Immaturity of Infection Control in Preterm and Term Newborns Is Associated with Impaired Toll‐Like Receptor Signaling (original) (raw)
Related papers
Attenuated innate immune defenses in very premature neonates during the neonatal period
Pediatric research, 2015
Anti-microbial responses are attenuated in very preterm neonates when examined on cord blood, although we lack data on the magnitude of these responses when these neonates are most vulnerable to neonatal infections. Multiple cytokine responses to two prototypic Toll-like receptor (TLR) agonists: LPS (TLR4) and R848 (TLR7/8) were prospectively measured in preterm neonates born ≤30 weeks of gestation (n=50) during the first 28 days of age using whole blood and single-cell multi-parameter flow cytometry. Results were compared to term neonates (n=30) and adult controls (n=25). LPS and R848 responses were attenuated during the neonatal period in preterm neonates, although they showed significant maturation over time, adjusting for gestational age. These attenuated responses were also confirmed on a per-cell basis in blood monocytes and dendritic cells. We detected no major contribution of chorioamnionitis, maternal antenatal corticosteroids or magnesium sulfate treatment, labor, or mode ...
Pediatric Research, 2013
Background: Although the immaturity of Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) at birth in preterm newborns is known, their development during the first few months of life remains unclear. Methods: Blood monocytes of preterm newborns (gestational age: 24-36 wk) were obtained every 2 wk when possible in order to perform serial measurements of TLR2 and TLR4 surface expression, as well as lipopolysaccharide (LPS)-induced cytokine production. Measurements using monocytes from term newborns and adults were also performed. results: The monocytes of preterm newborns obtained at birth displayed reduced surface expression of TLR2 and TLR4, and diminished responses of tumor necrosis factor-α (TNF-α) and interleukin (IL)-8 to LPS stimulation. Regardless of gestational age, monocyte expression of TLR2 and TLR4 in preterm newborns increased rapidly within the first 2 wk after birth, quickly reaching those of term newborns. These increases continued for the following 4-6 wk, although the increase began to plateau. By contrast, LPS-induced production of TNF-α and IL-8 did not elevate over this period in preterm newborns. conclusion: The blood monocytes of preterm newborns display rapid increase in TLR2 and TLR4 expression during the first few months of life, whereas LPS-induced cytokine production functionality did not improve in parallel.
Modulation of pro- and anti-inflammatory cytokine production in very preterm infants
Cytokine, 2003
Background: In premature infants, outcome of infection-associated complications is heterogeneous despite advances in antibiotic treatment and diagnosis. Information on the immune response in preterm infants is limited. Immune modulatory strategies require detailed analysis of mediators and their kinetics. Objective: To determine the kinetics of IL-1b, TNFa, IL-6, IL-8, IL-10, cINF and G-CSF in preterm and term infants in an ex vivo cord blood culture (CBC) endotoxin model. Design and methods: Cord blood of 25 infants was obtained immediately after birth from the fetal side of the placenta and incubated in culture medium (RPMI 1640) in the presence or absence of 500 pg/ml lipopolysaccharide (LPS) for 48 h. TNFa, IL-1b, IL-6 and IL-8 were measured by sequential immunometric assay (IMMULITE Ò , DPC Biermann, Germany); IL-10 (Milenia Biotec, Bad Nauheim, Germany), cINF (Diaclone, Besancon, France) and G-CSF (R & D Systems, Wiesbaden, Germany) were determined by ELISA in supernatants at 0, 4, 8, 12, 24 and 48 h. Infants were stratified into three gestational age groups (32 weeks, 33-36 weeks, !37 weeks). Variations between the groups were first analyzed for significance by Kruskal-Wallis test and pairs were compared by Mann-Whitney-U test. Effects of gestational age, leucocyte count, hematocrit and frequency of antenatal steroid exposure were tested by linear regression analysis. To correct a possible impact of variable, WBC count, cytokine levels were adjusted according to individual leucocyte numbers. Results: LPS-stimulated maximum levels of IL-6, IL-1b,TNFa and G-CSF in CBC were significantly lower in very preterm infants compared to more advanced gestational age groups. After adjusting the cytokine levels for 10 5 leucocytes, a significant effect of gestational age on IL-6 and G-CSF production ðp , 0:05Þ was detected. A non-significant trend towards reduced cytokine levels was observed following multiple antenatal steroid exposures. IL-10 : TNFa ratio increased in very preterm neonates when compared with the advanced gestational age, although the increase was not significant. Conclusions: Pro-inflammatory cytokine activity in CBC correlates with gestational age, whereas IL-10 does not. Although ex vivo synthesis of IL-1b, TNFa, IL-6, G-CSF in CBC depends in part on leucocyte numbers, IL-6 and G-CSF synthesis appeared to be related to immaturity. Non-significant effects of multiple antenatal steroid exposure and increased IL-10 : TNFa ratio in preterm neonates, observed in a small sample size, warrant further investigation.
TLR Responses in Preterm and Term Infant Cord Blood Mononuclear Cells
Pathogens
Preterm infants are more susceptible to severe bacterial and viral infectious diseases than their full-term counterparts. A major contributor to this increased susceptibility may be due to differences in their ability to respond to pathogens. While studies have demonstrated altered bacterial Toll-like receptor (TLR) responses, there is limited data on viral TLR responses in preterm infants. In this study, cord blood mononuclear cells (CBMCs) from 10 moderately preterm (30.4–34.1 wGA), 10 term (37–39.5 wGA) infants, and 5 adults were stimulated with TLR2 (lipoteichoic acid), TLR3 (poly I:C), TLR4 (lipopolysaccharide), TLR7/8 (R848), and TLR9 (CpG-ODN 2216) agonists. Following stimulation, the cellular response was measured by intracellular flow cytometry to detect cell-specific NF-κB (as a marker of the inflammatory response), and multiplex assays were used to measure the cytokine response. This study found that preterm and term infants exhibit very similar baseline TLR expression. I...
Role of Innate Immunity in Neonatal Infection
American Journal of Perinatology, 2013
Newborns are at increased risk of infection due to genetic, epigenetic, and environmental factors. Herein we examine the roles of the neonatal innate immune system in host defense against bacterial and viral infections. Full-term newborns express a distinct innate immune system biased toward T H 2-/T H 17-polarizing and anti-inflammatory cytokine production with relative impairment in T H 1-polarizing cytokine production that leaves them particularly vulnerable to infection with intracellular pathogens. In addition to these distinct features, preterm newborns also have fragile skin, impaired T H 17-polarizing cytokine production, and deficient expression of complement and of antimicrobial proteins and peptides (APPs) that likely contribute to susceptibility to pyogenic bacteria. Ongoing research is identifying APPs, including bacterial/ permeability-increasing protein and lactoferrin, as well as pattern recognition receptor agonists that may serve to enhance protective newborn and infant immune responses as stand-alone immune response modifiers or vaccine adjuvants.
Perinatal Inflammation Influences but Does Not Arrest Rapid Immune Development in Preterm Babies
2019
Infection and infection-related complications are important causes of death and morbidity following preterm birth. Despite this, there is limited understanding of the development of the immune system in those born prematurely and how it is influenced by perinatal factors. To investigate this, we prospectively and longitudinally followed a cohort of babies born before 32 weeks of gestation. We demonstrated that preterm babies, including those born extremely prematurely, were capable of rapidly acquiring adult levels of immune functionality; that immune maturation appeared to occur independently of the developing microbiome, which was highly heterogeneous across different infants; and that the biggest drivers of change in the trajectory of perinatal immune development was exposure to infection in utero or post-natally. Conspicuously, a unifying factor among infants who developed infection despite their growing immune potentials was an inability to mount adequate T cell CXCL8 responses...
Biological Research For Nursing, 2010
A growing body of literature supports the relationship of maternal inflammation with preterm birth and adverse neonatal outcomes, including infection and central nervous system (CNS) dysfunction. Mediators of inflammation, most notably proinflammatory cytokines, have been implicated as having an association with and perhaps playing a causal role in the pathogenesis, leading to adverse neonatal outcomes. Even though the association of cytokines with early adverse neonatal outcomes has been actively pursued as a line of research, there has been little integration of diverse findings across studies. Therefore, the purpose of this systematic review was to appraise and classify empirical evidence from human studies for the association of cytokine levels in blood (serum, plasma, or cells; maternal, cord, or neonatal) with two adverse early outcomes in preterm infants: early infection and increased risk of neurologic damage. The review revealed that the proinflammatory cytokines most frequently linked with sepsis are in the interleukin (IL) 1 family as well as tumor necrosis factor a (TNF-a) and IL-6. The proinflammatory cytokines most frequently linked to neurologic insult in the reviewed studies were IL-1b, IL-6, and IL-8. In all cases where IL-1b was studied, the levels were increased when there was neurologic insult. A better understanding of the relationship of these inflammatory substances with these adverse conditions is needed for the future development of maternal and neonatal biobehavioral nursing research.
Inflammatory cytokines in newborn infants
Mediators of Inflammation, 1998
Serum levels of IL-1β, IL-6 and TNF-α were measured in 48 healthy, termed neonates on the 1st (N1), 5th (N5) and 40th (N40) day after birth, compared with those in maternal serum (MS), umbilical cord (UC) and adult controls. Cytokine values in N1 and N5 were significantly elevated, than those in UC and in controls(p<0.0001). IL-1β and IL-6 declined significantly from N1 to N40(p<0.0001), while TNF-α increased significantly from N1 to N5 and declined thereafter. MS∞IL-1β and IL-6, but not MS∞TNF-α, were significantly higher than those of controls(p<0.0001). IL-1β values depended on the mode of delivery. In conclusion, the increased concentrations of IL-1 β, IL-6 and TNF-α during the perinatal period might suggest their involvement in an inflammation like process during normal parturition, and reflect also a newborn immune response to the stress of delivery and environmental changes.