Targeting Immune Activation in the Prevention of Pre-term Labor


mother throughout gestation. Immunologically active secretions such as lysozymes and defensins serve as biochemical barriers to invasive pathogens. The innate immune system has evolved to recognize non-self-utilising pattern recognition receptors (PRRs)21 recognize molecular signatures of pathogens.22


that PRRs are also capable of recognizing non-infections endogenous proteins such as Hsp70.23


TLRs are a major component of PRRs, and to date 11 members have been discovered in mammals.24


Evidence increasingly points toward


TLR-mediated inflammatory mechanisms as a trigger to infection-induced pre-term birth, with TLR receptors 2 and 4 particularly implicated. TLR 2 recognizes the products of Gram-positive bacteria and mycoplasma, whereas TLR 4 recognizes the products of Gram-negative bacteria.25


TLR 2


and 4 are expressed in immune cells within the placenta but also in the trophoblasts at different stages of pregnancy.26


Amnion epithelial cells


also express TLR 2 and 4, with an increase in messenger RNA (mRNA) in both term and pre-term labor.27


Similarly, both receptors are expressed


in myometrium, with protein levels of TLR2 increased in labor versus non-labor.28


An important activator downstream of TLRs is NF-κB, which


can lead to the production of immune-response proteins such as cytokines and chemokines.29


The Acquired Immune System in Pregnancy In contrast to the innate immune system, the adaptive immune system relies on B- and T-cells, which are responsible for the humoral and cellular responses.30


Activation of the innate immune system can


be seen as a prerequisite for triggering the acquired immune response, particularly aiding T-cell polarisation towards T helper 1 effector cells.31


Cytokines participate in either T helper 1 (Th1)-mediated responses (cell-mediated immunity) or T helper 2 (Th2) responses (humoral immunity). Pregnancy is largely represented by a shift toward Th2 activity,32–35


An important component of the adaptation of the immune system in pregnancy is the regulation of specific cytokine production.32


while the presence of infection and


inflammation triggers an opposite shift towards the Th1 response. Consistent with this, increases in the Th1-specific cytokine TNF-α are highly correlated with infection-related pre-term birth.36,37 Furthermore, the double-knockout TNF-α and IL-1β murine model does not suffer pre-term labor when administered lipopolysaccharide, a major component of Gram-negative bacteria cell walls.


A shift in the bias from Th1 to Th2 is evident both systemically and locally at the maternal–fetal interface. During pregnancy, peripheral blood lymphocytes show an increase in mRNA of the prototypical Th2 interleukin IL-4 and lower mRNA levels of the prototypical Th1 interleukin IFN-γ.38


Immune Activation in the Cervix


Throughout pregnancy, the cervix is rigid and tightly closed. At the beginning of parturition, the cervix undergoes a major remodeling process referred to as ‘ripening’. This occurs independently yet concurrently with the activation of the myometrium and involves an inflammatory cascade that induces the release of proinflammatory cytokines and the infiltration of leukocytes.48,50


These release matrix metalloproteinases (MMPs), which, along with activated collagenases, degrade the structural connective tissue and collagen fibres of the cervix.51


Immune Activation in the Uterus


Also, in vitro stimulation of peripheral lymphocytes in pregnant women displays increased production of IL-4 and reduced production of IFN-γ compared with non-pregnant controls.39


The


reduction in Th1 cytokine production is likely a result of downregulation of the NF-κB/IκB signaling pathway observed in T-cells throughout pregnancy.40


non-lymphoid cells in the placenta and decidua also contribute to the Th2 cytokine predominance.42 are capable of suppressing the Th1 interleukins,43


In addition to decidual leukocyte production of the Th2 cytokines IL-4 and IL-10,41


These Th2 interleukins IL-8, and prostaglandin


US OBSTETRICS & GYNECOLOGY


The myometrium is the muscle layer responsible for uterine contractility. It consists of smooth-muscle cells, myocytes, surrounded by connective tissue, vasculature, and infiltrating leukocytes capable of secreting cytokines.52


These infiltrating


Immune Activation in the Decidua and Fetal Membranes at the Maternal–Fetal Interface Activation of the fetal membranes and decidua involves a complex set of biochemical events culminating in the separation of the membranes from the decidua in the lower uterine segment and, ultimately, their rupture. As the decidua acts as an interface between the maternal and fetal tissues, it was proposed by Casey and MacDonald that it may also regulate maternal–fetal immunotolerance during pregnancy.47


In the


amnion, proinflammatory cytokines IL-1β and IL-8 are upregulated during labor, as are IL-6 and IL8 in the choriodecidua.48


IL-1β is known to


stimulate cyclo-oxygenase 2 (COX-2) production, which in turn leads to the production of prostaglandin E2 in the amnion, a major source of prostaglandins that acts on the uterus to stimulate contractions and on the cervix to aid cervical ripening.49


Immune Activation in Term Labor


We now have increasing evidence that inflammation in the fetal membranes, cervix, and uterus is a major player in the cascades leading to both term and pre-term birth.46


Term labor occurs at between 38 and 42 weeks of gestation, at which time the cervix undergoes remodeling and ripening to facilitate the expulsion of the fetus from the contractile uterus. Despite extensive research, the exact triggers and network coordination of biochemical and endocrinological components of these processes are poorly understood. This has created the biggest challenge for developing therapies for the prevention of pre-term labor. Although the initial triggers of pre-term and term labor may well differ, with term labor seen as physiological and pre-term labor seen as a pathological condition, the terminal events leading to delivery of the fetus are common to both conditions.45


production,44


which are likely to contribute to pregnancy maintenance and uterine quiescence while also contributing to immune tolerance of the fetus as an allograft.


During term labor, there is an massive influx of inflammatory cells into the myometrium, mainly the lower segment, including neutrophils, macrophages, and T lymphocytes.50


leukocytes are a source of proinflammatory interleukins and prostaglandins, which are likely to contribute to normal parturition.


A comprehensive study by Young et al. used immunohistochemistry to localise these cytokines to their cellular origin, comparing pre-labor term


105


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