The fetus and newborn face a complex set of immunological demands, including protection against infection, avoidance of harmful inflammatory immune responses that can lead to pre-term delivery, and balancing the transition from a sterile intra-uterine environment to a world that is rich in foreign antigens. These demands shape a distinct neonatal innate immune system that is biased against the production of pro-inflammatory cytokines. This bias renders newborns at risk of infection and impairs responses to many vaccines. This Review describes innate immunity in newborns and discusses how this knowledge might be used to prevent and treat infection in this vulnerable population.

Innate immunity of the newborn: basic mechanisms and clinical correlates

Inflammation plays a critical role in mediating brain injury induced by neonatal hypoxic ischemic encephalopathy (HIE). The mechanisms underlying inflammatory responses to ischemia may be shared by neonatal and adult brains; however, HIE exhibits a unique inflammation phenotype that results from the immaturity of the neonatal immune system. This review will discuss the current knowledge concerning systemic and local inflammatory responses in the acute and subacute stages of HIE. The key components of inflammation, including immune cells, adhesion molecules, cytokines, chemokines and oxidative stress, will be reviewed, and the differences between neonatal and adult inflammatory responses to cerebral ischemic injury will also be discussed.

Inflammatory responses in hypoxic ischemic encephalopathy

Bacterial infection is a major cause of death and long-term morbidity in preterm neonates. Infection rates among neonates undergoing intensive care range from 25% to 50% (Stoll et al, 1996; Cooke et al, 1997; Fanaroff et al, 1998) and, in spite of effective antibiotic therapy, sepsisrelated mortality has remained constant at 15±20% for nearly two decades (Gladstone et al, 1990). The reason for such high sepsis rates and attendant mortality are largely due to the immaturity of bactericidal mechanisms. Clinical evidence of the preterm neonate's immune incompetence is the pattern of bacterial infections which closely parallels that seen in patients with profound neutropenia (Stoll et al, 1996) and the frequent development of neutropenia in response to bacterial sepsis (Engle et al, 1984; Gessler et al, 1995). These two phenomena can be directly related to immaturity of neutrophil function and production.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1365-2141.2000.01992.x

Neutrophil Production and Function in Newborn Infants

The human fetus and neonate, particularly the premature neonate, are unduly susceptible to a wide variety of microbes. This susceptibility results from limitations of both innate and adaptive (antigen-specific) immunity, and from limitations in processes through which the innate immune system facilitates and directs the development of protective antigen-specific immunity. This chapter focuses on the ontogeny of the cellular and humoral components of the immune system and their function in the human fetus, neonate, and young infant. Antigen-specific immunity is discussed first, followed by innate mechanisms of host defense. The relationship between deficiencies in immune function in the neonate and fetus and their increased susceptibility to bacterial, viral, and protozoal infections are examined, followed by a brief review of current and potential applications of immunotherapy as therapeutic adjuncts or for the prevention of these infections.

Developmental Immunology and Role of Host Defenses in Fetal and Neonatal Susceptibility to Infection

Sepsis is a severe and life-threatening systemic inflammatory response to infection that affects all populations and age groups. The pathophysiology of sepsis is associated with aberrant interaction between leukocytes and the vascular endothelium. As inflammation progresses, the adhesion molecules that mediate these interactions become shed from cell surfaces and accumulate in the blood as soluble isoforms that are being explored as potential prognostic disease biomarkers. We critically review the studies that have tested the predictive value of soluble adhesion molecules in sepsis pathophysiology with emphasis on age, as well as the underlying mechanisms and potential roles for inflammatory shedding. Five soluble adhesion molecules are associated with sepsis, specifically, E-selectin, L-selectin and P-selectin, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. While increased levels of these soluble adhesion molecules generally correlate well with the presence of sepsis, their degree of elevation is still poorly predictive of sepsis severity scores, outcome and mortality. Separate analyses of neonates, children and adults demonstrate significant age-dependent discrepancies in both basal and septic levels of circulating soluble adhesion molecules. Additionally, a range of both clinical and experimental studies suggests protective roles for adhesion molecule shedding that raise important questions about whether these should positively or negatively correlate with mortality. In conclusion, while predictive properties of soluble adhesion molecules have been researched intensively, their levels are still poorly predictive of sepsis outcome and mortality. We propose two novel directions for improving clinical utility of soluble adhesion molecules: the combined simultaneous analysis of levels of adhesion molecules and their sheddases; and taking age-related discrepancies into account. Further attention to these issues may provide better understanding of sepsis pathophysiology and increase the usefulness of soluble adhesion molecules as diagnostic and predictive biomarkers.

/pdf/soluble-adhesion-molecules-as-markers-for-sepsis-and-the-2bvdsvnj34.pdf

Soluble adhesion molecules as markers for sepsis and the potential pathophysiological discrepancy in neonates, children and adults

The functional deficits of neonatal neutrophils are well documented and are thought to contribute to the increased susceptibility of newborn infants to infection. We measured the adhesion molecules L-selectin, CD11a/CD18 and CD11b/CD18 on neutrophils from the cord blood of term (n = 22) and premature (n = 32) infants using a whole blood method with flow cytometry and quantitative bead standards to enumerate cell surface receptors. We also assayed plasma for the shed form of L-selectin (sL-selectin). Our results suggested that L-selectin expression on term infant neutrophils is lower than that on adult neutrophils (unstimulated and stimulated, both P < 0.001), but that stimulated premature infant cell express higher L-selectin than term infants (P < 0.05); it is possible that this deficiency is caused by physiological changes occurring around the normal time of parturition. We observed reduced sL-selectin in term infants (P < 0.001) compared with adults, and even lower concentrations in premature infants (P < 0.001). The sL-selectin concentrations in plasma may be a reflection of granulopoiesis, which may be reduced in premature infants. Our results showed increased resting neonatal neutrophil expression of CD11b/CD18 compared with adults, and the absence of any neonatal deficit of the ability to up-regulate CD11b/CD18 expression on stimulation. These findings are contrary to previous reports. Further studies suggested that the isolation procedures used in previous reports reduces the capability of the cells to respond to a formyl methionine leucine phenylalanine (fMLP) stimulus. This effect is more marked in neonatal neutrophils, suggesting that the previously reported deficiency is in fact due to the isolation techniques used rather than the cells' innate ability to up-regulate CD11b/CD18 expression. The results of our study lead us to propose that the adhesive function of neonatal neutrophils may be less defective than previously thought.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2249.1995.tb02296.x

Neutrophil adhesion molecules in term and premature infants: normal or enhanced leucocyte integrins but defective L-selectin expression and shedding.

SUMMARY Thefunctional deficits ofneonatal neutrophils arewell documented andarethought tocontribute totheincreased susceptibility ofnewborn infants toinfection We measured theadhesion molecules L-selectin, CDlIa/CD1 8andCDllb/CD18 onneutrophils fromthecordbloodof term(n= 22)andpremature (n= 32)infants using awhole blood method withflow cytometry and quantitative beadstandards toenumerate cell surface receptors Wealso assayed plasma forthe shedformofL-selectin (sL-selectin) Ourresults suggested thatL-selectin expression onterm infant neutrophils islower thanthatonadult neutrophils (unstimulated andstimulated, both P <0001), butthat stimulated premature infant cells express higher L-selectin thanterminfants (P< 005); itispossible that this deficiency iscaused byphysiological changes occurring around thenormaltimeofparturition We observed reduced sL-selectin interminfants (P<0-001) compared withadults, andevenlower concentrations inpremature infants (P<0O001) ThesLselectin concentrations inplasma maybeareflection ofgranulopoiesis, whichmaybereduced in premature infants Ourresults showed increased resting neonatal neutrophil expression ofCD1lb/ CD18compared withadults, andtheabsence ofanyneonatal deficit oftheability toup-regulate CD1lb/CD 18expression onstimulation These findings arecontrary toprevious reports Further studies suggested that theisolation procedures usedinprevious reports reduces thecapability of thecells torespond toaformyl methionine leucine phenylalanine (fMLP) stimulus Thiseffect is moremarked inneonatal neutrophils, suggesting that thepreviously reported deficiency isinfact duetotheisolation techniques usedrather thanthecells' innate ability toup-regulate CDllb/ CD18expression Theresults ofourstudy leadustopropose thattheadhesive function of neonatal neutrophils maybeless defective thanpreviously thought

Neutrophil adhesion molecules intermandpremature infants: normalor enhanced leucocyte integrins butdefective L-selectin expression andshedding

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Neutrophil adhesion molecules in term and premature infants: normal or enhanced leucocyte integrins but defective L-selectin expression and shedding.

Neutrophil adhesion molecules intermandpremature infants: normalor enhanced leucocyte integrins butdefective L-selectin expression andshedding