Antimicrobial effector mechanisms are central to the function of the innate immune response in host defense against microbial pathogens. In humans, activation of Toll-like receptor 2/1 (TLR2/1) on monocytes induces a vitamin D dependent antimicrobial activity against intracellular mycobacteria. Here, we report that TLR activation of monocytes triggers induction of the defensin beta 4 gene (DEFB4), requiring convergence of the IL-1β and vitamin D receptor (VDR) pathways. TLR2/1 activation triggered IL-1β activity, involving the upregulation of both IL-1β and IL-1 receptor, and downregulation of the IL-1 receptor antagonist. TLR2/1L induction of IL-1β was required for upregulation of DEFB4, but not cathelicidin, whereas VDR activation was required for expression of both antimicrobial genes. The differential requirements for induction of DEFB4 and cathelicidin were reflected by differences in their respective promoter regions; the DEFB4 promoter had one vitamin D response element (VDRE) and two NF-κB sites, whereas the cathelicidin promoter had three VDREs and no NF-κB sites. Transfection of NF-κB into primary monocytes synergized with 1,25D3 in the induction of DEFB4 expression. Knockdown of either DEFB4 or cathelicidin in primary monocytes resulted in the loss of TLR2/1-mediated antimicrobial activity against intracellular mycobacteria. Therefore, these data identify a novel mechanism of host defense requiring the induction of IL-1β in synergy with vitamin D activation, for the TLR-induced antimicrobial pathway against an intracellular pathogen.

ABSTRACT:Over the past 20 y, a resurgence in vitamin D deficiency and nutritional rickets has been reported throughout the world, including the United States. Inadequate serum vitamin D concentrations have also been associated with complications from other health problems, including tuberculosis, cancer (prostate, breast, and colon), multiple sclerosis, and diabetes. These findings support the concept of vitamin D possessing important pleiotropic actions outside of calcium homeostasis and bone metabolism. In children, an association of nutritional rickets with respiratory compromise has long been recognized. Recent epidemiologic studies clearly demonstrate the link between vitamin D deficiency and the increased incidence of respiratory infections. Further research has also elucidated the contribution of vitamin D in the host defense response to infection. However, the mechanism(s) by which vitamin D levels contribute to pediatric infections and immune function has yet to be determined. This knowledge is particularly relevant and timely, because infants and children seem more A fter the discovery that vitamin D deficiency is the cause of nutritional rickets, the emphasis on vitamin D status in children was relegated to a discussion primarily focused on prevention and treatment of the disease. A few early clinicians, however, astutely recognized the increased incidence of respiratory infections among infants and children with rickets. Most presumed, however, that the increased incidence of respiratory infections in these children reflected compromised lung compliance from the rib deformities associated with severe rickets and an overall poor nutritional status. Now epidemiologic studies have identified a link between inadequate vitamin D concentrations and infectious disease. Furthermore, the contribution of vitamin D in host defense against infection has been elucidated. The goal of this study is to provide an overview on the current knowledge available regarding the role of vitamin D in immunologic function and the manifestations of infectious diseases in the pediatric population. Delineating Vitamin D Sufficiency, Insufficiency, and DeficiencyBy definition, vitamin D is not a true vitamin because adequate exposure to sunlight either negates or significantly diminishes the need for dietary supplementation. Instead, this imprecise descriptor refers to a group of steroid molecules also encompassing both vitamin D2 (derived from plants that use ergosterol rather than cholesterol) and vitamin D3 molecules (derived from cholesterol). The human body thus procures vitamin D through two independent pathways: the photochemical action of solar UVB light (ϳ295 to 320 nm) in the skin and some limited dietary sources (1).Given that vitamin D2 is produced by plants, dietary sources (naturally occurring and/or obtained via oral supplementation) are the only means for acquiring it. Vitamin D3, on the other hand, is predominantly procured via the sunlight driven cutaneous reaction described earlier or from dietary sources. For a...

Cord blood vitamin D deficiency, by its effects on TLR-induced antimicrobial production, altered in vitro monocyte responses. The observation that exogenous 25(OH)D(3) in vitro recovered TLR-induced antimicrobial responses suggests the need for additional prospective investigations to further delineate the role of vitamin D in the newborn immune response.

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ObjectiveNo validated biomarker at birth exists to predict which newborns will develop severe hyperbilirubinemia. This study’s primary aim was to build and validate a prediction model for severe hyperbilirubinemia using umbilical cord blood bilirubins (CBB) and risk factors at birth in neonates at risk for maternal-fetal blood group incompatibility. This study’s secondary aim was to compare the accuracy of CBB to the direct antigen titer.MethodsInclusion criteria for this prospective cohort study included: ≥35 weeks gestational age, mother with blood type O and/or Rh negative or positive antibody screen, and <24 hours of age. The primary outcome was severe hyperbilirubinemia, defined as phototherapy during the initial hospital stay. Secondary outcomes were a total serum bilirubin concentration >95th and >75th percentile during the initial hospital stay. The predictive performance and accuracy of the two tests (CBB and direct antigen titer) for each outcome was assessed using area under a receiver-operating characteristic curve (AUC), sensitivity, and specificity.ResultsWhen compared to neonates who did not receive phototherapy (n = 463), neonates who received phototherapy (n = 36) had a greater mean CBB ± standard deviation (2.5 ± 0.7 vs. 1.6 ± 0.4 mg/dL, p<0.001). For every 0.3 mg/dL increase in CBB, a neonate was 3.20 (95% confidence interval, 2.31–4.45), 2.10 (1.63–2.70), and 3.12 (2.44–3.99) times more likely to receive phototherapy or have a total serum bilirubin concentration >95th and >75th percentile, respectively. The AUC ± standard error (95% confidence interval) for CBB for phototherapy and a total serum bilirubin concentration >95th and >75th percentile was 0.89 ± 0.03 (0.82–0.95), 0.81 ± 0.04 (0.73–0.90), and 0.84 ± 0.02 (0.80–0.89), respectively. However, the AUC for gestational age and maternal Asian race for these outcomes was only 0.55 ± 0.05 (0.45–0.66), 0.66 ± 0.05 (0.56–0.76), and 0.57 ± 0.04 (0.05–0.64), respectively. When the CBB was combined with gestational age and maternal Asian race, the AUC for a total serum bilirubin concentration >95th percentile improved to 0.87 ± 0.03 (0.81–0.92) (p = 0.034 vs. the model with CBB only and p<0.001 vs. the model with clinical risk factors only). In a sub-group of subjects (n = 189), the AUC for the direct antigen titer for phototherapy was 0.64 ± 0.06 (0.52–0.77) with a 52% sensitivity and 77% specificity. In contrast, a CBB cut-point of 1.85 mg/dL was 92% sensitive and 70% specific for phototherapy with an AUC of 0.87 ± 0.04 (0.80–0.95).ConclusionCBB, in combination with gestational age and maternal race, may be a useful, non-invasive test to predict shortly after birth which neonates will develop severe hyperbilirubinemia.

ronchopulmonary dysplasia (BPD) is the most common morbidity of preterm birth affecting 50% of infants born less than 30 weeks' gestation in the US. 1 Despite preventive efforts, the incidence of BPD is increasing owing to the improved survival of infants born extremely preterm. 2 Recent studies suggest racial disparities may adversely affect outcomes for preterm infants experiencing common neonatal morbidities, including respiratory distress syndrome, intraventricular hemorrhage, and necrotizing enterocolitis, during the initial neonatal intensive care unit (NICU) hospitalization. [3][4][5] However, our knowledge of the association of racial disparities with outcomes for preterm infants with BPD remains unclear.Multiple prospective cohort studies have determined that Black maternal race is independently associated with a de-creased risk of severe BPD at 36 weeks' postmenstrual age (PMA), when the diagnosis of BPD is made. 6,7 Additional analyses of these cohorts, however, also identify Black maternal race as an independent risk factor for increased respiratory morbidity in early childhood. 6,8,9 The mechanisms underlying the finding that preterm infants born to Black mothers are at decreased risk of developing severe BPD but are nonetheless at increased risk of early childhood respiratory morbidity remain unknown.The 2001 National Institutes of Health (NIH) consensus criteria define severe BPD in infants born less than 32 weeks' gestation as the need for supplemental oxygen for 28 days or more and a fraction of inspired oxygen greater than 0.3 and/or positive pressure at 36 weeks' PMA. 10 Short-and long-term outcomes for patients with BPD are highly variable. In this study, IMPORTANCE Bronchopulmonary dysplasia (BPD) is the most common serious morbidity of preterm birth. Short-term respiratory outcomes for infants with the most severe forms of BPD are highly variable. The mechanisms that explain this variability remain unknown and may be mediated by racial disparities.OBJECTIVE To determine the association of maternal race with death and length of hospital stay in a multicenter cohort of infants with severe BPD.

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