Cytokine Expression in Response to Bacterial Antigens in Preterm and Term Infant Cord Blood Monocytes

Tatad, A.M. Francesca; Nesin, Mirjana; Peoples, J.; Cheung, Sandy; Lin, Hong; Sison, Cristina; Perlman, Jeffrey M.; Cunningham‐Rundles, Susanna

doi:10.1159/000112541

Cited by 44 publications

(39 citation statements)

References 85 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This suggests that the blood monocyte compartment of healthy, term infants is functionally competent in recognizing and responding to GBS. Several studies have demonstrated equivalent or greater inflammatory production by term MNC (in CBMC or whole blood) after GBS stimulation (27,47), with cytokine production predominantly monocyte derived (35,40,44). Our data, derived using live bacteria over a range of inocula, are therefore consistent with GBS exposure resulting in an overt inflammatory response in the newborn (16).…”

Section: Discussionsupporting

confidence: 83%

“…Similar GA-dependent responses are reported following LPS stimulation (6), with infants with a GA of Ͻ32 weeks having a lower proportion of IL-6-producing monocytes (35). A recent study examining intracellular cytokine responses to GBS and other bacterial stimuli in preterm infants did not find a significant impairment in IL-6, -8, -10, and -12 production in comparison to that of term infants or adults, although responses were monocyte driven (40). However, the levels of secreted cytokines produced by each group were not measured, and the study did not distinguish between extreme and moderate preterm infants.…”

Section: Discussionsupporting

confidence: 60%

See 1 more Smart Citation

Preterm Infants Have Deficient Monocyte and Lymphocyte Cytokine Responses to Group B Streptococcus

et al. 2011

View full text Add to dashboard Cite

Group B streptococcus (GBS) is an important cause of early-and late-onset sepsis in the newborn. Preterm infants have markedly increased susceptibility and worse outcomes, but their immunological responses to GBS are poorly defined. We compared mononuclear cell and whole-blood cytokine responses to heat-killed GBS (HKGBS) of preterm infants (gestational age [GA], 26 to 33 weeks), term infants, and healthy adults. We investigated the kinetics and cell source of induced cytokines and quantified HKGBS phagocytosis. HKGBSinduced tumor necrosis factor (TNF) and interleukin 6 (IL-6) secretion was significantly impaired in preterm infants compared to that in term infants and adults. These cytokines were predominantly monocytic in origin, and production was intrinsically linked to HKGBS phagocytosis. Very preterm infants (GA, <30 weeks) had fewer cytokine-producing monocytes, but nonopsonic phagocytosis ability was comparable to that for term infants and adults. Exogenous complement supplementation increased phagocytosis in all groups, as well as the proportion of preterm monocytes producing IL-6, but for very preterm infants, responses were still deficient. Similar defective preterm monocyte responses were observed in fresh whole cord blood stimulated with live GBS. Lymphocyte-associated cytokines were significantly deficient for both preterm and term infants compared to levels for adults. These findings indicate that a subset of preterm monocytes do not respond to GBS, a defect compounded by generalized weaker lymphocyte responses in newborns. Together these deficient responses may increase the susceptibility of preterm infants to GBS infection.Streptococcus agalactiae (group B streptococcus [GBS]) is the leading infectious cause of death in the newborn (17), causing both early-and late-onset neonatal sepsis (EOS and LOS), characterized by septicemia, shock, and meningitis (16,18,31). The proportion of infants surviving extreme prematurity is increasing (11), and as a result preterm delivery is now the leading cause of neonatal morbidity and mortality. Preterm infants are exquisitely susceptible to both EOS and LOS; they suffer approximately a quarter of invasive GBS EOS cases and half of GBS LOS cases, with a Ͼ8-fold-greater mortality for EOS and 3-fold for LOS compared to term infants (29). While a proportion of the increased susceptibility to infection in preterm infants relates to the absence of passively acquired maternal IgG antibody, deficiencies in the early immune response to bacterial pathogens likely play a critical role (23). Several studies have addressed neonatal adaptive and humoral immune responses, such as complement activation and antibody production, but there has been little focus on innate immunity to bacterial pathogens and its relation to adaptive responses in this population (23,39).Innate immunity provides the first line of defense against bacterial infection and is therefore particularly important in the neonatal period (9). Additionally, the innate immune system, through activation of specif...

show abstract

Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 60%

Preterm Infants Have Deficient Monocyte and Lymphocyte Cytokine Responses to Group B Streptococcus

et al. 2011

View full text Add to dashboard Cite

show abstract

“…However, differences in the study design regarding incubation times and their use of planktonic SE instead of the biofilm used in our study may explain these differences. Tatad et al showed that after stimulating monocytes for 18 h with SE, there was a significantly higher secretion of IL-6, IL-8, and IL-12 in adult blood as compared with blood from term neonates (35). It is possible that the adult cytokine secretion would reach the same level as that of neonates if longer incubation times had been used in our …”

Section: Discussionmentioning

confidence: 77%

Staphylococcus epidermidis biofilms induce lower complement activation in neonates as compared with adults

et al. 2012

View full text Add to dashboard Cite

Background: Staphylococcus epidermidis (se) is an important cause of late-onset sepsis in neonates. se frequently produces a polysaccharide intercellular adhesin (PIa) biofilm, important in the pathogenesis of these infections. Little is known about how the neonatal innate immune system reacts to se biofilm-associated infections. Our hypothesis was that se biofilms induce a lower complement activation in neonates as compared with adults. Methods: cord blood from term infants (n = 15) and blood from adults (n = 6) were studied in an ex vivo whole-blood sepsis model. a PIa biofilm-producing strain (se1457) and its isogenic mutant (M10), producing a non-PIa biofilm, were used. results: Both se biofilms induced stronger complement activation in adult than in cord blood (P ≤ 0.033). We found lower levels of antibodies toward both PIa (P = 0.002) and the whole bacterium (P = 0.001) in cord vs. adult blood. By contrast, the interleukin-8 (IL-8) and IL-6 secretion were higher in cord than in adult blood (P ≤ 0.002). The PIa biofilm induced stronger complement activation than the non-PIa biofilm. conclusion: We conclude that the neonatal complement system exhibits a maturational deficiency. This may reduce the ability of neonates to combat biofilm-associated se infections. Staphylococcus epidermidis (SE) is the most prevalent pathogen causing late-onset sepsis in neonates (1). These infections are seldom lethal, but they cause significant morbidity, especially in preterm infants (1,2). SE infections are often associated with biofilm production on the surface of foreignbody implants (3,4). Biofilms are adherent multicellular bacterial aggregates embedded in a self-produced extracellular matrix. The best-described matrix compound in SE biofilms is a β-(1,6)-linked N-acetylglucosamine named polysaccharide intercellular adhesin (PIA) (5,6).SE and SE biofilms interfere with the host immune response at different levels. PIA biofilms inhibit the action of antimicrobial peptides (7), decrease neonatal inflammatory response (8), and decrease phagocytosis and degranulation by neutrophils (7). Biofilms may "decoy" antibodies and complement on the bacterial surface and thereby decrease opsonization and phagocytosis (9-11). The ability of biofilm-producing bacteria to avoid immune clearance and the general immaturity of the neonatal immune system (12) are postulated to increase the risk of neonatal SE sepsis (13). As compared with adults, neonates have a lower quantitative and qualitative complement activation (14,15), reduced upregulation of cellular response (12), and an immature cytokine response pattern (16)(17)(18)(19). Preterm infants demonstrate a markedly reduced capacity to upregulate oxidative burst in leukocytes in response to SE (20). However, some authors have reported that SE may induce a similar proinflammatory cytokine response in neonates and adults (19,21), indicating a differential maturation of various parts of the neonatal innate immune system. Differences in maturation have also been described when challenging t...

show abstract

“…During neonatal infections, an exacerbated inflammatory response often occurs inducing the enhanced release of proinflammatory cytokines and chemokines, which may lead to septic shock and death (12,13). In fact, expression levels of TLR4 control the magnitude of the response to LPS.…”

mentioning

confidence: 99%

Distinct Roles of TLR4 and CD14 in LPS-Induced Inflammatory Responses of Neonates

et al. 2009

View full text Add to dashboard Cite

During infections, pathogens bind to toll-like receptor (TLR)4 and CD14 receptors and induce cytokine release, leading to inflammation. Here, we investigated TLR4 and CD14 expression on peripheral blood leukocytes (PBLs) and their roles in lipopolysaccharide (LPS)-induced cytokine and chemokine release. Full-term and preterm neonates and adults were studied. PBLs were pretreated with anti-TLR4 -and anti-CD14 -blocking antibodies and stimulated with LPS. Cytokine and chemokine levels were measured in supernatants. TLR4, CD14 expression, and LPS-induced CXCL8 release were higher in neonates, possibly contributing to aberrant inflammation. TLR4 blockade resulted in approximately 3-fold greater suppression of LPS-induced CXCL8 release in preterm neonates (38%) than in adults (14%). CD14 blockade (ϳ80%) in neonates induced approximately 3-fold greater inhibition of CXCL8 release, compared with anti-TLR4 (ϳ30%). Anti-TLR4 partly (50 -60%) inhibited IL-10 and TNF-␣, whereas anti-CD14 completely suppressed their release. Our findings reveal that neonates depend more on TLR4 for CXCL8 release. Furthermore, neonatal LPS-induced CXCL8 release, apart from TLR4/CD14-mediated signaling, is regulated by LPS interactions with other TLRs and/or immune receptors. IL-10 and TNF-␣ release depends on LPS binding not only to CD14/TLR4 but also to CD14 associated with another TLR. Our findings reveal the contribution of TLR4 and CD14 in neonatal cytokine and chemokine release and could aid in design of antagonists to prevent harmful inflammation. (Pediatr Res 66: 179-184, 2009) N eonates are highly susceptible to Gram-negative bacteria that induce high morbidity and mortality. The principal pathogenic agent involved in neonatal sepsis induced by Gramnegative bacteria is endotoxin lipopolysaccharide (LPS), an essential component of their surface. Defense against pathogens is offered by immune cells, such as granulocytes, monocytes, and dendritic cells (DCs), which express pattern-recognition receptors (PRRs) that recognize specific structures present on microorganisms, termed pathogen-associated molecular patterns (PAMPs) (1). Binding of PAMPs to PRRs triggers antimicrobial responses to combat the infection (1,2).LPS is one of the best characterized PAMPs that binds to the CD14/toll-like receptor (TLR)4/MD2 complex of PRRs and activates intracellular signaling (3). CD14 binds to LPS but lacks an intracellular component and is, thus, incapable of signaling. MD2 is a molecule necessary for LPS recognition by TLR4, which also cannot mediate signaling. TLR4, upon LPS binding, leads to intracellular activation of mitogenactivated protein kinase and nuclear factor-B that mediate the transcription of proinflammatory cytokine and chemokine genes (4). TLR4 signaling also activates DCs that subsequently present pathogenic peptides to T lymphocytes and, thus, stimulate T-cell-mediated immunity (5).The specific roles of TLR4 and CD14 in LPS-induced inflammatory responses by neonatal leukocytes remain not clearly defined. Studies in neona...

show abstract

Cytokine Expression in Response to Bacterial Antigens in Preterm and Term Infant Cord Blood Monocytes

Cited by 44 publications

References 85 publications

Preterm Infants Have Deficient Monocyte and Lymphocyte Cytokine Responses to Group B Streptococcus

Preterm Infants Have Deficient Monocyte and Lymphocyte Cytokine Responses to Group B Streptococcus

Staphylococcus epidermidis biofilms induce lower complement activation in neonates as compared with adults

Distinct Roles of TLR4 and CD14 in LPS-Induced Inflammatory Responses of Neonates

Contact Info

Product

Resources

About