Cord blood immune status: predicting health or allergy?


It has become more evident that immune status at birth may regulatory T cell (Treg) function or low numbers (18–20)
be an intrinsic feature of a newborn child that predisposes to were shown to be associated with later allergy development.
the development of allergic disease (1). By now, mainly three Smith et al. (18) demonstrated that children with egg allergy
predictive factors for later allergy development are evident: at the age of one had reduced neonatal regulatory T cell
cord blood cytokine production, regulatory T cell number/ function. In our LINA study, reduced maternal Treg fre-
function, and toll-like receptor (TLR) expression/function. quencies correlated with increased total IgE concentrations in
A characteristic feature of atopy is a T helper (Th) 2 cord blood (20), and, furthermore, it was evident that chil-
skewed immune response and its related cytokines IL-4, IL-5, dren developing atopic dermatitis during the first year of life
and IL-13, which are involved in the induction and mainte- had reduced Treg numbers at birth (19). Cord blood from
nance of the IgE synthesis. The importance of Th1 cytokines children born to atopic mothers was characterized by lower
like interferon-c (IFN-c) in atopy development is to antago- numbers and impaired Treg cell function (21).
nize the effect of Th2 cytokines. Although published data are The defective neonatal T, and in particular IFN-c
not completely consistent in this regard, the most common response, seems to be a result of the dysfunction of antigen-
abnormality detected early in life among children, who go on presenting cells and an altered innate immune responses (22).
to have an allergic disease, includes diminished IFN-c levels For instance, cord blood T cells are able to produce mark-
(2–4) and altered Th2 responses that are followed by skewing edly increased amounts of IFN-c when co-cultured with
of immune responses toward a Th2 phenotype (5–7). Hagen- adult macrophages. Vice versa neonatal macrophages can
dorens and colleagues (8) found that a significantly lower inhibit the IFN-c response of adult T cells (23). Moreover,
percentage of IFN-c-producing stimulated cord blood CD4+ when cultured with interleukin 12 (IL-12), a cytokine secreted
T cells was present in children, who developed an atopic der- by macrophages and other antigen-presenting cells that stim-
matitis during the first year of life. Our own data from the ulates T cells, neonatal T cells are capable of producing large
LISA study corroborate these findings: children with reduced amounts of IFN-c (24). Interleukin-12 and other macrophage
frequencies of IFN-c-producing CD4+ T cells in the cord or dendritic cell-derived cytokines are activated via toll-like
blood had a higher risk of developing atopic dermatitis, receptors (TLRs), known as pattern-recognition receptors
whereas a high percentage of IL-4-producing T cells in cord critically involved in innate immune responses. Thus, devia-
blood was associated with an increased risk for atopic derma- tions in innate immune responses can also contribute to aller-
titis during the first two years of life (7). Besides Th1/Th2 gic predisposition (25,26). A reduced expression of TLR5
cytokines, recent publications show the involvement of high and TLR9 was found in the cord blood of children who later
levels of cord blood Th2-associated chemokines CCL17 and developed an atopic dermatitis (27). Furthermore, children
CCL22 in the prediction of atopic dermatitis, allergic sensiti- with allergies have shown exaggerated innate cytokine pro-
zation, and asthma (9–11). duction at birth following activation by TLR ligands (28).
Although different studies have provided evidence of a pre- However, whether increased or rather decreased expression/
dictive cord blood cytokine value corresponding to the devel- function of TLRs may be the basis of allergy development is
opment of allergic diseases, other birth cohort studies failed still a matter of debate.
to show such associations (12–15). The apparent discrepancy Besides the genetic background (29–31), it is undoubtedly
in the reported results might be explained by differences in that environmental exposure also affects the prenatal devel-
the subject population, the length of follow-up, and more opment of immune cells, hence the allergic predisposition
importantly, the mode of cytokine measurement. Mainly cord (32–34). Microbial products that stimulate innate immune
blood cytokines measured at the cellular level revealed a cor- responses via TLRs can modulate the allergic propensity
relation to atopy, indicating that the source of cytokines is toward protective effects (28,35,36). On the other hand,
important in the clarification of allergy development (16). maternal chemical exposure during pregnancy can contribute
Certainly, by measuring protein concentrations in the super- to reduced Th1 responses, therefore increasing the risk of
natant of cord blood cell cultures, cytokines from additional developing allergies (37,38). However, the underlying mecha-
sources than T helper cells are also gathered that may hide/ nisms of these additional environmental impacts are fare
cover possible associations (17). away from being understood.
Recently, there has been emerging evidence that allergic Collectively, these data suggest a complex interplay of
disease or sensitization is also associated to regulatory T Th1/Th2/Treg as well as factors of the innate immune
cells. These cells downregulate Th2 cells by suppressing their response in relationship to immune maturation and the devel-
activity and proliferation. Consequently, attenuated neonatal opment of allergic diseases. An impaired Th1 and Treg func-

Allergy 67 (2012) 445–448 © 2012 John Wiley & Sons A/S 445

open questions remain. Furthermore. The production of IFN-c. FAS Allergy Y Y Y Y Y Y Y Y Y IgE Figure 1 Cord blood immune status in children prone for allergy – cell differentiation. expressed genes in unstimulated CD4+ T cells of allergic A study by Martino et al. which subsequently the fetal stage. down-regulated genes senting cell. 1). the group data of other studies reporting a Th2 bias in allergic chil- adopted a genome-wide approach measuring the gene dren (45–47). a pattern of different factors. Because scription (39–41). NFjB2. Diminished Th1/Treg activity or numbers contrib- known predictive parameters for allergy development. the developing immune system is influenced by increases the risk to develop allergic responses. NFKB2. toll-like in T cell signaling pathways (RELB. These data with other studies. it is still unclear how the different regulated gene early allergic outcomes (IgE-mediated food allergy in the sets at birth and age one are linked to the identified signaling first year of life) were compared with the ones from children pathways. impaired lymphoproliferation in allergic children may be ment by age 2 was not found to be associated with variations explained by the lower expression of these genes. also press Th2 responses in the early postnatal period. In addition. (43) recently published in infants included TCR pathway. at age one. and FAS. including molecular reflecting the immaturity of T cell responsiveness in that and cellular markers instead of single factors. Treg. LIF. LIF. T helper cell. At birth. the observed increase in IFN-c response (42). expression profile of stimulated cord blood CD4+ T cells. and IL-10 responsible for priming toward an allergic reactivity. IL-5. data from children with instance. By 12 month of age. Martino et al. antigen-pre- maternal and environmental factors. who remained nonallergic. At birth. might be group. In line in methylation patterns in cord blood T cells (40). The microarray analyses revealed that (Fig. treatment of cord blood T cells of the fact that the proliferative response of T cells depends with a demethylating agent did not lead to a significant on signals through the NF-jB/Rel complex. However. impaired innate immune signals may contribute to altered T helper tion at birth may contribute to a reduced capacity to sup. responses were increased in the allergic group. However. Furthermore. These findings clearly confirm the induced downstream of the T cell receptor. in a case–control study.44). factors. TLR. Th2 as well as Th1 cytokine relevant. To characterize the signaling cascades differentiation GATA3. including RELB. which result in impaired T cell function. genes belonging to the NF-jB family were responsible for the strong suppression of IFN-c gene tran. to predict allergic outcomes from cord blood-derived atopy at age one compared with the nonallergic group. regulatory T cell. IL-13. However. the allergen-specific responses to ovalbumin were activation and differentiation than single factors seem to be compared. APC. Par- sites in the IFN-c promoter in neonates as causative event ticularly. LIF. between these two rather imbalanced regulatory networks involved in T cell groups. For Thereby. atopy develop. Already at ute to enhanced generation of Th2 cells. increasing at molecularly level differences between the two children the likelihood for the development of an allergic reactivity groups were observed. differentially mechanisms. In spite of the recent progress. NFKB2. involved. FAS) in addition to receptors. anti-CD3 antibody-induced gene responses of isolated CD4+ Recent studies have attributed hypermethylation of CpG T cells were markedly reduced in the allergic children. There- was significantly lower at birth in children developing an fore.Editorial Genetic background Exposure Maternal allergy/ immune regulation Cord blood immune status Th1 APC 2 Th2 TLR IL-1 Treg ?? ? down-regulated genes in T cell signaling pathways RELB. the MAL T cell differentia- Allergy provided a deeper insight into the regulatory cascade tion pathway and as expected the master regulator of Th2 in neonatal T cells. Th. a deeper understanding of the 446 Allergy 67 (2012) 445–448 © 2012 John Wiley & Sons A/S . (43) demonstrated that the suggest that abnormalities in neonatal T cell function are differences in gene expression detected at birth are only regulated at the transcriptional level by so far unknown transient (28.

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