Maternal Innate Immune Responses Research Articles

Innate immune responses to malaria-infected erythrocytes in pregnant women: Effects of gravidity, malaria infection, and geographic location.

BackgroundMalaria in pregnancy causes maternal, fetal and neonatal morbidity and mortality, and maternal innate immune responses are implicated in pathogenesis of these complications. The effects of malaria exposure and obstetric and demographic factors on the early maternal immune response are poorly understood.MethodsPeripheral blood mononuclear cell responses to Plasmodium falciparum-infected erythrocytes and phytohemagglutinin were compared between pregnant women from Papua New Guinea (malaria-exposed) with and without current malaria infection and from Australia (unexposed). Elicited levels of inflammatory cytokines at 48 h and 24 h (interferon γ, IFN-γ only) and the cellular sources of IFN-γ were analysed.ResultsAmong Papua New Guinean women, microscopic malaria at enrolment did not alter peripheral blood mononuclear cell responses. Compared to samples from Australia, cells from Papua New Guinean women secreted more inflammatory cytokines tumor necrosis factor-α, interleukin 1β, interleukin 6 and IFN-γ; p<0.001 for all assays, and more natural killer cells produced IFN-γ in response to infected erythrocytes and phytohemagglutinin. In both populations, cytokine responses were not affected by gravidity, except that in the Papua New Guinean cohort multigravid women had higher IFN-γ secretion at 24 h (p = 0.029) and an increased proportion of IFN-γ+ Vδ2 γδ T cells (p = 0.003). Cytokine levels elicited by a pregnancy malaria-specific CSA binding parasite line, CS2, were broadly similar to those elicited by CD36-binding line P6A1.ConclusionsGeographic location and, to some extent, gravidity influence maternal innate immunity to malaria.

Expression and localization of interleukin 1 beta and interleukin 1 receptor (type I) in the bovine endometrium and embryo

The interleukin-1 (IL1) system likely mediates mammalian embryo–maternal communication. In cattle, we have reported that the uterine fluid of heifers carrying early embryos shows downregulated IL1 beta (IL1B), which could lead to reduced NFkB expression and dampening of maternal innate immune responses. In this work, we assessed the expression of IL 1 beta (IL1B) and its receptor, interleukin 1 receptor type I (IL1R1) in the bovine endometrium and embryos by RT-PCR, immunohistochemistry and Western blot at the time of blastocyst development. Day 8 endometrium, both collected from animals after transfer of day 5 embryos (ET) and sham transferred (ST), showed IL1B and IL1R1 mRNA transcription and protein co-localization. Similarly, day 8 blastocyst, from ET animals and entirely produced in vitro, showed IL1R1 mRNA transcription and IL1B and IL1R1 protein co-localization. IL1B mRNA was detected in the analyzed blastocysts, but at very low levels that precluded its quantification. IL1B and IL1R1 immunostaining was observed in luminal epithelial cells, glandular epithelium and stromal cells. The presence of embryos increased endometrial IL1B protein locally, while no differences regarding IL1R1 protein and IL1B and IL1R1 mRNA were detected. These results suggest that the early preimplantation bovine embryo in the maternal tract might interact with the maternal immune system through the IL1 system. Such a mechanism may allow the embryo to elicit local endometrial responses at early stages, which are required for the development of a receptive endometrium.

The Hygiene Hypothesis Revisited: Role of Materno-Fetal Interactions

For 20 years, the hygiene hypothesis has dominated attempts to explain the increasing prevalence of allergic disease. A causal link between maternal innate immune response during pregnancy and disease protection in the offspring was recently demonstrated. Central to this was a systemically diffused signal that downregulated Toll-like receptor expression in placental tissues. Herein we develop the hypothesis that maternal systemic regulatory mechanisms operational during pregnancy could impact allergic disease risk of the offspring, depending on the type of inflammatory response from which they originate. Classic microbial-derived, mild, subacute inflammation provides a protective signal, whereas allergic inflammation provides a negative one. Mild, subacute inflammation of pregnant women leads to systemically diffused signals manifest in the gestation-associated tissues and by the fetus and newborn as a dampened inflammatory response. The converse is true if the mother has allergic inflammation during pregnancy. In both cases, these impact on development of the airways and of balanced immune function at birth and in early postnatal life. Thus, we seem to be at the dawn of a new incarnation of the hygiene hypothesis in which the pregnant woman's inflammatory response is crucial to determining the child's likelihood of developing allergic disease.

The association of innate immune response gene polymorphisms and puerperal group A streptococcal sepsis

The objective of the study was to determine whether single-nucleotide polymorphisms (SNPs) that influence the maternal innate immune response are associated with puerperal group A streptococcal sepsis. Subjects with confirmed puerperal group A streptococal infection were prospectively identified in 2 tertiary care hospitals over 18 years. Controls were racially matched subjects with term, uncomplicated deliveries. Thirty-eight polymorphisms associated with the innate immune response to bacterial infection were analyzed. Allele and genotype frequencies for subjects and controls were compared. Forty-eight women with puerperal group A streptococcal infection were identified. DNA was obtained for 28 subjects and 54 controls. Allele frequencies were significantly different between subjects and controls for polymorphisms in Toll-like receptor (TLR) 9-1486 (P = .03) and heat shock protein (HSP) 70-2 1267 (P = .003). Genotype frequencies were significantly different between subjects and controls for TLR9-1486 (P = .025), HSP70-2 1267 (P = .02), and interleukin (IL)-1beta-511 (P = .016). Puerperal group A streptococcal sepsis may be associated with innate immune response gene polymorphisms in TLR9, HSP70-2, and IL1beta.

Preimplantation factor (PIF) upregulates first trimester toll like receptor-2, supporting the role of PIF as an embryo derived factor influencing maternal innate immunity

RECEPTOR-2, SUPPORTING THE ROLE OF PIF AS AN EMBRYO DERIVED FACTOR INFLUENCING MATERNAL INNATE IMMUNITY MICHAEL PAIDAS, GRACIELA KRIKUN, LYNN BUCHWALDER, FREDERICK SCHATZ, KARL GODLEWSKI, EYTAN R. BARNEA, Yale University School of Medicine, Department Obstetrics, Gynecology and Reproductive Sciences, CoDirector, Yale Blood Center for Women and Children, New Haven, Connecticut, Yale University, Obstetrics and Gynecology & Reproductive Sciences, New Haven, Connecticut, UMDNJ/Robert Wood Johnson Medical School, CAMcare Health Center, Cherry Hill, New Jersey OBJECTIVE: Preimplantation factor (PIF), is a novel, embryo-derived, small peptide which appears very early in pregnancy. The maternal host response in pregnancy must allow for tolerance of the implanting embryo, and preservation of maternal defense mechanisms against viral and bacterial pathogens. We posit that: a) PIF may act as an immune modulating agent, capable of augmenting maternal defense mechanisms via upregulation of Toll-like receptor (TLR)-2, a transmembrane protein involved in pathogen recognition; b) PIF may will influence decidual cell (DC) production of interleukins (IL), metalloproteinases (MMP) involved in extracellular matrix degradation, and angiogenesis. STUDY DESIGN: DCs were obtained from women undergoing first trimester (TRI) elective terminations or third TRI repeat Cesarean sections. DCs were isolated, purified, and seeded on polystyrene tissue culture dishes. The effects of PIF on TLR-2 protein expression was carried out using first TRI DCs. Third TRI DCs were used to study the effects of PIF on well characterized markers of DC function, as measured by ELISA. Western blotting for TLR-2 and beta actin was conducted using established methods. Densitometric analyses were carried out with the Image J NIH analysis software. PIF (10nM) was used as an agonist to DC culture. Values were expressed as TLR2/beta actin ratio, correcting for total DNA content. RESULTS: PIF incubation was associated with a two-fold increase in TLR-2 expression. We were unable to detect any change in secreted levels of the following third TRI DC products: IL-6, IL-8, IL-11, plasminogen activator inhibitor-1, MMP-3, vascular endothelial growth factor. CONCLUSION: In this preliminary study, PIF significantly upregulates first trimester TLR-2 expression, suggesting that PIF may augment the maternal innate immune response. Maintainence of host defense mechanisms must occur as the host prepares to accept the implanting embryo. Further studies are needed to confirm PIF’s effects on TLR-2, evaluate downstream effects, and determine whether PIF regulates first TRI DC function.