Maturation of the Immune System in Newborn and Children

Development of the immune response in childhood is a dynamic process initiated within the fetal period and expanding in time through months and even years of child’s life.  Physiological phenomenon of immune system maturation, type and timing of activating allergens, and microbial antigens in conjunction with genetic predisposition to allergy are of crucial importance in determination of the proallergic or tolerogenic phenotype.

Physiological phenomenon of maturation of the immune system, initiated within the fetal period, is dynamic in its character and is expanding in time through the first months and even years of child’s life. Hence, within the neonatal period, infancy and early childhood dysfunction of numerous components of the immune system is observed.

The maintenance of pregnancy requires suppression of the maternal immune system which would naturally recognize the developing fetus as an allograft and seek to destroy it by mounting a Th1 regulated cytotoxic immune response. During pregnancy a range of soluble factors are produced by the placenta which switch maternal immune regulation towards a protective Th2 phenotype. These factors also influence the developing fetal immune system and all newborns initially have an immunological milieu skewed towards Th2 immunity. Vaccination during the neonatal period must therefore overcome the dual challenge of the inhibitory effect of maternally derived antibody and this natural Th2 regulatory environment. One means of overcoming these obstacles is by the use of adjuvant systems that can redirect the neonatal immune response towards an appropriate Th1 regulated reaction that affords protection from infectious disease. In this overview, experiments are described in which viral antigens incorporated into immune stimulatory complexes (ISCOMs) are able to induce immune responses with balanced Th1 and Th2 regulation in neonatal mice, as evidenced by the nature of the IgG subclass response and cytokine profile, and the induction of cytotoxic lymphocytes. ISCOM adjuvanted vaccines are able to induce similar protective immunity in the newborn of larger animal species including cattle, horses and dogs.

Within the neonatal period, considerable immaturity characterizes the system of monocytes-macrophages. It consists in decreased expression of costimulatory molecules and diminished ability to differentiation into dendritic cells as well as weak production of IL-12 by monocytes . Macrophages exhibit diminished response to IFNγ, decreased activity upon phagocytosis , and impairment of intracellular killing .

In neonates, the immaturity concerns function of dendritic cells. This consists in downregulated expression of costimulatory molecules by myeloid (mDC) and of plasmacytoid (pDC)dendritic cells, defective maturation and synthesis of cytokines—IFNγ and IL-12 as the response to signaling pathways downstream of Toll-like receptors engagement, particularly TLR4 and TLR9 and CD40 molecule as well as impaired ability to stimulate the immune response by pDC. The proposed mechanisms to explain the dysfunction of neonatal DC comprise intrinsic immaturity, defective interaction between dendritic cells and T lymphocytes as well as modulatory effect of natural regulatory T cells (nTreg). These cells, playing an important role during pregnancy and maintaining maternal tolerance to the fetus, are present in high numbers in neonates and are critical in maintaining homeostasis, immunological tolerance, and preventing autoimmunity. Neonatal nTregs exert their immunosuppressive function by the mechanism of interaction between molecules CTLA-4 and CD80/CD86 on antigen-presenting cells and by secretion of L-10 and TGFβ .

Functional alterations of neonatal antigen-presenting cells may in turn lead to secondary defects of adaptive T-cell response. In neonates occurs a T-cell functional deficiency manifesting as downregulated expression of TCR/CD3 complex, adhesion molecules and CD40 ligand (CD40L, CD154), impaired cytotoxic activity of CD8+ T cells as well as decreased cytokine synthesis. Expression of a range of cytokines playing an essential role in the immune response, such as IL-4, IL-5, IFNγ, TNFα, and IL-12, is a dynamic process and their production increases with child’s age. Hodge et al. demonstrated a diminished number of neonatal T lymph cells and NK cells exhibiting expression of β chain of the IL-2 receptor. Moreover, the production level of cytokines such as IL-1α, IL-1β, and TNFα was lower compared to adults, pointing to decreased capacity to mount effective inflammatory response. On the contrary, the level and kinetics of expression of other functional molecules—CD71, HLA-DR; and CD152—were comparable to that in adults .

Predominance of the Th2-dependent immune response prevailing within the fetal period and expanding through the neonatal period and infancy may be among others as a result of exerted activity of regulatory T cells, suppressing the proinflammatory Th1-mediated response. Moreover, mechanisms of the innate immune response profiling development of the adaptive response towards advantageous Th1-or Th2-mediated immunity contribute to the predisposition or to the protection from asthma and allergy. Dose, settings, and timing of exposure to antigens are of crucial importance in modulating the immune response profile within the child’s early life.

Immaturity of the effector mechanisms and suppressive activity of the transplacentally transmitted maternal IgG antibodies contribute to the consequent deficiency of specific humoral response . In neonates, rapid increase of the immunoglobulin M active in primary immune response to antigens, relatively high concentration of IgG of maternal origin and weak production of child’s own immunoglobulins IgG and IgA manifest as dysgammaglobulinemia and reflect distinct dynamics of different isotype synthesis. In infants between the second and sixth months of life hypogammaglobulinemia continues as a result of still weak production of own and the breakdown of maternal immunoglobulin G. Delayed maturation of the humoral response manifests frequently as transient hypogammaglobulinemia of infancy (THI), which abates typically until the end of the second year of life, but may be prolonged even up to the fifth or sixth year of life  and hitherto the evaluation, if the immune defect in a child is transient or is signaling a permanent primary immune deficiency, may be difficult. In the recent study of Keles et al. , evaluating clinical and immunological features of THI children, asthma was the leading health problem present in 52% of patients.

Changes in intracellular TH1/TH2 cytokine production, immunoproliferative T lymphocyte response and natural killer cell activity in newborns and children

The percentage of CD4+ lymphocytes was significantly higher in newborns while CD8+ cells were higher at older ages, with a resulting gradual decline of the CD4+/CD8+ ratio. The percentage of IL-2-producing CD4+ and CD8+ cells was higher in all newborn groups than in children and adults, while the percentage of IL-4-producing cells was higher for CD8+ and lower for CD4+ cells in cord blood than in children and adults. Neonates had substantially lower percentages of CD4+ and CD8+ IFN-gamma-producing cells. A significant negative correlation was observed between gestational age and IFN-gamma-CD4+-, IL-2-CD8+-, and IL-10- CD4+-producing cells. In addition, a positive correlation was found between gestational age and IL-10-CD8+-producing cells. Percentages of CD4+/CD45RA+ cells were higher and CD4+/CD45RO+ percentages were lower in newborns than in children and adults. NKC activity in infants was significantly correlated with gestational age and significantly impaired compared to children and adults

The gradual development of immunity during gestation and show significant immaturity of cellular immune response at birth. The reduction of NKC activity, the lower proliferative response of T cells, the reduced cytotoxic response and a dysregulated cytokine production may contribute to the neonatal increased risk of infection and to the low incidence of graft-versus-host disease after cord blood transplantation.

Imbalanced cytokine secretion in newborns.

In adults, a balance between Th1 and Th2 cytokine networks has been proposed to be associated with a healthy status. Newborn babies are reported to express Th2-type immune reactions. Further, the impaired protection of newborn babies against infections has been attributed to a deficient secretion of interferon gamma (IFN-gamma) and interleukin-10 (IL-10). Using IFN-gamma and IL-10 as surrogate markers of Th1 and Th2 orientation, we compared the patterns of IFN-gamma and IL-10 secretion by peripheral blood mononuclear cells between 52 healthy newborns and 35 adults. The baseline secretion of IFN-gamma in adults was similar to that of newborns. The lipopolysaccharide-stimulated IFN-gamma secretion was higher in newborns than in adults, whereas the concanavalin-A-stimulated IFN-gamma secretion was higher in adults. The unstimulated and stimulated IL-10 secretion was significantly lower in newborns than in adults. Using a threshold level of 1,000 pg/ml, we classified neonates and adults on the basis of their stimulated IL-10 and IFN-gamma secretion. Four different groups were identified: IL-10-oriented secretion, IFN-gamma- oriented secretion, balanced high secretion, and balanced low secretion. Only 25% of the neonates had a high IL-10 and a high IFN-gamma secretion as compared with 77% of the adults. Eight percent of the newborns, but none of the adults, had a low secretion of both cytokines. Thirty-six percent of the neonates, but only 5% of the adults, had a high IL-10 and a low IFN-gamma secretion. Thirty-one percent of the neonates and 18% of the adults had a high IFN-gamma secretion, but a low IL-10 secretion. Neonates have an immature IL-10 and IFN-gamma response as compared with adults. However, individual neonates may have a mature cytokine secretion, whereas others may have a Th1- or a Th2-directed immune response.

References

  • Velilla PA, Rugeles MT, Chougnet CA. Defective antigen-presenting cell function in human neonates. Clinical Immunology. 2006;121(3):251–259.
  • Kotiranta-Ainamo A, Rautonen J, Rautonen N. Imbalanced cytokine secretion in newborns. Biology of the Neonate. 2004;85(1):55–60
  • Adkins B. Heterogeneity in the CD4 T cell compartment and the variability of neonatal immune responsiveness. Current Immunology Reviews. 2007;3(3):151–159.
  • Belderbos M, Levy O, Bont L. Neonatal innate immunity in allergy development. Current Opinion in Pediatrics. 2009;21(6):762–769
  • Saito F, Kuwata H, Oiki E, et al. Inefficient phagosome maturation in infant macrophages. Biochemical and Biophysical Research Communications. 2008;375(1):113–118
  • Härtel C, Adam N, Strunk T, Temming P, Müller-Steinhardt M, Schultz C. Cytokine responses correlate differentially with age in infancy and early childhood. Clinical and Experimental Immunology. 2005;142(3):446–453
  • Hodge S, Hodge G, Flower R, Han P. Cord blood leucocyte expression of functionally significant molecules involved in the regulation of cellular immunity. Scandinavian Journal of Immunology. 2001;53(1):72–78
  • Morein B, Blomqvist G, Hu K. Immune responsiveness in the neonatal period. Journal of Comparative Pathology. 2007;137(1):S27–S31
  • Gasparoni A, Ciardelli L, Avanzini A, et al. Age-related changes in intracellular Th1/Th2 cytokine production, immunoproliferative T lymphocyte response and natural killer cell activity in newborns, children and adults. Biology of the Neonate. 2003;84(4):297–303

 

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