Prominent epigenetic and transcriptomic changes in CD4+ and CD8+ T cells during and after pregnancy in women with multiple sclerosis and controls.

BACKGROUND: Multiple sclerosis (MS) is a neuroinflammatory disease in which pregnancy leads to a temporary amelioration in disease activity as indicated by the profound decrease in relapses rate during the 3rd trimester of pregnancy. CD4+ and CD8+ T cells are implicated in MS pathogenesis as being key regulators of inflammation and brain lesion formation. Although Tcells are prime candidates for the pregnancy-associated improvement of MS, the precise mechanisms are yet unclear, and in particular, a deep characterization of the epigenetic and transcriptomic events that occur in peripheral T cells during pregnancy in MS is lacking. METHODS: Women with MS and healthy controls were longitudinally sampled before, during (1st, 2nd and 3rd trimesters) and after pregnancy. DNA methylation array and RNA sequencing were performed on paired CD4+ and CD8+ T cells samples. Differential analysis and network-based approaches were used to analyze the global dynamics of epigenetic and transcriptomic changes. RESULTS: Both DNA methylation and RNA sequencing revealed a prominent regulation, mostly peaking in the 3rd trimester and reversing post-partum, thus mirroring the clinical course with improvement followed by a worsening in disease activity. This rebound pattern was found to represent a general adaptation of the maternal immune system, with only minor differences between MS and controls. By using a network-based approach, we highlighted several genes at the core of this pregnancy-induced regulation, which were found to be enriched for genes and pathways previously reported to be involved in MS. Moreover, these pathways were enriched for in vitro stimulated genes and pregnancy hormones targets. CONCLUSION: This study represents, to our knowledge, the first in-depth investigation of the methylation and expression changes in peripheral CD4+ and CD8+ T cells during pregnancy in MS. Our findings indicate that pregnancy induces profound changes in peripheral T cells, in both MS and healthy controls, which are associated with the modulation of inflammation and MS activity.

Chemokine and cytokine profiles in preterm and term labor, in preterm prelabor rupture of the membranes, and in normal pregnancy.

The objective of this study was to investigate the immune mechanisms involved in preterm labor (PTL), preterm prelabor rupture of the membranes (PPROM), and normal pregnancies. The second objective was to explore immune profiles in PTL for association with early ( < 34 gestational weeks (gw)) or instant ( < 48 h) delivery. This prospective observational multi-center study included women with singleton pregnancies with PTL (n = 80) or PPROM (n = 40) before 34 gw, women with normal pregnancies scheduled for antenatal visits (n = 44), and women with normal pregnancies in active labor at term (n = 40). Plasma samples obtained at admission were analyzed for cytokine and chemokine quantification using a multiplex bead assay in order to compare the immune profiles between PTL, PPROM, and normal pregnancies. In PTL, CXCL1 and CCL17 were significantly higher compared to gestational age-matched women at antenatal visits, whereas for PPROM, CXCL1 and IL-6 were increased. Women in term labor had a more pronounced inflammatory pattern with higher levels of CXCL1, CXCL8, and IL-6 compared with PTL (p = 0.007, 0.003, and 0.013, respectively), as well as higher levels of CCL17, CXCL1 and IL-6 (all p < 0.001) compared with the women at antenatal visits. In PTL, CXCL8 was higher in women with delivery before 34 gw, whereas CXCL8, GM-CSF, and IL-6 were significantly higher in women with delivery within 48 h. To conclude, PTL and PPROM were associated with a complex pattern of inflammation, both involving Th17 (CXCL1) responses. Although further studies are needed, CXCL8, GM-CSF, and IL-6 may be potential candidates for predicting preterm birth in PTL.

Maternal childbirth experience and time in labor: a population-based cohort study.

A negative childbirth experience may have long term negative effects on maternal health. New international guidelines allow a slower progress of labor in the early active phase. However, a longer time in labor may influence the childbirth experience. In this population-based cohort study including 26,429 women, who gave birth from January 2016 to March 2020, the association between duration of different phases of active labor and childbirth experience was studied. The women assessed their childbirth experience by visual analogue scale (VAS) score. Data was obtained from electronic medical records. The prevalence of negative childbirth experience (VAS 1-3) was 4.9%. A significant association between longer duration of all labor phases and a negative childbirth experience was found for primi- and multipara. The adjusted odds ratio (aOR (95%CI)) of negative childbirth experience and longer time in active labor (above the 90th percentile) in primipara was 2.39 (1.98-2.90) and in multipara 2.23 (1.78-2.79). In primi-and multipara with duration of labor ≥ 12 h or ≥ 6 h the aOR (95%CI) of negative childbirth experience were 2.22 (1.91-2.58) and 1.91 (1.59-2.26) respectively. It is of great importance to identify and optimize the clinical care of women with longer time in labor to reduce the risk of negative childbirth experience and associated adverse long-term effects.

Plasma protein profiling reveals dynamic immunomodulatory changes in multiple sclerosis patients during pregnancy.

Multiple sclerosis (MS) is a chronic autoimmune neuroinflammatory and neurodegenerative disorder of the central nervous system. Pregnancy represents a natural modulation of the disease course, where the relapse rate decreases, especially in the 3rd trimester, followed by a transient exacerbation after delivery. Although the exact mechanisms behind the pregnancy-induced modulation are yet to be deciphered, it is likely that the immune tolerance established during pregnancy is involved. In this study, we used the highly sensitive and specific proximity extension assay technology to perform protein profiling analysis of 92 inflammation-related proteins in MS patients (n=15) and healthy controls (n=10), longitudinally sampled before, during, and after pregnancy. Differential expression analysis was performed using linear models and p-values were adjusted for false discovery rate due to multiple comparisons. Our findings reveal gradual dynamic changes in plasma proteins that are most prominent during the 3rd trimester while reverting post-partum. Thus, this pattern reflects the disease activity of MS during pregnancy. Among the differentially expressed proteins in pregnancy, several proteins with known immunoregulatory properties were upregulated, such as PD-L1, LIF-R, TGF-ß1, and CCL28. On the other hand, inflammatory chemokines such as CCL8, CCL13, and CXCL5, as well as members of the tumor necrosis factor family, TRANCE and TWEAK, were downregulated. Further in-depth studies will reveal if these proteins can serve as biomarkers in MS and whether they are mechanistically involved in the disease amelioration and worsening. A deeper understanding of the mechanisms involved may identify new treatment strategies mimicking the pregnancy milieu.

Complement-Opsonized HIV Modulates Pathways Involved in Infection of Cervical Mucosal Tissues: A Transcriptomic and Proteomic Study.

Genital mucosal transmission is the most common route of HIV spread. The initial responses triggered at the site of viral entry are reportedly affected by host factors, especially complement components present at the site, and this will have profound consequences on the outcome and pathogenesis of HIV infection. We studied the initial events associated with host-pathogen interactions by exposing cervical biopsies to free or complement-opsonized HIV. Opsonization resulted in higher rates of HIV acquisition/infection in mucosal tissues and emigrating dendritic cells. Transcriptomic and proteomic data showed a significantly more pathways and higher expression of genes and proteins associated with viral replication and pathways involved in different aspects of viral infection including interferon signaling, cytokine profile and dendritic cell maturation for the opsonized HIV. Moreover, the proteomics data indicate a general suppression by the HIV exposure. This clearly suggests that HIV opsonization alters the initial signaling pathways in the cervical mucosa in a manner that promotes viral establishment and infection. Our findings provide a foundation for further studies of the role these early HIV induced events play in HIV pathogenesis.

Corrigendum: Complement-Opsonized HIV Modulates Pathways Involved in Infection of Cervical Mucosal Tissues: A Transcriptomic and Proteomic Study.

[This corrects the article DOI: 10.3389/fimmu.2021.625649.].

Preterm Birth: A Prominent Risk Factor for Low Apgar Scores.

OBJECTIVE: To determine predictive risk factors for Apgar scores < 7 at 5 minutes at two hospitals providing tertiary care and secondary care, respectively. METHODS: A retrospective registry cohort study of 21126 births (2006-2010) using data from digital medical records. Risk factors were analyzed by logistic regression analyses. RESULTS: AS(5 min) < 7 was multivariately associated with the following: preterm birth; gestational week 32 + 0-36 + 6, OR = 3.9 (95% CI 2.9-5.3); week 28 + 0-31 + 6, OR = 8 (5-12); week < 28 + 0, OR = 15 (8-29); postterm birth, OR = 2.0 (1.7-2.3); multiple pregnancy, OR = 3.53 (1.79-6.96); previous cesarean section, OR = 3.67 (2.31-5.81); BMI 25-29, OR = 1.30 (1.09-1.55); BMI ≥ 30 OR = 1.70 (1.20-2.41); nonnormal CTG at admission, OR = 1.98 (1.48-2.66). ≥ 1-para was associated with a decreased risk for AS(5 min) < 7, OR = 0.34 (0.25-0.47). In the univariate logistic regression analysis AS(5 min) < 7 was associated with tertiary level care, OR = 1.48 (1.17-1.87); however, in the multivariate analysis there was no significant difference. CONCLUSION: A number of partially preventable risk factors were identified, preterm birth being the most evident. Further, no significant difference between the two hospital levels regarding the risk for low Apgar scores was detected.

Increased IFN-gamma response to transplantation antigens measured by cytokine MLC: indications for a bi-phasic response pattern.

The immunological reactivity to major histocompatibility transplantation antigens (MHC) is important in clinical manifestations such as graft rejection and graft-vs.-host disease. To evaluate the allogeneic cytokine response pattern we used a newly developed cytokine mixed leukocyte culture (MLC) technique. Blood mononuclear cells from healthy women (n=6) were exposed to cells from another person and to pooled cells from 28 blood donors (MHC-pool). The secretion kinetics of IL-4 and IFN-gamma from the responder cells was analysed by ELISPOT. We found a higher IFN-gamma response to the MHC-pool compared with the IL-4 secretion. Both the total secretion of IFN-gamma for 7 days and the median value of IFN-gamma in each individual was increased compared with IL-4. The IFN-gamma response showed a bi-phasic pattern with the major peak on day 6-7. Our results indicate that allo-responses are mainly Th1-like responses, displaying a bi-phasic pattern. This knowledge may be useful, and the methods suitable, in the studies of allo-responses in transplantation and pregnancy.