Pregnancy is a proinflammatory and hypercoagulable state. Miscarriage concerns approximately 15% of pregnancies. Recurrent miscarriage is a rather rare condition with an estimated incidence of 1% to 3%. However, despite years of investigation, the etiology is not established in up to 50% of cases. A multidisciplinary approach in the evaluation of miscarriage is essential to understand the cause and risk of recurrence. Although genetic factors are the major cause of spontaneous miscarriages, their relationship with recurrent miscarriage is less frequent. Recently, many kinds of genetic polymorphisms have also been found to be associated. Endocrine disorders such as poorly controlled diabetes, polycystic ovary syndrome, and hypothyroidism are linked with recurrent miscarriage. The relationship between recurrent miscarriage and subclinical thyroid disorders and thyroid autoimmunity is disputed, especially in early miscarriages. Uterine malformations should be considered as a cause of recurrent miscarriage. Although autoimmune-based recurrent miscarriage has been described, mainly antiphospholipid antibodies, the role of alloimmune mechanisms remains poorly understood. The influence of congenital thrombophilia is controversial. Antiphospholipid syndrome or antiphospholipid antibody-related recurrent miscarriage, and some endocrinologic disorders, have a specific and effective treatment. Still, the effectiveness of some common treatments needs to be demonstrated.

Current concepts and new trends in the diagnosis and management of recurrent miscarriage.

Glycodelin is an example of a glycoprotein whose complex-type glycans mediate biological actions in human reproduction and immune reactions. Being attached to an identical protein backbone, glycodelin oligosaccharides vary significantly from one reproductive tissue to another and have an effect on its own secretion and role in cell communication. For instance, uterine glycodelin-A inhibits sperm-oocyte interaction by binding on the sperm head. This is a glycosylation-dependent phenomenon, in which fucosyltransferase-5 plays a key role. Glycodelin-S from seminal plasma binds evenly around the sperm head and maintains an uncapacitated state in the spermatozoa, until the isoform is detached during sperm passage through the cervix. Glycodelin-F from follicular fluid and Fallopian tube binds to the acrosomal region of the sperm head, thereby inhibiting both the sperm-oocyte binding and premature progesterone-induced acrosome reaction. The cumulus cells surrounding the oocyte can capture glycodelin-A and -F from the surrounding environment and convert these isoforms to a cumulus cell isoform, glycodelin-C. It differs by glycosylation from the other isoforms, and it too attaches on the sperm head, with the highest density in the equatorial region. Glycodelin-C is capable of detaching the sperm-bound inhibitory isoforms so that the sperm-oocyte binding is enhanced. Glycodelin-A also has immunosuppressive actions directed to cellular, humoral and innate immunity. Although these actions depend mainly on the protein backbone, glycosylation also plays a part. Glycosylated glycodelin may be involved in the protection of spermatozoa against maternal immune reactions, and glycodelin also has apoptogenic activity. Some glycosylation patterns of glycodelin may mask its apoptogenic domain. This review updates the recent research and clinical associations of glycodelin, highlighting the role of glycosylation.

Glycosylation related actions of glycodelin: gamete, cumulus cell, immune cell and clinical associations

Human chorionic gonadotrophin (hCG) is released within hours of fertilization and has a profound ability to downregulate maternal cellular immunity against trophoblastic paternal antigens. It also promotes angiogenic activity of the extravillous trophoblast, and impairment of this function may lead to inadequate placentation and an increased risk of preeclampsia. There is increasing evidence that hCG alters the activity of dendritic cells via an upregulation of indoleamine 2,3-dioxygenase activity. This reduces T-cell activation and cytokine production, as well as encouraging Treg cell recruitment to the fetal-maternal interface. These changes are critical in promoting maternal tolerance. hCG is also able to increase the proliferation of uterine natural killer cells, while reducing the activity of cytotoxic peripheral blood natural killer cells. There are rare reports of autoantibodies directed against hCG or the luteinizing hormone/hCG receptor in women with recurrent miscarriage. These autoantibodies are more frequent in women with thyroid autoimmunity. This may explain the association between thyroid autoimmunity and impaired fertility. Downregulating these anti-hCG and anti-luteinizing hormone/hCG receptor autoantibodies may be helpful in some women with early miscarriage or recurrent failed in vitro fertilization.

Mechanism of human chorionic gonadotrophin-mediated immunomodulation in pregnancy

Like other mucosal surfaces (eg, the gastrointestinal tract, the respiratory tract), the human female reproductive tract acts as an initial barrier to foreign antigens In this role, the epithelial surface and subepithelial immune cells must balance protection against pathogenic insults against harmful inflammatory reactions and acceptance of particular foreign antigens Two common examples of these acceptable foreign antigens are the fetal allograft and human semen/sperm Both are purposely deposited into the female genital tract and appropriate immunologic response to these non-self antigens is essential to the survival of the species In light of the weight of this task, it is not surprising that multiple, redundant and overlapping mechanisms are involved For instance, cells at the immunologic interface between self (female reproductive tract epithelium) and non-self (placental trophoblast cells or human sperm) express glycosylation patterns that mimic those on many metastatic cancer cells and successful pathogens The cytokine/chemokine milieu at this interface is altered through endocrine and immunologic mechanisms to favor tolerance of non-self The “foreign” cells themselves also play an integral role in their own immunologic acceptance, since sperm and placental trophoblast cells are unusual and unique in their antigen presenting molecule expression patterns Here, we will discuss these and other mechanisms that allow the human female reproductive tract to perform this delicate and indispensible balancing act

/pdf/manifestations-of-immune-tolerance-in-the-human-female-52qbhbz5n0.pdf

Manifestations of immune tolerance in the human female reproductive tract.

Abstract Extracellular vesicles (EVs) are promising carriers for the delivery of a variety of chemical and biological drugs. However, their efficacy is limited by the lack of cellular specificity. Available methods to improve the tissue specificity of EVs predominantly rely on surface display of proteins and peptides, largely overlooking the dense glycocalyx that constitutes the outermost layer of EVs. In the present study, we report a reconfigurable glycoengineering strategy that can endogenously display glycans of interest on EV surface. Briefly, EV producer cells are genetically engineered to co‐express a glycosylation domain (GD) inserted into the large extracellular loop of CD63 (a well‐studied EV scaffold protein) and fucosyltransferase VII (FUT7) or IX (FUT9), so that the engineered EVs display the glycan of interest. Through this strategy, we showcase surface display of two types of glycan ligands, sialyl Lewis X (sLeX) and Lewis X, on EVs and achieve high specificity towards activated endothelial cells and dendritic cells, respectively. Moreover, the endothelial cell‐targeting properties of sLeX‐EVs were combined with the intrinsic therapeutic effects of mesenchymal stem cells (MSCs), leading to enhanced attenuation of endothelial damage. In summary, this study presents a reconfigurable glycoengineering strategy to produce EVs with strong cellular specificity and highlights the glycocalyx as an exploitable trait for engineering EVs.

Cell‐specific targeting of extracellular vesicles though engineering the glycocalyx

Human amniotic fluid contains a variety of glycoproteins. Several of these substances have been shown to exert immunomodulatory effects. Glycodelin, previously known as placental protein 14, is one of these glycoproteins. It has a unique carbohydrate configuration, consistent with fucosylated LacdiNAc structures that are very unusual for mammals. Oligosaccharides with fucosylated LacdiNAc antennae have previously been shown to block selectin-mediated cell adhesion. Another glycoprotein, human transferrin, is also present in amniotic fluid in relatively high concentrations. This transferrin shows a different glycosylation compared with serum transferrin. Amniotic fluid transferrin carries sialylated Lewis X antigens. Glycodelin and transferrin were isolated from amniotic fluid and for comparison from serum of pregnant women by chromatographic methods. The purified proteins were used as ligands to block E-selectin-mediated HepG2 cell adhesion. Two types of binding assays with distinct receptor accommodations (immobilised E-selectin and activated HUVECs) were used to quantify inhibition efficiencies of the different proteins. We found that glycodelin is a strong inhibitor with a 10(3)-fold potency compared to the monovalent tetrasaccharide sialyl Lewis X whereas the potency of transferrin is rather low.

Glycodelin and amniotic fluid transferrin as inhibitors of E-selectin-mediated cell adhesion.

Objective: Human chorionic gonadotropin (hCG) is a placental glycoprotein hormone of clinical importance. It is secreted into maternal circulation, amniotic fluid, urine and is also found in the serum and urine of patients with malignant trophoblastic diseases. Depending on the source, we detected a remarkable expression of sialyl Lewis x on this protein. Sialyl Lewis x is known as a minimal ligand recognized by selectins, which are involved in cell adhesion processes in inflammatory and metastatic diseases. In this context, the purpose of the study was to explore the ability of hCG to serve as a selectin antagonist. Materials and Methods: We purified hCG from human amniotic fluid, serum and urine of pregnant women and from supernatants of the trophoblastic tumour cell lines Jeg3 and BeWo by immunoadsorption chromatography. The proteins were functionally tested for a specific blockade of the E-selectin-mediated cell adhesion in vitro. The efficiencies of hCG from different origins were compared. Results: We found that hCG isolated from serum, amniotic fluid and supernatant of the cell line Jeg3 were strong inhibitors with at least 10 3 -fold higher potency compared to the monovalent tetrasaccharide sialyl Lewis x . As expected from the carbohydrate expression, hCG isolated from the urine of pregnant women, but even from the supernatant of BeWo cells, showed no inhibitory effect. Conclusion: hCG is an effective selectin antagonist. This fact suggests that hCG may play a role in preventing leukocyte adhesion on the foetal syncytiotrophoblast or the metastatic activity of trophoblastic tumour cells. The physiological role of human chorionic gonadotropin (hCG) during pregnancy is not completely understood. It is generally believed that hCG production by trophoblast stimulates progesterone secretion and thus contributes to the maintenance of the corpus luteum of pregnancy. Expression of hCG is detectable as early as the 8-cell stage

Human chorionic gonadotropin (hCG) as inhibitior of E-selectin-mediated cell adhesion.

Human chorionic gonadotropin (hCG) is a placental hormone and marker for the differentiation process of cytotrophoblast cells to syncytial trophoblasts. It is secreted into the maternal circulation and urine. The glycoprotein hCG is also found in the serum and urine of patients with malignant trophoblastic diseases. For this study hCG was purified from pooled human mid-trimester amniotic fluid, serum and urine of pregnant women and from supernatants of trophoblast tumour cell cultures Jeg3 and BeWo by immunoadsorption chromatography with specific hCG-antibodies. The purity and identity of the isolated hCG were checked by Western blot analysis. Sialylated oligosaccharides of the Lewis type of isolated hCGs were analysed by dot blot and ELISA technique with monoclonal antibodies specific for sialyl Lewis x and sialyl Lewis a-carbohydrate epitopes. BeWo and Jeg 3 cells were additionally investigated by immunofluorescence. HCG isolated from the serum and amnion of pregnant women bear both sialyl Lewis x (sLex)-antigen and sialyl Lewis a (sLea)-antigen. The same result was observed for hCG isolated from the supernatants of the trophoblast tumour cell line Jeg3. On the contrary, hCG isolated from the supernatants of the trophoblast tumour cell line BeWo showed only a very weak expression of these antigens. HCG isolated from the urine of pregnant women was negative for both sialyl Lewis antigens. The results are discussed with respect to a possible relationship to selectin- mediated cell adhesion processes. This could play a role in the prevention of leukocyte adhesion on the foetal syncytiotrophoblast. Glycosylation of hCG in trophoblast tumour cells, on the other hand, could increase the metastatic activity of these cells.

hCG in trophoblast tumour cells of the cell line Jeg3 and hCG isolated from amniotic fluid and serum of pregnant women carry oligosaccharides of the sialyl Lewis X and sialyl Lewis a type.

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Glycodelin and amniotic fluid transferrin as inhibitors of E-selectin-mediated cell adhesion.

Human chorionic gonadotropin (hCG) as inhibitior of E-selectin-mediated cell adhesion.

hCG in trophoblast tumour cells of the cell line Jeg3 and hCG isolated from amniotic fluid and serum of pregnant women carry oligosaccharides of the sialyl Lewis X and sialyl Lewis a type.