Neonatal immunology: responses to pathogenic microorganisms and epigenetics reveal an “immunodiverse” developmental state

Abstract

Neonatal animals have heightened susceptibility to infectious agents and are at increased risk for the development of allergic diseases, such as asthma. Experimental studies using animal models have been quite useful for beginning to identify the cellular and molecular mechanisms underlying these sensitivities. In particular, results from murine neonatal models indicate that developmental regulation of multiple immune cell types contributes to the typically poor responses of neonates to pathogenic microorganisms. Surprisingly, however, animal studies have also revealed that responses at mucosal surfaces in early life may be protective against primary or secondary disease. Our understanding of the molecular events underlying these processes is less well developed. Emerging evidence indicates that the functional properties of neonatal immune cells and the subsequent maturation of the immune system in ontogeny may be regulated by epigenetic phenomena. Here, we review recent findings from our group and others describing cellular responses to infection and developmentally regulated epigenetic processes in the newborn.

Neonatal NET-inhibitory factor and related peptides inhibit neutrophil extracellular trap formation

“…Complex adaptations appear to have evolved that prevent excessive, injurious inflammation in the perinatal period and in the abrupt neonatal transition from the protected intrauterine environment to continuous microbial colonization and exposure (25)(26)(27). These adaptations may, however, be accompanied by increased susceptibility to infection (26,27). Earlier, we found that PMNs isolated from umbilical cord blood of preterm and term infants do not form NETs when stimulated and have a defect in NET-mediated bacterial killing, suggesting such an adaptation (28).…”

“…Selective inhibitors of NET formation may be parinterface, suggesting that unregulated NET formation can cause inflammatory pathology in the fetomaternal environment. Excessive intrapartum NET formation could also have additional negative consequences, including long-term neonatal immune dysregulation (2,3,25,26,56,59). Immediately after delivery, the neonate is at risk for NET-mediated vascular injury and thrombosis (1-3, 9, 13, 19, 38) triggered by microbial colonization (22,23) and consequent neutrophil mobilization (24) if NET formation is not tightly controlled.…”

“…In our initial screens, nNIF was not detected or was minimally present in plasma samples from healthy adults or adult patients with chronic inflammatory syndromes ( Figure 2B; our unpublished data). This suggests that nNIF expression may largely be a feature of the fetus and neonate, as are certain other immunoregulatory mechanisms (25)(26)(27). Additional studies of healthy and diseased adults, potentially with more sensitive assay methods, will be required to resolve this issue.…”

“…Furthermore, newborns are rapidly colonized with bacteria after delivery, a process associated with increases in circulating and bone marrow neutrophils (22)(23)(24). Complex adaptations appear to have evolved that prevent excessive, injurious inflammation in the perinatal period and in the abrupt neonatal transition from the protected intrauterine environment to continuous microbial colonization and exposure (25)(26)(27). These adaptations may, however, be accompanied by increased susceptibility to infection (26,27).…”

Altered mitochondrial response to activation of T-cells in neonate

“…Clinical experience and experimental data support that neonatal T-cells are immunologically less competent than those in the adult (1). Upon activation the production of inflammatory cytokines in CD3+ T-cells is lower in the neonate than in the adult (7,13).…”