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Mother-to-child-transmission (MTCT) of human immunodeficiency virus (HIV) remains a significant cause of new HIV infections in many countries. To examine whether fetal immune activation as a consequence of prenatal exposure to parasitic antigens increases the risk of MTCT, cord blood mononuclear cells (CBMCs) from Kenyan and North American newborns were examined for relative susceptibility to HIV infection in vitro. Kenyan CBMCs were 3-fold more likely to be infected with HIV than were North American CBMCs (P =.03). Kenyan CBMCs with recall responses to malaria antigens demonstrated enhanced susceptibility to HIV when compared with Kenyan CBMCs lacking recall responses to malaria (P =.03). CD4+ T cells from malaria-sensitized newborns expressed higher levels of CD25 and human leukocyte antigen DR ex vivo, which is consistent with increased immune activation. CD4+ T cells were the primary reservoir of infection at day 4 after virus exposure. Thus, prenatal exposure and in utero priming to malaria may increase the risk of MTCT. [ABSTRACT FROM AUTHOR]

Background: IgE in cord blood is thought to be a product of the fetus. A high level of total IgE is therefore used as a measure of atopic propensity in the newborn. We recently found strong evidence that allergen-specific IgE in cord blood was the result of transfer of maternal IgE to fetal blood or cord blood (maternofetal transfer) rather than fetal production. This also suggests that total IgE in cord blood might primarily be a maternal product. Objective: We sought to determine to what extent increased levels of total IgE in cord blood is the result of maternofetal transfer of IgE. Methods: Total IgE in cord blood was analyzed in a prospective birth cohort study. Maternofetal transfer of IgE was detected by means of high-sensitivity analyses of cord blood IgA and allergen-specific IgE and comparison with parental IgE levels and levels at 6 months of age. Results: Forty-six percent of cord blood samples with increased IgE levels (≥0.5 IU/mL) showed indication of maternofetal transfer of IgE. Maternal origin of IgE in these samples was validated by showing reduced levels of IgE at 6 months of age compared with samples with no indication of maternofetal transfer (geometric mean, 9.4 vs 5.4 IU/mL; P = .01). Maternofetal transfer was not appropriately accounted for by the conventional method of cord blood IgA measurement. Conclusions: Maternofetal transfer might be a common cause of increased cord blood IgE levels. Future studies should take potential maternofetal transfer into account or use other markers of atopy. [Copyright &y& Elsevier]

Abstract: Epidemiological studies with human populations indicate associations between maternal infection during pregnancy and increased risk in offspring for central nervous system (CNS) disorders including schizophrenia, autism and cerebral palsy. Since 2000, a large number of studies have used rodent models of systemic prenatal infection or prenatal immune activation to characterize changes in brain function and behavior caused by the prenatal insult. This review provides a comprehensive summary of these findings, and examines consistencies and trends across studies in an effort to provide a perspective on our current state of understanding from this body of work. Results from these animal modeling studies clearly indicate that prenatal immune activation can cause both acute and lasting changes in behavior and CNS structure and function in offspring. Across laboratories, studies vary with respect to the type, dose and timing of immunogen administration during gestation, species used, postnatal age examined and specific outcome measure quantified. This makes comparison across studies and assessment of replicability difficult. With regard to mechanisms, evidence for roles for several acute mediators of effects of prenatal immune activation has emerged, including circulating interleukin-6, increased placental cytokines and oxidative stress in the fetal brain. However, information required to describe the complete mechanistic pathway responsible for acute effects of prenatal immune activation on fetal brain is lacking, and no studies have yet addressed the issue of how acute prenatal exposure to an immunogen is transduced into a long-term CNS change in the postnatal animal. Directions for further research are discussed. [Copyright &y& Elsevier]

Nowadays, scientists are paying special attention to the increasing prevalence of obesity and associated co-morbidities, especially metabolic syndrome. This is due to observation of the spread of this syndrome from one generation to another and the growing number of obese pregnant women, which seems to exacerbate this situation. It is not yet well established whether the pathophysiological process underlying metabolic syndrome, namely insulin resistance, is due to changes in the receptor or in the cascade of intracellular processes. This narrative review aims to report on physiological and pathological changes occurring in pregnancy and the presence of Insulin receptor, Insulin Growth Factor-I receptor and the hybrid receptor, focusing on the presence of hyperinsulinemia in the growth and development of fetuses susceptible to metabolic syndrome. [ABSTRACT FROM AUTHOR]

Objective: Cell trafficking during pregnancy results in persistence of small populations of fetal cells in the mother, known as fetal microchimerism (FMc). Changes in cell-free fetal DNA during gestation have been well described, however, less is known about dynamic changes in fetal immune cells in maternal blood. We have investigated FMc in maternal peripheral blood mononuclear cells (PBMC) longitudinally across gestation.Study Design: Thirty-five women with normal pregnancies were studied. FMc was identified in PBMC, CD4+ and CD8+ subsets employing quantitative PCR assays targeting fetal-specific genetic polymorphisms. FMc quantities were reported as fetal genome equivalents (gEq) per 1,000,000 gEq mother's cells. Poisson regression modeled the rate of FMc detection.Main Outcome Measure: FMc in PBMC.Results: The probability of detecting one fetal cell equivalent increased 6.2-fold each trimester [Incidence Rate Ratio (IRR) 95% CI: 1.73, 21.91; p = 0.005]. Although FMc in PBMC was not detected for the majority of time points, 7 of 35 women had detectable FMc during pregnancy at one or more time points, with the majority of positive samples being from the third trimester. There was a suggestion of greater HLA-sharing in families where women had FMc in PBMC. FMc was detected in 9% of CD4+ (2/23) and 18% of CD8+ (3/25) subsets.Conclusions: FMc in PBMC increased as gestation progressed and was found within CD4+ and CD8+ subsets in some women in the latter half of gestation. A number of factors could influence cellular FMc levels including sub-clinical fetal-maternal interface changes and events related to parturition. Whether FMc during pregnancy predicts persistent FMc and/or correlates with fetal-maternal HLA relationships also merits further study. [ABSTRACT FROM AUTHOR]

BACKGROUND: Exposure to environmental tobacco smoke (ETS) is known to increase the risk of respiratory tract infections (RTI). Some children, however, may be more susceptible to the harmful effects of ETS than others. We examined whether early atopic status (defined by elevated neonatal total IgE (tIgE) or symptoms of atopic dermatitis) modified the association between ETS exposure and RTI. METHODS: The data of 2863 children from the Prevention and Incidence of Asthma and Mite Allergy birth cohort were collected to the age of 4 years. Neonatal tIgE was collected from a subset of 914 children, and clinical information by yearly parental questionnaires. The effect of pre- and/or postnatal ETS exposure, early atopic status and interaction between these factors was studied for various RTI. RESULTS: Children with elevated tIgE or atopic dermatitis and prenatal ETS exposure have a strongly increased risk of frequent RTI (aOR 6.18 (95% CI 1.45 to 26.34) and 5.69 (2.01 to 16.04), respectively; interaction p=0.006 and p=0.14, respectively) compared to non-atopic children without prenatal ETS exposure. Similar results were seen for lower RTI and otitis. This effect was less evident for postnatal ETS. CONCLUSION: Early atopic status enhances the risk of RTI in children with prenatal ETS exposure. This suggests that host factors modify the association between ETS and RTI. [ABSTRACT FROM AUTHOR]

Citation Liu L-P, Huang W, Lu Y-C, Liao A-H. Enhanced maternal anti-fetal immunity contributes to the severity of hypertensive disorder complicating pregnancy. Am J Reprod Immunol 2010 Problem The aim of this study was to evaluate how fetal monocyte activation and maternal anti-fetal antigen-specific antibody-secreting cells (ASC) affect the severity of hypertensive disorder complicating pregnancy (HDCP). Method of study Forty-six healthy third-trimester pregnant women and 20 patients with gestational hypertension, 20 with mild pre-ecalmpsia and another 20 with severe pre-eclampsia were included in the study. Interleukin-6 (IL-6) release from cord blood monocytes was examined by intracellular cytokine staining and flow cytometric analysis. Moreover, the maternal anti-fetal antigen-specific ASC were detected by enzyme-linked immunospot assay. Results A significantly increased percentage of IL-6-positive monocytes were detected in the cord blood of study groups compared with the controls ( P < 0.01). The percentage of IL-6-positive monocytes was increased as the disease progressed ( P < 0.05). There were more anti-fetal antigen-specific ASC in the study groups than those in the controls ( P < 0.001). Furthermore, the anti-fetal antigen-specific ASC showed difference in gestational hypertensive and severe pre-eclamptic groups ( P < 0.05). Conclusion We conclude that the fetal monocyte activation and the increase in maternal anti-fetal antigen-specific ASC were related to the incidence and severity of HDCP. These results provide both indirect and direct evidence for the occurrence of exaggerated maternal humoral immunity against the fetal antigens in HDCP. [ABSTRACT FROM AUTHOR]

Abstract: In mammalian reproduction, two immunologically disparate entities, the mother and her fetus, co-exist in close proximity and mutually tolerate each other. The maternal immune system plays a major contributing role in the reproductive outcome. A coordinated set of immunological events takes place between the maternal and fetal cells to ensure fetal survival. Among these, cytokines secreted by proximal maternal immune cells as well as fetal trophoblast cells play a major role in feto-maternal tolerance. In this review, we describe the role of the vacuolar ATPase (and more specifically the a2 isoform, a2V-ATPase) in controlling the expression of these vital cytokines. a2V-ATPase is a key enzyme that controls the acidification of intracellular vesicles and the extracellular environment, processes that play a major role in cellular function. The localization of a2V-ATPase in tissues and immune cells of the reproductive tract which are essential for pregnancy will be described. Information will be provided on the role of a2V-ATPase on aspects of cell development in pregnancy, from fertilization to implantation and fetal growth. Particular emphasis will be placed on the role of a2V-ATPase in (a) regulating parts of the cytokine network at the implantation site and (b) attenuating the potentially harmful maternal immune response against trophoblast cells. [Copyright &y& Elsevier]

CD4-positive cells are detectable in the human fetal gastrointestinal tract from 11 weeks of gestation. Interleukin-16 (IL-16) is a chemoattractant for CD4+ cells and, via fetal swallowing of amniotic fluid, could mediate the influx of CD4+ cells into the fetal gut. We have shown that IL-16 was detectable in human amniotic fluid at 16–18 weeks of gestation (mid-pregnancy) but was not detectable at term (late pregnancy; > 37 weeks of gestation). Similarly, mid-pregnancy, but not late pregnancy, amniotic fluid contained chemotactic activity for CD4+ T cells, this activity was reduced by 58% in the presence of a neutralizing anti-IL-16 antibody. The levels of IL-16 in fetal plasma at 16–24 weeks of gestation were very high, and decreased significantly by 25–36 weeks but at > 37 weeks remained significantly higher than adult levels. IL-16 transcripts were detectable in whole tissue extracts of fetal gut, skin and placenta but not in amniocytes, and IL-16 immunoreactivity was detectable in cells within the lamina propria of the fetal gut and within the skin, where it was associated with the basement membrane. Neither IL-16 levels nor chemotactic activity for CD4+ T cells in mid-pregnancy amniotic fluid was related to atopic outcomes at 1 year of age. IL-16 might have an important role in the early development of the human immune system and/or in regulating fetal and maternal immunological responsiveness during pregnancy. [ABSTRACT FROM AUTHOR]

Epidemiological studies suggest that intra-uterine exposure to inflammation may prime postnatal immune responses. In fetal sheep, intra-amniotic injection of lipopolysaccharide (LPS) induced chorioamnionitis, lung inflammation and maturation, matured lung monocytes to macrophages and initiated systemic tolerance of fetal monocytes to subsequent challenge with LPS. We hypothesized that LPS-mediated chorioamnionitis altered the response of lung and blood monocytes to Toll-like receptor (TLR) ligands such as PamCysK4 (TLR2), fiagellin (TLR5), and human CpG-DNA (TLR9). Time-mated ewes were given ultra-amniotic injections of LPS or saline. Blood and lung monocytes were assessed after 2 days, 7 days and 2 days and 7 days repetitive LPS injections before delivery at 124 days gestational age (term 150 days). Responsiveness of blood and lung monocytes to TLR-ligands in vitro was assessed by interleukin (IL)-6, tumor necrosis factor-α (TNF-α) and hydrogen peroxide. Monocytes from preterm controls had minimal responses. Lipopolysaccharide-mediated chorioamnionitis increased lL-6, TNF-α and hydrogen peroxide to all TLR agonists in blood and lung monocytes. Repetitive exposure to antenatal LPS reduced lL-6, TNF-α and hydrogen peroxide to TLR-ligands suggesting tolerance. Tolerance to TLR-ligands reduced IL- I receptor associated kinase-4 expression. Thus, repeated fetal exposure to LPS induced tolerance to other TLR-ligands. These modulations of fetal innate immunity have implications for host defense and injury responses in preterm infants. [ABSTRACT FROM AUTHOR]

Abstract: The role of maternal immune cells in early implantation sites has received special attention from reproductive biologists because immune cells participate in tissue transplant rejection. During normal pregnancy, endometrial immune cells differ from those in blood by subset distribution and appear to be activated but non-destructive of conceptuses. The immune system evolved well before placental mammals. By comparing the regulation and functions of endometrial immune cells between species in two phylogenetic clades that model differently evolved placental types (pig (Sus scrofa) versus mouse (Mus musculus) and human (Homo sapiens)), we seek to understand how “non-self” trophoblast cells thrive in most pregnancies. Our studies suggest recruitment of specific immune cells to conceptus-associated endometrium and immune cell-promoted endometrial angiogenesis are of key importance for mammalian conceptus well-being. [Copyright &y& Elsevier]

Background: Chorioamniotic membranes infection is a pathologic condition in which an abnormal secretion of proinflammatory cytokines halts fetal immune tolerance. The aim of the present study was to evaluate the functional response of human chorioamniotic membranes, as well as the individual contribution of the amnion and choriodecidua after stimulation with Escherichia coli, a pathogen associated with preterm labor. Methods: Explants of chorioamniotic membranes from 10 women (37-40 weeks of gestation) were mounted and cultured in a Transwell system, which allowed us to test the amnion and choriodecidua compartments independently. Escherichia coli (1 × 10 6 CFU/mL) was added to either the amniotic or the choriodecidual regions or both; after a 24-h incubation, the secretion of IL-1beta, IL-6, TNFalpha, IL-8, and IL-10 in both compartments was measured using a specific ELISA. Data were analyzed by Kruskal-Wallis one-way analysis of variance. Results: After stimulation with Escherichia coli, the choriodecidua compartment showed an increase in the secretion of IL-1beta (21-fold), IL-6 (2-fold), IL-8 (6-fold), and IL-10 (37-fold), regardless of which side of the membrane was stimulated; TNFalpha secretion augmented (22-fold) also but only when the stimulus was applied simultaneously to both sides. When the amnion was stimulated directly, the level of IL-1beta (13-fold) rose significantly; however, the increase in IL-8 secretion was larger (20-fold), regardless of the primary site of infection. TNFalpha secretion in the amnion compartment rose markedly only when Escherichia coli was simultaneously applied to both sides. Conclusion: Selective stimulation of fetal membranes with Escherichia coli results in a differential production of IL-1beta, IL-6, TNFalpha, IL-8, and IL-10. These tissues were less responsive when the amnion side was stimulated. This is in agreement with the hypothesis that the choriodecidua may play a primary role during an ascending intrauterine infection, being the main barrier to progression of the infection into the amniotic cavity. Therefore, the tissue-specific capacities for the secretion of these immune modulators could be a determining factor for the degree of severity of the inflammation process in fetal membranes. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses articles in the issue on topics including advances in the field of early life immunology, features of human fetal immune system development and the impact of commensal metabolites and xenobiotics on immunity.

Maternal passive immunity typically plays a critical role in protecting infants from new infections; however, the specific contribution of neutralizing antibodies in limiting mother-to-child transmission of human immunodeficiency virus type 1 is unclear. By examining cloned envelope variants from 12 transmission pairs, we found that vertically transmitted variants were more resistant to neutralization by maternal plasma than were maternal viral variants near the time of transmission. The vertically transmitted envelope variants were poorly neutralized by monoclonal antibodies biz, 2G12, 2F5, and 4E10 individually or in combination. Despite the fact that the infant viruses were among the most neutralization resistant in the mother, they had relatively few glycosylation sites. Moreover, the transmitted variants elicited de novo neutralizing antibodies in the infants, indicating that they were not inherently difficult to neutralize. The neutralization resistance of vertically transmitted viruses is in contrast to the relative neutralization sensitivity of viruses sexually transmitted within discordant couples, suggesting that the antigenic properties of viruses that are favored for transmission may differ depending upon mode of transmission. [ABSTRACT FROM AUTHOR]

Background: Maternal atopic background and stimulation of the adaptive immune system with allergen interact in the development of allergic disease. Stimulation of the innate immune system through microbial exposure, such as activation of the innate Toll-like-receptor 2 (TLR2), may reduce the development of allergy in childhood. However, little is known about the immunological effects of microbial stimulation on early immune responses and in association with maternal atopy. Methods: We analyzed immune responses of cord blood mononuclear cells (CBMC) from 50 healthy neonates (31 non-atopic and 19 atopic mothers). Cells were stimulated with the TLR2 agonist peptidoglycan (Ppg) or the allergen house dust mite Dermatophagoides farinae (Derf1), and results compared to unstimulated cells. We analyzed lymphocyte proliferation and cytokine secretion of CBMC. In addition, we assessed gene expression associated with T regulatory cells including the transcription factor Foxp3, the glucocorticoid-induced TNF receptor (GITR), and the cytotoxic lymphocyte antigen 4 (CTLA4). Lymphocyte proliferation was measured by ³H-Thymidine uptake, cytokine concentrations determined by ELISA, mRNA expression of T cell markers by real-time RT-PCR. Results: Ppg stimulation induced primarily IL-10 cytokine production, in addition to IFN-γ, IL-13 and TNF-α secretion. GITR was increased following Ppg stimulation (p = 0.07). Ppg-induced IL-10 production and induction of Foxp3 were higher in CBMC without, than with maternal atopy (p = 0.04, p = 0.049). IL-10 production was highly correlated with increased expression of Foxp3 (r = 0.53, p = 0.001), GITR (r = 0.47, p = 0.004) and CTLA4 (r = 0.49, p = 0.003), independent of maternal atopy. Conclusion: TLR2 stimulation with Ppg induces IL-10 and genes associated with T regulatory cells, influenced by maternal atopy. Increased IL-10 and Foxp3 induction in CBMC of non-atopic compared to atopic mothers, may indicate an increased capacity to respond to microbial stimuli. [ABSTRACT FROM AUTHOR]

Aims: Fetal hemoglobin (HbF) is an established serological indicator of cancer. However, its distribution in tumour tissues is rarely investigated. Therefore, HbF was studied immunohistologically in different cancers characterised by high blood HbF concentrations. Methods: Anti-HbF was immunoaffinity purified and used to study HbF immunohistochemically in the following cancers: germ cell tumour (GCT), trophoblastic disease (ID), lymphoma, myelodysplastic syndrome (MDS), multiple myeloma (MM), and ovarian adenocarcinoma (OA). Results: In GCTo distinction was made between tumours substantially without HbF positive red blood cells (F-RBC) and those with F-RBC. Those without F-RBC were non-metastatic mature teratomos and dermoid cysts. Those containing F-RBC were mainly embryonal carcinomas and metastatic teratomas. HbF positive myeloid cells (F-MLC), HbF positive normoblasts (F-NBS), and F-RBC were common in the bone marrow and in the lymphoid tissues of lymphoma, MDS, and MM. In ID, normal and nucleated F-RBC were seen in the trophoblastic villi in one case with incomplete molar pregnancy (1CM) but not in other cases of 1CM and complete molar pregnancy. However, F-RBC and F-MLC were seen in the deciduo of both types of TD. Generally, F-cells were observed either within blood vessels or concentrated in certain areas of the neoplastic tissue. Conclusions: HbF was evaluated as an inducible marker within different tumour tissue blood cells. The dual distribution of these cells-circulating in the blood or concentrated in areas of the neoplastic tissues-might reflect the two independent serological indicators of HbF: one in whole blood and the other in plasma of patients with cancer. [ABSTRACT FROM AUTHOR]

Breastfeeding - the main source of active and passive immunity in the vulnerable early months and years of life - is considered to be the most effective preventive means of reducing the death rate of children under five. Given this, one must wonder why it has slipped quietly down the priorities of the global health and development agendas. In this era of public-private partnerships, can its role as an irreplaceable immunological resource help keep it at the top of global agendas? [ABSTRACT FROM AUTHOR]

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Natural killer (NK) T cells are innate CD1d-restricted immune cells involved in regulation of immune tolerance, tumor immunity, and immunity to infectious pathogens. Human α-chain variable gene segment 24 (Vα24) NK T cells exist in the periphery as two functionally distinct subsets: one CD4+ and one CD4- subset. However, the developmental pathway of human Vα24 NK T cells is not well understood. Here, we show that Vα24 NK T cells develop in the fetal thymus. The relative number of intrathymic P4K T cell precursors decline in a linear manner with gestational age, and they are very rare in the neonatal thymus, indicating that these cells preferentially develop in the early fetal thymus. Their restriction element, CD1d, is expressed by a vast majority of thymocytes. A majority of intrathymic Vα24 NK T cell progenitors are CD4+, whereas a minority are CD4/8+/+˙ CD4+ Vα24 NK T cell precursors show features of mature NK T cells, such as high levels of their semiinvariant T cell receptor and CD3 and some expression of CD161, whereas the CD4/8+/+ precursors seem less mature. The cytokine IL-7 shows a biphasic effect on Vα24 NK T cell progenitors in fetal thymic organ culture, with high doses driving proliferation of immature CD161- progenitors and low doses supporting survival and maturation. Thus, the data demonstrate that human Vα24 NK T cells of the CD4+, but not the CD4-, subset develop in the early fetal thymus. Furthermore, data suggest an intrathymic pathway of CD4+ Vα24 NK T cell development that is regulated by IL-7. [ABSTRACT FROM AUTHOR]

Plasmid DNA (pcDNA1::MOMP D) expressing the major outer membrane protein (MOMP) of an avian Chlamydophila psittaci serovar D strain was tested for its ability to induce protective immunity against C. psittaci challenge in the presence of maternal antibodies. A combined parenteral (intramuscular injection) and mucosal route (DNA drops administered to the nares) of DNA inoculation was used. Following pcDNA1::MOMP vaccination, both T helper and B cell memory were primed. However, high maternal antibodies titres affected the induction of vaccine-specific antibody responses as assessed by MOMP-specific antibody levels in enzyme-linked immunosorbent assay (ELISA). Cell-mediated immunity was unaltered as demonstrated by the significantly heightened proliferative responses of peripheral blood lymphocytes (PBL) following vaccination. DNA vaccination could significantly reduce clinical symptoms, pharyngeal and cloacal excretion as well as Chlamydophila replication, even in the presence of maternal antibodies. [Copyright &y& Elsevier]

The more men by whom a woman has children, the more diverse will be the foetal antigens of paternal origin introduced into her bloodstream, and we investigated whether this has an impact on subsequent cancer risks. By using population registries we identified 64?704 women who had children with at least two different partners from 1973 to 1996 in Denmark. We compared their cancer incidence with that of women who during the same time period had at least two births with no indication of partner change, adjusting for age, parity, socioeconomic factors and residence. The overall cancer incidence was more than 50% higher in women with two or more partners. Women having children with multiple partners had a higher incidence of cancer of the cervix and corpus uteri, a lower incidence of melanoma but a similar incidence of breast and ovarian cancer. Uncontrolled differences in lifestyle factors may explain the higher cancer risk associated with having multiple partners. The strong protective effect for melanoma was unexpected and deserves further study.British Journal of Cancer (2004) 90, 1374-1377. doi:10.1038/sj.bjc.6601666 www.bjcancer.com Published online 24 February 2004 [ABSTRACT FROM AUTHOR]

Context: Vaccine development to prevent congenital cytomegalovirus (CMV) infection has been impeded by the uncertainty over whether maternal immunity protects the fetus. Objective: To determine whether the presence of maternal antibodies to CMV significantly reduces the risk of congenital CMV infection in future pregnancies. Design, Setting, and Participants: Cohort study of 3461 multiparous women from a population with a high rate of congenital CMV infection who delivered newborns screened for congenital CMV infection between 1993 and 1998, and whose cord serum specimen from a previous delivery could be retrieved and tested for antibody to CMV. Main Outcome Measure: Congenital CMV infection according to maternal immune status, age, race, parity, and socioeconomic status. Results: Of 604 newborns born to initially seronegative mothers, congenital CMV infection occurred in 18 (3.0%). In contrast, of 2857 newborns born to immune mothers, congenital CMV infection occurred in 29 (1.0%) Two factors, preconception maternal immunity (adjusted risk ratio, 0.31; 95% confidence interval, 0.17-0.58) and maternal age of 25 years or older (adjusted risk ratio, 0.19; 95% confidence interval, 0.07-0.49), were highly protective against congenital CMV infection. No other factors were associated with a reduction in the risk of congenital CMV infection. Conclusion: Naturally acquired immunity results in a 69% reduction in the risk of congenital CMV infection in future pregnancies. [ABSTRACT FROM AUTHOR]

This study investigated changes in the proportion of T helper (Th)1 and Th2 cells in cord blood after premature rupture of membranes (PROM), and evaluate the effects of PROM on the intrauterine fetal immune status. The proportion of CD3-positive T cells secreting interferon (IFN)-γ as an index of Th1 cells, and interleukin (IL)-4 as an index of Th2 cells in cord blood of 12 newborns with and without PROM, were analyzed by flow cytometry. In cord blood of newborns with PROM, the proportion of IFN-γ secreting cells significantly increased, and the proportion of IL-4 secreting cells was rather high but not significantly higher than that of newborns without PROM. These changes eventually caused a shift in the Th1/Th2 ratio to Th1 dominance in PROM. There was no significant correlation between the proportion of IFN-γ secreting cells and the duration of PROM before the onset of labor. These results suggest that the increase in the proportion of IFN-γ secreting cells after PROM, which eventually cause the Th1/Th2 ratios to show the Th1 predominance, may reflect in part intrauterine fetal immune responses to PROM. [ABSTRACT FROM AUTHOR]

OBJECTIVE:To assess the feasibility of using the middle cerebral artery peak systolic velocity (MCA-PSV) to predict the actual value of fetal hemoglobin in fetuses undergoing a first cordocentesis for detection of anemia caused by maternal red cell alloimmunization.METHODS:Doppler velocimetry of the MCA-PSV was performed in 18 fetuses before an initial cordocentesis. Hemoglobin and MCA-PSV values were expressed as multiples of the median to adjust for the changes that both parameters demonstrate with gestational age. In each fetus we determined: 1) the expected (using a cubic mathematical function describing the correlation between fetal hemoglobin and MCA-PSV) and the observed (determined at the time of the cordocentesis) hemoglobin value; and 2) the percentage differences between the expected and the observed hemoglobin values.RESULTS:Gestational age at the time of the Doppler study ranged from 19 to 31 weeks. On 15 occasions, the fetuses demonstrated anemia. A quadratic relationship was found between the hemoglobin multiples of the median and the percentage differences between the expected and the observed hemoglobin values. As the values of hemoglobin decreased, the percentage difference between expected and observed values significantly decreased (R2 = 0.48, P < .05). The cubic model estimated fetal hemoglobin well in severely anemic fetuses and less well when the fetus was not anemic.CONCLUSION:Doppler measurement of the MCA-PSV appears to be a valuable tool for estimating hemoglobin concentration in fetuses at risk for anemia. The correlation between hemoglobin and MCA-PSV becomes more accurate as the severity of anemia increases. [Copyright &y& Elsevier]

Examines cellular immune response, cell proliferation, and messenger ribonucleic acid cytokine expression in fetal pulmonary tissue in the presence or absence of chorioamnionitis. Association between chorioamnionitis and intrauterine inflammatory response of the fetal lung; Inflammatory response of fetal lung tissue with and without exposure to chorioamnionitis; Use of immunohistochemical staining.

SummaryHuman leucocyte antigen (HLA) -G is expressed on trophoblast cells during pregnancy, suggesting a role in protection of the semiallogeneic fetus. Published data suggest that HLA-G protects a cell against natural killer cell lysis. It has been hypothesized that HLA-G may also protect the fetus by preventing allo-cytotoxic T lymphocyte (CTL) responses. To test this hypothesis, we assayed the effects of various concentrations of purified HLA-G on CTL response in a mixed lymphocyte culture (MLC) system. We found that concentrations ≥ 0·1 µg/ml of HLA-G suppressed the allo-CTL response by 30–100% over the control, but, paradoxically, concentrations of 0·01–0·05 µg/ml of HLA-G augmented the allo-CTL response by 25–50% over the control. Concentrations ≤ 0·001 µg/ml HLA-G had no effect. Addition of HLA-G to preprimed allo-CTL effector cells did not affect their killing ability. Allo-CTL suppressive doses of HLA-G induced a T helper type 2 (Th2) cytokine response, whereas allo-CTL-enhancing doses of HLA-G induced a Th1-type cytokine response. HLA-G purified from first-trimester placenta does not affect allo-proliferative responses nor does it alter the percentage of CD4+ or CD8+ T cells in MLCs. These findings support a potential role for HLA-G-mediated suppression of allo-CTL formation in normal pregnancies. In addition, the effects observed at lower concentrations of HLA-G may have interesting implications for the condition of pre-eclampsia in which concentrations of this HLA class I molecule are reduced. [ABSTRACT FROM AUTHOR]

Neonates face a high risk of infection because of the immaturity of their immune systems. Although the transplacental transfer of maternal antibodies to the fetus may convey improved postnatal immunity, this transfer occurs late in gestation and may fail to prevent in utero infection. Both fetal immunization and in utero exposure to antigen can result in a state of immunologic tolerance in the neonate. Tolerance induction of fetal and premature infant lymphocytes has become a paradigm for neonatal responsiveness. However, fetal IgM responses have been demonstrated to maternal immunization with tetanus toxoid and to congenital infections such as rubella, toxoplasma, cytomegalovirus and human immunodeficiency virus. Moreover, 1-week-old infants can respond to standard pediatric vaccination, and neonates immunized with polysaccharide antigens do not develop immunologic tolerance. Here, direct immunization of the baboon fetus with recombinant hepatitis B surface antigen produced a specific fetal IgG antibody response. No specific maternal antibody response was detected, eliminating the possibility of vertical antibody transmission to the fetus. Some infants also responded to later vaccinations with hepatitis B surface antigen, indicating that no immunological tolerance was induced by prior fetal immunization. These results characterize the ability of the fetal immune system to respond to in utero vaccination. We demonstrate that active fetal immunization can serve as a safe and efficient vaccination strategy for the fetus and neonate. [ABSTRACT FROM AUTHOR]

Examines the influence of milk-borne cytokines and hormones to neonatal immune cell function. Composition of maternal milk; Neonatal immunodevelopment; Function of prolactin.

Studies the immune response in prematurely born children. Brief discussion of the immune system; T cells during fetal life and in neonates; B lymphocytes during fetal life and in neonates; Maternal contribution to immunity in the child via the placenta; Commentaries about the article.

We examined the expression ot the CD45RO antigen, which characterizes the antigen primed/memory phenotype of T lymphocytes, as a marker for congenital infection in blood samples of newborns and fetuses. CD45RO expression on T cells was determined by triple-colour fluorescence flow cytometry. In total 537 blood samples of newborns and infants up to an age of 3 months and 89 fetal blood samples from gestational weeks 19-31 were analysed. Of the newborns and infants. 74 had a clinically, serologically and/or antigenically evident infection, and four of the fetuses had a confirmed intra-uterine infection. In 35 infants with acute predominantly bacterial infections such as sepsis or pneumonia. 17 (48.6%) had elevated CD45RObright expression. In 39 infants with proven pre-, peri- or early post-natal infections with toxoplasmosis, cytomegalovirus (CMV). rubella, herpes simplex virus (HSV) or human herpes virus type 6 (HHV6), 25 (64.1%) exhibited enhanced CD45RObright expression. Three of four fetuses with confirmed intra-uterine infection (three with CMV, one with parvovirus 819) exhibited elevated CD45RObright expression. The specificity of the CD45RO assay for detecting microbial infections was 94.6% for newborns and infants up to 3 months and 90.6% for fetuses. It is concluded that elevated numbers of CD45RObright T cells in infants tip to 3 months of age strongly suggest an infection. However, the sensitivity of the CD45RO assay is not sufficient to enable the test to be used as a general marker for prescreening infants to detect pre-, pen- or early post-natally acquired infections. [ABSTRACT FROM AUTHOR]

Focuses on the maturation of B cells into antibody-producing plasma cells in human newborns. Generation of antigen binding diversity; Generation of immunoglobulin class diversity; Development of specific immunity in human fetuses.

Abstract. B cell development occurs in a series of discrete stages which can be distinguished on the basis of morphologic and functional criteria. Genesis of B cells begins within the fetal liver as early as eight weeks gestation, and is later maintained in bone marrow. The first recognizable developmental stage is the rapidly-dividing pre-B cell which synthesizes cytoplasmic IgM but lacks surface receptors for antigen. Immature B lymphocytes emerging from pre-B cells express surface IgM, but are uniquely susceptible to inactivation as a consequence of specific antigen binding. Progeny of these cells express different classes of cell surface immunoglobulin and become committed to differentiate into plasma cells synthesizing IgM, IgD, IgG, IgA, or IgE immunoglobulins, respectively. By the beginning of the second trimester, the human fetus has an adult proportion of B lymphocytes expressing different immunogobulin classes and capable of recognizing an extensive variety of antigens. The qualitative and quantitative deficiencies in antibody responses of newbores, as compared to adults, appear to reflect regulatory interactions with T cells and macrophages rather than absence of B lymphocytes capable of generating a response. Recent research with recombinant DNA technology has provided remarkable new knowledge of the structure and organization of immunoglobulin genes. This developing information, in concert with more detailed studies of the cellular expression of these genes during ontogeny, holds the promise of generating insights into the molecular mechanisms regulating gene expression during differentiation. Pediatrics 64:750-757, 1979; B lymphocyte... [ABSTRACT FROM AUTHOR]

Presents several abstracts related to maternofetal immunobiology. "Interactions Between Trophoblast and Large Granular Lymphocytes-Is There a Suitable Animal Model?," by G S Vince; "Differential Maternal Control of Development and Immune Responsiveness to the Invasive and Non-invasive Components of Equine Trophoblast," by W.R. Allen, Francesca Steward, and D.F. Antczak; "Mannan Binding Protein Deficiency Is Associated With Recurrent Miscarriage," by D.C. Kilpstrick, B.H. Bevan, and W.A. Liston.

Major differences in the maternal immune response to the fetus were observed in the placentomes and in the interplacentomal regions of the pregnant sheep uterus. Firstly, fewer lymphocytes were detected in the placentomes compared to the interplacentomal regions and to non-pregnant uterine tissue (Lee, Gogolin-Ewens & Brandon, 1988). Secondly, a large population of CD45R+ granulated lymphocytes was uniformly distributed in the interplacentomal uterine epithelium throughout pregnancy but never in the syncytial layer of the placentomes. Thirdly, monoclonal antibodies specific for the CD5 antigen consistently stained the endothelium of blood vessels within the placentomes but never blood vessels in the interplacentomal areas. Finally, OLA class I antigens were present on the interplacentomal uterine epithelial cells and on the maternal stromal cells, but no staining of the trophoblast or syncytium was observed. These observations suggest that different mechanisms to prevent immune rejection of the fetus may operate in the placentomes where trophoblast invasion of the maternal tissue occurs compared to the interplacentomal regions. [ABSTRACT FROM AUTHOR]

A total of fifty-two foetal sheep between 49 and 126 days gestation were injected with polymeric and monomeric flagellin, dinitrophenylated monomeric flagellin, chicken red blood cells, ovalburain, ferritin, chicken γ-globulin and the somatic antigens of Salmonella typhimurium in a variety of combinations. Immune responses were followed in these animals by taking serial blood samples from them through indwelling vascular cannulae and measuring the circulating titres of antibody. Of the antigens tested, ferritin induced immune responses in the youngest foetuses. A short time later in gestation, the majority of foetuses responded to chicken red blood cells, polymeric flagellin, monomeric flagellin and dinitrophenylated monomeric flagellin. Only older foetuses responded regularly to chicken γ-globulin and ovalbumin. However, antibodies to all these antigens were first detected over the relatively short period of development between 64 and 82 days gestation and this made it difficult to define any precise order in the development of immune responsiveness. Of the antigens tested only the somatic antigens of S. typhimurium failed to induce a primary antibody response during foetal life. The character and magnitude of the antibody responses in foetuses changed throughout in utero development. Both the total amount of antibody produced and the duration of the response increased with foetal age. Foetuses younger than 87 days gestation did not synthesize 2-mercaptoethanol resistant antibodies or IgG1 immunoglobulin to any of the antigens tested, whereas most foetuses older than this regularly did so. [ABSTRACT FROM AUTHOR]

Objectives: Altered cytokine expression at the fetoplacental interface may be a potential mechanism for the development of fetal immune dysfunction in children with fetal alcohol syndrome. This study was conducted to determine whether first-trimester trophoblasts respond to ethanol exposure by the induction of specific cytokines.Study Design: HTR-8/SVneo trophoblast cells were cultured in vitro in the presence of either ethanol (0.5% [vol/vol]), lipopolysaccharide (1 microg/mL), or ethanol and lipopolysaccharide. Expression of granulocyte colony-stimulating factor, regulated on activation normal T cell expressed and secreted, and interleukin-6 was examined by Northern analysis and enzyme-linked immunosorbent assay.Results: Culture in the presence of ethanol, lipopolysaccharide, or lipopolysaccharide and ethanol resulted in the increased transcription and secretion of granulocyte colony-stimulating factor, regulated on activation normal T cell expressed and secreted, and interleukin-6 at significantly greater levels (P < .01) than control cultures.Conclusions: Human first-trimester trophoblasts express high levels of cytokines when cultured in the presence of ethanol. Trophoblasts may therefore be an important exogenous source of cytokines for the fetus, and altered cytokine levels during early gestation may have an adverse effect on the development of the fetal immune system. [ABSTRACT FROM AUTHOR]

Determines whether activation of the monocyte-neutrophil system occurs in fetuses before premature birth. Patient characteristics; Clinical and laboratory results; Neonatal outcomes; Activation marker results.

Blood samples were obtained from fetuses and premature babies (n=51) (15-34 weeks gestation) to determine at what stage the fetal immune system was able to produce a positive proliferative response to common allergens. Peripheral blood mononuclear cells (PBMC) were stimulated with the mitogen, phytohaemagglutinin (PHA), and the allergens, house dust mite, cat fur, birch tree pollen, β-lactoglobulin, ovalbumin and bee venom (mellitin). Results were expressed as ratios of stimulated to unstimulated ³H thymidine incorporation, and as percent positive responders. There was an increase in proliferation ratio which correlated with increasing gestational age for PHA (p<0.0001), cat fur (p=0.042), birch pollen (p=0.022) and p-lactoglobulin (p=0,006). The point in gestation when cells from some individuals began responding to the allergens with a ratio of 2.0 was at approximately 22 weeks. PBMC proliferative response ratios were higher from samples from babies > 22 weeks gestation compared to < 22 weeks for the mitogen and all allergens, except mellitin. There was also a greater proportion of positive responders from samples > 22 weeks compared to < 22 weeks for the mitogen and all allergens, except mellitin. Maternal exposure to birch pollen, which has a discrete season, was assessed to determine whether exposure had occurred at 22 weeks gestation or beyond. Results showed a higher proliferative response in infant cells stimulated with birch pollen (p=0.005) and higher proportion of positive responders (p=0.01) in the group of babies whose mothers had been exposed to birch pollen beyond 22 weeks, compared to those whose mothers had not been so exposed. These results suggest that in utero fetal exposure to an allergen from around 22 weeks gestation may result in primary sensitisation to that allergen, leading to positive proliferative responses, at birth. [ABSTRACT FROM AUTHOR]

The methods successfully used to induce immunological tolerance in mice to a variety of antigens were applied to studies on mycobacterial antigens (whole tubercle bacilli). Mice were injected with approximately 5 × 105 living attenuated (BCG) or heat-killed virulent (H37Rv) tubercle bacilli on the 15th, 16th or 17th day of foetal life. Acid-fast bacilli were found in the lungs, spleens and livers of these mice after birth. Such mice subsequently developed normally and were not more susceptible to BCG than mice primarily infected in adult life. The immunological state of the mice exposed to mycobacteria in utero was determined by challenging 5 to 6 weeks after birth with either virulent or attenuated tubercle bacilli. These tests showed that an intra-embryonic injection of mycobacteria resulted in protective immunity and not tolerance. Furthermore, the mice also showed delayed-type hypersensitivity to mycobacteria. These results are discussed in relation to the ability of other antigens to induce immunological tolerance in mice and to the response of other animal species to mycobacteria. [ABSTRACT FROM AUTHOR]

The article presents the results of a study which investigated the possibility of the transfer of bacterial toxins from mother to fetus through the placenta. Rabbits, guinea pigs and rats were used as subjects for experiments involving the exotoxins of a variety of clostridia. An overview of related previous research is provided, along with details of the experimental protocol. It was found that the exotoxins of the clostridia in question failed to cross the placental barrier.

Presents several abstracts related to neonatal immunity. "Models of Maternal-foetal Transmission of Immune Cells," by B. Adkins and R. Levy; "CD8 T Cell Memory in Mice Primed as Neonates With a Retrovirus," by M. Sarzotti, S. Fadel and D. Ozaki; "Homeostatic Expansion and Differentiation of Newborn T-cells," by D. J. Reen; "Ontogeny and Functional Properties of Neonatal Dendritic Cells," by C. M. Sun, R. Lo-Man and C. Leclerc.

Mononuclear cells in umbilical-cord blood display allergen-specific reactivity, but how allergen exposure occurs in utero is unknown. We investigated the presence of a common inhalant allergen (Der p 1), to which mothers are exposed throughout pregnancy, by ELISA in matched maternal blood and amniotic fluid samples at 16-17 weeks of gestation, and in matched maternal and umbilical-cord blood at term (> 37 weeks of gestation). Der p 1 was detectable in 24 of 43 amniotic fluid samples where it was also present in maternal blood, and in 15 of 24 cord-plasma samples at significantly higher concentrations than in the maternal plasma (p=0.022). The detection of Der p 1 in the amniotic fluid and the fetal circulation provides direct evidence of transamniotic and transplacental allergen exposure. [ABSTRACT FROM AUTHOR]

As reported in this issue of Blood, Francis et al hypothesized that a cytomegalovirus (CMV) infection in utero or a perinatal infection can initiate immune dysregulation during the critical development of fetal immune development and thereby play a role in childhood acute lymphoblastic leukemia (ALL).1 [ABSTRACT FROM AUTHOR]

The article presents a commentary to a study published within the issue about the immunological and clinical complications of microchimerism, specifically on the relationship of microchimerism to maternal disease. A brief overview of the study is given, which suggests that fetal microchimerism was higher after caesarean delivery compared with vaginal delivery. According to the author, the study illustrates one of the key areas of maternal-fetal immunology that is enigmatic.

Problem: Human β‐defensins (HBDs) are antimicrobial peptides that participate in the soluble innate immune mechanisms against infection. Herein, we determined whether HBD‐1 was present in amniotic fluid during normal pregnancy and whether its concentrations change with intra‐amniotic inflammation and/or infection. Method of Study: Amniotic fluid was collected from 219 women in the following groups: (a) midtrimester who delivered at term (n = 35); (b) term with (n = 33) or without (n = 17) labor; (c) preterm labor with intact membranes who delivered at term (n = 29) or who delivered preterm with (n = 19) and without (n = 29) intra‐amniotic inflammation and infection or with intra‐amniotic inflammation but without infection (n = 21); and (d) preterm prelabor rupture of membranes (pPROM) with (n = 19) and without (n = 17) intra‐amniotic inflammation/infection. Amniotic fluid HBD‐1 concentrations were determined using a sensitive and specific ELISA kit. Results: (a) HBD‐1 was detectable in all amniotic fluid samples; (b) amniotic fluid concentrations of HBD‐1 were changed with gestational age (midtrimester vs term no labor), being higher in midtrimester; (c) amniotic fluid concentrations of HBD‐1 were similar between women with and without spontaneous labor at term; (d) among patients with spontaneous preterm labor, amniotic fluid concentrations of HBD‐1 in women with intra‐amniotic inflammation/infection and in those with intra‐amniotic inflammation without infection were greater than in women without intra‐amniotic inflammation or infection who delivered preterm or at term; and (e) the presence of intra‐amniotic inflammation and infection in patients with pPROM did not change amniotic fluid concentrations of HBD‐1. Conclusion: HBD‐1 is a physiological constituent of amniotic fluid that is increased in midtrimester during normal pregnancy and in the presence of culturable microorganisms in the amniotic cavity. These findings provide insight into the soluble host defense mechanisms against intra‐amniotic infection. Amniotic fluid concentrations of human beta defensin‐1 (HBD‐1) in women with spontaneous preterm labor and intact membranes. Red lines indicate medians with interquartile ranges. [ABSTRACT FROM AUTHOR]

Recurrent spontaneous abortion (RSA) is a growing problem worldwide. In a majority of cases, the cause remains unknown but there is increasing evidence that immunologic factors play an important role. Intravenous immunoglobulin (IVIg) therapy has been proposed to have immune modulatory effects and therefore been applicable for the treatment of patients with RSA. Although its efficacy is still controversial, several recent studies suggest that IVIg treatment may improve pregnancy outcomes. CD4+ T cells and their related cytokines play an important role in maternal‐fetal immune regulation, and an imbalance of Th17/Treg cell ratio has been proposed as a cause for RSA. We review the scientific evidence supporting a modulatory effect of IVIg on Th17/Treg cell balance and discuss the potential mechanisms how IVIg might enhance Treg cells function. We propose that correction of Th17/Treg cell dysregulation could be one of the mechanisms that can explain the positive therapeutic effects of IVIg therapy. Consequently, selecting patients with abnormal Th17/Treg cell ratios could increase the success of IVIg therapy. [ABSTRACT FROM AUTHOR]