Innate Immunity of Neonates and Infants

Abstract

Many important events occur at birth. The fetus is suddenly removed from a protected intra-uterine environment that is aquatic, warm, and nearly sterile, to the dry, cold external world laden with microbes. To survive, the neonate must interact with many organisms, making use of some, while vigorously defending against the others like a nation conducting trade with friendly countries and guarding against hostile ones from invading it, waging wars if necessary. Although, the neonatal immune system is plastic, however, it is highly tolerant which is due to both the fetal development during gestation as well as significant sudden changes in fetal environment and enormous exposure to the new antigens and intestinal bacteria and their products. This "quiescent mode" of innate immune system is part of a highly regulated process to fulfill all requirements of multi-layered process of early life, implemented effectively through the cells of innate immune system. While, most of the neonatal innate immune cells (e.g., neutrophils and monocytes) present contained activity and lower frequencies compared to their adult counterparts, innate lymphoid cells (ILCs), a distinct cellular component of innate immunity, show higher level of activity and presence during period of infancy compared to later stages of life and adulthood, which may suggest a role for ILCs in variable susceptibility to certain conditions during life time. In this review, while we focus on the characteristics and status of ILCs in neonatal immune system, we also draw an analogy from a national defense perspective because of the great similarities between that and the immune system by providing the known biological counterparts of all five core operational elements, the five Ds of defense, detection, discrimination, deployment, destruction, and de-escalation, with special focus on innate immunity, maternal support, and influence during the neonatal and infancy periods.

Keywords: innate immunity; innate lymphoid cell; microbiome; milk; neonate immunity.

Figure 1

Chronicle scheme of major factors affecting neonatal innate immunity. A wide range of genetic and epigenetic factors may influence the neonatal development during gestation (prenatal) as well as perinatal (post gestation) and neonatal stages. There maybe a level of overlap among factors.

Figure 2

Status of major immune cells at neonatal phase. The presence, frequency, and function of immune cells in neonates are varied in a chronicle fashion and based on the genetic and epigenetic factors at early stages of life. Abbreviations: NK cells, natural killer cells; DCs, dendritic cells; cDC, conventional dendritic cells; pDC, plasmacytoid dendritic cells; ILCs, innate lymphoid cells.

Figure 3

The presence of immune components in mammary glands. (A) Low power photomicrograph of lactating murine (C57BL/6) mammary gland showing lymphoid aggregates juxtaposed to the alveoli. These secondary lymphoid tissues (SLT) are the “base camps” for lymphocytes where further differentiation and acquisition of functionality such as cytokine production and cytotoxicity occur. The strategic location of SLT to the milk glands allows lymphocytes to defend the lactating breast as well as deployment to the infant through milk. (B) High magnification of the histology of lactating mouse mammary tissue, H and E stain, showing afferent and efferent lymphatic vessels, capillaries, and follicular formation with densely packed heterogeneous small lymphocytes in close proximity to active secretary units made up of cuboidal alveolar lactocytes. This is not different from the aerial photograph of a military base with tens of thousands recruits undergoing training where inbound and outbound roads bring in supplies and remove wastes.

Figure 4

Components of innate and acquired immunity in infants and neonates. Heuristically, the immune system defends the neonate and infant against infections in similar manners as the military and the police keeping the country safe. The young immune system must develop de novo to respond to some foreign antigens (pathogens) and more rarely, abnormal autoantigens (neoplastic and auto-reactive cells), while accepting some other foreign antigens (commensal microbes) and normal autoantigens. Multiple components from innate and adoptive immune system collaborate to accomplish the above tasks with multiple redundancies to ensure robustness. The active defense against pathogens, like many joint operations in the military, requires coordination of multiple units from different branches of the armed forces. Innate immunity is faster to respond (seconds to minutes) but the duration of action is shorter (3–5 days). In contrast, the adaptive immunity takes longer (4–7 days) to activate but the response is much more specific and sustained (weeks to years).

Figure 5

Innate immunity, the army inside. (A) A jet fighter must be able to detect any approaching air or sea craft, discriminate friend or foe, and deploy weapon systems that can destroy the foe, and then stand down. Mistaken friendly for foe will cause casualties to one’s own forces; however, failure to detect or discriminate a foe will result in destruction of the unit by the invader. The infrared-guided AIM-9 sidewinder missile carried in the port wingtip launcher is similar to an antibody: released at a distance and capable of target tracking and destruction (Photograph taken by Marian R. Lambert-Yu, 2016). (B) Transmission immune-electron microscopy of an innate lymphoid cell (ILC) with two sizes of gold particles labeling the cytokine profiles. This is an important cell, which can sense pathogen presence in its microenvironment and releases appropriate cytokines in response to the invader. Like the fighter jet, innate immune cells, such as macrophage, neutrophils, and NK cells faces the same demands and carries out the same tasks of detection, discrimination, deployment, destruction, and de-escalation. The immune-gold spheres label this ILC’s “payloads” and they many include tumor necrosis factor α, INFγ, IL-5, IL-13, IL-17, and IL-22, comparable to the sidewinder and sparrow missiles carried by the F-16. The difference is that ILC has no “pilot,” it makes its weapons, and its behavior is completely rule-based.