Type I interferons protect neonates from acute inflammation through interleukin 10–producing B cells

Zhang, Xiaoming; Dériaud, Edith; Jiao, Xinan; Braun, Déborah; Leclerc, Claude; Lo‐Man, Richard

doi:10.1084/jem.20062013

Cited by 132 publications

(136 citation statements)

References 55 publications

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“…It is noteworthy that, contrary to our findings, a recent study shows that the defective inflammatory response of neonatal mice due to increased IL-10 production by a B1 subset of B cells may increase their survival rate upon stimulation by various TLR agonists (18). The major difference between the studies is the use of D-GalN.…”

Section: 01) Data Are Presented As Mean Values (ϯSem) (D) Lethal contrasting

confidence: 53%

“…In human, it has been reported that mononuclear cells from cord blood secrete lower amounts of TNF than those from healthy adults in response to TLR agonists (10)(11)(12)(13), whereas other studies draw opposite conclusions (14)(15)(16). Results from studies in mice also conflict because neonates produce either lower (17,18) or higher (19) levels of TNF compared with adults. The most consistent observation, however, is that the ratio of IL-6 to TNF is higher, whereas IFN-␥ is defective in neonates (10,11,20).…”

contrasting

confidence: 39%

“…The increased morbidity and mortality characteristic of neonatal infection is thought to be caused by underdeveloped innate and adaptive immunity. A recent study indicates that neonates are more resistant to a lower dose of LPS than adult mice after being sensitized by D-GalN, presumably because of an impaired innate response in the newborn host (18). The LPS plus D-GalN system is widely used to study LPS-induced liver injury mediated by macrophages (23)(24)(25).…”

Section: Neonatal Mice Are More Resistant To Lps/d-galn Challenge Thamentioning

confidence: 99%

“…The increase in T cells might reflect an evolutionary adaptation for adult mammals to efficiently control both the divergent microbial intrusion and accompanying inflammation. Because different TLR agonists may activate distinctly innate and adaptive immune response in vitro or in vivo (18), further studies using other TLR stimuli or infections and better characterized T/innate cell interaction may help clarify the function of neonatal T cells.…”

Section: 01) Data Are Presented As Mean Values (ϯSem) (D) Lethal mentioning

confidence: 99%

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Hyper innate responses in neonates lead to increased morbidity and mortality after infection

Zhao

Kim

Yang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

146

129

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Neonates suffer high morbidity and mortality in infection, presumably because of the lack of a fully developed adaptive and innate immune system. Evidence of poor innate responses in neonates has been shown by using a model that sensitizes the host to Toll-like receptor (TLR)-mediated inflammation with D-galactosamine (DGalN). However, we show that neonatal mice demonstrate much stronger inflammatory responses than adult mice in response to LPS stimulation, and such hypersensitivity extends to other TLR agonists including actual viral infection. Our study reveals that the ensuing inflammatory reaction after D-GalN sensitization reflects preferential toxicity of D-GalN to adult liver cells, rather than accurately reflecting the TLR response to LPS. We show further that an uncontrolled proinflammatory innate response due to inadequate T cells makes neonates more vulnerable to TLR agonists or viral infection. Remarkably, through transfer of T cells into neonates or depletion of T cells in adult mice, we show that T cells are sufficient and necessary to control the early inflammatory response to LPS. Therefore, neonates might suffer from the unleashed innate responses caused by an insufficient number of T cells, which leads to increased morbidity and mortality.

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Section: 01) Data Are Presented As Mean Values (ϯSem) (D) Lethal contrasting

confidence: 53%

contrasting

confidence: 39%

Section: Neonatal Mice Are More Resistant To Lps/d-galn Challenge Thamentioning

confidence: 99%

Section: 01) Data Are Presented As Mean Values (ϯSem) (D) Lethal mentioning

confidence: 99%

See 2 more Smart Citations

Hyper innate responses in neonates lead to increased morbidity and mortality after infection

Zhao

Kim

Yang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

146

129

View full text Add to dashboard Cite

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“…These results showing no effect following elimination of the adaptive immune system are contrary to recently published data showing that CD5 ϩ B cells, a component of the neonatal adaptive immune system, are important in preventing lethal shock responses to CpG DNA in neonates through an anti-inflammatory pathway involving type I IFN and IL-10. 45 However, their model did not involve an infectious pathogen, whereas we used a model of severe polymicrobial sepsis with clinical relevance. Furthermore, since neonates exhibit an attenuated inflammatory response and increased sepsis mortality, 23 these cells may be contributing to the poor bacterial clearance and increased mortality induced by the infection.…”

Section: Discussionmentioning

confidence: 99%

Defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by TLR agonists

Wynn

Scumpia²,

Winfield³

et al. 2008

Blood

158

167

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Neonates exhibit an increased risk of sepsis mortality compared with adults. We show that in contrast to adults, survival from polymicrobial sepsis in murine neonates does not depend on an intact adaptive immune system and is not improved by T cell-directed adaptive immunotherapy. Furthermore, neonates manifest an attenuated inflammatory and innate response to sepsis, and have functional defects in their peritoneal CD11b ؉ cells. Activation of innate immunity with either a Toll-like receptor 4 (TLR4) or TLR7/8 agonist, but not a TLR3 agonist, increased the magnitude, but abbreviated the early systemic inflammatory response, reduced bacteremia, and improved survival to polymicrobial sepsis. TLR4 agonist pretreatment enhanced peritoneal neutrophil recruitment with increased oxidative burst production, whereas the TLR7/8 agonist also enhanced peritoneal neutrophil recruitment with increased phagocytic ability. These benefits were independent of the adaptive immune system and type I interferon signaling. Improving innate immune function with select TLR agonists may be a useful strategy to prevent neonatal sepsis mortality. IntroductionSepsis causes profound defects in innate and acquired immunity. In septic adults, circulating leukocytes fail to mount an attenuated inflammatory response, monocytes have defective antigen presentation in part due to reduced MHC class II expression, and dendritic cells and lymphocytes exhibit increased apoptosis. [1][2][3][4] These deficiencies contribute to a failure to clear primary pathogens, an increased propensity to develop superinfections, and an inability to mount adaptive immune responses. Considerable progress has been made in understanding the pathogenesis of and identifying potential immunomodulatory therapies for treating sepsis in adult animals. For example, MyD88 and type I interferon signaling pathways 5,6 are important requisites for innate and inflammatory host defense responses to pathogens. 7,8 Stimulating the innate immune system with Toll-like receptor (TLR) agonists improves survival in adult animal models of sepsis. 9,10 Similarly, absence of the adaptive immune system 11 or an inability of B cells to produce antibodies 12 predisposes adult mice to a poor outcome in sepsis. Correction of adaptive immune dysfunction by prevention of lymphocyte apoptosis or treatment with agonistic glucocorticoid-induced tumor necrosis factor (TNF) receptor antibody (anti-GITR) to stimulate effector T-cell function, improves survival in animal models of adult sepsis. 11,13 These studies highlight the importance of both the innate and adaptive immune systems in eliminating invading pathogens in adult mammals. However, the mechanisms of protective immunity in neonates that do not possess a fully intact immune system, and who develop sepsis at increased rates, 14 are less clear.More than 1 million babies die each year worldwide within the first 4 weeks of life from sepsis. 15 Neonatal sepsis mortality is higher than in children and adults, 16,17 peaking in premature infants, where r...

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Innate responses of B cells

Gray

Barr

2007

Eur J Immunol

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In this review, we describe the non-antibody-mediated functions of B cells within the immune system. In addition to antibody production, B cells also present antigen to T cells, programme T cell differentiation and regulate effector T cell responses and much of this is mediated by the cytokines they make. We focus on the potential of B cells to perform these functions simply as a result of activation via 'innate' receptors (e.g. Tolllike receptors) and often independently of BCR ligation. We feel an appreciation of these broad and often antigen-nonspecific functions is important at a time when there is an increasing use of B cell depletion as a therapy for autoimmune disease.

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Type I interferons protect neonates from acute inflammation through interleukin 10–producing B cells

Cited by 132 publications

References 55 publications

Hyper innate responses in neonates lead to increased morbidity and mortality after infection

Hyper innate responses in neonates lead to increased morbidity and mortality after infection

Defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by TLR agonists

Innate responses of B cells

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