Early Immune Stimulation Research Articles

Early immune stimulation and childhood acute lymphoblastic leukemia in Costa Rica: A comparison of statistical approaches

BackgroundAlthough epidemiologic studies suggest that early immune stimulation is protective against childhood leukemia, evidence for this relationship is equivocal for Hispanic children, who are disproportionately affected by this disease. The complex biological processes underlying immune stimulation and leukemogenesis may benefit from novel statistical approaches that account for mixed exposures and their nonlinear interactions. In this study, we utilized targeted machine learning and traditional statistical methods to investigate the association of multiple measures of early immune stimulation with acute lymphoblastic leukemia (ALL) in Costa Rican children. Materials and methodsWe used data from a population-based case-control study conducted in Costa Rica (2001–2003). Cases of ALL (n = 240) were diagnosed in 1995–2000 (age >1 year and <15 years at diagnosis) and were identified through the National Cancer Registry and National Children's Hospital. Population controls (n = 578) were frequency-matched to cases by birth year and drawn from the National Birth Registry. Data on surrogate measures of early immune stimulation were collected through in-home interviews. We fitted multivariable models, utilizing targeted causal inference (varimpact), unconditional logistic regression, and latent class analysis (LCA). ResultsIn varimpact analysis, contact with any pet [risk difference (RD) = −0.17, 95% CI: −0.25, −0.10)] or any farm animal (RD = −0.07, 95% CI: −0.13, 0.00) and allergies (RD = −0.08, 95% CI: −0.17, 0.01) were associated with a reduced risk of ALL, whereas experiencing a fever longer than one week was associated with an increased risk (RD = 0.23, 95% CI: 0.12, 0.33). In unconditional logistic regression models, contact with any pet or farm animal and a complete vaccination scheme were inversely associated with odds of ALL (OR = 0.44, 95% CI: 0.31, 0.62; OR = 0.66, 95% CI: 0.49, 0.90; OR = 0.45, 95% CI: 0.24, 0.83; respectively), whereas experiencing a fever longer than one week was positively associated with ALL (OR = 2.44, 95% CI: 1.61, 3.70). Two-class and three-class LCA revealed a group with elevated risk for ALL whose exposure profile was mainly characterized by reduced exposure to pets and farm animals. ConclusionsUsing distinct statistical approaches, we observed that exposure to pets and farm animals was inversely associated with ALL risk, whereas having a fever longer than one week (a putative proxy of severe infection) was associated with an increased risk. For multifactorial diseases such as childhood leukemia, we recommend estimating the joint effects of multiple exposures by applying diverse statistical methods and interpreting their results together. Overall, we found support for the hypothesis that early immune stimulation offers protection against childhood ALL.

Neonatal gut colonization by Staphylococcus aureus strains with certain adhesins and superantigens is negatively associated with subsequent development of atopic eczema.

Insufficient early immune stimulation may predispose to atopic disease. Staphylococcus aureus, a skin and gut colonizer, produces the B-cell mitogen protein A and T-cell-activating superantigens. Early gut colonization by S. aureus strains that possess the superantigens encoded by the enterotoxin gene (egc) cluster and elastin-binding protein is negatively associated with development of atopic eczema. To investigate (i) whether these findings could be replicated in a second birth cohort, FARMFLORA, and (ii) whether nasal colonization by S. aureus also relates to subsequent atopic eczema development. Faecal samples and nasal swabs from infants in the FARMFLORA birth cohort (n = 65) were cultured for S. aureus. Individual strains were distinguished by random amplified polymorphic DNA and assessed for adhesin and superantigen gene carriage by polymerase chain reaction. Atopic eczema at 18 months of age was related to nasal and gut S. aureus colonization patterns during the first 2 months of life (well before onset of eczema). Staphylococcus aureus colonization per se was unrelated to subsequent eczema development. However, gut S. aureus strains from the infants who subsequently developed atopic eczema less frequently carried the ebp gene, encoding elastin-binding protein, and superantigen genes encoded by egc, compared with strains from children who remained healthy. Nasal colonization by S. aureus was less clearly related to subsequent eczema development. The results precisely replicate our previous observations and may suggest that mucosal colonization by certain S. aureus strains provides immune stimulation that strengthens the epithelial barrier and counteracts the development of atopic eczema.

Early-Life Infections, Immune Dysregulation, and Childhood Acute Lymphocytic Leukemia in Costa Rica

Introduction: Despite the high incidence of leukemia in Hispanic children, few studies have examined the role of early immune stimulation in the etiology of leukemia in this high-risk population. Methods: We used data from a population-based retrospective case-control study conducted in Costa Rica (2001-2003) to examine the role of early-life infections and immune dysregulation on leukemia incidence among Hispanic children. Cases of ALL (n&amp;#61;239) were diagnosed in 1995-2000 (age &amp;lt;15 years at diagnosis) and were identified through the National Cancer Registry and National Children&amp;#8217;s Hospital. Population controls (n&amp;#61;579) were frequency-matched to cases by birth year and drawn from the National Birth Registry. Surrogate measures of early immune stimulation were collected through home interviews. Unconditional logistic regression models were adjusted for birth year, sex, and socioeconomic status. Results: Daycare attendance, contact with any pet or farm animal, and a complete vaccination scheme were inversely associated with odds of ALL (OR&amp;#61;0.67, 95% CI: 0.47-0.95; OR&amp;#61;0.39, 95% CI: 0.26-0.59; OR&amp;#61;0.35, 95% CI: 0.18-0.67; respectively). In contrast, experiencing a fever longer than one week (censored in the year prior to diagnosis) was positively associated with ALL (OR&amp;#61;2.53, 95% CI: 1.66-3.85). Breastfeeding, birth order, primary infections, and hospitalizations were not significantly associated with risk of childhood leukemia. Conclusion: Our findings are consistent with the epidemiology of childhood leukemia in non-Hispanic populations and provide additional support for Greaves hypothesis that exposure to infectious agents in early childhood is a protective factor. The observation that having a fever longer than a week increases risk supports an emerging theory that an abnormally strong immune response to infection increases susceptibility to leukemia.

Childhood brain tumours, early infections and immune stimulation: A pooled analysis of the ESCALE and ESTELLE case-control studies (SFCE, France)

BackgroundFew studies have investigated whether early infections and factors potentially related to early immune stimulation might be involved in the aetiology of childhood brain tumours (CBT). In this study, we investigated the associations between CBT with early day-care attendance, history of early common infections, atopic conditions (asthma/wheezing, eczema, allergic rhinitis), early farm residence/visits and contact with animals. MethodsWe pooled data from two nationwide French case-control studies, the ESCALE and ESTELLE studies. Children with a CBT diagnosed between 1 and 14 years of age were identified directly from the French National Registry of Childhood Cancers, while population controls were recruited from telephone subscribers. Odds-ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression adjusted for potential confounders. ResultsThe analyses included 469 cases and 2719 controls. We found no association between attending a day-care centre (OR: 0.9, 95%CI: 0.7–1.2) or having had repeated common infections (OR: 0.9, 95%CI: 0.7–1.2) in the first year of life and the risk of CBT. There was also no association with a history of asthma/wheezing (OR: 0.8, 95%CI: 0.56–1.1). Farm visits (OR: 0.6, 95%CI: 0.5–0.8) as well as contact with pets (OR: 0.8, 95%CI: 0.6–1.0) in the first year of life were inversely associated with CBT. ConclusionsOur findings suggest a protective effect of early farm visits and contact with pets, but not with other markers of early immune stimulation. This might be related to immune stimulation but needs further investigation.

Childhood acute lymphoblastic leukaemia and indicators of early immune stimulation: the Estelle study (SFCE).

Background:Factors related to early stimulation of the immune system (breastfeeding, proxies for exposure to infectious agents, normal delivery, and exposure to animals in early life) have been suggested to decrease the risk of childhood acute lymphoblastic leukaemia (ALL).Methods:The national registry-based case–control study, ESTELLE, was carried out in France in 2010–2011. Population controls were frequency matched with cases on age and gender. The participation rates were 93% for cases and 86% for controls. Data were obtained from structured telephone questionnaires administered to mothers. Odds ratios (OR) were estimated using unconditional regression models adjusted for age, gender, and potential confounders.Results:In all, 617 ALL and 1225 controls aged ⩾1 year were included. Inverse associations between ALL and early common infections (OR=0.8, 95% confidence interval (CI): 0.6, 1.0), non-first born (⩾3 vs 1; OR=0.7, 95% CI: 0.5, 1.0), attendance of a day-care centre before age 1 year (OR=0.7, 95% CI: 0.5, 1.0), breastfeeding (OR=0.8, 95% CI: 0.7, 1.0), and regular contact with pets (OR=0.8, 95% CI: 0.7, 1.0) in infancy were observed.Conclusions:The results support the hypothesis that conditions promoting the maturation of the immune system in infancy have a protective role with respect to ALL.

Biochemical, histopathological and morphological profiling of a rat model of early immune stimulation: relation to psychopathology.

Perinatal immune challenge leads to neurodevelopmental dysfunction, permanent immune dysregulation and abnormal behaviour, which have been shown to have translational validity to findings in human neuropsychiatric disorders (e.g. schizophrenia, mood and anxiety disorders, autism, Parkinson’s disease and Alzheimer’s disease). The aim of this animal study was to elucidate the influence of early immune stimulation triggered by systemic postnatal lipopolysaccharide administration on biochemical, histopathological and morphological measures, which may be relevant to the neurobiology of human psychopathology. In the present study of adult male Wistar rats we examined the brain and plasma levels of monoamines (dopamine, serotonin), their metabolites, the levels of the main excitatory and inhibitory neurotransmitters glutamate and γ-aminobutyric acid and the levels of tryptophan and its metabolites from the kynurenine catabolic pathway. Further, we focused on histopathological and morphological markers related to pathogenesis of brain diseases - glial cell activation, neurodegeneration, hippocampal volume reduction and dopaminergic synthesis in the substantia nigra. Our results show that early immune stimulation in adult animals alters the levels of neurotransmitters and their metabolites, activates the kynurenine pathway of tryptophan metabolism and leads to astrogliosis, hippocampal volume reduction and a decrease of tyrosine hydroxylase immunoreactivity in the substantia nigra. These findings support the crucial pathophysiological role of early immune stimulation in the above mentioned neuropsychiatric disorders.

Mechanisms of preventative and therapeutic role of probiotics in different allergic and autoimmune disorders

The prevalence of allergic and autoimmune diseases has been increasing from the last decades of 20th century. Intestinal microflora contributes to antigen exposure in early life and is one of the most abundant sources of early immune stimulation as well as adaptation. Because allergic and autoimmune responses manifest early in life, there has been obvious interest in the potential benefits of modifying the gastrointestinal flora by using probiotic supplementation. So far, there have been several studies to address the role of probiotics in primary prevention and therapy, with a reported suspicious reduction in the incidence of atopic and autoimmune diseases. Here, our aim is to evaluate the available knowledge of mechanisms of preventative and therapeutic role of probiotics in different allergic and autoimmune disorders. Promising mechanisms of probiotic effects may be categorized as local and systemic effects. Local influences of probiotics potentially include reduction of gut permeability and systemic penetration of antigens, increased local immunoglobulin A production, and alteration of local inflammation or tolerance induction. Some possible systemic effects consist of anti-inflammatory effects mediated by Th17 cells and Toll-like receptors, Th1 skewing of responses to allergens, activation of tolerogenic dendritic cells, in addition to T-regulatory cell production.

Neonatal exposure to LPS leads to heightened exploratory activity in adolescent rats

Although several reports have demonstrated physiological and behavioral changes in adult rats due to neonatal immune challenges, little is known about their effects in adolescence. Since neonatal exposure to lipopolysaccharide (LPS) alters the neural substrates involved in cognitive disorders, we tested the hypothesis that it may also alter the response to novel environments in adolescent rats. At 3 and 5 days of age, male Wistar rats received intraperitoneal injections of either vehicle solution or E. coli LPS (0.05 mg/kg) or were left undisturbed. In the mid-adolescent period, between 40 and 46 days of age, the rats were exposed to the following behavioral tests: elevated plus-maze, open-field, novel-object exploration task, hole-board and the modified Porsolt forced swim test. The results showed that, in comparison with control animals, LPS-treated rats exhibited (1) less anxiety-related behaviors and enhanced patterns of locomotion and rearing in the plus-maze and the open-field tests, (2) high levels of exploration of both objects in the novel-object task and of corner and central holes in hole-board test, and (3) more time spent diving, an active behavior in the forced swim test. The present findings suggest that neonatal LPS exposure has long-lasting effects on the behavior profile adolescent rats exhibit in response to novelty. This behavioral pattern, characterized by heightened exploratory activity in novel environments, also suggests that early immune stimulation may contribute to the development of impulsive behavior in adolescent rats.