Attenuated innate immune defenses in very premature neonates during the neonatal period

Abstract

Background: Antimicrobial responses have been shown to be profoundly attenuated in very preterm neonates when examined on cord blood. However, we lack data on these responses at the time these neonates are most vulnerable to infections. Methods: Multiple cytokine responses to two prototypic Toll-like receptor (TLR) agonists: lipopolysaccharide (LPS) (TLR4) and R848 (TLR7/8) were prospectively measured in preterm neonates born ≤30 wk of gestation (n = 50) during the first 28 d of age using whole blood and single-cell multiparameter flow cytometry assays. Results were compared to term neonates (n = 30) and adult controls (n = 25). results: In preterm neonates, LPS and R848 responses remained attenuated in both cord blood and in the first 28 d of age. These responses showed significant maturation over time after adjusting for gestational age and were confirmed in monocytes and dendritic cells on a per-cell basis. We detected no major contribution of chorioamnionitis, maternal antenatal corticosteroids or magnesium sulfate treatment, labor, or mode of delivery to the maturation of cytokine responses. conclusion: Innate immune antimicrobial defenses are profoundly attenuated developmentally in very preterm neonates during the neonatal period, suggesting that exogenous factors drive the sustained systemic inflammation that has been linked to increased morbidities in these infants.d espite improvements in neonatal health care, mortality from infections has continued to increase in very preterm neonates over the last two decades, owing to the improved survival of smaller and more vulnerable infants (1). However, the underlying immunological basis of their high morbidities and high vulnerability to sepsis remains poorly understood (2). To defend themselves against infection, neonates rely on first-line, innate immune defense mechanisms. These mechanisms include the detection of specific microbial molecular structures called pathogenassociated molecular patterns through specialized receptors termed pattern recognition receptors (PRR), but also other defense mechanisms such as phagocytosis and antigen presentation to the adaptive immune system.It is widely stated that the high risk of neonatal sepsis observed in these infants is due to immature immune defense mechanisms. However, data are lacking on the development of immune functions beyond measures performed on umbilical cord blood. Recent studies have reported reduced antigen-presenting receptor expression during the first week of age in infants born below 33 wk of gestation (3,4). In contrast, phagocytic functions in these infants are more comparable to term infants (5). Toll-like receptors (TLRs) play a predominant role as a major family of PRR that act as essential "detectors" in the recognition of microbial pathogens by the innate immune system. We and others have shown that TLR-induced cytokine immune reactivity are profoundly attenuated in cord blood of very preterm neonates and develops asynchronously over the last trimester of gestation (6-10). These infants als...

An Immunological Perspective on Neonatal Sepsis

“…Indeed, using both whole blood and single-cell flow cytometry analyses, Marchant et al have confirmed that PRR responses (e.g. TLR4, TLR7/8), remain attenuated in post-natal blood obtained from neonates born below 30 weeks of gestation [95]. These results provide important support to the premise that reduced immune activity is responsible for the high vulnerability to infections.…”

Cardiac Autonomic Function at Baseline and under Stress and Its Relationship to Circulatory Markers of Inflammation in Obese Compared to Nonobese Children: A Pilot Study

“…LPS is a Toll-like receptor 4 (TLR4) ligand. Interleukin-6 (IL-6), IL-1β and tumour necrosis factor-α (TNF-α) were measured in triplicate using commercially available ELISA kits (methods previously described [19]). For basal cytokine measurements, high-sensitivity ELISA assays were used (eBioscience, San Diego, Calif., USA).…”

The impact of respiratory viruses on lung health after preterm birth

“…In addition, the levels of antigen specific immunoglobulins are substantially reduced in preterm infants, since these antibodies are largely transferred across the placenta during the third trimester, particularly after the 32nd week of gestation [23]. Preterm birth is also associated with limited production and function of antimicrobial proteins, peptidases and soluble cytokines [22,24,25]. …”