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PROBLEM: Women with a previous uncomplicated pregnancy have lower risks of immune-associated pregnancy disorders in a subsequent pregnancy. This could indicate a different maternal immune response in multigravid women compared to primigravid women. In a previous study, we showed persistent higher memory T cell proportions with higher CD69 expression after uncomplicated pregnancies. To our knowledge no studies have reported on immune cells in general, and immune memory cells and macrophages specifically in multigravid and primigravid women.METHOD OF STUDY: T cells and macrophages were isolated from term decidua parietalis and decidua basalis tissue from healthy primigravid women (n = 12) and multigravid women (n = 12). Using flow cytometry, different T cell populations including memory T cells and macrophages were analyzed. To analyze whether a different immune phenotype is already present in early pregnancy, decidual tissue from uncomplicated ongoing pregnancies between 9 and 12 weeks of gestation from multigravida and primigravid women was investigated using qRT-PCR.RESULTS: Nearly all T cell subsets analyzed in the decidua parietalis had significantly higher CD69+ proportions in multigravid women compared to primigravid women. A higher proportion of decidual (CD50- ) M2-like macrophages was found in the decidua parietalis in multigravid women compared to primigravid women. In first trimester decidual tissue higher FOXP3 mRNA expression was found in multigravid women compared to primigravid women.CONCLUSIONS: This study shows that decidual tissue from multigravid women has a more activated and immunoregulatory phenotype compared to decidual tissue from primigravid women in early pregnancy and at term which could suggest a more balanced immune adaptation towards pregnancy after earlier uncomplicated pregnancies. This article is protected by copyright. All rights reserved.

SCOPE: Pectins have anti-inflammatory properties on intestinal immunity through direct interactions on Toll-like receptors (TLRs) in the small intestine or via stimulating microbiota-dependent effects in the large intestine. Both the degree of methyl-esterification (DM) and the distribution of methyl-esters (degree of blockiness; DB) of pectins contribute to this influence on immunity but whether and how the DB impacts immunity through microbiota-dependent effects in the large intestine is unknown. Therefore, we tested pectins that structurally differ in DB in a mouse model with Citrobacter rodentium-induced colitis and studied the impact on the intestinal microbiota composition and associated attenuation of inflammation.METHODS AND RESULTS: Both low and high DB pectins induced a more rich and diverse microbiota composition. These pectins also lowered the bacterial load of C. rodentium in caecal digesta. Through these effects, both low and high DB pectins attenuated C. rodentium-induced colitis resulting in reduced intestinal damage, reduced numbers of Th1-cells which are increased in case of C. rodentium-induced colitis, and reduced levels of GATA3+ Tregs which are related to tissue inflammation.CONCLUSION: Pectins prevent C. rodentium-induced colonic inflammation by lowering the C. rodentium load in the caecum independently of the DB. This article is protected by copyright. All rights reserved.

Problem: Preeclampsia is a major cause of fetal and maternal mortality and morbidity. Disturbed fetal-maternal immune tolerance, and therewith memory T cells, might be involved in its etiology. This study aims to give insight into memory T-cell populations and its associated cytokines in the decidual layers in early-onset preeclampsia (EO-PE) and late-onset preeclampsia (LO-PE). Method of Study: Lymphocytes were isolated from the decidua parietalis and basalis from EO-PE (n = 6), LO-PE (n = 8) and healthy (n = 15) pregnancies. CD4+ and CD8+ central- (CCR7+), effector- (CCR7−), tissue resident- (CD103+), and regulatory- (Foxp3+) memory cell (CD45RO+) populations and their activation status (CD69+) were analyzed using flow cytometry. qRT-PCR analysis was performed on decidua parietalis and basalis biopsies to detect mRNA expression of interferon-gamma, interleukin-1B, IL2, IL6, IL7, IL8, IL10, IL15, and IL23. Results: CD4+ central-memory (CM) cell proportions were lower in the decidua parietalis in LO-PE (P + memory (P + CM (P

Adaptations of the maternal immune response are necessary for pregnancy success. Insufficient immune adaption is associated with pregnancy pathologies such as infertility, recurrent miscarriage, fetal growth restriction, spontaneous preterm birth, and preeclampsia. The maternal immune system is continuously exposed to paternal-fetal antigens; through semen exposure from before pregnancy, through fetal cell exposure in pregnancy, and through microchimerism after pregnancy. This results in the generation of paternal-fetal antigen specific memory T cells. Memory T cells have the ability to remember previously encountered antigens to elicit a quicker, more substantial and focused immune response upon antigen reencounter. Such fetal antigen specific memory T cells could be unfavorable in pregnancy as they could potentially drive fetal rejection. However, knowledge on memory T cells in pregnancy has shown that these cells might play a favorable role in fetal-maternal tolerance rather than rejection of the fetus. In recent years, various aspects of immunologic memory in pregnancy have been elucidated and the relevance and working mechanisms of paternal-fetal antigen specific memory T cells in pregnancy have been evaluated. The data indicate that a delicate balance of memory T cells seems necessary for reproductive success and that immunologic memory in reproduction might not be harmful for pregnancy. This review provides an overview of the different memory T cell subtypes and their function in the physiology and in complications of pregnancy. Current findings in the field and possible therapeutic targets are discussed. The findings of our review raise new research questions for further studies regarding the role of memory T cells in immune-associated pregnancy complications. These studies are needed for the identification of possible targets related to memory mechanisms for studies on preventive therapies.

Obesity is seen as a low grade inflammatory state, and is associated with adverse pregnancy outcomes. Disturbed macrophage characteristics might be essential in obesity associated pregnancy pathology via effects on the regulation of angiogenesis and placental development. This study aims to address the effects of maternal obesity on macrophage subsets in the decidua of women with term uncomplicated pregnancies. Macrophages were isolated from the decidua basalis and decidua parietalis of women with pre-gravid BMI 30 (obese). Macrophages were characterized and quantified using multi-color flow cytometry. Placentas of 10 obese and 10 control women after an uncomplicated term pregnancy were included. The decidua parietalis, but not decidua basalis, showed significantly lower levels of M1-type (HLA-DR+, CD163(-)) macrophages (p

Pregnancies with a male fetus are associated with higher risks of pregnancy complications through maladaptation of the maternal immune system. The pathophysiology of this phenomenon is unknown. A possible pathway could be a fetal sex-dependent maternal immune response, since males have a Y chromosome encoding specific allogenic proteins, possibly contributing to a different response and higher complication risks. To analyze whether fetal sex affects mRNA expression of maternal immune genes in early pregnancy, real-time PCR quantification was performed in the decidual tissue from primigravid pregnancies (n=20) between 10 and 12 weeks with uncomplicated term outcomes. Early-pregnancy decidual mRNA expression of the regulatory T-cell marker, FOXP3, was sixfold lower (p<0.01) in pregnancies with a male fetus compared to pregnancies with a female fetus. Additionally, mRNA expression of IFNγ was sixfold (p<0.05) lower in pregnancies with a male fetus. The present data imply maternal immunologic differences between pregnancies with male and female fetuses which could be involved in different pregnancy pathophysiologic outcomes. Moreover, this study indicates that researchers in reproductive immunology should always consider fetal sex bias.

Introduction During pregnancy, tolerance towards the fetus is induced by adaptations in the maternal immune system. Maladaptation of the maternal immune system is associated with pregnancy complications like preeclampsia and fetal growth restriction. Memory T-cells might play an important role in fetal-maternal tolerance. It is at the fetal-maternal interface where the maternal immune system especially needs to create tolerance towards the fetus. Decidua basalis is the maternal part of the basal plate whereas decidua parietalis is the maternal part of the fetal membranes. Decidual distribution pattern of memory T-cells during pregnancy is not known. Objective Since it is unknown how memory T-cells are distributed in decidual tissue, memory T-cells in decidua basalis and decidua parietalis were evaluated. Methods Lymphocytes were isolated from decidua basalis and decidua parietalis from uncomplicated term pregnancies. Using flowcytometry, subsets of memory T-cells (central, effector, regulatory, and tissue resident) of uncomplicated term pregnancies were analysed (n = 27). To compare different subsets of memory T-cells between decidual tissues, a student’s t-test (p Results Levels of memory T-cells (CD45RO+) were higher in decidua parietalis compared to decidua basalis in both CD4+ and CD8+ cells. Moreover, CD8+ central memory cells (CD45RO+CCR7+) and CD8+ tissue resident cells (CD45RO+CD103+) were higher in decidua parietalis compared to decidua basalis. Lastly, activation status (CD69+) was higher for all memory subsets (except for CD4+ effector memory T-cells) in decidua parietalis compared to decidua basalis. Discussion This study shows that memory T-cell subsets are differently distributed in decidua parietalis and basalis, with higher percentages of memory T-cell subsets as well as more activated memory T-cell subsets found in decidua parietalis compared to decidua basalis. Since memory T-cells are found to be present at higher percentages in decidua parietalis, this could suggest that these cells are especially important for creating tolerance to the fetal membranes.