Retinoic acid-loaded liposomes induce human mucosal CD103+ dendritic cells that inhibit Th17 cells and drive regulatory T-cell development in vitro.

The active vitamin A metabolite, all-trans-retinoic acid (RA), primes precursor dendritic cells (DCs) into a mucosal phenotype with tolerogenic properties characterized by the expression of integrin CD103. CD103+ DCs can counteract pathogenic Th1 and Th17 in inflammatory bowel disease (IBD) or celiac disease (CD). Tolerogenic manipulation of DCs using nanoparticles carrying tolerogenic adjuvants and disease-specific antigens is a valuable treatment strategy to induce antigen-specific mucosal tolerance in vivo. Here, we investigated the effects of RA-loaded liposomes on human DC phenotype and function, including DC-driven T-cell development, both during the generation of monocyte-derived DCs (moDCs) as well as by priming immature moDCs. RA liposomes drove CD103+ DC differentiation as well as ALDH1A2 expression in DCs. Neutrophil-dependent Th17 cell development was reduced by RA-liposome-differentiated and RA-liposome-primed DCs. Moreover, RA liposome treatment shifted T-cell development toward a Th2 cell profile. Importantly, RA liposomes induced the development of IL-10-producing and FoxP3+ regulatory T cells (Tregs) of various Treg subsets, including ICOS+ Tregs, that were potent inhibitors of bystander memory T-cell proliferation. Taken together, RA-loaded liposomes could be a novel treatment avenue for IBD or CD patients.

Aberrant neutrophil degranulation in hospitalized patients with COVID-19 partially remains for 6 months.

Neutrophils are important players in COVID-19, contributing to tissue damage by release of inflammatory mediators, including ROS and neutrophil elastase. Longitudinal studies on the effects of COVID-19 on neutrophil phenotype and function are scarce. Here, we longitudinally investigated the phenotype and degranulation of neutrophils in COVID-19 patients (28 nonhospitalized and 35 hospitalized patients) compared with 17 healthy donors (HDs). We assessed phenotype, degranulation, CXCL8 (IL-8) release, and ROS generation within 8 days, at one or 6 month(s) after COVID-19 diagnosis. For degranulation and ROS production, we stimulated neutrophils, either with ssRNA and TNF or granulocyte-macrophage colony-stimulating factor and N-Formylmethionyl-leucyl-phenylalanine. During active COVID-19, neutrophils from hospitalized patients were more immature than from HDs and were impaired in degranulation and ROS generation, while neutrophils from nonhospitalized patients only demonstrated reduced CD66b+ granule release and ROS production. Baseline CD63 expression, indicative of primary granule release, and CXCL8 production by neutrophils from hospitalized patients were elevated for up to 6 months. These findings show that patients hospitalized due to COVID-19, but not nonhospitalized patients, demonstrated an aberrant neutrophil phenotype, degranulation, CXCL8 release, and ROS generation that partially persists up to 6 months after infection.

Interleukin-12 and -23 Control Plasticity of CD127(+) Group 1 and Group 3 Innate Lymphoid Cells in the Intestinal Lamina Propria.

Human group 1 ILCs consist of at least three phenotypically distinct subsets, including NK cells, CD127(+) ILC1, and intraepithelial CD103(+) ILC1. In inflamed intestinal tissues from Crohn's disease patients, numbers of CD127(+) ILC1 increased at the cost of ILC3. Here we found that differentiation of ILC3 to CD127(+) ILC1 is reversible in vitro and in vivo. CD127(+) ILC1 differentiated to ILC3 in the presence of interleukin-2 (IL-2), IL-23, and IL-1ß dependent on the transcription factor RORγt, and this process was enhanced in the presence of retinoic acid. Furthermore, we observed in resection specimen from Crohn's disease patients a higher proportion of CD14(+) dendritic cells (DC), which in vitro promoted polarization from ILC3 to CD127(+) ILC1. In contrast, CD14(-) DCs promoted differentiation from CD127(+) ILC1 toward ILC3. These observations suggest that environmental cues determine the composition, function, and phenotype of CD127(+) ILC1 and ILC3 in the gut.

Hyaluronic Acid in Synovial Fluid Prevents Neutrophil Activation in Spondyloarthritis.

Spondyloarthritis (SpA) patients suffer from joint inflammation resulting in tissue damage, characterized by the presence of numerous neutrophils in the synovium and synovial fluid (SF). As it is yet unclear to what extent neutrophils contribute to the pathogenesis of SpA, we set out to study SF neutrophils in more detail. We analyzed the functionality of SF neutrophils of 20 SpA patients and 7 disease controls, determining ROS production and degranulation in response to various stimuli. In addition, the effect of SF on neutrophil function was determined. Surprisingly, our data show that SF neutrophils in SpA patients have an inactive phenotype, despite the presence of many neutrophil-activating stimuli such as GM-CSF and TNF in SF. This was not due to exhaustion as SF neutrophils readily responded to stimulation. Therefore, this finding suggests that one or more inhibitors of neutrophil activation may be present in SF. Indeed, when blood neutrophils from healthy donors were activated in the presence of increasing concentrations of SF from SpA patients, degranulation and ROS production were dose-dependently inhibited. This effect was independent of diagnosis, gender, age, and medication in the patients from which the SF was isolated. Treatment of SF with the enzyme hyaluronidase strongly reduced the inhibitory effect of SF on neutrophil activation, indicating that hyaluronic acid that is present in SF may be an important factor in preventing SF neutrophil activation. This finding provides novel insights into the role of soluble factors in SF regulating neutrophil function and may lead to the development of novel therapeutics targeting neutrophil activation via hyaluronic acid or associated pathways.

Plasmodium sporozoites induce regulatory macrophages.

Professional antigen-presenting cells (APCs), like macrophages (Mϕs) and dendritic cells (DCs), are central players in the induction of natural and vaccine-induced immunity to malaria, yet very little is known about the interaction of SPZ with human APCs. Intradermal delivery of whole-sporozoite vaccines reduces their effectivity, possibly due to dermal immunoregulatory effects. Therefore, understanding these interactions could prove pivotal to malaria vaccination. We investigated human APC responses to recombinant circumsporozoite protein (recCSP), SPZ and anti-CSP opsonized SPZ both in monocyte derived MoDCs and MoMϕs. Both MoDCs and MoMϕs readily took up recCSP but did not change phenotype or function upon doing so. SPZ are preferentially phagocytosed by MoMϕs instead of DCs and phagocytosis greatly increased after opsonization. Subsequently MoMϕs show increased surface marker expression of activation markers as well as tolerogenic markers such as Programmed Death-Ligand 1 (PD-L1). Additionally they show reduced motility, produce interleukin 10 and suppressed interferon gamma (IFNγ) production by antigen specific CD8+ T cells. Importantly, we investigated phenotypic responses to SPZ in primary dermal APCs isolated from human skin explants, which respond similarly to their monocyte-derived counterparts. These findings are a first step in enhancing our understanding of pre-erythrocytic natural immunity and the pitfalls of intradermal vaccination-induced immunity.

Experiences and needs of women in vulnerable situations receiving additional interventions in maternity care: a qualitative study.

BACKGROUND: Tailoring an intervention to the needs and wishes of pregnant women in vulnerable situations (e.g., socioeconomic disadvantages) can reduce the risk of adverse outcomes and empower these women. A relatively high percentage of pregnant women in the North of the Netherlands are considered vulnerable to adverse pregnancy outcomes because of their low socioeconomic status and the intergenerational transmission of poverty. In order to improve perinatal and maternal health, next to standard prenatal care, various interventions for pregnant women in vulnerable situations have been developed. We do not know to what extent these additional interventions suit the needs of (pregnant) women. Therefore, the aim of this study is to gain insight into the experiences and needs of women in vulnerable situations who receive additional maternity care interventions in the Northern Netherlands. METHODS: Qualitative research was performed. We used a phenomenological framework, which is geared towards understanding people's experiences in the context of their everyday lives. In-depth semi-structured interviews were conducted with 17 pregnant women in vulnerable situations living in the Northern Netherlands. A thematic analysis was carried out. RESULTS: We found three themes that reflect the experiences and needs of pregnant women in vulnerable situations in relation to the intervention they receive. These themes relate to the care provided by health professionals, to the impact of being offered an intervention, and to practical issues related to receiving an additional intervention. We found that the needs of pregnant women in vulnerable situations who received an additional maternity care intervention varied. This variation in needs was mainly related to practical issues. Women also expressed common needs, namely the desire to have control over their situation, the wish to receive tailor-made information about the intervention, and the wish for the intervention to be specifically tailored to their circumstances. CONCLUSIONS: Living in vulnerable situations and being offered additional care evoked diverse reactions and emotions from pregnant women. We recommend that health professionals ensure open and clear communication with women, that they ensure continuity of care and relationship-centered care, and that they become aware of the process of stigmatization of women in vulnerable situations.

Schistosoma mansoni soluble egg antigen (SEA) and recombinant Omega-1 modulate induced CD4+ T-lymphocyte responses and HIV-1 infection in vitro.

Parasitic helminths evade, skew and dampen human immune responses through numerous mechanisms. Such effects will likely have consequences for HIV-1 transmission and disease progression. Here we analyzed the effects that soluble egg antigen (SEA) from Schistosoma mansoni had on modulating HIV-1 infection and cytokine/chemokine production in vitro. We determined that SEA, specifically through kappa-5, can potently bind to DC-SIGN and thereby blocks DC-SIGN mediated HIV-1 trans-infection (p<0.05) whilst not interfering with cis-infection. DCs exposed to SEA whilst maturing under Th2 promoting conditions, will upon co-culture with naïve T-cells induce a T-cell population that was less susceptible to HIV-1 R5 infection (p<0.05) compared to DCs unexposed to SEA, whereas HIV-1 X4 virus infection was unaffected. This was not observed for DCs exposed to SEA while maturing under Th1 or Th1/Th2 (Tmix) promoting conditions. All T-cell populations induced by SEA exposed DCs demonstrate a reduced capacity to produce IFN-γ and MIP-1ß. The infection profile of T-cells infected with HIV-1 R5 was not associated with down-modulation of CCR5 cell surface expression. We further show that DCs maturing under Tmix conditions exposed to plant recombinant omega-1 protein (rω-1), which demonstrates similar functions to natural ω-1, induced T-cell populations that were less sensitive for HIV-1 R5 infection (p<0.05), but not for X4 virus infection. This inhibition associated again with a reduction in IFN-γ and MIP-1ß expression, but additionally correlated with reduced CCR5 expression. We have shown that SEA parasite antigens and more specifically rω-1 can modulate HIV-1 infectivity with the potential to influence disease course in co-infected individuals.

Efficient Neutrophil Activation Requires Two Simultaneous Activating Stimuli.

Neutrophils are abundantly present in the synovium and synovial fluid of patients suffering from arthritis. Neutrophils can be activated by a multitude of stimuli and the current dogma states that this is a two-step process, consisting of a priming step followed by an activation step. Considering that neutrophil activation occurs in an inflammatory environment, where multiple stimuli are present, we argue that a two-step process is highly unlikely. Here, we indeed demonstrate that neutrophils require simultaneous ligation of two different receptors for efficient activation. We isolated human peripheral blood neutrophils and cultured them with various combinations of stimuli (GM-CSF, fMLF, TNF, and LPS). Next, we evaluated essential neutrophil functions, including degranulation and ROS production using flow cytometry, mediator release using ELISA, NETosis by a live cell imaging method, phagocytosis by imaging flow cytometry, and extracellular vesicle (EV) release quantified by high-resolution flow cytometry. Exposure of neutrophils to any combination of stimuli, but not to single stimuli, resulted in significant degranulation, and mediator and EV release. Furthermore, ROS production increased substantially by dual stimulation, yet appeared to be more dependent on the type of stimulation than on dual stimulation. Phagocytosis was induced to its maximum capacity by a single stimulus, while NETosis was not induced by any of the used physiological stimuli. Our data indicate that neutrophil activation is tightly regulated and requires activation by two simultaneous stimuli, which is largely independent of the combination of stimuli.

Signal Inhibitory Receptor on Leukocytes-1 is highly expressed on lung monocytes, but absent on mononuclear phagocytes in skin and colon.

Signal Inhibitory Receptor on Leukocytes-1 (SIRL-1) is expressed on human blood monocytes and granulocytes and inhibits myeloid effector functions. On monocytes, but not granulocytes, SIRL-1 expression is low or absent in individuals with the single nucleotide polymorphism (SNP) rs612529C. The expression of SIRL-1 in tissue and the influence of rs612529 hereon is currently unknown. Here, we used flow cytometry to determine SIRL-1 expression on immune cells in human blood and three barrier tissues; skin, colon and lung. SIRL-1 was expressed by virtually all neutrophils and eosinophils in these tissues. In contrast, SIRL-1 was not expressed by monocyte-derived cells in skin and colon, whereas it was highly expressed by lung classical monocytes. Lung monocytes from individuals with a rs612529C allele had decreased SIRL-1 expression, consistent with the genotype association in blood. Within the different monocyte subsets in blood and lung, SIRL-1 expression was highest in classical monocytes and lowest in nonclassical monocytes. SIRL-1 was not expressed by dendritic cells in blood and barrier tissues. Together, these results indicate that SIRL-1 is differentially expressed on phagocyte subsets in blood and barrier tissues, and that its expression on monocytes is genotype- and tissue-specific. Immune regulation of monocytes by SIRL-1 may be of particular importance in the lung.

Perinatal outcomes of frequent attendance in midwifery care in the Netherlands: a retrospective cohort study.

BACKGROUND: Over the last decade, a trend towards high utilisation of primary maternity care was observed in high-income countries. There is limited research with contradictory results regarding frequent attendance (FA) and perinatal outcomes in midwifery care. Therefore, this study examined possible associations between FA in midwifery care and obstetric interventions and perinatal outcomes. METHODS: A retrospective cohort study was performed in a medium-sized midwifery-led care practice in an urban region in the Netherlands. Frequent attenders (FAs) were categorised using the Kotelchuck-Index Revised. Regression analyses were executed to examine the relationship between FAs and perinatal outcomes, stratified by antenatal referral to an obstetrician. Main outcomes of interest were Apgar score ≤ 7 and perinatal death, birth weight, mode of delivery, haemorrhage, place of birth, transfer during labour, and a requirement for pain relief. RESULTS: The study included 1015 women, 239 (24%) FAs and 776 (76%) non-FAs, 538 (53%) were not referred and 447 (47%) were referred to an obstetrician. In the non-referred group, FA was significantly associated with a requirement for pain relief (OR 1.98, 95% CI 1.24-3.17) and duration of dilatation (OR 1.20, 95% CI 1.04-1.38). In the referred group, FA was significantly associated with induction of labour (OR 1.86, 95% CI 1.17-2.95), ruptured perineum (OR 0.50, 95% CI 0.27-0.95) and episiotomy (OR 0.48, 95% CI 0.24-0.95). In the non-referred and the referred group, FA was not associated with the other obstetric and neonatal outcomes. Due to small numbers, we could not measure possible associations of FA with an Apgar score ≤ 7 and perinatal death. CONCLUSION: In our study, perinatal outcomes differed by FA and antenatal referral to an obstetrician. In the non-referred group, FA was significantly associated with medical pain relief and duration of dilatation. In the referred group, FA was significantly associated with induction of labour, ruptured perineum, and episiotomy. Further research with a larger study population is needed to look for a possible association between FA and primary adverse birth outcomes such as perinatal mortality.

The Nature of Antibacterial Adaptive Immune Responses against Staphylococcus aureus Is Dependent on the Growth Phase and Extracellular Peptidoglycan.

Staphylococcus aureus has evolved different strategies to evade the immune response, which play an important role in its pathogenesis. The bacteria express and shed various cell wall components and toxins during different stages of growth that may affect the protective T cell responses to extracellular and intracellular S. aureus However, if and how the dendritic cell (DC)-mediated T cell response against S. aureus changes during growth of the bacterium remain elusive. In this study, we show that exponential-phase (EP) S. aureus bacteria were endocytosed very efficiently by human DCs, and these DCs strongly promoted production of the T cell polarizing factor interleukin-12 (IL-12). In contrast, stationary-phase (SP) S. aureus bacteria were endocytosed less efficiently by DCs, and these DCs produced small amounts of IL-12. The high level of IL-12 production induced by EP S. aureus led to the development of a T helper 1 (Th1) cell response, which was inhibited after neutralization of IL-12. Furthermore, preincubation with the staphylococcal cell wall component peptidoglycan (PGN), characteristically shed during the exponential growth phase, modulated the DC response to EP S. aureus PGN preincubation appeared to inhibit IL-12p35 expression, leading to downregulation of IL-12 and an increase of IL-23 production by DCs, enhancing Th17 cell development. Taken together, our data indicate that exponential-phase S. aureus bacteria induce a stronger IL-12-dependent Th1 cell response than stationary-phase S. aureus and that this Th1 cell response shifted toward a Th17 cell response in the presence of PGN.

Determinants and underlying causes of frequent attendance in midwife-led care: an exploratory cross-sectional study.

BACKGROUND: An adequate number of prenatal consultations is beneficial to the health of the mother and fetus. Guidelines recommend an average of 5-14 consultations. Daily practice, however, shows that some women attend the midwifery practice more frequently. This study examined factors associated with frequent attendance in midwifery-led care. METHODS: We conducted a cross-sectional study in a large midwifery practice in the Netherlands among low-risk women who started prenatal care in 2015 and 2016. Based on Andersen's behavioral model, we collected data on potential determinants from the digital midwifery's practice database. Prenatal healthcare utilization was measured by a revised version of the Kotelchuck Index, which measures a combination of care entry and numbers of visits. Logistic regression models were fitted to estimate the likelihood of frequent attendance compared to the recommended number of visits, adjusted for all relevant factors. Separate models were fitted on the non-referred and the referred group of obstetric-led care, as referral was found to be an effect modifier. RESULTS: The prevalence of frequent attendance was 23% (243/1053), mainly caused by worries and/or vague complaints (44%; 106/243). Among non-referred women, 53% (560/1053), frequent attendance was associated with consultation with an obstetrician (OR = 3.99 (2.35-6.77)) and exposure to sexual violence (OR = 2.17 (1.11-4.24)). Among the referred participants, 47% (493/1053), frequent attendance was associated with a consultation with an obstetrician (OR = 2.75 (1.66-4.57)), psychosocial problems in the past or present (OR = 1.85 (1.02-3.35) or OR = 2.99 (1.43-6.25)), overweight (OR = 1.88 (1.09-3.24)), and deprived area (OR = 0.50 (0.27-0.92)). CONCLUSION: Our exploratory study indicates that the determinants of frequent attendance in midwifery-led care differs between non-referred and referred women. Underlying causes for frequent attendance was mainly because of non-medical reasons. IMPLICATION FOR PRACTICE: A trustful midwife-client relationship is known to be needed for clients such as frequent attenders to share more detailed, personal stories in case of vague complaints or worries, which is necessary to identify their implicit needs.

The effect of medical and operative birth interventions on child health outcomes in the first 28 days and up to 5 years of age: A linked data population-based cohort study.

BACKGROUND: Spontaneous vaginal birth rates are decreasing worldwide, while cesarean delivery, instrumental births, and medical birth interventions are increasing. Emerging evidence suggests that birth interventions may have an effect on children's health. Therefore, the aim of our study was to examine the association between operative and medical birth interventions on the child's health during the first 28 days and up to 5 years of age. METHODS: In New South Wales (Australia), population-linked data sets were analyzed, including data on maternal characteristics, child characteristics, mode of birth, interventions during labor and birth, and adverse health outcomes of the children (ie, jaundice, feeding problems, hypothermia, asthma, respiratory infections, gastrointestinal disorders, other infections, metabolic disorder, and eczema) registered with the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Australian Modification codes. Logistic regression analyses were performed for each adverse health outcome. RESULTS: Our analyses included 491 590 women and their children; of those 38% experienced a spontaneous vaginal birth. Infants who experienced an instrumental birth after induction or augmentation had the highest risk of jaundice, adjusted odds ratio (aOR) 2.75 (95% confidence interval [CI] 2.61-2.91) compared with spontaneous vaginal birth. Children born by cesarean delivery were particularly at statistically significantly increased risk for infections, eczema, and metabolic disorder, compared with spontaneous vaginal birth. Children born by emergency cesarean delivery showed the highest association for metabolic disorder, aOR 2.63 (95% CI 2.26-3.07). CONCLUSION: Children born by spontaneous vaginal birth had fewer short- and longer-term health problems, compared with those born after birth interventions.

Microbes and asthma: Opportunities for intervention.

The worldwide incidence and prevalence of asthma continues to increase. Asthma is now understood as an umbrella term for different phenotypes or endotypes, which arise through different pathophysiologic pathways. Understanding the many factors contributing to development of the disease is important for the identification of novel therapeutic targets for the treatment of certain asthma phenotypes. The hygiene hypothesis has been formulated to explain the increasing prevalence of allergic disease, including asthma. This hypothesis postulates that decreased exposure at a young age to certain infectious agents as a result of improved hygiene, increased antibiotic use and vaccination, and changes in lifestyle and dietary habits is associated with changes in the immune system, which predispose subjects to allergy. Many microbes, during their coevolution with human subjects, developed mechanisms to manipulate the human immune system and to increase their chances of survival. Improving models of asthma, as well as choosing adequate end points in clinical trials, will lead to a more complete understanding of the underlying mechanisms, thus providing an opportunity to devise primary and secondary interventions at the same time as identifying new molecular targets for treatment. This article reports the discussion and conclusion of a workshop under the auspices of the Netherlands Lung Foundation to extend our understanding of how modulation of the immune system by bacterial, parasitic, and viral infections might affect the development of asthma and to map out future lines of investigation.

Acetylcholine-producing T cells in the intestine regulate antimicrobial peptide expression and microbial diversity.

The cholinergic anti-inflammatory pathway reduces systemic tumor necrosis factor (TNF) via acetylcholine-producing memory T cells in the spleen. These choline acetyltransferase (ChAT)-expressing T cells are also found in the intestine, where their function is unclear. We aimed to characterize these cells in mouse and human intestine and delineate their function. We made use of the ChAT-enhanced green fluorescent protein (eGFP) reporter mice. CD4Cre mice were crossed to ChATfl/fl mice to achieve specific deletion of ChAT in CD4+ T cells. We observed that the majority of ChAT-expressing T cells in the human and mouse intestine have characteristics of Th17 cells and coexpress IL17A, IL22, and RORC The generation of ChAT-expressing T cells was skewed by dendritic cells after activation of their adrenergic receptor ß2 To evaluate ChAT T cell function, we generated CD4-specific ChAT-deficient mice. CD4ChAT-/- mice showed a reduced level of epithelial antimicrobial peptides lysozyme, defensin A, and ang4, which was associated with an enhanced bacterial diversity and richness in the small intestinal lumen in CD4ChAT-/- mice. We conclude that ChAT-expressing T cells in the gut are stimulated by adrenergic receptor activation on dendritic cells. ChAT-expressing T cells may function to mediate the host AMP secretion, microbial growth and expansion.

Antenatal care use in urban areas in two European countries: Predisposing, enabling and pregnancy-related determinants in Belgium and the Netherlands.

BACKGROUND: Examining determinants of antenatal care (ANC) is important to stimulate equitable distribution of ANC across Europe. This study (1) compares ANC utilisation in Belgium and the Netherlands and (2) identifies predisposing, enabling and pregnancy-related determinants. METHODS: Secondary data analysis is performed using data from Belgium, and the Netherlands. The content and timing of care during pregnancy (CTP) tool measured ANC use. Non-parametric tests and ordinal logistic regression are performed to gain insight in the determinants of health care use. RESULTS: Dutch women receive appropriate ANC more often than Belgian women. Multivariate analysis showed that lower education, unemployment, lower continuity of care and non-attendance of antenatal classes are associated with a lower likelihood of having more appropriate ANC. CONCLUSIONS: Predisposing and pregnancy related variables are most important to influence the content and timing of ANC, irrespective of the country women live in. Lower health literacy in socially vulnerable women might explain the predisposing determinants of health care use in both countries. Stimulating accessibility to antenatal courses or organising public education are recommendations for practice. Regarding pregnancy-related determinants, improving continuity of care can optimise ANC use in both countries.

MicroRNA-146a regulates survival and maturation of human plasmacytoid dendritic cells.

During microbial infections, plasmacytoid dendritic cells (pDCs) are a main source of type I interferons α/ß (IFN-α/-ß). Nucleic acids from microbes are sensed by Toll-like receptors 7/9 (TLR7/9), which are selectively expressed in pDCs. Activated pDCs also produce proinflammatory cytokines and upregulate costimulatory molecules. Together, this equips pDCs with the ability to prime T, B, and NK cells and conventional DCs, thereby initiating adaptive immune responses. To avoid deleterious effects to the host, tight regulation of pDC activation is required. Despite data linking aberrant activation of pDCs with autoimmune diseases, little is known about mechanisms controlling pDC activation. Here, we investigated the role of microRNA-146a (miR-146a) in TLR pathway regulation in human pDCs. MiR-146a expression was induced upon TLR7/9 signaling. Furthermore, ectopic miR-146a expression effectively impaired TLR-mediated signaling in pDCs as TLR-induced nuclear factor-κB activation was reduced. This consequently diminished the production of proinflammatory cytokines and reduced pDC survival. Moreover, miR-146a-expressing pDCs had decreased ability to induce CD4(+) T-cell proliferation likely due to reduced expression levels of major histocompatibility complex class II and costimulatory molecules. Our data unravel the crucial immunomodulatory role of miR-146a in pDCs and may add to our understanding of aberrant responses in autoimmune diseases.

Explanatory factors for first and second-generation non-western women's inadequate prenatal care utilisation: a prospective cohort study.

BACKGROUND: Little research into non-western women's prenatal care utilisation in industrialised western countries has taken generational differences into account. In this study we examined non-western women's prenatal care utilisation and its explanatory factors according to generational status. METHODS: Data from 3300 women participating in a prospective cohort of primary midwifery care clients (i.e. women with no complications or no increased risk for complications during pregnancy, childbirth and the puerperium who receive maternity care by autonomous midwives) in the Netherlands (the DELIVER study) was used. Gestational age at entry and the total number of prenatal visits were aggregated into an index. The extent to which potential factors explained non-western women's prenatal care utilisation was assessed by means of blockwise logistic regression analyses and percentage changes in odds ratios. RESULTS: The unadjusted odds of first and second-generation non-western women making inadequate use of prenatal care were 3.26 and 1.96 times greater than for native Dutch women. For the first generation, sociocultural factors explained 43% of inadequate prenatal care utilisation, socioeconomic factors explained 33% and demographic and pregnancy factors explained 29%. For the second generation, sociocultural factors explained 66% of inadequate prenatal care utilisation. CONCLUSION: Irrespective of generation, strategies to improve utilisation should focus on those with the following sociocultural characteristics (not speaking Dutch at home, no partner or a first-generation non-Dutch partner). For the first generation, strategies should also focus on those with the following demographic, pregnancy and socioeconomic characteristics (aged ≤ 19 or ≥ 36, unplanned pregnancies, poor obstetric histories (extra-uterine pregnancy, molar pregnancy or abortion), a low educational level, below average net household income and no supplementary insurance.