Pregnancy-induced effects on memory B-cell development in multiple sclerosis.
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ABSTRACT:
SUBMITTER: Janssen M
PROVIDER: S-EPMC8190290 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Pregnancy affects the disease course in multiple sclerosis (MS), particularly in the third trimester, where the relapse rate is reduced by as much as two thirds. This study aimed at identifying changes in microRNA (miRNA) and immune cell phenotypes in pregnant MS patients. Discovery and validation studies to detect differentially expressed miRNAs were performed with quantitative real-time PCR on peripheral blood mononuclear cells (PBMC). Flow cytometry analysis was performed on PBMC stained with antibodies directed against surface markers of antigen presenting cells (APCs), NK-cells, NKT cells, CD4+ and CD8+ T cells and subsets of these cell types, including PDL1 and PDL2 expressing subsets. RNA was extracted from whole blood, monocytes, and NK-cells to investigate expression and correlation between regulated miRNAs and mRNAs. In total, 15 miRNAs were validated to be differentially expressed between third trimester pregnant and postpartum MS patients (Benjamini-Hochberg false discovery rate from p = 0.03-0.00004). Of these, 12 miRNAs were downregulated in pregnancy and 6 of the 15 miRNAs were altered by more than ±2-fold (+2.99- to -6.38-fold). Pregnant MS patients had a highly significant increase in the percentage of monocytes and a decrease of NK-cells and myeloid dendritic cells compared to non-pregnant MS patients. We confirm previous reports of a relative increase in CD56-bright NK-cells and a decrease in CD56-dim NK-cells in third trimester of pregnancy and report an increase in non-committed follicular helper cells. PDL1 and PDL2 expression was increased in pregnant patients together with IL10. Also, in monocytes IL10, PDL1, and PDL2 were upregulated whereas miR-1, miR-20a, miR-28, miR-95, miR-146a, miR-335, and miR-625 were downregulated between pregnant and untreated MS patients. IL10, PDL1, and PDL2 were predicted targets of MS pregnancy-changed miRNAs, further supported by their negative correlations. Additionally, previously identified pregnancy-regulated mRNAs were identified as predicted targets of the miRNAs. PDL1 and PDL2 bind PD-1 expressed on T cells with an inhibitory effect on T-cell proliferation and increase in IL10 production. These results indicate that some of the effects behind the disease-ameliorating third trimester of pregnancy might be caused by changed expression of miRNAs and immunoregulatory molecules in monocytes.
| S-EPMC7876450 | biostudies-literature
Project description:In multiple sclerosis (MS), relapse rate is decreased by 70-80% in the third trimester of pregnancy. However, the underlying mechanisms driving this effect are poorly understood. Evidence suggests that CD56bright NK cell frequencies increase during pregnancy. Here, we analyze pregnancy-related NK cell shifts in a large longitudinal cohort of pregnant women with and without MS, and provide in-depth phenotyping of NK cells. In healthy pregnancy and pregnancy in MS, peripheral blood NK cells showed significant frequency shifts, notably an increase of CD56bright NK cells and a decrease of CD56dim NK cells toward the third trimester, indicating a general rather than an MS-specific phenomenon of pregnancy. Additional follow-ups in women with MS showed a reversal of NK cell changes postpartum. Moreover, high-dimensional profiling revealed a specific CD56bright subset with receptor expression related to cytotoxicity and cell activity (e.g., CD16+ NKp46high NKG2Dhigh NKG2Ahigh phenotype) that may drive the expansion of CD56bright NK cells during pregnancy in MS. Our data confirm that pregnancy promotes pronounced shifts of NK cells toward the regulatory CD56bright population. Although exploratory results on in-depth CD56bright phenotype need to be confirmed in larger studies, our findings suggest an increased regulatory NK activity, thereby potentially contributing to disease amelioration of MS during pregnancy.
| S-EPMC9289470 | biostudies-literature
Project description:ObjectiveTo report outcomes of pregnancies that occurred during the fingolimod clinical development program.MethodsPregnancy outcomes from phase II, phase III, and phase IV clinical studies (with optional extensions) were reported by clinical trial investigators. Fingolimod exposure in utero was defined as fingolimod treatment at the time of conception or in the 6 weeks before conception.ResultsAs of October 31, 2011, 89 pregnancies were reported in completed or ongoing clinical studies, with 74 in fingolimod treatment arms. Of 66 pregnancies with in utero exposure to fingolimod, there were 28 live births, 9 spontaneous abortions, 24 elective abortions, 4 ongoing pregnancies, and 1 pregnancy with an unknown outcome (patient lost to follow-up). Two infants were born with malformations: 1 with congenital unilateral posteromedial bowing of the tibia and 1 with acrania. Elective abortions were performed for 1 case each of tetralogy of Fallot, spontaneous intrauterine death, and failure of fetal development. There were 5 cases (7.6%; 95% confidence interval 3%-17%) of abnormal fetal development in the 66 pregnancies that had in utero exposure to fingolimod. In all 5 cases, fetal exposure to the drug took place in the first trimester of pregnancy.ConclusionsThe number of patients becoming pregnant during fingolimod therapy remains small and does not permit firm conclusions to be drawn about fetal safety of fingolimod in humans. Given the known risks of teratogenicity in animals and the present data, women of childbearing potential should use effective contraception during fingolimod therapy and for 2 months after discontinuation.
| S-EPMC3945658 | biostudies-literature
Project description:Multiple sclerosis (MS) is influenced by pregnancy, sex and hormonal factors.A comprehensive understanding of the role of pregnancy, sex and hormonal factors can provide insights into disease mechanisms, and new therapeutic developments and can provide improved patient care and treatment.Based on an international conference of experts and a comprehensive PubMed search for publications on these areas in MS, we provide a review of what is known about the impact of these factors on disease demographics, etiology, pathophysiology and clinical course and outcomes.Recommendations are provided for counseling and management of people with MS before conception, during pregnancy and after delivery. The use of disease-modifying and symptomatic therapies in pregnancy is problematic and such treatments are normally discontinued. Available knowledge about the impact of treatment on the mother, fetus and newborn is discussed. Recommendations for future research to fill knowledge gaps and clarify inconsistencies in available data are made.
| S-EPMC5458871 | biostudies-other
Project description:B cell depleting therapies (BCDTs) are widely used as immunomodulating agents for autoimmune diseases such as multiple sclerosis. Their possible impact on development of immunity to severe acute respiratory syndrome virus-2 (SARS-CoV-2) has raised concerns with the coronavirus disease 2019 (COVID-19) pandemic. We here evaluated the frequency of COVID-19-like symptoms and determined immunological responses in participants of an observational trial comprising several multiple sclerosis disease modulatory drugs (COMBAT-MS; NCT03193866) and in eleven patients after vaccination, with a focus on BCDT. Almost all seropositive and 17.9% of seronegative patients on BCDT, enriched for a history of COVID-19-like symptoms, developed anti-SARS-CoV-2 T cell memory, and T cells displayed functional similarity to controls producing IFN-γ and TNF. Following vaccination, vaccine-specific humoral memory was impaired, while all patients developed a specific T cell response. These results indicate that BCDTs do not abrogate SARS-CoV-2 cellular memory and provide a possible explanation as to why the majority of patients on BCDTs recover from COVID-19.
| S-EPMC8410640 | biostudies-literature
Project description:Few studies have assessed the risk of adverse pregnancy outcomes in women with multiple sclerosis (MS). We used 2 large US administrative databases, the Truven Health MarketScan Database (2011-2015; Truven Health Analytics Inc., Ann Arbor, Michigan) and the Nationwide Inpatient Sample (2007-2011), to identify delivery cohorts. MS and pregnancy outcomes (infections, cesarean delivery, preterm delivery, poor fetal growth, preeclampsia, chorioamnionitis, postpartum hemorrhage, stillbirth, and infant malformations) were identified during pregnancy and at delivery. We calculated adjusted risk ratios according to MS status and relapse(s) in the year before delivery. Among over 5 million pregnancies, we identified 3,875 pregnancies in women with MS. Women with MS had an increased risk of infections during pregnancy (Truven Health: adjusted risk ratio (aRR) = 1.22, 95% confidence interval (CI): 1.16, 1.27) and preterm delivery (Truven Health: aRR = 1.19 (95% CI: 1.04, 1.35); Nationwide Inpatient Sample: aRR = 1.30 (95% CI: 1.16, 1.44)). The risks of other outcomes were similar for women with and without MS. In the Truven Health database, risk ratios for the pregnancy outcomes in women experiencing relapses versus those without relapses were between 0.9 and 1.4, and confidence intervals overlapped the null. Overall, women with MS had an increased risk of infections and preterm delivery; however, their risks for other adverse pregnancy outcomes were not elevated. Disease activity before delivery was not a strong predictor of outcomes.
| S-EPMC6321796 | biostudies-literature
Project description:BackgroundMultiple sclerosis (MS) preferentially affects females at childbearing age. For this reason patients and treating physicians were frequently confronted with questions concerning family planning, pregnancy and birth.ObjectiveThe aim of this study was to evaluate the expertise about pregnancy related topics in multiple sclerosis of neurologists in private practice.MethodsWe developed a survey with 16 multiple choice questions about pregnancy related topics and sent it to neurologists in private practice in Berlin, Germany.Results56 completed questionnaires were sent back. 54% of all questions were answered correctly, 21% of the questions were answered with "I don't know". Correct answers were more often given by physicians who treat more than 400 MS patients per year (p = 0.001). Further positive associations were found for assumed relevance of the topic (p = 0.002) and the degree of counseling (p<0.001).ConclusionTo provide a comprehensive counseling, MS patients with desire for children should be counseled by physicians with a lot of experience in MS treatment.
| S-EPMC4047092 | biostudies-literature
Project description:While many drugs are effective at reducing the relapse frequency of multiple sclerosis (MS), there is an unmet need for treatments that slow neurodegeneration resulting from secondary disease progression. The mechanism of neurodegeneration in MS has not yet been established. Here, we discovered a potential pathogenetic role of ferroptosis, an iron-dependent regulated cell death mechanism, in MS. We found that critical ferroptosis proteins (acyl-CoA synthetase long-chain family member 4, ACSL4) were altered in an existing genomic database of MS patients, and biochemical features of ferroptosis, including lipid reactive oxygen species (ROS) accumulation and mitochondrial shrinkage, were observed in the experimental autoimmune encephalitis (EAE) mouse model. Targeting ferroptosis with ferroptosis inhibitors or reducing ACSL4 expression improved the behavioral phenotypes of EAE mice, reduced neuroinflammation, and prevented neuronal death. We found that ferroptosis was an early event in EAE, which may promote T-cell activation through T-cell receptor (TCR) signaling in vitro and in vivo. These data indicate that ferroptosis may be a potential target for treating MS.
| S-EPMC9338013 | biostudies-literature
Project description:Autologous hematopoietic stem cell transplantation (AHSCT) has been approved for multiple sclerosis (MS) in many European countries. A large proportion of patients are women of child-bearing age. For them, AHSCT may have negative consequences for reproductive health, since the ovaries are particularly susceptible to alkylating agents. Anti-Müllerian hormone (AMH) reflects the ovarian reserve and has been suggested as a potential biomarker of fertility in women. The aim of this study was to investigate AMH levels in relation to age and reproductive potential in MS patients treated with AHSCT. The study cohort comprised 38 female patients, aged 20-44 years, who underwent AHSCT for MS using a cyclophosphamide (200 mg/kg)/rabbit-anti-thymocyte globulin (6 mg/kg) conditioning regimen between 2013-2020. Clinal follow-up visits were made 3 months after AHSCT and then yearly. AMH was analysed in blood samples. The median age at transplantation was 28 years (interquartile range, IQR 25-33). The median AMH concentration was 23 pmol/l at baseline (IQR 6.0-30), 0.5 pmol/l at 3 months (IQR 0-1.5) and 1.1 pmol/l at 2 years (IQR 0-2.9). A multiple linear regression model was used to determine if age and/or AHSCT influenced AMH values; both significantly did (age, -0.21 per year, p = 0.018; AHSCT -19, p <0.0001). Seven women became pregnant, six spontaneously and one both spontaneously and with IVF. One patient underwent an abortion, all other pregnancies led to live births. Six of the women became pregnant despite low or very low post-AHSCT serum concentrations of AMH, suggesting that low serum AMH concentrations do not necessarily reflect impaired fertility in patients treated with high-dose cyclophosphamide.
| S-EPMC10096464 | biostudies-literature
Project description:Episodic memory deficits are frequent symptoms in Multiple Sclerosis and have been associated with dysfunctions of the hippocampus, a key region for learning. However, it is unclear whether genetic factors that influence neural plasticity modulate episodic memory in MS. We thus studied how the Brain Derived Neurotrophic Factor Val(66)Met genotype, a common polymorphism influencing the hippocampal function in healthy controls, impacted on brain networks underlying episodic memory in patients with Multiple Sclerosis. Functional magnetic resonance imaging was used to assess how the Brain Derived Neurotrophic Factor Val(66)Met polymorphism modulated brain regional activity and functional connectivity in 26 cognitively unimpaired Multiple Sclerosis patients and 25 age- and education-matched healthy controls while performing an episodic memory task that included encoding and retrieving visual scenes. We found a highly significant group by genotype interaction in the left posterior hippocampus, bilateral parahippocampus, and left posterior cingulate cortex. In particular, Multiple Sclerosis patients homozygous for the Val(66) allele, relative to Met(66) carriers, showed greater brain responses during both encoding and retrieval while the opposite was true for healthy controls. Furthermore, a robust group by genotype by task interaction was detected for the functional connectivity between the left posterior hippocampus and the ipsilateral posterior cingulate cortex. Here, greater hippocampus-posterior cingulate cortex connectivity was observed in Multiple Sclerosis Met(66) carriers relative to Val(66) homozygous during retrieval (but not encoding) while, again, the reverse was true for healthy controls. The Val(66)Met polymorphism has opposite effects on hippocampal circuitry underlying episodic memory in Multiple Sclerosis patients and healthy controls. Enhancing the knowledge of how genetic factors influence cognitive functions may improve the clinical management of memory deficits in patients with Multiple Sclerosis.
| S-EPMC3623818 | biostudies-literature