Neonatal immunity is immature. Both defective adaptive immunity and innate immunity contribute to the impaired neonatal host defense. Adaptive immune response is impaired at birth due minimal preexisting antigen exposure and due to the impaired functions of effector B and T cells¹⁾. And adaptive immunity is slowly developing system after exposure of microorganisms. In contrast, innate immune response does not require immunologic experience to function well. And innate immunity is the critical first-line barrier of host defense, bridging the interval between exposure to the pathogen and the specific response of the adaptive immune system²⁾. Therefore, a neonate is largely dependent on passively acquired antibodies and defective innate immune responses in the defense against microorganisms³⁾. This review describes the current understanding of neonatal innate immunity and its important receptors, Toll-like receptors (TLRs).

Innate immunity is a natural host defense mechanism that operates effectively without exposure to a microorganism or its antigen. This system is made up of the surface barrier (such as skin and mucous membrane), many cells (such as neutrophil, monocyte, macrophage, dendritic cell, and natural killer cell) and humoral factors (such as complement)⁴⁾. There are limitations of exposure to antigens in utero and defective adaptive immunity in the newborn period, newborn must rely on their innate immune system for protection⁵⁾.

In mammals, a key factor of the innate immune system is a family of TLRs. Toll receptors were originally identified in Drosophila¹¹⁾ and not only function in determination of dorsal-ventral development in the fly embryo but also for antimicrobial function. In adult Drosophila, the Toll receptor recognize microorganism and activate a signaling pathway for induction of antifungal and antibacterial peptides about infection. In 1997, Janeway et al. identified TLR4, a human homologue of Toll receptor¹²⁾. They found out that the activation of TLR4 leads to activation of various inflammatory cytokines such as nuclear factor-κB (NF-κB), IL-1, IL-6, and IL-8. He first suggested the existence of a set of factors which he named pattern recognition receptor (PRR), were capable of detecting pathogen-associated molecular patterns (PAMPs). TLRs act as a main PRR to the various PAMPs of microorganisms¹³⁾. If a pathogen enters to the body, TLR recognizes microorganism PAMPs, and activates the signal pathway by utilization of an adaptor protein and results in activation of the transcription factor NF-κB and expression of inflammatory cytokine genes14,¹⁵⁾. As a result, various cytokines, chemokines and colony stimulating factors produced and these factors have a crucial role in the induction of immune response. Another key role is a link between detection and recognition of microbial pathogens and the activation of the adaptive immune system¹⁶⁾. TLRs are one kind of transmembrane receptors composed of extracellular leucine-rich repeat (LRR) motifs and a cytoplasmic Toll/interleukin-1 receptor (TIR) homology domain. They are expressed on the surface of monocytes, macrophages, dendritic cells and epithelial cells or in the cytoplasm of cells from different tissues. In humans, 10 TLRs have emerged to mediate the activation of innate effector cells. Some of the TLRs reside at the cell surface, and some of them are located in the endoplasmatic reticulum. TLR1, 2, 4, 5 and 6 are present on the cell membrane which recognize mainly microbial membrane components such as lipids, lipoproteins and proteins, whereas TLR3, 7, 8 and 9 appear to be confined to intracellular compartments where they recognize microbial nucleic acid. Each TLR has different ligand recognition and has a distinct function in terms of PAMP recognition and immune response (Table 1).

TLR4 responds to bacterial lipopolysaccharide (LPS), an outer membrance component of Gram-negative bacteria. In addition to LPS, TLR4 is involved in recognition of respiratory syncytial virus fusion proteins¹⁷⁾. TLR2 form a heterodimer with TLR1 or TLR6 recognize various microbial components, such as peptidoglycans, lipoprotein, and lipoteichoic acid from Gram-positive bacteria. TLR5 is involved in the recognition of flagellin protein component of bacterial flagella. TLR5 is expressed and functional to the basolateral site of the epithelial cell in intestine. TLR3, 7, 9 recognize the genomic RNA of virus including respiratory syncytial virus. TLR3 triggers mainly antiviral immune responses¹⁷⁾.

In newborn, basal expression of TLR, the accessory protein, and the adaptor protein are equivalent to adult level, but activation by the TLR appears to be reduced¹⁸⁾. This reduction is age dependent pattern. One study with monocytes from very low birth weight infant (VLBWI) found that decreased surface expression of TLR4, lower mRNA expression of TLR4 and reduced cytokine production after LPS stimulation in gestational age less than 30 weeks¹⁹⁾. Thus, monocytes in premature infants can be considered phenotypically and functionally immature. The other characteristic is impaired TLR4-mediated signaling in LPS-exposed newborn monocytes. Recent study provided evidence that TLR4-mediated, NF-κB dependent transcriptional activation of neonatal monocytes macrophages was depressed²⁰⁾. As a consequence, the defects of TLR activity cause the susceptibility to infection in the neonatal period.

So far, there are little human researches about association with neonatal diseases and TLRs. Most researches are animal based. Among them, the relation with TLRs and neonatal sepsis is most advanced part21-²³⁾. TLR2 and TLR4 expression is enhanced in preterm delivery with chorioamnionitis, and recent studies showed an association between preterm birth and TLR polymorphisms²⁴⁾. Recent study showed polymorphisms in TLR2, TLR5, IL10, and PLA2G2A genes were associated with preterm sepsis²⁵⁾.

The direct role of TLRs in neonatal brain injury is suspected26,²⁷⁾. The strong innate immune response in the central nervous system (CNS) is critical for pathogen elimination and vital to host survival. However, it is evident that chronic or acute dysregulated inflammation in the CNS can cause tissue damage and neurodegeneration. Animal studies described a relation between the TLR4 agonist LPS and brain injury in newborn animals²⁸⁾. In necrotizing enterocolitis (NEC), increased proinflammatory cytokines are found in intestinal samples, suggesting that these mediators play a role in NEC development. One study in a rat NEC model showed overexpression of TLR2, as well as NFκB in intestinal epithelial cells that was correlated with the severity of mucosal damage29,³⁰⁾.

Also, the intestinal expression of TLRs and cytokines precedes histological injury in the experimental NEC³¹⁾. NEC is also associated with increased expression of TLR4 in the intestinal mucosa and physiological stressors such as exposure to LPS and hypoxia. These findings demonstrate a critical role for TLR4 in the development of NEC through effects on enterocyte injury and repair³²⁾.

The innate immune system in neonate is immature which results in increased susceptibility to various infections. On the other hand, newborn innate immunity has a characteristic feature that the balance of Th1 and Th2 type immunity and impairment of TLRs signaling downstream pathway. However, the functional state of the various components of innate immunity in newborn largely unknown and only recently a number of studies have assessed this feature of the innate immune system. Thus, more researches need to include the discovery of neonatal immune mechanism so that prevention and treatment of neonatal infections can more safely be targeted.