Pattern Recognition at the Maternal-Fetal Interface

Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510, USA.
Immunological Investigations (Impact Factor: 1.99). 02/2008; 37(5):427-47. DOI: 10.1080/08820130802191599
Source: PubMed


Intrauterine infections represent a significant threat to fetal well-being and pregnancy outcome. Recent studies suggest that non-immune cells of the maternal-fetal interface can actively recognize and respond to microbes through pattern recognition receptors, in order to control pathogens that may compromise the pregnancy. However, these same innate immune responses may inadvertently lead to excessive inflammation or apoptosis at the maternal-fetal interface. Thus, pattern recognition receptors may play a key role in infection-related pregnancy complications. This review discusses what is currently known about the role of Toll-like receptors and NOD-like receptors in controlling infections at the maternal-fetal interface, and what impact their function may have on pregnancy.

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    • "The cellular effectors of innate immunity in the zebrafish embryo are primitive macrophages and granulocytes, and molecular components include pattern recognition receptor Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD) proteins, cytokines such as interleukin 1b (IL-1b) and interferon g (IFN-g), and transcription factors such as nuclear factor kB (NF-kB) and IFN regulatory factors (IRFs) (Oehlers et al. 2011). The mammalian fetus is likewise protected from pathogens by a robust innate immune system at the maternal/fetal interface, the maternal decidual components of which are stromal and immune cells (Abrahams 2008). Macrophages, which are of maternal origin initially and are replaced at E9.5 by macrophages that are YS-derived, also play an important role in fetal innate immune responses (Bertrand et al. 2005). "
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    ABSTRACT: Identifying signaling pathways that regulate hematopoietic stem and progenitor cell (HSPC) formation in the embryo will guide efforts to produce and expand HSPCs ex vivo. Here we show that sterile tonic inflammatory signaling regulates embryonic HSPC formation. Expression profiling of progenitors with lymphoid potential and hematopoietic stem cells (HSCs) from aorta/gonad/mesonephros (AGM) regions of midgestation mouse embryos revealed a robust innate immune/inflammatory signature. Mouse embryos lacking interferon γ (IFN-γ) or IFN-α signaling and zebrafish morphants lacking IFN-γ and IFN-ϕ activity had significantly fewer AGM HSPCs. Conversely, knockdown of IFN regulatory factor 2 (IRF2), a negative regulator of IFN signaling, increased expression of IFN target genes and HSPC production in zebrafish. Chromatin immunoprecipitation (ChIP) combined with sequencing (ChIP-seq) and expression analyses demonstrated that IRF2-occupied genes identified in human fetal liver CD34(+) HSPCs are actively transcribed in human and mouse HSPCs. Furthermore, we demonstrate that the primitive myeloid population contributes to the local inflammatory response to impact the scale of HSPC production in the AGM region. Thus, sterile inflammatory signaling is an evolutionarily conserved pathway regulating the production of HSPCs during embryonic development.
    Genes & Development 11/2014; 28(23). DOI:10.1101/gad.253302.114 · 10.80 Impact Factor
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    • "During pregnancy, pathogen infection can inadvertently lead to excessive inflammation or apoptosis at the maternal-fetal interface [38]. Costello et al. demonstrated that ectopic expression of NOD2 in a first trimester trophoblast cell line, H8, produced higher levels of cytokines than with vehicle treatment alone [22], suggesting that intracellular NOD2 expression levels affect baseline production of cytokines. "
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    ABSTRACT: NOD2, one of the cytosolic proteins that contain a nuclear oligomerization domain (NOD), is a pattern recognition receptor (PRR) involved in innate immune responses to intracellular pathogens. Little is known, however, about the effect of NOD2 expression on the maternal-fetal relationship. Our aim was to elucidate the functions of NOD2 in normal decidual stromal cells (DSCs) from the first trimester. Tissues and DSCs were isolated from 26 patients with normal pregnancies that required abortion. The expression of NOD2 in deciduas/decidual stromal cells (DSCs) was examined by real-time PCR, immunohistochemistry, and In-cell western. DSCs containing NOD2 were stimulated by its ligand, muramyl dipeptide (MDP). The secretion of various cytokines and chemokines were measured by ELISA and the apoptotic rate was determined by flow cytometry. Treatment with MDP significantly elevated the expression of both NOD2 mRNA and protein levels in DSCs. In addition, MDP activation of NOD2 significantly increased IL-1β and MCP-1 cytokine expression in a dose dependent manner but had no effect on IL-12 expression. IL-1β and TNF-α also significantly increased the expression of NOD2 in DSCs, suggesting a positive feedback loop mechanism. Moreover, MDP stimulation augmented DSC apoptosis. In summary, the results suggest that NOD2 expression in DSCs plays an important role in protecting the embryo and preventing infection in the maternal-fetal interface.
    PLoS ONE 06/2014; 9(6):e99612. DOI:10.1371/journal.pone.0099612 · 3.23 Impact Factor
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    • "The immune innate system enables human amniochorionic membranes and other tissues of the fetal-maternal interface to recognize potentially infectious threats [41] and secrete AMP’s that act as the first defense line to delimit and control an infectious process [10,15]. The key role of fetal membranes as an effective barrier against C. albicans has been demonstrated in different animal experimental models [42,43]. "
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    ABSTRACT: Background During intrauterine infection, amniochorionic membranes represent a mechanical and immunological barrier against dissemination of infection. Human beta defensins (HBD)-1, HBD-2, and HBD-3 are key elements of innate immunity that represent the first line of defense against different pathogen microorganisms associated with preterm labor. The aim of this work was to characterize the individual contribution of the amnion (AMN) and choriodecidua (CHD) regions to the secretion of HBD-1, HBD-2 and HBD-3, after stimulation with Candida albicans. Methods Full-thickness human amniochorionic membranes were obtained after delivery by elective cesarean section from women at 37-40 wk of gestation with no evidence of active labor. The membranes were cultured in a two-compartment experimental model in which the upper compartment is delimited by the amnion and the lower chamber by the choriodecidual membrane. One million of Candida albicans were added to either the AMN or the CHD face or to both and compartmentalized secretion profiles of HBD-1, HBD-2, and HBD-3 were quantified by ELISA. Tissue immunolocalization was performed to detect the presence of HBD-1, -2, -3 in tissue sections stimulated with Candida albicans. Results HBD-1 secretion level by the CHD compartment increased 2.6 times (27.30 [20.9-38.25] pg/micrograms protein) when the stimulus with Candida albicans was applied only on this side of the membrane and 2.4 times (26.55 [19.4-42.5] pg/micrograms protein) when applied to both compartments simultaneously. HBD-1 in the amniotic compartment remained without significant changes. HBD-2 secretion level increased significantly in the CHD when the stimulus was applied only to this region (2.49 [1.49-2.95] pg/micrograms protein) and simultaneously to both compartments (2.14 [1.67- 2.91] pg/micrograms protein). When the stimulus was done in the amniotic compartment HBD-2 remained without significant changes in both compartments. HBD-3 remained without significant changes in both compartments regardless of the stimulation modality. Localization of immune-reactive forms of HBD-1, HBD-2, and HBD-3 was carried out by immunohistochemistry confirming the cellular origin of these peptides. Conclusion Selective stimulation of amniochorionic membranes with Candida albicans resulted in tissue-specific secretion of HBD-1 and HBD-2, mainly in the CHD, which is the first region to become infected during an ascending infection.
    Reproductive Biology and Endocrinology 09/2012; 10(1):70. DOI:10.1186/1477-7827-10-70 · 2.23 Impact Factor
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