Abstract
Although most causes of death and morbidity in premature infants are related to immune maladaptation, the premature immune system remains poorly understood. We provide a comprehensive single-cell depiction of the neonatal immune system at birth across the spectrum of viable gestational age (GA), ranging from 25 weeks to term. A mass cytometry immunoassay interrogated all major immune cell subsets, including signaling activity and responsiveness to stimulation. An elastic net model described the relationship between GA and immunome (R=0.85, p=8.75e-14), and unsupervised clustering highlighted previously unrecognized GA-dependent immune dynamics, including decreasing basal MAP-kinase/NFκB signaling in antigen presenting cells; increasing responsiveness of cytotoxic lymphocytes to interferon-α; and decreasing frequency of regulatory and invariant T cells, including NKT-like cells and CD8+CD161+ T cells. Knowledge gained from the analysis of the neonatal immune landscape across GA provides a mechanistic framework to understand the unique susceptibility of preterm infants to both hyper-inflammatory diseases and infections.
Highlights
Prematurity is one of the most pressing clinical imperatives of our day: it affects approximately 1015% of pregnancies and kills more than one million babies every year, making it the leading cause of death in children under five [1]
Epidemiologic evidence and animal studies implicate fetal and neonatal inflammation in long-term neurodevelopmental impairments common in prematurity [10, 20]. These morbidities develop over time, studies suggest that the immune status at the time of birth may be a key indicator for which infants are most vulnerable; several authors have demonstrated that cytokine levels in umbilical cord blood correlate with neurodevelopmental outcomes [21,22,23,24], retinopathy of prematurity (ROP) [25], bronchopulmonary dysplasia (BPD) [26, 27], periventricular leukomalacia [24], and necrotizing enterocolitis (NEC) [28]
An overarching motif was a progressive increase in the ligand-specific responsiveness to stimulation of the immune system as illustrated by a transition from a system characterized by low-amplitude antigen (LPS)- and cytokine (IFNa, IL-2, IL-4, and IL-6)- specific immune responses with high basal signaling tone to one more capable of eliciting ligand-specific reactions to immunologic challenges (Figures 3C and 7)
Summary
Prematurity is one of the most pressing clinical imperatives of our day: it affects approximately 1015% of pregnancies and kills more than one million babies every year, making it the leading cause of death in children under five [1]. Bronchopulmonary dysplasia (BPD, a cause of life-pulmonary insufficiency), necrotizing enterocolitis [NEC, a devastating inflammatory disease of the gut with a 30-40% mortality rate [4]], retinopathy of prematurity [ROP, one of the top three causes of blindness in Neonatal Immune System Across GA children in the developed world [5]], and neurodevelopmental impairment afflict well over half of infants born extremely preterm at less than 28 weeks gestational age (GA) [2]. These morbidities develop over time, studies suggest that the immune status at the time of birth may be a key indicator for which infants are most vulnerable; several authors have demonstrated that cytokine levels in umbilical cord blood correlate with neurodevelopmental outcomes [21,22,23,24], ROP [25], BPD [26, 27], periventricular leukomalacia (a major cause of adverse neurodevelopmental outcomes) [24], and NEC [28]
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