Evidence for age-related and individual-specific changes in DNA methylation profile of mononuclear cells during early immune development in humans.

Environment induced epigenetic effects on gene expression in early life are likely to play important roles in mediating the risk of several immune-related diseases. In order to investigate this fully, it is essential to first document temporal changes in epigenetic profile in disease-free individuals as a prelude to defining environmentally mediated changes. Mononuclear cells (MC) were collected longitudinally from a small number of females at birth, 1 year, 2.5 years and 5 years of age and examined for changes in genome-scale DNA methylation profiles using the Illumina Infinium HumanMethylation27 BeadChip array platform. MC from two males were included for comparative purposes. Flow cytometry was used to define MC cell populations in each sample in order to exclude this as the major driver of epigenetic change. The data underwent quality control and normalization within the R programming environment. Unsupervised hierarchical clustering of samples clearly delineated neonatal MC from all other ages. A further clear distinction was observed between 1 year and 5 year samples, with 2.5 year samples showing a mixed distribution between the 1 and 5 year groups. Gene ontology of probes significantly variable over the neonatal period revealed methylation changes in genes associated with cell surface receptor and signal transduction events. In the postnatal period, methylation changes were mostly associated with the development of effector immune responses and homeostasis. Unlike all other chromosomes tested, a predominantly genetic effect was identified as controlling maintenance of X-chromosome methylation profile in females, largely refractory to change over time. This data suggests that the primary driver of neonatal epigenome is determined in utero, whilst postnatally, multiple genetic and environmental factors are implicated in the development of MC epigenetic profile, particularly between the ages of 1-5 years, when the highest level of inter individual variation is apparent. This supports a model for differential sensitivity of specific individuals to disruption in the developing epigenome during the first years of life. Further studies are now needed to examine evolving epigenetic variations in specific cell populations in relation to environmental exposures, immune phenotype and subsequent disease susceptibility.

Differences in innate immune function between allergic and nonallergic children: new insights into immune ontogeny.

BACKGROUND: Microbial products are of central interest in the modulation of allergic propensity. OBJECTIVE: We sought to explore whether allergic children show differences in microbial Toll-like receptor (TLR)-mediated responses over their first 5 years of life. METHODS: Mononuclear cells isolated from 35 allergic and 35 nonallergic children at birth and 1, 2.5, and 5 years of age were stimulated with TLR2-TLR9 ligands to study innate immune function and with allergens or mitogen to assess adaptive T-cell responses. Cytokine production was measured by using Luminex multiplexing technology. RESULTS: Nonallergic children show progressive and significant age-related increases in innate cytokine responses (IL-1ß, IL-6, TNF-α, and IL-10) to virtually all TLR ligands. This innate maturation corresponds with a parallel increase in adaptive T(H)1 (IFN-γ) responses to allergens and mitogens. In contrast, allergic children show exaggerated innate responses at birth (P < .01) but a relative decrease with age thereafter, so that by age 5 years, TLR responses are attenuated compared with those seen in nonallergic subjects (P < .05). This early hyperresponsiveness in allergic subjects fails to translate to a corresponding maturation of T(H)1 function, which remains attenuated relative to that seen in nonallergic subjects but is associated with a characteristic age-dependent increase in allergen-specific T(H)2 responses (P < .01). CONCLUSION: Our findings suggest significant differences in the developmental trajectory of innate immune function in children with allergic disease that might contribute to the recognized differences in postnatal adaptive T-cell immunity.

Progress in understanding postnatal immune dysregulation in allergic disease.

It is increasingly unlikely that allergic disease is the result of isolated immune defects, but rather the result of altered gene activation patterns in intricate immune networks. This appears to be driven by complex environmental changes, including microbial exposure, diet, and pollutants, which are known to modify immune development in early life, beginning in pregnancy. The first models showing possible epigenetic mechanisms for these effects are beginning to emerge. This review focuses on recent advances in our knowledge of the consequent effects on postnatal immune development, highlighting recognized differences in children with and without allergies. Although we characterized essential differences in longitudinal T-cell development more than 10 years ago, new technologies using whole genome microarrays are now being used to examine for differential gene expression in T cells from individuals with allergies. We have also recently performed the first comprehensive study of the longitudinal development of innate toll-like receptor responses in children with and without allergies during the first 5 years of life, identifying significant differences in these pathways as well. Finally, although there are preliminary differences in regulatory T-cell function at birth, longitudinal studies are limited by difficulties isolating these cells in sufficient numbers from young children for functional studies. Thymic tissue isolated during cardiac surgery is a rich source of regulatory T-cell function in children and may provide further avenues for assessing differences in maturation of these cells in individuals with allergies. To further understand the pathogenesis of these altered patterns of immune response, future research needs to encompass the complexity of gene-environmental interactions, which confer individual susceptibility to environmental exposures.

Thymic indoleamine 2,3-dioxygenase-positive eosinophils in young children: potential role in maturation of the naive immune system.

Eosinophils expressing indoleamine 2, 3-dioxygenase (IDO) may contribute to T-helper cell (Th)2 predominance. To characterize human thymus IDO+ eosinophil ontogeny relative to Th2 regulatory gene expression, we processed surgically obtained thymi from 22 children (age: 7 days to 12 years) for immunohistochemistry and molecular analysis, and measured cytokine and kynurenine levels in tissue homogenates. Luna+ eosinophils ( approximately 2% of total thymic cells) decreased in number with age (P = 0.02) and were IDO+. Thymic IDO immunoreactivity (P = 0.01) and kynurenine concentration (P = 0.01) decreased with age as well. In addition, constitutively-expressed interleukin (IL)-5 and IL-13 in thymus supernatants was highest in youngest children. Eosinophil numbers correlated positively with expression of the Th2 cytokines IL-5, IL-13 (r = 0.44, P = 0.002), and IL-4 (r = 0.46, P = 0.005), transcription factor signal transducer and activator of transcription-6 (r = 0.68, P = 0.001), and the chemokine receptor, CCR3 (r = 0.17, P = 0.04), but negatively with IL-17 mRNA (r = -0.57, P = 0.02) and toll-like receptor 4 expression (r = -0.74, P = 0.002). Taken together, these results suggest that functional thymic IDO+ eosinophils during human infant life may have an immunomodulatory role in Th2 immune responses.

Algorithmic models to predict allergic disease using multiple neonatal markers.

Childhood blindness and visual impairment are as important and perhaps more devastating and disabling than adult onset blindness, because of the long span of life still remaining to be lived. Refractive errors and more particularly myopia, place a substantial burden on the individual and society. School-age children constitute a particularly vulnerable group where uncorrected refractive errors may have a dramatic impact on learning capability and educational potential. This article provides an overview of school eye screening from the perspective of National Program for Control of Blindness (NPCB), Government of India; and challenges, future directions and thrust area envisaged under the program for amelioration of childhood blindness.