Auswahl der wissenschaftlichen Literatur zum Thema „Placenta, OPG, Pregnancy, Multiple Sclerosis“

Women with multiple sclerosis (MS) can safely become pregnant and give birth, with no side effects or impediments. Pregnancy is generally accepted as a period of well-being in which relapses have a softer evolution, particularly in the third trimester. Herein, we hypothesized that the placenta, via its “secretome”, could contribute to the recognized beneficial effects of pregnancy on MS activity. We focused on a well-known receptor/ligand/decoy receptor system, such as the one composed by the receptor activator of nuclear factor-kB (RANK), its ligand (RANKL), and the decoy receptor osteoprotegerin (OPG), which have never been investigated in an integrated way in MS, pregnancy, and placenta. We reported that pregnancy at the term of gestation influences the balance between circulating RANKL and its endogenous inhibitor OPG in MS women. We demonstrated that the placenta at term is an invaluable source of homodimeric OPG. By functional studies on astrocytes, we showed that placental OPG suppresses the mRNA expression of the CCL20, a chemokine responsible for Th17 cell recruitment. We propose placental OPG as a crucial molecule for the recognized beneficial effect of late pregnancy on MS and its potential utility for the development of new and more effective therapeutic approaches.

ObjectiveTo investigate differences in pregnancy-related and perinatal outcomes in women with multiple sclerosis (MS) compared with the general population.MethodsWe conducted a cross-sectional study including pregnancies from January 1, 1997, to December 31, 2016, to women registered in the Danish Multiple Sclerosis Registry (the study cohort). Pregnancy-related and perinatal outcomes were compared with a randomly selected subcohort of pregnancies from the general population (the comparison cohort) using logistic regression adjusted for possible confounders.ResultsIn total, 2,930 pregnancies were included in the study cohort and 56,958 pregnancies in the comparison cohort. No differences were found in pregnancy-related complications (preeclampsia/gestational diabetes or placenta complications), emergency caesarean section (c-section), instrumental delivery, low Apgar score, stillbirth, preterm birth, or congenital malformations. Elective c-section (odds ratio [OR] 1.89 [95% confidence interval (CI) 1.65–2.16]), induced delivery (OR 1.15 [95% CI 1.01–1.31]), and being born small for gestational age (SGA) (OR 1.29 [95 %CI 1.04–1.60]) had a higher prevalence in the study cohort, whereas the prevalence of signs indicating asphyxia was lower in the study cohort (OR 0.87 [95% CI 0.78–0.97]) relative to the comparison cohort.ConclusionWe found a higher prevalence of elective c-sections, induced delivery, and infants being SGA among newborns to women with MS, whereas the prevalence of asphyxia was lower in the study cohort. There were no significant differences in severe adverse perinatal outcomes when comparing women with MS and their newborns with those of the general population.

Purpose of ReviewThere is considerable heterogeneity in the use of B-cell depletion in women of childbearing age, likely driven at least in part by the discrepancy between the product labels and what is known about the physiology of IgG1, including breastmilk and placental transfer.Recent FindingsWe provide practical considerations on the use of this medication class in women of childbearing potential. We discuss prepregnancy planning including vaccinations, safety of B-cell depletion during pregnancy, and postpartum considerations including breastfeeding.SummaryB-cell–depleting monoclonal antibodies have shown to be effective for prepregnancy and postpartum prevention of inflammatory activity in MS and neuromyelitis optica spectrum disorder. B-cell–depleting therapies are large IgG1 monoclonal antibodies, which have minimal transfer across the placenta and into breastmilk. Consideration of risks and benefits of these therapies should be considered in counseling women planning pregnancy and postpartum.

Pregnancy is a unique situation of physiological immunomodulation, as well as a strong Multiple Sclerosis (MS) disease modulator whose mechanisms are still unclear. Both maternal (decidua) and fetal (trophoblast) placental cells secrete extracellular vesicles (EVs), which are known to mediate cellular communication and modulate the maternal immune response. Their contribution to the MS disease course during pregnancy, however, is unexplored. Here, we provide a first phenotypic and functional characterization of EVs isolated from cultures of term placenta samples of women with MS, differentiating between decidua and trophoblast. In particular, we analyzed the expression profile of 37 surface proteins and tested the functional role of placental EVs on mono-cultures of CD14+ monocytes and co-cultures of CD4+ T and regulatory T (Treg) cells. Results indicated that placental EVs are enriched for surface markers typical of stem/progenitor cells, and that conditioning with EVs from samples of women with MS is associated to a moderate decrease in the expression of proinflammatory cytokines by activated monocytes and in the proliferation rate of activated T cells co-cultured with Tregs. Overall, our findings suggest an immunomodulatory potential of placental EVs from women with MS and set the stage for a promising research field aiming at elucidating their role in MS remission.

Accumulating evidence highlights the pathogenetic role of human endogenous retroviruses (HERVs) in eliciting and maintaining multiple sclerosis (MS). Epigenetic mechanisms, such as those regulated by TRIM 28 and SETDB1, are implicated in HERV activation and in neuroinflammatory disorders, including MS. Pregnancy markedly improves the course of MS, but no study explored the expressions of HERVs and of TRIM28 and SETDB1 during gestation. Using a polymerase chain reaction real-time Taqman amplification assay, we assessed and compared the transcriptional levels of pol genes of HERV-H, HERV-K, HERV-W; of env genes of Syncytin (SYN)1, SYN2, and multiple sclerosis associated retrovirus (MSRV); and of TRIM28 and SETDB1 in peripheral blood and placenta from 20 mothers affected by MS; from 27 healthy mothers, in cord blood from their neonates; and in blood from healthy women of child-bearing age. The HERV mRNA levels were significantly lower in pregnant than in nonpregnant women. Expressions of all HERVs were downregulated in the chorion and in the decidua basalis of MS mothers compared to healthy mothers. The former also showed lower mRNA levels of HERV-K-pol and of SYN1, SYN2, and MSRV in peripheral blood. Significantly lower expressions of TRIM28 and SETDB1 also emerged in pregnant vs. nonpregnant women and in blood, chorion, and decidua of mothers with MS vs. healthy mothers. In contrast, HERV and TRIM28/SETDB1 expressions were comparable between their neonates. These results show that gestation is characterized by impaired expressions of HERVs and TRIM28/SETDB1, particularly in mothers with MS. Given the beneficial effects of pregnancy on MS and the wealth of data suggesting the putative contribution of HERVs and epigenetic processes in the pathogenesis of the disease, our findings may further support innovative therapeutic interventions to block HERV activation and to control aberrant epigenetic pathways in MS-affected patients.

La placenta è un organo di fondamentale importanza per il successo della gravidanza; è coinvolta nel dialogo tra la madre e il feto, non solo fornendo ossigeno e nutrienti essenziali al bambino in via di sviluppo, ma ha anche un ruolo attivo nella sintesi e nel rilascio di fattori nella circolazione materna e fetale. La gravidanza è anche nota per sopprimere la risposta infiammatoria in alcune malattie autoimmuni, come ad esempio la sclerosi multipla. Questi effetti benefici della gravidanza sono sempre stati ricondotti ai cambiamenti che il sistema immunitario materno mette in atto per accettare la nuova vita, ma ben poco sappiamo sul ruolo della placenta. Di particolare interesse è il potenziale coinvolgimento della placenta nella produzione del recettore esca Osteoprotegerina (OPG), che controlla il legame del recettore “receptor activator of NF-kB” (RANK) con il suo ligando (RANKL). Tuttavia, il ruolo della placenta nell'asse RANK/RANKL/OPG è elusivo e poco chiaro. Questo lavoro di tesi mira a determinare i livelli di espressione di OPG e RANKL nella placenta umana durante la gestazione. E’ stato ipotizzato che l’OPG secreto dalla placenta potesse modulare l'attività del sistema RANK/RANKL e quindi contribuire ad un esito positivo della gravidanza. Gli studi in vitro sono stati eseguiti utilizzando tessuto placentare fresco e colture di espianti placentari per monitorare i cambiamenti nel sistema RANK/RANKL/OPG durante la gravidanza. Abbiamo dimostrato che la gravidanza a termine della gestazione influenza l'equilibrio tra il RANKL circolante e il suo inibitore endogeno OPG nelle donne con sclerosi multipla. Abbiamo anche scoperto che la placenta a termine è una fonte inestimabile di OPG dimerico, noto per esercitare la massima attività come recettore esca. E’ stata posta poi l’attenzione sull'asse placenta-cervello, essendo centrale in condizioni associate a una significativa insufficienza placentare, che rappresenta un fattore di rischio per lo sviluppo di malattie legate al sistema nervoso. L’ipotesi è che il secretoma placentare possa regolare la fisiologia di un particolare tipo di cellule gliali: gli astrociti. Attraverso studi funzionali sugli astrociti, abbiamo dimostrato che l’OPG placentare sopprime l'espressione genica di alcune chemochine responsabili del reclutamento dei linfociti Th17 promuovendo l’infiammazione. Sulla base di questi risultati è possibile affermare che la placenta sia fonte di fattori "protettivi" come l’OPG, che questa sia una molecola cruciale per il riconosciuto effetto benefico della tarda gravidanza sulla sclerosi multipla e che abbia una potenziale utilità per lo sviluppo di nuovi e più efficaci approcci terapeutici.
The placenta is an organ of fundamental importance for a successful pregnancy; it’s involved in cross-talk between mother and fetus, not only delivering essential oxygen and nutrients to the developing baby but also playing an active role in the synthesis and release of “information” factors in maternal and fetal circulation. Pregnancy is also known to suppress the inflammatory response in some autoimmune diseases, like multiple sclerosis. These beneficial effects of pregnancy have always been traced back to the changes that the maternal immune system makes to accept new life. Of particular interest is the potential involvement of the placenta in the production of the decoy receptor Osteoprotegerin (OPG), which controls the binding of the receptor activator of nuclear factor-kB (RANK) to its ligand (RANKL). However, the role of the placenta in the RANK/RANKL/OPG axis is currently elusive. We hypothesized that OPG secreted by the placenta could modulate the activity of the RANK/RANKL system and thus contribute to a positive pregnancy outcome. Therefore, this study aimed to determine the expression levels of OPG and RANKL in the physiological human placenta during gestation. To this end, fresh placental tissue and cultures of placental explants were collected at different times of gestation, to monitor changes in the RANK/RANKL/OPG system during pregnancy. We also focused on the placenta-brain axis, being central in pathological conditions associated with significant placental insufficiency, which represents a risk factor for the development of diseases related to the nervous system. We hypothesized that the placental secretome regulates the physiology of a particular type of glial cell: the astrocytes. Using human placenta explants conditioned media, we investigate the astrocyte response following their activation towards an inflammatory phenotype. In vitro studies have highlighted the pivotal role of the placenta in the production and release of OPG. Furthermore, we found that OPG levels were higher in maternal blood than in cord blood and they increase as pregnancy progresses, reaching maximum levels at the end of gestation. The results for soluble RANKL (sRANKL) showed an increase in serum during pregnancy but no change in its production by the placenta. Concerning the analysis conducted on the serum of patients with multiple sclerosis, we can highlight that the levels of sRANKL remain high, both in pregnancy and not. Interesting is the behaviour of the molecule OPG, whose levels increase in pregnancy going to balance the high levels of sRANKL. Finally, by analysing the gene expression of in vitro activated astrocytes towards a pro-inflammatory phenotype, an up-regulation of pro-inflammatory chemokines was seen, which returned to physiological levels when treated with placental secretome containing 'protective' molecules such as OPG.