[The relationship between inflammatory and immunological processes during pregnancy. Practical aspects]. / A gyulladásos és immunológiai folyamatok kapcsolata a várandósság alatt. Gyakorlati vonatkozások.

The aim of this review is to explore, in addition to revealing the biological background, new conceptual and therapeutic approaches for reproductive clinicians to provide better and more effective care for sterile and infertile couples. In humans, 75% of unsuccessful pregnancies are the result of failures of implantation, and implantation failure is the limiting factor for in vitro fertilization treatment. A modified "good" inflammation is necessary for implantation and parturition, but for most of pregnancy, inflammation threatens the continuation of pregnancy. During this period, maintaining the non-inflammatory condition is extremely important, enabling the maternal epigenetic effects to occur in the fetus, making it possible for the offspring to adapt as much as possible to the extrauterine life. In the maintenance of the non-inflammatory condition of pregnancy, a large amount of progesterone hormone produced by the placenta (after the luteo-placental shift) plays a crucial role. It has been reported that the role of inflammation during implantation is an ancestral response to the embryo as a foreign body. During normal pregnancy, this inflammation is initiated by the trophoblast and involves the suppression of neutrophil infiltration, the recruitment of natural killer cells to the site of implantation as well as the production of a range of proinflammatory cytokines. During the "implantation window", the uterus is primed to produce several inflammatory signals such as prostaglandin E2 and a range of proinflammatory cytokines, including TNF, IL6 and IFNγ. The feto-placental unit is a semi-foreign graft called a "semi allograft", and the recognition of pregnancy by the mother (host) and the resulting maternal immune tolerance is an essential part of successful pregnancy and the birth of a healthy fetus. Because of the functional or absolute reduction of circulating progesterone (due to the decreasing hormone production of the physiologically "aging" placenta after around the 36th week of pregnancy) progesterone effects become insufficient. Therefore it is unable to suppress the production of IL8 and other inflammatory cytokines and the term inflammation, leading to cervical ripening, uterus contractions and parturition ("good" inflammation). Orv Hetil. 2019; 160(32): 1247-1259.

Human chorionic gonadotropin and IL-35 contribute to the maintenance of peripheral immune tolerance during pregnancy through mediating the generation of IL-10+ or IL-35+ Breg cells.

Regulatory B cells (Breg cells) play critical roles in modulating immune responses during autoimmune diseases and infection. Here we explored the participation of two main Breg subsets, including IL-10+ Breg (B10) and IL-35+ Breg cells, in maintaining successful pregnancy. We first observed an elevated percentage of B10 cells in peripheral blood from first-trimester pregnant women compared with non-pregnant controls. Serum from pregnancy induced the augmentation of B10  in peripheral blood mononuclear cells from non-pregnant women. In animal models, we demonstrated that there were significant augmentation of B10 cells and obvious increase of IL-10 level in splenic B cells from normal pregnant mice compared to that in abortion-prone pregnant mice and virgin mice. Further analysis showed that both hCG and IL-35 suppressed the proliferation of mouse splenic B cells. Moreover, IL-35 induced the expansion of both mouse splenic B10 and IL-35+ Breg cells while hCG only mediated the generation of B10 cells. Subsequent study in mice demonstrated that the activation of STAT1 and STAT3 in B cells caused by IL-35 and the activation of STAT3 caused by hCG were the predominant mechanism of IL-35+ Breg and B10 cells augmentation. These findings suggested that hCG and IL-35 induced the amplification of B10 and IL-35+ Breg cells which played a vital peripheral regulatory role during pregnancy.

Molecular profiling demonstrates modulation of immune cell function and matrix remodeling during luteal rescue†.

The corpus luteum (CL) is essential for maintenance of pregnancy in all mammals and luteal rescue, which occurs around day 16-19 in the cow, is necessary to maintain luteal progesterone production. Transcriptomic and proteomic profiling were performed to compare the day 17 bovine CL of the estrous cycle and pregnancy. Among mRNA and proteins measured, 140 differentially abundant mRNA and 24 differentially abundant proteins were identified. Pathway analysis was performed using four programs. Modulated pathways included T cell receptor signaling, vascular stability, cytokine signaling, and extracellular matrix remodeling. Two mRNA that were less in pregnancy were regulated by prostaglandin F2A in culture, while two mRNA that were greater in pregnancy were regulated by interferon tau. To identify mRNA that could be critical regulators of luteal fate, the mRNA that were differentially abundant during early pregnancy were compared to mRNA that were differentially abundant during luteal regression. Eight mRNA were common to both datasets, including mRNA related to regulation of steroidogenesis and gene transcription. A subset of differentially abundant mRNA and proteins, including those associated with extracellular matrix functions, were predicted targets of differentially abundant microRNA (miRNA). Integration of miRNA and protein data, using miRPath, revealed pathways such as extracellular matrix-receptor interactions, abundance of glutathione, and cellular metabolism and energy balance. Overall, this study has provided a comprehensive profile of molecular changes in the corpus luteum during maternal recognition of pregnancy and has indicated that some of these functions may be miRNA-regulated.

Comportamiento de las células asesinas naturales, las dendríticas y los macrófagos, en el embarazo / Behavior of the natural killer cells, dendritic cells and macrophages in pregnancy

La implantación de un embrión semialogénico en el útero materno constituye una paradoja inmunológica y es uno de los fenómenos que abre más interrogantes dentro del campo de la Inmunología. Mientras que en un determinado momento se consideró que la interfase materno-fetal era un sitio inmunológicamente privilegiado, hoy se sabe que ocurre un reconocimiento del feto semialogénico por el sistema inmune de la madre. Sin embargo, a pesar de este reconocimiento inmunológico se han descubierto varios mecanismos que pueden explicar el porqué la madre no rechaza al feto antigénicamente diferente. Estos mecanismos incluyen, tanto factores fetales como factores locales maternos, donde están incluidos los elementos de la respuesta inmunitaria adaptativa e innata. En este trabajo se hace referencia a la importante función que desempeñan las células asesinas naturales, las células dendríticas y los macrófagos en el embarazo(AU)

The implantation of a semiallogenic embryo in the womb is an immunological paradox and is one of the phenomena that open more questions in the field of immunology. While at one point it was considered that the maternal-fetal interface was an immunologically privileged site, now it is known that a fetus semiallogenic recognition by the immune system of the mother occurs. However, despite this immune recognition several mechanisms have been discovered that may explain why the mother does not reject the fetus antigenically different. These mechanisms include both fetal factors and local maternal factors, where the elements of innate and adaptive immune response are included. In this paper we refer to the important role of natural killer cells, dendritic cells and macrophages in pregnancy(AU)

Comportamiento de las células asesinas naturales, las dendríticas y los macrófagos, en el embarazo / Behavior of the natural killer cells, dendritic cells and macrophages in pregnancy

La implantación de un embrión semialogénico en el útero materno constituye una paradoja inmunológica y es uno de los fenómenos que abre más interrogantes dentro del campo de la Inmunología. Mientras que en un determinado momento se consideró que la interfase materno-fetal era un sitio inmunológicamente privilegiado, hoy se sabe que ocurre un reconocimiento del feto semialogénico por el sistema inmune de la madre. Sin embargo, a pesar de este reconocimiento inmunológico se han descubierto varios mecanismos que pueden explicar el porqué la madre no rechaza al feto antigénicamente diferente. Estos mecanismos incluyen, tanto factores fetales como factores locales maternos, donde están incluidos los elementos de la respuesta inmunitaria adaptativa e innata. En este trabajo se hace referencia a la importante función que desempeñan las células asesinas naturales, las células dendríticas y los macrófagos en el embarazo(AU)

The implantation of a semiallogenic embryo in the womb is an immunological paradox and is one of the phenomena that open more questions in the field of immunology. While at one point it was considered that the maternal-fetal interface was an immunologically privileged site, now it is known that a fetus semiallogenic recognition by the immune system of the mother occurs. However, despite this immune recognition several mechanisms have been discovered that may explain why the mother does not reject the fetus antigenically different. These mechanisms include both fetal factors and local maternal factors, where the elements of innate and adaptive immune response are included. In this paper we refer to the important role of natural killer cells, dendritic cells and macrophages in pregnancy(AU)

Síndrome antifosfolípido en mujeres con pérdidas recurrentes de embarazo: diagnóstico de laboratorio / Antiphospholipid syndrome in women with recurrent pregnancy loss: laboratory diagnosis

El síndrome antifosfolípido es el tipo de trombofilia adquirida más frecuente y se define como un estado de hipercoagulabilidad de causa autoimnune, que puede provocar trombosis arterial, venosa, o ambas; así como una amplia gama de complicaciones obstétricas por lo general asociadas a insuficiencia placentaria. Entre ellas están: la pérdida gestacional recurrente, la muerte fetal, la preclampsia grave precoz, la restricción del crecimiento intrauterino, el desprendimiento precoz de placenta y los partos prematuros. En general, en los países en vías de desarrollo se desconoce la magnitud del problema ocasionado por estos anticuerpos antifosfolípidos en mujeres con pérdidas recurrentes de embarazo, debido a que para el diagnóstico de esta entidad se precisa de pruebas que resultan costosas, que requieren de personal calificado para su interpretación y por otra parte, no existe uniformidad en los criterios de laboratorio utilizados por diferentes instituciones para realizar el diagnóstico. En Cuba contamos con posibilidades diagnósticas para la identificación de los anticuerpos antifosfolípidos, lo que constituye un pilar fundamental en el análisis diferencial de esta entidad obstétrica; por ello, la combinación de un diagnóstico adecuado, un minucioso seguimiento y un tratamiento certero redundarán en el éxito del embarazo(AU)

The antiphospholipid syndrome is the most common type of acquired thrombophilia and is defined as a hypercoagulable state of autoimmune cause, which can provoke arterial and/or venous thrombosis, as well as a wide range of adverse obstetric complications associated to placental insufficiency. Among them are the recurrent pregnancy loss, stillbirth, early severe preeclampsia, intrauterine growth restriction, premature placental abruption and premature births. In general, in developing countries the magnitude of the problem caused by these antiphospholipid antibodies in women with recurrent pregnancy losses is high, as tests of elevated cost for the diagnosis of this disease are needed, which also requires qualified personnel for the interpretation of results and there is no uniformity in the laboratory criteria used for diagnosis by different institutions In Cuba we have diagnostic possibilities for the identification of these antiphospholipids which is a fundamental pillar in the differential analysis of this obstetric entity; therefore, the combination of an accurate diagnosis, careful monitoring and the proper treatment, guarantees pregnancy success(AU)

Which types of regulatory T cells play important roles in implantation and pregnancy maintenance?

Regulatory T cells (Treg) play essential roles in implantation and allogeneic pregnancy maintenance in mice and humans. Recent data have shown the heterogeneity of Treg, such as thymic (naturally occurring) Treg, extrathymic (inducible or peripheral) Treg, naïve Treg, effector Treg, resting (non-proliferating) Treg and activated (proliferating) Treg. Importantly, Foxp3, which was believed to be a specific marker for Treg, is transiently expressed in T cells when conventional T cells are activated and proliferating in humans showing that Foxp3 is not a specific marker for Treg. Therefore, we should evaluate the true Treg level and clarify which types of Treg cells play important roles in implantation and pregnancy maintenance in mice and humans.

The role of B cells in pregnancy: the good and the bad.

B lymphocytes are pleiotropic cells belonging to the adaptive arm of the immune system. Although B cells were classically regarded for their capacity to produce antibodies, in the recent years, several other functions were attributed to these cells. B cells can uptake, process and present antigens as well as produce several cytokines that further influence immunity.Mammalian pregnancies represent a fascinating phenomenon in which the maternal immune system must be able to 'tolerate' the semi-allogenic fetus while simultaneously protecting the mother and the fetus against external pathogens. This requires a finely regulated balance between immune activation and tolerance. In this regard, B cells and the antibodies they produced were shown to actively participate in both, pregnancy well-being as well as pregnancy-associated pathologies.We discuss here the currently available information concerning the role of B cells in the context of pregnancy.

Células natural killer endometriais: o que são? O que fazem? O que devemos saber? / Endometrial natural killer cells: what are they? What do they do? What do we need to know?

As células natural killer endometriais, também chamadas células natural killer uterinas, têm recebido especial atenção no campo da imunologia reprodutiva. Teorias que consideram alterações na resposta imune como uma causa de infertilidade conjugal e de falhas nos tratamentos de reprodução assistida têm ponderado um possível envolvimento negativo das células natural killer endometriais. As células natural killer são linfócitos que podem ser identificados no sangue periférico e no endométrio, apresentando diferenças fenotípicas e funcionais importantes. As células periféricas não se alteram com a fase do ciclo menstrual e implantação, sendo que as células natural killer endometriais apresentam variações durante o ciclo menstrual e período peri-implantacional, com menores concentrações durante a fase proliferativa e aumentando na segunda fase do ciclo. A célula natural killer endometriais participam nas várias fases da implantação, invasão trofoblástica, placentação e desenvolvimento fetal e no desenvolvimento da gestação humana até aproximadamente 20 semanas.

Endometrial natural killer cells have been given special attention in reproductive immunology. The relation between the endometrial natural killer cells and alterations in the immune response as a cause of couples infertility and failure in assisted reproduction treatment have been studied in several theories. Natural killer cells are lymphocytes that may be identified in peripheral blood and endometrium, with phenotypical and functional differences between them. Peripheral natural killer cells do not change with the menstrual cycle or implantation, as opposed to endometrial natural killer cells which present lower concentration in the proliferative phase and higher concentration in the luteal phase. Endometrial natural killer cells play an important role in the implantation, trophoblastic invasion, placentation, fetal development and development of the human pregnancies up to 20 weeks of gestation.

[Immunological role of progesterone in the maintenance of pregnancy]. / Papel inmunológico de la progesterona en el mantenimiento del embarazo.

Progesterone is an essential hormone for pregnancy maintenance. This hormone acts by binding to its intracellular receptor or by rapid non-genomic actions to regulate a wide variety of biological functions in the feto-placental unit. Progesterone regulates blastocyst implantation and placental development by inducing immunosuppression through type Th2 cytokines secretion. This review summarizes current research about the role of progesterone as critical regulator of expression and secretion of cytokines by T-cell and other placental cells.

Papel inmunológico de la progesterona en el mantenimiento del embarazo / Immunological role of progesterone in the maintenance of pregnancy

Progesterone is an essential hormone for pregnancy maintenance. This hormone acts by binding to its intracellular receptor or by rapid non-genomic actions to regulate a wide variety of biological functions in the feto-placental unit. Progesterone regulates blastocyst implantation and placental development by inducing immunosupression through type Th2 cytokines secretion. This review summarizes current research about the role of progesterone as critical regulator of expression and secretion of cytokines by T-cell and other placental cells.

La progesterona es una hormona esteroide muy versátil y esencial para el mantenimiento del embarazo. El principal mecanismo de acción de la progesterona es el clásico, vía receptor intracelular, regulando diversas funciones, aspectos celulares y vías moleculares implicadas en el proceso de la implantación. Asimismo existen mecanismos adicionales que no dependen de la interacción del complejo hormona receptor con la maquinaria transcripcional y que son capaces de regular rápidamente cascadas de señalización que determinarán la respuesta de la célula. En particular se ha demostrado que la progesterona ejerce efectos inmunosupresores durante la gestación al favorecer la secreción de citocinas de tipo Th2 por los linfocitos T, evento importante para regular el sistema inmunológico materno y evitar el rechazo de la placenta. El objetivo de esta revisión se centra en analizar la influencia de la progesterona en la interfase materno-fetal sobre la expresión y secreción de citocinas por las células T y no T como es el caso del trofoblasto.

Immunoregulation in normal pregnancy and pre-eclampsia: an overview.

Pre-eclampsia is a major disorder of human pregnancy, which may have an immunological basis. It is a disease of two stages. The first stage concerns the relative failure of early trophoblast invasion and remodelling of the spiral arteries, leading to a poor blood supply to the placenta, exposing it to oxidative stress. The inadequate trophoblast invasion may result from decreased expression of human leukocyte antigen-G (HLA-G) leading to an abnormal interaction with decidual natural killer (NK) cells, which are believed to play a major role in these processes through the production of immunoregulatory cytokines and angiogenic factors. Recent evidence suggests that the interaction between trophoblast human leukocyte antigen-C (HLA-C) molecules and decidual NK cell receptors may be the point at which the apparent partner specificity of the disease originates. The second stage is the maternal syndrome, which is characterized by a generalized systemic inflammatory response involving both leukocytes and endothelium. The inflammatory stimulus is believed to come from the placenta. In pre-eclampsia, placental oxidative stress may lead to increased shedding of apoptotic and/or necrotic syncytiotrophoblast debris into the maternal circulation. There is evidence that such trophoblast debris interacts with maternal leukocytes and endothelial cells to stimulate the release of proinflammatory cytokines, which could then trigger the maternal disease.

The significance of the women's repertoire of natural killer cell receptors in the maintenance of pregnancy.

Large numbers of decidual natural killer (dNK) cells are in direct contact with the invading trophoblast and are considered to be important for pregnancy, since they can produce cytokines and other mediators involved in the control of trophoblast invasion, trophoblast differentiation, decidual artery remodeling and placental augmentation. The dNK cells are also the main candidate cells to attack trophoblast in cases of alloimmune abortions, where the fetus is 'rejected' by the pregnant woman. The function of NK cells is regulated by a balance between activating and inhibitory signals provided by their heterocladic receptor repertoire upon recognition of specific ligands, most of which are HLA molecules (HLA-C, HLA-G, HLA-E) expressed on invading trophoblast. It is a challenge to investigate abortions in regard to the receptors that dNK cells bear and the MHC molecules that the trophoblast expresses. Our studies in couples with recurrent spontaneous abortion as well as in random cases of abortion revealed that aborting women usually have a limited repertoire of inhibitory receptors of the KIR family (inhKIR), and that many of them lack inhKIRs specific for the fetal HLA-Cw antigens. We suggest that some spontaneous abortions are caused because of a limited maternal inhKIR repertoire and a lack of maternal inhKIR-fetal HLA-C epitope matching. Among the different interactions of NK receptors with their specific counterparts on trophoblast, the inhKIR-HLA-C interactions appear to be those mainly involved in the function of an NK cell-mediated allorecognition system in pregnancy.

Nerve growth factor in reproductive biology: link between the immune, endocrine and nervous system?

Successful pregnancy outcome requires balanced networking of the immune and endocrine system. In addition, numerous sophisticated adaptive mechanisms promote invasion of fetal tissue and facilitate tolerance. This highly sensitive and vulnerable environment may be challenged from either the maternal or the fetal site. In this overview we collect evidence of a functional role of neurotrophins, predominately nerve growth factor (NGF), in pregnancy maintenance. We demonstrate several pathways through which NGF may be involved in maintaining pregnancy and/or--if exaggerated--inducing pregnancy failure. Due to the pleiotropism of NGF, we hypothesize that NGF is mandatory for the success of pregnancy, e.g. via inhibition of paternal MHC II molecule expression on trophoblast cells. This is supported by published evidence on progesterone, the hormone of pregnancy, which maintains local levels of NGF. On the other hand, if levels of NGF are upregulated in response to environmental challenges, e.g. stress, this may result in a threat to pregnancy maintenance due to a skew towards proinflammatory cytokines and increased apoptotic cell death. Hence, we strongly suggest that NGF constitutes a functional link between the nervous, endocrine and immune system translating environmental or endocrine signals during pregnancy into an immunological answer.

Treatment of recurrent IVF failure and human leukocyte antigen similarity by intravenous immunoglobulin.

This study sought to assess the efficacy of intravenous immunoglobulin (IVIg) in improving pregnancy rates and outcome, in a select group of patients with repeated IVF failure and human leukocyte antigen (HLA) similarity. Couples suffering from recurrent IVF failure, defined as at least seven attempts at embryo transfer with no successful implantations, who were found to share at least three HLA loci, and a negative cross-match test, were included in the study. The treatment consisted of two 30 g IVIg doses: one before oocyte retrieval, and a second as soon as a fetal pulse was identified on ultrasound. Ten couples comprised the study group. In total, these couples had undergone 98 IVF cycles with no successful pregnancies prior to initiation of the study. Following a total of 18 IVIg courses, seven women conceived, two women twice. Up to date, five women have delivered at least one live fetus, at 27 weeks or later. One woman is currently in the early third trimester of a twin pregnancy, and one woman had a late abortion at 19 weeks. The results suggest that couples with recurrent IVF failure and HLA similarity, may benefit from IVIg treatment.

Depletion of CD8+ cells abolishes the pregnancy protective effect of progesterone substitution with dydrogesterone in mice by altering the Th1/Th2 cytokine profile.

One of the most remarkable immunological regulations is the maternal immune tolerance toward the fetal semiallograft during pregnancy, which has been referred to as immunity's pregnant pause. Rejection of the semiallogeneic trophoblast cells must be selectively inhibited and pathways presumably include Th2 cytokines unopposed by Th1 cytokines. Steroid hormones, including progesterone, have similar effects. Low levels of progesterone and Th2 cytokines and high levels of Th1 cytokines are attributable for increased abortions in mammalians, which may be triggered by psychoemotional stress. Thus, the aim of the present study was to provide experimental evidence for the mechanism involved in the mediation of immune responses by endocrine signals during pregnancy and stress-triggered pregnancy failure. DBA/2J-mated CBA/J female mice were randomized in three groups: 1) control females, 2) mice exposed to stress on gestation day 5.5, and 3) mice exposed to stress and substituted with dydrogesterone, a progestogen with a binding profile highly selective for the progesterone receptor on gestation day 5.5. On gestation days 7.5, 9.5, and 10.5, mice of each group were sacrificed, and the frequency of CD8(+) cells and cytokine expression (IL-4, IL-12, TNF-alpha, IFN-gamma) in blood and uterus cells was evaluated by flow cytometry. Additionally, some mice were depleted of CD8 cells by injection of mAb. We observed that progesterone substitution abrogated the abortogenic effects of stress exposure by decreasing the frequency of abortogenic cytokines. This pathway was exceedingly CD8-dependent, because depletion of CD8 led to a termination of the pregnancy protective effect of progesterone substitution.

Fetal and maternal transforming growth factor-beta 1 may combine to maintain pregnancy in mice.

One of the mysteries of pregnancy is why a mother does not reject her fetuses. Cytokine-modulation of maternal-fetal interactions is likely to be important. However, mice deficient in transforming growth factor-beta1 (TGF beta 1) and other cytokines are able to breed, bringing this hypothesis into question. The phenotype of TGF beta 1 null-mutant mice varies with genetic background. We report here that, in outbred mice, the loss of TGF beta 1-deficient embryos is influenced by the parity of their mother. This is consistent with the loss of mutants being due to immune rejection. An inbred line of TGF beta 1(+/-) mice that supported TGF beta 1-deficient fetuses had high levels of TGF beta 1 in their plasma. Analysis of the amniotic fluids in this line indicated that biologically relevant levels of maternal TGF beta 1 were present in the TGF beta 1(-/-) fetuses. These data are consistent with maternal and fetal TGF beta 1 interacting to maintain pregnancy, within immune-competent mothers.

Shall we properly re-examine the status of allogeneic lymphocyte therapy for recurrent early pregnancy failure?

PROBLEM: How to evaluate immunological therapy advocated for recurrent spontaneous abortion and implantation failure. I was invited to comment on the opinion article of Chaouat (AJRI December 2003). METHODS: A critical examination of key beliefs and application of the principles of evidence and logic utilizing current data. RESULTS AND CONCLUSIONS: Although rationale has no bearing on efficacy of proposed treatments and is not sufficient justification for routine practice, insufficient attention to data concerning patient selection, insufficient attention to treatment methodology, and lack of full disclosure in some clinical trials needs to be corrected. A more systematic collection of follow-up data is needed.

Mothers of very low birth weight infants have less atopy than mothers of full-term infants.

BACKGROUND: Studies on the pregnancy outcome of asthmatic mothers have suggested an increased rate of preterm deliveries. In contrast, our earlier study suggests that mothers of very low birth weight (VLBW) (<1500 g) infants less frequently had atopy than did mothers of full-term infants. METHODS: We inquired about symptoms of atopy and doctor-diagnosed atopy in parents of 370 infants of VLBW (<1500 g) and 544 parents of full-term infants. Odds ratios for atopic symptoms and diagnosed atopy were calculated, and groups were compared with a trend test. RESULTS: Mothers of preterm infants of birth weight (BW) <1000 g significantly less often had physician-diagnosed allergic rhinitis (AR) (P=0.02). Among all the mothers, a trend test showed that maternal AR was significantly (P=0.03) higher in parallel with a higher infant BW. Fathers of infants with different BWs showed no differences in prevalence of atopic symptoms. CONCLUSION: We thus infer that maternal balance between T-helper type 1 (Th1) and Th2 cells, shifted towards Th2 in those with AR, may have a favourable effect on maintenance of pregnancy before gestational week 30.