Differences in Immune phenotype in decidual tissue from multigravid women compared to primigravid women.

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.

Pectins that Structurally Differ in the Distribution of Methyl-Esters Attenuate Citrobacter rodentium-Induced Colitis.

INTRODUCTION: 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, this study tests pectins that structurally differ in DB in a mouse model with Citrobacter rodentium induced colitis and studies the impact on the intestinal microbiota composition and associated attenuation of inflammation. METHODS AND RESULTS: Both low and high DB pectins induce a more rich and diverse microbiota composition. These pectins also lower the bacterial load of C. rodentium in cecal digesta. Through these effects, both low and high DB pectins attenuate 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.

Decidual memory T-cell subsets and memory T-cell stimulatory cytokines in early- and late-onset preeclampsia.

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 < .0001) and EO-PE (P < .01) compared to healthy pregnancies. CD8+ memory (P < .05) and CD8+ CM (P < .01) cell proportions were also lower in the decidua parietalis in EO-PE compared to healthy pregnancies. This was accompanied by higher IL15 (P < .05) and IL23 (P < .05) and lower IL7 (P < .05) mRNA expression in decidua basalis biopsies from EO-PE compared to healthy pregnancies, analyzed by qPCR. CONCLUSION: In conclusion, decidual memory T-cell proportions, their activation status, and associated cytokines are altered in preeclampsia and might therefore be involved in fetal-maternal immune tolerance and the pathophysiology of preeclampsia.

Memory T Cells in Pregnancy.

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.

Lower FOXP3 mRNA Expression in First-Trimester Decidual Tissue from Uncomplicated Term Pregnancies with a Male Fetus.

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.