Labor resembles an inflammatory response that includes secretion of cytokines/chemokines by resident and infiltrating immune cells into reproductive tissues and the maternal/fetal interface. Untimely activation of these inflammatory pathways leads to preterm labor, which can result in preterm birth. Preterm birth is a major determinant of neonatal mortality and morbidity; therefore, the elucidation of the process of labor at a cellular and molecular level is essential for understanding the pathophysiology of preterm labor. Here, we summarize the role of innate and adaptive immune cells in the physiological or pathological activation of labor. We review published literature regarding the role of innate and adaptive immune cells in the cervix, myometrium, fetal membranes, decidua and the fetus in late pregnancy and labor at term and preterm. Accumulating evidence suggests that innate immune cells (neutrophils, macrophages and mast cells) mediate the process of labor by releasing pro-inflammatory factors such as cytokines, chemokines and matrix metalloproteinases. Adaptive immune cells (T-cell subsets and B cells) participate in the maintenance of fetomaternal tolerance during pregnancy, and an alteration in their function or abundance may lead to labor at term or preterm. Also, immune cells that bridge the innate and adaptive immune systems (natural killer T (NKT) cells and dendritic cells (DCs)) seem to participate in the pathophysiology of preterm labor. In conclusion, a balance between innate and adaptive immune cells is required in order to sustain pregnancy; an alteration of this balance will lead to labor at term or preterm.

/pdf/immune-cells-in-term-and-preterm-labor-2g468h0vbp.pdf

Immune cells in term and preterm labor

Premature rupture of fetal membranes

A successful pregnancy requires a fine-tuned and highly regulated balance between immune activation and embryonic antigen tolerance. Since the fetus is semi-allogeneic, the maternal immune system should exert tolerant to the fetus while maintaining the defense against infection. The maternal-fetal interface consists of different immune cells, such as decidual natural killer (dNK) cells, macrophages, T cells, dendritic cells, B cells, and NKT cells. The interaction between immune cells, decidual stromal cells, and trophoblasts constitute a vast network of cellular connections. A cellular immunological imbalance may lead to adverse pregnancy outcomes, such as recurrent spontaneous abortion, pre-eclampsia, pre-term birth, intrauterine growth restriction, and infection. Dynamic changes in immune cells at the maternal-fetal interface have not been clearly stated. While many studies have described changes in the proportions of immune cells in the normal maternal-fetus interface during early pregnancy, few studies have assessed the immune cell changes in mid and late pregnancy. Research on pathological pregnancy has provided clues about these dynamic changes, but a deeper understanding of these changes is necessary. This review summarizes information from previous studies, which may lay the foundation for the diagnosis of pathological pregnancy and put forward new ideas for future studies.

/pdf/dynamic-function-and-composition-changes-of-immune-cells-285pzpa2w0.pdf

Dynamic Function and Composition Changes of Immune Cells During Normal and Pathological Pregnancy at the Maternal-Fetal Interface.

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.

/pdf/novel-concepts-on-pregnancy-clocks-and-alarms-redundancy-and-1j6ij60k3z.pdf

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

No other organ in the body undergoes such an invasion of selective cells (leukocytes) and release of homing molecules, CAMs, proinflammatory cytokines, and mediators or undergoes similar extensive remodeling of tissues over such a short period of time as the pregnant uterus. This is especially interesting, as an infectious process involving microorganisms does not exist in a healthy pregnancy and delivery. Furthermore, after delivery of the baby and placenta, the uterus involutes and returns to its normal monthly cycling, and most of the leukocytes are swept away or leave. In this review, we discuss leukocyte infiltration and recruitment and the potential roles of each subpopulation of leukocytes in relation to pregnancy and the problems of preterm birth, pre-eclampsia, and intrauterine growth restriction.

https://jlb.onlinelibrary.wiley.com/doi/pdf/10.1189/jlb.1209796

Invasion of the leukocytes into the fetal-maternal interface during pregnancy

Problem

Spontaneous labor at term involves leukocyte recruitment and infiltration into the choriodecidua; yet, characterization of these leukocytes and their immunological mediators is incomplete. The purpose of this study was to characterize the immunophenotype of choriodecidual leukocytes as well as the expression of inflammatory mediators in human spontaneous parturition at term.



Method of study

Choriodecidual leukocytes were analyzed by FACS, immunohistochemistry, and RT-PCR in three different groups: (i) preterm gestation delivered for medical indications without labor; (ii) term pregnancy without labor; and (iii) term pregnancy after spontaneous labor.



Results

Two T-cell subsets of memory-like T cells (CD3+CD4+CD45RO+ and CD3+CD4−CD8−CD45RO+ cells) were identified in the choriodecidua of women who had spontaneous labor. Evidence for an extensive immune signaling network composed of chemokines (CXCL8 and CXCL10), chemokine receptors (CXCR1-3), cytokines (IL-1β and TNF-α), cell adhesion molecules, and MMP-9 was identified in these cells during spontaneous labor at term.



Conclusions

The influx of memory-like T cells in the choriodecidua and the evidence that they are active by producing chemokines and cytokines, and expressing chemokine receptors, cell adhesion molecules, and a matrix-degrading enzyme provides support for the participation of the adaptive immune system in the mechanisms of spontaneous parturition at term.

Karen Cubeiro-Arreola

Papers

Evidence for a Role for the Adaptive Immune Response in Human Term Parturition

T cell recruitment and contribution to an inflammatory microenvironment in the choriodecidua during human labor