Skewed pattern of Toll-like receptor 4-mediated cytokine production in human neonatal blood: Low LPS-induced IL-12p70 and high IL-10 persist throughout the first month of life

Belderbos, Mirjam E.; Bleek, Grada M. van; Levy, Ofer; Blanken, Maarten O; Houben, Michiel L.; Schuijff, Leontine; Kimpen, Jan L. L.; Bont, Louis

doi:10.1016/j.clim.2009.07.003

Cited by 140 publications

(151 citation statements)

References 38 publications

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“…Multiple developmental alterations of innate host response capabilities are present in neonates compared with older age groups, including pathogen recognition receptors, inflammatory signaling pathways and overall innate immune cellular function (19)(20)(21)(22)(23). Consistent with these observations, our current data demonstrate reduced expression of genes corresponding to the pathogen recognition receptor and TREM-1 pathways, as well as their TREM-1 signaling is critical for amplification of the inflammatory responses to microbial products in adults.…”

Section: Discussionsupporting

confidence: 85%

The Influence of Developmental Age on the Early Transcriptomic Response of Children with Septic Shock

Wynn

Cvijanovich²,

Allen

et al. 2011

Mol Med

126

109

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Septic shock is a frequent and costly problem among patients in the pediatric intensive care unit (PICU) and is associated with high mortality and devastating survivor morbidity. Genome-wide expression patterns can provide molecular granularity of the host response and offer insight into why large variations in outcomes exist. We derived whole-blood genome-wide expression patterns within 24 h of PICU admission from children with septic shock. We compared the transcriptome between septic shock developmental-age groups defined as neonates (≤28 d, n = 17), infants (1 month to 1 year, n = 62), toddlers (2-5 years, n = 54) and schoolage (≥6 years, n = 47) and age-matched controls. Direct intergroup comparisons demonstrated profound changes in neonates, relative to older children. Neonates with septic shock demonstrated reduced expression of genes representing key pathways of innate and adaptive immunity. In contrast to the largely upregulated transcriptome in all other groups, neonates exhibited a predominantly downregulated transcriptome when compared with controls. Neonates and school-age subjects had the most uniquely regulated genes relative to controls. Age-specific studies of the host response are necessary to identify developmentally relevant translational opportunities that may lead to improved sepsis outcomes.

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Section: Discussionsupporting

confidence: 85%

The Influence of Developmental Age on the Early Transcriptomic Response of Children with Septic Shock

Wynn

Cvijanovich²,

Allen

et al. 2011

Mol Med

126

109

View full text Add to dashboard Cite

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“…Moreover, in that study, we also showed that abrogation of either IL-10 or IL-10 signaling conferred protection to neonates against GBS strains (21). Several reports showed that leukocytes from newborn mice (32,34,41,42) and human neonates (33,43,44) are highly committed to produce increased amounts of IL-10 upon infection. Using a model of GBS-induced neonatal sepsis, we showed in this study that inhibition of either TLR2 or IL-10 signaling leads to an increased survival of newborns due to an efficient neutrophil migration into infected tissue and subsequent bacterial clearance.…”

Section: Discussionmentioning

confidence: 54%

TLR2-Induced IL-10 Production Impairs Neutrophil Recruitment to Infected Tissues during Neonatal Bacterial Sepsis

Andrade

Alves

Madureira

et al. 2013

The Journal of Immunology

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Sepsis is the third most common cause of neonatal death, with Group B Streptococcus (GBS) being the leading bacterial agent. The pathogenesis of neonatal septicemia is still unsolved. We described previously that host susceptibility to GBS infection is due to early IL-10 production. In this study, we investigated whether triggering TLR2 to produce IL-10 is a risk factor for neonatal bacterial sepsis. We observed that, in contrast to wild-type (WT) pups, neonatal TLR2-deficient mice were resistant to GBS-induced sepsis. Moreover, if IL-10 signaling were blocked in WT mice, they also were resistant to sepsis. This increased survival rate was due to an efficient recruitment of neutrophils to infected tissues that leads to bacterial clearance, thus preventing the development of sepsis. To confirm that IL-10 produced through TLR2 activation prevents neutrophil recruitment, WT pups were treated with the TLR2 agonist Pam3CSK4 prior to nebulization with the neutrophil chemotactic agent LTB4. Neutrophil recruitment into the neonatal lungs was inhibited in pups treated with Pam3CSK4. However, the migration was restored in Pam3CSK4-treated pups when IL-10 signaling was blocked (either by anti–IL-10R mAb treatment or by using IL-10–deficient mice). Our findings highlight that TLR2-induced IL-10 production is a key event in neonatal susceptibility to bacterial sepsis.

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“…Severe RSV infections that require hospitalization are most frequent in infants 2 to 4 months of age (44). Therefore, it has been proposed that inadequate innate or adaptive responses of the immature immune system contribute to disease severity; in particular, Th2 bias of the immature immune system has been suggested to be an important factor contributing to RSV disease (5,36).…”

Section: R Espiratory Syncytial Virus (Rsv) a Pneumovirus In The Familymentioning

confidence: 99%

Specific Dietary Oligosaccharides Increase Th1 Responses in a Mouse Respiratory Syncytial Virus Infection Model

Schijf

Kruijsen

Bastiaans

et al. 2012

J Virol

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dBreast feeding reduces the risk of developing severe respiratory syncytial virus (RSV) infections in infants. In addition to maternal antibodies, other immune-modulating factors in human milk contribute to this protection. Specific dietary prebiotic oligosaccharides, similar to oligosaccharides present in human milk, were evaluated in a C57BL/6 mouse RSV infection model. During primary RSV infection, increased numbers of RSV-specific CD4 ؉ T cells producing gamma interferon (IFN-␥) were found in the lungs at days 8 to 10 postinfection in mice receiving diet containing short-chain galactooligosacharides, long-chain fructooligosaccharides, and pectin-derived acidic oligosaccharides (termed scGOS/lcFOS/pAOS). In a Th2-skewed formalin-inactivated (FI)-RSV vaccination model, the prebiotic diet reduced RSV-specific Th2 cytokine (interleukin-4 [IL-4], IL-5, and IL-13)-producing CD4؉ T cells in the lung and the magnitude of airway eosinophilia at day 4 and 6 after infection. This was accompanied by a decreased influx of inflammatory dendritic cells (CD11b ؉ /CD11c ؉ ) and increased numbers of IFN-␥-producing CD4 ؉ and CD8؉ T cells at day 8 after viral challenge. These findings suggest that specific dietary oligosaccharides can influence trafficking and/or effector functions of innate immune, CD4؉ , and CD8 ؉ T cell subsets in the lungs of RSV-infected mice. In our models, scGOS/lcFOS/pAOS had no effect on weight but increased viral clearance in FI-RSV-vaccinated mice 8 days after infection. The increased systemic Th1 responses potentiated by scGOS/lcFOS/pAOS might contribute to an accelerated Th1/Th2 shift of the neonatal immune system, which might favor protective immunity against viral infections with a high attack rate in early infancy, such as RSV. R espiratory syncytial virus (RSV), a pneumovirus in the familyParamyxoviridae, infects nearly all children within the first 3 years of life (15). Primary RSV infections can cause severe bronchiolitis and pneumonia, which are associated with significantly increased risk of developing wheeze during childhood that lasts until teenage years (31,45,46). Symptomatic reinfections occur in every age group, but the frequency and severity of symptoms are highest in children below 5 years of age. The mechanism behind the onset of severe RSV infections is still not completely clear. Severe RSV infections that require hospitalization are most frequent in infants 2 to 4 months of age (44). Therefore, it has been proposed that inadequate innate or adaptive responses of the immature immune system contribute to disease severity; in particular, Th2 bias of the immature immune system has been suggested to be an important factor contributing to RSV disease (5, 36).Formation of the intestinal microbiota population, starting directly after birth, is shaped during infancy and is unique for each individual throughout life (23, 37). The intestinal microbiota composition is important for establishment of gut homeostasis and affects local mucosal immunity (20). Although it has been documented tha...

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Skewed pattern of Toll-like receptor 4-mediated cytokine production in human neonatal blood: Low LPS-induced IL-12p70 and high IL-10 persist throughout the first month of life

Cited by 140 publications

References 38 publications

The Influence of Developmental Age on the Early Transcriptomic Response of Children with Septic Shock

The Influence of Developmental Age on the Early Transcriptomic Response of Children with Septic Shock

TLR2-Induced IL-10 Production Impairs Neutrophil Recruitment to Infected Tissues during Neonatal Bacterial Sepsis

Specific Dietary Oligosaccharides Increase Th1 Responses in a Mouse Respiratory Syncytial Virus Infection Model

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