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.

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Immune cells in term and preterm labor

Membrane progesterone receptor expression in mammalian tissues: A review of regulation and physiological implications

Immunological analogy between allograft rejection, recurrent abortion and pre-eclampsia - the same basic mechanism?

Immune cells adapt their phenotypic and functional characteristics in response to the tissue microenvironment within which they traffic and reside The fetomaternal interface, consisting of placental trophoblasts and the maternal decidua, is a highly specialized tissue with a unique and time-limited function: to nourish and support development of the semiallogeneic fetus and protect it from inflammatory or immune-mediated injury It is therefore important to understand how immune cells within these tissues are educated and adapt to fulfill their biological functions This review article focuses on the local regulatory mechanisms ensuring that both innate and adaptive immune cells appropriately support the early events of implantation and placental development through direct involvement in promoting immune tolerance of fetal alloantigens, suppressing inflammation, and remodeling of maternal uterine vessels to facilitate optimal placental function and fetal growth

Immune Cells at the Fetomaternal Interface: How the Microenvironment Modulates Immune Cells To Foster Fetal Development.

Peripheral lymphocytes from healthy pregnant women secrete a mediator protein named the progesterone-induced blocking factor (PIBF) that exerts an immunomodulatory function and contributes to the maintenance of pregnancy in mice. The gene coding for PIBF mRNA has been cloned and sequenced, and now the recombinant human protein is available. The aim of this study was to develop an ELISA test for determining PIBF concentrations in biological samples of pregnant women. We determined urinary PIBF concentrations of 86 healthy nonpregnant individuals and from almost 500 pregnant women by ELISA. During normal pregnancy, the concentration of PIBF continuously increased until the 37th gestational week and was followed by a sharp decrease after the 41st week of gestation. In pathological pregnancies, urinary PIBF levels failed to increase. The onset of labor was predictable on the basis of this test, whether it was term or preterm delivery. In urine of patients with preeclampsia, PIBF concentrations were significantly lower than in normal pregnancy and showed a correlation with the number of symptoms presented. These data, in line with previous in vivo findings, suggest that PIBF production is a characteristic feature of normal pregnancy, and determination of PIBF concentration in urine might be of use for the diagnosis of threatened premature pregnancy termination.

Urinary Progesterone-Induced Blocking Factor Concentration Is Related to Pregnancy Outcome

PROBLEM: Protecting antibodies against trophoblast surface molecules were previously described. Here we analysed the synthesis of asymmetric IgG by placental B-lymphocytes. METHOD OF STUDY: B cells were isolated from human term placenta and cord blood, stimulated with anti-CD40 IgG and cocultured with transfected Fcγ R-expressing mice Ltk-fibroblast. Interleukin-4, IL-6, IL-10, IL-11 and IL-13 were added to cultures for 14 days. Asymmetric IgG were assessed in culture supernatants by concanavalin A (Con A) fixation and enzyme-linked immunosorbent assay. RESULTS: When IL-6 was added to the cultures, the percentages of asymmetric IgG synthesized by placental B cells were: IL-6: 29 ± 10; IL-6 + IL-10: 24 ± 7; IL-4 + IL-10 + IL-6: 38 ± 9. The last combination induced the highest increase in the asymmetric IgG synthesis as compared with control (19 ± 10%, P < 0.05). Additionally, placental B cells synthesized more asymmetric IgG than umbilical cord blood B-lymphocytes (P = 0.0015). CONCLUSIONS: Isolated placental B-lymphocytes synthesized asymmetric IgG in response to Th2 interleukins, more notably IL-6 in combination with IL-4 and IL-10. The in vitro increase of protective asymmetric IgG synthesis in response to Th2-cytokines support the hypothesis that a local Th2-switch is beneficial for pregnancy outcome.

A. Keil

Papers

Interleukin Regulation of Asymmetric Antibody Synthesized by Isolated Placental B Cells