Neonatal immune function and inflammatory illnesses in later life: Lessons to be learnt from the developing world?

With the emergence of allergic and autoimmune diseases in populations that have started to transit to a western lifestyle, there has been an increasing interest in the role of environmental factors modulating early immune function. Yet, most of the information concerning neonatal immune function has been derived from studies in westernized countries. We postulate that comparative studies of early immune development in children born under conditions that are typical for a westernized vs. that of a still more traditional setting will provide a crucial insight into the environmental-driven immunological mechanisms that are responsible for the world-wide rise in inflammatory disorders. In this review, we summarize the current understanding of early-life immune function in humans in general and the literature on some major lifestyle factors that may influence neonatal immune function and potentially the risk for disease in later life. An understanding of the mechanisms of ‘prenatal/early-life programming’ in populations living in traditional compared with modern societies is crucial to develop strategies to prevent a further rise in ‘western diseases’ such as allergic disorders. Indications exist that prenatal conditioning of the innate immune system by low-grade inflammatory responses is key to inducing more tightly regulated postnatal adaptive immune responses

An Unopposed Proinflammatory Response Is Beneficial for Survival in the Oldest Old. Results of the Leiden 85-Plus Study

The capacity to generate an efficient innate immune response is pivotal for survival. The objective of this study was to investigate innate immune function in relation to long-term survival in the oldest old. We measured ex vivo lipopolysaccharide-induced proinflammatory and antiinflammatory cytokine responses in 562 participants aged 85 years of the general population who were followed for mortality during 10 years. Compared with participants with a high proinflammatory and antiinflammatory response profile, 85 year olds with an overall low proinflammatory and antiinflammatory response had a significant higher mortality risk (hazard ratio: 1.79, 95% confidence interval: 1.29-2.50), whereas participants with a high proinflammatory and low antiinflammatory response had a survival benefit (hazard ratio: 0.74, 95% confidence interval: 0.57-0.97). This benefit was even more pronounced in survivors past 90 years of age (hazard ratio: 0.50, 95% confidence interval: 0.26-0.96). In old age, the capacity to generate an unopposed proinflammatory innate immune response is predictive of long-term survival.Pathophysiology, epidemiology and therapy of agein

Comparison of neonatal T regulatory cell function in Papua New Guinean and Australian newborns

Background:  Environmental changes, including declining microbial exposure, have been linked with the rising incidence of allergic and autoimmune diseases in ‘western’ populations. This potentially occurs by altering early development of immuno-regulatory pathways including T regulatory cells (Treg). There is now increasing evidence that such conditioning begins in utero. Methods:  We compared neonatal Treg from children born under typical western conditions (Australia, AUS) with those of neonates born under more traditional conditions of high microbial burden (Papua New Guinea, PNG). Results:  The frequency of neonatal Treg, defined as CD4+ Foxp3+ CD127− CD25+/high was found to be higher in the cord blood of AUS compared to PNG newborns. However, cord Tregsuppressive function in a small subset of children was qualitatively similar between PNG and AUS newborns in both a Treg depletion assay and a Treg supplementation assay. Conclusions:  These findings do not support the hypothesis that living in a ‘western’ versus more traditional environment leads to poor induction or suppressive function of neonatal Treg. However, environmentally-induced immuno-regulation may potentially occur via alternative mechanisms in PNG newborns that should now be investigated further

Neonatal antigen-presenting cells are functionally more quiescent in children born under traditional compared with modern environmental conditions

Background One explanation for the high burden of allergic and autoimmune diseases in industrialized countries is inappropriate immune development under modern environmental conditions. There is increasing evidence that the process of immune deviation already begins in utero, but the underlying immunologic mechanisms are not clear. Objective We sought to identify differences in the function of neonatal antigen-presenting cells (APCs) in children born in settings that are more traditional versus those of modern societies. Methods Cord blood mononuclear cells were collected from newborns from Papua New Guinea (PNG; traditional) and Australia (modern) and compared for differences in APCs and T-cell phenotype and function. Results Australian cord naive T cells (CD4+CD25−CD127+ cells) showed an enhanced and more rapid proliferative response in an autologous, APC-dependent culture system, a result of differences in neonatal APCs rather than T-cell function. This included an increased capacity to process antigen and to upregulate activation markers after stimulation. In contrast, resting PNG APCs exhibited higher baseline levels of activation and inhibitory markers and were less responsive or nonresponsive to stimulation in vitro. Conclusions This study supports the hypothesis that prenatal environments can influence the developing immune system in utero. Children born under modern environmental conditions exhibit increased APC reactivity at birth compared with children born under traditional environmental conditions. The functionally more quiescent nature of PNG neonatal APCs might protect against the development of harmful inflammatory responses in early life

Effect of early carriage of streptococcus pneumoniae on the development of pneumococcal protein-specific cellular immune responses in infancy

Background: The aim of this study was to examine the relationship between nasopharyngeal pneumococcal colonization in early life and the subsequent development of pneumococcal-specific T cell responses. <p/>Methods: Pernasal swabs were collected from Papua New Guinean infants at the ages of 1 and 2 weeks (n = 279). At 9 months, in vitro cellular immune responses to choline-binding protein A (n = 132), pneumococcal surface protein A (n = 132), pneumolysin (n = 99), and the pneumococcal conjugate vaccine carrier CRM197 were determined. Responses were compared based on the children's carriage status within the first 2 weeks of life. <p/>Results: Within the first 2 weeks of life, 40% of the study children carried Streptococcus pneumoniae. Early carriage was associated with lower interferon-γ and interleukin 10 responses to pneumococcal proteins at age 9 months when children had not received pneumococcal conjugate vaccines during the study period. <p/>Conclusions: Early pneumococcal carriage may result in enhanced disease susceptibility and suboptimal vaccine responses by modulating the development of pneumococcal immune responses