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.

Preterm birth (PTB) is commonly accompanied by in utero fetal inflammation, and existing tocolytic drugs do not target fetal inflammatory injury. Of the candidate proinflammatory mediators, IL-1 appears central and is sufficient to trigger fetal loss. Therefore, we elucidated the effects of antenatal IL-1 exposure on postnatal development and investigated two IL-1 receptor antagonists, the competitive inhibitor anakinra (Kineret) and a potent noncompetitive inhibitor 101.10, for efficacy in blocking IL-1 actions. Antenatal exposure to IL-1β induced Tnfa, Il6, Ccl2, Pghs2, and Mpges1 expression in placenta and fetal membranes, and it elevated amniotic fluid IL-1β, IL-6, IL-8, and PGF_2α, resulting in PTB and marked neonatal mortality. Surviving neonates had increased Il1b, Il6, Il8, Il10, Pghs2, Tnfa, and Crp expression in WBCs, elevated plasma levels of IL-1β, IL-6, and IL-8, increased IL-1β, IL-6, and IL-8 in fetal lung, intestine, and brain, and morphological abnormalities: e.g., disrupted lung alveolarization, atrophy of intestinal villus and colon-resident lymphoid follicle, and degeneration and atrophy of brain microvasculature with visual evoked potential anomalies. Late gestation treatment with 101.10 abolished these adverse outcomes, whereas Kineret exerted only modest effects and no benefit for gestation length, neonatal mortality, or placental inflammation. In a LPS-induced model of infection-associated PTB, 101.10 prevented PTB, neonatal mortality, and fetal brain inflammation. There was no substantive deviation in postnatal growth trajectory or adult body morphometry after antenatal 101.10 treatment. The results implicate IL-1 as an important driver of neonatal morbidity in PTB and identify 101.10 as a safe and effective candidate therapeutic.

Seminal fluid factors modulate the female immune response at conception to facilitate embryo implantation and reproductive success. Whether sperm affect this response has not been clear. We evaluated global gene expression by microarray in the mouse uterus after mating with intact or vasectomized males. Intact males induced greater changes in gene transcription, prominently affecting pro-inflammatory cytokine and immune regulatory genes, with TLR4 signaling identified as a top-ranked upstream driver. Recruitment of neutrophils and expansion of peripheral regulatory T cells were elevated by seminal fluid of intact males. In vitro, epididymal sperm induced IL6, CXCL2, and CSF3 in uterine epithelial cells of wild-type, but notTlr4null females. Collectively these experiments show that sperm assist in promoting female immune tolerance by eliciting uterine cytokine expression through TLR4-dependent signaling. The findings indicate a biological role for sperm beyond oocyte fertilization, in modulating immune mechanisms involved in female control of reproductive investment.

Oxidative stress and elevated levels of seminal and sperm reactive oxygen species (ROS) may contribute to up to 80% of male infertility diagnosis, with sperm ROS concentrations at fertilization important in the development of a healthy fetus and child. The evaluation of ROS in semen seems promising as a potential diagnostic tool for male infertility and male preconception care with a number of clinically available tests on the market (MiOXSYS, luminol chemiluminescence and OxiSperm). While some of these tests show promise for clinical use, discrepancies in documented decision limits and lack of cohort studies/clinical trials assessing their benefits on fertilization rates, embryo development, pregnancy and live birth rates limit their current clinical utility. In this review, we provide an update on the current techniques used for analyzing semen ROS concentrations clinically, the potential to use of ROS research tools for improving clinical ROS detection in sperm and describe why we believe we are likely still a long way away before semen ROS concentrations might become a mainstream preconception diagnostic test in men.

Context Despite extensive searches for novel non-invasive diagnostics, laparoscopy remains the reference test for endometriosis. Circulating microRNAs (miRNAs) are purported endometriosis biomarkers however, the miRNA species and their diagnostic accuracy differ between studies and haven’t been validated in independent cohorts. Objective Identify endometriosis-specific plasma miRNAs and determine their diagnostic test accuracy. Setting Two university-based, public hospitals and a private gynaecology practice in Australia. Design and participants Four phases: 1. Explorative Phase: Plasma miRNA menstrual cycle fluctuations were evaluated in women with endometriosis and asymptomatic controls (n=16); 2. Biomarker Discovery: Endometriosis-specific plasma miRNAs were identified in a) women with endometriosis and asymptomatic controls (n=16) and b) women with and without surgically defined endometriosis (n=20); 3. Biomarker Selection: Plasma miRNAs with the best diagnostic potential for endometriosis were selected in a surgically-defined selection cohort (n=78); 4. Biomarker Validation: The diagnostic test accuracy of these miRNAs was calculated in an independent, surgically-defined validation cohort (n=119). Results Forty-nine miRNAs were differentially expressed in women with endometriosis. Nine maintained dysregulation in the selection cohort, but only three (miR-155, miR-574-3p and miR139-3p) in the validation cohort. Combined, these three miRNAs demonstrated a sensitivity and specificity of 83% and 51%. Conclusion Plasma miRNAs demonstrated modest sensitivity and specificity as diagnostic tests or triage tools for endometriosis. Other groups’ findings were not replicated and concorded poorly with our results. Circulating miRNAs demonstrate diagnostic potential but stringent, standardized methodological approaches will be required for the development of a clinically applicable tool.