Maternal stress and T-cell differentiation of the developing immune system: possible implications for the development of asthma and atopy

The constant increase in asthma and atopy prevalences--despite improved treatment and knowledge of many aspects of the diseases--has raised growing concern. Accumulating evidence suggests that these increases in atopic diseases are largely attributable to environmental and lifestyle factors, and the lack of systemic childhood infections has in many studies emerged as a major factor. In addition to current high standards of hygiene and the lack or scarcity of such infections, another factor characteristic of our present-day lives could be involved. This review briefly outlines the possibility that prolonged maternal stress associated with sustained excessive cortisol secretion could affect the developing immune system--especially T(H)1/T(H)2 cell differentiation--and further increase the susceptibility to asthma and atopy in genetically predisposed individuals. This hypothesis is critically evaluated in the light of current knowledge.     

The role of farm exposures in occupational asthma and allergy

Agriculture is very diverse. Farmers commonly grow several different crops, and may also raise animals. They are exposed to a variety of antigens from plants, animals, insects and molds, to which they may become allergic. However, several large epidemiological studies conducted recently in various regions of the world indicate that the prevalence of asthma and allergy is no higher in farmers than in other populations. There is increasing evidence that growing up on a farm may protect against developing asthma and allergic rhinoconjunctivitis.     

Genetic and environmental interaction in allergy and asthma

Asthma is an inflammatory disorder of the airways involving coordinate up-regulation of T(H)2-type cytokines encoded in a cluster on chromosome 5q(31-33) on T cells and inflammatory cells. There is also a requirement for local airway susceptibility factors that, together with T(H)2 polarization, results in hyperresponsiveness, variable airflow obstruction, and, over time, remodeling of the airway wall. Asthma has strong genetic and environmental components that interact both in the induction and subsequent expression of the disease phenotypes. Multiple genes are involved and probably interact. Whole genome screens are beginning to identify gene-rich regions of special relevance to asthma and atopy, although a novel disease-related gene has yet to be discovered from these. By contrast, there are a plethora of candidate genes whose function in relation to disease pathophysiologic mechanisms and response to treatment are known. Two examples are polymorphisms involving IL-4 receptors and the enzymes controlling cysteinyl leukotriene production. Abnormal signaling between the epithelium, which is in contact with the environment, and the underlying (myo)fibroblasts and dendritic cells indicating reactivation of the epithelial mesenchymal trophic unit, which is involved in fetal lung development and branching, provide a basis for asthma that encapsulates both T(H)2 polarization and airway wall remodeling.     

Childhood infections, the developing immune system, and the origins of asthma

Asthma is an immune-mediated inflammatory condition characterized by increased responsiveness to bronchoconstrictive stimuli. Viruses have been shown to play an important role in asthma, with viral infection being present during about 85% of exacerbations. However, the role they play in the onset of asthma is more controversial. Some respiratory viral infections might be protective, but there is a strong association between respiratory syncytial virus-induced bronchiolitis in infancy and recurrent wheeze up to 12 years of age. Both the respiratory tract and the immune system undergo rapid maturation during the first year of life, and it seems that postnatal development is affected by and affects responses to viral infections. Understanding postnatal developmental changes in the immune system might help to explain the origins and pathogenesis of asthma and thus the effectiveness or ineffectiveness of specific asthma therapies.     

Effects of environmental tobacco smoke on the developing immune system of infant monkeys

BACKGROUND: Exposure to environmental tobacco smoke (ETS) is associated with an increased incidence of allergic and infectious diseases among children that is thought to be partly due to the immaturity of the immune system. OBJECTIVE: We sought to investigate the effects of ETS exposure on immune development during the first year of life in the nonhuman primate. METHODS: Fifteen neonatal rhesus monkeys studied to 13 months of postnatal age were randomized into 3 groups: (1) exposure to filtered air, (2) continuous ETS exposure beginning at gestation day 50 (perinatal ETS); and (3) exposure to ETS beginning at 6 months of age (6-month ETS). Complete blood counts, lymphocyte subsets, and mRNA levels of 12 cytokines in PBMCs were measured. RESULTS: Fetal/infant exposure to ETS altered the normal maturation of mRNA levels of IFN-gamma, IL-2, and IL-10, as well as the ratio of CD4 to CD8 lymphocytes, compared with filtered-air control levels. Blood lymphocyte subset distribution also significantly differed based on the onset of exposure to ETS. Subacute exposure to ETS for 2 weeks in 6-month-old infants was found to increase levels of peripheral blood neutrophils and IL-6 mRNA. CONCLUSIONS: Short-term exposure to ETS can induce an acute systemic inflammatory response in the neonatal nonhuman primate, and long-term exposure to ETS beginning in utero or at 6 months of postnatal age can significantly alter immune effectors. CLINICAL IMPLICATIONS: Normal immune system development is compromised by in utero and postnatal exposure to ETS and might contribute to ETS-related childhood diseases.     

17q12-21 and asthma: interactions with early-life environmental exposures

Background17q12-21 polymorphisms are associated with asthma presence and severity across different populations.ObjectiveTo extensively investigate the genes in this region among Croatian schoolchildren in a case-control study, taking account of early-life environmental exposures.MethodsWe included 423 children with asthma and 414 controls aged 5 to 18 years. Fifty-one haplotype tagging single-nucleotide polymorphisms (SNPs) were genotyped (GSDMA, GSDMB, ORMDL3, IKZF3, ZPBP2, and TOP2). Data on exposure to smoking and furry pet ownership were collected using a validated questionnaire. Information on severe asthma exacerbations with hospital admission were retrieved from hospital notes. All patients underwent spirometry.ResultsWe found 2 SNPs (1 novel rs9635726 in IKZF3) to be associated with asthma. Among children with asthma, 4 SNPs (in ZPBP2, GSDMB, and GSDMA) were associated with hospital admissions and 8 SNPs with lung function. One SNP (rs9635726) remained significantly associated with a predicted forced expiratory volume in 1 second after false discovery rate correction. Nine markers across 5 genes showed interaction with early-life environmental tobacco smoke (ETS) exposure in relation to asthma and 2 with furry pet ownership. Among children with asthma, we observed significant interactions between early-life ETS exposure and 3 SNPs for lung function and among early-life ETS exposure, 3 SNPs (in ORMDL3 and GSDMA), and hospital admission with asthma exacerbation. Three SNPs (in ORMDL3) interacted with current furry pet ownership in relation to hospital admissions for asthma exacerbation.ConclusionOur results indicate that several genes in the 17q12-21 region may be associated with asthma. This study confirms that environmental exposures may need to be included into the genetic association studies.     

Multiple microbial exposures in the home may protect against asthma or allergy in childhood

Background Experimental animal data on the gram‐negative bacterial (GNB) biomarker endotoxin suggest that persistence, dose, and timing of exposure are likely to influence its effects on allergy and wheeze. In epidemiologic studies, endotoxin may be a sentinel marker for a microbial milieu, including gram‐positive bacteria (GPB) as well as GNB, that may influence allergy and asthma through components (pathogen‐associated molecular patterns) that signal through innate Toll‐like receptor pathways. Objective To determine the influence of current GNB and GPB exposures on asthma and allergic sensitization in school‐aged children. Methods We examined the relationship between bacterial biomarkers and current asthma and allergic sensitization in 377 school‐aged children in a birth cohort study. We then evaluated the effects of school‐aged endotoxin, after controlling for exposure in early life. Results Exposure to GNB was inversely associated with asthma and allergic sensitization at school age [for >median endotoxin: prevalence odds ratio (POR)=0.34, 95% CI=0.2–0.7, for current asthma and prevalence ratio=0.77, 95% CI=0.6–0.97, for allergic sensitization]. In contrast, elevated GPB in the bed was inversely associated with current asthma (POR=0.41, 95% CI=0.2–0.9) but not with allergic sensitization (POR=1.07, 95% CI=0.8–1.4). School‐aged endotoxin exposure remained protective in models for allergic disease adjusted for early‐life endotoxin. Conclusion Both GNB and GPB exposures are associated with decreased asthma symptoms, but may act through different mechanisms to confer protection. Endotoxin exposure in later childhood is not simply a surrogate of early‐life exposure; it has independent protective effects on allergic disease.     

Influence of gastrointestinal commensal bacteria on the immune responses that mediate allergy and asthma

The human intestine contains more than 100 trillion microorganisms that maintain a symbiotic relationship with the host. Under normal conditions, these bacteria are not pathogenic and in fact confer health benefits to the host. The microbiota interacts with the innate and adaptive arms of the host's intestinal?mucosal immune system and through these mechanisms drives regulatory cell differentiation in the gut that is?critically involved in maintaining immune tolerance. Specifically, the microbiota can activate distinct tolerogenic dendritic cells in the gut and through this interaction can drive regulatory T-cell differentiation. In addition, the microbiota is important in driving T(H)1 cell differentiation, which corrects the T(H)2 immune skewing that is thought to occur at birth. If appropriate immune tolerance is not established in early life and maintained throughout life, this represents a risk factor for the development of inflammatory, autoimmune, and allergic diseases.?Early-life events are instrumental in establishing the microbiota, the composition of which throughout life is influenced?by various environmental and lifestyle pressures. Significant efforts are now being made to establish interventional approaches that can create a healthy microbiota that confers maximum tolerogenic immunomodulatory effects in the gut and that will protect against systemic inflammatory disease pathologies.     

Vitamin D,the immune system and asthma

The effects of vitamin-D on bone metabolism and calcium homeostasis have long been recognized. Emerging evidence has implicated vitamin-D as a critical regulator of immunity, playing a role in both the innate and cell-mediated immune systems. Vitamin-D deficiency has been found to be associated with several immune-mediated diseases, susceptibility to infection and cancer. Recently, there has been increasing interest in the possible link between vitamin-D and asthma. Further elucidation of the role of vitamin-D in lung development and immune system function may hold profound implications for the prevention and treatment of asthma.     

Toxicopathology of the developing immune system: investigative and development strategies

Developmental immunotoxicity (DIT) has gained attention with the recognition that environmental chemicals can potentially affect the developing immune system and the incidence of childhood allergic diseases. Preclinical safety assessment of pharmaceuticals for men and women of childbearing potential as well as for pediatric and juvenile indications may require DIT assessments. Draft documents from environmental and chemical regulatory agencies propose strategies that use the rat as a test species and incorporate histopathology and functional testing as endpoints. While there are no guidelines for DIT assessment of pharmaceuticals, current discussions suggest that combining immunotoxicity and developmental and reproductive toxicology studies may serve this purpose. Knowledge of the principles and applications of DIT will facilitate participation in strategy development and effective conduct of relevant studies.     

Alternative medicine for allergy and asthma

Orthodox medical approaches to asthma and allergic respiratory diseases are provided in guidelines developed by professional societies and national or state organizations that represent organized medicine. Alternative therapies may include such orthodox medical therapies as obsolescent formerly used agents, unusual but accepted agents, and agents that are in favor for orthodox therapy in other countries. However, the current growth of complementary and alternative medicine is based on the use of nonorthodox remedies that are becoming increasingly popular with patients and that should be familiar to physicians. Asthma and allergies are frequently treated with such remedies by patients, either as part of self-therapy or on the advice of a complementary and alternative medicine practitioner. The most popular alternative medical treatments are herbs (Western and Asiatic), acupuncture, various types of body manipulation, psychologic therapies, homeopathy, and unusual allergy therapies. There is little evidence in favor of most of these unorthodox treatments, although they are very often reported on favorably by patients. The published evidence that might support some alternative medical practices is reviewed so as to help physicians select alternatives that could appropriately be integrated into orthodox practice.