Advantages and Limitations of the Neonatal Immune System

Abstract

During early post-natal life, neonates must adjust to the transition from the sheltered intra-uterine environment to the microbe-laden external world, wherein they encounter a constellation of antigens and the colonization by the microbiome. At this vulnerable stage, neonatal immune responses are considered immature and present significant differences to those of adults. Pertinent to innate immunity, functional and quantitative deficiencies in antigen-presenting cells and phagocytes are often documented. Exposure to environmental antigens and microbial colonization is associated with epigenetic immune cell reprogramming and activation of effector and regulatory mechanisms that ensure age-depended immune system maturation and prevention of tissue damage. Moreover, neonatal innate immune memory has emerged as a critical mechanism providing protection against infectious agents. Still, in neonates, inexperience to antigenic exposure, along with enhancement of tissue-protective immunosuppressive mechanisms are often associated with severe immunopathological conditions, including sepsis and neurodevelopmental disorders. Despite significant advances in the field, adequate vaccination in newborns is still in its infancy due to elemental restrictions associated also with defective immune responses. In this review, we provide an overview of neonatal innate immune cells, highlighting phenotypic and functional disparities with their adult counterparts. We also discuss the effects of epigenetic modifications and microbial colonization on the regulation of neonatal immunity. A recent update on mechanisms underlying dysregulated neonatal innate immunity and linked infectious and neurodevelopmental diseases is provided. Understanding of the mechanisms that augment innate immune responsiveness in neonates may facilitate the development of improved vaccination protocols that can protect against pathogens and organ damage.

Keywords: brain injury; infections; innate immunity; neonates; neurodevelopment; sepsis.

Figure 1

Innate immune responses in neonates. The quantitative and functional characteristics of neonatal innate immune responses are depicted and compared to those of adults. These features of innate immune cells render newborns vulnerable to severe infections and organ damage.

Figure 2

Dysregulated neuro-immune communication underlies the pathology of infections and CNS disorders in neonates. Infections, such as chorioamnionitis, dermatitis, meningitis, necrotizing enterocolitis, and respiratory infections, can lead to systemic inflammation and severe sepsis in newborns. Pathogen associated molecular patterns (PAMPs), generated during infections, are recognized via PRRs by innate immune cells and this induces cell activation and the production of pro-inflammatory mediators in the periphery and the CNS. On the other hand, maternal infections during pregnancy and/or EOS, and intrapartum asphyxia can induce brain injury and HIE, respectively, and further activate innate immune responses. Dysregulated neuro-immune communications underlie the pathogenesis of systemic infections and brain damage in neonates and may lead to neurodevelopmental and neuropsychiatric disorders.