae (mouse), Cricetidae (hamster) and Nesomyidae (giant pouched rat). All Psgs are located, as previously described for mouse and rat, in a region of the genome separated from the Cea gene family locus by several megabases, further referred to as the rodent Psg locus. In the suborders Castorimorpha (beaver), Hystricognatha (guinea pig) and Sciuromorpha (squirrel), neither Psg genes nor so called CEA-related cell adhesion molecule (Ceacam) genes were found in the Psg locus. There was even no evidence for the existence of Psgs in any other genomic region. In contrast to the Psg-harboring rodent species, which do not have activating CEACAMs, we were able to identify Ceacam genes encoding activating CEACAMs in all other rodents studied. In the Psg locus, there are genes encoding three structurally distinct CEACAM/PSGs: (i) CEACAMs composed of one N- and one A2-type domain (CEACAM9, CEACAM15), (ii) composed of two N domains (CEACAM11-CEACAM14) and (iii) composed of three to eight N domains and one A2 domain (PSGs). All of them were found to be secreted glycoproteins preferentially expressed by trophoblast cells, thus they should be considered as PSGs. CONCLUSION: In rodents Psg genes evolved only recently in the suborder Myomorpha shortly upon their most recent common ancestor (MRCA) has coopted the retroviral genes syncytin-A and syncytin-B which enabled the evolution of the three-layered trophoblast. The expansion of Psgs is limited to the Psg locus most likely after a translocation of a CEA-related gene - possibly encoding an ITAM harboring CEACAM. According to the expression pattern two waves of gene amplification occurred, coding for structurally different PSGs.

Placental glycotype of the caviomorph rodent Lagostomus maximus and its evolution within Eutheria.

The main evolutionary milestone in the oviparity-viviparity transition is placentation. The placenta is an organ with great morphological diversity among eutherians. The expression of different glycosidic residues (Gr) in the near-term placenta constitutes its glycotype. In this study, the expression of different Gr was determined by lectin histochemistry in early, midterm, and near-term placentas of the plains viscacha (Lagostomus maximus), a caviomorph rodent with the highest poliovulatory rate and embryonic resorption rate among eutherians. Besides, a matrix with the expression of each Gr in the exchange trophoblast of viscacha and other eutherians was constructed to map and infer phylogenetic and evolutionary relationships. Between early, midterm, and near-term placentas, variations in the pattern expression of Gr were observed. The glycotype of the near-term placenta is composed of a high diversity of Gr. Reconstruction of the ancestral state for each Gr present in the near-term placenta showed a diverse scenario: some sugars were common to the species of Placentalia included in this study. In the analyzed species with synepitheliochorial and epitheliochorial placentas, no differential glycosylation patterns between them were observed. In species with invasive placentas, such as the endotheliochorial placentas of Carnivora, some common Gr were detected among them, while others were species-specific. In species with hemochorial placenta, the same Gr are shared. Particularly, in the viscacha greater differences with species of the Hominidae and even Muridae families were observed. Nevertheless, greater similarities with other caviomorph rodents were detected. Placental glycotype of each species constitutes an excellent tool to achieve phylogenetic and evolutionary inferences among eutherians.

The immune-modulating pregnancy-specific glycoproteins evolve rapidly and their presence correlates with hemochorial placentation in primates.

BACKGROUND: Pregnancy-specific glycoprotein (PSG) genes belong to the carcinoembryonic antigen (CEA) gene family, within the immunoglobulin gene superfamily. In humans, 10 PSG genes encode closely related secreted glycoproteins. They are exclusively expressed in fetal syncytiotrophoblast cells and represent the most abundant fetal proteins in the maternal blood. In recent years, a role in modulation of the maternal immune system possibly to avoid rejection of the semiallogeneic fetus and to facilitate access of trophoblast cells to maternal resources via the blood system has been suggested. Alternatively, they could serve as soluble pathogen decoy receptors like other members of the CEA family. Despite their clearly different domain organization, similar functional properties have also been observed for murine and bat PSG. As these species share a hemochorial type of placentation and a seemingly convergent formation of PSG genes during evolution, we hypothesized that hemochorial placentae support the evolution of PSG gene families. RESULTS: To strengthen this hypothesis, we have analyzed PSG genes in 57 primate species which exhibit hemochorial or epitheliochorial placentation. In nearly all analyzed apes some 10 PSG genes each could be retrieved from genomic databases, while 6 to 24 PSG genes were found in Old World monkey genomes. Surprisingly, only 1 to 7 PSG genes could be identified in New World monkeys. Interestingly, no PSG genes were found in more distantly related primates with epitheliochorial placentae like lemurs and lorises. The exons encoding the putative receptor-binding domains exhibit strong selection for diversification in most primate PSG as revealed by rapid loss of orthologous relationship during evolution and high ratios of nonsynonymous and synonymous mutations. CONCLUSION: The distribution of trophoblast-specific PSGs in primates and their pattern of selection supports the hypothesis that PSG are still evolving to optimize fetal-maternal or putative pathogen interactions in mammals with intimate contact of fetal cells with the immune system of the mother like in hemochorial placentation.

Extracellular matrix proteins in healthy and retained placentas, comparing hemochorial and synepitheliochorial placentas.

The placenta expresses structural and biologically active proteins. Their synthesis is mainly regulated by genomic or nongenomic signals and modulated by hormones. These protein profiles are altered during different stages of pregnancy. The biological properties of extracellular matrix (ECM) proteins were defined and described in a number of tissues including placenta. These properties enable them to be the main players in the processes of attachment or invasion into the endometrium during initial placenta formation and its timely separation after delivery and detachment. In this review, we focused on the role of ECM proteins during attachment of the placenta to the uterine wall, its timely separation, and the implications of this process on retained or pathologically attached placenta. Although the amount of published information in this area is relatively scant, some of the key proteins and processes are well defined. We focused on the available data detailing the ECM protein profiles of human (histologically thin; hemochorial) and bovine (histologically thick; epitheliochorial) placentas and compared the shared and unique ECM proteins that are relevant to placental attachment and separation.

The placental barrier of Kerodon rupestris (Rodentia: caviidae) / A barreira placentária do Mocó (Rodentia: caviidae)

The placenta of the rodents generally has a chorial-allantoic, discoid and hemochorial shape. Since they resemble the process of human placentation, such characteristics make this order an interesting experimental model for understanding placentation, placental barrier and the physiological mechanisms involved in maternal-fetal exchanges. Due to the fact that Kerodon rupestris may be used as placental model, current analysis characterizes the rodent´s placental barrier ultrastructure. Current assay used three and two placentas, obtained from the Centro de Multiplicação de Animais Silvestres da Universidade Federal Rural do Semi-Árido (CEMAS/UFERSA) in Mossoró RN Brazil, respectively at the mid-third period of pregnancy and at the final third period of pregnancy. Samples, measuring approximately 1.0 cm, were collected and fixed in paraformaldehyde solution in a phosphate buffer 0.1 M, pH 7.4, at 4°C, while 0.5 mm2 fragments were fixed in glutaraldehyde solution 2.5%, buffered with sodium phosphate at 0.1 M, pH 7.4, and analyzed, respectively, under light and electron transmission microscope. The Kerodon rupestris´s placenta had a discoid form and resulted from the interaction between the chorion and the allantois. It was thus classified as a model chorioallantoic placenta which, macro and microscopically, consisted of lobes predominantly made up of fetal capillaries that interposed mostly in gaps or maternal spaces. The inter-hematic space or maternal-fetal barrier placenta of K. rupestris is composed of three distinct elements represented by the fetal capillary wall, basement membrane and a single layer of trophoblast cells of a syncytial nature or strictly syncytiotrophoblast, which separate maternal from fetal blood, and at the same time is the medium through which all metabolic exchange between mother and fetus are processed. These characteristics are typical of hemochorial placentas. Since the barrier contains a single syncytiotrophoblast layer, it is classified within the hemomonochorial subtype, a behavior similar to that reported in hystricomorph rodents such as the agouti, paca, capybara and cavy.

A placenta dos roedores, de uma forma geral, é do tipo corioalantóidea, discoidal e hemocorial, características que se assemelham aos processos de placentação em humanos, o que torna esta ordem um interessante modelo experimental para a compreensão da placentação, da barreira placentária e os mecanismos fisiológicos envolvidos nas trocas materno-fetais. Neste aspecto, sabendo que o Kerodon rupestris pode ser utilizado como modelo placentário, objetivou-se caracterizar ultraestruturalmente a barreira placentária deste roedor. No experimento utilizaram-se três placentas provenientes de fêmeas de mocó no terço médio e duas no terço final da gestação obtidas no Centro de Multiplicação de Animais Silvestres da Universidade Federal Rural do Semi-Árido (CEMAS/UFERSA), Mossoró-RN, Brasil. Amostras com cerca de 1,0 cm foram coletadas e fixadas em solução de paraformoldeído em tampão fostafo 0,1 M, pH 7,4 a 4°C, enquanto fragmentos de 0,5 mm2 foram fixadas em solução de glutaraldeído a 2,5%, tamponado com fosfato de sódio a 0,1 M, pH 7,4, e depois de processadas foram analisados no microscópio de luz e eletrônico de transmissão, respectivamente. A placenta do mocó apresentou-se quanto à forma como sendo do tipo discoidal. Além disto, resultou da interação entre o córion e o alantóide, fato que foi classificada como sendo um modelo de placenta corioalantoídea. Macro e microscopicamente era constituída de lóbulos predominantemente formados por capilares fetais que se interpunham na sua grande maioria às lacunas ou espaços maternos. O espaço inter hemático ou barreira materno-fetal da placenta de mocós é constituído por três elementos distintos representados pela parede do capilar fetal, a membrana basal e uma única camada de células trofoblásticas de natureza sincicial ou sinciciotrofoblasto propriamente dito, que separa o sangue