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  • Review Article
  • Published:

Innate immunity of the newborn: basic mechanisms and clinical correlates

Nature Reviews Immunology volume 7, pages 379–390 (2007)Cite this article

Key Points

  • The fetus is an allograft onto the mother and is at risk of rejection, so there is a strong T helper 2 (TH2)-cell bias to fetal innate immune responses, a tendency also initially manifest in the newborn. The production of pro-inflammatory/TH1-cell-polarizing cytokines such as tumour-necrosis factor (TNF), interferon-γ (IFNγ), and interleukin-12 (IL-12) is impaired.

  • Neonatal monocytes and antigen-presenting cells (APCs) show reduced production of TNF, IL-12 and IFNγ, but preserved production of IL-6, IL-10 and IL-23. Mechanisms for this polarization include elevated cytosolic concentrations of the second messenger cyclic AMP (cAMP), reduced myeloid differentiation primary-response gene 88 (MyD88) expression and defects in nucleosome remodelling.

  • Birth initiates an acute-phase response characterized by rising serum levels of IL-6 and increases in IL-6-inducible hepatocyte products such as C-reactive protein (CRP) and lipopolysaccharide (LPS)-binding protein. It is speculated that this response might serve to clear microbes and/or microbial products that might translocate across mucosal barriers during birth and/or initial colonization.

  • Shortly after birth, upon initial microbial colonization, the neonatal intestinal tract downregulates its inflammatory responses to endotoxin to avoid over-exuberant and potentially harmful reactions to common Gram-negative bacterial flora.

  • The neonatal respiratory tract manifests age-dependent maturation of Toll-like receptor (TLR) responses and expression of antimicrobial proteins and peptides (APPs). As a major portal for aeroallergens and aeroadjuvants (for example, microbial products that are TLR agonists), the respiratory tract might mediate maturation of neonatal and infant TH1-cell-type responses by repeated low-dose exposure to environmental TLR agonists, as posited by the hygiene hypothesis.

  • Neonatal neutrophils show qualitative defects in reduced integrin and selectin expression, reduced expression of some antimicrobial proteins and impaired priming of the phagocyte oxidase. In addition, neonates experience a quantitative neutrophil deficiency during stress conditions.

  • Robust responses to certain microbial stimuli, including viral single-stranded RNAs and related imidazoquinoline compounds that activate cells through TLR8, represent exceptions to the generally impaired production of pro-inflammatory/TH1-cell-polarizing cytokines.

  • On-going efforts seek to leverage our newfound knowledge of innate immunity to diagnose, prevent and treat neonatal diseases. Such approaches might include measuring components of innate immunity to diagnose infection, using APPs as anti-infective agents or using TLR agonists as vaccine adjuvants.

Abstract

The fetus and newborn face a complex set of immunological demands, including protection against infection, avoidance of harmful inflammatory immune responses that can lead to pre-term delivery, and balancing the transition from a sterile intra-uterine environment to a world that is rich in foreign antigens. These demands shape a distinct neonatal innate immune system that is biased against the production of pro-inflammatory cytokines. This bias renders newborns at risk of infection and impairs responses to many vaccines. This Review describes innate immunity in newborns and discusses how this knowledge might be used to prevent and treat infection in this vulnerable population.

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Figure 1: Expression of antimicrobial proteins and peptides (APPs) in utero.
Figure 2: Postnatal microbial colonization and the acute-phase response.
Figure 3: Mechanisms for distinct function of human neonatal monocytes and antigen-presenting cells.

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Acknowledgements

I thank P. Elsbach, R. Geha, R. Munford, P. Pizzo, J. Weiss and M. Wessels for their mentorship. P. Bibbins created concept illustrations for Figs 2,3. O.L.'s laboratory is supported by the National Institutes of Health, a Dana Human Immunology Award and by XOMA (U.S.) L.L.C.

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  1. Department of Medicine, Division of Infectious Diseases, Children's Hospital Boston and Harvard Medical School, Boston, 02115, MA, USA

    Ofer Levy

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Among the funding sources to the author's laboratory is research support from XOMA (U.S.) L.L.C. that manufactures recombinant BPI.

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Glossary

Hygiene hypothesis

The theory that exposure to microbial components, including Toll-like receptor (TLR) agonists during the neonatal, infancy and early-childhood phases of development serves to polarize the immune response towards T helper 1 (TH1)-cell, and away from TH2-cell, responses, thereby reducing the likelihood of allergy and/or atopy. Consistent with this hypothesis, there are inverse epidemiological relationships between the rates of infection and autoimmunity — for example, as the rates of common infections have dropped in wealthy industrialized countries, the rates of allergy and autoimmune disease have risen.

Erythema toxicum neonatorum

A common, transient and benign rash of the newborn, characterized by raised lesions on an erythematous base. Recent evidence reveals that erythema toxicum probably reflects an innate immune response to initial skin colonization by Gram-positive bacteria (for example, coagulase-negative staphylococci) that penetrate neonatal skin through hair follicles. This bacterial penetration is associated with the activation of tissue macrophages and production of interleukin-1 (IL-1) and IL-6, which are capable of contributing to a systemic acute-phase response.

Crypts

Tubular invaginations of the intestinal epithelium. Paneth cells are found at the base of the crypts and produce antimicrobial proteins and peptides, including phospholipase A2 and defensins, as well as stem cells, which continuously divide and are the source of all intestinal epithelial cells. Villi are projections into the lumen and have an outer layer of cells that mainly consists of mature, absorptive enterocytes but also contain mucus-secreting goblet cells.

Necrotizing enterocolitis

(NEC). A gastrointestinal disease predominantly affecting premature low-birth-weight infants. NEC involves infection and inflammation that causes destruction of the intestine. Although the pathophysiology of NEC is not yet completely defined, increasing evidence indicates that immaturity of intestinal innate immune function of the premature gut, characterized by over-exuberant interleukin-8 responses of intestinal epithelial cells to lipopolysaccharide, is a major factor.

Chorioamnionitis

Infection of the placental tissues and amniotic fluid as a result of ascending infection by bacteria that can be present in the vagina, such as Escherichia coli and group B Streptococcus. Chorioamnionitis can cause maternal bacteremia and can lead to pre-term delivery and neonatal infection.

Bronchopulmonary dysplasia

(BPD). A disease of the respiratory system that is most frequent in pre-term infants, and is characterized by inflammation and scarring of the lungs resulting in abnormal development of lung tissue. Recent evidence shows that Toll-like-receptor-mediated inflammatory responses can reproduce the pulmonary histological findings characteristic of BPD, raising the possibility that innate immune responses may contribute to its pathophysiology.

Cerebral palsy

A disorder of posture and movement due to damage to motor areas of the brain, often associated with a history of perinatal complications. The pathophysiology of cerebral palsy is still under investigation, but recent evidence indicates that a combination of hypoxic–ischemic insult and Toll-like-receptor-mediated inflammation can synergistically trigger neurodegeneration.

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Levy, O. Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat Rev Immunol 7, 379–390 (2007). https://doi.org/10.1038/nri2075

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