The future concept of innate cellular immune responses in newborns

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. Innate immunity assures the first line of defense against pathogenic microorganisms. Innate immune responses induced by bacteria, fungi, or viral replication are triggered by granulocytes, monocytes, macrophages, dentritic cells, and natural killer cells. Neonatal deficiency of innate cellular immunity includes a decreased production of interferons, IL-12/IL-23, and IL-18, and other proinflammatory cytokines, an impaired type-1 response of macrophages to IFN-gamma, the most potent macrophage-activating agent in vivo, and to lipopolysaccharide, the primary constituent of the outer membrane of Gram-negative bacteria. An increasing body of evidence suggests impaired responses of neonatal monocytes and macrophages to multiple TLR ligands. Innate immunity in newborns what knowledge might be used to prevent and treat infection in this vulnerable population.

Neonates and infants are unduly susceptible to a wide variety of infections (1). This increased susceptibility is thought to reflect deficiencies in both innate and adaptive immunity compared with adults. The innate immune system is central to all immunity because it decodes the nature of microbial threats and then produces mediators to help provide appropriate immediate protection and determine the quality and magnitude of the subsequent adaptive immune response. However, the extent to which innate immune responses to microbial stimuli differ between adults and neonates, and the contribution of such differences to the neonate’s increased susceptibility, are still only incompletely characterized.

In general, neonatal cord blood mononuclear cells have been found to produce less IL-1α, IL-1β, TNF-α, IL-18, and IL-12p70 but equal or greater IL-6 or IL-10 compared with adult cells in response to the TLR4 ligand LPS and some other TLR ligands.  However, strikingly different and even contradictory results have been reported. For example, neonatal cells have been reported to produce significantly less, as much, or even more TNF-α as adults. It is difficult to reconcile these discordant findings because the information was accrued in an incremental fashion, through studies differing in experimental design, assessing either one or only a few cytokines produced in response to a single or only a limited set of TLR ligands (often of uncertain purity), and under conditions in which the contribution of specific cell types was not addressed, or using cells whose phenotype and function were conditioned by prior culture in vitro.

A more complete picture of how neonatal and adult innate immune responses differ could be obtained through a comprehensive side-by-side analysis of responses to well-defined ligands for TLRs, done using approaches that allow to the extent possible responses attributable to conventional dendritic cells (cDCs),3 plasmacytoid DCs (pDCs), and monocytes to be identified using cells studied directly ex vivo. Conducting such a study in a sample set large enough to allow a well-powered statistical analysis, we confirmed and extended findings suggesting that the neonatal as compared with the adult innate immune responses to TLR stimulation were not so much deficient in quantity, but differed in quality.

Innate cellular immunity in human neonates, with respect to selected aspects of immune functions that may be related to increased susceptibility to infections. Components of TLR signaling and the immune consequence that may result from neonatal deficiencies will be highlighted. A better understanding of innate immunity can make the development of techniques possible by which physicians more accurately tailor prevention and treatment of neonatal infections.

Neonatal innate TLR-mediated responses

The human neonate and infant are unduly susceptible to infection with a wide variety of microbes. This susceptibility is thought to reflect differences from adults in innate and adaptive immunity, but the nature of these differences is incompletely characterized. The innate immune response directs the subsequent adaptive immune response after integrating information from TLRs and other environmental sensors. We set out to provide a comprehensive analysis defining differences in response to TLR ligation between human neonates and adults. In response to most TLR ligands, neonatal innate immune cells, including monocytes and conventional and plasmacytoid dendritic cells produced less IL-12p70 and IFN-alpha (and consequently induced less IFN-gamma), moderately less TNF-alpha, but as much or even more IL-1beta, IL-6, IL-23, and IL-10 than adult cells.

At the single-cell level, neonatal innate cells generally were less capable of producing multiple cytokines simultaneously, i.e., were less polyfunctional. Overall, our data suggest a robust if not enhanced capacity of the neonate vs the adult white-blood cell TLR-mediated response to support Th17- and Th2-type immunity, which promotes defense against extracellular pathogens, but a reduced capacity to support Th1-type responses, which promote defense against intracellular pathogens.

Cytokine responses to LPS and other Toll-like receptor agonists.

Human newborns are at increased risk of microbial invasion and display diminished responses to many vaccines indicating a functional immaturity of the immune system at birth. Such altered immune reactivity may reflect the demands of in utero existence, including the need to avoid potentially harmful inflammatory immune reactions. Despite normal basal expression of Toll-like receptors and membrane CD14, innate immune responses of neonatal mononuclear cells to lipopolysaccharide are characterized by markedly reduced release of the pro-inflammatory Th1-polarizing cytokines TNF-alpha and interferon-gamma with relative preservation of anti-inflammatory Th2-polarizing cytokines.

Differences between newborns and adults with respect to TLR-induced TNF-alpha release extend to a range of TLR agonists, including bacterial lipopeptides, and are due to differences in soluble factors present in blood plasma. Soluble factors in neonatal blood plasma suppress TLR-induced TNF-alpha release from monocytes and efforts to identify and characterize these inhibitors are on-going. Such altered immunity to TLR agonists is likely to alter both innate and adaptive immune responses in newborns profoundly. Definition of the mechanisms underlying distinct neonatal immunity promises to identify novel ways to prevent and treat infection in this relatively high-risk population.

Neonatal innate immunity in allergy development.

The neonate is born with a distinct immune system that is biased against the production of T-helper cell 1 (Th1) cytokines. Birth imposes a great challenge on the neonatal immune system, which is confronted with an outside world rich in foreign antigens. Exposure to these antigens shapes the developing neonatal immune system. Inducing Th-1 or Th-2 polarized responses that may extend beyond the neonatal age and counteract or promote allergic sensitization. This review describes how engagement of the innate immune system might contribute to the development of allergy in children.

Dose, site and timing of allergen exposure are likely to modulate the innate immune response, polarizing the maturing neonatal immune system towards Th1 or Th2-type responses, thereby protecting from or predisposing to asthma and allergies. Modulation of neonatal innate immune responses may be a novel approach to prevent asthma and allergies.

Neonatal interleukin-12 and allergen-specific immune responses

A reduced capacity of antigen presenting cells (APC) to provide pro-T helper 1 (Th1) signals, such as IL-12, to T cells during early life may be implicated in the development of T helper 2 (Th2)-mediated allergic disease. The relationships between the capacity for IL-12 responses in the neonatal period and atopic risk (family allergy), in vitro T cell responses to allergens, and the subsequent development of allergic disease at 6 years.

Reduced APC IL-12 production in the perinatal period was associated with reduced T cell activation (lymphoproliferation), stronger neonatal Th2 responses, and weaker Th1 responses to allergen in the postnatal period. This supports the notion that variations in APC function in early life may contribute to altered allergen-specific cytokine responses associated with later allergy.

The role of innate immunity in the pathogenesis of asthma.

The increase in prevalence of allergic diseases, in particular of asthma, poses great difficulties to healthcare institutions in industrialized countries. According to the hygiene hypothesis, a linkage exists between exposure towards microbes in early childhood and the development of allergies; however, the original view that stimulation of the host’s immune system by microbes exclusively protects against the development of allergies and asthma has been challenged by recent studies.

Recent studies in mice revealed that infection with a series of microbes in the context of allergen exposure enhances antigen sensitization. Furthermore, in studies using purified toll-like receptor ligands and live bacteria, innate immune activation via MyD88 has been shown to be a causative factor in sensitization. The view that innate immune activation, under circumstances yet to be elucidated, may be a causative factor for the development of allergies is backed by epidemiologic data showing a protective effect of genetic variants, which impair toll-like receptor signaling. Recent studies in mice suggest that innate immune stimulation via microbes or their compounds, in a dose and time-dependent manner, can cause allergen sensitization, and this notion has lately been supported by epidemiologic data.

Type 2 innate immune responses and the natural helper cell.

The T helper type 2 (Th2) inflammatory responses are characterized by the recruitment and activation of mast cells, basophils and eosinophils, and goblet cell hyperplasia in airway and intestinal epithelia.These immune responses are induced against helminths invading cutaneous or mucosal sites and function as protective immunity against those pathogens. Interestingly, Th2 cytokines are induced soon after helminth infection and before pathogen-specific Th2 cells are established. Although the final expulsion of helminths usually requires Th2-mediated immunity, an early Th2-type innate immune response is important in the restriction of helminth invasion before the adaptive immune response initiates. Similar Th2 responses play important roles in the pathophysiology of allergic diseases such as asthma and allergic diarrhoea.

Studies on the relatively new cytokines, thymic stromal lymphopoietin (TSLP), interleukin-25 (IL-25) and IL-33, revealed that epithelial cells play important roles in inducing Th2 immune responses against allergens and helminths.Various types of epithelial cells produce TSLP, IL-25 and IL-33 in response to allergens and helminths.For example, house dust mites stimulate lung epithelial cells through Toll-like receptor 4.

Interleukin-4 is a key cytokine that triggers antigen-specific Th2 responses. Although the initial source of IL-4 is still unknown, CD1d-restricted natural killer T (NKT) cells,mast cells and basophilsare able to produce IL-4 upon stimulation. Basophils produce IL-4 and accumulate in the liver and lung after Nippostrongylusbrasiliensis infection. Many allergens are associated with cysteine protease activities. Incubation of basophils with one of cysteine proteases, papain, leads to the production of IL-4. Intriguingly, basophils are transiently recruited to the draining lymph node where Th2 cells are predominantly induced after Trichurismuris and Shistosoma mansoni infectionbut it is controversial whether basophils present antigens to T cells.

Although the antigen-specific Th2 response plays a central role in protective immunity against helminths and antigen-specific allergic responses, accumulating evidence indicates the involvement of innate immune cells in the onset of Th2 responses. Administration of IL-25 and IL-33 induces rapid production of Th2 cytokines such as IL-5 and IL-13 in mice independently of T or B cells.Recent studies identified a previously unrecognized cell population(s) capable of producing large amounts of IL-5 and IL-13 in response to IL-25 and IL-33. We discuss here the characteristics and functions of such Th2 cytokine-producing innate cells. In particular, we focus on natural helper (NH) cells found in fat-associated lymphoid clusters (FALCs) present in visceral adipose tissue

The T helper type 2 (Th2) immune response, characterized by the production of interleukin-4 (IL-4), IL-5 and IL-13, is a critical immune response against helminths invading cutaneous or mucosal sites. It also plays a critical role in the pathophysiology of allergic diseases such as asthma and allergic diarrhoea. The Th2 cytokines are induced soon after helminth infection, even before a pathogen-specific adaptive immune response is established. Recent studies have shed light on such innate Th2 cytokine production by formerly uncharacterized innate immune cells such as natural helper cells capable of producing Th2 cytokines in response to IL-25 and IL-33 independently of adaptive immune responses. These cells produce large amounts of Th2 cytokines, most notably IL-5 and IL-13, leading to eosinophilia and goblet cell hyperplasia. The mechanisms of innate production of Th2 cytokines in host immune responses against helminth infection as well as allergic immune responses and the similarities and differences between recently identified Th2-cytokine producing cells.

Impairment of T helper and T regulatory cell responses at birth.

There is strong evidence that reduced exposures to microbial compounds triggering innate immune responses early in life are critical for the development of allergic illnesses. The underlying mechanisms remain unknown, but will include T-cell responses either along T helper type 1 (Th1)/Th2 pathways or via T regulatory and Th17 cells. Yet, little is known about innate immune responses and the function of T regulatory/Th17 cells at birth. The aim of this study was to investigate T-cell responses to innate (Lipid A/LpA, peptidoglycan/Ppg) and adaptive (phytohemagglutinin) stimuli at birth and to compare these findings with adult immune responses.

Proliferation and cytokine responses to innate stimuli were less mature at birth than in adulthood. T regulatory and Th17 cells were less expressed in cord than in adult blood. Mitogen-induced suppression of T-regulatory cells on T-effector cell function was less efficient in cord than in adult blood. At both ages, Th17 cells were correlated with Th1/Th2 cells, but not with interleukin-10 secretion following innate-stimulation.

Innate immune responses are immature at birth. Furthermore, the function of T regulatory and Th17 cells is impaired. Th17 cells in association with Th1/Th2 cells may be involved in early immuno-modulation. Potent innate immune stimulation early in life can potentially contribute to protection from allergic diseases.

Impairment of T-regulatory cells in cord blood of atopic mothers.

Maternal atopy is a strong predictor for the development of childhood allergic diseases. The underlying mechanisms are ill defined, yet regulatory T (Treg) and T(H)17 cells may play a key role potentially shaping the early immune system toward a proallergic or antiallergic immune regulation.

Cord blood from offspring of atopic mothers showed fewer innate-induced Treg cells (CD4(+)CD25(+)high), lower mRNA expression of associated markers (glucocorticoid-induced tumor necrosis factor receptor-related protein/lymphocyte activation gene 3), and a trend toward lower Forkhead box transcription factor 3 (Foxp3) expression. Treg cell function was impaired in mitogen-induced suppression of T effector cells in cord blood of offspring from atopic mothers . Furthermore, IL-10 and IFN-gamma secretion were decreased in innate-stimulated cord blood of offspring from atopic mothers . Innate-induced IL-17 was independent of maternal atopy and highly correlated with IL-13 secretion. In offspring of atopic mothers, Treg cell numbers, expression, and function were impaired at birth. T(H)17 cells were correlated with T(H)2 cells, independently of maternal atopy.


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  • Dr Narulita Dewi SpKFR, Physical Medicine & Rehabilitation
  • Dr Widodo Judarwanto SpA, Pediatrician
  • Fisioterapis

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Dr Widodo Judarwanto, pediatrician email :, Curiculum Vitae

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