Differential Maturation of the Innate Immune Response in Human Fetuses

Abstract

Newborns and especially preterm infants show a unique susceptibility to severe bacterial infections that cause significant morbidity and mortality. As very few data are available on innate immune functions in human fetuses, we conducted a comprehensive study to investigate the expression of several adhesion molecules essentially involved in migration (CD11a, CD11b, CD11c, CD18, and CD62L). Furthermore, phagocytic activity, generation of respiratory burst products, and production of several proinflammatory cytokines were assessed. Various functions of the fetal innate immune system were demonstrated to be essentially different from those observed in term neonates or adults. Expression of several surface markers was significantly diminished on fetal granulocytes. Furthermore, a significantly reduced phagocytic activity of fetal granulocytes and monocytes was found, contrasted by an enhanced generation of reactive oxygen products. In addition, we demonstrate that significant numbers of fetal monocytes are capable of the production of proinflammatory cytokines in response to stimulation. However, the pattern of cytokine production is different from the more mature individuals: the number of IL-6 -and tumor necrosis factor-␣-positive monocytes were significantly diminished, whereas more IL-8 -producing monocytes were found compared with adults. The results of our study add significantly to our understanding of the maturation and impairment of the innate immune response. Neonates, especially preterm infants, are prone to severe and overwhelming bacterial infection with substantial morbidity and mortality. Despite intensive supportive care and early use of antibiotics, the rate of morbidity and mortality caused by infections remains high (1). Although multiple factors contribute to this susceptibility, the immaturity of the innate immune system, especially production of phagocytes and several phagocyte functions (e.g. chemotaxis, phagocytosis, respiratory burst, cytokine production) are of paramount importance (2,3). Evidence of this is provided by the pattern of infections closely resembling that seen in profound neutropenia (4). Depleted neutrophil storage pools and neutropenia were described to be associated with neonatal sepsis and are negative predictors of outcome (5,6). Several qualitative deficiencies of phagocyte function were demonstrated earlier in preterm infants and stressed or septic neonates. The functional deficiencies comprised migration, phagocytosis, and bactericidal potency, for example, release of bactericidal/permeabilityincreasing protein (7-15). However, normal or even enhanced spontaneous neutrophil respiratory burst activity in term and preterm neonates was reported in other studies (16,17). In contrast, little is known to date about the phagocytic and oxidative capacity as well as the adhesion molecule expression of fetal neutrophils and monocytes. The expression of several adhesion molecules essentially involved in migration was reported to be significantly impaired in neonates and to contri...

Responsiveness of human monocytes to the commensal bacterium Staphylococcus epidermidis develops late in gestation

“…Phagocytosis and intracellular killing by neonatal monocytes are comparable to those achieved by adult MNCs (25)(26)(27)(28)(29). However, these data are derived from stimulation studies using early-onset sepsis pathogens or latex particles; there are no analogous data on phagocytosis of SE by monocytes in preterm infants.…”

Phagocytosis of neonatal pathogens by peripheral blood neutrophils and monocytes from newborn preterm and term infants

“…There are no definitive comparisons of phagocytosis between adults and neonates; studies have identified positive (12,13), negative (14), and neutral (11,13) trends in functionality between the groups (15). Similarly, the reported correlation between GA and phagocytosis functionality is inconsistent (12,16). Discrepancies are also evident when comparing specific cell types, including monocytes and neutrophils (12)(13)(14)(15).…”

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

“…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).…”