Elizabeth A. Bonney

Immune mechanisms at the maternal-fetal interface: perspectives and challenges

Leaders gathered at the US National Institutes of Health in November 2014 to discuss recent advances and emerging research areas in aspects of maternal-fetal immunity that may affect fetal development and pregnancy success.

Novel concepts on pregnancy clocks and alarms: redundancy and synergy in human parturition

The signals and mechanisms that synchronize the timing of human parturition remain a mystery and a better understanding of these processes is essential to avert adverse pregnancy outcomes. Although our insights into human labor initiation have been informed by studies in animal models, the timing of parturition relative to fetal maturation varies among viviparous species, indicative of phylogenetically different clocks and alarms; but what is clear is that important common pathways must converge to control the birth process. For example, in all species, parturition involves the transition of the myometrium from a relaxed to a highly excitable state, where the muscle rhythmically and forcefully contracts, softening the cervical extracellular matrix to allow distensibility and dilatation and thus a shearing of the fetal membranes to facilitate their rupture. We review a number of theories promulgated to explain how a variety of different timing mechanisms, including fetal membrane cell senescence, circadian endocrine clocks, and inflammatory and mechanical factors, are coordinated as initiators and effectors of parturition. Many of these factors have been independently described with a focus on specific tissue compartments.In this review, we put forth the core hypothesis that fetal membrane (amnion and chorion) senescence is the initiator of a coordinated, redundant signal cascade leading to parturition. Whether modified by oxidative stress or other factors, this process constitutes a counting device, i.e. a clock, that measures maturation of the fetal organ systems and the production of hormones and other soluble mediators (including alarmins) and that promotes inflammation and orchestrates an immune cascade to propagate signals across different uterine compartments. This mechanism in turn sensitizes decidual responsiveness and eventually promotes functional progesterone withdrawal in the myometrium, leading to increased myometrial cell contraction and the triggering of parturition. Linkage of these processes allows convergence and integration of the gestational clocks and alarms, prompting a timely and safe birth. In summary, we provide a comprehensive synthesis of the mediators that contribute to the timing of human labor. Integrating these concepts will provide a better understanding of human parturition and ultimately improve pregnancy outcomes.

Resistance to Lipopolysaccharide-Induced Preterm Delivery Mediated by Regulatory T Cell Function in Mice

Abstract Intrauterine or intraperitoneal administration of lipopolysaccharide (LPS) into normal mice at midgestation induces preterm delivery (PTD) within 24 h through a mechanism dependent on Toll-like receptor signaling and expression of inflammatory cytokines. The exact participants in the cellular network involved in PTD are not known. Although the activities of innate immune cells are thought to be important, the extent to which this process depends on T and B cells has yet to be examined. Mice deficient in T and B cells due to genetic deficiency in the recombination activating gene 1 (Rag1−/−) were given LPS intraperitoneally on Day 15 of gestation and found to be susceptible to LPS-induced PTD. This was found to involve many of the inflammatory mediators reported as important in normal mice. Moreover, at a low dose (3 μg), pregnant Rag1−/− mice were found to be more susceptible to PTD than a cohort of normal mice on the same genetic background. This increased susceptibility was partially reversed by transfer, on Day 10 of gestation, of whole lymphocytes or purified CD4+ T cells. Transfer of purified CD4+ T cells to Rag1−/− mice resulted in a uterine draining node population of FOXP3+ cells, suggesting that these cells may contribute to resistance to LPS-induced PTD. Overall, the data suggest that, although T and B lymphocytes are not critical positive regulators of LPS-induced PTD, CD4+ T cells play a protective and regulatory role, and thus could be a target for preventive or therapeutic manipulation.

Normal Establishment of Virus-Specific Memory CD8 T Cell Pool following Primary Infection during Pregnancy

Suppression of cell-mediated immunity has been proposed as a mechanism that promotes maternal tolerance of the fetus but also contributes to increased occurrence and severity of certain infections during pregnancy. Despite decades of research examining the effect of pregnancy on Ag-specific T cell responses, many questions remain. In particular, quantitative examination of memory CD8 T cell generation following infection during pregnancy remains largely unknown. To examine this issue, we evaluated the generation of protective immunity following infection during pregnancy with a nonpersistent strain of lymphocytic choriomeningitis virus (LCMV) in mice. The CD8 T cell response to LCMV occurred normally in pregnant mice compared with the nonpregnant cohort with rapid viral clearance in all tissues tested except for the placenta. Despite significant infiltration of CD8 T cells to the maternal-fetal interface, virus persisted in the placenta until delivery. Live pups were not infected and generated normal primary immune responses when challenged as adults. Memory CD8 T cell development in mice that were pregnant during primary infection was normal with regards to the proliferative capacity, number of Ag-specific cells, cytokine production upon re-stimulation, and the ability to protect from re-infection. These data suggest that virus-specific adaptive memory is normally generated in mice during pregnancy.

Interrelationship of Cytokines, Hypothalamic-Pituitary-Adrenal Axis Hormones, and Psychosocial Variables in the Prediction of Preterm Birth

Background/Aims: To examine the relationship of biological mediators (cytokines, stress hormones), psychosocial, obstetric history, and demographic factors in the early prediction of preterm birth (PTB) using a comprehensive logistic regression model incorporating diverse risk factors. Methods: In this prospective case-control study, maternal serum biomarkers were quantified at 9–23 weeks’ gestation in 60 women delivering at <37 weeks compared to 123 women delivering at term. Biomarker data were combined with maternal sociodemographic factors and stress data into regression models encompassing 22 preterm risk factors and 1st-order interactions. Results: Among individual biomarkers, we found that macrophage migration inhibitory factor (MIF), interleukin-10, C-reactive protein (CRP), and tumor necrosis factor-α were statistically significant predictors of PTB at all cutoff levels tested (75th, 85th, and 90th percentiles). We fit multifactor models for PTB prediction at each biomarker cutoff. Our best models revealed that MIF, CRP, risk-taking behavior, and low educational attainment were consistent predictors of PTB at all biomarker cutoffs. The 75th percentile cutoff yielded the best predicting model with an area under the ROC curve of 0.808 (95% CI 0.743–0.874). Conclusion: Our comprehensive models highlight the prominence of behavioral risk factors for PTB and point to MIF as a possible psychobiological mediator.

Dendritic cells: a family portrait at mid‐gestation

Recent advances in our understanding of dendritic cells (DCs) and their role in tolerance and immunity has fuelled study of their normal development and function within the reproductive tract. The common hypothesis that pregnancy is a state of immune suppression or deviation now includes the idea that alterations in DC phenotype and function are critical for maternal tolerance. We chose to study DCs in the uterus and lymphoid tissue in non‐pregnant and pregnant mice at mid‐gestation to understand what DC‐related factors may be involved in premature birth. We used a mouse model where the mother’s immune system has been shown to respond to the male antigen H‐Y. Observed differences among DCs in the uterus, uterine draining nodes and spleen, even in non‐pregnant mice, suggest the existence of a specialized uterus‐specific subset of DCs. We further found that, amongst CD45+ CD11c+ cells in the uterus and peripheral lymphoid tissue of pregnant mice, expression of major histocompatibility complex class II (MHC II) and costimulatory molecules (i.e. CD80) was similar to that in the non‐pregnant state. Moreover, there was no pregnancy‐related decrease in the proportion of CD11c+ cells in the uterus or in the uterine node that were CD11b− CD8+. Pregnancy increased the CD11b+ subsets and the expression of chemokine (C‐C motif) ligand 6 (CCL6) in DCs of the uterine draining nodes. Finally, DC subsets showed variable expression, with respect to tissue and pregnancy, of the cytokine interleukin‐15, which is important in lymphoid cell homeostasis. For DCs, pregnancy is not a state of immune paralysis, but of dynamic developmental change.

Evidence that CD8 T-cell homeostasis and function remain intact during murine pregnancy

Evolving models of immune tolerance have challenged the view that the response of the maternal immune system to environmental or fetal antigens must be suppressed or deviated. CD8 T cells play a central role in the immune response to viruses and intracellular pathogens so the maintenance of both the number and function of these cells is critical to protect both the mother and fetus. We show that the numbers of maternal CD8 T cells in both the spleen and the uterine draining lymph nodes are transiently increased at mid‐gestation and this correlates with enhanced CD8 T‐cell proliferation and an increased relative expression of both pro‐survival and pro‐apoptotic molecules. In transgenic mice bearing T‐cell antigen receptors specific for the male HY or allo‐antigens, the transgenic CD8 T cells retain the ability to proliferate and function during pregnancy. Moreover, anti‐HY T‐cell receptor transgenic mice have normal numbers of male pups despite the presence of CD8 T cells at the maternal–fetal interface. These data suggest that pregnancy is a dynamic state in which CD8 T‐cell turnover is increased while the function and ending size of the CD8 T‐cell compartment are maintained.

Pregnancy Alters the Proliferation and Apoptosis of Mouse Splenic Erythroid Lineage Cells and Leukocytes

Pregnancy induces dynamic changes in the maternal environment that include reversible modifications in response to systemic mediators and local signals. The spleen can be used to determine the effects of pregnancy on multiple cellular populations, including those of the erythroid lineage and the immune system. Current evidence suggests that the transient increase in the size of the spleen during pregnancy is due to the expansion of erythroid precursors. However, it is unclear what factors contribute to this increase. Moreover, the additional erythroid cells may compete with neighboring leukocytes for growth factors or space, and this may in turn alter the function of these populations. Therefore, we assessed proliferation and apoptosis throughout gestation using in vivo bromodeoxyuridine incorporation and the TUNEL assay, respectively. Here, we show that erythroid-lineage TER-119+ cells expanded significantly in midgestation because of enhanced proliferation and diminished apoptosis. This correlated with increased expression of the erythropoietin receptor (Epor) and decreased expression of the death receptor Fas, respectively. Leukocytes demonstrated population-specific responses. Natural killer cells proliferated in early pregnancy. Both lymphocytes and CD11B+ cells underwent enhanced proliferation during midgestation. In contrast, neutrophils exhibited augmented proliferation throughout pregnancy. These subset-specific alterations in proliferation and death in the spleen suggest that complex regulation of population dynamics exists during pregnancy.

Immune Regulation in Pregnancy: A Matter of Perspective?

The maternal immune system is complex and governed by multiple hormonal and metabolic factors, including those provided to the mother via the fetus. Understanding of the balance between maternal tolerance and protection of the fetus may require thinking from multiple theoretical approaches to the general problem of immune activation and tolerance. This article provides a brief review of the immune system, with aspects relevant to pregnancy. The references include reviews that expand on the elements discussed. The article also uses different models of immune system activation and tolerance to provide a theoretical understanding of the problem of maternal tolerance.

Influenza, immune system, and pregnancy.

Influenza is a major health problem worldwide. Both seasonal influenza and pandemics take a major toll on the health and economy of our country. The present review focuses on the virology and complex immunology of this RNA virus in general and in relation to pregnancy. The goal is to attempt to explain the increased morbidity and mortality seen in infection during pregnancy. We discuss elements of innate and adaptive immunity as well as placental cellular responses to infection. In addition, we delineate findings in animal models as well as human disease. Increased knowledge of maternal and fetal immunologic responses to influenza is needed. However, enhanced understanding of nonimmune, pregnancy-specific factors influencing direct interaction of the virus with host cells is also important for the development of more effective prevention and treatment options in the future.